Clinical trial NCT05109702
Conditions: Dry Eye
Sponsor: HanAll BioPharma Co., Ltd.
Start date: 2021-11-18; Completion date: 2022-05-06
Enrollment: 260 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this study was to compare the safety and efficacy of tanfanercept ophthalmic solution 0.25% with placebo for the treatment of the signs and symptoms of dry eye.

Detailed description:

Arms: arm 1: Participants self-administered placebo ocular drops, twice daily (BID) in both eyes for 14 days in the Placebo Run-in Period. arm 2: Participants self-administered tanfanercept 0.25 percent (%) ophthalmic solution as topical ophthalmic drops, BID for up to 8 weeks in Treatment Period. arm 3: Participants self-administered tanfanercept placebo (vehicle solution) solution as topical ophthalmic drops, BID for up to 8 weeks in Treatment Period.
Interventions: intervention 1: 0.25% Tanfanercept Ophthalmic Solution intervention 2: Placebo
Intervention descriptions: intervention 1: Tanfanercept ophthalmic solution. intervention 2: Placebo vehicle solution.

Protocol documents:
Prot_000.pdf: 





















































































































































































SAP_001.pdf: 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
A Phase 3, Multicenter, Randomized, Double Masked and Placebo
Controlled Study Evaluating the Efficacy and Safety of Tanfanercept 
Ophthalmic Solution 0.25% Compared to Placebo in Subjects with 
Dry Eye 
 
 
 
Sponsor: 
 
HanAll Biopharma Co., Ltd. 
 
 
 
 
 
Protocol Number: 
HL036-DED-US-P302 
 
 
Author:  
 
 
 
 
Statistics & Data Corporation 
 
Date: 
 
 
07-FEB-2022 
Version: 
 
0.1 
 






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Table of Contents 
Table of Contents ........................................................................................................................................ 4 
List of Abbreviations .................................................................................................................................. 7 
1. 
Introduction ................................................................................................................................... 11 
2. 
Study Objectives ........................................................................................................................... 11 
2.1 Primary Variables ................................................................................................................... 11 
2.2 Secondary Variables .............................................................................................................. 11 
2.3 Safety Variables ..................................................................................................................... 12 
2.4 Other Variables ...................................................................................................................... 12 
2.5 Statistical Hypotheses ............................................................................................................ 12 
2.6 Estimands ............................................................................................................................... 13 
3. 
Study Design and Procedures ..................................................................................................... 15 
3.1 General Study Design ............................................................................................................ 15 
3.2 Schedule of Visits and Assessments ..................................................................................... 16 
4. 
Study Treatments .......................................................................................................................... 16 
4.1 Method of Assigning Subjects to Treatment Groups ............................................................. 16 
4.2 Masking and Unmasking ........................................................................................................ 16 
5. 
Sample Size and Power Considerations ..................................................................................... 17 
6. 
Data Preparation ........................................................................................................................... 17 
7. 
Analysis Populations .................................................................................................................... 17 
7.1 Intent-to-Treat (ITT) Population .............................................................................................. 17 
7.2 Per Protocol (PP) Population ................................................................................................. 17 
7.3 Safety Population ................................................................................................................... 18 
8. 
General Statistical Considerations ............................................................................................. 18 
8.1 Unit of Analysis....................................................................................................................... 18 
8.2 Missing or Inconclusive Data Handling .................................................................................. 18 
8.3 Definition of Baseline ............................................................................................................. 19 
8.4 Data Analysis Conventions .................................................................................................... 19 
8.5 Adjustments for Multiplicity ..................................................................................................... 19 
9. 
Disposition ..................................................................................................................................... 20 
9.1 Subject Disposition ................................................................................................................. 20 
9.2 Protocol Deviations ................................................................................................................ 20 
10. 
Demographic and Pretreatment Variables ................................................................................. 21 
10.1 Demographic Variables .......................................................................................................... 21 
10.2 Pretreatment Variables .......................................................................................................... 21 


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11. 
Medical History and Concomitant Medications ......................................................................... 21 
11.1 Medical History ....................................................................................................................... 21 
11.2 Prior and Concomitant Medications ....................................................................................... 22 
11.3 Concomitant Procedures ........................................................................................................ 22 
12. 
Dosing Compliance and Treatment Exposure ........................................................................... 22 
12.1 Dosing Compliance ................................................................................................................ 22 
12.2 Treatment Exposure ............................................................................................................... 23 
13. 
Efficacy Analyses .......................................................................................................................... 23 
13.1 Primary Analyses ................................................................................................................... 23 
13.1.1 
Central Corneal Staining Score (CCSS) .................................................................... 24 
13.1.2 
Eye Dryness Score on Visual Analog Scale (EDS-VAS) ........................................... 24 
13.2 Secondary Analyses .............................................................................................................. 25 
13.2.1 
Analyses of Secondary Endpoints ............................................................................. 25 
13.2.2 
Fluorescein Staining ................................................................................................... 25 
13.2.3 
Lissamine Green Staining .......................................................................................... 26 
13.2.4 
Conjunctival Redness ................................................................................................ 26 
13.2.5 
Unanesthetized Schirme
 ................................................................................ 26 
13.2.6 
Tear Film Break-Up Time ........................................................................................... 27 
13.2.7 
Visual Analog Scale of Ocular Dryness ..................................................................... 27 
13.2.8 
Ocular Surface Disease Index© .................................................................................. 27 
13.2.9 
Ora Calibra® Ocular Discomfort Scale ....................................................................... 28 
13.2.10 
Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire ................................... 28 
14. 
Summary of Efficacy Analyses .................................................................................................... 29 
15. 
Safety Analyses ............................................................................................................................. 29 
15.1 Adverse Events ...................................................................................................................... 29 
15.2 Visual Acuity (VA) .................................................................................................................. 31 
15.3 Slit-Lamp Biomicroscopy Examination ................................................................................... 32 
15.4 Dilated Fundoscopy Examination........................................................................................... 32 
15.5 Intraocular Pressure (IOP) ..................................................................................................... 32 
15.6 Immunogenicity to Tanfanercept Ophthalmic Solution 0.25% in Serum................................ 33 
16. 
Other Endpoints ............................................................................................................................ 33 
16.1 Ora Calibra® Drop Comfort Scale and Questionnaire ............................................................ 33 
16.1.1 
Ora Calibra® Drop Comfort Scale .............................................................................. 33 
16.1.2 
Ora Calibra® Drop Comfort Questionnaire ................................................................. 33 
17. 
Interim Analyses ........................................................................................................................... 34 


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18. 
Changes from Protocol-Stated Analyses ................................................................................... 34 
19. 
References ..................................................................................................................................... 34 
20. 
Revision History ............................................................................................................................ 34 
21. 
Tables ............................................................................................................................................. 34 
22. 
Listings ........................................................................................................................................... 38 
23. 
Figures ........................................................................................................................................... 41 
24. 
Appendix 1 ..................................................................................................................................... 43 
25. 
Appendix 2 ..................................................................................................................................... 45 
 
 
 
 
 






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1. Introduction 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and reporting for 
protocol HL036-DED-US-P302 Version 4.0, dated 22-JUN-2022 
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, E9(R1) Statistical Principles for Clinical Trials: Addendum: Estimands and 
Sensitivity Analysis in Clinical Trials, and the most recent ICH E3 Guideline entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports. 
This SAP describes the data that will be analyzed and the subject characteristics, efficacy, and safety 
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 clinical study report. 
2. Study Objectives 
The objective of this study is to compare the safety and efficacy of Tanfanercept Ophthalmic Solution 0.25% 
to placebo for the treatment of the signs and symptoms of dry eye. 
2.1 
Primary Variables 
The primary efficacy variables of the study are: 
 
Central corneal staining score (CCSS; sign), mean change from baseline (V2) to Day 57 ± 3 (V6, 
Week 8)  
 
Eye dryness score on Visual Analog Scale (EDS-VAS; symptom), mean change from baseline (V2) 
to Day 57 ± 3 (V6, Week 8) 
2.2 
Secondary Variables 
The secondary efficacy variables include the following: 
 
Fluorescein staining (Ora Calibra® scale) by region: central, superior, inferior, temporal, nasal, 
corneal sum, conjunctival sum, and total staining 
 
Conjunctival lissamine green staining (Ora Calibra® scale) by region: central, superior, inferior, 
temporal, nasal, corneal sum, conjunctival sum, and total staining  
 
Conjunctival redness 
 
Unanesthetized 
 
 
Tear film break-up time (TFBUT) 
 
Visual Analog Scale (VAS) (reported symptoms include burning/stinging, itching, foreign body 
sensation, blurred vesion, eye dryness, photophobia, and pain) 
 
Ocular Surface Disease Index© (OSDI©) 


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Ora Calibra® Ocular Discomfort Scale 
 
Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire 
2.3 
Safety Variables 
The safety variables include the following: 
 
Adverse event (AE) query 
 
Visual acuity (VA) 
 
Slit-lamp evaluation  
 
Intraocular Pressure (IOP) 
 
Dilated fundoscopy 
 
Immunogenicity to Tanfanercept Ophthalmic Solution 0.25% in serum 
2.4 
Other Variables 
The other variables include the following: 
 
Ora Calibra® Drop Comfort Scale  
 
Ora Calibra® Drop Comfort Questionnaire  
2.5 
Statistical Hypotheses 
The statistical hypotheses are stated in terms of two-sided hypotheses, although statistical inference will 
be one-sided, with the direction of interest in the differences in treatment group means as stated in Section 
13.1. The primary endpoints will be tested in a hierarchical fixed sequence in the following order. 
H01: There is no difference between Tanfanercept Ophthalmic Solution 0.25% and placebo 
in the change from baseline (Visit 2 [Day 1]) of the CCSS at Day 57 ± 3 (Visit 6, Week 
8) in the ITT Population, using the Ora Calibra® scale (Ex. H01
t 
p). 
HA1: The change from baseline (Visit 2 [Day 1]) of the CCSS at Day 57 ± 3 (Visit 6, Week 
8) using the Ora Calibra® scale is not equal with Tanfanercept Ophthalmic Solution 
0.25% than with placebo in the ITT Population (Ex. HA1
t  
p). 
H02: There is no difference between Tanfanercept Ophthalmic Solution 0.25% and placebo 
in the change from baseline (Visit 2 [Day 1] of the EDS on VAS at Day 57 ± 3 (Visit 6, 
Week 8) in the ITT Population (Ex. H02
t 
p). 
HA2: The change from baseline (Visit 2 [Day 1]) of the EDS on VAS is not equal with 
Tanfanercept Ophthalmic Solution 0.25% than with placebo at Day 57 ± 3 (Visit 6, 
Week 8) in the ITT Population (Ex. HA2
t  
p). 


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2.6 
Estimands 
The primary analysis of the primary endpoints will use the Intent-to-Treat (ITT) population for the primary 
endpoints of Change from Baseline (CFB) of CCSS at Day 57 ± 3 and CFB of EDS-VAS at Day 57 ± 3, and 
the primary analysis will be executed using mixed model repeated measures (MMRM) with multiple 
imputation methodology using the following estimand: 
Estimand 1: 
 
Population: 
o 
ITT population 
 
Endpoints: 
o 
CFB in CCSS in the study eye at Day 57 ± 3 in the ITT population 
o 
CFB in EDS from VAS at Day 57 ± 3 in the ITT population 
 
Intercurrent events: 
o 
Discontinuation of study medications is ignored. Measures obtained after discontinuation 
of study medication will be analyzed. [treatment policy strategy] 
o 
Non-optimal compliance is ignored. Measures will be analyzed regardless of treatment 
compliance. [treatment policy strategy] 
o 
Use of prohibited concomitant medications is ignored. Measures obtained after use of 
prohibited concomitant medications will be analyzed. [treatment policy strategy] 
o 
Withdrawal due to lack of efficacy or adverse events: Missing values assumed to be 
missing not at random will be multiply imputed using placebo group-based PMM 
imputation. [hypothetical strategy] 
o 
Missing data with withdrawal or withdrawal due to reasons other than lack of efficacy or 
adverse events: Missing values assumed to be missing at random will be multiply imputed 
using randomized treatment group-based MCMC imputation. [hypothetical strategy] 
 
Population-level summary: 
o 
Difference in the mean CFB in CCSS in the study eye at Day 57 ± 3 between Tanfanercept 
and placebo in the ITT population. 
o 
Difference in the mean CFB in EDS (VAS) at Day 57 ± 3 between Tanfanercept and 
placebo in the ITT population. 
If the rate of missing data for EDS-VAS 
exact test with a p-value of <0.05) and the rate of missing data for EDS-VAS 
 
the primary analyses will utilize the ITT population using the permutation test with trimmed means 
methodology, as detailed in Estimand 2. 
Estimand 2: 


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Population: 
o 
ITT population 
 
Endpoint: 
o 
CFB in CCSS in the study eye at Day 57 ± 3 in the ITT population 
o 
CFB in EDS from VAS at Day 57 ± 3 in the ITT population 
 
Intercurrent event: 
o 
Discontinuation of study medications is ignored. Measures obtained after discontinuation 
of study medication will be analyzed. [treatment policy strategy] 
o 
Non-optimal compliance is ignored. Measures will be analyzed regardless of treatment 
compliance. [treatment policy strategy] 
o 
Use of prohibited concomitant medications is ignored. Measures obtained after use of 
prohibited concomitant medications will be analyzed. [treatment policy strategy] 
o 
Withdrawal or missed assessments for any reason. Missing values will be removed, 
following the trimmed means methodology laid out in Permutt T, Li F. [hypothetical 
strategy]. The trimmed means strategy is as follows: 
 
Using an analysis of covariance (ANCOVA), a linear model is fit to the data with 
treatment as factor and baseline value as covariate. The beta coefficient for 
treatment is discarded and only the Y (outcome) value, the beta coefficient for 
baseline score, and X (baseline score) are considered. Y  
calculated for each subject for the purpose of ranking. 
 
Next, the proportions of subjects with missing values in the control and treatment 
arms are identified. The greater proportion of the two arms is then used as the 
percentile floor in which observations must be better. Those observations that are 
not better than the floor are trimmed (removed). Missing values are included in the 
calculation of the percentile floor value as values worse than the percentile. 
 
After trimming is done, MMRM is used on the two analysis sets to find an observed 
treatment effect. The MMRM model will be based on the final model as described 
in Section 13.1.1.To determine the p-value and 95% CI, 10,000 permutations of 
the data will be run and the trimming methodology will be repeated. The number 
of permutation datasets that result in an effect size greater than the observed effect 
size divided by the number of permutations will be the p-value. The 95% CI will be 
calculated using the 2.5th and 97.5th percentiles of the permutation distribution.  
 
Population-level summary: 
o 
Difference in the mean CFB in EDS-VAS at Day 57 ± 3 between Tanfanercept and placebo 
in the ITT population. 
3. Study Design and Procedures 
3.1 
General Study Design 
This is a Phase 3, multicenter, randomized, prospective, double-masked, placebo-controlled, parallel-arm 
design. Subjects will be randomized to one of the following treatment arms at Visit 2 (Day 1) and will be 
instructed to follow a twice daily (BID) dosing regimen: 




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If there is a tie on the number of days prior to planned study day and post planned study day, then 
the results/observation reported prior to planned study day will be selected. 
3.2 
Schedule of Visits and Assessments 
The schedule of visits and assessments is provided in Appendix 2. 
4. Study Treatments 
4.1 
Method of Assigning Subjects to Treatment Groups 
Prior to initiation of study run-in at Day -14, each subject who qualifies for entry will be assigned a screening 
number. All screening numbers will be assigned in strict numerical sequence at a site and no numbers will 
be skipped or omitted. If all inclusion criteria are met and none of the exclusion criteria are met at Day -14 
and Day 1, each qualifying subject will then be assigned a randomization number (assigning them to 
Tanfanercept Ophthalmic Solution 0.25% or Placebo Ophthalmic Solution) at the end of Day 1 using the 
Interactive Response Technlogy (IRT). The randomization number will be recorded on the 
s source 
document and the electronic Case Report Form (eCRF) .  
The randomization number will be recorded on the Subject Record Page and eCRF. A new kit will be 
dispensed at Day 1, Day 15, and Day 29
Day 1 kit will be re-
dispensed at Day 8. At Day 29, subjects will receive two assigned study drug kits with sufficient supply to 
last until Day 57. The Sponsor, investigators, and study staff will be masked during the randomization 
process and throughout the study. 
4.2 
Masking and Unmasking 
All subjects, investigators, and study personnel involved with the conduct of the study will be masked with 
regard to treatment assignments. When medically necessary, the investigator may need to determine what 
treatment arm has been assigned to a subject. When possible (i.e., in non-emergent situations), Ora and/or 
the study sponsor should be notified before unmasking study drug. The unmasked subject will be 
discontinued from the study. 
5. Sample Size and Power Considerations 
The primary objective of the study is to demonstrate a statistically significant difference between the active 
treatment and placebo. 
Per the protocol, this study was expected to randomize 150 subjects in each of the two treatment arms, for 
a total of 300 randomized subjects. Assuming a 10% drop out rate, 135 subjects per group are expected to 
complete the study. 


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Assuming a common standard deviation (SD) in the change from baseline (Day 1) to Day 57 for CCSS of 
a sample size of 135 evaluable subjects per group will have 99.4% power to detect a difference 
of
between the active treatment group and the placebo group at a significance level of 0.05. 
After randomizing 260 subjects, the Sponsor conducted a masked interim assessment of the sample size 
(section 3.1). The power was recalculated based on the reduced sample size following the original 
assumptions descriped above.  
After randomizing 130 subjects in each of the two treatment arms, for a total of 260 randomized 
subjects and assuming a 10% drop out rate, 119 subjects per group are expected to complete the 
study. 
Assuming a common standard deviation (SD) in the change from baseline (Day 1) to Day 57 for 
CCSS of
 a sample size of 119 evaluable subjects per group will have 98.7% power to 
detect a difference of
between the active treatment group and the placebo group at a 
significance level of 0.05. 
6. Data Preparation 
All the datasets used for the analyses and presentations of summary results will be implemented using 
Clinical Data Interchange Standards Consortium (CDISC, Implementation Guide [IG] Version 3.2) and the 
analysis data model (ADaM, Implementation Guide [IG] Version 2.0) format. The ADaM datasets will be 
created using SDTM datasets. 
7. Analysis Populations 
The following analysis populations will be considered: 
7.1 
Intent-to-Treat (ITT) Population 
The ITT population includes all randomized subjects. The primary analysis will be performed on the ITT 
population with the primary estimand detailed in Section 2.6 of this SAP. Subjects in the ITT population will 
be analyzed as randomized. 
7.2 
Per Protocol (PP) Population 
The PP population includes subjects in the ITT population who do not have significant protocol deviations. 
Protocol deviations will be assessed prior to database lock and unmasking. The PP population will be 
analyzed using observed data only for efficacy variables. Subjects in the PP population will be analyzed as 
treated. 
7.3 
Safety Population 
The Safety population includes all randomized subjects who have received at least one dose of the 
investigational product (IP). The Safety population will be analyzed for all safety assessments. Subjects in 
the Safety population will be analyzed as treated. 


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8. General Statistical Considerations 
8.1 
Unit of Analysis 
Safety endpoints will be analyzed for both eyes. For subject-level efficacy endpoints, the unit of analysis 
will be the subject. For eye-level efficacy endpoints, the unit of analysis will be the study eye as defined by 
the following: 
Study Eye: Eyes are eligible for analysis if they meet all of the inclusion criteria. In the case that both eyes 
are eligible for analysis, the study eye will be the eye with worse (higher) central corneal fluorescein staining 
score at Day 1. If the central corneal fluorescein staining score is the equivalent in both eyes, then the right 
eye will be selected as the study eye. 
8.2 
Missing or Inconclusive Data Handling 
The primary efficacy analyses will be performed using the multiple imputation methodology specified in 
Estimand 1. If the rate of missing data for EDS-VAS is imbalanced between treatment groups, then trimmed 
means methodology will be executed as specified in Estimand 2. Full descriptions of Estimands 1 and 2 
are provided in Section 2.6 of this SAP. Additional sensitivity and supportive analyses may be executed, 
including: 
 
Multiple imputation via placebo group-based pattern-mixture model (PMM) imputation with the ITT 
population under the assumption of missing not at random for all missing. 
 
A tipping point sensitivity analysis with corresponding imputations of increasingly more 
the 
treatment group difference is no longer significant. 
 
Multiple imputation via randomized treatment group-based Markov Chain Monte Carlo (MCMC) 
with the ITT population under the assumption of missing at random for all missing. 
 
Last observation carried forward (LOCF) imputation methodology using the ITT population. 
 
Observed data only using ITT and PP populations. 
No secondary efficacy endpoints or safety endpoints will be imputed. 
8.3 
Definition of Baseline 
Baseline measures are defined as the last measure prior to the initiation of study treatment, usually at 
Day 1. 
8.4 
Data Analysis Conventions 
All data analyses 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. Output will be provided in RTF (rich text format) for tables, listings, and figures using landscape 
orientation. All study data will be listed by subject, treatment, and visit (as applicable) based on all enrolled 
subjects unless otherwise specified. 


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All summaries will be presented by treatment group and visit where appropriate, unless otherwise specified. 
Listings will be presented for all data collected on the eCRFs, sorted by subject id number and visit.  
Summaries for continuous and ordinal variables will include the number of observations (n), arithmetic 
mean, SD, median, minimum, and maximum. Minima and maxima will be reported with the same precision 
as the raw values; means and medians will be presented to one additional decimal place than reported in 
the raw values. Standard deviations will be presented to two additional decimal places than reported in the 
raw values. Summaries for discrete variables will include frequency counts and percentages. All 
percentages will be rounded to one decimal place (i.e., XX.X%).   
All statistical tests will be two-
 
Confidence intervals (CI) will be two-sided at 95% confidence levels where appropriate. All p-values will be 
rounded to four decimal places; p-
-values greater 
.  
8.5 
Adjustments for Multiplicity 
Hierarchical fixed sequence testing will be used to maintain the type I error rate. The primary analysis will 
first test the difference in CFB (Day 1) of CCSS in the study eye at Day 57 in the ITT population using the 
primary estimand. If the test of the difference between treatment groups is statistically significant at the two-
sided alpha = 0.05 level in favor of Tanfanercept, then the study will be considered a success, Tanfanercept 
will be declared to be superior to placebo in the change from baseline (Day 1) of CCSS at Day 57, and the 
difference in the change from baseline (Day 1) of EDS at  Day 57 will then be tested at the two-sided alpha 
= 0.05 level in the ITT population. 
If, in addition to a statistically significant test of the difference in change from baseline (Day 1) of CCSS in 
the study at Day 57 in favor of Tanfanercept, the test of the difference in the change from baseline (Day 1) 
of EDS at Day 57 in the ITT population with the primary estimand is also statistically significant in favor of 
Tanfanercept, then Tanfanercept will be declared superior to placebo in both the change from baseline 
(Day 1) of CCSS and the change from baseline (Day 1) of EDS at Day 57. 
Secondary efficacy analyses will not be type-I error controlled and will be considered hypothesis generating. 
9. Disposition  
9.1 
Subject Disposition 
Subject disposition will be presented in terms of the numbers and percentages of subjects who completed 
the study and discontinued from the study. Subjects who are not discontinued from the study will be 
considered study completers. Disposition will be summarized by treatment group and for all subjects. The 
total number of screened subjects with the number and percentage of screen failure subjects will be 
summarized as well. 


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The number of randomized subjects in each analysis population (ITT, PP, and Safety) will be displayed by 
treatment. The ITT population uses treatment as randomized; PP and Safety populations use treatment as 
treated. Percentages are based on the total number of subjects randomized in each treatment group. 
The number and percentage of subjects 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 that will be summarized include: Pregnancy, AE, Lack of Efficacy, Unmasking When 
Medically Necessary, Protocol Violation, Administrative Reasons (e.g., Inability to Continue, Lost to Follow 
Up), Study Termination by Sponsor, Subject Choice, and Other. A subject listing of disposition will be 
provided that includes the date of and reason for premature study discontinuation. 
9.2 
Protocol Deviations 
The number and percentage of subjects with any, major, and minor protocol deviations will be summarized 
by treatment group for all randomized subjects. The number and percentage of subjects with any protocol 
deviation will also be summarized for the following categories: Informed Consent, Inclusion / Exclusion and 
Randomization, Test Article / Study Drug Instillation and Assignment at Site, Improper Protocol Procedures 
Serious Adverse Event (SAE) 
-
Follow Instructions, and Other. A subject listing will be provided that includes the date, visit at which the 
deviation occurred (if applicable), deviation code, description of each deviation, whether the deviation was 
COVID-19 related, and the classification of whether the deviation was judged to be major or minor. 
In addition, subject listings will be provided that include date of randomization, randomization number, 
randomization arm, actual treatment, and
 whether inclusion and exclusion criteria 
were met, and inclusion in the analysis populations. A listing of subjects affected by COVID-19 
discontinuations and protocol deviations will be generated as well. 
A table summarizing the number of randomized subjects enrolled by site with percentages will be 
generated.  
10. Demographic and Pretreatment Variables 
10.1 
Demographic Variables 
The demographic variables collected in this study include age, sex, race, ethnicity, and iris color. 
Demographic variables will be summarized for the ITT and Safety populations separately. 
Age (years) will be summarized, overall and by treatment, using continuous descriptive statistics. Age will 
also be categorized as follows: 
 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 


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The number and percentage of subjects will be presented, overall and by treatment, for age category, sex, 
race, ethnicity, iris color for the right eye (OD) and left eye (OS),
A subject listing that includes all demographic variables will be provided. 
10.2 
Pretreatment Variables 
Baseline disease characteristics will be summarized by treatment group using continuous descriptive 
statistics for central corneal staining score (CCSS), eye dryness score (EDS), total OSDI© score, 
best-corrected visual acuity (BCVA), and IOP. All summaries will be for the 
study eye, except for OSDI© which is a subject-level assessment. The scale for each assessment is 
provided in the 
respective subsections in Section 13.2 of this SAP. Baseline disease 
characteristics will be displayed for the ITT population. 
11. Medical History and Concomitant Medications 
11.1 
Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) Version 24.0. 
Medical history will be summarized using counts and percentages and presented by treatment group at the 
subject and event level by System Organ Class (SOC) and Preferred Term (PT) using the ITT population. 
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, that SOC will 
only be reported once. In the summaries, SOCs and PTs within an SOC are presented in ascending 
alphabetical order. 
Listings of medical history will be generated separately for ocular and non-ocular data. 
11.2 
Prior and Concomitant Medications 
WHODrug) Global B3 (March 2021) and coded to the therapeutic drug class (Anatomical 
Therapeutic Chemical [ATC] 4 classification) and preferred name.  
Concomitant medications are defined as those medications listed as having been taken (1) prior to initiation 
of randomized study drug administration (Day 1) and continuing for any period of time following the first 
administration of randomized study drug or (2) at any time following the first administration of randomized 
study drug (Day 1). Prior medications are reported medications that have been taken prior to and not on or 
after initiation of randomized study drug administration. 
medications will be summarized 
medications will be tabulated 
for each treatment group and for all subjects using frequencies and percentages. 


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Listings of 
will be generated separately for ocular and non-ocular data. 
11.3 
Concomitant Procedures 
Concomitant procedures will be coded using Medical Dictionary for Regulatory Activities (MedDRA) Version 
24.0. 
Concomitant procedures will be summarized using discrete summary statistics and presented by treatment 
group at the subject and event level by System Organ Class (SOC) and Preferred Term (PT) using the ITT 
population. 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, 
that SOC will only be reported once. In the summaries, SOCs and PTs within an SOC are presented in 
ascending alphabetical order. 
Listings of concomitant procedures will be generated separately for ocular and non-ocular data. 
12. Dosing Compliance and Treatment Exposure 
12.1 
Dosing Compliance 
Dosing compliance will be calculated as: 
Dosing Compliance (%) = (Number of doses taken from Day 1 to study completion/discontinuation visit / 
Number of expected doses from Day 1 to study completion/discontinuation visit) * 100 
The number of doses taken will be calculated by subtracting the number of unused vials from the number 
of vials dispensed plus the total number of vials missed reported in the electronic case report form (eCRF). 
For subjects who do not receive a dose of randomized study drug, the number of expected doses will be 0 
and compliance will be defined as 0. Otherwise, the number of expected doses will be calculated as 2 x 
[Date of Study Completion/Discontinuation  Date of Day 1 +1]. If a subject discontinues on Day 1 then the 
number of expected doses is 1. 
Dosing compliance will be summarized using continuous descriptive statistics including mean, SD, median, 
minimum, and maximum for the Safety Population. Additionally, a categorical summary display frequencies 
and percentages of those deemed compliant, under-compliant (<80%), and over-compliant (>125%). 
12.2 
Treatment Exposure 
Extent of treatment exposure for completed or discontinued subjects will be calculated in days using the 
following: 


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Extent of Exposure (days) = (Date of Study Completion/Discontinuation  Date of Day 1) + 1 
Extent of treatment exposure (days) for each subject exposed to study drug will be summarized with 
continuous descriptive statistics for each treatment group, using the Safety population. A subject listing of 
treatment exposure and dosing compliance will also be produced. 
13. Efficacy Analyses 
13.1 
Primary Analyses 
The primary efficacy endpoints of this study include mean CFB to Day 57 of central corneal staining score 
(CCSS) and eye dryness score on Visual Analog Scale (EDS-VAS). 
CCSS will be graded using the Ora Calibra® Corneal and Conjunctival Fluorescein Staining Scale. The 
Ora Calibra® Corneal and Conjunctival Staining Scale ranges from
EDS will be subjectively graded by the subjects using the VAS at all scheduled visits. Subjects are asked 
to rate each ocular symptom due to ocular dryness by placing a vertical mark on the horizontal line to 
indicate the current level of discomfort. 0% corre
 
For both endpoints, CFB to each post-baseline protocol visit (Section 3.1) will be calculated using actual 
scores and resulting scores from multiple imputation methodology specified in Estimand 1 (Section 2.6). 
The imputation methods will be performed using the SAS® procedure PROC MI. Refer to Appendix 1 for 
examples of SAS® codes for obtaining randomized treatment group-based MCMC multiple imputation data. 
CFB to a post-baseline visit timepoint will be calculated as Post-baseline visit result minus 
Baseline visit results 
Note: Positive difference indicates a worsening of dry eye signs or symptoms. In addition, treatment 
comparisons between active and placebo will be calculated as Active minus Placebo, such that a 
negative result indicates a better score for the active treatment (i.e., tanfanercept group demonstrated 
less severity in dry eye signs or symptoms than the placebo group).   
13.1.1 
CENTRAL CORNEAL STAINING SCORE (CCSS)  
CCSS CFB to Day 57 will be analyzed using the ITT population with multiple imputation methodology 
specified in Estimand 1 (Section 2.6). The initial MMRM model will include terms for baseline CCSS, site, 
visit (as categorical term), treatment group and the interaction of treatment group and visit as fixed effects 
with correlated errors. The inclusion of site in the final model will be evaluated at an alpha level of 0.1. All 
post-baseline visits will be used in the model. 


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If site is retained in the final primary analyses, the site by treatment interaction will be explored in a 
separate analysis to evaluate how the treatment effect may differ across sites. All post-baseline visits will 
be used in the model.  
An alternate MMRM will be executed as supportive analysis. This additional model will include all terms in 
the final model of the primary analyses with,
Sensitivity analyses to compare CCSS CFB between treatment groups using imputation by Last 
Observation Carried Forward (LOCF), multiple imputation by placebo group-based pattern mixture 
models (PMM), and analyses of observed data only using the ITT and PP populations will be conducted. 
The Least Square (LS) means, LS mean difference, Standard Errors (SEs), two-sided 95% CIs, and p-
values of the LS mean difference will be reported from the MMRM model. Two-sample t-tests will also be 
conducted as supportive analyses of the mean CFB to Day 57. The sample means, sample mean 
difference, SEs, two-sided 95% CIs, and two-sided p-values will be reported from the two-sample t-test.  
The MMRM LS means of the CCSS CFB in the study eye at Day 57 and CCSS CFB at each visit will be 
displayed graphically in a bar chart with SE bars by treatment group. 
13.1.2 
EYE DRYNESS SCORE ON VISUAL ANALOG SCALE (EDS-VAS) 
EDS-VAS CFB to Day 57 will be analyzed as described above for the analysis of CCSS with adjustment 
for baseline EDS-VAS instead of CCSS. Estimand 2 will be used for the analysis of EDS-VAS in the 
presence of an imbalance of missing data between the two treatment groups (Section 2.6). 
13.2 
Secondary Analyses 
The following secondary efficacy endpoints will be tested: 
 
Fluorescein staining (Ora Calibra® scale) by region: central, superior, inferior, temporal, 
nasal, corneal sum, conjunctival sum, and total staining 
 
Lissamine green staining (Ora Calibra® scale) by region: central, superior, inferior, 
temporal, nasal, corneal sum, conjunctival sum, and total staining 
 
Conjunctival Redness 
 
 
 
TFBUT 
 
VAS 
 
OSDI© 
 
Ora Calibra® Ocular Discomfort Scale 
 
Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire 


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Ora Calibra® Drop Comfort assessment 
13.2.1 ANALYSES OF SECONDARY ENDPOINTS 
Actual scores will be summarized by visit and region/symptom using quantitative summary statistics. Two-
sample t-tests will be employed to compare active treatment and placebo means of actual scores at each 
visit. The differences in samples means, SEs, two-sided 95% CIs for the difference in means and p-values 
will be reported.  
Changes from baseline at each post-baseline visit will be summarized similarly. Analysis of the change 
from baseline at each post-baseline visit will utilize MMRM models similar to the primary analysis 
(substituting appropriate baseline and week variables) using observed data, The LS means, LS mean 
differences, SEs, two-sided 95% CIs for the difference in means and two-sided p-values will be reported 
from the models. Two sample t-tests will also be conducted. Within each treatment arm, paired t-tests will 
be conducted for changes from baseline. Analyses will be performed on the ITT population with observed 
data only. For assessments on both eyes, only the study eye will be analyzed and summarized. 
Subject listings of each secondary efficacy assessment will be generated. 
13.2.2 FLUORESCEIN STAINING 
Corneal and conjunctival fluorescein staining will be performed at all scheduled visits, on both eyes and 
graded using the Ora Calibra® Corneal and Conjunctival Staining Scale. The scale will grade the cornea 
and conjunctiva by five regions: inferior, superior, central, temporal, and nasal. The Ora Calibra® Corneal 
and Conjunctival Staining Scale ranges from 
The corneal sum score will be the sum of scores 
from the inferior, superior, and central regions. The conjunctival sum score will be the sum of scores from 
the nasal and temporal regions. The total eye score will be the sum of scores from all five regions. 
Fluorescein staining scores will be summarized and analyzed by visit and region including sums as 
described in section 13.2.1.  
Sample means of the fluorescein staining scores in the study eye will be displayed graphically in a line chart 
with SE bars by visit and treatment group for each region or sum separately. 
13.2.3 LISSAMINE GREEN STAINING 
Corneal and conjunctival lissamine green staining will be performed at all visits, on both eyes and graded 
using the Ora Calibra® Corneal and Conjunctival Staining Scale. The scale will grade the cornea and 
conjunctiva by five regions: inferior, superior, central, temporal, and nasal. The Ora Calibra® Corneal and 
Conjunctival Staining Scale ranges from 
The corneal sum score will be the sum of scores 


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from the inferior, superior, and central regions. The conjunctival sum score will be the sum of scores from 
the nasal and temporal regions. The total score will be the sum of scores from all five regions. 
Lissamine green staining scores will be summarized and analyzed by visit and region including sums as 
described in section 13.2.1.  
Sample means of the lissamine green staining scores in the study eye will be displayed graphically in a line 
chart with SE bars by visit and treatment group for each region or sum separately. 
13.2.4 CONJUNCTIVAL REDNESS 
The Ora Calibra® Conjunctival Redness Scale for Dry Eye will be performed on all scheduled visits. The 
conjunctival redness scale ranges from
Conjunctival redness scores will be summarized and analyzed by visit as described in section 13.2.1. 
13.2.5 UNANESTHETIZED SCHIRMER S TEST 
Day -14, Day 1, Day 15, Day 29, and 
Day 57. 
 After 5 minutes, 
the test strip will be removed and the length of the moistened area will be recorded in millimeters (mm) for 
each eye. Lower values indicate less tears produced in the eye.  
 and analyzed for the study eye by visit as described 
in section 13.2.1. 
Sample means of the u
test scores in the study eye will be displayed graphically 
in a line chart with SE bars by visit and treatment group. 
13.2.6 TEAR FILM BREAK-UP TIME 
Tear film break-up time will be measured at all scheduled visits on all scheduled visist in both eyes. For 
each eye, two measurements will be recorded in seconds and averaged unless the two measurements are 
> 2 seconds apart and are each < 10 seconds, in which case, a third measurement will be taken and the 
two closest of the three will be averaged and used for analyses. If the differences between two sequential 
pairs of measurements are the same (e.g., 3, 6, 9 seconds), then the median of the three readings will be 
used for analysis. 
Tear film break-up time will be summarized and analyzed for the study eye by visit as described in section 
13.2.1. 


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13.2.7 VISUAL ANALOG SCALE OF OCULAR DRYNESS 
At each visit, subjects will be asked to rate each ocular symptom due to ocular dryness by placing a vertical 
rt 
symptoms as experienced while completing the questionnaire. Reported symptoms include 
burning/stinging, itching, foreign body sensation, blurred vesion, eye dryness, photophobia, and pain. 
Visual analog scale will be summarized and analyzed by visit and symptom as described in section 13.2.1. 
Sample means of the VAS symtoms will be displayed graphically in a line chart with SE bars by visit and 
treatment group for each symptom separately. 
13.2.8 OCULAR SURFACE DISEASE INDEX© 
The OSDI© is assessed on a scale of 0 to 100, with higher scores representing greater disability. The OSDI© 
asks the following 12 questions at the subject level: 
Have you experienced any of the following during the last week? 
1) Eyes that are sensitive to light? 
2) Eyes that feel gritty? 
3) Painful or sore eyes? 
4) Blurred vision? 
5) Poor vision? 
Have problems with your eyes limited you in performing any of the following during the last week? 
6) Reading? 
7) Driving at night? 
8) Working with a computer or bank machine (ATM)? 
9) Watching TV? 
Have your eyes felt uncomfortable in any of the following situations during the last week? 
10) Windy conditions? 
11) Places or areas with low humidity (very dry)? 
12) Areas that are air conditioned? 
OSDI© will be assessed at each visit at the subject level. The 5-unit scale for responses to the OSDI© is 
given by the following:
The total OSDI© score is calculated by the following: 
OSDI© = 
(Sum of Scores) x 25 


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# of Questions Answered 
Note that the number of questions answered in the denominator should exclude those questions with a 
.  
OSDI© will be summarized and analyzed by visit and by question, subgroup, and total score as described 
in section 13.2.1. 
13.2.9 ORA CALIBRA® OCULAR DISCOMFORT SCALE 
Ocular discomfort scores will be subjectively graded by the subjects using the Ora Calibra® Ocular 
Discomfort Scale at all scheduled visits. The ocular discomfort scale ranges from 
Ocular Discomfort Scale will be summarized and analyzed by visit as described in section 13.2.1. 
Sample means of the Ocular Discomfort Scale scores in the study eye will be displayed graphically in a line 
chart with SE bars by visit and treatment group. 
13.2.10 ORA CALIBRA® OCULAR DISCOMFORT & 4-SYMPTOM QUESTIONNAIRE 
Ocular discomfort and dry eye symptoms will be assessed at all scheduled visits at the subject level in 
regard to how both eyes feel. The Ora Calibra® Ocular Discomfort &
Ocular Discomfort & 4-Symptom Questionnaire will be summarized and analyzed by visit as described in 
section 13.2.1. 
Sample means of the symtoms from the Ocular Discomfort & 4-Symptom Questionnaire will be displayed 
graphically in a line chart with SE bars by visit and treatment group for each symptom separately. 
14. Summary of Efficacy Analyses 
A summary of all efficacy analyses will be presented. For MMRM models, treatment group LS means, LS 
mean differences, SEs for the LS mean differences, and p-values for the treatment group comparisons will 
be presented. For t-tests, treatment group sample means, sample mean differences, SEs for sample mean 
differences, and p-values for treatment group comparisons will be presented. 
15. Safety Analyses 
All safety analyses will be conducted using the Safety population. 


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15.1 
Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of 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 IP, without any 
judgment about causality. An AE can arise from any use of the IP (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 will be coded using MedDRA Version 24.0. 
Treatment-emergent adverse events (TEAEs) are defined as any event that occurs or worsens on or after 
the day that randomized study treatment is initiated. 
An overall summary will be presented that includes the number of AEs, TEAEs, SAEs, treatment-emergent 
serious adverse events (TE-SAEs), number of subjects with TEAEs by maximum severity, and number of 
subjects with TEAEs by relationship to study drug. The summary will also include the number and 
percentage of subjects with treatment discontinuation due to an AE, the number and percentage of subjects 
with an AE resulting in death, and the number and percentage of subjects who experienced at least one 
AE, TEAE, SAE, and TE-SAE by treatment group and for all subjects. This summary will include 
breakdowns of AEs and TEAEs further categorized as ocular or non-ocular as well as the number and 
percentage of resolved ocular AEs and the mean and SD number of days until AE resolution for resolved 
ocular AEs. 
Additional summaries of TEAEs will be provided showing the number and percentage of subjects who 
experienced at least one TEAE. These summaries will be presented by SOC and PT. Non-ocular TEAEs 
will be summarized using discrete summary statistics and presented by treatment group at the subject and 
event level by SOC and PT. Ocular TEAEs will be similarly summarized at the subject and event level by 
SOC and PT. 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, 
that SOC will only be reported once. In the summary, SOC will be listed in order of descending frequency 
for all subjects; PTs will be listed in order of descending frequency for all subjects within each SOC.  
Conjunctivitis AEs will also summarized by number of AEs and number and percentages of subjects who 
experienced at least one conjunctivitis AE. Categories of conjunctivitis AEs (bacterial, viral, and 
hypersensitivity) will be further summarized as described. Additionally, the number of subjects with a 
conjunctivitis AE that experience any of the following symptoms will be summarized: 
 
Injected Sclera 
 
Redness 
 
Burning 
 
Eye Discharge 
 
Unusual Crusting on Eye When Awakening 


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Ocular Itchiness 
 
Nasal Itchiness  
 
Sneezing  
 
Excessive Tearing 
 
Other Signs or Symptoms. 
A subject listing of conjunctivitis AEs will be generated for all randomized subjects. 
Additionally, separate summaries will be provided for the following categories of AEs:  
 
Ocular AEs 
 
Non-ocular AEs 
 
Ocular TEAEs  
 
Non-ocular TEAEs  
 
Ocular treatment-related TEAEs 
 
Non-ocular treatment-related TEAEs 
 
SAEs 
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 subject. The assessment of severity is made irrespective 
of relationship to study drug 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 
 
 
Moderate: Event is bothersome, possibly requiring additional therapy, and may interfere with the 
 
 
Severe: Event is intolerable, necessitates additional therapy or alteration of therapy, and interferes 
 
Summaries of TEAEs by maximal severity will be presented for ocular AEs and non-ocular AEs separately. 
The number of subjects with any TEAEs (along with percentages) will be tabulated by SOC and PT within 
each SOC by treatment group. To count the number of subjects with any TEAEs, if a subject has multiple 
TEAEs coded to the same PT within the same SOC, the subject will be counted once under the maximal 
severity.  
The occurrence of non-ocular and ocular TEAEs will also be tabulated by SOC, PT, and study day of onset 
(prior to Day 9, Day 9 to Day 29, After Day 29). 
The relationship of each AE to the IP should be determined by the investigator (in a masked manner) using 
these explanations: 


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Suspected: A reasonable possibility exists that the IP caused the AE. A suspected AE can be 
further defined as: 
o 
Definite: Relationship exists when the AE follows a reasonable sequence from the time of 
IP administration, follows a known response pattern of the drug class, is confirmed by 
improvement on stopping the IP and no other reasonable cause exists. 
o 
Probable: Relationship exists when the AE follows a reasonable sequence from the time 
of IP administration, follows a known response pattern of the drug class, is confirmed by 
improvement on stopping the IP and the suspect IP is the most likely of all causes. 
o 
Possible: Relationship exists when the AE follows a reasonable sequence from the time of 
adm
drugs administered to the subject. 
 
Not Suspected: A reasonable possibility does not exist that the IP caused the AE. A not suspected 
AE can further be defined as:  
o 
Not Related: Concurrent illness, concurrent medication, or other known cause is clearly 
responsible for the AE, the administration of the IP and the occurrence of the AE are not 
reasonably related in time, OR exposure to IP has not occurred. 
All possible, probable, and definite TEAEs are considered as treatment-related TEAEs.  
All AEs will be presented in a subject listing for all screened subjects. Separate listings will be produced for 
Conjunctivitis AEs, SAEs, AEs leading to treatment discontinuation, and AEs leading to death for all 
randomized subjects. 
15.2 
Visual Acuity (VA) 
The VA procedure will be performed at each scheduled visit. The logarithm of the minimum angle of 
resolution (logMAR) VA must be assessed using an Early Treatment of Diabetic Retinopathy Study 
(ETDRS) chart. The procedure used will be consistent with the recommendations provided for using the 
ETDRS eye chart. Visual Acuity should be evaluated at the beginning of each visit in the study (i.e., prior 
to slit-lamp examination). Subjects should use their most recent correction to attain their best-corrected 
visual acuity (BCVA). 
The observed VA and change from baseline in VA will be summarized for each eye (study eye and fellow 
eye) using continuous descriptive statistics by visit for each treatment group. The number and percentage 
+0.22 will be summarized for each eye by treatment 
group. The worst on-treatment value also will be summarized, and the CFB for the worst on-treatment value 
will be summarized analogously. 


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A subject listing of VA will also be produced. 
15.3 
Slit-Lamp Biomicroscopy Examination 
A slit-lamp biomicroscopy examination of the cornea, conjunctiva, anterior chamber, iris, lens, and eyelid 
will be performed at each visit. The results will be graded as Normal, Abnormal Not Clinically Significant 
(NCS), or Abnormal Clinically Significant (CS). Abnormal findings will be described. 
The results will be summarized using counts and percentages for each treatment group at each visit for 
each eye (study eye and fellow eye). Percentages will be based on the number of subjects in each treatment 
group with responses. Shift tables for the slit-lamp biomicroscopy parameters will also be provided 
comparing each follow-up visit to baseline. The worst on-treatment value and the shift from baseline for the 
worst on-treatment value also will be summarized. 
A subject listing of the slit-lamp biomicroscopy parameters will also be produced. 
15.4 
Dilated Fundoscopy Examination 
A dilated fundoscopy exam will be performed during the study at Day -14 and Day 57, and potentially at 
unscheduled visit assessments. Observations of the vitreous, retina, macula, choroid, and optic nerve will 
be graded as Normal, Abnormal NCS, or Abnormal CS. Abnormal findings will be described. 
The results will be summarized using counts and percentages for each treatment group at each visit for 
each eye (study eye and fellow eye). Percentages will be based on the number of subjects in each treatment 
group with responses. Shift tables for the dilated fundoscopy parameters will also be provided comparing 
Day 57 to baseline. The worst on-treatment value and the shift from baseline for the worst on-treatment 
value also will be summarized. 
A subject listing of the dilated fundoscopy parameters will also be produced. 
15.5 
Intraocular Pressure (IOP) 
Intraocular pressure will be measured in each eye by contact tonometry by the examiner and the results 
will be recorded in mmHg at Day -14 and Day 57. A single measurement is made to obtain a determination 
study. In addition, all reasonable efforts will be made to have the same examiner obtain all IOP 
measurements for a given subject. 
The IOP values and changes from baseline for each eye (study eye and fellow eye) will be summarized 
using continuous descriptive statistics by visit and eye for each treatment group. The worst on-treatment 
value also will be summarized, and the CFB for the worst on-treatment value will be summarized 
analogously. 
A subject listing of IOP will also be produced.  


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15.6 
Immunogenicity to Tanfanercept Ophthalmic Solution 0.25% in Serum 
Serum blood draws will be collected at Day 1, Day 29, and Day 57 for immunogenicity testing. Instructions 
for the collection, handling, and shipping of blood for immunogenicity testing are given in a separate 
laboratory manual. Analyses of immunogenicity data will be conducted as ad-hoc analyses. The anticipated 
ad-hoc analyses of immunogenicity are as follows. 
Immunogenicity will be summarized using discrete summary statistics. Counts and proportions of subjects 
with anti-drug antibodies (ADA) will be presented by visit and treatment group. Exact 95% Clopper-Pearson 
confidence intervals for the pairwise proportion differences will be constructed. 
Antibody titer of subjects positive for ADA will be summarized using continuous descriptive statistics and 
presented by visit and treatment group. Treatment groups will be compared using two-sample t-tests. The 
differences in means, two-sided 95% CIs for the difference in means, and p-values will be reported.  
16. Other Endpoints 
16.1 
Ora Calibra® Drop Comfort Scale and Questionnaire  
16.1.1 ORA CALIBRA® DROP COMFORT SCALE 
Drop comfort will be assessed for each eye immediately upon instillation, and at 1 and 2 minutes following 
initial dosing at Day 1 and Day 8 using the Ora Calibra® Drop Comfort Scale. 
Drop comfort will be summarized by visit and 
time point using quantitative summary statistics. Two-sample t-tests will be employed to compare the actual 
scores of the active treatment and placebo. The differences in means, SEs, two-sided 95% CIs for the 
difference in means, and p-values will be reported. Analyses will be performed on the ITT population with 
observed data only for the study eye. 
16.1.2 ORA CALIBRA® DROP COMFORT QUESTIONNAIRE 
Descriptions of drop comfort will be assessed at 3 minutes following initial dosing at Day 1 and Visit 3 (Day 
8) using the Ora Calibra® Drop Comfort Questionnaire. On this questionnaire, subjects will be asked to 
choose three words that best describe how each eye drop feels in both of his/her eyes. 
their choosing, which may be either a positive or a negative response. Drop Comfort Questionnaire 
responses will be summarized by treatment group using qualitative summary statistics. Subjects with at 
least one negative response as well as subjects with at least one positive response will also be summarized 
by treatment group. Analyses will be performed on the ITT population with observed data only. 
17. Interim Analyses 
No interim analyses are planned for this study. 




















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24. Appendix 1 
The multiple imputation methodology will employ a combination of treatment group-based MCMC 
imputation and placebo-based PMM imputation. Imputation methods will be performed using the SAS® 
procedure PROC MI. The SAS® code for obtaining randomized treatment group-based MCMC multiple 
imputation data is: 
PROC MI DATA = INDATA SEED = 425754 OUT = OUTDATA NIMPUTE = 30 
MINIMUM = 0 MAXIMUM = 4 ROUND = 0.5; 
    BY TREATMENT; 
    MCMC INITIAL = EM; 
    VAR BASE V3 V4 V5 V6; 
RUN; 
where 
- INDATA is the name of the input dataset 
- OUTDATA is the name of the output dataset 
- TREATMENT is the name of the treatment group variable  
-
- V3  V6 are the CCSS in the study eye at Visit 3 through Visit 6. 
After obtaining 30 complete data sets and calculating changes from baseline, the following SAS® code will 
be used to run the MMRM model on each multiply imputed data set and combine the results from the 30 
analyses: 
PROC MIXED DATA = OUTDATA; 
    BY _IMPUTATION_; 
    CLASS TREATMENT; 
    
COVB; 
    LSMEANS TREATMENT / CL PDIFF; 
    ODS OUTPUT LSMEANS = OUTLS DIFFS = OUTDIFFS; 
RUN; 
 
 
 
PROC SORT DATA=OUTLS; BY TREATMENT _IMPUTATION_; RUN; 
 
PROC MIANALYZE DATA=OUTLS; 
    BY TREATMENT; 
    MODELEFFECTS ESTIMATE; 
    STDERR STDERR; 
RUN; 
 
PROC SORT DATA=OUTDIFFS; BY _IMPUTATION_; RUN; 
 
PROC MIANALYZE DATA=OUTDIFFS; 
    MODELEFFECTS ESTIMATE; 
    STDERR STDERR; 
RUN; 
 
where 


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- 
TREATMENT is the name of the treatment group variable 
- 
SITE is the study site id as a random effect  
- 
BASELINE is the baseline CCSS in the study eye 
- 
CFB is the change from baseline in CCSS in the study eye at Day 57 
- 
OUTLS is the name of the output dataset that contains the statistical results for the treatment 
mean from the MMRM model that is run on each of the twenty imputation datasets 
- 
OUTDIFFS is the name of the output dataset that contains the statistical results for the difference 
in treatment mean from the MMRM model that is run on each of the twenty imputation datasets 
Similar SAS® code will be used to conduct MCMC multiple imputation analysis for the two sample t-test. 
Furthermore, the SAS® code for obtaining the placebo-based PMM imputation data is: 
 
 
PROC MI DATA = INDATA SEED = 988416 OUT = MDATA NIMPUTE = 30 
 
 
 
MINIMUM = 0 MAXIMUM = 4 ROUND = 0.5; 
 
 
    MCMC IMPUTE=MONOTONE; 
 
 
    VAR BASE V3 V4 V5 V6; 
 
 
RUN; 
 
PROC MI DATA = MDATA SEED = 253464 OUT = OUTDATA NIMPUTE = 1 
MINIMUM = . 0 0 0 0 0 
MAXIMUM = . 4 4 4 4 4 
ROUND = . 0.5 0.5 0.5 0.5 0.5; 
    CLASS TREATMENT; 
    MONOTONE REG(V6 = V5 V4 V3 BASE / DETAILS); 
MONOTONE REG(V5 = V4 V3 BASE / DETAILS); 
MONOTONE REG(V4 = V3 BASE / DETAILS); 
MONOTONE REG(V3 = BASE / DETAILS); 
 
 
    
 
    VAR TREATMENT BASE V3 V4 V5 V6; 
RUN; 
where 
- 
INDATA is the name of the input dataset 
- 
MDATA is the name an intermediary dataset with a monotone missing pattern 
- 
OUTDATA is the name of the output dataset 
- 
TREATMENT is the name of the treatment group variable 
- 
BASE is the baseline CCSS in the study eye 
- 
V3 - V6 is the CCSS in the study eye at Visit 3 through Visit 6  
 
An example of the SAS® code implementation of the MMRM model for the observed data only is as follows: 
PROC MIXED; 


Protocol HL036-DED-US-P302 SAP, Version 1.0 
 
23-JAN-2023 
Confidential & Proprietary 
Page 43 of 45 
 
CLASS PATIENT WEEK TREATMENT; 
MODEL CFB = WEEK BASELINE TREATMENT / SOLUTION COVB; 
LSMEANS TREATMENT / CL PDIFF; 
RUN; 




Protocol HL036-DED-US-P302 SAP, Version 1.0 
 
23-JAN-2023 
Confidential & Proprietary 
Page 45 of 45 
 
Placebo Run-In 
DIspensation and 
Instillation 
X 
 
 
 
 
 
 
Blood Sampling for 
Immunogenicity 
 
X 
 
 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
Study Drug Instillation 
 
X 
X 
 
 
 
 
Drop Comfort Scale 
 
X 
X 
 
 
 
 
Drop Comfort 
Questionnaire 
 
X 
X 
 
 
 
 
Adverse Event Query 
X 
X 
X 
X 
X 
X 
X 
Study Drug Dispensation 
 
X1 
X 
X 
X 
 
 
Exit Subject from Study 
 
 
 
 
 
X3 
 
1 The Visit 2 study drug kit is re-dispensed at Visit 3 (as each kit includes 2-week supply of study drug). 
2 To women of child-bearing potential. 
3 For subjects with negative immunogenicity results at Visit 6. 
4 Subjects will be asked to return for Blood Sample for Immunogenicity Testing if they test positive for immunogenicity at Visit 6. Visit 
7 will occur approximately 6-12 months after Visit 6. If subject tests positive for immunogenicity at Visit 7, they will be asked to 
return for Visit 8 approximately 12 months after Visit 7. If subject tests positive for immunogenicity at Visit 8, subject will be asked 
to return for Visit 9 approximately 12 months after Visit 8. 
 




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