Clinical trial NCT03925727
Conditions: Keratoconjunctivitis Sicca Dry Eye
Sponsor: Mimetogen Pharmaceuticals USA, Inc.
Start date: 2019-03-28; Completion date: 2020-06-11
Enrollment: 623 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the safety and efficacy of 5% tavilermide and 1% tavilermide ophthalmic solutions compared with placebo ophthalmic solution in treating the signs and symptoms of dry eye.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: Tavilermide ophthalmic solution intervention 2: Placebo
Intervention descriptions: intervention 1: BID topical dosing intervention 2: BID topical dosing

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol: MIM-728 
A Phase 3, Multi-Center, Randomized, Double-Masked, Vehicle-Controlled 
Clinical Study to Assess the Safety and Efficacy of 1% Tavilermide and 5% 
Tavilermide Ophthalmic Solutions for the Treatment of Dry Eye 
 
Sponsor: Mimetogen Pharmaceuticals USA, Inc. 
 
Protocol Number: MIM-728 
NCT Number: NCT03925727 
Document Date: 03 July 2019 


Clinical Trial Protocol: MIM-728 
1 GENERAL INFORMATION 
Protocol Title: 
A Phase 3, Multi-Center, Randomized, Double-
Masked, Vehicle-Controlled Clinical Study to 
Assess the Safety and Efficacy of 1% Tavilermide 
and 5% Tavilermide Ophthalmic Solutions for the 
Treatment of Dry Eye  
Protocol Number: 
MIM-728 
Study Phase: 
3 
Investigational Product 
Name: 
Tavilermide Ophthalmic Solution 
IND Number: 
105181 
Indication: 
Dry Eye Disease (keratoconjunctivitis sicca) 
Investigators: 
Multi-Center 
Sponsor: 
Mimetogen Pharmaceuticals USA, Inc. 
67 Batterymarch St., 5th Floor 
Boston, MA 02110 
Contract Research 
Organization: 
Ora, Inc. 
300 Brickstone Square, 3rd Floor 
Andover, MA 01810 
IRB/IEC: 
Alpha IRB 
1001 Avenida Pico 
Suite C, #497 
San Clemente, CA 92673 
 
 
Date 
Original Protocol: 
07 March 2019 
Amendment 1: 
03 July 2019 
 
Confidentiality Statement 
 
This protocol contains confidential, proprietary information of Ora, Inc. and/or 
Mimetogen Pharmaceuticals USA, Inc. Further dissemination, distribution or copying of 
this protocol or its contents is strictly prohibited. 
 
 


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SPONSOR PERSONNEL 
Vice President, 
Clinical Development: 
 
 
 
 
ORA PERSONNEL 
Department Vice President: 
 
 
 
 
Department Director: 
 
 
 
 
Project Manager: 
 
 
 
 
 
MEDICAL MONITOR 
Medical Monitor: 
 
 
 
 
 
 
 


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PROTOCOL SYNOPSIS 
Title: 
A Phase 3, Multi-Center, Randomized, Double-
Masked, Vehicle-Controlled Clinical Study to 
Assess the Safety and Efficacy of 1% Tavilermide 
and 5% Tavilermide Ophthalmic Solutions for the 
Treatment of Dry Eye  
Number: 
MIM-728 
Primary Objective: 
To compare the efficacy and safety of 5% 
tavilermide ophthalmic solution to placebo for the 
treatment of the symptoms and signs of dry eye 
disease (DED). 
Secondary Objective: 
To compare the efficacy and safety of 1% 
tavilermide ophthalmic solution to placebo for the 
treatment of the symptoms and signs of DED. 
Design: 
Multi-center, double-masked, randomized, vehicle-
controlled, parallel-group study. 
Study Duration 
An individual’s participation is approximately 100 
days (i.e., about 14 weeks). This includes a 2-week 
run-in period and a 12-week treatment period. 
Summary of Visit Schedule: 
Visit 1 (Day -14 ± 2): Screening 
Visit 2 (Day 1): Baseline and Randomization 
Visit 3 (Day 15 ± 2): 2-Week Follow-Up 
Visit 4 (Day 29 ± 2): 4-Week Follow-Up 
Visit 5 (Day 57 ± 3): 8-Week Follow-Up 
Visit 6 (Day 85 ± 4): 12-Week Follow-Up and 
Study Exit 
Interventions: 
1) 5% tavilermide ophthalmic solution 
2) 1% tavilermide ophthalmic solution 
3) Placebo ophthalmic solution (vehicle of 
tavilermide ophthalmic solution) 
Subjects are to administer 1 drop (GTT) of their 
assigned treatment to both eyes (OU), topically 
(TOP), and twice per day (BID). 


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Number of Subjects 
Approximately 1034 subjects are to be screened to 
enroll approximately 600 subjects at 15 to 20 sites. 
Study Population Characteristics – Inclusion Criteria: 
Each subject must: 
a. Be at least 18 years of age; 
b. Provide written informed consent; 
c. Have a subject-reported history of dry eye disease in both eyes for at least 6 
months prior to Visit 1; 
d. Have a history of use of artificial tear eye drops for dry eye symptoms; 
e. Report a total score (i.e., the square root of the product of the scores for each 
question) of 
 in Dry Eye (SANDE) 
Questionnaire at Visits 1 and 2; 
f. Have a tear film break up time (TFBUT) 
 at Visits 1 and 2; 
g. Have a total corneal fluorescein staining (CFS) score of 
 NEI 
scale 
 at Visits 1 and 2 
h. Have a total conjunctival lissamine green staining score of 
 
 according to the NEI scale 
 at Visits 1 and 2; 
i. Have an Unanesthetized Schirmer’s Test score of 
 
 at Visit 1; and 
j. Have at least one eye, the same eye, satisfy all criteria for i at Visit 1 and f, g, and 
h at Visits 1 and 2. 
Study Population Characteristics – Exclusion Criteria: 
Each subject must not: 
a. Have any clinically significant (CS) anterior chamber findings that may include 
active ocular infection (bacterial, viral, or fungal), lid margin 
inflammation/disorders (e.g., clinically significant blepharitis including 
staphylococcal, demodex, or seborrheic; clinically significant meibomian gland 
disease; floppy eye syndrome), clinically significant ocular rosacea , active ocular 
inflammation (iritis, uveitis), follicular conjunctivitis, or allergic conjunctivitis 
(seasonal and/or perennial) that require therapeutic treatment, and/or in the opinion 
of the Investigator may interfere with study parameters; 
b. Have any clinically significant (CS) posterior chamber findings, or a history of 
such findings/disorders, that may include exudative (i.e., wet) age-related macular 
degeneration, retinal vein occlusion, diabetic retinopathy, glaucoma, ocular 
hypertension, or any other retinal or optic nerve disease/disorder that require 
therapeutic treatment and/or in the opinion of the Investigator may interfere with 
study parameters; 


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c. Have worn contact lenses within 30 days of Visit 1 or anticipate using contact 
lenses during the study; 
d. Have had laser-assisted in situ keratomileusis (LASIK) or similar type of corneal 
refractive surgery and/or any other ocular surgical procedure within 12 months 
prior to Visit 1; or have any ocular surgical procedure scheduled to be conducted 
during the study period; 
e. Have had eyelid surgery within 12 weeks prior to Visit 1 or planned eyelid surgery 
during the study period; 
f. Have a history of lacrimal duct obstruction in either eye within 12 months prior to 
Visit 1; 
g. Have used temporary (i.e., collagen) punctal plugs within 12 weeks prior to Visit 1 
or anticipate their use during the study period; 
h. Have had permanent punctal plugs inserted or removed – including falling out – or 
have had surgical punctal occlusion within 12 weeks prior to Visit 1 or anticipate 
any such event at any time during the study period; 
i. Have used any of the following treatments in the period indicated before Visit 1 or 
anticipate their use at any time during the study. 
Day of Visit 1 
1. All topical ophthalmic preparations (e.g., medications for glaucoma, over-the 
counter-solutions, artificial tears, gels, scrubs, ointments) 
72 hours prior to Visit 1 
2. Antihistamines (including topical ophthalmic antihistamines) 
30 days prior to Visit 1 
3. Topical ophthalmic non-steroidal anti-inflammatories 
4. Topical ophthalmic corticosteroids  
5. Topical ophthalmic autologous serum 
6. Topical ophthalmic antibiotics 
7. Mast cell stabilizers 
8. Oral aspirin or aspirin-containing products except in the case that it was 
taken on a stable dosing regimen for at least 30 days prior to Visit 1 and is 
expected to be taken on the same regimen throughout the study period 
9. Any other medication known to cause ocular drying (e.g., antidepressants, 
beta blockers) except in the case that it was taken on a stable dosing regimen 
for at least 30 days prior to Visit 1 and is expected to be taken on the same 
regimen throughout the study period 
12 weeks prior to Visit 1 


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10. Restasis® 
11. Xiidra® 
12. CEQUA™ 
13. LipiFlow® or other similar meibomian gland dysfunction (MGD) therapy 
14. TrueTear® 
15. Corticosteroids (e.g., systemic steroids including intravenous, intramuscular, 
intraarticular, and oral steroids; facial topical steroids; dermatological 
steroids with high potency or large treatment areas); 
16. Tetracyclines (tetracycline, doxycycline, minocycline, etc.) 
j. Be monocular or have best corrected visual acuity 
 
as assessed by the Early Treatment of Diabetic 
Retinopathy Study (ETDRS) scale at Visit 1; 
k. Have a severe/serious systemic disease, chronic illness or uncontrolled medical 
condition including, but not limited to, severe cardiopulmonary disease, poorly 
controlled hypertension, poorly controlled diabetes and/or clinically significant 
(CS) hematologic, renal or liver disease that in the opinion of the Investigator 
could interfere with study assessments or limit compliance; 
l. Be a woman who is pregnant, nursing or planning a pregnancy; 
m. Be unwilling to submit a urine pregnancy test at Visit 1 and Visit 6 (or early 
termination visit) if of childbearing potential. Non-childbearing potential is 
defined as a woman who is permanently sterilized (e.g., has had a hysterectomy, 
bilateral tubal ligation, or bilateral oophorectomy), or is post-menopausal (i.e., 
without menses for 12 consecutive months); 
n. Be a woman of childbearing potential who is not using an acceptable means of 
birth control. Acceptable methods of contraception include hormonal (e.g., oral, 
implantable, injectable, or transdermal contraceptives), mechanical (e.g., 
spermicide in conjunction with a barrier such as a diaphragm or a condom), 
intrauterine device (IUD), or surgical sterilization of partner. For non-sexually 
active females, abstinence may be regarded as an adequate method of birth 
control; however, if the subject becomes sexually active during the study, she must 
agree to use adequate birth control as defined above for the remainder of the study; 
o. Have a known hypersensitivity or contraindication to the investigational products 
(IPs) or their components; 
p. Have a condition or be in a situation which the Investigator feels may put the 
subject at significant risk, may confound the study results, or may interfere 
significantly with the subject’s participation in the study (e.g., any planned 
procedure or surgery during the study period); 
q. Be currently enrolled in an investigational drug or device study or have used an 
investigational drug or device within 45 days prior to Visit 1; 


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r. Have previously participated in a clinical trial with tavilermide (MIM-D3); 
s. Be, in the opinion of the Investigator, unable or unwilling to comply with the 
study protocol, including participation in all study assessments, visits, and dosing, 
or be unable to instill eye drops successfully. Subject non-compliance with dosing 
during the run-in period, 
 
may be exclusionary if, in the opinion of the Investigator, the subject is likely to be 
non-compliant with subsequent dosing regimens or other study assessments; or 
t. Be an employee of the site that is directly involved in the management, 
administration, or support of this study or be an immediate family member of the 
same. 
Efficacy Measures and Endpoints: 
Primary Endpoints: 
The following primary endpoints will be tested in order using hierarchical fixed 
sequence testing: 
 Change from baseline in the Eye Dryness Score (EDS) at Visit 6 (Day 85) as 
measured by the Visual Analog Scale (VAS), comparing 5% tavilermide 
ophthalmic solution to placebo. 
 Change from baseline in total CFS score at Visit 6 (Day 85) as measured by the 
NEI scale for grading of fluorescein staining, comparing 5% tavilermide 
ophthalmic solution to placebo. 
Key Secondary Endpoints: 
The following key secondary endpoints will be tested in order following the two 
primary endpoints using hierarchical fixed sequence testing: 
 Change from baseline in the EDS at Visit 4 (Day 29) 
 
. 
 Change from baseline in total CFS score at Visit 4 (Day 29) 
 
 
 
 Change from baseline in the EDS at Visit 6 (Day 85) 
 
. 
 Change from baseline in total CFS score at Visit 6 (Day 85) 
 
 
 
 
 Change from baseline in the EDS at Visit 4 (Day 29) 
 
. 
 Change from baseline in total CFS score at Visit 4 (Day 29) 
 
 
 


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Other Secondary Endpoints: 
 Eye dryness, discomfort, grittiness, pain, blurred vision, and photophobia 
 
 
 
 Frequency, severity, and total score 
 
 
 
 
 at Visits 3, 4, 5, and 6, and the 
 at Visits 3, 4, 5, 
and 6. 
 CFS in the inferior, superior, central, temporal, nasal, and corneal (i.e., sum of 
all regions) regions 
 
 
 
 Conjunctival lissamine green staining in the temporal, superior temporal, 
inferior temporal, superior nasal, inferior nasal, nasal, and conjunctival (i.e., 
sum of all regions) regions 
 
 
 
 
 scores at Visit 6 and the 
 
 (Visit 1) at Visit 6. 
Safety Measures: 
 Concomitant Medication Review 
 Visual Acuity (ETDRS) 
 Slit-Lamp Biomicroscopy 
 Intraocular Pressure (IOP) 
 Dilated Fundoscopy 
 Ora Calibra® Drop Comfort Scale and Questionnaire 
 Adverse Event (AE) Query 
General Statistical Methods and Types of Analyses 
Analysis Populations 
 
 
 
 
 
 
 


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Sample Size 
 
 
 
 
 
 
 
 
 
 
 
Multiplicity Considerations 
 
 
 
 
Primary Efficacy Analyses  
 
 
 
 
 
 
 
 
 
 
 
 


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Key Secondary Efficacy Analyses 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other Secondary Efficacy Analyses 
 
 
 
 
 
 
Safety Analyses 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
1 
GENERAL INFORMATION .....................................................................................1 
PROTOCOL SYNOPSIS ....................................................................................................3 
TABLE OF CONTENTS ...................................................................................................12 
LIST OF ABBREVIATIONS ............................................................................................15 
2 
BACKGROUND INFORMATION .........................................................................17 
 
Characterization of Tavilermide .....................................................................17 
 
Summary of the Nonclinical Program ............................................................17 
 
Summary of the Clinical Program ..................................................................18 
 
Summary of Known and Potential Risks and Benefits ..................................18 
 
Dose Selection and Study Rationale ..............................................................19 
 
Compliance Statement ....................................................................................19 
 
Intended Study Population .............................................................................19 
3 
STUDY OBJECTIVES .............................................................................................19 
 
Primary Objective ...........................................................................................19 
 
Secondary Objective .......................................................................................19 
4 
STUDY DESIGN......................................................................................................20 
 
Type of Study .................................................................................................20 
 
Number of Subjects ........................................................................................20 
 
Expected Duration of Study ...........................................................................20 
 
Primary and Secondary Outcome Measures ..................................................22 
4.4.1 
Primary Endpoints ............................................................................22 
4.4.2 
Key Secondary Endpoints .................................................................22 
5 
STUDY TREATMENTS ..........................................................................................24 
 
Description and Labelling of Investigational Product ....................................24 
5.1.1 
Study Treatment Formulation ...........................................................24 
5.1.2 
Run-In Formulation ..........................................................................24 
 
Dosage and Route of Administration .............................................................25 
5.2.1 
Run-In Period ....................................................................................25 
5.2.2 
Treatment Period ...............................................................................25 
 
Storage and Dispensation of Investigational Product .....................................26 
 
Investigational Product Accountability ..........................................................26 
 
Subject Compliance with Protocol .................................................................27 
 
Prohibited Medications/Treatments ...............................................................27 
5.6.1 
Concomitant Medications .................................................................27 
 
Non-IP Study Supplies ...................................................................................28 
6 
SUBJECT ENROLLMENT AND RANDOMIZATION .........................................28 
 
Subject Inclusion Criteria ...............................................................................29 
 
Subject Exclusion Criteria ..............................................................................29 
 
Randomization Procedures .............................................................................32 
 
Arrangements Taken to Prevent Unmasking ..................................................33 
 
Procedures for Unmasking .............................................................................33 
 
Early Termination ...........................................................................................34 
6.6.1 
Reasons for Discontinuation .............................................................34 


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6.6.2 
Reasons for Withdrawal ....................................................................34 
6.6.3 
Documenting Early Termination and Subjects Lost to Follow-Up ..34 
7 
STUDY VISITS AND PROCEDURES SCHEDULE .............................................35 
 
Unscheduled Visits .........................................................................................36 
8 
ASSESSMENT OF EFFICACY ..............................................................................37 
8.1.1 
Primary and Key Secondary Endpoints ............................................37 
8.1.2 
Other Secondary Endpoints ..............................................................37 
9 
ASSESSMENT OF SAFETY ...................................................................................37 
 
Safety Parameters ...........................................................................................38 
 
Adverse Events ...............................................................................................38 
9.2.1 
Severity .............................................................................................39 
9.2.2 
Relationship to Investigational Product ............................................39 
9.2.3 
Expectedness .....................................................................................40 
9.2.4 
Action Taken with Investigational Product ......................................40 
9.2.5 
Outcome ............................................................................................40 
 
Serious Adverse Events ..................................................................................41 
 
Procedures for Reporting Adverse Events .....................................................41 
9.4.1 
Reporting an Adverse Event .............................................................41 
9.4.2 
Reporting a Serious Adverse Event ..................................................42 
9.4.3 
Reporting a Suspected Unexpected Adverse Reaction .....................43 
 
Type and Duration of Follow-Up of Subjects after Adverse Events .............43 
 
Pregnancy .......................................................................................................43 
10 
STATISTICS ............................................................................................................43 
 Analysis Populations ......................................................................................43 
10.1.1 Intent-to-Treat Population .................................................................43 
10.1.2 Per Protocol Population ....................................................................44 
10.1.3 Safety Population ..............................................................................44 
 Statistical Hypotheses .....................................................................................44 
10.2.1 Primary Endpoints ............................................................................44 
10.2.2 Key Secondary Endpoints .................................................................44 
 Sample Size ....................................................................................................45 
10.3.1 Multiplicity Considerations ..............................................................46 
 Statistical Analysis .........................................................................................46 
10.4.1 General Considerations .....................................................................46 
10.4.2 Unit of Analysis ................................................................................46 
10.4.3 Missing Data .....................................................................................47 
10.4.4 Primary Efficacy Analyses ...............................................................47 
10.4.5 Key Secondary Efficacy Analyses ....................................................47 
10.4.6 Other Secondary Efficacy Analyses .................................................48 
10.4.7 Safety Analyses .................................................................................48 
10.4.8 Interim Analyses ...............................................................................48 
11 
DATA HANDLING AND RECORDKEEPING .....................................................48 
 Data Collection ...............................................................................................48 
 Data Directly Recorded on the Electronic Case Report Forms ......................49 
 Retention of Documentation ..........................................................................49 
12 
ADMINISTRATIVE ASPECTS ..............................................................................50 


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 Ethics ..............................................................................................................50 
 Subject Confidentiality ...................................................................................50 
 Institutional Review Board Approval .............................................................50 
 Subject Informed Consent ..............................................................................50 
 Modifications of the Protocol .........................................................................51 
 Quality Control and Quality Assurance .........................................................51 
 Financing and Insurance .................................................................................51 
13 
PUBLICATION POLICY ........................................................................................52 
14 
REFERENCES .........................................................................................................52 
15 
APPENDICES ..........................................................................................................53 
Appendix 1: Schedule of Visits and Measurements ..........................................................53 
Appendix 2: Examination Procedures, Tests, Equipment, and Techniques ......................54 
Visual Analog Scale (VAS) ......................................................................................54 
Symptom Assessment in Dry Eye (SANDE) Questionnaire ....................................55 
Visual Acuity Procedures (ETDRS Chart) ...............................................................56 
Slit-Lamp Biomicroscopy Procedures ......................................................................58 
Tear Film Break-Up Time (TFBUT) ........................................................................59 
Fluorescein Staining .................................................................................................60 
NEI/Industry Workshop Scale for Grading of Fluorescein Staining ........................60 
Lissamine Green Staining .........................................................................................62 
NEI/Industry Workshop Scale for Grading of Lissamine Green Staining ...............62 
Unanesthetized Schirmer’s Test ...............................................................................63 
Intraocular Pressure ..................................................................................................64 
Dilated Fundoscopy ..................................................................................................65 
Ora Proprietary Scale – Not for Distribution without Permission ............................66 
Drop Comfort Assessments ......................................................................................66 
Subject-Reported Drop Comfort ....................................................................66 
Ora Calibra® Drop Comfort Scale ..................................................................66 
Subject-Reported Drop Comfort Questionnaire .............................................66 
Ora Calibra® Drop Comfort Questionnaire ....................................................66 
Appendix 3: Adverse Event (AE) Definitions ...................................................................67 
Severity .....................................................................................................................67 
Relationship to Investigational Product (IP) .............................................................67 
Expectedness .............................................................................................................67 
Appendix 5: Protocol Amendment Summary ....................................................................68 
Appendix 6: Sponsor and Ora Approvals ..........................................................................69 
Appendix 7: Investigator’s Signature ................................................................................70 
 
 


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LIST OF ABBREVIATIONS 
AE 
adverse event 
ANCOVA 
Analysis of Covariance 
BID 
twice daily 
CAE 
Controlled Adverse Environment 
CFR 
Code of Federal Regulations 
CFS 
corneal fluorescein staining 
CI 
confidence interval 
CS 
clinically significant 
DED 
dry eye disease 
DHHS 
Department of Health and Human Services 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EDS 
eye dryness score 
ERC 
Ethical Review Committee 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GTT 
drop 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
investigational new drug application 
IOP 
intraocular pressure 
IP 
investigational product 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
ITT 
intent to treat 
IUD 
intrauterine device 
KCS 
keratoconjunctivitis sicca 
kg 
kilogram 
LASIK 
laser in situ keratomileusis 
LDPE 
low-density polyethylene 
LOCF 
last observation carried forward 
logMAR 
logarithm of the minimum angle of resolution 


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MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MGD 
meibomian gland dysfunction 
mL 
milliliter 
mm 
millimeter 
mmHg 
millimeter of mercury 
NCS 
not clinically significant 
NEI 
National Eye Institute 
NGF 
nerve growth factor 
NOAEL 
no-observed-adverse-effect-level 
OU 
both eyes 
PP 
per protocol 
QID 
four times each day 
SAE 
serious adverse event 
SANDE 
Symptom Assessment in Dry Eye 
SDC 
Statistics and Data Corporation 
SOP 
standard operating procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
treatment emergent adverse event 
TFBUT 
tear film break-up time 
TMF 
trial master file 
TOP 
topically 
TrkA 
tropomyosin receptor kinase A 
VA 
visual acuity 
VAS 
Visual Analog Scale 
 
 


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2 BACKGROUND INFORMATION 
 Characterization of Tavilermide 
Tavilermide (previously designated by its laboratory name, MIM-D3) ophthalmic 
solution is a proteolytically stable, cyclic peptidomimetic that mimics a β-turn region of 
nerve growth factor (NGF) formulated as a preservative-free, aqueous, sterile ophthalmic 
solution. Biochemical and cellular assays showed that tavilermide is a partial 
tropomyosin-related kinase A (TrkA) receptor agonist, activating and potentiating the 
effects of suboptimal concentrations of the natural ligand NGF,1 and acts synergistically 
with NGF in vivo.2–4 Tavilermide is a new chemical entity. 
Mimetogen Pharmaceuticals USA, Inc. (Sponsor) is developing tavilermide as a potential 
therapeutic agent for the treatment of dry eye disease (DED). 
 Summary of the Nonclinical Program 
Nonclinical data have demonstrated that tavilermide has physiologic effects that lead to 
amelioration of the signs associated with dry eye5 without causing any significant ocular, 
systemic, genotoxic, embryo-fetal development or safety concerns related to any organ 
system. 
Intravenous toxicity studies in rats and dogs (28 days) revealed no adverse findings and 
no target organ toxicity for doses up to 150 and 40 mg/kg tavilermide, respectively. No 
evidence of mutagenicity or genotoxicity was observed, nor were any significant effects 
noted on the central nervous system, respiratory system or cardiovascular system. 
Repeat-dose ocular toxicity studies of up to 6-months duration were conducted in rabbits 
at concentrations up to 5% administered topically four times per day (QID). No test 
article-related morbidity/mortality was noted, and no test article-related ocular effects 
were observed macroscopically or microscopically. No marked or significant 
toxicological effects were noted in any organ system, and the product did not accumulate 
in the body after repeated topical ocular instillations. No significant gender-related effects 
were noted for tavilermide. 
In an embryo-fetal development study in rats, a slight reduction in maternal body weight 
gain was apparent at the high dose (350 mg/kg). There was no evidence of effects on fetal 
growth and embryo-fetal mortality. Fetal abnormalities noted at 100 and 350 mg/kg did 
not indicate a clear effect of tavilermide. The no-observed-adverse-effect-level (NOAEL) 
for maternal toxicity was considered to be 350 mg/kg/day and for embryo-fetal 
development was considered to be 35 mg/kg/day. In a rabbit embryo-fetal development 
study, there were no effects on embryo-fetal growth or dysmorphology (teratogenicity) or 
embryo-fetal mortality at the highest dose. The NOAEL for maternal toxicity and 
embryo-fetal development was considered to be 200 mg/kg/day. 


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 Summary of the Clinical Program 
To date, one Phase 2 and three Phase 3 multicenter, randomized, double-masked, vehicle-
controlled studies conducted in adult subjects with dry eye disease in the U.S. of similar 
design are completed. The Phase 2 study was 7 weeks in duration, whereas the Phase 3 
studies were 10 weeks. There was a one-week open-label run-in with Bausch & Lomb 
Sensitive Eyes® Drops followed by a 4-week and 8-week treatment period in the Phase 2 
and Phase 3 studies, respectively. The Phase 2 study also had a 2-week follow up after 
treatment cessation. Treatment in each study was administered as a single drop twice 
daily (morning and evening) in each eye. These previous studies used the Controlled 
Adverse Environment® (CAE®) model both for screening and efficacy endpoints. 
In the Phase 2 study (MIM-724), 150 subjects with dry eye were randomized to 1% 
tavilermide ophthalmic solution, 5% tavilermide ophthalmic solution, or placebo 
ophthalmic solution (i.e., vehicle of tavilermide ophthalmic solution). The 1% and 5% 
tavilermide ophthalmic solutions were numerically superior to placebo in reducing the 
signs and symptoms of dry eye, but not for the study pre-specified primary efficacy 
endpoints.6 Post hoc analyses suggested that the greatest treatment effect was observed 
with the 1% tavilermide ophthalmic solution. Therefore, 1% tavilermide ophthalmic 
solution was chosen for further investigation in Phase 3 studies. 
In each of the three Phase 3 studies (MIM-725, MIM-726, and MIM-727), 400 subjects 
with dry eye were randomized to 1% tavilermide ophthalmic solution or placebo 
ophthalmic solution. 1% tavilermide ophthalmic solution was numerically superior to 
placebo in reducing the signs and symptoms of dry eye, but not for the study pre-
specified primary efficacy endpoints. 
 Summary of Known and Potential Risks and Benefits 
In the Phase 2 study (MIM-724), which investigated the 1% and 5% concentrations of 
tavilermide versus placebo, there were no deaths or serious ocular treatment emergent 
adverse events (TEAEs). The total TEAEs reported during the study were distributed 
fairly evenly among the treatment groups: 1% tavilermide had 22 TEAEs, 5% tavilermide 
had 35, and placebo had 30. Furthermore, ocular TEAEs also were distributed somewhat 
evenly among the treatment groups: 1% tavilermide had 10 TEAEs, 5% tavilermide had 
8, and placebo had 8. The majority of the ocular TEAEs were mild. Ophthalmic 
examinations yielded no concerns. The MIM-724 trial suggested that the tavilermide 
ophthalmic solutions, both 1% and 5%, are safe and well-tolerated. 
In the Phase 3 studies, no deaths or serious ocular TEAEs occurred; TEAEs occurred in 
less than 5% of subjects. No clinically significant (CS) safety findings were observed by 
intraocular pressure (IOP) measurement, slit-lamp biomicroscopy, or dilated fundoscopy, 
and there were no changes in safety parameters due to the tavilermide or vehicle 
treatments. All abnormal findings reported at baseline were considered not clinically 
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1% tavilermide ophthalmic solution was well tolerated, and there was no difference in 
the comfort of 1% tavilermide ophthalmic solution compared to placebo, as reported by 
subjects. 
Results from the previous Phase 2 and Phase 3 trials suggest that tavilermide ophthalmic 
solution is a promising new treatment for DED with an acceptable safety profile. 
 Dose Selection and Study Rationale 
Tavilermide ophthalmic solution is to be administered as a single drop, bilaterally (i.e., 
both eyes), and twice daily (morning and evening). The previous Phase 3 studies were 
performed with 1% tavilermide for 8 weeks and did not meet the pre-specified primary 
endpoints. Consequently, this trial is powered to study the efficacy of 5% tavilermide 
with a longer treatment period of 12 weeks, while simultaneously continuing to examine 
1% tavilermide. 
 Compliance Statement 
This study will be conducted in compliance with the protocol, current Good Clinical 
Practices (GCPs), including the International Conference on Harmonisation (ICH) 
Guidelines, and in general, consistent with the Declaration of Helsinki. In addition, all 
applicable local, state, and federal requirements relevant to the use of investigational 
product (IP) in the countries involved will be adhered to. 
 Intended Study Population 
The population for this study will be patients with moderate DED who are at least 18 
years of age and of any gender and race who satisfy all of the inclusion criteria and meet 
none of the exclusion criteria outlined in this protocol. 
3 STUDY OBJECTIVES 
 Primary Objective 
To compare the efficacy and safety of 5% tavilermide ophthalmic solution to placebo for 
the treatment of the symptoms and signs of DED. 
 Secondary Objective 
To compare the efficacy and safety of 1% tavilermide ophthalmic solution to placebo for 
the treatment of the symptoms and signs of DED. 


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4 STUDY DESIGN 
 Type of Study 
This Phase 3 trial is a multi-center, double-masked, randomized, vehicle-controlled, 
parallel-group clinical study. There will be two active treatment groups – 1% tavilermide 
ophthalmic solution and 5% tavilermide ophthalmic solution – and one control group – 
placebo ophthalmic solution (vehicle of tavilermide ophthalmic solution). 
Figure 1 (Page 21) provides an outline of the study assessments and phases of the trial. 
A subject’s participation is to start with screening and baseline safety measurements at 
Visit 1. If the subject is considered eligible for the study at the end of Visit 1, the subject 
will participate in a 14-day run-in period. Isotonic ophthalmic solution – also known as 
placebo ophthalmic solution (vehicle of tavilermide ophthalmic solution) – is the 
designated run-in and is to be administered to both eyes (OU), topically (TOP), and twice 
per day (BID) throughout the run-in period. 
Baseline efficacy measurements are to be obtained at Visit 2. Should a subject qualify for 
final study entry at the end of Visit 2, they are to be randomly assigned to one of three 
treatment groups: 
 5% tavilermide ophthalmic solution, 
 1% tavilermide ophthalmic solution, or 
 Placebo ophthalmic solution. 
During the treatment period, the subject is to dose with their assigned treatment OU, 
TOP, and BID for approximately 85 days. 
 Number of Subjects 
Approximately 1034 subjects are to be screened to enroll approximately 600 subjects. A 
maximum of 40 subjects will be enrolled at each of 15 to 20 sites in the United States. 
 Expected Duration of Study 
The duration of an individual’s participation in the study, from the start of subject 
screening to study exit, is six clinic visits over approximately 100 days (i.e., about 14 
weeks). 
The duration of the study – from first patient, first visit to last patient, last visit – is 
expected to be approximately 10 months. 
 
 


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Visit 1 (Day -14 ± 2): 
Screening 
Informed Consent / HIPAA 
Medical / Medication History and 
Demographics 
Urine Pregnancy Test (as needed) 
Sign and Symptom Assessments 
Safety Assessments 
Dispensation of Run-In 
 
 
Visit 2 (Day 1): 
Baseline and 
Randomization 
Run-In Collection and Accountability 
Medical Status Update / AE Query 
Sign and Symptom Assessments 
Safety Assessments  
Randomization 
Dispensation of Randomized Treatment Kit 
In-Office Randomized Treatment Dose 
Drop Comfort Assessments 
Visit 3 (Day 15 ± 2): 
2-Week Follow-Up 
IP Collection and Accountability 
Medical Status Update / AE Query 
Sign and Symptom Assessments 
Safety Assessments  
Dispensation of Randomized Treatment Kit 
Visit 4 (Day 29 ± 2): 
4-Week Follow-Up 
IP Collection and Accountability 
Medical Status Update / AE Query 
Sign and Symptom Assessments 
Key Secondary Sign and Symptom Assessments 
Safety Assessments 
Dispensation of 2 Randomized Treatment Kits 
Visit 5 (Day 57 ± 3): 
8-Week Follow-Up 
IP Collection and Accountability 
Medical Status Update / AE Query 
Sign and Symptom Assessments 
Safety Assessments 
Dispensation of 2 Randomized Treatment Kits 
In-Office Randomized Treatment Dose 
Drop Comfort Assessments 
Visit 6 (Day 85 ± 4): 
12-Week Follow-Up 
and Study Exit 
IP Collection and Accountability 
Medical Status Update / AE Query 
Urine Pregnancy Test (as needed) 
Primary Endpoint Assessment 
Key Secondary Sign and Symptom Assessments 
Other Sign and Symptom Assessments 
Safety Assessments 
Figure 1     Trial design, procedure outline, and phases. 
 
 
 
Run-In Phase 
~ 14 Days 
Treatment 
Phase 
~ 85 Days 


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 Primary and Secondary Outcome Measures 
4.4.1 Primary Endpoints 
The following primary endpoints will be tested in order using hierarchical fixed sequence 
testing: 
 Change from baseline in the Eye Dryness Score (EDS) at Visit 6 (Day 85) 
 
 
 
 Change from baseline in total corneal fluorescein staining score (CFS) at Visit 6 
(Day 85) 
 
. 
Clinical Hypotheses: 
The hierarchical clinical hypotheses for the primary endpoint, to be tested in the order 
indicated below, are that the 5% tavilermide ophthalmic solution is superior to the 
placebo for the treatment of the symptoms and signs of DED at Day 85. 
1. Subjects receiving 5% tavilermide ophthalmic solution will have a statistically 
significantly lower change from baseline in EDS when compared to placebo 
 
 
If the above hypothesis is successful at the 0.05 confidence level, then the second 
hypothesis is to be tested. 
2. Subjects receiving 5% tavilermide ophthalmic solution will have a statistically 
significantly lower total change from baseline in total CFS score when compared 
to placebo 
 
4.4.2 Key Secondary Endpoints 
The following key secondary endpoints will be tested in order following the two primary 
endpoints using hierarchical fixed sequence testing: 
 Change from baseline in the EDS at Visit 4 (Day 29) 
 
 
 Change from baseline in total CFS score at Visit 4 (Day 29) 
 
 
 
 Change from baseline in the EDS at Visit 6 (Day 85) 
 
 
 Change from baseline in total CFS score at Visit 6 (Day 85) 
 
 
 
 Change from baseline in the EDS at Visit 4 (Day 29) 
 
 


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 Change from baseline in total CFS score at Visit 4 (Day 29) 
 
 
 
Clinical Hypotheses: 
The hierarchical clinical hypotheses for the key secondary endpoint, to be tested in the 
order indicated below following the primary clinical hypotheses, are that the 5% 
tavilermide ophthalmic solution is superior to the placebo for the treatment of the 
symptoms and signs of DED at Day 29 and that the 1% tavilermide ophthalmic solution 
is superior to the placebo for the treatment of the symptoms and signs of DED at Day 85. 
If the second primary hypothesis is successful 
 then the third 
hypothesis is to be tested. 
3. Subjects receiving 5% tavilermide ophthalmic solution will have a statistically 
significantly lower change from baseline in EDS when compared to placebo as 
measured by the VAS at Visit 4 (Day 29). 
If the above hypothesis is successful 
, then the fourth 
hypothesis is to be tested. 
4. Subjects receiving 5% tavilermide ophthalmic solution will have a statistically 
significantly lower total change from baseline in total CFS score when compared 
to placebo as measured by the NEI scale at Visit 4 (Day 29). 
If the above hypothesis is successful 
, then the fifth 
hypothesis is to be tested. 
5. Subjects receiving 1% tavilermide ophthalmic solution will have a statistically 
significantly lower change from baseline in EDS when compared to placebo as 
measured by the VAS at Visit 6 (Day 85). 
If the above hypothesis is successful 
, then the sixth 
hypothesis is to be tested. 
6. Subjects receiving 1% tavilermide ophthalmic solution will have a statistically 
significantly lower total change from baseline in total CFS score when compared 
to placebo as measured by the NEI scale at Visit 6 (Day 85). 
If the above hypothesis is successful 
, then the seventh 
hypothesis is to be tested. 
7. Subjects receiving 1% tavilermide ophthalmic solution will have a statistically 
significantly lower change from baseline in EDS when compared to placebo as 
measured by the VAS at Visit 4 (Day 29). 
If the above hypothesis is successful 
, then the eighth 
hypothesis is to be tested. 
8. Subjects receiving 1% tavilermide ophthalmic solution will have a statistically 
significantly lower total change from baseline in total CFS score when compared 
to placebo as measured by the NEI scale at Visit 4 (Day 29). 


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5 STUDY TREATMENTS 
 Description and Labelling of Investigational Product 
5.1.1 Study Treatment Formulation 
The trial has three investigational products: 
 5% tavilermide ophthalmic solution (10 mg/day total dose), 
 1% tavilermide ophthalmic solution (2 mg/day total dose), and 
 Placebo ophthalmic solution (vehicle of tavilermide ophthalmic solution). 
The active ingredient in the 5% and 1% tavilermide ophthalmic solutions is tavilermide 
hydrochloride salt. The vehicle for tavilermide is a sterile, preservative-free, buffered, 
isotonic solution for topical administration. Tavilermide ophthalmic solution contains 
drug substance and pharmaceutically acceptable excipients commonly used in ophthalmic 
solutions. The manufacturer of the IP is Holopack Verpackungstechnik GmbH, which has 
a place of business at Bahnhofstraße 20, 73453 Abtsgmünd, Germany. 
The IP is contained in sterile, single-use, low-density polyethylene (LDPE) vials (0.3 
mL/vial). A card of five vials of the same formulation is sealed in a foil pouch. Eight foil 
pouches containing vials of the same formulation are packaged into a box to make one 
clinical kit. One clinical kit is sufficient for 14 days of dosing with an additional 12 extra 
vials. All IP is labeled according to applicable regulatory requirements. 
IP for the treatment phase of the study is labeled as “Tavilermide Ophthalmic Solution or 
Placebo Ophthalmic Solution.” Kit packaging and labeling, except for an identifier, are 
identical for each of the three treatment arms. Treatment kits are identifiable by a unique, 
five-digit kit number. Kit numbers are randomly associated with clinical kits from the 
three treatment arms and range from 30001 to 36600. 
The IP for the three arms are visually distinct. The discrepancies in appearance mandate 
that there is at least one technician designated as unmasked at each clinical site. Once 
open, a treatment kit is to be handled by only the subject to which it was assigned and 
unmasked designees. 
5.1.2 Run-In Formulation 
The run-in is the placebo ophthalmic solution. The run-in is packaged in the same manner 
as randomized treatment kits. 
IP for the run-in phase of the study is labeled “Isotonic Ophthalmic Solution.” Run-in kits 
are identifiable by a unique, four-digit kit number. Run-in kit numbers range from 1001 
to 3880. 
Subjects are not to be made aware that the run-in is the placebo ophthalmic solution 
because the placebo is visually distinct from the active treatments. Should a subject note 
an appearance change from the run-in phase to the treatment phase, and be aware that the 
placebo ophthalmic solution is the IP for the run-in phase and one of the three 
randomized treatment arms, they may infer that they were assigned to one of the active 


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treatments. Therefore, IP for the run-in phase is to be labeled as “Isotonic Ophthalmic 
Solution” so as to mask from the subjects that the run-in is the placebo ophthalmic 
solution. 
 Dosage and Route of Administration 
5.2.1 Run-In Period 
For the run-in phase of the trial, subjects qualified at the end of Visit 1 to continue to 
Visit 2 are to administer 1 drop (GTT) of isotonic ophthalmic solution (i.e., placebo 
ophthalmic solution) OU, TOP, and BID – morning and evening before bed – for 
approximately 14 days. The first dose of run-in is to be in the evening before bed on the 
day of Visit 1. The last dose of run-in is to be in the evening before bed on the day before 
Visit 2. 
The subject is not to dose with run-in on the day of Visit 2 before their appointment. 
Should a subject dose with run-in on the day of Visit 2 before their appointment, the time 
of the dose is to be recorded, and the subject should wait at least 4 hours from the time of 
the dose to the start time of any efficacy assessments. 
The subject is to return their run-in kit, including used and unused vials at Visit 2. 
5.2.2 Treatment Period 
At the end of Visit 2, enrolled subjects are to be randomly assigned one of the three IPs to 
use during the treatment phase of the trial (i.e., Visit 2 to Visit 6). During the treatment 
phase, subjects are to administer 1 GTT of their assigned treatment OU, TOP, and BID – 
morning and evening before bed – for approximately 85 days. The first dose of the 
assigned treatment is to be in the office at Visit 2. The first at-home dose is to be in the 
evening before bed on the day of Visit 2. The last dose is to be in the evening before bed 
on the day before Visit 6. 
On the days of Visits 3, 4, 5, and 6, subjects are not to dose with IP before their 
appointments. Should a subject dose with IP on the day of a visit before their 
appointment, the time of the dose is to be recorded, and the subject should wait at least 4 
hours from the time of the dose to the start time of any efficacy assessments. 
Subjects are to self-administer an in-office dose of their assigned treatment at Visits 2 and 
5. After Visits 2 and 5, subjects are to take their next dose of IP in the evening before 
bed. Subjects will not dose in-office at Visits 3 and 4. After Visits 3 and 4, subjects are to 
resume dosing at home immediately following the visit and take a second dose in the 
evening before bed. 
Subjects are to return each kit, used and unused vials, the visit after which it was 
originally assigned. Used vials are to be returned to the site in a resealable, opaque bag. 
The bag and the unused vials should be kept in the closed kit box. Furthermore, subjects 
are to be instructed not to show their drops to, or discuss the drops with, clinical trial staff 
– unless specifically told otherwise – or other subjects. 
Escape medications and special diet or activities are not applicable. 


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The follow-up period for the IP in the run-in and treatment phases ends with the subject’s 
exit from the study. Adverse Events (AEs) ongoing at the end of Visit 6 are to be 
followed as specified in Section 9.5. 
 Storage and Dispensation of Investigational Product 
The IP must be stored in a secure area accessible only to the Investigator and his/her 
designees. The IP will be administered only to subjects entered into the clinical study, in 
accordance with the conditions specified in this protocol. 
IP is to be stored at 15-25 °C and protected from light; IP is never to be frozen or 
refrigerated. 
Subjects are to be instructed on the proper use and storage of the IP at the end of each 
visit at which IP is dispensed. Written instructions detailing the proper use and storage of 
the IP are also to be provided to the subjects. 
Kits are to be dispensed in their entirety to the appropriate subjects. At Visit 1, each 
eligible subject is to receive one run-in kit. Run-in kits should be assigned in sequential 
order to subjects as they become eligible from the list of available kits at the site. 
At Visits 2 and 3, each eligible subject is to receive one kit of their randomly assigned 
treatment. At Visits 4 and 5, each eligible subject is to receive two kits of their randomly 
assigned treatment. Randomized treatment kits are to be assigned by the Interactive 
Response Technology (IRT) system. Subjects are to return all used vials and unused IP at 
the visit after the one at which the IP was originally dispensed. 
Replacement kits are available as needed for dispensation. Replacement kits are to be 
assigned using the IRT system after receiving approval from Ora and the Sponsor. 
 Investigational Product Accountability 
The IP is only to be prescribed by the Principal Investigator or his/her named Sub-
Investigator(s) and is only to be used in accordance with this protocol. The IP must only 
be distributed to subjects properly qualified under this protocol to receive IP. 
The Investigator must keep an accurate record and accounting of the IP on site received 
from the supplier, including dates of receipt. In addition, accurate records will be kept 
regarding the amount of IP dispensed to subjects, amount of IP returned to the 
Investigator by the subjects, and the amount returned or disposed upon the completion of 
the study. A detailed inventory must be completed for the IP, and reasons for departure 
from the expected dispensing regimen will be recorded. 
At the end of the study, there will be a final reconciliation of unused investigational 
product that was returned to the site by subjects or was not dispensed by the site. There is 
to be no reconciliation of used or missing vials. Any discrepancies will be investigated, 
resolved and documented by the study team. All IP, used and unused, will be returned to 
the Sponsor or their designee in compliance with applicable regulations. The return of IP 
will be specified in writing. 


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 Subject Compliance with Protocol 
The compliance and accountability guidelines below are to be used by the Investigator 
for determining subject compliance with this protocol and for recording deviations from 
the stated compliance. The site-calculated dosing compliance is not to be transcribed to 
the electronic Case Report Forms (eCRFs). 
Run-in is to be collected at Visit 2. A technician is to calculate dosing compliance from 
Visit 1 to Visit 2 by dividing the number of used vials by the number of expected doses 
and 
 
 
 
 
 Non-compliance with dosing during the run-in phase may be 
grounds for screen failure at Visit 2 as determined by the Investigator (Section 6.2, 
Exclusion s). 
Randomized treatment is to be collected at Visits 3, 4, 5, and 6. At each of these visits, 
the subject compliance with dosing from the previous visit is to be calculated. At Visits 3 
and 6, the in-office doses at Visits 2 and 5 will be included in the expected vial count for 
the purpose of site-calculated dosing compliance, respectively. 
 
 
 
 
 
 Prohibited Medications/Treatments 
Disallowed medications and treatments during the study and applicable washout periods 
are outlined in the Exclusion Criteria (Section 6.2). In addition, the site is responsible for 
reviewing subject-reported concomitant medications for prohibited treatments such as 
medications with ocular drying effects, antihistamines, mast cell stabilizers, 
corticosteroids, or other exclusionary medications. 
Concurrent enrollment in another investigational drug or medical device study is not 
permitted. 
5.6.1 Concomitant Medications 
The use of any concomitant medication, prescription or over-the-counter, is to be 
recorded on the subject’s source document and corresponding eCRF along with the 
reason the medication was taken. 
Common medications that may be permissible for use as needed by trial subjects for pain 
relief or the treatment of a cold or flu during the study are outlined below. The site is 
responsible for reviewing any medication taken by the subject for compliance with the 
disallowed medications as listed in the Exclusion Criteria (Section 6.2). 
 Pain Relief / Fever Reducers 


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o Active Ingredients: acetaminophen, ibuprofen, naproxen sodium 
o Brands: Tylenol®, Advil®, Aleve® 
 Daytime Cold Medicines 
o Active Ingredients: acetaminophen, phenylephrine, dextromethorphan, 
guaifenesin 
o Brands: Tylenol® Cold Multi-Symptom Daytime, DayQuil® Cold and Flu 
 Nasal Decongestants 
o Active Ingredients: phenylephrine 
o Brands: Sudafed® PE Maximum Strength Congestion & Sinus Pressure 
Relief 
 Expectorants 
o Active Ingredients: guaifenesin 
o Brands: Mucinex® 
 Cough Suppressants 
o Active Ingredients: dextromethorphan 
o Brands: Robitussin® 
 Non-IP Study Supplies 
Additional, non-IP study supplies required at each site include urine pregnancy tests, 
medical examination gloves, urine collection cups, clear 100 mm rulers, ETDRS Series 
2000 Chart 1, occluder, alcohol swabs, pipette(s), pipette tips, stopwatch(es), 2% 
preservative free fluorescein sodium, Wratten #12 yellow filter, lissamine green 
ophthalmic strips, sterile saline solution, Schirmer’s tear test strips, timer(s), fluorescein 
sodium and benoxinate hydrochloride ophthalmic solution (e.g., Fluress®, Altafluor 
Benox), and 1% tropicamide ophthalmic solution. 
6 SUBJECT ENROLLMENT AND RANDOMIZATION 
Before performing any study-specific procedure – including screening procedures to 
determine eligibility – a signed informed consent form (ICF) will be obtained for each 
subject. The consent form will describe the purpose of the study, the procedures to be 
performed, and the risks and potential benefits of participation. The Investigator or an 
appropriately trained and delegated staff member is to conduct the informed consent 
discussion, check that the subject comprehends the information provided, and answer any 
questions about the study. The subject and the individual that conducted the consent 
discussion are to sign the ICF. A copy of the consent form is to be given to the subject 
and consent is to be documented on the subject’s record. 


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Each subject who signs an ICF is to be assigned a screening number. All screening 
numbers are to be assigned in strict numerical sequence at each site, and no numbers are 
to be skipped or omitted. The first screening number at each site is to be 001. A unique, 
two-digit, numeric identifier is to be assigned to each site (e.g., 70). The site number and 
the screening number are to be concatenated to create a unique subject identifier (e.g., 70-
001). 
Qualified subjects are to be assigned to a randomized study treatment only if they meet 
all of the inclusion criteria and none of the exclusion criteria. 
 Subject Inclusion Criteria 
Subjects may be of either gender and of any race. Each subject must meet all of the 
following criteria to be enrolled in this study: 
a. Be at least 18 years of age; 
b. Provide written informed consent; 
c. Have a subject-reported history of dry eye disease in both eyes for at least 6 
months prior to Visit 1; 
d. Have a history of use of artificial tear eye drops for dry eye symptoms; 
e. Report a total score (i.e., the square root of the product of the scores for each 
question) of 
 in Dry Eye (SANDE) 
Questionnaire at Visits 1 and 2; 
f. Have a tear film break up time (TFBUT) 
 Visits 1 and 2; 
g. Have a total corneal fluorescein staining (CFS) score of 
 according to the NEI 
scale 
 at Visits 1 and 2 
h. Have a total conjunctival lissamine green staining score of 
 with a score of 
 
 according to the NEI scale 
 at Visits 1 and 2; 
i. Have an Unanesthetized Schirmer’s Test score of 
 
 at Visit 1; and  
j. Have at least one eye, the same eye, satisfy all criteria for I at Visit 1 and f, g, and 
h at Visits 1 and 2. 
 Subject Exclusion Criteria 
Subjects meeting any of the following criteria will be excluded from the study: 
a. Have any clinically significant (CS) anterior chamber findings that may include 
active ocular infection (bacterial, viral, or fungal), lid margin 
inflammation/disorders (e.g., clinically significant blepharitis including 
staphylococcal, demodex, or seborrheic; clinically significant meibomian gland 
disease; floppy eye syndrome), clinically significant ocular rosacea , active ocular 
inflammation (iritis, uveitis), follicular conjunctivitis, or allergic conjunctivitis 


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(seasonal and/or perennial) that require therapeutic treatment, and/or in the 
opinion of the Investigator may interfere with study parameters; 
b. Have any clinically significant (CS) posterior chamber findings, or a history of 
such findings/disorders, that may include exudative (i.e., wet) age-related macular 
degeneration, retinal vein occlusion, diabetic retinopathy, glaucoma, ocular 
hypertension, or any other retinal or optic nerve disease/disorder that require 
therapeutic treatment and/or in the opinion of the Investigator may interfere with 
study parameters; 
c. Have worn contact lenses within 30 days of Visit 1 or anticipate using contact 
lenses during the study; 
d. Have had laser-assisted in situ keratomileusis (LASIK) or similar type of corneal 
refractive surgery and/or any other ocular surgical procedure within 12 months 
prior to Visit 1; or have any ocular surgical procedure scheduled to be conducted 
during the study period; 
e. Have had eyelid surgery within 12 weeks prior to Visit 1 or planned eyelid 
surgery during the study period; 
f. Have a history of lacrimal duct obstruction in either eye within 12 months prior to 
Visit 1; 
g. Have used temporary (i.e., collagen) punctal plugs within 12 weeks prior to Visit 
1 or anticipate their use during the study period; 
h. Have had permanent punctal plugs inserted or removed – including falling out – 
or have had surgical punctal occlusion within 12 weeks prior to Visit 1 or 
anticipate any such event at any time during the study period; 
i. Have used any of the following treatments in the period indicated before Visit 1 
or anticipate their use at any time during the study. 
Day of Visit 1 
1. All topical ophthalmic preparations (e.g., medications for glaucoma, over-
the counter-solutions, artificial tears, gels, scrubs, ointments) 
72 hours prior to Visit 1 
2. Antihistamines (including topical ophthalmic antihistamines) 
30 days prior to Visit 1 
3. Topical ophthalmic non-steroidal anti-inflammatories 
4. Topical ophthalmic corticosteroids  
5. Topical ophthalmic autologous serum 
6. Topical ophthalmic antibiotics 
7. Mast cell stabilizers 


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8. Oral aspirin or aspirin-containing products except in the case that it was 
taken on a stable dosing regimen for at least 30 days prior to Visit 1 and is 
expected to be taken on the same regimen throughout the study period 
9. Any other medication known to cause ocular drying (e.g., antidepressants, 
beta blockers) except in the case that it was taken on a stable dosing 
regimen for at least 30 days prior to Visit 1 and is expected to be taken on 
the same regimen throughout the study period 
12 weeks prior to Visit 1 
10. Restasis® 
11. Xiidra® 
12. CEQUA™ 
13. LipiFlow® or other similar meibomian gland dysfunction (MGD) therapy 
14. TrueTear® 
15. Corticosteroids (e.g., systemic steroids including intravenous, 
intramuscular, intraarticular, and oral steroids; facial topical steroids; 
dermatological steroids with high potency or large treatment areas); 
16. Tetracyclines (tetracycline, doxycycline, minocycline, etc.) 
j. Be monocular or have best corrected visual acuity 
 
in either eye as assessed by the Early Treatment of Diabetic 
Retinopathy Study (ETDRS) scale at Visit 1; 
k. Have a severe/serious systemic disease, chronic illness or uncontrolled medical 
condition including, but not limited to, severe cardiopulmonary disease, poorly 
controlled hypertension, poorly controlled diabetes and/or clinically significant 
(CS) hematologic, renal or liver disease that in the opinion of the Investigator 
could interfere with study assessments or limit compliance; 
l. Be a woman who is pregnant, nursing or planning a pregnancy; 
m. Be unwilling to submit a urine pregnancy test at Visit 1 and Visit 6 (or early 
termination visit) if of childbearing potential. Non-childbearing potential is 
defined as a woman who is permanently sterilized (e.g., has had a hysterectomy, 
bilateral tubal ligation, or bilateral oophorectomy), or is post-menopausal (i.e., 
without menses for 12 consecutive months); 
n. Be a woman of childbearing potential who is not using an acceptable means of 
birth control. Acceptable methods of contraception include hormonal (e.g., oral, 
implantable, injectable, or transdermal contraceptives), mechanical (e.g., 
spermicide in conjunction with a barrier such as a diaphragm or a condom), 
intrauterine device (IUD), or surgical sterilization of partner. For non-sexually 
active females, abstinence may be regarded as an adequate method of birth 
control; however, if the subject becomes sexually active during the study, she 
must agree to use adequate birth control as defined above for the remainder of the 
study; 


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o. Have a known hypersensitivity or contraindication to the investigational products 
(IPs) or their components; 
p. Have a condition or be in a situation which the Investigator feels may put the 
subject at significant risk, may confound the study results, or may interfere 
significantly with the subject’s participation in the study (e.g., any planned 
procedure or surgery during the study period); 
q. Be currently enrolled in an investigational drug or device study or have used an 
investigational drug or device within 45 days prior to Visit 1; 
r. Have previously participated in a clinical trial with tavilermide (MIM-D3); 
s. Be, in the opinion of the Investigator, unable or unwilling to comply with the 
study protocol, including participation in all study assessments, visits, and dosing, 
or be unable to instill eye drops successfully. Subject non-compliance with dosing 
during the run-in period, defined as 
 of expected doses taken, 
may be exclusionary if, in the opinion of the Investigator, the subject is likely to 
be non-compliant with subsequent dosing regimens or other study assessments; or 
t. Be an employee of the site that is directly involved in the management, 
administration, or support of this study or be an immediate family member of the 
same. 
 Randomization Procedures 
A patient who meets all of the inclusion criteria and none of the exclusion criteria is 
eligible for randomization at Visit 2. Subjects are to be randomized to one of three 
treatment arms: 
1) 
5% tavilermide ophthalmic solution, 
2) 
1% tavilermide ophthalmic solution, or 
3) 
Placebo ophthalmic solution. 
A statistician not directly involved in the analysis of the study results will prepare the 
randomization schedule using block randomization to maintain balance between 
treatment arms. Randomization is to be done in a 
 respectively, by the IRT 
system. 
Subjects are to be stratified by site and EDS as measured by the VAS at Visit 2 using the 
following strata: 
 
 
 
 
Details required for stratification are to be entered into the IRT which will randomize the 
subject and assign a randomization number. Randomization numbers are to be four digits 
and will allow for the identification of a subject’s treatment arm. The IRT is also to be 
used to assign treatment kits; each treatment kit is identifiable by a five-digit kit number. 


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The randomization number and all treatment kit numbers are to be recorded on the 
subject’s source document and the appropriate eCRFs. 
 Arrangements Taken to Prevent Unmasking 
All subjects, investigators, and study personnel involved with the conduct of the study 
will be masked with regard to treatment assignments. 
Randomization is to be accomplished by IRT. A dedicated IRT manager is to be 
responsible for overseeing the IRT system including randomization and treatment kit 
assignment. 
The discrepancies in visual appearance among the IP mandate that there is at least one 
technician designated as unmasked at each clinical site. Once open, a treatment kit is to 
be handled by only the subject to which it was assigned and unmasked designees. 
Unmasked technicians are uniquely delegated for facilitating the in-office dose and drop 
comfort assessments and performing randomized treatment kit accountability. Unmasked 
technicians may not participate in any other aspect of the trial that has a bearing on trial 
efficacy including symptom questionnaires, scribing for the Investigator, and data 
transcription. Unmasked technicians are not to have access to the electronic data capture 
(EDC) system. Clinical trial monitors who are designated as unmasked are to be 
responsible for reviewing randomized IP accountability. After unmasking, a clinical trial 
monitor is not to participate in other aspects of trial monitoring. 
 Procedures for Unmasking 
When medically necessary, the Investigator may need to determine what treatment has 
been assigned to a subject. When possible (i.e., in non-emergent situations), Ora and/or 
the Sponsor should be notified before unmasking IP. 
If the Investigator identifies a medical need for unmasking the assigned treatment of a 
subject, they should, if possible, contact Ora and/or the Medical Monitor before 
completing the unmasking. Ora is to ask the site to complete the appropriate parts of the 
Unmasking Request Form and then to return the form. After receiving the form, Ora is to 
notify Mimetogen, and jointly they are to determine whether to approve the unmasking; 
Ora or Mimetogen may consult with the Medical Monitor as needed during this process. 
The result of the request is to be documented on the Unmasking Request Form. 
If the request to unmask a subject is approved, the Investigator is to be provided the 
approval in writing via the Unmasking Request Form. The Investigator is to unmask the 
subject using the IRT and complete the Unmasking Memo. The Unmasking Memo is to 
be filed with the subject’s study file, and a copy is to be sent to project management so 
that it may be included in the Trial Master File (TMF). For each unmasking request, the 
reason for the request, the date of the request, and the name and signature of the 
individual unmasking the subject are to be noted in the subject’s study file. 


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 Early Termination 
6.6.1 Reasons for Discontinuation 
Subjects may be discontinued by the Investigator, Sponsor, or Medical Monitor prior to 
their completion of the study due to: 
 AEs, 
 Protocol violations, 
 Administrative reasons (e.g., inability to continue due to scheduling, lost to 
follow-up), 
 Sponsor termination of study, or 
 Other. 
If at any time, the Investigator determines that a subject’s safety has been compromised, 
the Investigator may discontinue the subject from the study treatment. The Investigator, 
Sponsor, or Medical Monitor may discontinue any subject for any valid medical reason or 
non-compliance. 
Ora, the Sponsor, or the Investigator may terminate the trial at any time with appropriate 
notification. 
6.6.2 Reasons for Withdrawal 
Subjects may choose to end their participation in the study at any time by withdrawing 
consent (i.e., subject choice). 
6.6.3 Documenting Early Termination and Subjects Lost to Follow-Up  
The site is to notify Ora of any subject discontinuation or withdrawal and the reason. The 
discontinuation or withdrawal and the reason are to be clearly documented in the subject 
source and eCRF. 
If a subject is discontinued or withdraws from the study before Visit 6, all safety and 
efficacy evaluations performed at Visit 6 are to be done on the day of discontinuation or 
at the discretion of the Investigator. Sites are to use the Visit 6 section of the source 
document to record an early termination visit. 
Any subject who is discontinued or withdraws is to be instructed to return all IP to the 
clinic for accountability. 
Subjects who are discontinued or withdraw from the study are not to be replaced. 
Follow-up for subjects who end treatment with IP is to be performed at the Investigator’s 
discretion. Any AEs that are ongoing as of withdrawal or discontinuation are to be 
followed as outlined in Section 9.5. 
In the case that the site is unable to contact a subject, the site is to make two documented 
phone calls to the subject and send a certified letter before deeming the subject lost to 
follow-up. 


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7 STUDY VISITS AND PROCEDURES SCHEDULE 
The following outlines the order of procedures to be performed at the indicated visit with 
regard to the study objectives. See Appendix 2 for detailed descriptions of the 
procedures. 
Visit 1 (Day -14 ± 2): Screening 
 
Informed consent / HIPAA 
 
Medical / medication history and 
demographics 
 
Urine pregnancy test for women of 
childbearing potential 
 
VAS questionnaire 
 
SANDE questionnaire 
 
Visual acuity (ETDRS) 
 
Slit-lamp biomicroscopy 
 
TFBUT 
 
Fluorescein staining (NEI scale) 
 
Lissamine staining (NEI scale) 
 
Unanesthetized Schirmer’s Test 
 
IOP 
 
Dilated fundoscopy 
 
Review of qualification criteria 
 
Run-in kit assignment and dispensation 
 
AE query 
Visit 2 (Day 1): Baseline and Randomization 
 
Run-in collection and kit accountability 
 
Medical status update / AE query 
 
Concomitant medication review 
 
VAS questionnaire 
 
SANDE questionnaire 
 
Visual acuity (ETDRS) 
 
Slit-lamp biomicroscopy 
 
TFBUT 
 
Fluorescein staining (NEI scale) 
 
Lissamine staining (NEI scale) 
 
Review of qualification criteria 
 
Randomization 
 
Randomized treatment kit assignment and 
dispensation (1 kit) 
 
In-office randomized treatment dose 
 
Ora Calibra® Drop Comfort Scale and 
Questionnaire 
 
AE query 
 
Visit 3 (Day 15 ± 2): 2-Week Follow-Up 
 
Randomized treatment kit collection and 
accountability 
 
Medical status update / AE query 
 
Concomitant medication review 
 
VAS questionnaire 
 
SANDE questionnaire 
 
Visual acuity (ETDRS) 
 
Slit-lamp biomicroscopy 
 
TFBUT 
 
Fluorescein staining (NEI scale) 
 
Lissamine staining (NEI scale) 
 
Randomized treatment kit assignment and 
dispensation (1 kit) 
 
AE query 
Visit 4 (Day 29 ± 2): 4-Week Follow-Up 
 
Randomized treatment kit collection and 
accountability 
 
Medical status update / AE query 
 
Concomitant medication review 
 
VAS questionnaire 
 
SANDE questionnaire 
 
Visual acuity (ETDRS) 
 
Slit-lamp biomicroscopy 
 
TFBUT 
 
Fluorescein staining (NEI scale) 
 
Lissamine staining (NEI scale) 
 
Randomized treatment kit assignment and 
dispensation (2 kits) 
 
AE query 
 
 
 


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Visit 5 (Day 57 ± 3): 8-Week Follow-Up 
 
Randomized treatment kit collection and 
accountability 
 
Medical status update / AE query 
 
Concomitant medication review 
 
VAS questionnaire 
 
SANDE questionnaire 
 
Visual acuity (ETDRS) 
 
Slit-lamp biomicroscopy 
 
TFBUT 
 
Fluorescein staining (NEI scale) 
 
Lissamine staining (NEI scale) 
 
Randomized treatment kit assignment and 
dispensation (2 kits) 
 
In-office randomized treatment dose 
 
Ora Calibra® Drop Comfort Scale and 
Questionnaire 
 
AE query 
Visit 6 (Day 85 ± 4): 12-Week Follow-Up and 
Study Exit 
 
Randomized treatment kit collection and 
accountability 
 
Medical status update / AE query 
 
Concomitant medication review 
 
Urine pregnancy test for women of 
childbearing potential 
 
VAS questionnaire 
 
SANDE questionnaire 
 
Visual acuity (ETDRS) 
 
Slit-lamp biomicroscopy 
 
TFBUT 
 
Fluorescein staining (NEI scale) 
 
Lissamine staining (NEI scale) 
 
Unanesthetized Schirmer’s Test 
 
IOP 
 
Dilated fundoscopy 
 
AE query 
 
Study exit 
 Unscheduled Visits 
An Unscheduled Visit may be performed in order to ensure subject safety or at the 
Investigator’s discretion. Assessments performed at an Unscheduled Visit are to be 
documented on the Unscheduled Visit pages of the subject source document and then 
transcribed to the Unscheduled Visit eCRFs. Any assessment listed as a potential 
Unscheduled Visit assessment in the subject source or the EDC that is not performed is to 
be documented as “Not Done.” 
Evaluations that may be conducted at an Unscheduled Visit include 
 Urine pregnancy test, 
 Visual acuity (ETDRS), 
 Slit-lamp biomicroscopy, 
 Intraocular pressure (IOP), 
 Dilated fundoscopy, 
 Unanesthetized Schirmer’s Test 
 Assessment of Adverse Events, 
 Assessment of concomitant medications and/or treatments, or 
 Any other assessments needed in the judgment of the Investigator. 


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8 ASSESSMENT OF EFFICACY 
8.1.1 Primary and Key Secondary Endpoints 
Parameters for assessing efficacy for the primary and key secondary endpoints are EDS 
 
fluorescein staining at Visit 2 (Day 1), Visit 4 (Day 29) and Visit 6 (Day 85). Instructions 
for the completion of these assessments are in Appendix 2. 
8.1.2 Other Secondary Endpoints 
Other secondary endpoints for assessing efficacy are below. Instructions for the 
completion of these assessments are in Appendix 2. 
 Eye dryness, discomfort, grittiness, pain, blurred vision, and photophobia 
 
 
 
 Frequency, severity, and total score 
 
 
 
 
at Visits 3, 4, 5, and 6, and the 
 at Visits 3, 4, 5, and 
6. 
 CFS in the inferior, superior, central, temporal, nasal, and corneal (i.e., sum of all 
regions) regions 
 
 
 
 Conjunctival lissamine green staining in the temporal, superior temporal, inferior 
temporal, superior nasal, inferior nasal, nasal, and conjunctival (i.e., sum of all 
regions) regions 
 
 
 
 
 Visit 6 and the 
 
(Visit 1) at Visit 6. 
9 ASSESSMENT OF SAFETY 
AEs (both elicited and observed) will be monitored throughout the study. All AEs (both 
elicited and observed) will be promptly reviewed by the Investigator for accuracy and 
completeness. All AEs will be documented on the appropriate source document pages 
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necessitates surgical intervention is to be considered an adverse event if the occurrence or 
detection of the condition is temporally associated with the use of study drug. 
The worsening of a medical condition that was present before the administration of study 
drug is to be considered a new adverse event and reported as such. The improvement or 
lack of change of a medical condition that was present before the administration of study 
drug is not to be recorded as a TEAE at subsequent visits unless it worsens during 
treatment. 
The worsening of DED is to be considered an adverse event only if the exacerbation of 
the signs or symptoms exceed what the subject has previously experienced. The 
determination to record worsening of DED as an AE is to be made by the Investigator 
and the subject. 
Study drug includes the IP under evaluation, any comparator drug, the vehicle, and any 
other medications required by the protocol given during any stage of the study. 
Therefore, AE reporting begins with the administration of the topical, local anesthetic 
used to measure IOP at Visit 1. 
9.2.1 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 subject. The 
assessment of severity is made irrespective of relationship to IP 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. 
 Severe: Event is intolerable, necessitates additional therapy or alteration of therapy, 
and interferes with the subject’s daily activities. 
9.2.2 Relationship to Investigational Product 
The relationship of each AE to the IP should be determined by the Investigator using 
these explanations: 
 Suspected: A reasonable possibility exists that the IP caused the AE. A suspected 
AE can be further defined as: 
 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. 
 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. 


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 Possible: Relationship exists when the AE follows a reasonable sequence 
from the time of IP administration, but could also have been produced by the 
subject’s clinical state or by other drugs administered to the subject. 
 Not Suspected: A reasonable possibility does not exist that the IP caused the AE. 
 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. 
9.2.3 Expectedness 
The expectedness of an AE should be determined based upon existing safety information 
about the IP using these explanations: 
 Unexpected: An AE that is not listed in the Investigator’s Brochure (IB) 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 IP. 
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. 
9.2.4 Action Taken with Investigational Product 
If an AE occurs and the Investigator alters the IP dose or administration in any way, this 
should be documented in the source document and reported in the eCRF. 
Available options within the eCRF for reporting actions taken with the IP due to an AE 
include: 
 Dose Not Changed 
 Drug Interrupted 
 Drug Withdrawn 
 Not Applicable (if subject has not been exposed to IP) 
9.2.5 Outcome 
The outcome of an AE should be documented in the source document and in the eCRF 
using the following categories: 
 Fatal 
 Not Recovered/Not Resolved 


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 Recovered/Resolved 
 Recovered/Resolved with Sequelae 
 Recovering/Resolving 
 Unknown 
 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: 
 Death; 
 A life-threatening AE; 
Note: An AE is considered “life-threatening” if, in the view of either the Investigator or 
Sponsor, its occurrence places the 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; 
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. 
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; or 
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 subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
 Procedures for Reporting Adverse Events 
9.4.1 Reporting an Adverse Event 
All AEs and their outcomes must be reported to Ora, the Sponsor, and the Institutional 
Review Board (IRB) / Independent Ethics Committee (IEC) as required by the IRB/IEC, 


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federal, state, or local regulations and governing health authorities and recorded on the 
appropriate eCRF. AEs are to be collected from the first administration of study drug to 
the subject’s exit from the study. 
9.4.2 Reporting a Serious Adverse Event 
To ensure subject safety, all SAEs, regardless of relationship to the IP, must be 
immediately reported. All information relevant to the SAE must be recorded on the 
appropriate eCRFs. The Investigator is obligated to pursue and obtain information 
requested by Ora and/or the Sponsor in addition to that information reported on the 
eCRF. All subjects experiencing an SAE must be followed until the SAE is resolved or 
reaches a clinically stable outcome, with or without sequelae, and the outcome reported. 
In the event of an SAE, the Investigator should inform the clinical project manager, 
, that an SAE occurred by phone, fax, or email immediately. 
 
 
 
 
 
 
 
 
 
 
 
 
The site is to complete the initial SAE Report Form and submit the form to the clinical 
project manager as soon as is feasible but no more than 24 hours after becoming aware of 
the event. Furthermore, the site is to transcribe the requisite SAE information to the 
appropriate eCRF no more than 24 hours after becoming aware of the event. After the 
initial report, all additional follow-up evaluations must be reported to Ora within one 
business day of receipt of the information. 
The Ora clinical project manager will notify the Medical Monitor and the Sponsor of the 
SAE as soon as is feasible but no more than 24 hours after becoming aware of the event. 
The Investigator must 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 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 IP; and inform the IRB of the SAE within their guidelines for reporting 
SAEs. If an SAE is considered reportable per Alpha IRB’s guidelines, the site should 
report the SAE promptly but no more than 10 business days after becoming aware of the 
event. 
For questions regarding the seriousness of an AE, the site is to contact the Medical 
Monitor directly. The site may also consult with the Medical Monitor additionally as 
needed. 
 
 


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9.4.3 Reporting a Suspected Unexpected Adverse Reaction 
All AEs that are ‘suspected’ and ‘unexpected’ are to be reported to Ora, the Sponsor, and 
the IRB/IEC as required by the IRB/IEC, federal, state, or local regulations and 
governing health authorities. 
 Type and Duration of Follow-Up of Subjects after Adverse Events 
AEs that are ongoing at the subject’s exit from the study are to be marked as such in the 
subject’s source document and eCRF. Sites are to follow AEs ongoing at the subject’s 
exit from the study until resolution or until the condition is considered ongoing and 
stable. Documentation of AE follow-up is to be maintained at the clinical site. 
 Pregnancy 
Pregnancy in itself is not considered an AE or SAE (unless there is a suspicion that an IP 
may have interfered with the effectiveness of a contraceptive medication), but it is an 
important medical event that must be followed up. Any pregnancy that occurs during the 
clinical trial where the fetus could have been exposed to the study drug(s) must be 
followed through the outcome of the pregnancy. 
If a female has a positive pregnancy test during the study, then the Investigator will notify 
Ora immediately. The Investigator shall request from the subject and/or the subject’s 
physician copies of all related medical reports during the pregnancy and shall document 
the outcome of the pregnancy. The Investigator will retain these reports together with the 
subject’s source documents and will provide a copy of all documentation to Ora. 
10 STATISTICS 
 Analysis Populations 
10.1.1 Intent-to-Treat Population 
 
 
 
 
 


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. 
10.1.2 Per Protocol Population 
 
 
 
 
10.1.3 Safety Population  
 
 
 
  Statistical Hypotheses 
10.2.1 Primary Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
. 
10.2.2 Key Secondary Endpoints 
 
 
 
 
 
 
 
 


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 Sample Size 
 
 
 
 
 
 
 
 
 




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10.4.3 Missing Data 
 
 
 
 
 
 
 
10.4.4 Primary Efficacy Analyses 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.4.5 Key Secondary Efficacy Analyses 
 
 
 
 
 
 
 
 
 


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10.4.6 Other Secondary Efficacy Analyses 
 
 
 
 
 
 
 
10.4.7 Safety Analyses 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.4.8 Interim Analyses 
 
11 DATA HANDLING AND RECORDKEEPING 
 Data Collection 
The Investigator is responsible for ensuring that study data is completely and accurately 
recorded on each subject’s eCRF, source document, and all study-related material. All 
study data should also be attributable, legible, contemporaneous, and original. Recorded 
datum should only be corrected in a manner that does not obliterate, destroy, or render 
illegible the previous entry (e.g., by drawing a single line through the incorrect entry and 


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writing the revision next to the corrected data). An individual who has corrected a data 
entry should make clear who made the correction and when by adding to the correction 
his/her initials as well as the date of the correction. 
Source document entries are to be transcribed to eCRFs. iMedNet is to be the EDC 
system and Statistics & Data Corporation (SDC) is the contracted data management firm. 
Transcription to eCRFs is to be accomplished using software that conforms to 21 CFR 
Part 11 requirements. Only staff who are masked and who have received training on the 
iMedNet system and the study-specific eCRFs will be allowed access to this study’s EDC 
environment. The EDC system is to maintain an audit trail to capture all changes made to 
the eCRFs. Each investigative site is to be supplied with their subject data on compact 
disks that are to be maintained on file by the Investigator. 
Source documents may include a subject’s medical records, hospital charts, clinic charts, 
the Investigator’s study subject files, as well as the results of diagnostic tests such as X-
rays, laboratory tests, and EKGs. The Investigator’s copy of the eCRFs serves as the 
Investigator’s record of a subject’s study-related data. 
 Data Directly Recorded on the Electronic Case Report Forms 
The results of all trial assessments are to be documented and then transcribed to the 
eCRFs. No data is to be recorded directly on the eCRFs and considered source data with 
the exception of the IRT-assigned randomization number, the treatment arm, and any kit 
numbers. 
 Retention of Documentation 
All study-related correspondence, subject records, consent forms, record of the 
distribution and use of all IP, and copies of eCRFs should be maintained on file for at 
least two 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 
until at least two years have elapsed since the formal discontinuation of clinical 
development of the IP. These documents will be retained for a longer period if required 
by the applicable regulatory requirements or by an agreement with the Sponsor. It is the 
responsibility of the Sponsor to inform the Investigator/institution as to when these 
documents no longer need to be retained. 
If the responsible Investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping study records, custody must be transferred to a person who will 
accept the responsibility. The Sponsor must be notified in writing of the name and 
address of the new custodian. 


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12 ADMINISTRATIVE ASPECTS 
 Ethics 
This study will be conducted in accordance with the ethical principles that originated 
with the Declaration of Helsinki. 
This study will be conducted in compliance with the protocol and current GCPs, 
including the ICH Guidelines. In addition, all applicable local, state, and federal 
requirements relevant to the use of IP in the countries involved will be adhered to. 
 Subject Confidentiality 
All personal study subject data collected and processed for the purposes of this study 
should be maintained by the Investigator and his/her staff with adequate precautions as to 
ensure that the confidentiality of the data is in accordance with local, state, and federal 
laws and regulations. 
Monitors, auditors and other authorized representatives of Ora, the Sponsor, the IRB/IEC 
approving this study, the US Food and Drug Administration (FDA), the US Department 
of Health and Human Services (DHHS), other domestic government agencies, and other 
foreign regulatory agencies will be granted direct access to the subject’s original medical 
and study records for verification of the data and/or clinical trial procedures. Access to 
this information will be permitted to the aforementioned individuals to the extent 
permitted by law. 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the IP may ultimately be marketed, but the subject’s 
identity will not be disclosed in these documents. 
 Institutional Review Board Approval 
This protocol and the informed consent document and any subsequent modifications will 
be reviewed and approved in accordance with IRB regulations (U.S. 21 CFR Part 
56.103). The Investigator must obtain appropriate IRB approval before initiating the 
study and re-approval at least annually. 
Only an IRB/IEC approved version of the informed consent form will be used. 
 Subject Informed Consent 
Informed consent/assent must take place before any study-specific procedures are 
initiated. Signed and dated written informed consent must be obtained from each subject 
and/or from the subject’s parent or legal guardian prior to enrollment into the study. If the 
subject is under the legal age of consent, the consent form must be signed by a legal 
guardian or as required by state and/or local laws and regulations. 
All informed consent/assent forms must be approved for use by the Sponsor and receive 
approval/favorable opinion from an IRB/IEC prior to their use. If the consent form 


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requires revision (e.g., due to a protocol amendment or significant new safety 
information), it is the Investigator’s responsibility to ensure that the amended informed 
consent is reviewed and approved by Ora prior to submission to the governing IRB/IEC 
and that it is read, signed and dated by all subjects subsequently enrolled in the study as 
well as those currently enrolled in the study. 
If informed consent is taken under special circumstances (e.g., oral informed consent), 
then the procedures to be followed must be determined by Ora and/or Sponsor and 
provided in writing by Ora and/or Sponsor prior to the consent process. 
 Modifications of the Protocol 
This study will be conducted in compliance with the most recently approved version of 
the protocol. Any change to the protocol or ICF that affects the scientific intent, study 
design, or subject safety or may affect a subject’s willingness to continue participation in 
the study is considered an amendment to this protocol and/or ICF. All such amendments 
will be submitted to the IRB for approval prior to becoming effective. 
 Quality Control and Quality Assurance  
Each Investigator and site participating in this clinical trial are to permit trial-related 
monitoring, audits, IRB/IEC review, and regulatory inspections and provide direct access 
to source data/documents and trial records. 
During the course of the study a monitor, or designee, will make routine site visits to 
review protocol compliance, assess IP accountability, and ensure the study is being 
conducted according to the pertinent regulatory requirements. The review of the subjects’ 
medical records will be performed in a manner that adequately maintains subject 
confidentiality. Further details of the study monitoring will be outlined in a monitoring 
plan. 
Regulatory authorities of domestic and foreign agencies, Ora, Inc. quality assurance, the 
Sponsor and/or the designees of these parties may carry out on-site inspections and/or 
audits which may include source data checks. Therefore, direct access to the original 
source data will be required for inspections and/or audits. All inspections and audits will 
be carried out giving consideration to data protection as well as subject confidentiality to 
the extent that local, state, and federal laws apply. 
 Financing and Insurance 
Financing and insurance are addressed in an agreement separate from this clinical trial 
protocol. 


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13 PUBLICATION POLICY 
Authorship and manuscript composition will reflect cooperation among all parties 
involved in the study. Authorship will be established before writing the manuscript. Ora 
and the Sponsor will have the final decision regarding the manuscript and publication. 
14 REFERENCES 
1.  
Maliartchouk S, Feng Y, Ivanisevic L, et al. A Designed Peptidomimetic Agonistic 
Ligand of TrkA Nerve Growth Factor Receptors. Mol Pharmacol. 2000;57(2):385-
391. 
2.  
Bruno MA, Clarke PBS, Seltzer A, et al. Long-lasting rescue of age-associated 
deficits in cognition and the CNS cholinergic phenotype by a partial agonist 
peptidomimetic ligand of TrkA. J Neurosci. 2004;24(37):8009-8018. 
doi:10.1523/JNEUROSCI.1508-04.2004 
3.  
Lebrun-Julien F, Morquette B, Douillette A, Saragovi HU, Di Polo A. Inhibition of 
p75(NTR) in glia potentiates TrkA-mediated survival of injured retinal ganglion 
cells. Mol Cell Neurosci. 2009;40(4):410-420. doi:10.1016/j.mcn.2008.12.005 
4.  
Shi Z, Birman E, Saragovi HU. Neurotrophic rationale in glaucoma: a TrkA agonist, 
but not NGF or a p75 antagonist, protects retinal ganglion cells in vivo. Dev 
Neurobiol. 2007;67(7):884-894. doi:10.1002/dneu.20360 
5.  
Jain P, Li R, Lama T, Saragovi HU, Cumberlidge G, Meerovitch K. An NGF 
mimetic, MIM-D3, stimulates conjunctival cell glycoconjugate secretion and 
demonstrates therapeutic efficacy in a rat model of dry eye. Exp Eye Res. 
2011;93(4):503-512. doi:10.1016/j.exer.2011.06.014 
6.  
Meerovitch K, Torkildsen G, Lonsdale J, et al. Safety and efficacy of MIM-D3 
ophthalmic solutions in a randomized, placebo-controlled Phase 2 clinical trial in 
patients with dry eye. Clin Ophthalmol. 2013;7:1275-1285. 
doi:10.2147/OPTH.S44688 
 


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15 APPENDICES 
APPENDIX 1: SCHEDULE OF VISITS AND MEASUREMENTS 






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Visual Acuity Procedures (ETDRS Chart) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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Slit-Lamp Biomicroscopy Procedures 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Tear Film Break-Up Time (TFBUT) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Fluorescein Staining  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Lissamine Green Staining 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Unanesthetized Schirmer’s Test 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Intraocular Pressure 
 
 
 
 
 
 
 
 
 


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Dilated Fundoscopy 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 




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APPENDIX 3: ADVERSE EVENT (AE) DEFINITIONS 
Severity 
 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. 
 Severe: Event is intolerable, necessitates additional therapy or alteration of 
therapy, and interferes with the subject’s daily activities. 
Relationship to Investigational Product (IP) 
 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 IP administration, but could also have been produced by 
the subject’s clinical state or by other drugs administered to the subject. 
 Not Suspected: A reasonable possibility does not exist that the IP caused the AE. 
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. 
Expectedness 
 Unexpected: An AE that is not listed in the Investigator’s Brochure (IB) 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 IP. 
 


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APPENDIX 5: PROTOCOL AMENDMENT SUMMARY 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX 6: SPONSOR AND ORA APPROVALS 
Protocol Title: 
A Phase 3, Multi-Center, Randomized, Double-Masked, 
Vehicle-Controlled Clinical Study to Assess the Safety and 
Efficacy of 1% Tavilermide and 5% Tavilermide Ophthalmic 
Solutions for the Treatment of Dry Eye 
Protocol Number: 
MIM-728 
Final Date: 
Amendment 1: 
07 March 2019 
03 July 2019 
This clinical study protocol was subject to critical review and has been approved by the 
Sponsor. The following personnel contributed to writing and/or approving this protocol. 


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APPENDIX 7: INVESTIGATOR’S SIGNATURE 
Protocol Title: 
A Phase 3, Multi-Center, Randomized, Double-Masked, 
Vehicle-Controlled Clinical Study to Assess the Safety and 
Efficacy of 1% Tavilermide and 5% Tavilermide Ophthalmic 
Solutions for the Treatment of Dry Eye 
Protocol Number: 
MIM-728 
Final Date: 
Amendment 1: 
07 March 2019 
03 July 2019 
I agree to implement and conduct the study diligently and in strict compliance with the 
protocol, good clinical practices and all applicable laws and regulations. I agree to 
maintain all information supplied by Ora and the Sponsor in confidence and, when this 
information is submitted to an Institutional Review Board (IRB), Ethical Review 
Committee (ERC) or another group, it will be submitted with a designation that the 
material is confidential. 
I have read this protocol in its entirety, including the above statement, and I agree to all 
aspects. 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
A Phase 3, Multi-Center, Randomized, Double-Masked, Vehicle-Controlled 
Clinical Study to Assess the Safety and Efficacy of 1% Tavilermide and 5% 
Tavilermide Ophthalmic Solutions for the Treatment of Dry Eye 
 
Sponsor: Mimetogen Pharmaceuticals USA, Inc. 
 
Protocol Number: MIM-728 
NCT Number (NCT03925727) 
Document Date: 15 July 2020 


 
 
STATISTICAL ANALYSIS PLAN  
A Phase 3, Multi-Center, Randomized, Double-Masked, Vehicle-Controlled 
Clinical Study to Assess the Safety and Efficacy of 1% Tavilermide and 5% 
Tavilermide Ophthalmic Solutions for the Treatment of Dry Eye 
 
 
 
Sponsor:  
 
Mimetogen Pharmaceuticals USA, Inc. 
 
 
 
 
 
 
Protocol Number: 
MIM-728 
 
 
Author:  
 
 
 
 
 
 
 
 
Date:   
 
15 July 2020 
Version:  
 
2.0 
 
 


sdc
A Phase 3, Multi-Center, Randomized, Double-Masked, Vehicle-Controlled
Clinical Study to Assess the Safety and Efficacy of loh Tavilermide and 5o/o
Tavilermide Ophthalmic Solutions for the Treatment of Dry Eye
Page 2 of 67


Protocol MIM-728 SAP, Version 2.0 
 
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Table of Contents 
1. 
Introduction .................................................................................................................. 7 
2. 
Study Objectives .......................................................................................................... 7 
2.1 Primary Endpoints ....................................................................................................... 7 
2.2 Key Secondary Endpoints ............................................................................................ 8 
2.3 Other Secondary Endpoints ......................................................................................... 8 
2.4 Safety Variables ........................................................................................................... 9 
2.5 Statistical Hypotheses ................................................................................................ 10 
2.5.1 
Primary Endpoints: ........................................................................................... 10 
2.5.2 
Key Secondary Endpoints: ................................................................................ 10 
3. 
Study Design and Procedures .................................................................................... 12 
3.1 General Study Design ................................................................................................ 12 
3.2 Schedule of Visits and Assessments .......................................................................... 13 
4. 
Study Treatments ....................................................................................................... 15 
4.1 Method of Assigning Subjects to Treatment Groups ................................................. 15 
4.2 Masking and Unmasking ........................................................................................... 16 
5. 
Sample Size and Power Considerations ..................................................................... 17 
6. 
Data Preparation ........................................................................................................ 18 
7. 
Analysis Populations .................................................................................................. 19 
7.1 Intent-to-Treat ............................................................................................................ 19 
7.2 Modified Intent-to-Treat ............................................................................................ 19 
7.3 Per Protocol ................................................................................................................ 20 
7.4 Safety ......................................................................................................................... 20 
8. 
General Statistical Considerations ............................................................................. 20 
8.1 Unit of Analysis ......................................................................................................... 20 
8.2 Missing or Inconclusive Data Handling .................................................................... 20 
8.3 Definition of Baseline ................................................................................................ 21 
8.4 Data Analysis Conventions ........................................................................................ 21 
8.5 Adjustments for Multiplicity...................................................................................... 22 
9. 
Disposition of Subjects .............................................................................................. 24 
10. 
Demographic and Pretreatment Variables ................................................................. 25 


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10.1 Demographic Variables ............................................................................................. 25 
10.2 Pretreatment Variables ............................................................................................... 25 
11. 
Medical History and Concomitant Medications ........................................................ 26 
11.1 Medical History ......................................................................................................... 26 
11.2 Concomitant Medications .......................................................................................... 26 
12. 
Dosing Compliance and Treatment Exposure ........................................................... 27 
12.1 Dosing Compliance .................................................................................................... 27 
12.2 Treatment Exposure ................................................................................................... 28 
13. 
Efficacy Analyses ...................................................................................................... 28 
13.1 Primary Efficacy Analysis ......................................................................................... 32 
13.1.1 
EDS at Visit 6 (Day 85), 5% Tavilermide vs Placebo................................... 32 
13.1.2 
Total CFS at Visit 6 (Day 85), 5% Tavilermide vs Placebo.......................... 38 
13.2 Key Secondary Efficacy Analyses ............................................................................. 39 
13.2.1 
EDS at Visit 4 (Day 29), 5% Tavilermide vs Placebo................................... 40 
13.2.2 
Total CFS at Visit 4 (Day 29), 5% Tavilermide vs Placebo.......................... 41 
13.2.3 
EDS at Visit 6 (Day 85), 1% Tavilermide vs Placebo................................... 42 
13.2.4 
Total CFS at Visit 6 (Day 85), 1% Tavilermide vs Placebo.......................... 43 
13.2.5 
EDS at Visit 4 (Day 29), 1% Tavilermide vs. Placebo .................................. 44 
13.2.6 
Total CFS at Visit 4 (Day 29), 1% Tavilermide vs. Placebo......................... 45 
13.3 Other Secondary Efficacy Analyses .......................................................................... 46 
13.3.1 
Visual Analog Scale ...................................................................................... 47 
13.3.2 
Symptom Assessment in Dry Eye Questionnaire .......................................... 48 
13.3.3 
Tear Film Break-Up Time ............................................................................. 48 
13.3.4 
Corneal Fluorescein Staining......................................................................... 49 
13.3.5 
Conjunctival Lissamine Green Staining ........................................................ 50 
13.3.6 
Unanesthetized Schirmer’s Test .................................................................... 51 
13.4 Summary of Efficacy Analyses ................................................................................. 52 
14. 
Safety Analyses .......................................................................................................... 52 
14.1 Adverse Events .......................................................................................................... 52 
14.2 Visual Acuity (ETDRS) ............................................................................................. 55 
14.3 Slit-Lamp Biomicroscopy .......................................................................................... 55 


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14.4 Dilated Fundoscopy ................................................................................................... 56 
14.5 Intraocular Pressure ................................................................................................... 57 
14.6 Ora Calibra® Drop Comfort Scale and Questionnaire ............................................... 57 
15. 
Interim Analyses ........................................................................................................ 57 
16. 
Changes from Protocol-Stated Analyses ................................................................... 58 
17. 
Revision History ........................................................................................................ 58 
18. 
Tables ......................................................................................................................... 59 
19. 
Listings ....................................................................................................................... 65 
20. 
Figures ....................................................................................................................... 66 
 
 
List of Abbreviations 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical 
BID 
Bis in die (Twice Daily) 
CFS 
Corneal Fluorescein Staining 
CI 
Confidence Interval 
COVID-19 
Coronavirus Disease 2019 
CS 
Clinically Significant 
DED 
Dry Eye Disease 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EDS 
Eye Dryness Score 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
HIPAA 
Health Information Portability and Accountability Act 
ICH 
International Conference on Harmonisation 
IOP 
Intraocular Pressure 
IP 
Investigational Product 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 
LS 
Least Squares 
LOCF 
Last Observation Carried Forward 
logMAR 
Logarithm of the Minimum Angle of Resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCMC 
Markov Chain Monte Carlo 
NCS 
Not Clinically Significant 


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NEI 
National Eye Institute 
ODO 
Observed Data Only 
OU 
Both Eyes 
PDF 
Portable Document Format 
PMM 
Pattern Mixture Model 
PP 
Per Protocol 
PT 
Preferred Term 
RTF 
Rich Text Format 
SAE 
Serious Adverse Event 
SANDE 
Symptom Assessment in Dry Eye 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SD 
Standard Deviation 
SDC 
Statistics & Data Corporation, Incorporated 
SE 
Standard Error 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
TE-SAE 
Treatment-Emergent Serious Adverse Event 
TFBUT 
Tear Film Break-Up Time 
TMF 
Trial Master File 
TOP 
Topically 
VAS 
Visual Analog Scale 
WHO 
World Health Organization 
 
 


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1. Introduction 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and 
reporting for protocol MIM-728, version 2.0 dated 03-JUL-2019. 
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. 
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 primary objective of the study is to compare the efficacy and safety of 5% tavilermide 
ophthalmic solution to placebo for the treatment of the symptoms and signs of Dry Eye Disease 
(DED). 
The secondary objective of the study is to compare the efficacy and safety of 1% tavilermide 
ophthalmic solution to placebo for the treatment of the symptoms and signs of DED. 
2.1 
Primary Endpoints 
The primary efficacy endpoints are: 
• Change from baseline in the Eye Dryness Score (EDS) at Visit 6 (Day 85) 
 
 
 
• Change from baseline in total corneal fluorescein staining (CFS) score at Visit 6 (Day 85) 
 
. 


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2.2 
Key Secondary Endpoints 
The key secondary efficacy endpoints are: 
• Change from baseline in the EDS at Visit 4 (Day 29) 
 
; 
• Change from baseline in total CFS score at Visit 4 (Day 29) 
 
 
 
• Change from baseline in the EDS at Visit 6 (Day 85) 
 
  
• Change from baseline in total CFS score at Visit 6 (Day 85) 
 
 
 
• Change from baseline in the EDS at Visit 4 (Day 29) 
 
 
• Change from baseline in total CFS at Visit 4 (Day 29) 
 
 
 
2.3 
Other Secondary Endpoints 
Other secondary endpoints will be compared between treatment groups: 5% tavilermide 
ophthalmic solution to placebo, 1% tavilermide ophthalmic solution to placebo, and 5% 
tavilermide ophthalmic solution to 1% tavilermide ophthalmic solution. The other secondary 
endpoints include the following: 
• Eye dryness, discomfort, grittiness, pain, blurred vision, and photophobia 
 
 
 
• Frequency, severity, and total score 
 
 


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• 
 at Visits 3 (Day 15), 4 (Day 29), 5 (Day 57), and 6 
(Day 85), and the 
at Visits 3 (Day 15), 4 (Day 29), 5 
(Day 57), and 6 (Day 85); 
• CFS in the inferior, superior, central, temporal, and nasal regions, and total corneal (i.e., 
sum of all regions) 
 
 
 
• Conjunctival lissamine green staining in the temporal, superior temporal, inferior 
temporal, superior nasal, inferior nasal, and nasal regions, and total conjunctival (i.e., 
sum of all regions) 
 
 
 
• 
 at Visit 6 (Day 85) and the 
 
 (Visit 1 [Day -14]) at Visit 6 (Day 85). 
2.4 
Safety Variables 
The safety variables are: 
• Incidence and severity of ocular Adverse Events (AE); 
• Incidence and severity of non-ocular AEs; 
• Concomitant medication monitoring/review; 
• Visual acuity (Early Treatment of Diabetic Retinopathy Study [ETDRS]) at all visits; 
• Slit-lamp biomicroscopy at all visits; 
• Intraocular Pressure (IOP) at Visits 1 (Day -14) and 6 (Day 85); 
• Dilated fundoscopy at Visits 1 (Day -14) and 6 (Day 85); and 
• Ora Calibra® Drop Comfort Scale and Questionnaire at Visits 2 (Day 1) and 5 (Day 57). 


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2.5 
Statistical Hypotheses 
2.5.1 PRIMARY ENDPOINTS: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.5.2 KEY SECONDARY ENDPOINTS: 
 
 
 
 
 
 
 
 
 
 


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3. Study Design and Procedures 
3.1 
General Study Design 
This Phase 3 trial is a multi-center, double-masked, randomized, vehicle-controlled, parallel-
group clinical study. There will be two active treatment groups, 1% tavilermide ophthalmic 
solution and 5% tavilermide ophthalmic solution, and one control group, placebo ophthalmic 
solution (vehicle of tavilermide ophthalmic solution). 
A subject’s participation is to start with screening at Visit 1 (Day -14). If the subject is 
considered eligible for the study at the end of Visit 1 (Day -14), the subject will participate in a 
14-day run-in period. Isotonic ophthalmic solution – also known as placebo ophthalmic solution 
(vehicle of tavilermide ophthalmic solution) – is the designated run-in and is to be administered 
to both eyes (OU), topically (TOP), and twice per day (BID) throughout the run-in period. 
Baseline efficacy measurements are to be obtained at Visit 2 (Day 1). Should a subject qualify 
for final study entry at the end of Visit 2 (Day 1), 
 
 
 
 
 
 
 
 
During the treatment period, the subject is to dose with their assigned treatment OU, TOP, and 
BID for approximately 85 days. 
Study visits will be referred to in all tables and listings as the expected study day corresponding 
to the visit to enable reviewers to understand the assessment timing without referring to the 
protocol visit schedule.  Table 1 shows the scheduled study visits, their planned study day (note 


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that there is no Day 0 and that Day 1 corresponds to the day of randomization), and the 
acceptable visit window for each study visit: 
Table 1. Scheduled Visits, Planned Study Days, and Visit Windows 
Scheduled Visit 
Planned Study Day 
Visit Window 
Visit 1 
Day -14 
± 2 Days 
Visit 2  
Day 1 
N/A 
Visit 3  
Day 15 
± 2 Days 
Visit 4  
Day 29 
± 2 Days 
Visit 5  
Day 57 
± 3 Days 
Visit 6  
Day 85 
± 4 Days 
3.2 
Schedule of Visits and Assessments 
The schedule of visits and assessments is provided in Table 2. 
 
 


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Table 2. Schedule of Visits and Assessments 


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4. Study Treatments 
4.1 
Method of Assigning Subjects to Treatment Groups 
A patient who meets all of the inclusion criteria and none of the exclusion criteria is eligible for 
randomization at Visit 2 (Day 1). 
 
 
 
 
A statistician not directly involved in the analysis of the study results will prepare the 
randomization schedule using block randomization to maintain balance between treatment 
groups. Randomization is to be done in a 
 respectively, by the interactive response 
technology (IRT) system. 
Subjects are to be stratified by site and EDS as measured by the VAS at Visit 2 (Day 1) using the 
following strata: 
 
 
Details required for stratification are to be entered into the IRT which will randomize the subject 
and assign a randomization number. Randomization numbers are to be four digits and will 
associate a subject to their assigned treatment group. The IRT will allocate a subject to treatment 
kits containing their randomized treatment; each treatment kit is identifiable by a five-digit kit 
number. The randomization number and all treatment kit numbers are to be recorded on the 
subject’s source document and the appropriate electronic case report forms (eCRF). At Visits 2 


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(Day 1) and 3 (Day 15), each eligible subject is to receive one kit of their randomly assigned 
treatment. At Visits 4 (Day 29) and 5 (Day 57), each eligible subject is to receive two kits of 
their randomly assigned treatment. 
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. 
The discrepancies in visual appearance among the investigational product (IP) mandate that there 
is at least one technician designated as unmasked at each clinical site. Once open, a treatment kit 
is to be handled by only the subject to which it was assigned and unmasked designees. 
Unmasked technicians are uniquely delegated for facilitating the in-office dose and drop comfort 
assessments and performing randomized treatment kit accountability. Unmasked technicians may 
not participate in any other aspect of the trial that has a bearing on trial efficacy including 
symptom questionnaires, scribing for the Investigator, and data transcription. Unmasked 
technicians are not to have access to the electronic data capture (EDC) system. Clinical trial 
monitors who are designated as unmasked are to be responsible for reviewing randomized IP 
accountability. After unmasking, a clinical trial monitor is not to participate in other aspects of 
trial monitoring. 
When medically necessary, the Investigator may need to determine what treatment has been 
assigned to a subject. When possible (i.e., in non-emergent situations), Ora and/or the Sponsor 
should be notified before unmasking IP. 
If the Investigator identifies a medical need for unmasking the assigned treatment of a subject, 
they should, if possible, contact Ora and/or the Medical Monitor before completing the 
unmasking. Ora is to ask the site to complete the appropriate parts of the Unmasking Request 
Form and then to return the form. After receiving the form, Ora is to notify Mimetogen, and 
jointly they are to determine whether to approve the unmasking; Ora or Mimetogen may consult 
with the Medical Monitor as needed during this process. The result of the request is to be 
documented on the Unmasking Request Form. 


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If the request to unmask a subject is approved, the Investigator is to be provided the approval in 
writing via the Unmasking Request Form. The Investigator is to unmask the subject using the 
IRT and complete the Unmasking Memo. The Unmasking Memo is to be filed with the subject’s 
study file, and a copy is to be sent to project management so that it may be included in the Trial 
Master File (TMF). For each unmasking request, the reason for the request, the date of the 
request, and the name and signature of the individual unmasking the subject are to be noted in 
the subject’s study file. 
5. Sample Size and Power Considerations 
Approximately 1034 subjects are to be screened to enroll approximately 600 subjects at 15 to 20 
sites. Subjects are to be randomized 
 to one of the three treatment groups as indicated 
below: 
1. 250 subjects to 5% tavilermide ophthalmic solution, 
2. 100 subjects to 1% tavilermide ophthalmic solution, and 
3. 250 subjects to placebo ophthalmic solution. 
Subjects are to be stratified by site and EDS as measured by the VAS at Visit 2 (Day 1) using the 
following strata: 
 
 
Power calculations conservatively account for missing data; however, the primary analysis will 
impute missing data for all subjects. Assuming a 10% drop out rate, 225 subjects are expected to 
complete the study in each of the 5% tavilermide and placebo arms. 
 
 
 
 
 
 
 


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6. Data Preparation 
Electronic Case Report Forms will be developed by Statistics & Data Corporation, Incorporated 
(SDC). Data from source documents will be entered into the eCRF by site personnel. All users 
will complete role-based system and study-specific eCRF training prior to receiving access to the 
study database. User access will be granted based on a user’s role in the study and will be 
controlled through individual login credentials including a unique User ID and password. 
The clinical study database will be developed and tested in iMedNet™ v1.183.4 or higher. 
iMedNet™ is delivered as a single-instance multi-tenant Software-as-a-Service (SaaS) EDC 
system and is developed, maintained, and hosted by MedNet Solutions located in Minnetonka, 
Minnesota. Therefore, over the duration of the study, MedNet Solutions may apply system 
updates to the EDC system as part of their continuous improvement efforts.  
After data are entered into the clinical study database, electronic edit checks and data review will 
be performed. All data validation specifications and procedures are detailed in the Data 
Validation Manual as a separate document. When the database has been declared to be complete 
and accurate, the database will be locked. Any changes to the database after data have been 
locked can only be made with the approval of Mimetogen and Ora in consultation with SDC.  
All analyses outlined in this document will be carried out after the following have occurred: 
• All data management requirements are met according to SDC standard operating 
procedures (SOP), including data entry, performance of edit and validation checks, 
documentation and resolution of data queries, and database lock with written 
authorization provided by appropriate SDC, Mimetogen and Ora personnel. 
• Protocol deviations have been identified and status defined (major/minor deviations). 
• Analysis populations have been determined. 
• Randomized treatment codes have been unmasked. 


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7. Analysis Populations 
7.1 
Intent-to-Treat 
 
 
 
 
 
 
 
 
 
 
7.2 
Modified Intent-to-Treat 
 
 
 
 
 
  
 
 
 
 
 
 
 


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7.3 
Per Protocol 
 
 
 
7.4 
Safety 
 
 
 
8. General Statistical Considerations 
8.1 
Unit of Analysis 
 
 
 
 
 
 
 
 
8.2 
Missing or Inconclusive Data Handling 
The primary and key secondary efficacy analyses will use the ITT population with MCMC 
multiple imputation methodology under the assumption that data are missing at random. 
Additional sensitivity analyses will be performed using multiple imputation under the 
assumption that data are missing not at random using a control-based pattern mixture model 
(PMM), the last observation carried forward (LOCF) imputation method for missing data as well 
as using the observed data only on the ITT population. Further sensitivity analyses will include 


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MCMC imputation with the mITT population to examine the effect of COVID-19 related 
discontinuations and COVID-19 related significant protocol deviations. Additionally, the PP 
population with observed data only will be used to assess sensitivity. 
No other 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. 
Change from baseline will be calculated as Follow-up Visit – Baseline Visit.  
 
 
 
 
8.4 
Data Analysis Conventions 
All data analysis will be performed by SDC 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 rich text format (RTF) for tables 
and portable document format (PDF) for tables, listings, and figures using landscape orientation. 
All study data will be listed by subject, treatment, and visit (as applicable) based on all 
randomized subjects unless otherwise specified. 
All summaries will be presented by treatment group and visit where appropriate, unless 
otherwise specified. Summaries will be provided for demographics, baseline medical history, 
concurrent therapies, and subject disposition. For the purpose of summarization, medical history, 
concurrent therapies, and adverse events will be coded to Medical Dictionary for Regulatory 
Activities (MedDRA) and World Health Organization (WHO) Drug dictionaries, as appropriate. 
Summaries for continuous and ordinal variables will include the number of observations (n), 
arithmetic mean, standard deviation (SD), median, minimum, maximum, and two-sided 95% 
confidence intervals (CI) for the mean. Minima and maxima will be reported with the same 
precision as the raw values; means, medians and confidence interval bounds will be presented to 


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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%). Differences between active treatment groups and 
placebo will be calculated as Active minus Placebo and change from baseline will be calculated 
as Follow-up Visit - Baseline. The baseline measure will be defined as the last non-missing 
measure prior to initiation of investigational treatment.  
All statistical tests will be two-sided with a significance level of 0.05 (α = 0.05) unless otherwise 
specified. 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.” 
Unless otherwise specified, summaries will be presented by treatment group and, where 
appropriate, visit. 
8.5 
Adjustments for Multiplicity 
 
 
 
 
 
 
The hierarchical testing sequence will proceed as follows: 
Primary Endpoints: 
1. Change from baseline in the EDS at Visit 6 (Day 85) 
 
 
 
 
2. Change from baseline in total CFS score at Visit 6 (Day 85) 
 
 


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Key Secondary Endpoints: 
3. Change from baseline in the EDS at Visit 4 (Day 29) 
 
 
 
 
4. Change from baseline in total CFS score at Visit 4 (Day 29) 
 
 
 
 
5. Change from baseline in the EDS at Visit 6 (Day 85) 
 
 
 
 
6. Change from baseline in total CFS score at Visit 6 (Day 85) 
 
 
 
 
7. Change from baseline in EDS at Visit 4 (Day 29) 
 
 
 
 
8. Change from baseline in total CFS score at Visit 4 (Day 29) 
 
 
 


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9. Disposition of Subjects 
Subject disposition will be presented in terms of the numbers and percentages of subjects who 
were randomized, 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 randomized subjects and the number of randomized subjects in each of the 
analysis populations (ITT, mITT, PP, and Safety) will be displayed by treatment.  The number of 
randomized subjects in the ITT population + Site 88 will also be displayed by treatment. The 
ITT, mITT populations use 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 subjects who 
discontinued the study. The reasons for study discontinuation that will be summarized include: 
AE, protocol violation, administrative reasons, sponsor termination of study, subject choice, and 
other. COVID-19 related discontinuations will be summarized as well. A subject listing will be 
provided that includes the date of and reason for premature study discontinuation. COVID-19 
related discontinuations will be summarized in a separate listing. 
The number and percentage of subjects with major protocol deviations will be summarized by 
treatment group for all randomized subjects. The protocol deviations that will be summarized 
include: Informed Consent, Inclusion / Exclusion and Randomization, Test Article / Study Drug 
Instillation and Assignment at Site, Improper Protocol Procedures at Site, Site’s Failure to 
Report Severe Adverse Event (SAE) / AE, Visit Out of Window (missed, early, late), Subject’s 
Non-compliance with Test Article, Subject’s Use of Prohibited Concomitant Medication, 
Subject’s Failure to Follow Instructions, and Other. COVID-19 related protocol deviations will 
be summarized. A subject listing will be provided that includes the date of the deviation, the 
deviation code, the deviation description, and the classification of whether the deviation was 


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judged to be major or minor. COVID-19 related protocol deviations will be provided in a 
separate listing. 
In addition, subject listings will be provided that include informed consent date, inclusion and 
exclusion criteria violations, and exclusions from any analysis population. A listing of screen 
failure subjects will also be provided that includes screen failure date, visit of screen failure, 
reason for screen failure and date of dry eye diagnosis.  
A subject listing of all subjects affected by COVID-19 will be generated. 
10. Demographic and Pretreatment Variables 
10.1 
Demographic Variables 
The demographic variables collected in this study include age, sex, ethnicity, race, and iris color. 
Subjects who record more than one race will be grouped into a single category denoted as 
Multiple. Demographic variables will be summarized for the ITT, mITT, PP, 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: 
 
The number and percentage of subjects will be presented, overall and by treatment, for age 
category, sex, race, ethnicity and iris color by eye (OD and OS).  
A subject listing that includes all demographic variables will be provided. 
10.2 
Pretreatment Variables 
Baseline disease characteristics will be summarized for the ITT, mITT, PP, and Safety 
populations, separately by treatment group using continuous descriptive statistics for VAS ocular 
symptoms (eye dryness, discomfort, grittiness, pain, blurred vision, and photophobia), CFS 
(inferior, superior, central, temporal, nasal, and corneal regions), SANDE questionnaire 
(frequency, severity, and total), TFBUT, and conjunctival lissamine green staining. 


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Unanesthetized Schirmer’s test for screening Visit 1 (Day -14) will also be summarized using 
continuous descriptive statistics. Discrete summary statistics will be used to summarize visual 
acuity and IOP at screening Visit 1 (Day -14). Discrete summary statistics will also be used to 
summarize slit-lamp biomicroscopy, dilated fundoscopy, and Ora Calibra® Drop Comfort Scale 
and Questionnaire at baseline.  For assessments by eye, separate summaries will be presented for 
the study eye and fellow eye. 
11. Medical History and Concomitant Medications 
11.1 
Medical History 
Medical history will be coded using MedDRA version 22.0. 
Ocular medical history 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. Non-ocular medical history will be similarly summarized at the 
subject and event level. 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.  
Listings of medical history will be generated separately for ocular and non-ocular data. 
11.2 
Concomitant Medications 
Concomitant medications will be coded using WHO Drug Global B3 (March 2019) and 
summarized to the therapeutic drug class (Anatomical Therapeutic Chemical [ATC] 4 
classification) and preferred name. If the ATC 4 classification is not provided, the next lowest 
classification that is provided in the coding dictionary will be used. The preferred name will be 
defined as the active ingredient; if the active ingredient is not provided or includes more than two 
ingredients (eg, multivitamins) then the drug name will be summarized as the preferred name.   
Concomitant medications are defined as those medications listed as having been taken (1) prior 
to initiation of study drug administration and continuing for any period of time following the first 
administration of study drug or (2) at any time following the first administration of study drug. 
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Concomitant medications will be summarized separately using the Safety and ITT populations, 
and separately for ocular and non-ocular medications. Medications will be tabulated for each 
treatment group using frequencies and percentages. Prior medications will be provided in subject 
listings with concomitant medications, but will not be summarized. Subjects may have more than 
1 medication per ATC text. At each level of subject summarization, a subject will be counted 
once if he/she reports 1 or more medications. Percentages will be based on the number of 
subjects in each treatment group. Listings of concomitant and prior medications will be 
generated separately for ocular and non-ocular medications. 
12. Dosing Compliance and Treatment Exposure 
12.1 
Dosing Compliance 
Dosing compliance will be based off of the unused vial count. 
 
 
 
Dosing compliance (% compliance) will be assessed by calculating the number of actual vials 
used and comparing that to the expected number of used vials as follows: 
The number of doses taken will be calculated from  
 
recorded in the eCRF. The expected number of used vials that will be used for calculating 
compliance will be calculated as:  
 
for all subjects. If a randomized subject discontinues from the study on Day 1, the number of 
expected doses will be 1.  


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A categorical dosing compliance variable will also be derived as non-compliant 
, 
compliant 
 and over compliant
 
Dosing compliance (%) will be summarized with continuous descriptive statistics for each 
treatment group using the ITT population. The compliance category defined above will be 
summarized with discrete summary statistics.  
Subject listing of dosing compliance, study drug accountability, and study drug instillation will 
also be produced. 
12.2 
Treatment Exposure 
Extent of treatment exposure for completed or discontinued subjects will be calculated in days 
using the following: 
 
 
If a randomized subject discontinues from the study on Day 1, the extent of exposure will be 1. 
Extent of treatment exposure for subjects who were lost to follow-up will be calculated in days 
using the following: 
 
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 will also be produced. 
 
13. Efficacy Analyses 
The following table presents a summary of the primary, key secondary, and secondary efficacy 
analyses that will be performed for this study. 
 
 


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Analyses of the Primary, Key Secondary and Secondary Efficacy Variables 


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13.1 
Primary Efficacy Analysis 
The primary efficacy endpoints of the study are: 
• Change from baseline in the EDS at Visit 6 (Day 85) 
 
 
• Change from baseline in total CFS at Visit 6 (Day 85) 
 
 
 
 
 
 
 
 
13.1.1 
EDS AT VISIT 6 (DAY 85), 5% TAVILERMIDE VS PLACEBO 
 
 
 
 
 
 
 
 
 
 
 
  


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13.1.2 
TOTAL CFS AT VISIT 6 (DAY 85), 5% TAVILERMIDE VS PLACEBO 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


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13.2 
Key Secondary Efficacy Analyses 
The following are key secondary endpoints: 
• Change from baseline in the EDS at Visit 4 (Day 29) 
 
 


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• Change from baseline in total CFS score at Visit 4 (Day 29) 
 
 
 
• Change from baseline in the EDS at Visit 6 (Day 85) 
 
 
• Change from baseline in total CFS score at Visit 6 (Day 85) 
 
 
 
• Change from baseline in the EDS at Visit 4 (Day 29) 
 
 
• Change from baseline in total CFS score at Visit 4 (Day 29) 
 
 
 
 
13.2.1 
EDS AT VISIT 4 (DAY 29), 5% TAVILERMIDE VS PLACEBO 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


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13.2.2 
TOTAL CFS AT VISIT 4 (DAY 29), 5% TAVILERMIDE VS PLACEBO 
 
 
 
 
 
 
 
  
 
 
 
 


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13.2.3 
EDS AT VISIT 6 (DAY 85), 1% TAVILERMIDE VS PLACEBO 
 
 
 
 
 
 
 
 
 
 
 
 
  


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13.2.4 
TOTAL CFS AT VISIT 6 (DAY 85), 1% TAVILERMIDE VS PLACEBO 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


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13.2.5 
EDS AT VISIT 4 (DAY 29), 1% TAVILERMIDE VS. PLACEBO 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


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13.2.6 
TOTAL CFS AT VISIT 4 (DAY 29), 1% TAVILERMIDE VS. PLACEBO 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 


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13.3 
Other Secondary Efficacy Analyses 
 
 
 
 
 
 
 
 
 
 
 
 
The following other secondary efficacy endpoints will be tested: 
• Eye dryness, discomfort, grittiness, pain, blurred vision, and photophobia 
 
 
• Frequency, severity, and total score 
 
• 
 
• CFS in the inferior, superior, central, temporal, nasal, and corneal (i.e., sum of all 
regions) regions 
 
• Conjunctival lissamine green staining in the temporal, superior temporal, inferior 
temporal, superior nasal, inferior nasal, nasal, and conjunctival (i.e., sum of all regions) 
regions 
 
• 
 


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13.3.1 VISUAL ANALOG SCALE 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


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13.3.2 SYMPTOM ASSESSMENT IN DRY EYE QUESTIONNAIRE 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
13.3.3 TEAR FILM BREAK-UP TIME 
 
 


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13.3.4 CORNEAL FLUORESCEIN STAINING 
 
 
 
 
 
 
  
 
 


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13.3.5 
CONJUNCTIVAL LISSAMINE GREEN STAINING 
 
 
 
 
 
 
 
  
 
 


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13.3.6 
UNANESTHETIZED SCHIRMER’S TEST 
 
 
 
  
 
 
  
 
 
 
 
 
 
 


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13.4 
Summary of Efficacy Analyses 
 
 
 
   
 
 
 
 
14. Safety Analyses 
 
14.1 
Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of an 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 a study drug, 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. An AE can arise from any 
delivery, implantation, or use of a medical device, including medical device failure, subject 
characteristics that may impact medical device performance (e.g., anatomical limitations), and 


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therapeutic parameters (e.g., energy applied, sizing, dose release, and anatomic fit) associated 
with medical device use. All AEs will be coded using the MedDRA 22.0.  
Treatment-emergent adverse events (TEAE) are defined as any event that occurs or worsens on 
or after the day that randomized study treatment is initiated. Adverse events recorded in the 
eCRF which began prior to treatment will not be included in the summary tables but will be 
included in the AE data listings. 
An overall summary will be presented that includes the number of AEs, TEAEs, SAEs, and 
treatment-emergent serious adverse events (TE-SAE). The summary will also include the 
number and percentage of subjects withdrawn due to a TEAE, the number and percentage of 
subjects with a TEAE 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 further categorized as ocular or non-ocular.  
Separate summaries will be provided for the following categories of AEs:  
• Ocular TEAEs  
• Non-ocular TEAEs  
• TEAEs that led to premature discontinuation  
• TE-SAEs 
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 system organ class (SOC) 
and preferred term (PT). TEAEs 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). 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 ascending alphabetical order; PTs will be listed in order of descending frequency for 
all subjects within each SOC.  
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 


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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 subject’s daily activities. 
• Moderate: Event is bothersome, possibly requiring additional therapy, and may interfere 
with the subject’s daily activities. 
• Severe: Event is intolerable, necessitates additional therapy or alteration of therapy, and 
interferes with the subject’s daily activities. 
The relationship of each AE to the study drug should be determined by the Investigator using 
these explanations: 
• 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 IP administration but could also have been produced by the subject’s clinical 
state or by other drugs administered to the subject. 
• Not Suspected: A reasonable possibility does not exist that the IP caused the AE. 
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. 
Only suspected TEAEs are considered as treatment-related TEAEs.  


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All AEs will be presented in a subject listing. Listings of ocular AEs, non-ocular AEs, and all 
serious AEs will be presented in separate listings. 
14.2 
Visual Acuity (ETDRS) 
 
 
 
 
 
 
 
 
 
 
 
 
  
14.3 
Slit-Lamp Biomicroscopy  
 
 
 
 
 
  
 
 


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• 
 
 
 
 
 
 
 
 
 
 
 
 
14.4 
Dilated Fundoscopy  
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 


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14.5 
Intraocular Pressure  
 
 
 
 
 
 
  
14.6 
Ora Calibra® Drop Comfort Scale and Questionnaire 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
15. Interim Analyses 
 


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16. Changes from Protocol-Stated Analyses 
There are no changes from the protocol-stated analyses. 
17. Revision History 


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18. Tables 
Tables that will be included in the topline delivery are shown in boldface font.  


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19. Listings 


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