A Multicenter, Vehicle-controlled, Double-Masked, Randomized Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Exploratory Efficacy of AGN-242428 and AGN-231868 in Participants With Dry Eye Disease
Phase: PHASE1
Conditions: Dry Eye Disease, Dry Eye Syndrome
Sponsor: AbbVie



CONFIDENTIAL
Protocol 2012-201-005 Amendment 3
AGN-242428 and AGN-231868
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Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Amendment 3
14 July 2021
Amendment 2
28 April 2020
Amendment 1
18 Dec 2019
Original Protocol
06 May 2019
Amendment 3 (July 2021)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union 
because it neither significantly impacts the safety or physical/mental integrity of participants nor 
the scientific value of the study.
Overall Rationale for the Amendment:
The key changes made in Protocol Amendment 3 are summarized in the table below. 
Grammatical corrections and minor edits for internal document consistency have also been made 
and are not specified in the table below.
 
 
 
 
 

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Section Number and Name
Description of Change
Brief Rationale
Title Page
Update safety contact to sponsor/emergency 
medical contact
Update signatory names/titles
Provide the current contact 
information and also include 
a 24 hour emergency 
number
Current signatories
Section 1.2, Figure 1-2
Fixed footnotes in Figure 1-2 to include both 
footnote ‘a’ and ‘b’ 
For clarification
Section 1.3, Table 1-2; Section 8
Clarified that after completion of Informed 
Consent and Inclusion/Exclusion Criteria, for 
assessments listed with an ‘#’ flexibility in
procedure order is allowed; all other 
assessments will be performed in order listed.
For clarification
Section 1.3, Table 1-2
Added a note to clarify the timing of the 
collection of used and unused study 
intervention.
For clarification
Section 1.3, Table 1-2; 
Section 8.4.3; Section 8.8.1
At the baseline visit (V3), the study eye is not 
identified at the time of tear collection. Since 
the process for sample collection is the same, 
tear samples will be collected, one eye 
followed by the other, and labelled as OS and 
OD. The samples will be assigned to 
biomarker or PK analysis depending on the 
study eye assignment.
For clarification
Section 8.1.3
Eligibility based on mean of 2 or median of 3 
IOP measurements.
Clarification
Amendment 2 (April 2020)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union 
because it neither significantly impacts the safety or physical/mental integrity of participants nor 
the scientific value of the study.
Overall Rationale for the Amendment:
The key changes made in Protocol Amendment 2 are summarized in the table below. 
Grammatical corrections and minor edits for internal document consistency have also been made 
and are not specified in the table below.
 
 
 
 
 

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Section Number and Name
Description of Change
Brief Rationale
Section 1.3 Tables 1-1 and 1-2, 
Section 8.1.1 Best-corrected 
Visual Acuity
Added manifest refraction to the SoA: at all 
visits in Stage 1 and at Visits 1, 6, and ET in 
Stage 2.
For clarification of when
manifest refraction was 
required.
Section 5.1.2 Exclusion Criteria 
for Stage 1, Section 5.2.2 
Exclusion Criteria for Stage 2
Added “or anticipated participation during the 
study” to the exclusion criterion (3.02) 
prohibiting blood and plasma donation prior to 
study participation.
For clarification that this 
criterion applies to blood 
and plasma donation before 
and during the study.
Section 5.1.2 Exclusion Criteria 
for Stage 1
Removed “lissamine green” from exclusion 
criterion 4.01 in Stage 1, which lists known 
allergies and sensitivities to study treatments
or study diagnostic agents.
Lissamine green is not 
needed because it is not 
used in Stage 1.
Section 5.1.2 Exclusion Criteria 
for Stage 1, Section 5.2.2 
Exclusion Criteria for Stage 2, 
Section 6.5.1 Tables 6-2 and 6-3, 
Section 6.5.2 Permitted 
Interventions, Section 6.5.4 
Prohibited Interventions During 
the Study
Excluded flax seed oil, fish oil, and omega-3 
supplements from the list of systemic 
medications that may impact DED or vision.
These medications are not 
expected to affect the study 
endpoints so their use 
should not be prohibited.
Section 6.1.1.2 Dosing Regimen 
in Stage 2, Section 6.3.2 
Masking
Updated wording to clarify that unmasked
staff will perform dosing in Stage 2 and that
masked staff should not be present during 
Stage 2 dosing in order to prevent unmasking.
For clarification.
Section 8.1.7 
Electrocardiograms
Extended window to perform predose ECG in 
Stage 2 from 120 minutes to 240 minutes.
To accommodate all other 
procedures that are required 
predose in Stage 2.
 
 
 
 
 

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Section Number and Name
Description of Change
Brief Rationale
Amendment 1 (December 2019)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union 
because it neither significantly impacts the safety or physical/mental integrity of participants nor 
the scientific value of the study.
Overall Rationale for the Amendment:
The key changes made in Protocol Amendment 1 are summarized in the table below. 
Grammatical corrections and minor edits for internal document consistency have also been made 
and are not specified in the table below.
Section Number and Name
Description of Change
Brief Rationale
Section 1 Synopsis, Section 1.3 
Tables 1-1 and 1-2, Section 4.1 Overall 
Design, Section 4.2.1 Duration of 
Treatment in Stage 1 and Stage 2, 
Section 6.1 Table 6-1, Section 6.1.1.1 
Dosing Regimen in Stage 1, 
Section 6.1.1.2 Dosing Regimen in 
Stage 2, Section 6.3.1 Method of 
Intervention Assignment, Section 10.6 
Appendix 6: Study Tabular Summary
Clarified that twice daily is 
approximately 12 hours apart 
dosing.
For clarification.
 
 
 
 
 

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Section Number and Name
Description of Change
Brief Rationale
Section 6.2 
Preparation/Handling/Storage/ 
Accountability
Clarified instructions for 
storage and accountability.
For clarification.
Section 6.3.2 Masking
Clarified that there will be 
unmasked pharmacy staff in 
Stage 1.
For clarification.
Section 8.1.1 Best-corrected Visual 
Acuity
Removed language regarding 
low luminance BCVA 
measurements. 
Only normal luminance BCVA will 
be performed.
Section 8.1.7 Electrocardiograms
Clarified that sites will 
transmit ECG data to the 
central reader after 
interpretation of the results is 
performed by a qualified 
physician or designee at the 
site.
For clarification.
Section 8.1.8 Clinical Safety Laboratory 
Assessments
Adjusted the language on 
capturing local lab data in 
EDC.
For clarification.
Section 8.1.11 Suicidal Risk Monitoring
Removed section stating this 
is not applicable. 
As this is not applicable, removed 
unnecessary section.
Section 8.4.1 Pharmacokinetic Blood 
Draw Schedule, Section 8.4.3 
Pharmacokinetic Tear Sampling 
Schedule, Section 8.8.1 Tears
Removed requirement for 
"atomic clocks."
To allow for use of other precise 
systems such as pyramid system 
clocks.
Section 1.3 Table 1-1, Section 8.4.3 
Pharmacokinetic Tear Sampling 
Schedule
Removed predose tear 
sampling for PK analysis from 
Visits 2 and 4 in Stage 1.
The samples collected at predose on 
these visits will be used for 
biomarker assay optimization 
instead of PK. 
Section 10.9 Appendix 9: Study 
Schedule Supplement
Removed this appendix. 
Removed this appendix as it is a 
duplication of the information in the 
SoA.  
 
 
 
 
 

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1.
Protocol Summary
1.1.
Synopsis
Protocol Title: A Multicenter, Vehicle-controlled, Double-Masked, Randomized Study to 
Evaluate the Safety, Tolerability, Pharmacokinetics, and Exploratory Efficacy of AGN-242428 
and AGN-231868 in Participants with Dry Eye Disease 
Protocol Number: 2012-201-005
Brief Title: Safety, Tolerability, Pharmacokinetics, and Efficacy of AGN-242428 and 
AGN-231868 in Participants with Dry Eye Disease
Study Phase: 1/2a 
Study Rationale:
This is the first-in-human study to evaluate the safety, tolerability, pharmacokinetics (PK), and 
exploratory efficacy of AGN-242428 and AGN-231868 administered through topical ocular 
instillation. Data collected from animal studies suggest that both interventions have a good safety 
profile and the potential to reduce the signs and symptoms of dry eye disease (DED). Data from 
this study will guide the future development of either or both of these compounds for the 
treatment of DED.
Objectives and Endpoints:
Objectives
Assessments/Endpoints
Stage 1
Primary

To evaluate the safety and tolerability of 
AGN-242428 and AGN-231868 and their 
respective vehicles in participants with DED

Adverse events (AEs), clinical laboratory values, vital 
signs, electrocardiogram (ECG) findings, intraocular 
pressure (IOP), best-corrected visual acuity (BCVA), 
slit lamp biomicroscopy, dilated fundus examination, 
Drop Tolerability Questionnaire score

To characterize the plasma and tear PK of
AGN-242428 and AGN-231868 in 
participants with DED following a single
bilateral dose and 13 days of twice daily 
administration followed by a single dose 
administration to both eyes

The PK parameters to be calculated following a single 
dose administration: area under the plasma or tear 
concentration versus time curve from time 0 to time of 
the last measurable concentration (AUC0-tlast),
maximum plasma or tear drug concentration (Cmax), 
time of maximum plasma or tear drug concentration 
(Tmax), and terminal elimination half-life (t1/2)

The PK parameters to be calculated following repeat 
dose administration: area under the plasma or tear 
concentration versus time curve from time 0 to the end 
of the dosing interval (AUC0-τ), Cmax, Tmax, minimum 
plasma or tear drug concentration at steady state 
(Cmin,ss), accumulation index (AI), and t1/2

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Objectives
Assessments/Endpoints
Stage 2
Primary

To evaluate the safety and tolerability of 
AGN-242428 and AGN-231868 and their 
respective vehicles in participants with DED

AEs, clinical laboratory values, vital signs, ECG 
findings, IOP, BCVA, slit lamp biomicroscopy, dilated 
fundus examination, Drop Tolerability Questionnaire 
score
Secondary

To assess the plasma exposure of
AGN-242428 and AGN-231868; and tear 
exposure of AGN-242428, AGN-231868, and 
lifitegrast in participants with DED following 
twice daily dosing for up to 6 weeks

Trough plasma or tear concentration (Ctrough) and 
plasma or tear concentration at 0.5 hours postdose 
(C0 5h)
a
The exact statistical comparisons will be described in detail in the statistical analysis plan and will include, but will not be 
limited to, assessments of changes from baseline and responder analyses.
Overall Study Design:  
This will be a Phase 1/2a, multicenter, vehicle-controlled, double-masked, randomized study 
conducted in 2 consecutive stages in participants with DED. 
Stage 1 will evaluate the safety, tolerability, and PK (plasma and tear) of a maximum of 3 dose 
levels of AGN-242428 (
) and AGN-231868 (
 in 
participants with DED. Participants in Cohort 1A will be randomized 3:3:1:1 to receive 1 drop of 
 AGN-242428,
 AGN-231868, or their respective vehicles (4 dosing arms total) to 
the left eye on Day 1. In the absence of significant study intervention-related safety findings, 
starting on Day 2, participants will administer 1 drop of the same randomized study intervention 
twice daily (approximately every 12 hours) to both eyes for an additional 13 days (through 
Day 14), followed by a single dose administration to both eyes on Day 15. The sponsor will 
decide whether to proceed to Cohort 1B after review of Cohort 1A data by the data monitoring 
committee (DMC). The DMC will be masked to the interventions but can request to be 
unmasked at any time. 

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1.3.
Schedule of Activities (SoA)
Table 1-1
Schedule of Activities – Stage 1
Study Day 
(Unless otherwise specified, all 
examinations/procedures for a 
timepoint must be performed in the 
order listed below)
Visit 1 
Screening
Intervention Period
Notes
Visit 2 
(Baseline)
Visit 3
Visit 4
Visit 5 (Exit)
or Early 
Termination
Day -14 to 
Day -1
Day 1
Day 2
Day 8 (+1)
Day 15 (+2)
Informed consent
X
Inclusion and exclusion criteria
X
X
Recheck participant eligibility before 
randomization and/or first dose of study 
intervention.
Demographics
X
Medical, ophthalmic, and surgical 
history (includes substance usage)
X
X
Prior or concomitant medication 
review
========================================================
AE review
========================================================
Vital signs (RR, height, and weight)
X
X
Height measurement will not be performed
at Visit 5 or the Early Termination visit.
Vital signs (blood pressure, pulse rate, 
and temperature)
X
X
X
X
X
Physical examination
X
X
12-lead ECG
X
X
At the Exit visit, ECG will be performed at 
0 hour (predose) and 45 ± 15 minutes 
postdose.
Pregnancy test (WOCBP only)
X
X
X
Serum pregnancy test will be performed at 
Screening; at all other indicated visits, 
serum or urine pregnancy test will be 
performed.
Drugs of abuse screen
X
X
Breathalyzer may be used for alcohol.
Hematology, chemistry, and urinalysis
X
X
Participants will be instructed to fast 
(ie, water only) for at least 10 hours prior to 
blood collection for safety laboratory tests.
Serology
X

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Study Day 
(Unless otherwise specified, all 
examinations/procedures for a 
timepoint must be performed in the 
order listed below)
Visit 1 
Screening
Intervention Period
Notes
Visit 2 
(Baseline)
Visit 3
Visit 4
Visit 5 (Exit)
or Early 
Termination
Day -14 to 
Day -1
Day 1
Day 2
Day 8 (+1)
Day 15 (+2)
Tear sample collection for PK analysis
X
X
X
Tear samples for PK analysis will be 
collected at Visits 3 and 5 at 0 hour 
(predose) and 0.5, 2, 4, 8, and 12 hours 
postdose. In addition, at Visit 4, a sample 
will be collected at 0.5 hours postdose. Tear 
samples will be collected from both eyes. 
For the full tear sample collection schedule, 
refer to Table 8-14.
Tear collection will not be performed at the 
Early Termination visit.
Administration of study intervention
X
X
X
X
Study interventions will be administered as 
a single drop to the left eye on Day 1 and as 
a single drop to both eyes, twice daily
(approximately 12 hours apart) for 13 days 
(Days 2-14), followed by a single dose 
administration to both eyes on Day 15.
The morning dose will be administered by 
site staff on visit days.
Dosing will not be performed at the Early 
Termination visit.
Drop Tolerability Questionnaire
X
X
X
X
Drop Tolerability Questionnaire must be 
administered within approximately 
5 minutes following morning 
administration of study intervention.
Drop Tolerability Questionnaire will not be 
administered at the Early Termination visit.
Dispensing of study intervention to 
participant
X
X
Collection of used and unused study 
intervention
X
X
AE = adverse event; ECG = electrocardiogram; 
; PK = pharmacokinetic; RR = respiration rate; WOCBP = women of childbearing potential

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3.
Objectives and Endpoints
3.1.
Stage 1
Objectives
Assessments/Endpoints
Primary

To evaluate the safety and tolerability of 
AGN-242428 and AGN-231868 and their 
respective vehicles in participants with DED

Adverse events (AEs), clinical laboratory values, vital 
signs, electrocardiogram (ECG) findings, intraocular 
pressure (IOP), best-corrected visual acuity (BCVA), 
slit lamp biomicroscopy, dilated fundus examination, 
Drop Tolerability Questionnaire score

To characterize the plasma and tear PK of
AGN-242428 and AGN-231868 in participants 
with DED following a single bilateral dose and 
13 days of twice daily administration followed by 
a single dose administration to both eyes

The PK parameters to be calculated following a single 
dose administration: area under the plasma or tear 
concentration versus time curve from time 0 to time of 
the last measurable concentration (AUC0-tlast) 
maximum plasma or tear drug concentration (Cmax), 
time of maximum plasma or tear drug concentration 
(Tmax), and terminal elimination half-life (t1/2)

The PK parameters to be calculated following repeat 
dose administration: area under the plasma or tear 
concentration versus time curve from time 0 to the 
end of the dosing interval (AUC0-τ), Cmax, Tmax, 
minimum plasma or tear drug concentration at steady 
state (Cmin,ss), accumulation index (AI), and t1/2

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3.2.
Stage 2
Objectives
Assessments/Endpoints
Primary

To evaluate the safety and tolerability of 
AGN-242428 and AGN-231868 and their 
respective vehicles in participants with DED

AEs, clinical laboratory values, vital signs, ECG 
findings, IOP, BCVA, slit lamp biomicroscopy, 
dilated fundus examination, Drop Tolerability 
Questionnaire score
Secondary

To assess the plasma exposure of AGN-242428 
and AGN-231868; and tear exposure of 
AGN-242428, AGN-231868, and lifitegrast in 
participants with DED following twice daily
dosing for up to 6 weeks

Trough plasma or tear concentration (Ctrough) and 
plasma or tear concentration at 0.5 hours postdose 
(C0 5h)
Tertiary/Exploratory
a
The exact statistical comparisons will be described in detail in the statistical analysis plan and will include, but will not be 
limited to, assessments of changes from baseline and responder analyses.

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5.
Study Population
All participants will have DED. In addition, participants enrolled in Stage 2 of this study will 
have to respond to the CAE challenge with increased signs and symptoms of DED (see 
Sections 4.1 and 4.2.4 for more details).
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
5.1.
Stage 1 
5.1.1.
Inclusion Criteria for Stage 1
Participants are eligible to be included in Stage 1 of the study only if all of the following criteria 
apply:
1.
Age
1.01
Participant must be ≥ 18 years of age at the time of signing the informed consent
2.
Type of Participant and Disease Characteristics
2.01
Both of the following signs of DED in at least 1 eye at Screening and Baseline 
visits (the same eye does not need to qualify at both visits):

Total corneal fluorescein staining score ≥ 2 and ≤ 9 based on the NEI 
grading scale, with no score > 2 in any 1 region 

Schirmer test with topical anesthesia score ≥ 1 and ≤ 10 mm/5 min
2.02
Symptoms of DED at both the Screening and Baseline visits as defined by an OSDI 
total score of ≥ 13 with ≤ 3 responses of “not applicable (NA)”.
2.03
BCVA of 20/100 or better in both eyes at the Screening visit
2.04
Good general and ocular health, as determined by the investigator using medical 
history, ophthalmic examination and history, physical examination, fasting blood 
chemistry and hematology, urinalysis, vital signs, and 12-lead ECG results at the 
Screening and Baseline visits, as applicable per the SoA (Section 1.3).
3.
Sex
3.01
Male or female

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4.
Contraceptives
4.01
Male participants willing to minimize the risk of inducing pregnancy for the 
duration of the clinical study

A male participant with a heterosexual partner who is a woman of 
childbearing potential (WOCBP) must agree to use contraception as detailed 
in Appendix 7 during the intervention period and refrain from donating 
sperm during this period
4.02
Female participants willing to minimize the risk of inducing pregnancy for the 
duration of the clinical study

A female participant is eligible to participate if she is either: 
o
Not a WOCBP as defined in Appendix 7 (proper documentation 
must be provided to confirm non-WOCBP status)
OR
o
A WOCBP who is not pregnant (ie, has a negative serum pregnancy 
test result at the Screening visit and has a negative serum or urine 
pregnancy test result at the Baseline visit), and agrees to follow the 
contraceptive guidance in Appendix 7 during the intervention period
5.
Informed Consent
5.01
Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol
5.02
Written informed consent from the participant has been obtained prior to any 
study-related procedures
6.
Other
6.01
Able, as assessed by the investigator, and willing to follow study instructions and 
likely to complete all required study visits

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5.1.2.
Exclusion Criteria for Stage 1
Participants are excluded from Stage 1 of the study if any of the following criteria apply:
1.
Medical Conditions
1.01
Current diagnosis of glaucoma or ocular hypertension; evidence of glaucoma or 
mean intraocular pressure > 21 mm Hg determined by Goldmann applanation 
tonometry, in either eye
1.02
History or presence of any ocular disorder or condition (other than DED) in either 
eye that would, in the opinion of the investigator, likely interfere with the 
interpretation of the study results or participant safety, such as: significant corneal or 
conjunctival scarring; pterygium or nodular pinguecula; conjunctivitis, or 
inflammation not associated with DED; anterior (epithelial) basement membrane 
corneal dystrophy or other clinically significant corneal dystrophy or degeneration; 
evidence of keratoconus; etc. (Note: Blepharitis and/or Meibomian gland disease not 
requiring treatment are allowed.)
1.03
Diagnosis of recurrent, ongoing, or active ocular infection including, but not limited 
to herpes simplex or zoster, vaccinia, varicella, tuberculosis of the eye, 
acanthamoeba, or fungal disease
1.04
History of ocular surgery within 12 months prior to Screening visit, including 
punctal cautery, corneal refractive, or anterior segment surgeries that affect corneal 
sensitivity (eg, cataract surgery or any surgery involving limbal or corneal incision)
1.05
Have had a corneal transplant in either or both eyes
1.06
At the Screening visit, at the investigator’s discretion, have active or uncontrolled, 
severe:

Systemic allergy

Chronic seasonal allergies at risk of being active during the study

Rhinitis or sinusitis 
1.07
History or presence of significant cardiovascular, pulmonary, hepatic, renal, 
hematologic, coagulation, gastrointestinal, endocrine, immunologic, dermatologic, 
ophthalmologic, neurologic or psychiatric disease. Significant is defined as any 
disease that, in the assessment of the investigator, would put the safety of the 
participant at risk through participation, or which would prevent or confound 
protocol-specified assessments (eg, severe Sjögren’s syndrome, severe rheumatoid 
arthritis, severe systemic lupus erythematosus, uncontrolled immunodeficiency 
disease, etc.)

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2.
Prior/Concomitant Therapy
2.01
Use of artificial tears within 24 hours prior to the Screening visit or anticipated use 
during the study
2.02
Use of systemic immunomodulators (eg, hydroxychloroquine, methotrexate, 
cyclosporine) within 14 days prior to the Screening visit or anticipated use during the 
study  
2.03
Use of corticosteroids administered through any route within 7 days of the Screening 
visit or anticipated use during the study
2.04
Use of any form of topical ophthalmic cyclosporine (eg, RESTASIS or other 
ophthalmic form) within 7 days prior to the Screening visit or anticipated use during 
the study
2.05
Use of topical ocular glaucoma medications or topical ocular allergy medications 
(over-the-counter [OTC], herbal, prescription, or nutritional supplements including 
all mast cell stabilizers and antihistamines) within 7 days prior to the Screening visit 
or anticipated use during the study
2.06
Use of Xiidra (lifitegrast ophthalmic solution, 5%) or TrueTear™ within 7 days prior 
to the Screening visit or anticipated use during the study
2.07
Use of medications associated with the treatment of severe DED and/or Meibomian 
gland disease such as oral antimuscarinics, cevimeline, oral macrolides, 
tetracyclines, tetracycline derivatives, and retinoids within 14 days prior to the 
Screening visit or anticipated use during the study  
2.08
Use of contact lenses in either eye within 14 days prior to the Screening visit or 
planned use during the study
2.09
Punctal or intracanalicular plug present in either eyelid within 1 year of the 
Screening visit or anticipated plug insertion or occlusion at any time during the study
2.10
Use of lid-heating therapy (ie, LipiFlow, iLUX, etc.), Meibomian gland probing, or 
therapeutic Meibomian gland expression in either eye within 3 months prior to the 
Screening visit or anticipated use during the study

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2.11
The start date of any systemic medication (including OTC, herbal, prescription, or 
nutritional supplements), which may affect DED or vision is < 7 days prior to the 
Screening visit or a change in dosage is anticipated during the study. Systemic 
medications, which may affect DED or vision, include but are not limited to the 
following: antihistamines, cholinergic agents, anticholinergics, beta blocking agents, 
tricyclic antidepressants, and phenothiazines.
2.12
The start date of hormone replacement therapy program, oral or transdermal 
contraception, other estrogen or progesterone treatments, or other medications 
required for long-term treatment of chronic diseases is < 7 days prior to the 
Screening visit or a change in dosage is anticipated during the study
2.13
The start date of any androgen therapy is < 7 days prior to the Screening visit or a 
change in dosage is anticipated during the study
2.14
Use of inhalable or ingestible cannabis products, or transdermal patches containing 
THC within 30 days prior to the Screening visit or anticipated use during the study
3.
Prior/Concurrent Clinical Study Experience
3.01
Current enrollment in an investigational drug, device, or any observational study or 
participation in such a study within 30 days prior to the Screening visit 
3.02
Participation in a blood or plasma donation program within 60 or 30 days, 
respectively, prior to study intervention administration, or anticipated participation 
during the study
4.
Other
4.01
Known allergies or sensitivity to the study interventions or study diagnostic agents 
including sodium fluorescein, etc.
4.02
The participant has a condition or is in a situation that, in the investigator’s opinion, 
may put the participant at significant risk, may confound the study results, or may 
interfere significantly with the participant’s participation in the study
4.03
Positive test results for anti–HIV type 1 and 2, hepatitis B surface antigen, or 
anti-hepatitis C virus at the Screening visit
4.04
Positive test results for benzoylecgonine (cocaine), methadone, barbiturates, 
amphetamines, benzodiazepines, alcohol, cannabinoids, opiates, or phencyclidine at 
the Screening or Baseline visits
4.05
Positive pregnancy test at Screening or Baseline visits

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4.
Contraceptives
4.01
Male participants willing to minimize the risk of inducing pregnancy for the duration 
of the clinical study

A male participant with a heterosexual partner who is a WOCBP must agree 
to use contraception as detailed in Appendix 7 during the intervention period 
and refrain from donating sperm during this period.
4.02
Female participants willing to minimize the risk of inducing pregnancy for the 
duration of the clinical study

A female participant is eligible to participate if she is either: 

Not a WOCBP as defined in Appendix 7 (proper documentation must 
be provided to confirm non-WOCBP status)
OR

A WOCBP who is not pregnant (ie, has a negative serum pregnancy 
test result at the Screening visit and has a negative serum or urine 
pregnancy test result at the Baseline visit), and agrees to follow the 
contraceptive guidance in Appendix 7 during the intervention period
5.
Informed Consent
5.01
Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol
5.02
Written informed consent from the participant has been obtained prior to any 
study-related procedures
6.
Other
6.01
Able, as assessed by the investigator, and willing to follow study instructions and 
likely to complete all required study visits

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5.2.2.
Exclusion Criteria for Stage 2
Participants are excluded from Stage 2 of the study if any of the following criteria apply:
1.
Medical Conditions
1.01
Current diagnosis of glaucoma or ocular hypertension; evidence of glaucoma or mean 
(or median) intraocular pressure > 21 mm Hg determined by Goldmann applanation 
tonometry, in either eye at the Screening visit
1.02
History or presence of any ocular disorder or condition (other than DED) in either 
eye that would, in the opinion of the investigator, likely interfere with the 
interpretation of the study results or participant safety, such as: significant corneal or 
conjunctival scarring; pterygium or nodular pinguecula; conjunctivitis, or 
inflammation not associated with DED; anterior (epithelial) basement membrane 
corneal dystrophy or other clinically significant corneal dystrophy or degeneration; 
evidence of keratoconus; etc. (Note: Blepharitis and/or Meibomian gland disease not 
requiring treatment are allowed.)
1.03
Diagnosis of recurrent, ongoing, or active ocular infection including, but not limited 
to herpes simplex or zoster, vaccinia, varicella, tuberculosis of the eye, 
acanthamoeba, or fungal disease
1.04
History of ocular surgery within 12 months prior to the Screening visit, including 
punctal cautery, corneal refractive, or anterior segment surgeries that affect corneal 
sensitivity (eg, cataract surgery or any surgery involving limbal or corneal incision)
1.05
Have had a corneal transplant in either or both eyes
1.06
At the Screening visit, at the investigator’s discretion, have active or uncontrolled, 
severe:

Systemic allergy

Chronic seasonal allergies at risk of being active during the study

Rhinitis or sinusitis 

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1.07
History or presence of significant cardiovascular, pulmonary, hepatic, renal, 
hematologic, coagulation, gastrointestinal, endocrine, immunologic, dermatologic, 
ophthalmologic, neurologic or psychiatric disease. Significant is defined as any 
disease that, in the assessment of the investigator, would put safety of the participant 
at risk through participation, or which would prevent or confound protocol-specified 
assessments (eg, severe Sjögren’s syndrome, severe rheumatoid arthritis, severe 
systemic lupus erythematosus, uncontrolled immunodeficiency disease, etc.)
2.
Prior/Concomitant Therapy
2.01
Use of artificial tears within 24 hours prior to the Screening visit or anticipated use 
during the study, with the exception of 
2.02
Use of systemic immunomodulators (eg, hydroxychloroquine, methotrexate, 
cyclosporine) within 3 months prior to the Screening visit or anticipated use during 
the study  
2.03
Use of corticosteroids administered through any route within 3 months prior to the 
Screening visit or anticipated use during the study
2.04
Use of cyclosporine administered through any route within 3 months prior to the 
Screening visit or anticipated use during the study
2.05
Use of topical ocular glaucoma medications or topical ocular allergy medications 
(over-the-counter [OTC], herbal, prescription, or nutritional supplements including 
all mast cell stabilizers and antihistamines) within 30 days prior to the Screening 
visit or anticipated use during the study
2.06
Use of Xiidra (lifitegrast ophthalmic solution, 5%) within 3 months prior to the 
Screening visit; or anticipated use during the study, with the exception of those 
participants who are randomized to receive Xiidra during the study
2.07
Use of TrueTear within 14 days prior to the Screening visit or anticipated use during 
the study
2.08
Use of medications associated with the treatment of severe DED and/or Meibomian 
gland disease such as oral antimuscarinics, cevimeline, oral macrolides, 
tetracyclines, tetracycline derivatives, and retinoids within 3 months prior to the 
Screening visit or anticipated use during the study  
2.09
Use of contact lenses in either eye within 14 days prior to the Screening visit or 
planned use during the study

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2.10
Punctal or intracanalicular plug present in either eyelid within 1 year of the 
Screening visit or anticipated plug insertion or occlusion at any time during the study
2.11
Use of lid-heating therapy (ie, LipiFlow, iLUX, etc), Meibomian gland probing, or 
therapeutic Meibomian gland expression in either eye within 6 months prior to the 
Screening visit or anticipated use during the study
2.12
The start date of any systemic medication (including OTC, herbal, prescription, or 
nutritional supplements), which may affect DED or vision is < 3 months prior to the 
Screening visit or a change in dosage is anticipated during the study. Systemic 
medications, which may affect DED or vision, include but are not limited to the 
following: antihistamines, cholinergic agents, anticholinergics, beta blocking agents, 
tricyclic antidepressants and phenothiazines
2.13
The start date of hormone replacement therapy program, oral or transdermal 
contraception, other estrogen or progesterone treatments, or other medications 
required for long-term treatment of chronic diseases is < 3 months prior to the 
Screening visit or a change in dosage is anticipated during the study
2.14
The start date of any androgen therapy is < 3 months prior to the Screening visit or a 
change in dosage is anticipated during the study
2.15
Use of inhalable or ingestible cannabis products, or transdermal patches containing
THC within 30 days prior to the Screening visit or anticipated use during the study
3.
Prior/Concurrent Clinical Study Experience
3.01
Current enrollment in an investigational drug, device, or any observational study or 
participation in such a study within 30 days prior to the Screening visit 
3.02
Participation in a blood or plasma donation program within 60 or 30 days, 
respectively, prior to study intervention administration, or anticipated participation 
during the study
4.
Other
4.01
Known allergies or sensitivity to the study interventions or study diagnostic agents 
.
4.02
The participant has a condition or is in a situation that, in the investigator’s opinion, 
may put the participant at significant risk, may confound the study results, or may 
interfere significantly with the participant’s participation in the study

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4.03
Positive test results for anti–HIV type 1 and 2, hepatitis B surface antigen, or 
anti-hepatitis C virus at Screening visit
4.04
Positive test results for benzoylecgonine (cocaine), methadone, barbiturates,
amphetamines, benzodiazepines, alcohol, cannabinoids, opiates, or phencyclidine at 
the Screening or Baseline visits
4.05
Positive pregnancy test at Screening or Baseline visits
4.06
Currently breastfeeding or plans to breastfeed during the study 
4.07
Has symptoms that, in the opinion of the investigator, may be associated with 
COVID-19 or in the last 14 days came into contact with someone diagnosed with 
COVID-19
5.3.
Lifestyle Considerations
5.3.1.
Meals and Dietary Restrictions
Participants will be instructed to fast (ie, water only) for at least 10 hours prior to blood 
collection for safety laboratory tests. Fasting will not be required for the blood PK sample 
collections. In Stage 2, fasting will not be required.
In Stage 1, participants will be served meals at appropriate times at Visits 3 and 5.
5.3.2.
Caffeine, Alcohol, Tobacco, and Cannabis
Participants must abstain from drinking alcohol for at least 3 days before each blood collection 
for safety laboratory tests (Stage 1: Visits 1 and 5 or Early Termination; Stage 2: Visits 1, 3, 5, 6, 
or Early Termination). This will not be required for the blood PK sample collections.
There are no restrictions on the consumption of caffeine or use of tobacco. However, the 
participant’s current smoking status or use of nicotine-containing products will be assessed at the 
Screening visit and recorded on the eCRF.
Participants must abstain from using inhalable or ingestible cannabis products or transdermal 
patches containing THC for at least 30 days before the Screening Visit and throughout the 
duration of the study. 
5.3.3.
Activity
Participants must abstain from strenuous exercise for at least 12 hours before each blood 
collection for safety laboratory tests. This will not be required for the blood PK sample 
collections.

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6.5.1.
Prohibited Interventions and Washout Before the Study
Participants must discontinue the use of any of the medications or interventions listed in 
Table 6-2 or Table 6-3 in both eyes for the specified period prior to the Screening visit. 
Table 6-2
Stage 1: Required Washout Intervals for Prohibited Medications or Interventions
Prior to the Screening Visit
Drug Class/Treatment
Washout Required Prior to the Screening Visit
Artificial tears
24 hours
Systemic immunomodulators (eg, hydroxychloroquine, 
methotrexate, cyclosporine)
14 days
Corticosteroids administered through any route
7 days
Topical ophthalmic cyclosporine 
7 days
Lifitegrast ophthalmic solution (Xiidra)
7 days
TrueTear
7 days
Topical ocular glaucoma medications or topical ocular 
allergy medications (OTC, herbal, prescription, or 
nutritional supplements including all mast cell stabilizers 
and antihistamines)
7 days
Medications associated with the treatment of severe 
DED and/or Meibomian gland disease such as oral 
antimuscarinics, cevimeline, oral macrolides, 
tetracyclines, tetracycline derivatives, and retinoids
14 days
Contact lenses
14 days
Punctal or intracanalicular plugs
1 year
Lid-heating therapy, Meibomian gland probing, or 
therapeutic Meibomian gland expression
3 months
Systemic medication (including OTC, herbal, 
prescription, or nutritional supplements) which may 
affect DED or vision, including but not limited to:
antihistamines, cholinergic agents, anticholinergics, beta 
blocking agents, tricyclic antidepressants and
phenothiazines
7 days if the medication was stopped or dosage 
changeda
Hormone replacement therapy program, oral or 
transdermal contraception, other estrogen, or 
progesterone treatments, or other medications required 
for long-term treatment of chronic diseases
7 days if the medication was stopped or dosage 
changeda
Any androgen therapy
7 days if the medication was stopped or dosage 
changeda
Inhalable or ingestible cannabis products or transdermal 
patches containing THC
30 days
a
The use of these medications is allowed during Stage 1 of the study provided that the dosing regimen is stable for at least 7
days prior to the Screening visit and does not change at any time during the study.

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Table 6-3
Stage 2: Required Washout Intervals for Prohibited Medications or Interventions
Prior to the Screening Visit 
Drug Class/Treatment
Washout Required Prior to the Screening Visit
Artificial tears
24 hours
Systemic immunomodulators (eg, hydroxychloroquine, 
methotrexate, cyclosporine)
3 months
Corticosteroids administered through any route
3 months
Cyclosporine administered through any route
3 months
Lifitegrast ophthalmic solution (Xiidra)
3 months
TrueTear
14 days
Topical ocular glaucoma medications or topical ocular allergy 
medications (OTC, herbal, prescription, or nutritional 
supplements including all mast cell stabilizers and 
antihistamines)
30 days
Medications associated with the treatment of severe DED
and/or Meibomian gland disease such as oral antimuscarinics, 
cevimeline, oral macrolides, tetracyclines, tetracycline 
derivatives, and retinoids
3 months
Contact lenses
14 days
Punctal or intracanalicular plugs
1 year
Lid-heating therapy, Meibomian gland probing, or therapeutic 
Meibomian gland expression
6 months
Systemic medication (including OTC, herbal, prescription, or 
nutritional supplements) which may affect DED or vision, 
including but not limited to: antihistamines, cholinergic 
agents, anticholinergics, beta blocking agents, tricyclic 
antidepressants and phenothiazines
3 months if the medication was stopped or dosage 
changeda
Hormone replacement therapy program, oral or transdermal 
contraception, other estrogen, or progesterone treatments, or 
other medications required for long-term treatment of chronic 
diseases
3 months if the medication was stopped or dosage 
changeda
Any androgen therapy
3 months if the medication was stopped or dosage 
changeda
Inhalable or ingestible cannabis products or transdermal 
patches containing THC
30 days
a
The use of these medications is allowed during Stage 2 of the study provided that the dosing regimen is stable for at least 
3 months prior to the Screening visit and does not change at any time during the study.
6.5.2.
Permitted Interventions
Therapy considered necessary for the participant’s welfare may be given at the discretion of the 
investigator. If the permissibility of a specific medication/intervention is in question, please 
contact the sponsor.

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8.1.2.2.
Conjunctiva 
Hyperemia
Bulbar and palpebral hyperemia will be graded separately. Grading will be based on comparison 
to the appearance of standard photographs (Allergan Bulbar Hyperemia Grading Guide), 
illustrating none, trace, mild, moderate, and severe hyperemia as described in Table 8-3. No lid 
retraction is to be performed when examining the conjunctiva. 
Table 8-3
Allergan Bulbar Hyperemia Grading Guide Photo Descriptions (Conjunctiva)
Grade
Grade Equivalent
Description
0
None
Normal. Vessels of bulbar conjunctiva easily observed
+ 0.5
Trace
Trace flush, reddish pink
+ 1
Mild
Mild flush, reddish color
+ 2
Moderate
Bright red color 
+ 3
Severe
Deep, bright diffuse redness
Following grading of hyperemia, the presence and severity of edema and subconjunctival 
hemorrhage in either the bulbar or palpebral conjunctiva are to be assessed using the scales in
Table 8-4 and Table 8-5, respectively.
Table 8-4
Grading Scale for the Presence and Severity of Edema (Conjunctiva)
0
None
No edema
+0.5
Trace
Localized, minimal (trace) swelling
+1
Mild
Localized, mild swelling
+2
Moderate
Diffuse, moderate swelling  
+3
Severe
Diffuse, severe swelling
Table 8-5
Grading Scale for the Presence and Severity of Subconjunctival Hemorrhage 
(Conjunctiva)
0
None
No hemorrhage
+0.5
Trace
Flat hemorrhage ≤ 1 quadrant
+1
Mild
Elevated hemorrhage ≤ 1 quadrant, or flat and > 1 quadrant
+2
Moderate
Elevated hemorrhage > 1 but ≤ 2 quadrants
+3
Severe
Elevated hemorrhage > 2 quadrants
8.1.2.3.
Cornea 
The grading scales for corneal edema and superficial punctate keratopathy are shown in 
Table 8-6 and Table 8-7, respectively.

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Table 8-6
Edema Grading Scale (Cornea)
0
None
No edema 
+0.5
Trace
Localized, minimal (trace) epithelial haze
+1
Mild
Dull glass appearance of epithelium that may include fine localized microcystic 
changes
+2
Moderate
Dull glass appearance of epithelium with large number of cystic changes with or 
without stromal edema
+3
Severe
Epithelial bullae and/or stromal edema, localized or diffuse, with or without 
stromal striae
Table 8-7
Grading Scale for Superficial Punctate Keratopathy (Cornea)
0
=
No superficial punctate keratopathy
+0.5
=
Trace
+1
=
Mild
+2
=
Moderate
+3
=
Severe
8.1.2.4.
Anterior Chamber 
For the measurements of cells and flare based on standardized uveitis nomenclature 
(SUN Working Group, 2005), the settings in Table 8-8 must be used. The scales for the 
measurement of anterior chamber cells and flare are shown in Table 8-9 and Table 8-10, 
respectively. 
Table 8-8
Settings for Measurements of Cells and Flare in the Anterior Chamber

1 x 1 mm slit 

High magnification

Highest slit lamp voltage 

Low ambient lighting

Illumination angle of 45 degrees

Same grader and slit lamp whenever possible
Table 8-9
Grading Scale for Cells in the Anterior Chamber
0
=
0 cells 
+0.5
=
1 to 5 cells (trace) 
+1
=
6 to 15 cells
+2
=
16 to 25 cells
+3
=
26 to 50 cells
+4
=
> 50 cells 

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Table 8-10
Grading Scale for Flare in the Anterior Chamber
0
=
None:  no flare seen
+1
=
Faint:  faint flare seen
+2
=
Moderate:  iris and lens details clear
+3
=
Marked:  iris and lens details hazy
+4
=
Intense:  fibrin or plastic aqueous
8.1.2.5.
Iris/Pupil
The iris/pupil will be evaluated for pathology. If pathology is present, it will be described.
8.1.3.
Intraocular Pressure
The IOP must be measured only after the biomicroscopic exam is completed and must be 
measured prior to pupil dilation. At least 2 measurements will be taken by qualified study site 
personnel using a Goldmann applanation tonometer affixed to a slit lamp with the participant 
seated. If the 2 independent measurements differ by ≤ 2 mm Hg, a third measurement is not 
required, and the 2 measurements will be recorded. If the first 2 measurements differ by 
> 2 mm Hg, a third measurement must be made, and all 3 measurements will be recorded. The 
mean of the 2 or median of the 3 measures will be used to determine participant eligibility as per 
the exclusion criteria.
8.1.4.
Dilated Fundus Exam
Biomicroscopic examination, indirect lenses, direct/indirect ophthalmoscopy, etc. are to be used 
as appropriate to visualize. Dilating drops should not be administered until slit lamp
biomicroscopy and IOP measurements are completed.  
8.1.4.1.
Lens
Lens Status
Lens status will be assessed as phakic, pseudophakic, or aphakic. The lens (including the 
posterior capsule for participants who have undergone lens extraction) will also be evaluated for 
pathology. If pathology is present, it will be described.
Cataract Assessment (phakic eyes only)
Under dilated examination, the presence and severity of nuclear, cortical and posterior 
subcapsular cataract lens opacities will be evaluated. At the first dilated examination, each type 
of cataract, if present, will be graded using the scale below. At the last follow-up dilated 
examination, each type of cataract will be assessed for change from baseline and if changed, the 
current severity will be graded using the scale in Table 8-11.

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Table 8-11
Grading Scale for Cataract Assessment
0
=
None
+1
=
Mild
+2
=
Moderate
+3
=
Severe
8.1.4.2.
Vitreous
The vitreous will be evaluated for pathology. If pathology is present, it will be described. Note if 
the condition is not evaluable.
8.1.4.3.
Fundus
The fundus (posterior pole; periphery, when dilated) will be evaluated for pathology. If 
pathology is present, it will be described. Note if the condition is not evaluable.
8.1.4.4.
Optic Nerve
The optic nerve will be evaluated for pathology. If pathology is present, it will be described. 
Note if the condition is not evaluable.
The cup/disc ratio will be reported using a 0.0 to 1.0 scale. The Armaly chart, supplied by the 
sponsor, provides a pictorial scale of cup/disc ratio of 0.0 to 0.8. Note if the condition is not 
evaluable.
8.1.5.
Physical Examinations
The physical examination will consist of a routine evaluation of organ systems including: 
head/EENT (eye, ear, nose, and throat), neck, cardiovascular, pulmonary, abdomen, 
skin/extremities, neurological, lymph nodes, and musculoskeletal. At the Exit visit, the physical 
exam will also include a query of the participant to determine whether changes in physical 
condition have occurred since the Screening examination.
8.1.6.
Vital Signs
Systolic and diastolic blood pressure will be measured using an appropriate sphygmomanometer 
after participants have been at rest (seated) for at least 5 minutes. Blood pressure will be 
recorded in mm Hg.
Pulse rate will be measured in beats per minute (bpm) after the participant has been in a resting 
state (seated) for at least 5 minutes. 
Respiration rate will be measured after the participant has been in a resting state (seated) for at 
least 5 minutes and will be assessed over a 60 second interval.

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8.1.9.
Pregnancy Test (WOCBP Only)
All WOCBP will have serum pregnancy tests performed at the Screening visit. At all other visits 
where a pregnancy test is required, either serum or urine test may be used based on site 
preference.
The definitions of WOCBP and female participants not considered WOCBP, along with the 
required documentation needed to waive the need for pregnancy testing, are provided in 
Appendix 7.
8.1.10.
Other Assessments
Drop Tolerability Questionnaire
Participants will be asked to rate the acute overall tolerability attributes of study interventions on 
an 8-question visual analog scale (VAS) Drop Tolerability Questionnaire. Rating will commence 
5 (± 1) minutes after the in-office eye drop administration. Participants will be instructed to mark 
a vertical line on the anchored VAS that best captures their experience with the study eye drops. 
This is an overall evaluation, not per eye. The questionnaire will include the following questions:

How comfortable are the study eye drops in your eyes?

How soothing are the study eye drops in your eyes?

How moistening/lubricating are the study eye drops in your eyes?

How clear is your vision with the study eye drops in your eyes?

How much stickiness do you have with the study eye drops in your eyes?

How much blur do you have with the study eye drops in your eyes?

How much burning/stinging do you have with the study eye drops in your eyes?

How much discomfort do you have with the study eye drops in your eyes?
Each question will be accompanied by the VAS scale. The assessment line length of the scale 
will be 100 mm and will be similar to the following depiction (Figure 8-1). 
Figure 8-1
Drop Tolerability Questionnaire: Visual Analog Scale Assessment
How comfortable are the study eye drops in your eyes?
__________________________________________
0
100
(Not at all comfortable) 
(Very comfortable)

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8.2.6.
AEs of Special Interest
The AESI that warrant ongoing monitoring and rapid communication by the investigator to the 
sponsor are outlined in Appendix 3.
8.2.7.
Medication Errors
Medication error refers to any unintended error in the dosing and/or administration of the study 
intervention as per instructions in the protocol. Medication errors generally fall into 4 categories 
as follows:

Wrong study intervention

Wrong dose (including dosing regimen, strength, form, concentration, amount)

Wrong route of administration, including wrong site of administration (eg, wrong eye)

Wrong participant (ie, not administered to the intended participant)
8.3.
Treatment of Overdose
Treatment of overdose is not applicable to this ophthalmology study.
8.4.
Pharmacokinetics
As indicated in the SoA (Section 1.3), at each timepoint, the blood sample will be collected first, 
followed by collection of the tear samples for biomarker analysis (if applicable) and PK analysis.
8.4.1.
Pharmacokinetic Blood Draw Schedule
Blood samples for PK analysis will be collected according to the schedules presented in 
Table 8-12 and Table 8-13. A single blood sample will also be collected at Early Termination 
visit in both stages, when applicable.
Table 8-12
Blood Sampling Schedule for Pharmacokinetics – Stage 1
Blood Sampling Time
Visit 2
(Day 1)
Visit 3
(Day 2)
Visit 4
(Day 8)
Visit 5
(Day 15)
Prior to the morning dose: 0 hour (predose)
X
X
X
X
Following the morning dose: 0.5 h ± 5 min
X
Following the morning dose: 0.5 h ± 5 min, 1 h ± 5 min, 
2 h ± 15 min, 4 h ± 15 min, 8 h ± 30 min, 12 h ± 30 min
X
X

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Table 8-13
Blood Sampling Schedule for Pharmacokinetics – Stage 2
Blood Sampling Time
Visit 3
(Day 1)
Visit 4
(Day 14)
Visit 5
(Day 28)
Visit 6
(Day 42)
Prior to the morning dose (prior to CAE exposure)
X
X
X
X
Following the morning dose: at 0.5 h ± 5 min
X
X
CAE = controlled adverse environment
Blood samples to determine plasma AGN-242428 and AGN-231868 concentrations should be 
drawn at the nominal times specified in Table 8-12 for Stage 1 and Table 8-13 for Stage 2, 
relative to dosing, and the actual time of the blood draw must be recorded in the source 
documents and eCRFs. Samples taken outside of the specified time window in Table 8-12 and 
Table 8-13 will be noted as protocol deviations, and the reason for deviation must be recorded in 
the source documents and eCRFs. Predose samples will be drawn approximately at the time of 
predose tear sample collection and tear sample collection for biomarker analysis (see SoA in 
Section 1.3).
Study center staff will record the times of all blood draws for each participant and will label 
Vacutainer and polypropylene tubes with a coded label that corresponds to the participant 
number and blood draw time. 
Drug concentration information that may unmask the study will not be reported to investigative 
sites or masked personnel until the study has been unmasked.
Bioanalytical representatives will be unmasked for PK sample bioanalysis during the conduct of 
the study. The unmasking of bioanalytical representatives is to be carried out in a secure manner 
following the sponsor’s standard operating procedures. Extreme care and diligence will be taken 
to ensure no other individuals outside the bioanalytical team will be unmasked. Only blood 
samples collected from participants who received AGN-242428 or AGN-231868 are to be
analyzed.
The exact postdose sample collection time in Stage 2 may be adjusted based on PK data (Tmax) 
from Stage 1. The sponsor’s clinical pharmacology representative will remain masked for the 
analysis of Stage 1 data to provide the recommendation for blood sampling timepoint selection 
for Stage 2. The selected timepoints will remain the same for all intervention groups to retain 
masking. Any changes in the timing or addition of timepoints for any planned study assessments 
will ensure masking in Stage 2 and must be documented and approved by the relevant study team 
member and then archived in the sponsor and site study files but will not constitute a protocol 
amendment. 
8.4.2.
Pharmacokinetic Blood Sampling Procedure
Required blood collection tubes, processing instructions, and storage instructions will be 
provided in the Study Procedure Manual.

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8.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7.
Genetics
Genetics are not evaluated in this study.

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8.8.1.1.
Tear Sampling Procedure
Information on required tear collection methods, supplies, processing instructions, and storage 
instructions will be provided in the Study Procedure Manual.

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9.
Statistical Considerations
There will be an interim database lock at the end of Stage 1 and a final database lock after 
completion of Stage 2. Separate statistical analysis plans (SAPs) for each stage will be developed 
and finalized before the interim database lock for Stage 1 and before the final database lock for 
Stage 2 and will describe the participant populations to be included in the analyses, and 
procedures for accounting for missing, unused, and spurious data. This section is a summary of 
the planned statistical analyses for this study. 
Separate PK analysis plans will be developed for each stage and finalized before the interim 
database lock for Stage 1 and before the final database lock for Stage 2. 
9.1.
Statistical Hypotheses
No hypothesis testing will be performed. 
9.2.
Sample Size Determination
For Stages 1 and 2, the sample size is not based on statistical considerations and is determined 
empirically. 
9.3.
Populations for Analyses
The analysis populations will consist of participants as defined in Table 9-1.
Table 9-1
Analysis Populations
Population
Definition
Intent-to-Treat (ITT) 
(Stage 2)
All randomized participants in Stage 2. Participants will be summarized according to 
the randomized study intervention.
Pharmacokinetic (Stage 1)
All participants who have evaluable PK parameters in Stage 1
Pharmacokinetic (Stage 2)
All participants with available plasma or tear concentrations in Stage 2
Safety (Stages 1 and 2)
All participants who received ≥ 1 administration of study intervention for the stage
Biomarker (Stages 1 and 2)
All participants who have evaluable tear biomarker samples for the stage
Exploratory efficacy analyses will be performed on ITT population. PK analyses will be 
performed on PK population. Safety analyses will be performed on safety population.
 
9.4.
Statistical Analyses

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10.2.
Appendix 2: Clinical Laboratory Tests

The protocol-required tests detailed in Table 10-1 will be performed by the central 
laboratory. 

Nonprotocol-specified laboratory tests may be performed by the central laboratory or a local 
laboratory. The results from any local laboratory tests must be entered in the eCRF.

Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.

Additional tests may be performed at any time during the study as determined necessary by 
the investigator or required by local regulations.
Table 10-1
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet count
RBC indices:
MCV
MCH
MCHC
WBC count with differential (absolute):
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC count
Hemoglobin
Hematocrit
Clinical Chemistrya
BUN
Creatinine
Glucose (fastinge) 
Total protein 
Albumin
Potassium
Sodium
Calcium
Cholesterol
Chloride
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Alkaline phosphatase 
Total, direct and indirect bilirubin 
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase by 
dipstick
Microscopic examination (if blood or protein is abnormal)
Drugs of Abuseb
Benzoylecgonine (cocaine), methadone, barbiturates, amphetamines, benzodiazepines, 
alcoholc, cannabinoids, opiates, or phencyclidine at the Screening visit or Baseline
Serologyd
Hepatitis B surface antigen, anti-hepatitis C virus, and anti-human immunodeficiency 
virus type 1 and type 2
Pregnancy testb
(WOCBP only)
Serum β-hCG pregnancy test at Screening; serum or urine test on all other visits
a 
In Stage 1, blood samples will be collected following 10-hour fasting period. In Stage 2, fasting will not be required.
b
Urine dipstick kits may be used to conduct drugs of abuse and pregnancy tests; however, serum pregnancy test will be 
required at Screening
c
Breathalyzer may be used for alcohol
d
For screening purposes only
e
Fasting requirement is for Stage 1 only 
Investigators must document their review of each laboratory safety report.

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In addition, a potential Hy’s Law case is also an AESI. Criteria for potential Hy’s Law cases 
are as follows:

ALT and/or AST ≥ 3 × ULN AND

TBL ≥ 2 × ULN AND

Alkaline phosphatase < 2 × ULN
Study site personnel must report every participant who meets these potential criteria. 
Typically, all 3 analytes will be obtained from the same sample, but they may come from 
multiple samples taken within a 24-hour period. This requirement applies from the time the 
participant signs the ICF for the study until the Exit visit or Early Termination visit.
A laboratory alert for potential Hy’s Law cases will be in place and must notify investigators 
and the sponsor immediately when the above criteria have been met. A potential Hy’s Law 
case must be reported as a SAE by completing an Adverse Event of Interest Abnormal Liver 
Function Reporting Form and sent to IR-Clinical-SAE@allergan.com (or faxed to the SAE fax 
number) as soon as possible (within 24 hours of learning of the potential Hy’s Law case). The 
eCRF for potential Hy’s Law cases must be completed within 7 calendar days. Every effort to 
determine the cause of the liver enzyme abnormalities must be made, and close monitoring 
should be initiated in conjunction with the MSP and in accordance with the FDA Guidance for 
Industry, Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009.

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d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle), which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.
Examples of such events include invasive or malignant cancers, intensive intervention in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse.

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10.4.
Appendix 4: Abbreviations
Abbreviation
Definition
λz
terminal elimination rate constant
AE
adverse event
AESI
adverse event of special interest
AI
accumulation index
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the curve
AUC0-tlast
area under the plasma or tear concentration versus time curve from time 0 to time of 
the last measurable concentration
AUC0-τ
area under the plasma or tear concentration versus time curve from time 0 to the end 
of the dosing interval
BCVA
best-corrected visual acuity
BID
twice daily
BUN
blood urea nitrogen
CAE
controlled adverse environment
CCR
C-C motif chemokine receptor
Cmax
maximum plasma or tear drug concentration
Cmin,ss
minimum plasma or tear drug concentration at steady state
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CRF
case report form
DED
dry eye disease
DMC
data monitoring committee
EAE
experimental autoimmune encephalomyelitis
ECG
electrocardiogram
eCRF
electronic case report form
ETDRS
Early Treatment Diabetic Retinopathy Study
FDA
Food and Drug Administration
FIH
first-in-human
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
hCG
human chorionic gonadotropin
HRT
hormonal replacement therapy
IC50
50% inhibitory concentration 
ICF
informed consent form

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Abbreviation
Definition
ICH
International Council on Harmonisation
IND
investigational new drug
IRB
institutional review board
ITT
intent-to-treat
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IWRS
interactive web response system
LFT
liver function test
MCV
mean corpuscular volume
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MSP
medical safety physician
NA
not applicable
NOAEL
no observed adverse effect level
OD
right eye
OS
left eye
OTC
over-the-counter
PCS
potentially clinically significant
PK
pharmacokinetic
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SoA
schedule of activities
t1/2
terminal elimination half-life
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
THC
tetrahydrocannabinol
Tmax
time of maximum plasma drug concentration
ULN
upper limit of normal
WBC
white blood cell
WOCBP
woman of childbearing potential

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10.5.
Appendix 5: Standard Discontinuation Criteria
This table provides participant discontinuation criteria for this protocol. CDISC terminology is 
used, and thus subject or patient is used instead of participant (as used elsewhere in this 
protocol). These terms are interchangeable.  
CDISC Submission Value
CDISC Definition
Adverse event
Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and 
which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, 
whether or not related to the medicinal (investigational) product. 
For further information, see the ICH Guideline for Clinical Safety 
Data Management: Definitions and Standards for Expedited 
Reporting (modified from ICH E2A) Synonyms: side effect, 
adverse experience. See also serious adverse event, serious adverse 
experience. (CDISC glossary)
Death
The absence of life or state of being dead (NCI)
Disease relapse
The return of a disease after a period of remission
Failure to meet randomization criteria
An indication that the subject has been unable to fulfill/satisfy the 
criteria required for assignment into a randomized group
Lost to follow-up
The loss or lack of continuation of a subject to follow-up
Noncompliance with study drug
An indication that a subject has not agreed with or followed the 
instructions related to the study medication (NCI)
Other
Different than the one(s) previously specified or mentioned (NCI)
Physician decision
A position, opinion, or judgment reached after consideration by a 
physician with reference to subject (NCI)
Pregnancy
Pregnancy is the state or condition of having a developing embryo 
or fetus in the body (uterus), after union of an ovum and 
spermatozoon, during the period from conception to birth. (NCI)
Progressive disease
A disease process that is increasing in extent or severity (NCI)
Protocol deviation
An event or decision that stands in contrast to the guidelines set out 
by the protocol (NCI)
Screen failure
The potential subject who does not meet one or more criteria 
required for participation in a trial
Site terminated by sponsor
An indication that a clinical study was stopped at a particular site 
by its sponsor (NCI)
Study terminated by sponsor
An indication that a clinical study was stopped by its sponsor 
(NCI)
Technical problems
A problem with some technical aspect of a clinical study, usually 
related to an instrument (NCI)
Withdrawal by subject
An indication that a study participant has removed itself from the 
study (NCI)

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10.6.
Appendix 6: Study Tabular Summary
This table is intended for use in posting study information to registries (eg, ClinicalTrials.gov).  
Parameter Group
Parameter
Value
Trial information
Trial Title
A Multicenter, Vehicle-controlled, 
Double-Masked, Randomized Study to Evaluate 
the Safety, Tolerability, Pharmacokinetics, and 
Exploratory Efficacy of AGN-242428 and 
AGN-231868 in Participants with Dry Eye 
Disease
Clinical Study Sponsor
Allergan Sales LLC
Trial Phase Classification
Phase 1/2a trial
Trial Indication
Dry eye disease
Trial Indication Type
Treatment
Trial Type
Exploratory Efficacy
Safety
Tolerability
Pharmacokinetics
Trial Length
The approximate duration of participation for 
each participant in the study: 
Stage 1: 1 month
Stage 2: 2.5 months
Planned Country of Investigational 
Sites
United States
Planned Number of Subjects
Stage 1: 72
Stage 2: 250
FDA-regulated Device Study
No
FDA-regulated Drug Study
Yes 
Pediatric Study
No
Subject 
information
Diagnosis Group
Dry eye disease
Healthy Subject Indicator
No
Planned Minimum Age of Subjects
18 years
Planned Maximum Age of Subjects
Not applicable
Sex of Participants
Both
Stable Disease Minimum Duration
Not applicable

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Parameter Group
Parameter
Value
Randomization Quotient
Stage 1: Cohort 1a – 3:3:1:1 (
 
AGN-242428, 
 AGN-231868, or their 
respective vehicles) 
Stage 1: Cohort 1b – 3:3:1:1 (
 
AGN-242428, 
 AGN-231868, or their 
respective vehicles)
Stage 1: Cohort 1c – 3:3:1:1 ( 
 
AGN-242428, 
 AGN-231868, or their 
respective vehicles)
Stage 2: Participants will be randomized 
1:1:1:1:1 within each site (AGN-242428, 
AGN-242428 vehicle, AGN-231868, 
AGN-231868 vehicle, or Xiidra)
Trial Blinding Schema
Double masked
Stratification Factor
No
Adaptive Design
No
Study Stop Rules
Study intervention dosing may be paused due to 
safety concerns at any time by the site 
investigator. The sponsor may stop the study 
(and/or the study site) for any reason with 
appropriate notification.

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Nonvasectomized male participants with a pregnant or breastfeeding partner must agree to 
remain abstinent from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration for the duration of the study.
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 10-2.
Table 10-2
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependenta
Failure rate of < 1% per year when used consistently and correctly
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation

Oral 

Intravaginal 

Transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation

Oral 

Injectable 
Highly Effective Methods That Are User Independenta

Implantable progestogen-only hormonal contraception associated with inhibition of ovulation

IUD

IUS

Etonogestrel implant (ie, Nexplanon®)

Bilateral tubal occlusion (eg, Essure®, bilateral tubal ligation)

Intrauterine copper contraceptive (ie, ParaGard®)
Vasectomized Partner 
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male 
sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used.
Sexual Abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the participant.
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies.