Clinical trial NCT04030962
Conditions: Dry Eye Disease Dry Eye Syndrome
Sponsor: AbbVie
Start date: 2020-03-04; Completion date: 2022-03-18
Enrollment: 292 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a 2-stage study in which Stage 1 evaluated the safety of AGN-242428 and AGN-231868, how well they are tolerated, and how they move through the body when administered. After the sponsor's determination of adequate safety and tolerability of the interventions in Stage 1, Stage 2 began. Stage 2 also evaluated the safety and tolerability of AGN-242428 and AGN-231868, how effective they are in treating dry eye disease (DED), and assessed the plasma and tear exposure of both ophthalmic solutions.

Detailed description:
Participants with DED in Cohort 1A were randomized 3:3:1:1 to receive AGN-242428 (Low Dose), AGN-231868 (Low Dose), or their respective vehicles (4 treatment groups total) to the left eye on Day 1 (Visit 2). If there were no significant study drug-related safety findings, starting on Day 2, participants administered the same randomized study drug twice daily to both eyes through Day 14, followed by a single dose administration to both eyes on Day 15 (Visit 5).

Upon completion of Cohort 1A, an independent data monitoring committee reviewed the data before proceeding to the next cohort. Cohort 1B participants were randomized 3:3:1:1 to receive AGN-242428 (High Dose), AGN-231868 (High Dose), or their respective vehicles (4 treatment groups total) and followed the same dosing regimen used in Cohort 1A.

All subjects enrolled in Stage 2 had DED. In addition, subjects were selected based on their response to a controlled adverse environment (CAE). Only subjects with DED who responded to the CAE exposure with an increase in the signs and symptoms of DED were enrolled in Stage 2.

During Stage 2, participants were randomized in a 1:1:1:1:1 ratio (within each site), to receive AGN-242428 (High Dose), AGN-242428 vehicle, AGN-231868 (High Dose), AGN-231868 vehicle, or Lifitegrast Ophthalmic Solution (Xiidra). Participants administered the assigned study drug in each eye twice daily for 41 days, followed by a single administration during the morning on Day 42.

Arms: arm 1: Administration of AGN-242428 ophthalmic solution arm 2: Administration of matching placebo (vehicle) ophthalmic solution arm 3: Administration of AGN-231868 ophthalmic solution arm 4: Administration of matching placebo (vehicle) ophthalmic solution arm 5: Administration of AGN-242428 ophthalmic solution arm 6: Administration of matching placebo (vehicle) ophthalmic solution arm 7: Administration of AGN-231868 ophthalmic solution arm 8: Administration of matching placebo (vehicle) ophthalmic solution arm 9: Administration of AGN-242428 ophthalmic solution arm 10: Administration of matching placebo (vehicle) ophthalmic solution arm 11: Administration of AGN-231868 ophthalmic solution arm 12: Administration of matching placebo (vehicle) ophthalmic solution arm 13: Administration of Lifitegrast ophthalmic solution
Interventions: intervention 1: AGN-242428 intervention 2: AGN-231868 intervention 3: AGN-242428 Vehicle intervention 4: AGN-231868 Vehicle intervention 5: Lifitegrast 5% Ophthalmic Solution
Intervention descriptions: intervention 1: Ophthalmic solution administered as a topical eye drop intervention 2: Ophthalmic solution administered as a topical eye drop intervention 3: Matching placebo (vehicle) ophthalmic solution administered as a topical eye drop intervention 4: Matching placebo (vehicle) ophthalmic solution administered as a topical eye drop intervention 5: Ophthalmic solution administered as a topical eye drop

Protocol documents:
Prot_000.pdf: 


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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Protocol 2012-201-005 Amendment 3
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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


CONFIDENTIAL
Protocol 2012-201-005 Amendment 3
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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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Protocol 2012-201-005 Amendment 3
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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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Protocol 2012-201-005 Amendment 3
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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. 









SAP_001.pdf: 
AGN-242428 and AGN-231868
2012-201-005 – Statistical Analysis Plan (Stage 2)
Version 1.0 – 07 December 2021
1
Statistical Analysis Plan for Study 2012-201-005 
Stage 2
A Multicenter, Vehicle-controlled, Randomized Study 
to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of AGN-242428 and 
AGN-231868 in Participants with Dry Eye Disease
Date:  07 December 2021
Version 1.0
 
NCT04030962


AGN-242428 and AGN-231868
2012-201-005 – Statistical Analysis Plan (Stage 2)
Version 1.0 – 07 December 2021
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Table of Contents
1.0
Introduction .............................................................................5
2.0
Study Design and Objectives..................................................5
2.1
Objectives and Hypothesis.........................................................................5
2.2
Study Design Overview .............................................................................6
2.3
Treatment Assignment and Masking .........................................................8
2.4
Sample Size Determination........................................................................9
3.0
Endpoints..................................................................................9
3.1
Safety Endpoints ........................................................................................9
3.2
Secondary endpoints ................................................................................10
3.3
.................................................10
4.0
Analysis Populations .............................................................11
5.0
Subject Disposition................................................................12
6.0
Study Drug Duration and Compliance................................13
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ....................13
7.1
Demographics and Baseline Characteristics............................................13
7.2
Medical History .......................................................................................13
7.3
Prior and Concomitant Medications ........................................................14
8.0
Efficacy Analyses...................................................................14
8.1
General Considerations............................................................................14
8.2
Handling of Missing Data........................................................................15
8.3
8.3.1
8.3.2
8.3.3
8.3.4
8.4
9.0
Safety Analyses ......................................................................17
9.1
General Considerations............................................................................17
9.2
Adverse Events ........................................................................................18
9.2.1
Treatment-Emergent Adverse Events ......................................................18
 


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9.2.2
Adverse Event Overview .........................................................................19
9.2.3
Treatment-Emergent Adverse Events by SOC and/or PT .......................20
9.2.4
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation...............................................................................20
9.2.5
Adverse Events of Special Interest ..........................................................21
9.3
Analysis of Laboratory Data....................................................................21
9.4
Analysis of Vital Signs ............................................................................21
9.5
Analysis of Electrocardiograms...............................................................22
9.6
Analysis of Best-corrected Visual Acuity................................................22
9.7
Intraocular Pressure .................................................................................22
9.8
Biomicroscopy and Ophthalmoscopy......................................................22
9.9
Safety Subgroup Analyses (if applicable)................................................23
10.0
Interim Analyses....................................................................24
11.0
Version History......................................................................24
12.0
Appendices .............................................................................24
List of Tables
Table 1.
Stage 2 - Study Objectives and Assessments/Endpoints ...........................6
Table 2.
.................................................11
Table 3.
Analysis Populations................................................................................12
Table 4.
SAP Version History Summary...............................................................24
Table 5.
List of Preferred Terms for Adverse Events of Special Interest..............26
Table 6.
Potentially Clinically Significant Criteria for Clinical Laboratory 
Parameters................................................................................................27
Table 7.
Potentially Clinically Significant Criteria for Vital Signs 
Parameters................................................................................................28
Table 8.
Potentially Clinically Significant Criteria for ECG Parameters ..............29
List of Figures
Figure 1.
Study Schematic - Stage 2 .........................................................................8
 


AGN-242428 and AGN-231868
2012-201-005 – Statistical Analysis Plan (Stage 2)
Version 1.0 – 07 December 2021
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List of Appendices
Appendix A.
Protocol Deviations..................................................................................25
Appendix B.
Definition of Adverse Events of Special Interest ....................................26
Appendix C.
Potentially Clinically Significant Criteria for Safety Endpoints..............27
Appendix D.
List of Abbreviations ...............................................................................30
Appendix E.
Changes to Protocol-planned Analyses ...................................................31
 


AGN-242428 and AGN-231868
2012-201-005 – Statistical Analysis Plan (Stage 2)
Version 1.0 – 07 December 2021
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1.0
Introduction
This Statistical Analysis Plan (SAP) provides a technical and detailed elaboration of the 
statistical analyses of the efficacy and safety data for Stage 2 of this study as outlined and 
specified in the 2012-201-005 protocol amendment 3 (approved version dated 19 July 
2021). Specifications of tables, figures and data listings are contained in a separate 
document. Details of the analyses of pharmacokinetic data 
 
 will be documented separately before final database lock.
The SAP will not be updated in case of administrative changes or amendments to the 
protocol unless the changes impact the analysis.
Unless noted otherwise, all analyses will be performed using SAS Version 9.4 (SAS 
Institute Inc., Cary, NC  27513) or later under the Linux operating system.
2.0
Study Design and Objectives
2.1
Objectives and Hypothesis
This is the first-in-human study to evaluate the safety, tolerability, PK, and 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 future development of either or both compounds for the treatment of 
DED.
 


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Table 1.
Stage 2 - Study Objectives and Assessments/Endpoints
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 
post-dose (C0 5h)
Tertiary/Exploratory
2.2
Study Design Overview
This is a Phase 1/2a, multicenter, vehicle-controlled, double-masked, randomized study 
conducted in 2 consecutive stages in participants with DED.  Stage 1 was conducted at 
2 sites in the United States and Stage 2 will be conducted at up to approximately 8 sites in 
the United States. 
 


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Stage 1 was planned to evaluate the safety, tolerability, and PK (plasma and tear) of 
3 dose strengths of AGN-242428 (
) and AGN-231868 (
 
) in participants with DED. 
The AGN-242428 and AGN-231868 dose strengths used in Stage 2 were selected based 
on safety and tolerability assessed in Stage 1; the highest safe and tolerated dose strength 
of each intervention (AGN-242428
 and AGN-231868 
) was selected for testing 
in Stage 2.  All participants enrolled in Stage 2 will have DED.  In addition, participants 
will be selected based on their response to the controlled adverse environment (CAE).  
Only participants with DED who respond to the CAE with an increase in the signs and 
symptoms of DED will be enrolled in Stage 2. 
In Stage 2, 
 
 
 participants will undergo another assessment of the signs and symptoms 
of DED with and without the use of the CAE.  Only participants who requalify, based on 
inclusion/exclusion criteria, will be continued in the study.
 participants will be randomized at 
baseline, in a 1:1:1:1:1 ratio within each site, to receive AGN-242428, AGN-242428 
vehicle, AGN-231868, AGN-231868 vehicle, or Xiidra. 
All randomized participants will be administered 1 drop of assigned study intervention in 
each eye twice daily (approximately 12 hours apart) for 41 days, followed by a single 
dose administration on Day 42.  
 will be assessed on 
Day 42 with and without the use of the CAE.  In addition, 
 without 
the use of the CAE will be assessed on Days 1, 14 and 28.
Assuming no early termination, the duration of participation for each participant in this 
stage of the study will be approximately 2.5 months (up to 14 days prior to Visit 2 on 
Day -14 through the last assessment on Day 42).
 


AGN-242428 and AGN-231868
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Version 1.0 – 07 December 2021
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The Stage 2 schematic for the study is shown in Figure 1.
Figure 1.
Study Schematic - Stage 2
2.3
Treatment Assignment and Masking
Participants will be randomized to one of the following study interventions in a 1:1:1:1:1 
ratio:
●
AGN-242428
●
AGN-242428 vehicle 
●
AGN-231868 
 


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2012-201-005 – Statistical Analysis Plan (Stage 2)
Version 1.0 – 07 December 2021
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●
AGN-231868 vehicle 
●
Xiidra 
Randomization will not be stratified.  The study eye will be defined as 
 
 at baseline.  
If both eyes qualify and have 
, then study 
eye will be defined as the eye with 
.  If both eyes still 
qualify, the right eye will be designated as the study eye.  Unless otherwise specified, all 
the applicable assessments will be performed in both eyes.
 
 
 
  After randomization, the investigator, site staff, and 
participants will be masked to study intervention.
The AGN-242428, AGN-231868 and their vehicles will be provided in identical single-
use vials.  Xiidra will be supplied in single-use, commercially available vials that will 
have the original label overlaid with a new clinical label to prevent unmasking.  
2.4
Sample Size Determination
For Stages 1 and 2, the sample size is not based on statistical considerations and is 
determined empirically.  Approximately 322 participants (72 in Stage 1 and 250 in 
Stage 2) will be enrolled in the study.  No participant can be enrolled in more than 1 
cohort and/or stage of the study.
3.0
Endpoints
3.1
Safety Endpoints
Safety endpoints are listed as the following:
 


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●
adverse events (AEs),
●
clinical laboratory values at the Exit/Early Termination visit,
●
vital signs at each post-baseline visit,
●
electrocardiogram (ECG) findings at the Exit/Early Termination visit,
●
intraocular pressure (IOP) at each post-baseline visit,
●
best-corrected visual acuity (BCVA) at each post-baseline visit,
●
slit-lamp biomicroscopy findings at each post-baseline visit,
●
dilated fundus (ophthalmoscopy) examination findings at the Exit/Early 
Termination visit,
●
Drop Tolerability Questionnaire score at each post-baseline visit.
For eye-related endpoints, both eyes will be included in the analysis.
3.2
Secondary endpoints
The secondary endpoints are trough plasma or tear concentration (Ctrough) and plasma or 
tear concentration at 0.5 hours post-dose (C0.5h).  Details of endpoint and analysis will be 
included in a separate PK SAP.
3.3
Tertiary/Exploratory Efficacy Endpoints
 


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4.0
Analysis Populations
The analysis populations related to the statistical analysis detailed in this document will 
consist of participants as defined in Table 3.  Additional analysis populations, such as PK 
population and biomarker population will be described separately in other analysis plans. 
There are a run-in period and a randomized study intervention period in Stage 2. 
 


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Table 3.
Analysis Populations
Population
Definition
Intent-to-Treat (ITT) 
All participants who are randomized. Participants will be summarized 
according to the randomized study intervention. 
Safety 
All participants who receive ≥ 1 administration of study intervention for 
Stage 2.

Safety population in randomized study intervention period includes 
all participants who receive ≥ 1 administration of randomized study 
intervention. 

The safety analysis will mainly be performed based on safety 
population in randomized study intervention period. 

Participants will be summarized according to the study drug that they 
actually received.

Unless otherwise specified, study intervention and safety population 
will refer to the study intervention and safety population in 
randomized study intervention period in this SAP. 
5.0
Subject Disposition
The number of participants who are screened and enter the run-in period for the study will 
be provided.  The number of participants in the study populations (ITT population and 
Safety population) will be summarized by study intervention group.
The summary of study disposition post-randomization will be provided by study 
intervention group as randomized for the following:
●
Number of participants randomized (this frequency count will be used as the 
denominator to calculate the percentages described below)
●
Number and percentage of participants treated
●
Number and percentage of participants completing the study 
●
Number and percentage of participants discontinued from the study
●
Reasons for discontinuation from the study
In addition, a listing will be provided for participant disposition.  A participant is counted 
as completing the study if he/she has completed all study visits including Day 42 (Exit) 
 


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Visit.  Participants that exit the study prior to the Day 42 visit will be considered 
discontinued from the study.
6.0
Study Drug Duration and Compliance
The exposure to study intervention, calculated as (last study intervention date - first study 
intervention date + 1), will be summarized using descriptive statistics by study
intervention for the Safety population.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
7.1
Demographics and Baseline Characteristics 
Demographic parameters (age [years]; sex; race; ethnicity) will be summarized 
descriptively by study intervention group for the ITT population.
Baseline characteristics including 
 BCVA, IOP values and 
 
 
weight, height, and body mass index will be summarized descriptively by study 
intervention group for the ITT population. 
7.2
Medical History
Medical history including prior procedures data will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA), version 24.1 or higher.  The actual 
version of the MedDRA coding dictionary will be noted in the statistical tables and 
clinical study report. 
The number and percentage of participants in each medical history category (by MedDRA 
primary system organ class and preferred term) will be summarized.  The system organ 
class (SOC) will be presented in alphabetical order, and the preferred terms will be 
presented in alphabetical order within each SOC.  Participants reporting more than one 
condition/diagnosis will be counted only once in each row (SOC or preferred term).
 


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An ophthalmic history will be determined as indicated on the Medical History form of 
eCRF (marked "OD," "OS," or "OU" to the question of "What was the location of the 
medical history condition/event?").  The ophthalmic medical history will be summarized 
in a similar way to medical history. 
7.3
Prior and Concomitant Medications
Medication terms will be coded using the World Health Organization (WHO) Drug 
Dictionary (Version WHODDMAR21B3G).  The version of the dictionary will be noted 
in the statistical tables and clinical study report.
A prior medication is defined as any medication taken prior to the date of the first dose of 
study intervention.  A concomitant medication is defined as any medication that starts 
prior to the date of the first dose of study intervention and continues to be taken after the 
first dose of study intervention or any medication that starts on or after the date of the first 
dose of study intervention. 
The number and percentage of participants taking medications will be summarized by 
preferred drug name based on the World Health Organization (WHO) Drug Dictionary for 
both prior and concomitant medications, respectively.
 


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8.4
Efficacy Subgroup Analyses
No subgroup analyses are planned.
9.0
Safety Analyses
9.1
General Considerations
The below general considerations will be applied to safety analyses, unless specified 
otherwise.
●
Safety analyses will be based on safety data using the safety population based 
on the actual treatment received.
 


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●
A participant's actual treatment will be determined by the first dose of study 
drug.
●
In general, baseline is defined as the last non-missing scheduled assessment 
prior to the first administration of study intervention (non-missing assessment 
before Day 1 study intervention). 
●
The change from baseline values at a visit will be computed as the value for the 
post baseline visit minus the baseline value, unless otherwise indicated. 
●
Descriptive statistics for continuous variables include the sample size (n, mean, 
standard deviation, median, 1st and 3rd quartiles, minimum, and maximum).
●
Summary statistics for categorical variables include the sample size (n), 
frequency count, and percentage. 
●
AEs and findings from biomicroscopy and ophthalmoscopy examinations will 
be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 24.1 or higher, according to the version of the MedDRA coding 
dictionary used for the study at the time of database lock. 
9.2
Adverse Events
AEs will be summarized and presented using primary MedDRA SOCs and preferred 
terms (PTs). Specific adverse events will be counted once for each participant for 
calculating percentages, unless stated otherwise.  In addition, if the same adverse event 
occurs multiple times for a participant, the highest severity and level of relationship to 
investigational product will be reported.
9.2.1
Treatment-Emergent Adverse Events
An AE will be considered a treatment-emergent adverse event (TEAE) if the AE began or 
worsened (increased in severity or became serious) on or after the date of the first dose of 
study drug.  Events where the onset date is the same as the study drug start date are 
assumed to be treatment emergent. 
In general, the number and percentage of participants experiencing TEAEs will be 
summarized overall, as well as by primary MedDRA SOC and PT.  The SOCs will be 
 


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presented in alphabetical order, and the PTs will be presented in decreasing frequency 
order on active study drug within each SOC.  The number and percentage of participants 
experiencing TEAEs will also be summarized by PT for identifying common AEs.  
TEAEs by PT summaries will be presented in decreasing frequency order on active study 
drug.
9.2.2
Adverse Event Overview
Adverse events will be classified into ocular AEs and non-ocular AEs. An ocular AE will 
be determined as indicated on the AE form of eCRF (marked "OD" or "OS" to the 
question of "what was the location of the adverse event?"), and thus are not limited to AEs 
with primary SOCs of eye disorders.
An overview of AEs will be presented consisting of the number and percentage of 
participants experiencing at least one event for each of the following AE categories:
●
TEAEs
○
Ocular TEAEs
○
Non-ocular TEAEs
●
TEAEs related to study drug 
○
Ocular TEAEs related to study drug according to the investigator
○
Non-ocular TEAEs related to study drug according to the investigator
●
Severe TEAEs
●
Serious TEAEs
○
Ocular serious TEAEs
○
Non-ocular serious TEAEs
●
TEAEs leading to withdrawal of study treatment
○
Ocular leading to withdrawal of study treatment  
○
Non-ocular leading to withdrawal of study treatment  
●
TEAEs of special interest
●
TEAEs leading to death
 


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●
All deaths
●
COVID-19 infection.  
9.2.3
Treatment-Emergent Adverse Events by SOC and/or PT
Treatment-emergent adverse events will be summarized for each of the following AE 
categories:
●
TEAEs by SOC and PT
○
Ocular TEAEs by SOC and PT
○
Non-ocular TEAEs by SOC and PT
●
TEAEs by PT
●
TEAEs related to study drug by SOC and PT
○
Ocular TEAEs related to study drug by SOC and PT 
○
Non-ocular TEAEs related to study drug by SOC and PT
●
TEAEs by SOC, PT, and maximum severity
○
Ocular TEAEs by SOC, PT, and maximum severity
○
Non-ocular TEAEs by SOC, PT, and maximum severity
Specific adverse events will be counted once for each participant for calculating 
percentages, unless stated otherwise.
If the same adverse event occurs multiple times for a participant, the highest severity and 
level of relationship to investigational product will be reported.
9.2.4
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation
SAEs (including deaths) and AEs leading to study drug discontinuation will be 
summarized by SOC and PT and in listing format.
 


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9.2.5
Adverse Events of Special Interest 
Summary table by PT will be provided for Adverse Events of Special Interest (AESI) as 
defined in Appendix B, which will also be provided in a listing. 
9.3
Analysis of Laboratory Data
Descriptive statistics for values and changes from the baseline in standard units at each 
assessment time point will be presented by study intervention group.
Clinical laboratory test values will be considered potentially clinically significant (PCS) if 
they meet either the lower-limit or upper-limit PCS criteria listed in Appendix C.  The 
number and percentage of participants who have PCS post-baseline clinical laboratory 
values will be tabulated by study intervention for all scheduled postbaseline visit.  The 
percentages will be calculated relative to the number of participants who have available 
non-PCS baseline values and at least 1 postbaseline assessment.  The numerator will be 
the total number of participants with at least 1 PCS postbaseline value.
9.4
Analysis of Vital Signs
Descriptive statistics for vital signs (systolic and diastolic blood pressure, pulse rate, 
weight, respiration rate, and temperature) and their changes from baseline at each 
assessment timepoint will be presented by study intervention group.
Selected vital signs will be considered potentially clinically significant (PCS) if they meet 
either the lower-limit or upper-limit PCS criteria listed in Appendix C.  The number and 
percentage of participants who have PCS postbaseline vital sign values will be tabulated 
by study intervention for each postbaseline visit assessments.  The percentages will be 
calculated relative to the number of participants who have available baseline values for 
those parameters with the change from baseline value criterion or non-PCS baseline 
values for those vital sign parameters without the change from baseline value criterion and 
at least 1 postbaseline assessment.  The numerator will be the total number of participants 
with at least 1 PCS postbaseline value.
 


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9.5
Analysis of Electrocardiograms
Descriptive statistics for ECG parameters (heart rate, PR interval, QRS duration, 
QT interval, and QTc) at baseline, Exit visit (pre-CAE and post-CAE) or Early 
Termination visit, and changes from baseline at the Exit visit will be presented by study 
intervention group.
ECG values will be considered potentially clinically significant (PCS) if they meet either 
the lower-limit or upper-limit PCS criteria listed in Appendix C.  The number and 
percentage of participants who have PCS postbaseline ECG values will be tabulated by 
study intervention for Exit visit (pre-CAE and post-CAE) and Early Termination visit 
assessments.  The percentages will be calculated relative to the number of participants 
who have available non-PCS baseline values and at least 1 postbaseline assessment.  The 
numerator will be the total number of participants with at least 1 PCS postbaseline value.
9.6
Analysis of Best-corrected Visual Acuity
BCVA will be quantified using the Early Treatment Diabetic Retinopathy Study (ETDRS) 
visual acuity protocol.  Descriptive statistics for BCVA and changes from baseline at each 
post-baseline visit will be presented by study intervention, and by study eye and nonstudy 
eye.  Change from baseline will also be summarized by study intervention for each eye at 
each visit in a categorical tabulation as severe (≥30 letters decrease from baseline), 
moderate (≥15 and < 30 letters decrease from baseline) and no loss or mild (< 15 letters 
decrease from baseline).
9.7
Intraocular Pressure
Descriptive statistics for IOP and changes from baseline at each post-baseline visit will be 
presented by study intervention for each eye.
9.8
Biomicroscopy and Ophthalmoscopy
Biomicroscopy will be performed in each eye at each visit, by slit-lamp examination, 
without pupil dilation, including but not limited to lids/lashes, conjunctiva, cornea, and 
 


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anterior chamber.  Observations for the examination will be graded on a 5-point scale 
(0=none, 0.5=trace, 1=mild, 2=moderate, 3=severe) except for a) the anterior chamber 
cells: 0=0 cells, +0.5=1-5 cells, +1=6-15 cells, +2=16-25 cells, +3=26-50 cells, and 
+4=> 50 cells; and b) flare: 0=none, +1=faint, +2=moderate, +3= marked and 
+4=intense).
 will be summarized 
using descriptive statistics at all post-baseline visits and pre-/post-CAE when applicable.  
For Pre-CAE change from baseline, the Day 1 Pre-CAE value prior to the administration 
of the first administration of study intervention will be used as baseline.  For Post-CAE 
change from baseline, the Day 1 Post-CAE value prior to the administration of the first 
administration of study intervention will be used as baseline.
The number of participants with biomicroscopy findings of ≥ 2-grade severity increase 
from baseline will be generated for MedDRA preferred terms recorded on the Ocular 
Biomicroscopic Exam eCRFs at each post-baseline visit by study intervention for each 
eye.  For findings under other pathology which are not associated with a severity grade, a 
status change from absent to present will be treated as a 2-grade increase in the analysis.  
At least 2-grade increase in severity from baseline is defined as a change from no finding 
to 2 and above, from 0.5 to 2 and above, or from 1 to 3 and above from baseline at any of 
the follow-up visits.  The number and percentage of participants with clinically significant 
biomicroscopy findings (at least 2-grade increase in severity from baseline) will be 
tabulated by finding category, and study intervention group. 
The ophthalmoscopy findings will be summarized similarly. 
9.9
Safety Subgroup Analyses (if applicable)
No safety subgroup analyses are planned.
 


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10.0
Interim Analyses
An interim database lock occurred after completion of Stage 1, and the unmasking and 
data analyses were performed.  This doesn't affect masking of Stage 2.  At the end of 
study, the final database lock will occur. 
11.0
Version History
Table 4.
SAP Version History Summary
Version
Date
Summary
1.0
07 December 2021
Original version
12.0
Appendices
 


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Appendix A.
Protocol Deviations
According to ICH E3 2012 guideline, only important protocol deviations will be reported 
in CSR.  The number and percentage of randomized participants with important protocol 
deviations will be summarized overall and by study intervention group for participants 
reported by protocol deviation categories:
●
Participants who entered the study even though they did not satisfy the entry 
criteria
●
Participants with inclusion criteria not met, overall and by inclusion criteria
●
Participants with exclusion criteria met, overall and by exclusion criteria
●
Participants developed withdrawal criteria during the study but were not 
withdrawn
●
Participants received wrong treatment or incorrect dose of study treatment
●
Participants took prohibited concomitant medication
 


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Appendix B.
Definition of Adverse Events of Special Interest
The following adverse events of special interest (AESI) (serious or nonserious) are 
defined in the protocol and will be summarized by PT terms listed in Table 5:
●
AST and/or ALT increased to ≥5 ULN
●
AST and/or ALT increased to ≥ 3 × ULN AND total bilirubin increased to ≥ 2 
× ULN.  Typically, all analytes will be obtained from the same sample, but they 
may come from multiple samples taken within a 24-hour period.
●
AST and/or ALT increased to ≥ 3 × ULN with symptoms believed to be related 
to liver injury (e.g., fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness or jaundice) or hypersensitivity (such as fever, rash, or eosinophilia 
> 5%)
●
Potential Hy's Law cases:
○
ALT and/or AST ≥ 3 × ULN AND
○
TBL ≥ 2 × ULN AND
○
Alkaline phosphatase < 2 × ULN
Table 5.
List of Preferred Terms for Adverse Events of Special Interest  
Preferred Term (PT)
PT Code
Aspartate aminotransferase increased
10003481
Alanine aminotransferase increased
10001551
Blood bilirubin increased
10005364
Blood alkaline phosphatase increased
10059570
 


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Appendix C.
Potentially Clinically Significant Criteria for Safety Endpoints
The potentially clinically significant criteria for clinical laboratory parameters, vital signs 
and ECG parameters are provided in the following sections. 
Table 6.
Potentially Clinically Significant Criteria for Clinical Laboratory 
Parameters
Laboratory
Group
Parameter
SI Unit
PCS Low
Limit
PCS High
Limit
Hematology
Eosinophils absolute cell count
109/L
—
> 1.5 × ULN
Hematocrit
%
< 0.8 × LLN
≥ 1.2 × ULN
Hemoglobin
g/L
< 0.8 × LLN
≥ 1.2 × ULN
Lymphocytes absolute cell count
109/L
< 0.8 × LLN
> 1.2 × ULN
Neutrophils absolute cell count
109/L
< 0.6 × LLN
> 1.6 × ULN
Platelet count (thrombocytes)
109/L
< 0.5 × LLN
> 1.5 × ULN
Red blood cell count
1012/L
< 0.8 × LLN
> 1.2 × ULN
White blood cell count
109/L
< 0.7 × LLN
> 1.8 × ULN
Chemistry
Alanine aminotransferase
U/L
—
> 3 × ULN
Albumin
g/L
< 0.9 × LLN
> 1.1 × ULN
Alkaline phosphatase
U/L
—
> 3 × ULN
Aspartate aminotransferase
U/L
—
> 3 × ULN
Bilirubin, total
µmol/L
—
> 1.5 × ULN
Blood urea nitrogen
mmol/L
—
> 1.3 × ULN
Calcium
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Cholesterol, total
mmol/L
—
> 1.2 × ULN
Creatinine
µmol/L
—
> 1.8 × ULN
Glucose, fasting
mmol/L
< 0.8 × LLN
> 1.2 × ULN
Glucose, nonfasting
mmol/L
< 0.8 × LLN
> 1.4 × ULN
Phosphorus
mmol/L
< 0.8 × LLN
> 1.2 × ULN
Potassium
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Protein, total
g/L
< 0.9 × LLN
> 1.1 × ULN
Sodium
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Uric acid (urate)
µmol/L
—
> 1.2 × ULN
 


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Laboratory
Group
Parameter
SI Unit
PCS Low
Limit
PCS High
Limit
Urinalysis
Glucose
µmol/L
—
≥ 0.015
Glucose (alternate units)
—
—
≥ 2+
pH
—
< 0.9 × LLN
> 1.1 × ULN
Protein
g/L
—
≥ 1.0
Protein (alternate units)
—
—
≥ 2+
Specific gravity
—
—
> 1.1 × ULN
LLN = lower limit of normal (value provided by the laboratory); PCS = potentially clinically significant; SI = Le 
Système International d'Unités (International System of Units); ULN = upper limit of normal (value provided by the 
laboratory)
Table 7.
Potentially Clinically Significant Criteria for Vital Signs 
Parameters
Parameter
Unit
PCS Category
PCS Criteria
Actual Value
Change from Baseline
Sitting Systolic BP
mmHg
High
≥180
Increase of ≥20
Low
≤ 90
Decrease of ≥20
Sitting Diastolic BP
mmHg
High
≥105
Increase of ≥15
Low
≤50
Decrease of ≥15
Sitting Pulse rate
bpm
High
≥120
Increase of ≥15
Low
≤50
Decrease of ≥15
Weight
kg
High
—
Increase of ≥7%
Low
—
Decrease of ≥7%
Respiratory Rate 
bpm
High
≥ 28
—
Low
≤ 8
—
Temperature
°C
High
> 38
—
Low
< 35
—
BP = blood pressure; bpm = beats/breaths per minute
ECG values meeting either the actual value or change from baseline PCS high criteria will 
be categorized as PCS.
 


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Table 8.
Potentially Clinically Significant Criteria for ECG Parameters
Parameter
Unit
PCS High Criteria
Actual Value
Change from Baseline
QRS interval
msec
≥ 150
—
PR interval
msec
≥ 250
—
QTcF
msec
> 500
Increase > 60
QTcF = QTc Fridericia
 


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Appendix D.
List of Abbreviations
Abbreviation
Definition
AE
adverse event
AESI
adverse event of special interest
AGN
Allergan
ATC
Anatomical therapeutic chemical
BCVA
best corrected visual acuity
CAE
controlled adverse environment 
DED
dry eye disease 
DMC
data monitoring committee
DMC
data monitoring committee 
ECG
electrocardiogram
eCRF
electronic case report form
ETDRS
Early Treatment Diabetic Retinopathy Study 
IOP
intraocular pressure
ITT
Intent-to-Treat
MedDRA 
Medical Dictionary for Regulatory Activities
NEI
National Eye Institute
ODS
Ocular Discomfort Scale 
PCS 
potentially clinically significant 
PK
pharmacokinetic
PT
preferred term
SAP
statistical analysis plan
SD
standard deviation
SOC
system organ class
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
 
WHO
World Health Organization 
 


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Appendix E.
Changes to Protocol-planned Analyses
No statistical comparisons/tests among the study intervention groups will be performed 
for the safety data. 
 


CONFIDENTIAL
AGN-242428
AGN-231868
Safety Statistical Analysis Plan             2012-201-005 [Stage 1]
Page 1 of 34
Title Page
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 [Stage 1]
Compound Number: AGN-242428 and AGN-231868
Short Title: 
Safety, Tolerability, Pharmacokinetics, and Efficacy of AGN-242428 and AGN-231868 in 
Participants with Dry Eye Disease
Sponsor Name: Allergan Sales LLC
Legal Registered Address: 2525 Dupont Drive, Irvine, CA 92612, USA
Regulatory Agency Identifier Number(s)
Registry
ID
IND
139391, 139392


CONFIDENTIAL
AGN-242428
AGN-231868
Safety Statistical Analysis Plan             2012-201-005 [Stage 1]
Page 2 of 34
Table of Contents
Title Page .........................................................................................................................................1
Table of Contents.............................................................................................................................2
List of Tables ...................................................................................................................................3
SAP Version History........................................................................................................................5
1.
Introduction.......................................................................................................................6
1.1.
Objectives and Endpoints .................................................................................................6
1.2.
Study Design.....................................................................................................................7
2.
Statistical Hypotheses.......................................................................................................8
3.
Sample Size Determination ..............................................................................................9
4.
Analysis Sets...................................................................................................................10
5.
Statistical Analyses.........................................................................................................11
5.1.
General Considerations...................................................................................................11
5.2.
Participant Disposition....................................................................................................12
5.3.
Primary Endpoint(s) Analysis.........................................................................................13
5.4.
Secondary Endpoint(s) Analysis.....................................................................................13
5.5.
....................................................................13
5.6.
Safety Analyses...............................................................................................................13
5.6.1.
Extent of Exposure..........................................................................................................13
5.6.2.
Adverse Events ...............................................................................................................14
5.6.2.1. Adverse Events of Special Interest .................................................................................15
5.6.3.
Additional Safety Assessments.......................................................................................16
5.6.3.1. Clinical Laboratory Parameters ......................................................................................16
5.6.3.2. Potential Hy’s Law .........................................................................................................17
5.6.3.3. Vital Signs.......................................................................................................................17
5.6.3.4. Electrocardiogram...........................................................................................................18
5.6.3.5. Physical Exam.................................................................................................................19
5.6.3.6. Best-corrected Visual Acuity..........................................................................................19
5.6.3.7. Intraocular Pressure ........................................................................................................20
5.6.3.8. Biomicroscopy................................................................................................................20
5.6.3.9. Dilated Fundus Examination...........................................................................................21
5.6.3.10. Drop Tolerability Questionnaire Score...........................................................................21
5.7.
Other Analyses................................................................................................................22
5.7.1.
Other Variables and/or Parameters.................................................................................22
5.7.1.1. Pharmacokinetic Analyses..............................................................................................22
5.7.2.
Subgroup Analyses .........................................................................................................22
5.8.
Interim Analyses.............................................................................................................22
5.8.1.
Data Monitoring Committee...........................................................................................22


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6.
Supporting Documentation.............................................................................................23
6.1.
Appendix 1: List of Abbreviations .................................................................................24
6.2.
Appendix 2: Changes to Protocol-planned Analyses .....................................................26
6.3.
Appendix 3: Supporting Study Information ...................................................................27
6.3.1.
Demographics .................................................................................................................27
6.3.2.
Baseline and Disease Characteristics..............................................................................27
6.3.3.
Protocol Deviations.........................................................................................................27
6.3.4.
Medical and Ophthalmic History....................................................................................27
6.3.5.
Prior/Concomitant Medications (Including Dictionary).................................................28
6.3.6.
Potentially Clinically Significant Criteria for Safety Endpoints.....................................28
6.3.6.1. Potentially Clinically Significant Criteria for Clinical Laboratory 
Parameters.......................................................................................................................29
6.3.6.2. Potentially Clinically Significant Criteria for Vital Signs..............................................30
6.3.6.3. Potentially Clinically Significant Criteria for ECG Parameters .....................................30
6.4.
Data Handling Conventions............................................................................................31
6.4.1.
Study Intervention Conventions .....................................................................................31
6.4.1.1. Analysis Days .................................................................................................................31
6.4.1.2. Analysis Window............................................................................................................31
6.4.1.3. Missing/Incomplete Intervention End Date....................................................................31
6.4.2.
Repeated or Unscheduled Assessments..........................................................................31
6.4.3.
Missing Date Imputation.................................................................................................32
6.4.3.1. Missing/Incomplete AE Start Date.................................................................................32
6.4.3.2. Missing/Incomplete Medication Start Date ....................................................................33
6.4.3.3. Missing/Incomplete AE/Medication End Date...............................................................33
6.4.4.
Safety Endpoint Conventions .........................................................................................33
6.4.4.1. Adverse Events ...............................................................................................................33
7.
References.......................................................................................................................34
List of Tables
Table 1-1
Stage 1 Objectives................................................................................................... 6
Table 4–1
Analysis Sets......................................................................................................... 10
Table 5-1
Statistical Methodology ........................................................................................ 11
Table 5-2
Participant Disposition Summaries....................................................................... 13
Table 5-3
Baseline Definitions.............................................................................................. 13
Table 5-4
TEAE Summaries ................................................................................................. 15
Table 5-5
Adverse Events of Special Interest ....................................................................... 16
Table 5-6
Safety Laboratory Assessments............................................................................ 16


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Table 5-7
Clinical Laboratory Summaries............................................................................ 17
Table 5-8
Potential Hy’s Law Summaries ............................................................................ 17
Table 5-9
Vital Signs Summaries.......................................................................................... 18
Table 5-10
Derivations of QTcF ............................................................................................. 19
Table 5-11
ECG Summaries.................................................................................................... 19
Table 5-12
BCVA Summaries ................................................................................................ 20
Table 5-13
IOP Summaries ..................................................................................................... 20
Table 5-14
Biomicroscopy...................................................................................................... 21
Table 5-15
Dilated Fundus Examination................................................................................. 21
Table 5-16
Drop Tolerability Questionnaire Score................................................................. 21
Table 6-1
Abbreviations and Definitions of Terms............................................................... 24
Table 6-2
Demographic Summaries...................................................................................... 27
Table 6-3
Baseline and Disease Characteristics Summaries................................................. 27
Table 6-4
Medical History Summary.................................................................................... 28
Table 6-5
Clinical Laboratory PCS Criteria.......................................................................... 29
Table 6-6
Vital Sign PCS Criteria......................................................................................... 30
Table 6-7
ECG PCS Criteria ................................................................................................. 30
Table 6-8
Analysis Day Definitions...................................................................................... 31
Table 6-9
Analysis Visit Definitions for Stage 1 .................................................................. 31
Table 6-10
Imputation Scenarios ............................................................................................ 32
Table 6-11
Initial Imputed Date Algorithm ............................................................................ 32
Table 6-12
Missing AE Severity and Relationship Imputation Algorithms ........................... 33


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SAP Version History
This Safety Statistical Analysis Plan (SAP) for Stage 1 of study 2012-201-005 is based on the 
protocol amendment 2, dated 27 April 2020.
SAP Version History Summary
SAP 
Version
Approval 
Date
Change
Rationale
1
Not Applicable
Original version
 
 
  


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1.
Introduction
This SAP provides a technical and detailed elaboration of the statistical analyses of the Stage 1 
safety data as outlined and specified in the final protocol of 2012-201-005 (Amendment 2, 27
April 2020). Specifications of tables and data listings are contained in a separate document.
A separate SAP will be developed for Stage 2 data.
1.1.
Objectives and Endpoints
Table 1-1
Stage 1 Objectives
Stage 1
Primary Objectives:

To evaluate the safety and tolerability of up to three dose strengths of AGN-242428 and AGN-231868 
and their respective vehicles in participants with dry eye disease (DED)

To characterize the plasma and tear pharmacokinetics of AGN-242428 and AGN-231868 in participants 
with DED following a single bilateral administration; and 13 days of twice daily administration followed 
by a single administration to both eyes on the final day of administration
Objective
Clinical 
Category
Statistical 
Category
Estimand/Variable
Safety
Primary

Variables: 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

Population: Safety Population

Analyses: Descriptive summary
Pharmacokineticsa
Primary

Variables: Systemic and tear pharmacokinetic parameters 

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)

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

Population: Pharmacokinetics population

Analyses: Descriptive summary
Note: All estimand attributes explicitly identified for primary estimands only. 
a Analyses of Pharmacokinetics data will be described in a separate Pharmacokinetic Data Analysis Plan.
 
 
  


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1.2.
Study Design
Study 2012-201-005 is a Phase 1/2a, multicenter, vehicle-controlled, double-masked, 
randomized study conducted in 2 consecutive stages in participants with DED. Stage 1 will be 
conducted at 1 to 2 sites in the United States.
Stage 1
Stage 1 will evaluate the safety, tolerability, and pharmacokinetics (plasma and tear), of a 
maximum of 3 dose strengths of AGN-242428 (
) and AGN-231868 
(
) in up to 3 consecutive cohorts (1A, 1B [high dose], and 1C [mid dose]) 
of participants with DED. There will be 24 participants in each cohort, with participants in each 
cohort randomized into 1 of 4 intervention arms:

AGN-242428 (N = 9)

AGN-231868 (N = 9)

AGN-242428 vehicle (N = 3)

AGN-231868 vehicle (N = 3)
All participants will receive 1 drop of the assigned intervention administered by the site staff to 
the left eye on Day 1 (Visit 2). In the absence of significant study intervention-related safety 
findings from this administration at the site, on Days 2 to 14, the participants will self-administer 
a single drop to both eyes, twice daily. On Day 15 (Visit 5), the participants will be administered 
a single drop to both eyes by the site staff.
The sponsor will decide whether to proceed to the next cohort after DMC review of safety data. 
If no significant safety or tolerability findings are identified in Cohort 1B, Cohort 1C will not be 
initiated.
Stage 2
Analysis of Stage 2 data will be discussed in a separate SAP.
No participant can be enrolled in more than 1 cohort and/or stage of the study.
If all doses are well tolerated, the duration of participation for each participant in the study will 
be as follows: 

For participants in Stage 1: approximately 1 month (Day -14 through collection of the last 
PK sample on Day 15)


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2.
Statistical Hypotheses
No hypothesis testing will be performed for Stage 1 safety data.


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3.
Sample Size Determination
For Stage 1, the sample size is not based on statistical considerations and is determined 
empirically.


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4.
Analysis Sets
The analysis set for safety will consist of the population as defined below:
Table 4–1
Analysis Sets
Population
Definition
Study Intervention
Safety
All participants who received at least one administration of 
study intervention for stage 1
Actual received
 
 
  


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5.
Statistical Analyses
5.1.
General Considerations
The methodologies specified to individual variables are defined as follows:
Table 5-1
Statistical Methodology
Methodology
Description
Categorical 
descriptives

Number and percentage of participants in individual categories
o
Participants with ≥ 1 qualifying event counted once per individual 
category
PCS descriptives

Number and percentage of participants meeting potentially clinically 
significant (PCS) criteria
o
Participants with ≥ 1 qualifying event counted once per PCS category 

Percentage denominator = number of participants with available (non-missing)
non-PCS baseline value(s) or available (non-missing) baseline and ≥1 non-
missing postbaseline assessment
o
Unevaluable assessments considered missing
Continuous 
descriptives

N1, mean, standard deviation (SD), Q1, Q3, median, minimum, maximum

N1 = participants with non-missing value
CFB descriptives

Continuous descriptives for baseline, postbaseline, and change from baseline 
(CFB) values

N1 = participants with non-missing values at both baseline and the specified 
postbaseline analysis by visit/timepoint
Supportive data 
listing

After table listings, i.e. the listing supports the findings from a table.

Fully defined in the tables, figure, and listing specification document
CFB = change from baseline; PCS = potentially clinically significant; SD = standard deviation.

An interim database lock will occur after completion of Stage 1. At the end of the study
(completion of Stage 2), the final database lock will occur.

All data will be provided in data listings which will be fully defined in the table, figure, 
and listing specification document. For these data listings, missing or incomplete dates or 
missing AE severity or relationship will be listed as is.

The change from baseline values will be computed as the value for the post baseline visit 
minus the baseline value, unless otherwise indicated. 

Safety analyses will be based on the observed data. No imputation of missing values will 
be performed.
 
 
  


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
Partial dates will be treated as missing in computations but will be listed in the data 
listings as they appear on the eCRFs unless otherwise specified. No imputation of 
missing values will be performed, unless otherwise specified.

All statistical analysis will be performed using SAS version 9.4 or higher.

MedDRA will be used to code adverse events and medical history.

WHO Drug Dictionary will be used to code medications.

Relative study day is defined as the number of days from the first dose date and will be 
presented in all data listings where a complete date is presented.

The baseline for safety parameters will be the last assessment prior to the first 
administration of study intervention.

Day 1 is the study day on which study intervention is first administered.

The end of study for a participant is the last date that he/she participated in the study. The 
date will be captured on the end of intervention eCRF page.
5.2.
Participant Disposition
Number of participants screened for the study will be provided.
For each cohort, summary of study disposition will be provided by study intervention for the 
following:

Number of participants randomized

Number of participants treated

Number of participants that completed the study

Number of participants discontinued from the study

eCRF-reported discontinuation reasons
In addition, a listing will be provided for participant disposition.


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Table 5-2
Participant Disposition Summaries
Parameter
Description
Timing
Methodology
Study disposition
Distribution in the Safety Population by 
study intervention for each cohort.
—
Categorical 
descriptives/ 
Supportive data 
listing
5.3.
Primary Endpoint(s) Analysis
Not applicable.
5.4.
Secondary Endpoint(s) Analysis
Not applicable.
5.5.
Tertiary/Exploratory Endpoint(s) Analysis
Not applicable.
5.6.
Safety Analyses
Safety analyses will be based on the Safety Population.
Baseline assessments for applicable safety parameters are defined as follows:
Table 5-3
Baseline Definitions
Parameter
Baseline definition

Clinical laboratory evaluations

Vital signs

ECGs

BCVA

IOP
Last non-missing assessment before the first dose for each 
participant in Stage 1
5.6.1.
Extent of Exposure
Exposure to the study treatment for the Safety Population will be summarized for treatment 
duration, calculated as last study intervention date - first study intervention date + 1. Descriptive 
statistics will be presented by cohort and study intervention group.
 
 
  


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5.6.2.
Adverse Events
An AE will be considered a TEAE if:

The AE began on or after the first administration of study intervention, or

The AE was present before the first administration of study intervention, but worsened 
(increased in severity or became serious) on or after the first dose of study intervention
An AE that occurs after the Exit or Early Termination visits will not be counted as a TEAE.
An AE will be considered a TESAE if it is a TEAE that additionally meets any SAE criterion.
TEAEs will be summarized by cohort and study intervention group using the Safety population.
If more than 1 AE is coded to the same preferred term for the same participant, the participant will 
be counted only once for that preferred term using the most severe and most related occurrence for 
the summarizations by severity and by relationship to study intervention.
Listings of all TEAEs, TESAEs, TEAEs leading to discontinuation by participant, and deaths will 
be presented. 
AEs will be coded using MedDRA version 23.0 or newer. Unique participants reporting AEs in 
the following AE categories will be summarized by cohort and study intervention group for the 
Safety Population as follows:


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Table 5-4
TEAE Summaries
Parameters
Description
Methodology
AE
Overall summary by cohort and study intervention group only for 
the following categories:

TEAEs

Treatment-related TEAEs

TESAEs

Treatment-related TESAEs

TEAEs leading to study discontinuation

Deaths
Categorical 
descriptives
TEAEs
Overall summary by cohort and study intervention group and by 
SOC and PT

Participants categorized overall and within each SOC and PT in 
decreasing frequency
Categorical 
descriptives
TEAEs by severity
Overall summary by cohort and study intervention group and by 
SOC, PT, and severity

Participants categorized overall and within each SOC and PT in 
decreasing frequency for the most severe occurrence
Categorical 
descriptives
Treatment-related 
TEAEs
Overall summary by cohort and study intervention group and by 
SOC and PT

Participants categorized overall and within each SOC and PT in 
decreasing frequency
Categorical 
descriptives
TESAEs
Overall summary by cohort and study intervention group and by 
SOC and PTa
Categorical 
descriptives1
Supportive data 
listing
TEAEs leading to 
discontinuation
Overall summary by cohort and study intervention group and by 
SOC and PTa
Categorical 
descriptives1
Supportive data 
listing
AESI
Overall summary by cohort and study intervention group and by 
SOC and PTa
Categorical 
descriptives1
Supportive data 
listing
a Create summary tables only if at least 5 participants reported SAE, AEs leading to study discontinuation or 
AESI.
5.6.2.1.
Adverse Events of Special Interest 
Any report of the following AESIs will be provided in a listing. A summary table will be created 
only if there are reports by at least 5 participants.
 
 
  


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Table 5-5
Adverse Events of Special Interest
Preferred Term (PT)
PT Code
Aspartate aminotransferase increased
10003481
Alanine aminotransferase increased
10001551
Blood bilirubin increased
10005364
Blood alkaline phosphatase increased
10059570
5.6.3.
Additional Safety Assessments
5.6.3.1.
Clinical Laboratory Parameters
Table 5-6
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 (fastingb) 
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)
a In Stage 1, blood samples will be collected following 10-hour fasting period.
b Fasting requirement is for Stage 1 only 
Descriptive statistics for quantitative clinical laboratory values (in SI units) at Screening, Exit 
visit, and changes from baseline at Exit/Early Termination visit will be presented by cohort and 
study intervention group for each clinical laboratory assessment.
Clinical laboratory test values will be considered PCS if they meet either the lower-limit or 
higher-limit PCS criteria listed in Table 6-5. The number and percentage of participants who 
have at least one PCS post-baseline clinical laboratory values will be tabulated by cohort and 
study intervention group at Exit visit. The percentages will be calculated based on the 
denominator of the number of participants with available non-PCS baseline values and at least 
one post-baseline value and the numerator of the number of participants with non-PCS baseline 
value and at least one PCS post-baseline value. 
 
 
  


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A supportive listing of participants with postbaseline PCS values will be provided, including the 
participant number and baseline and postbaseline values, for the safety population. A listing of 
conversion factors to convert SI units to conventional units will be provided.
Table 5-7
Clinical Laboratory Summaries
Endpoint
Description
Timing
Methodology
PCS valuesa
Summary by laboratory category, 
laboratory test, and PCS criteria

Participants with baseline 
PCS values excluded from 
analysis

Parameters and PCS criteria 
specified in Sections 6.5.2.2
and 6.5.2.1, respectively
Screeningb, Exitc
PCS descriptives/ 
Supportive data 
listing
Descriptives 
Summary by laboratory category 
and laboratory test in SI and /or 
CV units and analysis visit

Parameters specified in 
Section 6.5.2.2
Screeningb, Exitc
CFB descriptives
a Participants who report ≥ 1 postbaseline PCS value and all clinical laboratory for those participants will be listed.
b Visit will be used as baseline for change from baseline summaries.
c Exit: Final or early termination visit.
5.6.3.2.
Potential Hy’s Law
Potential Hy’s Law criteria will be listed for the Safety Population as follows:
Table 5-8
Potential Hy’s Law Summaries
Parameter
Description
Timing
Methodology
Potential Hy’s Law 
within 24-hour 
window
Postbaseline assessment of the following 
laboratory parameters based on blood 
draws collected within a 24-hour period:

ALT or AST ≥ 3 × ULN

TBL ≥ 2 × ULN

ALP < 2 × ULN
Study Intervention
Period 
Supportive data 
listing
5.6.3.3.
Vital Signs
Descriptive statistics for vital signs (systolic and diastolic blood pressures, pulse rate, weight, 
respiration rate, and temperature) at Screening, Baseline (Day 1) and changes from baseline 
values at each visit and at the Exit/Early Termination visit will be presented by cohort and study 
intervention group.
 
 
  


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Vital sign values will be considered PCS if they meet either the lower-limit or higher-limit PCS 
criteria listed in Table 6-6. The number and percentage of participants who have at least one PCS 
post-baseline vital sign value will be tabulated by cohort and study intervention group. The 
percentages will be calculated based on the denominator of the number of participants with 
available baseline values or non-PCS baseline values (respiratory rate and temperature) and at 
least one post-baseline value and the numerator of the number of participants with non-PCS 
baseline value and at least one PCS post-baseline value. 
A supportive listing of participants with postbaseline PCS values will be provided, including the 
participant number and baseline and postbaseline values, for the safety population.
Table 5-9
Vital Signs Summaries
Endpoint
Description
Timing
Methodology
PCS valuesa
Summary by parameter and PCS 
criteria

Denominator: available 
baseline or non-PCS baseline 
(respiratory rate or 
temperature) and at least one 
end-of-study or postbaseline 
values

Parameters and PCS criteria 
specified in Sections 6.5.3.2
and 6.5.3.1 respectively 
Blood pressure, pulse rate, 
temperature:
Day 1b, Day 2, Day 8, Exitc
Respiration rate, weight:
Screening b, Exitc
PCS 
descriptives/ 
Supportive 
data listinga
Descriptives 
Summary by parameter and 
analysis visit

Parameters specified in 
Section 6.5.3.2
Blood pressure, pulse rate,
temperature:
Screening, Day 1b, Day 2, Day 8, 
Exitc
Respiration rate, weight:
Screeningb, Exitc
CFB 
descriptives
a Participants who report ≥ 1 postbaseline PCS value and all vital signs will be listed.
b Visit will be used as baseline for change from baseline summaries.
c Exit: Final or early termination visit.
5.6.3.4.
Electrocardiogram
Descriptive statistics for ECG parameters (heart rate, RR interval, PR interval, QRS interval, QT 
interval, and QTc) at Baseline and Exit/Early Termination visits, and changes from baseline 
values at Exit/Early Termination visit will be presented by cohort and study intervention group. 
The QTc will be calculated using the Fridericia correction (if the vendor does not provide). QTcF 
are derived as follows:
 
 
  


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Table 5-10
Derivations of QTcF
Parameter
Derivation if RR available
Derivation if RR unavailable
QTcF
(QTc Fridericia)
QT
cubic root of RR
QT
cubic root of 60/HR
ECG parameter values will be considered PCS if they meet either the lower-limit or higher-limit 
PCS criteria listed in Table 6-7. The number and percentage of participants who have at least one 
PCS post-baseline ECG values will be tabulated for all participants by cohort and study 
intervention group. The percentages will be calculated based on the denominator of the number 
of participants with available non-PCS baseline values and at least one post-baseline value and 
the numerator of the number of participants with non-PCS baseline value and at least one PCS 
post-baseline value. 
A supportive listing of participants with postbaseline PCS values will be provided, including the 
participant number and baseline and postbaseline values, for the safety population.
Table 5-11
ECG Summaries
Endpoint
Description
Timing
Methodology
PCS values
Summary by parameter and PCS 
criteria

Participants with baseline PCS 
values excluded from analysis

Parameters and PCS criteria 
specified in Sections 6.5.4.2 and 
6.5.4.3, respectively.
Screeningb, Exitc
PCS 
descriptives/ 
Supportive 
data Listinga
Descriptives 
Summary by parameter and analysis 
visit

Parameters specified in 
Section 6.5.4.3
Screeningb, Exitc
CFB 
descriptives
a Participants who report ≥ 1 postbaseline PCS value and all ECG will be listed.
b Visit will be used as baseline for change from baseline summaries.
c Exit: Final or early termination visit.
5.6.3.5.
Physical Exam
Abnormalities in PEs during Stage 1 of the study will be captured in medical history or AE data 
panels. Therefore, there will be no separate analyses for physical examination.
5.6.3.6.
Best-corrected Visual Acuity
BCVA will be measured in each eye using the ETDRS chart. Descriptive statistics for BCVA at 
Screening, Baseline (Day 1), and changes from baseline at each postbaseline visit will be 
presented by cohort, and study intervention group for each eye. Vision loss will also be 
 
 
  


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summarized by study intervention group for each eye at each visit in a categorical tabulation as 
severe (≥30 letters decrease from baseline), moderate (≥15 and < 30 letters decrease from 
baseline) and no loss or mild (< 15 letters decrease from baseline).
Table 5-12
BCVA Summaries
Parameter
Description
Timing
Methodology
Vision loss

Severe vision loss 
(>= 30 letters decrease from baseline)

Moderate vision loss 
(>= 15 and < 30 letters decrease from 
baseline)

No loss or mild vision loss 
(<15 letters decrease from baseline)
Treatment Period
Categorical 
descriptives
BCVA
Raw values and change from baseline
Treatment Period
CFB descriptives
5.6.3.7.
Intraocular Pressure
IOP will be measured in each eye using the Goldmann applanation tonometer. At least 2 
measurements will be taken for each eye.  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 3) measures will be used as the IOP value. If, for any 
reason, only a single measurement is obtained, then this measurement will be used as the IOP 
value.
Descriptive statistics for IOP at Screening, Baseline (Day 1), and changes from baseline and 
number of participants reporting IOP > 21 mm Hg at each postbaseline visit will be presented by 
cohort and study intervention group for each eye.
Table 5-13
IOP Summaries
Parameter
Description
Timing
Methodology
IOP category
IOP > 21 mmHg (raw value)
Treatment period
Categorical 
descriptives
IOP
Raw values and change from baseline
Treatment period
CFB descriptives
5.6.3.8.
Biomicroscopy
Slit-lamp biomicroscopy exam will be performed in each eye.
The number of participants with biomicroscopy findings of any severity increase from baseline 
at one or more visits will be generated for each MedDRA preferred terms by cohort and study 
 
 
  


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intervention group for each eye. For findings under “other pathology” which are not associated 
with a severity grade, a status change from absent to present will be treated as an increase of 
severity in the analysis.
Table 5-14
Biomicroscopy
Parameter
Description
Timing
Methodology
Biomicroscopy
Any severity increase from baseline for 
each eye
Treatment period
Categorical 
descriptives
5.6.3.9.
Dilated Fundus Examination
Lens, vitreous, fundus, and optic nerve will be evaluated for pathology. If pathology is present, it 
will be recorded.
Cup/disc ratio will be reported using 0.0 to 1.0 scale according to an Armaly chart. Lens status 
will be assessed as phakic, pseudophakic, or aphakic. Cataract assessment for presence and 
severity of nuclear, cortical and posterior subcapsular cataract lens opacities will be evaluated. 
Each type of cataract severity and change from baseline will be evaluated. These data will be 
presented as listings only.
Table 5-15
Dilated Fundus Examination
Parameter
Description
Timing
Methodology
Dilated Fundus 
Examination
Listing for the following data:

Cup/disc ratio

Lens status

Cataract assessment
Treatment period
Listing
5.6.3.10.
Drop Tolerability Questionnaire Score
Participants will be asked to rate the acute overall tolerability attributes of study interventions on 
an 8-question VAS Drop Tolerability Questionnaire. Descriptive statistics for each question at 
Baseline (Day 1), and changes from baseline at each postbaseline visit will be presented by 
cohort and study intervention group.
Table 5-16
Drop Tolerability Questionnaire Score
Parameter
Description
Timing
Methodology
Drop Tolerability 
Questionnaire VAS 
score
Raw values and change from baseline
Treatment period
CFB descriptives
 
 
  


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5.7.
Other Analyses
5.7.1.
Other Variables and/or Parameters
5.7.1.1.
Pharmacokinetic Analyses
Pharmacokinetic blood and tear (both eyes) sampling times and plasma and tear concentrations 
of AGN-242428 and AGN-231868 will be listed for the Safety Population. PK analyses will be 
described in the PK data analysis plan.
5.7.2.
Subgroup Analyses
No subgroup analysis is planned for this study.
5.8.
Interim Analyses 
There is no interim analysis planned.
There are 2 database locks planned. The first database lock will take place after completion of 
Stage 1. At this time, the data for Stage 1 will be unmasked and topline data analyses will be 
performed. A topline report will be created in lieu of an interim CSR.
5.8.1.
Data Monitoring Committee
The DMC will be composed of the sponsor’s internal members who will be masked to the 
interventions. However, data can be unmasked at the DMC’s discretion at any time.
In Stage 1, at the end of each cohort, the DMC will review the safety data and provide a 
recommendation on whether the study can proceed to the next cohort. In Stage 1, it is possible 
that only 1 of the interventions will proceed to the next cohort and/or to Stage 2.
All details of the committee membership, procedures for safety review, frequency of review, and 
communication between the safety review committee and other information will be detailed in 
the DMC charter.


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6.
Supporting Documentation
Additional study population, baseline characteristics, and pre-defined safety criteria can be found 
in Section 6.3.


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6.1.
Appendix 1: List of Abbreviations
Table 6-1
Abbreviations and Definitions of Terms
Abbreviation/Term
Definition
AE
adverse event
AESI
adverse event of special interest
AI
accumulation index
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ALP
alkaline phosphatase
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
BP
Blood pressure
bpm
beats/breaths per minute
BUN
blood urea nitrogen
CAE
controlled adverse environment
CFB
change from baseline
Cmax
maximum plasma or tear drug concentration
Cmin,ss
minimum plasma or tear drug concentration at steady state
CRF
case report form
CSR
Clinical Study Report
DED
dry eye disease
DMC
data monitoring committee
ECG
electrocardiogram
eCRF
electronic case report form
ETDRS
Early Treatment Diabetic Retinopathy Study
FDA
Food and Drug Administration
hCG
human chorionic gonadotropin
ICH
International Council on Harmonization
IND
investigational new drug
IOP
intra-ocular pressure
LD
last day of the month
LLN
lower limit of normal
MedDRA
Medication Dictionary for Regulatory Activities
MCV
mean corpuscular volume
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MM
available start date month
 
 
  


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Abbreviation/Term
Definition
MSP
medical safety physician
NA
not applicable
OD
right eye
OS
left eye
OTC
over-the-counter
PE
physical examination
PCS
potentially clinically significant
PK
pharmacokinetic
PT
Preferred Term
QTc
QT Interval Corrected for Heart Rate
QTcF
QT Interval Corrected for Heart Rate Using the Fridericia Formula (Qtcf = QT/(RR)⅓)
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SAS
Statistical Analysis System
SD
Standard deviation
SI
Le Système International d’Unités (International System of Units)
SOC
System Organ Class
SoA
schedule of activities
t1/2
terminal elimination half-life
TBL
total bilirubin 
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
THC
tetrahydrocannabinol
ULN
upper limit of normal
WBC
white blood cell
WHO
World Health Organization
WOCBP
woman of childbearing potential
YYYY
available start date year
 
 
  


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6.2.
Appendix 2: Changes to Protocol-planned Analyses
There are no changes from the protocol-planned analyses.




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events and surgical history will be summarized using MedDRA SOC and PT by cohort and study 
intervention group for the Safety Population. Medical history includes prior medical history 
(prior to Day 1, first dose date) and still ongoing.
Table 6-4
Medical History Summary
Parameter
Description
Timing
Methodology
Medical history
Abnormalities and surgeries 
—
Categorical 
descriptives
Ophthalmic history
Abnormalities and surgeries 
—
Categorical 
descriptives
SOCs will be sorted alphabetically; PTs will be sorted in descending frequency in the highest dose strength group.
6.3.5.
Prior/Concomitant Medications (Including Dictionary)
The medication data will be coded using the WHO Drug Dictionary Enhanced, version MAR
2017 or newer. Prior medication is defined as any medication taken prior to the start of study 
intervention regardless of stop date of the medication. Concomitant medication is defined as any 
medication taken after the start of study intervention regardless of the start date of the 
medication.
Prior and concomitant medications will be coded using the Anatomical Therapeutic Chemical 
code (4th level, or most specific level available if 4th level is unavailable).
Medications data along with prior or concomitant medication flag will be listed for the Safety 
Population.
6.3.6.
Potentially Clinically Significant Criteria for Safety Endpoints
The potentially clinically significant criteria for clinical laboratory parameters, vital signs, and 
ECG parameters are provided in the following sections.
 
 
  


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6.3.6.1.
Potentially Clinically Significant Criteria for Clinical Laboratory 
Parameters
Laboratory assessments values meeting any of the following PCS low or PCS high criteria will 
be categorized as PCS:
Table 6-5
Clinical Laboratory PCS Criteria
Laboratory
Group
Parameter
SI Unit
PCS Low
Limit
PCS High
Limit
Hematology
Eosinophils absolute cell count
109/L
—
> 1.5 × ULN
Hematocrit
%
< 0.8 × LLN
≥ 1.2 × ULN
Hemoglobin
g/L
< 0.8 × LLN
≥ 1.2 × ULN
Lymphocytes absolute cell count
109/L
< 0.8 × LLN
> 1.2 × ULN
Neutrophils absolute cell count
109/L
< 0.6 × LLN
> 1.6 × ULN
Platelet count (thrombocytes)
109/L
< 0.5 × LLN
> 1.5 × ULN
Red blood cell count
1012/L
< 0.8 × LLN
> 1.2 × ULN
White blood cell count
109/L
< 0.7 × LLN
> 1.8 × ULN
Chemistry
Alanine aminotransferase
U/L
—
> 3 × ULN
Albumin
g/L
< 0.9 × LLN
> 1.1 × ULN
Alkaline phosphatase
U/L
—
> 3 × ULN
Aspartate aminotransferase
U/L
—
> 3 × ULN
Bilirubin, total
µmol/L
—
> 1.5 × ULN
Blood urea nitrogen
mmol/L
—
> 1.3 × ULN
Calcium
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Cholesterol, total
mmol/L
—
> 1.2 × ULN
Creatinine
µmol/L
—
> 1.8 × ULN
Glucose, fasting
mmol/L
< 0.8 × LLN
> 1.2 × ULN
Glucose, nonfasting
mmol/L
< 0.8 × LLN
> 1.4 × ULN
Phosphorus
mmol/L
< 0.8 × LLN
> 1.2 × ULN
Potassium
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Protein, total
g/L
< 0.9 × LLN
> 1.1 × ULN
Sodium
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Uric acid (urate)
µmol/L
—
> 1.2 × ULN
Urinalysis
Glucose
µmol/L
—
≥ 0.015
Glucose (alternate units)
—
—
≥ 2+
pH
—
< 0.9 × LLN
> 1.1 × ULN
Protein
g/L
—
≥ 1.0
Protein (alternate units)
—
—
≥ 2+
Specific gravity
—
—
> 1.1 × ULN
 
 
  


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6.3.6.2.
Potentially Clinically Significant Criteria for Vital Signs
Vital sign values meeting both the actual value and change from baseline PCS criteria will be 
categorized as PCS:
Table 6-6
Vital Sign PCS Criteria
Parameter
Unit
PCS Category
PCS Criteria
Actual Value
Change from Baseline
Sitting Systolic BP
mmHg
High
≥180
Increase of ≥20
Low
≤ 90
Decrease of ≥20
Sitting Diastolic BP
mmHg
High
≥105
Increase of ≥15
Low
≤50
Decrease of ≥15
Sitting Pulse rate
bpm
High
≥120
Increase of ≥15
Low
≤50
Decrease of ≥15
Weight
kg
High
—
Increase of ≥7%
Low
—
Decrease of ≥7%
Respiratory Rate 
bpm
High
≥ 28
—
Low
≤ 8
—
Temperature
°C
High
> 38
—
Low
< 35
—
6.3.6.3.
Potentially Clinically Significant Criteria for ECG Parameters
ECG values meeting either the actual value or change from baseline PCS high criteria will be 
categorized as PCS:
Table 6-7
ECG PCS Criteria
PCS High Criteria
Parameter
Unit
Actual Value
Change from Baseline
QRS interval
msec
≥ 150
—
PR interval
msec
≥ 250
—
QTcF
msec
> 500
Increase > 60
 
 
  
 
 
 
 
 


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6.4.
Data Handling Conventions
6.4.1.
Study Intervention Conventions
6.4.1.1.
Analysis Days
Study days are defined as follows:
Table 6-8
Analysis Day Definitions
Term
Description
Study Day
Relative to study intervention start date
If analysis date ≥ intervention start date:

Day = analysis date – study intervention start date + 1
o
Day 1 = study intervention start date
If analysis date < intervention start date:

Day = analysis date – study intervention start date
o
Day -1 = day before study intervention start date
o
There is no Day 0
6.4.1.2.
Analysis Window
Table 6-9
Analysis Visit Definitions for Stage 1
Scheduled Visit
Target Day of the 
Visit
Analysis Visit Window
Visit 2/Baseline
Day 1 
Day 1
Visit 3
Day 2
Days [2, 5]
Visit 4
Day 8
Days [6, 11] 
Visit 5
Day 15
Day 12 to study exit day
6.4.1.3.
Missing/Incomplete Intervention End Date
If the investigator is unable to provide the study intervention end date, study intervention end 
date will be imputed to the last available dosing record date.
6.4.2.
Repeated or Unscheduled Assessments
If postbaseline assessments are repeated or if unscheduled assessments occur, the last 
postbaseline assessment will be used as the postbaseline assessment for generating summary 
statistics. However, all postbaseline assessments will be used for PCS value determinations, and 
all assessments will be presented in the supportive data listings.
 
 
  


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6.4.3.
Missing Date Imputation
Dates may be imputed with year, month, and day values under certain scenarios:
Table 6-10
Imputation Scenarios
Complete
Scenario
Year
Month
Day
Imputable
1
Yes
Yes
Yes
Complete
2
Yes
Yes
—
Yes
3
Yes
—
Yes
Noa
4
Yes
—
—
Yes
5
—
Yes
Yes
Noa
6
—
Yes
—
Noa
7
—
—
Yes
Noa
8
—
—
—
Yes
a Not allowed per database design.
Dates will be imputed initially toward a specified target date for imputable scenarios 2, 4, and 8, 
and adjusted against the latest reasonable dates. The initial imputed date is determined by the 
following algorithm:
Table 6-11
Initial Imputed Date Algorithm
Available Year
Available Month (MM)
(YYYY)
Missing
< Target Month
= Target Month
> Target Month
Missing
Target Date
—
< Target Year
YYYY-12-31
YYYY-MM-LD
= Target Year
Target Date
YYYY-MM-LD
Target Date
YYYY-MM-01
> Target Year
YYYY-01-01
YYYY-MM-01
6.4.3.1.
Missing/Incomplete AE Start Date
Imputation of dates with missing day and/or month is only applied to TEAEs. If adequate 
information is available, no imputation is needed. TEAE start dates with missing day or month 
will be imputed as following:

If day and month are missing but year is available, then the imputed day and month will 
be 01 Jan or the initial study intervention administration date if they have the same year, 
whichever is later (because TEAE onset is not expected prior to administration of study 
intervention)

If day is missing but the month and year are available, then the imputed day will be the 
first day of the month or the initial injection date if they have the same month and year, 
whichever is later.
 
 
  
 
 
 
 


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6.4.3.2.
Missing/Incomplete Medication Start Date
Medication start dates will be imputed as the minimum of the following:

Initial imputed date, where target date = Treatment start date – 1

Complete end date
6.4.3.3.
Missing/Incomplete AE/Medication End Date
Imputation of dates with missing day and/or month is only applied to TEAEs when AE duration 
is calculated. If adequate information is available, no imputation is needed. TEAE end dates with 
missing day or month will be imputed as following:

If day and month are missing but year is available, then the imputed day and month will 
be 31 Dec or the study exit date if they have the same year, whichever is earlier 
If day is missing but the month and year are available, then the imputed day will be the last day 
of the month or the study exit date if they have the same month and year, whichever is earlier.
6.4.4.
Safety Endpoint Conventions
6.4.4.1.
Adverse Events
6.4.4.1.1.
Missing Intensity or Relationship
If the investigator is unable to provide the actual values, the following imputations will be 
applied:
Table 6-12
Missing AE Severity and Relationship Imputation Algorithms
Missing Value
Imputation
Timing
Severity
Mild
AEs before the first dose of the study 
intervention in the study
Severe
AEs on or after the first dose of the 
study intervention in the study
Relationship
NA
AEs before the first dose of the study 
intervention in the study
Related
AEs on or after the first dose of the 
study intervention in the study
 
 
  


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7.
References
Not applicable.