Conditions: Dry Eye Syndromes
Keywords: EDE evaporative dry eye
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 36
Healthy volunteers: no

Brief summary:
The objectives of this study are twofold

* To evaluate the safety and efficacy of 0.1% AGN-195263 administered twice daily compared to its vehicle in patients with evaporative dry eye (EDE)
* To evaluate the systemic pharmacokinetics of 0.1% AGN-195263 administered twice daily in patients with EDE

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: AGN-195263 intervention 2: Vehicle
Intervention descriptions: intervention 1: 1 drop of AGN-195263 will be instilled in each eye twice daily. intervention 2: 1 drop of AGN-195263 vehicle (placebo) will be instilled in each eye twice daily.

Protocol document:
Prot_SAP_000.pdf: 
 
   
 
 
 
         NCT02815293 
 
Study ID: 195263-009  
 
 
Title: TOPICAL OPHTHALMIC AGN-195263 FOR THE 
TREATMENT OF EVAPORATIVE DRY EYE 
 
                Protocol Amendment 2 Date: October 26, 2016 


Approval Date: 	
Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
1 
GDD-TA-T-004 v2015.10 
 
 
irstTitle Page 
ALLERGAN – CONFIDENTIAL 
The following contains confidential, proprietary information 
which is the property of Allergan 
TOPICAL OPHTHALMIC AGN-195263 FOR THE TREATMENT OF 
EVAPORATIVE DRY EYE 
Protocol Number:   
195263-009 Amendment 2 
Phase: 
3 
Name of Investigational 
Product: 
0.1% 
 Ophthalmic 
 (AGN-195263) 
Sponsor: 
Allergan (North America) 
2525 Dupont Drive 
Irvine, California USA 
92612 
+1-714-246-4500 
+1-800-347-4500 
Allergan Ltd. 
1st Floor, Marlow 
International, 
The Parkway, Marlow 
Buckinghamshire 
SL7 1YL United Kingdom 
Tel: +44 (0) 1628 494444 
Fax: +44 (0) 1628 494449 
Emergency Telephone 
Numbers: 
Refer to the Study Contacts Page 
 
 
 
 
 
 
 
 
 
 
 
 
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Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
2 
GDD-TA-T-004 v2015.10 
 
 
 
  
  
 
 
 
Refer to the final page of this protocol for electronic 
signature and date of approval. 
 
The following information can be found on United States FDA Form 1572 and/or study 
contacts page and/or the Trial Master File:  Name and contact information of Allergan study 
personnel and Emergency Telephone Numbers; name, address, and statement of 
qualifications of each investigator; name of each subinvestigator working under the 
supervision of the investigator; name and address of each reviewing Institutional Review 
Board (IRB); US 21 CFR 312.23 section 6(iii)b. 
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Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
3 
GDD-TA-T-004 v2015.10 
 
 
INVESTIGATOR SIGNATURE PAGE 
INVESTIGATOR: 
 
 
 
 
I agree to: 
 Implement and conduct this study diligently and in strict compliance with the protocol, 
good clinical practices and all applicable laws and regulations. 
 Maintain all information supplied by Allergan in confidence and, when this information 
is submitted to an Institutional Review Board (IRB), Independent Ethics Committee 
(IEC) or another group, it will be submitted with a designation that the material is 
confidential. 
 Ensure that all persons assisting with the trial are adequately informed about the protocol, 
the investigational product(s), and their trial-related duties and functions. 
I have read this protocol in its entirety and I agree to all aspects. 
 
 
 
 
 
Investigator Printed Name 
 
Signature 
 
Date 
 
 
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Allerg
 
 
 
 
Table
List o
List o
Proto
1.
B
2.
S
2
2
3.
S
3
4.
S
4
4
4
4
4
5.
S
5
5
5
5
5
5
5
6.
R
6
gan Confidentia
e of Contents
of Tables .....
of Figures ...
ocol Summar
Background 
Study Object
2.1
Study 
2.2
Clinica
Study Design
3.1
Additio
Study Popula
4.1
Numbe
4.2
Study 
4.3
Inclusi
4.4
Exclus
4.5
Permis

4.5.1

4.5.2

4.5.3
Study Treatm
5.1
Study 
5.2
Contro
5.3
Metho
5.4
Treatm
5.5
Metho
5.6
Treatm
5.7
Storag
Response M
6.1
Efficac

6.1.1
al 
s .................
...................
...................
ry ...............
and Clinical
tives and Cl
Objectives .
al Hypothese
n .................
onal Study D
ation and En
er of Patient
Population C
ion Criteria .
sion Criteria
ssible and Pr
Permissi
Prohibite
Rescue M
ments ..........
Treatments a
ol Treatment 
ds for Mask
ment Allocati
d for Assign
ment Regime
e of Study M
easures and 
cy Measures
Primary 
 
Tabl
....................
....................
....................
....................
l Rationale ..
inical Hypot
....................
es ................
....................
Design Detai
ntry Criteria .
ts ..................
Characteristi
....................
....................
rohibited Me
ible Medicat
ed Medicatio
Medications 
....................
and Formula
...................
king ..............
ion Ratio and
nment to Tre
en and Dosin
Medications/
Summary of
s ...................
Efficacy Me
4 
 
le of Cont
....................
....................
....................
....................
....................
theses ..........
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ils ................
....................
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edications/Tr
tions/Treatm
ons/Treatme
or Treatmen
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f Data Colle
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6
6
6
6
7.
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7
7
7
7
7
7
7
8.
S
8
8
8
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6.1.2

6.1.3

6.1.4
6.2
Pharm
6.3
Safety 
6.4
Other S
6.5
Summ
Statistical Pr
7.1
Analys
7.2
Collec

7.2.1

7.2.2

7.2.3
7.3
Hypoth

7.3.1

7.3.2

7.3.3

7.3.4
7.4
Subgro
7.5
Pharm
7.6
Sample
7.7
Interim
Study Visit S
8.1
Patient

8.1.1

8.1.2

8.1.3
8.2
Proced
8.3
Visits a

8.3.1

8.3.2

8.3.3

8.3.4

8.3.5
al 
Seconda
Other Ef
Health O
macokinetic M
Measures ..
Study Suppl
mary of Metho
rocedures ....
sis Populatio
tion and Der
Primary 
Seconda
Other Ef
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Primary 
Seconda
Other Ef
Safety A
oup Analyse
macokinetic A
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Schedule and
t Entry Proc
Overview
Informed
Washout
dures for Fin
and Associat
Screenin
Standard
Vehicle R
Baseline
Month 1
 
ary Efficacy 
fficacy Meas
Outcomes M
Measures......
....................
lies ..............
ods of Data 
....................
ons ...............
rivation of P
Efficacy Va
ary Efficacy V
fficacy Varia
ethods of An
Efficacy An
ary Efficacy A
fficacy Analy
Analyses .......
s ..................
Analysis .......
ulation .........
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d Procedures
edures .........
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d Consent an
t Intervals/R
nal Study Ent
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ng Visit (Day
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Protocol 19526
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8
8
8
8
8
8
9.
A
9
9
9
9
10. A
1
1
1
1
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8.3.6

8.3.7

8.3.8

8.3.9
8.4
Instruc
8.5
Unsche
8.6
Compl
8.7
Early D
8.8
Withdr
8.9
Study 
Adverse Eve
9.1
Definit

9.1.1

9.1.2

9.1.3

9.1.4
9.2
Proced
9.3
Proced
9.4
Proced
Administrati
10.1 Protect

10.1.1

10.1.2

10.1.3

10.1.4
10.2 Chang
10.3 Patient

10.3.1
10.4 Docum

10.4.1

10.4.2

10.4.3
al 
Month 3
Month 6
Month 9
Month 1
ctions for the
eduled Visit
liance with P
Discontinuat
rawal Criteri
Termination
ents .............
tions ...........
Adverse
Serious A
Severity
Relation
dures for Rep
dures for Rep
dures for Unm
ive Items ....
tion of Hum
Complia
and Rele
Complia
Complia
Complia
(US 21C
es to the Pro
t Confidentia
Patient P
mentation ....
Source D
Case Rep
Study Su
 
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6 Visit (± 7 d
9 Visit (± 14 
2/Study Exi
e Patients .....
s ..................
Protocol .......
tion of Patie
ia .................
n ...................
....................
....................
 Event .........
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y ...................
nship to Stud
porting Adve
porting a Ser
masking of S
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man Patients .
ance with Inf
evant Countr
ance With IR
ance With Go
ance With El
CFR Part 11)
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ality ............
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....................
Documents ..
port Form C
ummary .......
6 
 
days) ............
days) ............
days) ..........
it (Early Exit
....................
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nts ..............
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ent ...............
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erse Events .
rious Advers
Study Medic
....................
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ry Regulatio
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ood Clinical
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1
1
1
1
1
11. R
12. A
1
1
1
 
gan Confidentia

10.4.4
10.5 Labelin

10.5.1

10.5.2

10.5.3
10.6 Monito
10.7 Handli
10.8 Public
10.9 Coordi
References ..
Attachments
12.1 Exami

12.1.1

12.1.2

12.1.3

12.1.4

12.1.5

12.1.6

12.1.7

12.1.8

12.1.9
12.1.10
12.1.11
12.1.12
12.1.13
12.1.14
12.1.15
12.1.16
12.2 Glossa
12.3 Protoc

12.3.1

12.3.2
al 
Retentio
ng, Packagin
Labeling
Clinical 
Return o
oring by the 
ing of Biolog
ations .........
inating Inves
...................
s ..................
nation Proce
Pregnanc
Vital Sig
Patient O
Hair Eva
Tear Film
Corneal 
Lower L
Ocular S
EQ-5D H

Biomicro
0

Dilated O
1

Schirme
2

Visual A
3

Intraocu
4

Blood an
5

Blood Sa
6
ary of Abbrev
ol Amendme
Amendm
Amendm
 
on of Docum
ng, and Retu
g/Packaging .
Supply Inve
or Disposal o
Sponsor .....
gical Specim
....................
stigator .......
....................
....................
edures, Tests
cy Test ........
gns ...............
Ocular Symp
aluation .......
m Break-up 
and Conjunc
Lid Margin M
Surface Dise
Health Ques
oscopy ........
Ophthalmos
r’s Tear Test
Acuity (logM
ular Pressure
nd Urine Sam
ample Colle
viations .......
ent Summar
ment 2 ..........
ment 1 ..........
7 
 
mentation ......
urn or Dispos
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....................
mens.............
....................
....................
....................
....................
s, Equipmen
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ptoms Quest
....................
Time Evalua
ctival Sodiu
Meibomian G
ase Index ....
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....................
copy ...........
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MAR Chart) ..
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ction for Ph
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Protocol 19526
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tic Analysis .
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ts . 76
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es . 77
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.. 107
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Approval Date: 	
Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
8 
GDD-TA-T-004 v2015.10 
 
 
List of Tables 
Table 1
Schedule of Visits and Procedures .................................................................. 17
Table 2
Permissible Medications That Require Stable Dosing Prior to the 
Standardization (Day -21) Visit and Anticipated Continuation on the Same 
Dose Until at Least the Month 6 Visit ............................................................ 33
Table 3
Prohibited Medications Within the Period Indicated Prior to the 
Standardization (Day -21) Visit to Month 6 Visit ........................................... 35
Table 4
Prohibited Medications Within the Period Indicated Prior to the 
Standardization (Day -21) Visit and Throughout the Duration of the Study .. 36
Table 5
Stratification Groups ....................................................................................... 38
Table 6
Early Discontinuation Requirements .............................................................. 69
 
List of Figures 
Figure 1
Schematic of Study Design ............................................................................. 16
Figure 2
Schematic to Illustrate the Lower Eyelid Margin Meibomian Gland 
Evaluation ....................................................................................................... 93
 
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Approval Date: 	
Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
9 
GDD-TA-T-004 v2015.10 
 
 
Protocol Summary 
 
Study Compound:  0.1% 
 (AGN-195263) 
Phase:  3 
Study Objectives:   
 
To evaluate the safety and efficacy of 0.1% AGN-195263 administered twice daily compared to its 
vehicle in patients with evaporative dry eye (EDE) 
 
To evaluate the systemic pharmacokinetics of 0.1% AGN-195263 administered twice daily in patients 
with EDE 
Clinical Hypotheses:   
 
One drop of
 0.1% AGN-195263 administered twice daily to each eye: 
o 
is more effective than its vehicle as measured by the proportion of patients with complete 
overall ocular discomfort response at month 6 
o 
has an acceptable safety profile throughout the study treatment duration of 12 months 
Study Design 
Structure:  Multicenter, global, randomized, parallel-group, vehicle-controlled study with 6 months of double-
masked treatment followed by a 6 month open label treatment extension phase  
Duration:  The total duration of this study is up to approximately 14 months for each patient 
Study Treatment Groups:  0.1% 
 (AGN-195263) 
Controls:  vehicle of 0.1%
  
Dosage/Dose Regimen:  One drop of 0.1% AGN-195263
 or its vehicle 
administered in each eye twice daily from day 1 to up to month 6.  One drop of 0.1% AGN-195263 topical 
 in each eye twice daily from month 6 up to month 12.  Prior to baseline (randomization), 
patients will receive a 2-week patient-masked run-in on vehicle (days -14 to -1) administered twice daily in 
each eye. 
In addition to the study treatment, Allergan will supply a marketed artificial tear, which will be referred to as 
the study artificial tear (SAT).  The brandname of the SAT may vary in each country.  A full list of SAT 
brandnames (ie, REFRESH PLUS®, REFRESH CONTACTS®, REFRESH COMFORT®, CELLUFRESH®) is 
found in the Study Procedure Manual.  For simplicity, throughout the study protocol, in lieu of listing by brand 
name, “SAT” will  refer to the Allergan supplied study artificial tear. 
Use of lid hygiene (ie, warm compress, lid massage, lid scrub) or artificial tears (other than the SAT) are 
prohibited from the standardization (day -21) visit until after the month 6 visit.  Starting at the standardization 
(day -21) visit, all eligible patients will administer SAT twice daily in each eye for 6 days. 
From the vehicle run-in (day -14) visit until the month 6 visit, use of SAT will be considered rescue therapy for 
intolerable symptoms.  After the month 6 visit until the month 12/study exit visit, use of lid hygiene and/or any 
artificial tear product(s) will be unrestricted except for the use of artificial tears 24 hours prior to any study visit.  
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The morning dose of SAT (day -21 only) or study treatment will be administered by site staff on days when 
there is a study visit.  All other doses will be administered by the patient.   
All procedures are described in Table 1 and study design is diagrammed in Figure 1. 
Randomization/Stratification:  Patients will be randomized to receive 0.1% AGN-195263, or its vehicle in a 
1:1 ratio.  The randomization will be stratified by gender and by baseline (day 1) overall ocular discomfort 
score (1 vs 2 to 3).  
Visit Schedule:  Up to 9 scheduled visits:  screening (day -51), standardization (day -21), vehicle run-in 
(day -14), baseline (randomization, day 1), months 1, 3, 6 (primary and secondary efficacy assessment), 9, and 
12/study exit (safety assessment).  For patients who discontinue the study early, the month 12/study exit visit 
procedures should be completed when possible.   
For patients not participating in the collection of blood samples for pharmacokinetic analysis: in office study 
treatment should be administered in the morning at approximately the same time of day during each office visit 
(± 1 hour from the study administration time at baseline [day 1]). At any time, the morning dose time should not 
exceed 1:00 pm local time. 
For patients that participate in the collection of blood samples for pharmacokinetic analysis: 
1) the time of the pre-dose blood sample collection should be scheduled in the morning at approximately 
the same time of day during each office visit (± 1 hour from the pre dose blood sample collection time 
at the standardization (day -21) visit). 
2) SAT or study treatment should be administered in the morning at approximately the same time of day 
during each office visit and within 10  min after the time the pre-dose blood sample collection was 
performed that day. 
 
Study Population Characteristics 
Number of Patients:  Approximately 527 patients are planned to be enrolled in this study across approximately 
50 global sites. 
Condition/Disease:  Evaporative dry eye (EDE) 
Key Inclusion Criteria:   
 
Male, 18 years of age or older, at the screening (day -51) visit 
OR  
 
Females, 18 years of age or older, who are naturally postmenopausal (permanent cessation of 
menstrual periods for at least 12 consecutive months) or are permanently sterilized (ie, eg, tubal 
occlusion, hysterectomy, bilateral salpingectomy, and/or bilateral oophorectomy) at the screening  
(day -51) visit 
 
In at least 1 eye, all of the following objective measures of EDE must be present at the 
standardization (day -21) and baseline (day 1) visits.  The same eye must qualify at both visits 
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o 
Tear film break-up time (TBUT)  2 seconds and  7 seconds 
o 
Corneal sodium fluorescein staining score  1 and < 4 (Oxford scheme) 
o 
Anesthetized Schirmer’s tear test score  10 mm after 5 minutes 
 
At the standardization (day -21) and baseline (day 1) visits, patients must have: 
o 
Ocular Surface Disease Index© (OSDI) score > 12 (0 to 100 scale) 
o 
Overall ocular discomfort score  1 and < 4 (0 to 4 scale; 0 = none, 4 = very severe) 
o 
Ocular burning score  1 and < 4 (0 to 4 scale; 0 = none, 4 = very severe) 
o 
Blurred vision score  1 and < 4 (0 to 4 scale; 0 = none, 4 = very severe) 
 
In at least 1 eye, a lower lid margin meibum quality global assessment score  1 at the standardization 
(day -21) and baseline (day 1) visits.  The same eye must qualify at both visits 
 
In at least 1 eye, the number of lower lid margin expressible meibomian glands must be  3 at the 
standardization (day -21) and baseline (day 1) visits.  The same eye must qualify at both visits 
 
Use of an artificial tear product, lid hygiene (ie, warm compress, lid massage, lid scrub), omega-3 
supplementation (topical ocular or systemic), or antibiotics (ie: systemic or topical macrolides, 
tetracyclines, tetracycline derivative drugs [including doxycycline and minocycline]) for the treatment 
of dry eye disease or meibomian gland disease within 1 year of the  standardization (day -21) visit 
Additional inclusion criteria are provided in Section 4.3 
Key Exclusion Criteria: 
 
Male patients with a history of known, or suspected prostate cancer 
 
Male patients with a prostate-specific antigen (PSA) level  4 μg/L 
 
Female patients with a history of known or suspected breast, cervical, ovarian, or uterine cancer 
 
Female patients who are of child-bearing potential 
 
At standardization (day -21) and / or  baseline (day 1) visits, a lower lid margin meibum quality global 
assessment score of non-expressible (NE) in either eye 
 
Patients who are currently using estrogen and / or progesterone containing products (including herbal 
and nutritional supplements) and not on a stable dose (at least 90 days prior to the standardization visit 
[day-21]) and / or anticipate initiating use and / or changing use during the study   
 
Patients who are currently using or have used any androgen or anti-androgen treatment (including 
herbal and nutritional supplements), within 90 days of the standardization (day -21) visit or anticipated 
use during the study 
 
Patients who are currently using or have used any hair growth product within 90 days of the 
standardization (day -21) visit or anticipated use during the study 
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Patients who are currently using or have used topical corticosteroids in the eyes or on the eyelids 
within 60 days prior to the standardization visit (day -21) or any such use anticipated prior to the 
month 6 visit 
 
Patients who are currently using or have used oral or topical macrolides, tetracyclines, tetracycline 
derivative drugs (including doxycycline and minocycline), retinoids (eg, isotretinoin), calcineurin 
inhibitors (ie, RESTASIS®, Ikervis®), oral (systemic) corticosteroids, lifitegrast (Xiidra™) or any other 
therapeutic dry eye treatment within 60 days of the standardization visit (day -21), or anticipated use 
prior to the month 6 visit 
Additional exclusion criteria are provided in Section 4.4. 
 
Response Measures 
Primary Efficacy: 
 
 overall ocular discomfort score (0 to 4 scale; 0 = none, 4 = very severe) 
Secondary Efficacy: 
 
TBUT (seconds) 
 
blurred vision score (0 to 4 scale; 0 = none, 4 = very severe) 
 
corneal sodium fluorescein staining score (0 to 5 Oxford scheme) 
 
ocular burning score (0 to 4 scale; 0 = none, 4 = very severe) 
 
derived variables based on overall ocular discomfort score (change from baseline,  1 grade 
improvement from baseline,  2 grade improvement from baseline, and  50% improvement from 
baseline) 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
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o 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
   
 
 
Safety:   
 
adverse events 
 
best-corrected visual acuity (BCVA, logarithm of the minimum angle of resolution [LogMAR] chart) 
 
biomicroscopy 
 
ophthalmoscopy 
 
intraocular pressure (IOP) 
 
urine pregnancy test (female patients only) 
 
PSA (male patients only) 
 
hematology, serum chemistry, and urinalysis 
 
vital signs 
 
 
 
 
 
 
 
 
General Statistical Methods and Types of Analyses:   
The primary analysis will be performed after all patients complete the month 6 visit or discontinue from the 
study prior to the month 6 visit.  The final analysis will be performed after all patients exit the study.  There will 
be separate database locks for the primary and final analyses. 
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The intent-to-treat (ITT) population comprises all randomized patients.  The efficacy variables will be analyzed 
per the randomization schedule using the ITT population. 
The per-protocol (PP) population comprises all randomized and treated patients who met the key inclusion and 
exclusion criteria; did not artificial tears, including SAT, lid hygiene; or other prohibited treatments that impact 
the overall ocular discomfort score at month 6; and had no other major protocol deviations. The PP population 
will be determined prior to database lock.  The primary efficacy variables will be analyzed using the PP 
population on an as-treated basis. 
The safety population is comprised of all patients who received at least 1 dose of study medication.  All safety 
measures will be analyzed on an as-treated basis using the safety population. 
 
 
In general, continuous data will be summarized with descriptive statistics (number of patients, mean, standard 
deviation, median, minimum, and maximum) and will be analyzed using an analysis of variance (ANOVA) 
model or 2-sample t-test for between-group comparisons, and paired t-test for within-group analyses.  
Categorical variables will be summarized by number of patients, frequency count, and percent, and will be 
analyzed using Pearson's chi-square or Fisher's exact test (if the expected cell count is less than 5 in 25% or 
more of the cells).  Ordinal variables will be analyzed using the Cochran-Mantel-Haenszel (CMH) test or the 
Wilcoxon rank-sum test for between-treatment comparisons and the signed-rank test for within-treatment 
comparisons.  Descriptive statistics will be provided for the open-label treatment extension phase.  No statistical 
testing will be performed for this phase. 
Efficacy: 
The primary and secondary efficacy analyses will be performed for the ITT population at the month 6 visit.  
The primary efficacy variable is the complete overall ocular discomfort response at month 6.  A patient will be 
considered to be a complete ocular discomfort responder if the overall ocular discomfort score is 0 at month 6.  
The between-group difference in the proportion of  responders will be analyzed using the CMH method 
stratified by gender and baseline overall ocular discomfort score (1 vs 2 to 3).  
The secondary efficacy variables include change from baseline in TBUT, complete blurred vision response, 
complete corneal sodium fluorescein staining response, complete ocular burning response, change from baseline 
in overall ocular discomfort score, at least 1 grade improvement in overall ocular discomfort score, at least 
2-grade improvement in overall ocular discomfort score, and at least 50% improvement in overall ocular 
discomfort score.  For each of blurred vision, corneal sodium fluorescein staining, and ocular burning, a 
complete responder is a patient with a score of 0.  The continuous secondary efficacy variable, change from 
baseline in TBUT, will be analyzed using an analysis of covariance (ANCOVA) model with treatment, gender, 
baseline overall ocular discomfort score (1 vs 2 to 3) as factors and baseline TBUT as a covariate.  The 
dichotomous secondary efficacy variables (complete blurred vision response, complete corneal staining 
response, and complete ocular burning response) will be analyzed using the CMH method stratified by gender 
and baseline value (1 vs 2 to 3) of the corresponding variable.  Other dichotomous secondary efficacy variables 
derived from the overall ocular discomfort score at month 6 (ie,   1 grade improvement from baseline,  
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 2-grade improvement from baseline, and  50% grade improvement from baseline) will be analyzed using the 
CMH method stratified by gender and baseline overall ocular discomfort score (1 vs 2 to 3).  The change from 
baseline in overall ocular discomfort will be analyzed by an ANCOVA model with treatment and gender as 
factors and baseline overall ocular discomfort score as a covariates.     
Safety: 
Safety measures will be analyzed using the safety population.  Medical Dictionary for Regulatory Activities 
(MedDRA) nomenclature will be used to code adverse events.  Incidence rates of each treatment-emergent 
adverse event will be summarized by primary system organ class and preferred term.  Summary tables will be 
generated for all treatment-emergent adverse events regardless of causality as well as for those considered to be 
treatment-related. 
Sample Size Calculation: 
The total number of patients planned for this study is 527 patients including an estimated 10% attrition rate.  
The sample size was estimated based on the primary efficacy analysis to compare the proportion of patients 
with complete overall ocular discomfort response (defined as overall ocular discomfort score equals 0) at 
Month 6. 
Based on the final analysis of an Allergan phase 2 study (protocol 195263-006), the observed proportion of 
patients with complete overall ocular discomfort response over a 7-day average is 20.0% vs 9.8% (between-
group difference of 10.2%) for 0.1% AGN-195263 versus vehicle, respectively.  A total of 237 patients per 
treatment group will achieve 85% power with type I error rate of 0.05 to detect a between-group difference of 
10.2% in the proportion of patients with complete overall ocular discomfort response at Month 6.  This is based 
on the two-sided z-test (pooled variance with continuity correction), as implemented in the commercial 
software, PASS 2008 (Inequality Tests for Two Proportions), version 08.0.13 (Hintze, 2008).  Accounting for 
an anticipated attrition rate of 10%, enrollment of a total of 527 patients at multiple sites is planned. 
 
 
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1. 
Background and Clinical Rationale 
In 2007, the International Dry Eye Workshop (DEWS, 2007) defined dry eye disease (DED) 
as “a multifactorial disease of the tears and ocular surface that results in symptoms of 
discomfort, visual disturbance, and tear instability with potential damage to the ocular 
surface.  It is accompanied by increased osmolarity of the tear film and inflammation of the 
ocular surface.” 
DED is broadly attributed to either impaired tear production (aqueous deficient dry eye 
[ADDE]) or evaporative dry eye (EDE) or both.  Either of these changes to the tear film can 
compromise the health of the ocular surface with associated epithelial damage and symptoms 
of discomfort and visual disturbances.  Epidemiological data suggest the prevalence of DED 
falls in the range of 5% to 34% of the global population  50 years (Baudouin et al, 2014; 
Bron et al, 2014; DEWS, 2007; Rolando et al, 2010) and contributes to approximately 25% 
of visits to ophthalmic clinics (Alves et al, 2013; Gayton, 2009).  Epidemiological data 
further suggest that EDE alone may account for 30% to 47% of the overall DED population 
(Lemp and Nichols, 2009; Lemp et al, 2012; Rege et al, 2013).  The tear film lipid layer is 
the major barrier to evaporation from the ocular surface.  A decrease in lipid layer thickness 
or functional integrity is generally considered the primary mechanism leading to EDE.  Such 
changes to the lipid layer are attributed to a reduction in the quality or quantity of meibum 
secretions from the meibomian glands. 
Alterations in meibomian gland physiology can lead to a change in the composition of the 
meibum delivered to the tear film.  Significant changes in meibum composition may lead to 
obstruction of the meibomian glands, producing meibum stagnation and potentially leading 
to gland atrophy.  These changes can act as self-enforcing feedback loops leading to 
progressively larger alterations in the quality or quantity of lipid delivered to the tear film and 
consequently greater tear film instability and more rapid tear evaporation 
(Nelson et al, 2011).  A shorter tear film break-up time (TBUT) based on greater tear film 
instability is characteristic of EDE, resulting in symptoms of ocular discomfort and impaired 
vision. 
Current recommendations for the management and treatment of EDE include:  1) artificial 
tears; 2) lid hygiene (lid heating, massage, and cleaning); 3) thermodynamic treatment such 
as the LipiFlow® System; 4) topical antibiotic and/or topical steroids; and 5) systemic anti-
inflammatory antibiotics (eg, tetracycline).  To date, there is no approved pharmaceutical 
treatment indicated for EDE. 
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Reported risk factors for EDE and MGD have traditionally included age and female gender 
(particularly postmenopausal women), which are both associated with declining androgen 
levels (Azcarate et al, 2014; Gagliano et al, 2014; Nanavaty et al, 2014; Sullivan et al, 2009; 
Truong et al, 2014).  In recent years, EDE has become a more frequently reported 
observation among younger demographics (Cuevas et al, 2012; Lemp and Nichols, 2009).  In 
addition to age and gender, EDE has also been linked to factors which include diet, 
occupational habits, medications, and contact lens wear (Bron et al, 2014). 
 
 
 
 
To date, Allergan has completed 1 phase 1 and 2 phase 2 clinical studies totaling 352 patients 
investigating the safety and efficacy of AGN-195263 
 for DED 
and MGD, and an additional phase 2 study with a 
 formulation 
of AGN-195263 was completed. 
The phase 1 clinical study (Study 195263-001) evaluated the safety and pharmacokinetics of 
AGN-195263 
 in postmenopausal 
women administered twice daily for 14 days.  The first phase 2 study (Study 195263-003) 
evaluated the dose response relative to safety, tolerability, and efficacy of 
AGN-195263 0.01%, 0.1%, and 0.3% 
 in patients with 
keratoconjunctivitis sicca (KCS), also called DED, administered twice daily for 4 months.  
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The second phase 2 study (Study 195263-004) evaluated the safety and efficacy of 
AGN-195263 0.01%, 0.03%, and 0.1%
 in patients with MGD 
administered twice daily for 6 months. 
In all 3 studies with AGN-195263
, all concentrations were safe 
and well-tolerated.  
 
 
 
 
 
 
 
 
 
 
Efficacy data from Studies 195263-003 and 195263-004 suggested that treatment with 
AGN-195263 
 was associated with a reduction in overall ocular 
discomfort and with an increase in TBUT. 
 
 
 
 
 
 
 
 
 
 
 
 
 
A phase 2 study evaluating the safety and efficacy of AGN-195263 0.01%, 0.03%, and 0.1% 
 was recently completed.  All concentrations were safe and well 
tolerated.  Efficacy data  demonstrated that the percentage of patients who were overall 
ocular discomfort responders at month 6 (a patient is considered to be an ocular discomfort 
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responder if the overall ocular discomfort score is 0 on a 0 to 4 scale; 0 = none, 4 = very 
severe) was numerically greater in patients receiving active compared to vehicle at month 6.  
In addition, an improvement in the mean change in TBUT at month 6 relative to baseline in 
patients receiving active compared to vehicle was also observed.  Overall, the 0.1% 
concentration of the 
 formulation most consistently demonstrated improvements in 
both symptoms as well as in TBUT relative to vehicle.  An exploratory analysis of patients 
with low TBUT ( 7 seconds) characteristics of EDE was also performed.  In this subgroup 
of patients, the 0.1% concentration continued to demonstrate the most consistent overall 
improvement relative to vehicle across symptoms and TBUT after 6 months of treatment. 
Overall, the clinical data collected supports the safety of the topical ophthalmic formulation 
of AGN-195263 in patients with DED and patients with MGD.  Data from the 2 phase 2 
studies with 
 formulation of AGN-195263 and 1 phase 2 study with the
 
formulation of AGN-195263, demonstrate improvement in overall ocular discomfort and 
TBUT, with the most consistent overall improvement achieved with the 0.1% concentration. 
Given our current understanding of DED, 0.1% AGN-195263 
 
represents a potential therapeutic treatment option for EDE.  The phase 3 pivotal superiority 
study proposed herein is designed to provide required safety, efficacy, and systemic 
pharmacokinetic data to support an indication for the treatment of EDE with 0.1% 
AGN-195263
 
2. 
Study Objectives and Clinical Hypotheses  
2.1 
Study Objectives 
 To evaluate the safety and efficacy of 0.1% AGN-195263 administered twice daily 
compared to its vehicle in patients with EDE 
 To evaluate the systemic pharmacokinetics of 0.1% AGN-195263 administered twice 
daily in patients with EDE 
2.2 
Clinical Hypotheses 
One drop of 0.1% AGN-195263 administered twice daily to each eye: 
 Is more effective than vehicle as measured by the proportion of patients with 
complete overall ocular discomfort response at month 6 
 Has an acceptable safety profile throughout the study treatment duration of 12 months 
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3. 
Study Design 
This is a multicenter, global, randomized, parallel-group, vehicle-controlled study with 
6 months of double-masked treatment followed by a 6 month open label treatment extension 
phase evaluating the safety, efficacy, and systemic pharmacokinetics of 0.1% AGN-195263 
in patients with EDE. 
Patients will be randomized to receive 0.1% AGN-195263 or its vehicle in a 1:1 ratio.  The 
randomization will be stratified by gender and by baseline (day 1) overall ocular discomfort 
score (1 vs 2 to 3). 
There will be up to 9 study visits including:  screening (day -51), standardization (day -21), 
vehicle run-in (day -14), baseline (randomization, day 1), months 1, 3, 6 (primary and 
secondary efficacy assessments), 9, and 12/study exit (safety assessments). 
The duration of the study for each patient will be up to approximately 14 months. 
Use of lid hygiene (ie, warm compress, lid massage, lid scrub) or artificial tears (other than 
study artificial tears [SAT]) are prohibited from the standardization (day -21) visit until the 
end of the month 6 visit.  Allergan will supply SAT (see Study Procedures Manual for further 
details).  Starting at the standardization (day -21) visit, all eligible patients will administer 
SAT twice daily in each eye for 6 days.  From the vehicle run-in (day -14) visit until the 
month 6 visit, use of SAT will be considered rescue therapy for intolerable symptoms.  After 
the month 6 visit until the month 12/study exit visit, use of lid hygiene and/or any artificial 
tear product(s) will be unrestricted. 
3.1 
Additional Study Design Details 
With respect to details described below for each study visit: 
1. For patients not participating in the collection of blood samples for pharmacokinetic 
analysis, study treatment should be administered in the morning at approximately the 
same time of day during each office visit (± 1 hour from the study administration time 
at baseline [day 1]).  At any time, the morning dose time should not exceed 1:00 pm 
local time. 
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2. For patients that participate in the collection of blood samples for pharmacokinetic 
analysis: 
a. the time of the pre-dose blood sample collection should be scheduled in the 
morning at approximately the same time of day during each office visit 
(± 1 hour from the pre dose blood sample collection time at the standardization 
(day -21) visit). 
b. SAT or study treatment should be administered in the morning at approximately 
the same time of day during each office visit and within 10  min after the time 
the pre-dose blood sample collection was performed that day. 
Screening Visit (day -51): A patient may enter a screening period if, at the screening visit, 
applicable medications or treatments are required to be washed out or administered at a stable 
dose (Section 4.5), prior to commencement of the standardization (day -21) visit.  If a 
screening period is not applicable, the screening and standardization visits may occur on the 
same day (day -21).  For those patients that do enter the screening period, their 
standardization visit should be scheduled 7±1 days prior to the vehicle run-in (day -14) visit. 
Standardization Visit (day -21):  Eligible patients will discontinue use of any lid hygiene 
(ie, warm compress, lid massage, lid scrub) or artificial tears (other than SAT) and will begin 
administering 1 drop of SAT in each eye twice daily (morning and evening, spaced 
approximately by 12 hours) for 6 days.  For selected patients, blood sample collection for 
systemic pharmacokinetics will occur prior to in-office administration of SAT and for 
12 hours after administration of SAT at the following intervals: 5 ± 1 min; 10 ± 1 min; 
30 ± 5 min; 2 hrs ± 15 min;4 hrs ± 30 min; 6 hrs ± 30 min; 12 hrs ± 30 min.  Following the 
12 hour sample collection, site staff will remind patient to administer 1 drop of SAT in each 
eye prior to leaving site. 
Vehicle Run-in Visit (day -14):  All patients will enter a 2-week, patient-masked run-in on 
vehicle, where 1 drop of 0.1% AGN-195263 vehicle will be administered twice daily 
(morning and evening, spaced approximately by 12 hours) in each eye.   
Baseline Visit (Randomization to Study Treatment and Initiation of Twice Daily Dosing 
[day 1]):  Patients will be randomized on day 1 to receive either 0.1% AGN-195263 or its 
vehicle, administered as a single drop, twice daily (morning and evening, spaced 
approximately by 12 hours) in each eye.  Both patient and investigator will be masked. 
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Month 1 Visit: Office visit during the randomized study treatment period.  For selected 
patients, blood sample collection for systemic pharmacokinetics will occur (at same time ± 1 
hour of pre-dose blood sample collection at the standardization (day -21) visit) prior to in-
office administration of study treatment and for 12 hours after administration of study 
treatment at the following intervals:  5 ± 1 min; 10 ± 1 min; 30 ± 5 min; 2 hrs ± 15 min; 4 hrs 
± 30 min; 6 hrs ± 30 min; 12 hrs ± 30 min.  Following the 12 hour sample collection, site 
staff will remind patient to administer 1 drop of study treatment in each eye prior to leaving 
site. 
Month 3 Visit:  Office visit during the randomized study treatment period.  For selected 
patients, a single blood sample collection for systemic pharmacokinetics will occur (at same 
time ± 1 hour of pre-dose blood sample collection at the standardization (day -21) visit) prior 
to in-office administration of study treatment. 
Month 6 Visit:  Primary and secondary efficacy will be assessed at the month 6 visit, after 
which the open-label treatment extension period starts.  All patients will receive 
0.1% AGN-195263, administered as a single drop, twice daily (morning and evening, spaced 
approximately by 12 hours) in each eye.  Both patient and investigator will be unmasked.  
For selected patients, blood sample collection for systemic pharmacokinetics will occur (at 
same time  ± 1 hour of pre-dose blood sample collection at the standardization (day -21) 
visit) prior to in-office administration of study treatment and 10 ± 1 min  after administration 
of study treatment. 
Month 9 Visit:  Office visit during the open-label treatment extension period.  For selected 
patients, a single blood sample collection for systemic pharmacokinetics will occur (at same 
time  ± 1 hour of pre-dose blood sample collection at the standardization (day -21) visit), 
prior to in-office administration of study treatment. 
Month 12 / Study Exit / Early Exit Visit: For selected patients, a single blood sample 
collection for systemic pharmacokinetics will occur (at same time  ± 1 hour  of pre-dose 
blood sample collection at the standardization (day -21) visit), prior to in-office 
administration of study treatment. 
The patient or patient’s caregiver may instill the study treatment.  Patients will be instructed 
to not administer their morning dose of study treatment the day of each study visit.  The 
morning dose of SAT at the standardization visit (day -21) and of study treatment at the 
vehicle run-in (day -14), baseline (day 1) and month 1, 3, 6 and 9 visits will be administered 
by site staff. 
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4. 
Study Population and Entry Criteria 
4.1 
Number of Patients 
Approximately 527 patients are planned to be enrolled in this study across approximately 
50 global sites. 
4.2 
Study Population Characteristics 
Evaporative dry eye (EDE) 
4.3 
Inclusion Criteria 
The following are requirements for entry into the study: 
 
 
 
 
 
 
3. Male, 18 years of age or older, at the screening (day -51) visit 
OR  
Females, 18 years of age or older, who are naturally menopausal (permanent cessation of 
menstrual periods for at least 12 consecutive months) or are permanently sterilized (eg, 
tubal occlusion, hysterectomy, bilateral salpingectomy, and/or bilateral oophorectomy) at 
the screening (day -51) visit 
4. In at least 1 eye, all of the following objective measures of EDE must be present at the 
standardization (day -21) and baseline (day 1) visits.  The same eye must qualify at both 
visits. 
 TBUT  2 seconds and  7 seconds 
 Corneal sodium fluorescein staining score  1 and < 4 (Oxford scheme) 
 Anesthetized Schirmer’s tear test score  10 mm after 5 minutes 
5. At the standardization visit (day -21) and baseline (day 1) visits, patients must have: 
 Ocular Surface Disease Index© (OSDI) score > 12 (0 to 100 scale) 
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Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
28 
GDD-TA-T-004 v2015.10 
 
 
 Overall ocular discomfort score  1 and < 4 (0 to 4 scale; 0 = none, 4 = very 
severe) 
 Ocular burning score  1 and < 4 (0 to 4 scale; 0 = none, 4 = very severe) 
 Blurred vision score  1 and < 4 (0 to 4 scale; 0 = none, 4 = very severe) 
6. In at least 1 eye, a lower lid margin meibum quality global assessment score  1 at the 
standardization (day -21) and baseline (day 1) visits.  The same eye must qualify at both 
visits. 
7. In at least 1 eye, the number of lower lid margin expressible meibomian glands must be 
 3 at the standardization (day -21) and baseline (day 1) visits.  The same eye must 
qualify at both visits. 
 
 
 
 
 
 
11. Use of an artificial tear product, lid hygiene (ie, warm compress, lid massage, lid scrub), 
omega-3 supplementation (topical ocular or systemic), or antibiotics (ie, systemic or 
topical macrolides, tetracyclines, tetracycline derivative drugs [including doxycycline 
and minocycline]) for the treatment of dry eye disease or meibomian gland disease 
within 1 year of the standardization (day -21) visit. 
4.4 
Exclusion Criteria 
The following are criteria for exclusion from participating in the study: 
 
 
2. At standardization (day -21) and/or  baseline (day 1) visits, a lower lid margin meibum 
quality global assessment score of NE (non-expressible) in either eye 
 
 
 
 
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Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
29 
GDD-TA-T-004 v2015.10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol 195263-009 Amendment 2 
 
 
 
 
30 
GDD-TA-T-004 v2015.10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
16. Male patients with a history of, known, or suspected prostate cancer 
17. Male patients with a prostate-specific antigen (PSA) level  4 μg/L 
 
 
19. Female patient who is of child-bearing potential 
20. Female patients with a history of known or suspected breast, cervical, ovarian, or 
uterine cancer 
 
 
 
 
 
 
 
 
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Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
31 
GDD-TA-T-004 v2015.10 
 
 
 
  
 
 
25. Patients who are currently using or have used any androgen or anti-androgen treatment 
(including herbal and nutritional supplements) 
 
 
 
 
 
 
 
within 90 days of the standardization (day -21) visit or anticipated use during 
the study 
 
 
 
 
27. Patients who are currently using or have used systemic or topical macrolides, 
tetracyclines, tetracycline derivative drugs (including doxycycline and minocycline), 
retinoids (eg, isotretinoin), calcineurin inhibitors (ie, RESTASIS, Ikervis), oral 
(systemic) corticosteroids, lifitegrast (Xiidra™) or any other therapeutic dry eye 
treatment within 60 days of the standardization visit (day -21), or anticipated use 
before the month 6 visit 
28. Patients who are currently using or have used any hair growth product within 90 days 
of the standardization (day -21) visit or anticipated use during the study 
 
 
 
 
 
   
 
 
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Approval Date: 	
Allerg
 
 
 
 
4.5 
4.5.1
The f
stand
the m
antici
gan Confidentia
Pe
 
Pe
1
following me
dardization (d
minimum num
ipated contin
al 
ermissible
ermissible
edications li
day -21) visi
mber of days
nuation on th
e and Proh
e Medicati
sted in Table
it and the mo
s listed in Ta
he same dose
 
32 
 
hibited Me
ions/Treat
e 2 are perm
onth 12/stud
able 2 prior t
e until at lea
P
edications/
tments 
missible durin
dy exit visits
to the standa
ast the month
Protocol 19526
GD
/Treatmen
ng the interv
if they have
ardization (d
h 6 visit: 
63-009 Amendm
DD-TA-T-004 v2
nts 
val between t
e been taken 
day -21) visit
ment 2 
2015.10 
the 
for 
t and 
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Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
33 
GDD-TA-T-004 v2015.10 
 
 
Table 2 
Permissible Medications That Require Stable Dosing Prior to the 
Standardization (Day -21) Visit and Anticipated Continuation on 
the Same Dose Until at Least the Month 6 Visit 
30 Days 
Before Standardization (day -21) Visit 
60 Days 
Before Standardization Visit 
90 Days  
Before Standardization Visit 
Systemic antihistamines 
Systemic beta-blocking agents 
 
Systemic antimuscarinics 
Systemic cholinergic agonists 
Systemic medications used to 
treat mild to moderate systemic 
autoimmune disorders1 
 
Estrogen and/or progesterone 
containing products (including 
herbal and nutritional 
supplements) 
Diuretics 
Inhaled corticosteroids 
 
Tricyclic antidepressants 
 
 
Phenothiazines 
 
 
Systemic vitamins and/or systemic 
supplements containing:  omega 3 
fatty acids; vitamins A, B, and E; 
fish oil; biotin, or Evening Primrose 
oil 
 
 
Note:  any medication previously noted as an exclusion criteria (ie: systemic corticosteroids, calcineurin inhibitors, etc) must 
follow details noted for prohibited medications. 
 
In addition, the following medications are permissible during the interval between the 
standardization (day -21) visit and the month 12/study exit visits: 
 oral nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen (as needed) 
 dermal or nasal corticosteroids (as needed) 
The use of any artificial tear product is permissible after the month 6 visit to the 
month 12/study exit visit. 
The use of lid hygiene (ie, warm compress, lid massage, lid scrub) on either eye is 
permissible after the month 6 visit to the month 12/study exit. 
Therapy considered necessary for the patient's welfare may be given at the discretion of the 
investigator.  If the permissibility of a specific medication/treatment is in question, please 
contact Allergan. 
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Approval Date: 	
Allerg
 
 
 
 
4.5.1
For p
are na
bilate
perm
exper
physi
For m
recom
the ph
If a fe
notify
(1) ob
progr
pregn
4.5.2
Lid h
interv
Conta
(day 
The f
are pr
 
 
The f
scree
 
gan Confidentia
1.1 
D
A
purposes of t
aturally post
eral salpinge
manent cessat
rienced 12 m
iological cau
male patients
mmended tha
hase 3 study
female partne
y Allergan im
btain consen
ress of the pr
nancy and pr
 
Pr
2
hygiene (ie, w
val between 
act lens wea
-21) visit an
following fac
rohibited for
plucking o
laser, wax
days of an
following pr
ning (day -5
punctal ca
al 
efinition o
Acceptable 
his study, fe
tmenopausal
ectomy, and/o
tion of mens
months of am
use. 
s with a preg
at a barrier m
y and for 24 h
er of a male 
mmediately 
nt from the fe
regnancy to 
rovide a copy
rohibited 
warm compr
the standard
ar in either ey
nd month 12/
cial hair rem
r female pati
or shaving w
xing, sugarin
ny study visi
ocedures are
51) visit and 
autery 
of Females
Contrace
males will b
l or permane
or bilateral o
trual periods
menorrhea wi
gnant partner
method of co
hours follow
patient beco
after the pre
emale partne
term.  The in
y of the docu
Medicatio
ress, lid mas
dization (day
ye is prohibi
/study exit v
moval proced
ients during 
within 14 day
ng, depilatory
it 
e prohibited 
month 12/st
 
34 
 
s of Childb
eptive Met
be considered
ently sterilize
oophorectom
s, determine
ithout any ot
r or a female
ontraception 
wing the last 
omes pregnan
egnancy is co
er for pregna
nvestigator m
umentation t
ons/Treatm
sage, lid scru
y -21) visit an
ited during th
visit. 
dures applied
the interval 
ys of any stu
y product, or
in either eye
tudy exit vis
P
bearing Po
thods 
d of childbea
ed (ie, tubal 
my).  Natural
d retrospecti
ther obvious
e partner of c
be employe
dose of stud
nt during the
onfirmed.  T
ancy follow-
must docum
to Allergan.
ments/Proc
rub) on eithe
nd month 6
he interval b
d to chin, che
prior to each
udy visit 
r any other r
e during the 
it: 
Protocol 19526
GD
otential an
aring potent
occlusion, h
l menopause
ively after a 
s pathologica
child bearing
ed for the ent
dy treatment
e study, the i
The investiga
-up and (2) f
ment the outc
cedures 
er eye is proh
visit. 
between the 
eek, upper li
h study visit
removal proc
interval betw
63-009 Amendm
DD-TA-T-004 v2
nd/or 
tial unless th
hysterectomy
e is defined a
woman has
al or 
g potential, i
tire duration
t. 
investigator 
ator will  
follow the 
ome of the 
hibited durin
standardizat
ip, and/or br
t:  
cess within 3
ween the 
ment 2 
2015.10 
hey 
y, 
as the 
 
it is 
n of 
will 
ng the 
tion 
row 
30 
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Approval Date: 	
Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
35 
GDD-TA-T-004 v2015.10 
 
 
 anterior segment surgery in either eye which could affect corneal sensitivity 
(eg, cataract surgery, corneal refractive surgery, or any surgery involving a limbal or 
corneal incision) 
 use of any type of punctal plug (eg, nondissolvable or collagen)  
 use of any type of scleral lenses 
 use of LipiFlow or other lid-heating therapy, meibomian gland probing, or therapeutic 
gland expression 
 use of sealed compartment ocular frames 
 upper or lower lid tattooing 
The following medications listed in Table 3 are prohibited during the interval between the 
standardization (day -21) visit and the month 6 visit: 
Table 3 
Prohibited Medications Within the Period Indicated Prior to the 
Standardization (Day -21) Visit to Month 6 Visit 
At the Standardization Visit 
Within 60 Days 
Before Standardization Visita 
All artificial Tears except SAT  
Systemic or topical macrolides 
 
Topical corticosteroids in the eyes or on the eyelids 
Oral (systemic) corticosteroids 
Tetracycline 
 
Tetracycline derivatives (eg, doxycycline, 
minocycline) 
 
Retinoids (eg, isotretinoin) 
 
Calcineurin inhibitors (eg, RESTASIS, Ikervis) 
Lifitegrast (Xiidra) 
Other therapeutic treatments of dry eye 
a  all medications listed in table are permissible following the Month 6 visit. 
The following medications listed in Table 4 are prohibited during the interval between the 
standardization (day -21) visit and the month 12/study exit visits: 
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Approval Date: 	
Allerg
 
 
 
 
Table
Within
Before
Visit 
Topica
medic
Topica
(includ
supple
 
 
 
 
 
 
 
GnRH
 
The d
study
befor
4.5.3
Aller
the st
rescu
medi
the st
gan Confidentia
e 4 
n 30 Days 
e Standardizati
al ocular glauc
ations 
al ocular allerg
des herbal and 
ements) 
H = gonadotrop
decision to a
y participant 
re the prohib
 
R
3
rgan provide
tudy (from th
ue medication
cation, SAT 
tudy treatme
al 
Prohib
Standa
the Stu
ion (day -21) 
coma 
gy medications
nutritional 
pin-releasing ho
administer a 
as the prima
bited medicat
Rescue Med
d artificial te
he vehicle ru
n for intolera
should be in
ent. 
bited Medic
ardization (
udy 
Within 60 
Before Sta
Visit 
Eyelash gr
LATISSE)
 
 
 
 
 
 
 
 
 
ormone 
prohibited m
ary considera
tion/treatme
dications o
ears (SAT, se
un-in (day -1
able sympto
nstilled at lea
 
36 
 
cations With
(Day -21) Vi
Days 
ndardization (d
rowth stimulato
) 
medication/tr
ation.  When
nt is admini
or Treatm
ee Study Pro
14) visit unti
ms.  In orde
ast 30 minut
P
hin the Peri
isit and Thr
day -21) 
W
B
V
ors (eg, 
A
tr
n
5
(
b
i
S
I
(
A
(
n
G
n
g
d
C
H
reatment is d
n possible, A
stered. 
ments 
ocedures Ma
il the month 
er to avoid di
tes before or
Protocol 19526
GD
iod Indicate
roughout th
Within 90 Day
Before Standar
Visit 
Androgen or an
treatment (inclu
nutritional supp
5-alpha reducta
(eg, finasteride
bexlosteride, ep
zonsteride, lap
Spironolactone
Inhibitors of ste
(eg, ketoconazo
Androgen recep
(eg, flutamide, 
nilutamide, gal
GnRH agonists
nafarelin, leupr
goserelin, tripto
deslorelin) 
Cyproterone ac
Hair growth pro
done with th
Allergan shou
anual) may b
6 visit) only
ilution of the
r 30 minutes 
63-009 Amendm
DD-TA-T-004 v2
ed Prior to t
he Duration
s 
rdization (day -
nti-androgen 
udes herbal and
plements) 
ase inhibitors 
, dutasteride, 
pristeride, 
pisteride, turost
e 
eroidogenesis 
ole, abiraterone
ptor antagonist
bicalutamide, 
leterone, MDV
s (eg, deslorelin
rolide, busereli
orelin, histrelin
cetate 
oducts 
he safety of th
uld be notifi
be used durin
y as needed a
e study 
after each u
ment 2 
2015.10 
the 
 of 
-21) 
d 
teride) 
e) 
ts 
V3100) 
n, 
in, 
n, 
he 
ied 
ng 
as 
use of 
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Approval Date: 	
Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
37 
GDD-TA-T-004 v2015.10 
 
 
Patients will be asked to refrain from use of SAT for 1 day prior to each study visit.  “One 
day prior to each study visit” is defined as the morning of the day before the study visit and 
continues until the end of the study visit. 
At each visit, patients will be asked about their use of artificial tears (SAT) by responding to 
the following 2 questions:  1) number of times used during the day prior to the study visit, 
and 2) how many times used per day on average over the week prior to the study visit. 
5. 
Study Treatments 
5.1 
Study Treatments and Formulations 
0.1% 
 (AGN-195263)
 
 
 
 
 
5.2 
Control Treatment 
The control treatment in this study is a vehicle of 0.1%
 
(AGN-195263)
  The vehicle contains the same inactive ingredients as that of the 
0.1% AGN-195263, but does not contain the drug substance. 
5.3 
Methods for Masking 
During the vehicle run-in period (days -14 to -1), the patient will be masked to the run-in 
study treatment he/she receives.  In order to maintain the masking of study vehicle during the 
vehicle run-in period (and to obtain unbiased ocular symptoms), patients will be informed 
and consented that they will receive vehicle for a 2-week period during their study 
participation.  Following the vehicle run-in period, the investigator and patient will be 
masked during the randomized study treatment phase (baseline (day 1) to month 6 visit).  All 
study treatments will be provided in identical unit dose vials and cartons to maintain masking 
of the study.  From the end of the month 6 visit until the month 12/study exit visit (the open-
label treatment extension phase), the investigator and patient will be unmasked. 
5.4 
Treatment Allocation Ratio and Stratification 
At the time of randomization (baseline, day 1), patients will be randomly assigned in a 
1:1 ratio to receive either 0.1% AGN-195263
 or its vehicle 
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Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
38 
GDD-TA-T-004 v2015.10 
 
 
during the randomized study treatment phase.  Patients will be stratified by gender and 
baseline (day 1) overall ocular discomfort score (1 vs 2 to 3).  There will be 4 stratification 
groups as shown in Table 5. 
Table 5 
Stratification Groups 
Stratification Group 
Gender 
Baseline Overall Ocular Discomfort Score 
1 
Male 
1 
2 
Male 
2 to 3 
3 
Female 
1 
4 
Female 
2 to 3 
 
5.5 
Method for Assignment to Treatment Groups/Randomization 
Prior to initiation of screening procedures, each patient will provide informed consent.  At the 
standardization (day -21) visit the site will call the interactive voice response system (IVRS) 
or log onto the interactive web response system (IWRS) to obtain the patient number that 
will serve as the patient identification number on all study documents. 
An automated interactive (telephone or web) response system (IxRS) will be used to manage 
the run-in and randomization study treatment assignment based on randomization schemes 
prepared by Allergan Biostatistics.  Study medication, including the run-in vehicle, will be 
labeled with medication kit numbers and shipped to each site. 
At the time of enrollment at the vehicle run-in visit (day -14), all eligible patients will be 
assigned vehicle.  At the patient’s vehicle run-in visit, the IxRS system will provide the site 
with the specific medication kit number(s) to use for each qualified patient. 
At the time of the baseline visit (randomization, day 1), patients meeting the 
inclusion/exclusion criteria (Sections 4.3 and 4.4) will be placed into 1 of 4 stratification 
groups as described in Section 5.4.  Eligible patients will be randomly assigned to receive 
either 0.1% AGN-195263
 or its vehicle in a 1:1 treatment 
allocation.  Based on the randomization scheme, a randomization number associated with 1 
of the 2 treatment arms will be assigned to each patient sequentially according to the order of 
enrollment within the patient’s stratification group.  That is, IxRS will assign the next 
available randomization number for the stratification group to the patient at the time the 
investigator requests randomization.  IVRS/IWRS will report a medication kit number to use 
for each patient corresponding to the randomization number. 
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Approval Date: 	
Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
39 
GDD-TA-T-004 v2015.10 
 
 
The site will dispense the study medication kit assigned by the IxRS according to the 
IVRS/IWRS instructions.  Sites will also call the IVRS or log onto the IWRS at all 
subsequent visits to obtain a study medication kit number for dispensing study medication.  
Sites will receive the IxRS confirmation notifications for each transaction.  All notifications 
are to be maintained with the study source documents. 
5.6 
Treatment Regimen and Dosing 
All eligible patients will receive a 2-week (days -14 to -1) patient-masked run-in on vehicle 
instilled as a single drop twice daily in each eye.  At baseline (randomization, [day 1]), upon 
meeting inclusion/exclusion criteria, patients will be randomized to 0.1% AGN-195263 or its 
vehicle to be administered as a single drop, twice daily (morning and evening) in each eye 
for 6 months (baseline [day 1] to month 6 visits).  Starting at the month 6 visit, all patients 
will administer 0.1% AGN-195263 as a single drop, twice daily (morning and evening) in 
each eye for an additional 6 months (month 6 to month 12). 
The patient or patient’s caregiver may instill the SAT (during standardization period) and 
study treatment.  Twice-daily (morning and evening) SAT (during standardization period) and 
study medication should be instilled approximately 12 hours apart each day at approximately 
the same times.  Patients will be instructed to not administer their morning dose of SAT 
(prior to Vehicle Run-In (day -14) visit) or study treatment on the day of each study visit. 
5.7 
Storage of Study Medications/Treatments 
The study treatment  and SAT must be stored in a secure isolated area (ie, with no other 
medication, supplies, documents, etc) and administered only to patients entered into the 
clinical study, at no cost to the patient, in accordance with the conditions specified in this 
protocol.  Since the active study treatment includes 
, the site and all 
principal/sub-investigators must have the appropriate national prescribing registration for 
handling controlled substances for the same location (ie, address) where patient visits take 
place or per applicable country regulations. 
All study treatments must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorized site staff.  Sites should monitor temperature 
conditions and report any temperature excursions to their site monitor or Allergan personnel.  
Please refer to the Procedure Manual for further details on drug storage and instructions on 
reporting temperature excursions. Study treatment and SAT are not to be frozen. 
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


Approval Date: 	
Allerg
 
 
 
 
Aller
6. 
6.1 
6.1.1
 
6.1.2
 
 
 
 
 
gan Confidentia
rgan or Aller
Re
Ef
 
Pr
1
Overall oc
 
Se
2
TBUT (se
blurred vi
corneal so
ocular bur
derived va
 1 grade 
 50%  im
al 
rgan designe
esponse M
fficacy Me
rimary Ef
cular discom
econdary E
econds) 
ision score (0
odium fluore
rning score (
ariables base
improveme
mprovement 
e will perfor
Measures a
easures 
fficacy Me
mfort score (0
Efficacy M
0 to 4 scale; 
escein stainin
(0 to 4 scale
ed on overal
nt from base
from baselin
 
40 
 
rm reconcilia
and Summ
easure 
0 to 4 scale; 
Measures
0 = none, 4 
ng (0 to 5 Ox
; 0 = none, 4
ll ocular disc
eline,  2 gra
ne) 
P
ation on unu
mary of Da
 0 = none, 4 
 = very seve
xford schem
4 = very seve
comfort scor
ade improve
Protocol 19526
GD
used study tr
ata Collect
 = very seve
ere) 
me) 
ere) 
re (change fr
ement from b
63-009 Amendm
DD-TA-T-004 v2
reatment. 
tion Metho
ere) 
rom baseline
baseline and 
ment 2 
2015.10 
ods 
e, 
d
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
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


Approval Date: 	
Allerg
 
 
 
gan Confidential 
 
41 
 
Protocol 19526
GD
63-009 Amendm
DD-TA-T-004 v2
ment 2 
2015.10 
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
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


Approval Date: 	
Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
42 
GDD-TA-T-004 v2015.10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.3 
Safety Measures 
 adverse events 
 BCVA (LogMAR)  
 biomicroscopy 
 ophthalmoscopy 
 intraocular pressure (IOP) 
 urine pregnancy test (female patients only) 
 PSA (male patients only) 
 hematology, serum chemistry, and urinalysis 
 vital signs 
 male scalp hair evaluation assessed by the investigator using the Norwood Male 
Pattern Baldness grading scale 
 female hair evaluation (upper lip, chin, cheeks, and scalp) assessed by the investigator 
using the Ferriman and Gallwey scoring (0 to 4) scale for facial hair and the Female 
Androgenetic Alopecia Ludwig grading scale for the scalp 
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


Approval Date: 	
Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
43 
GDD-TA-T-004 v2015.10 
 
 
6.5 
Summary of Methods of Data Collection 
This protocol will use electronic case report forms (eCRFs) with remote data capture through 
a qualified third-party vendor.  Data entered into the eCRF will correspond to, and be 
supported by, source documentation maintained at the sites.  The investigator is responsible 
for ensuring that data are properly recorded on each patient’s eCRFs and related documents.  
The data will be entered on the eCRFs in a timely manner and on an ongoing basis.  Site data 
and images will be transferred to Allergan via electronic media. 
An IxRS will be used to assign patient identification numbers, randomize patients, and 
manage study medication inventory.  Data will be transferred to Allergan on a periodic basis 
throughout the study. 
	

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Approval Date: 	
Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
44 
GDD-TA-T-004 v2015.10 
 
 
7. 
Statistical Procedures 
The primary efficacy analysis will be performed after all patients complete the month 6 visit 
or discontinue from the study prior to the month 6 visit.  The final analysis will be performed 
after all patients exit the study.  There will be separate database locks for the primary analysis 
and final analysis.  Prior to the first database lock a detailed analysis plan (AP) will be 
approved. 
7.1 
Analysis Populations 
There are 3 analysis populations defined for this study: intent-to-treat (ITT), per-protocol 
(PP), and safety. 
The ITT population comprises all randomized patients.  The efficacy variables will be 
analyzed using the ITT population.  The analyses will be performed per the randomization 
schedule. 
The PP population comprises all randomized and treated patients who met the key inclusion 
and exclusion criteria; did not use artificial tears, including SAT, lid hygiene, or other 
prohibited treatments that could impact the overall ocular discomfort score at month 6 and 
had with no other major protocol deviations.  The PP population will be determined prior to 
database lock.  The primary efficacy variable will be analyzed using the PP population on an 
as-treated basis. 
The safety population is defined as all patients who received at least 1 dose of study 
medication.  Safety analyses will be performed on an as-treated basis.  All safety measures 
will be analyzed using the safety population. 
7.2 
Collection and Derivation of Primary and Secondary Efficacy 
Assessments 
Patients will have both eyes treated although only 1 eye is required to qualify based on the 
inclusion/exclusion criteria.  For patients with only 1 qualified eye, the qualified eye will be 
designated as the study eye.  For patients with both eyes qualified, the study eye will be the 
eye with the lower TBUT  at the baseline (day 1) visit.  For patients having both eyes 
qualified and the same TBUT in both eyes, the study eye will be the right eye.  Efficacy 
analyses will be based on the data of the study eye. 
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Allerg
 
 
 
 
7.2.1
The p
The o
which
score
7.2.2
There
 
 
 
 
 
gan Confidentia
 
Pr
1
primary effic
overall ocula
h 0 = none, 
e of 0 will be
 
Se
2
e are total 8 
Change f
The chang
variable.  
each eye. 
Complete
Similar to
based on 
defined as
variable. 
Complete
The comp
efficacy v
fluorescei
Complete
Similar to
assess the
complete 
a seconda
Change f
In additio
discomfor
al 
rimary Ef
cacy variable
ar discomfor
1 = mild, 2 =
e considered 
econdary E
secondary e
from Baselin
ge from base
For TBUT, 
 The mean v
e Blurred Vis
o overall ocu
a 0 to 4 scal
s a blurred v
e Corneal So
plete corneal
variable.  A r
in staining sc
e Ocular Bur
o overall ocu
e burning sym
ocular burni
ary efficacy v
from Baselin
on to the resp
rt score will 
fficacy Var
e is  complet
rt will be ass
= moderate, 
to be a com
Efficacy V
fficacy varia
ne in TBUT
eline in TBU
the mean of
value of the 
sion Respon
ular discomfo
e.  Proportio
vision score o
odium Fluor
l sodium fluo
responder is 
core of 0 bas
rning Respo
ular discomfo
mptom expe
ing response
variable. 
ne in Overal
ponder analy
be compute
 
45 
 
riable 
te overall oc
sessed on a q
3 = severe, a
mplete overal
Variables
ables evaluat
UT will be an
f 3 measurem
study eye w
nse 
ort, blurred v
on of patient
of 0 will be a
rescein Stain
orescein stai
defined as a
sed on the O
onse 
ort and blurr
erienced by p
e defined as 
ll Ocular Dis
ysis, the chan
ed and analyz
P
cular discom
questionnaire
and 4 = very
ll ocular disc
ted at month
nalyzed as th
ments will be
will be used f
vision will b
ts with comp
analyzed as 
ning Respon
ining respon
a patient with
Oxford schem
red vision, a 
patients.  Pro
a burning sc
scomfort Sc
nge from bas
zed as a seco
Protocol 19526
GD
mfort respons
e using a 0 to
y severe.  A p
comfort resp
h 6 as listed b
he first secon
e computed a
for the analy
be assessed b
plete blurred 
a secondary
nse 
nse is defined
h a corneal s
me. 
0 to 4 scale 
oportion of p
core of 0 wil
core 
seline in ove
ondary effica
63-009 Amendm
DD-TA-T-004 v2
se at month 6
o 4 scale on 
patient with 
ponder. 
below.   
ndary efficac
at each visit 
sis. 
by each patie
vision respo
y efficacy 
d as a second
sodium 
will be used
patients with
ll be analyze
erall ocular 
acy variable
ment 2 
2015.10 
6.  
the 
cy 
for 
ent 
onse  
dary 
d to 
h 
ed as 
e. 
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gan Confidentia
 1 Grade
The propo
discomfor
analyzed 
 2 Grade
The propo
change fro
a seconda
 50%  Im
The perce
be compu
[(O
Patients w
responder
variable. 
al 
e Improvem
ortion of pat
rt score from
as a seconda
e Improvem
ortion of pat
om baseline 
ary efficacy v
mprovement
ent change in
uted for each
OODS at mo
with a percen
rs and the pr
ent from Ba
tients who ac
m baseline (ie
ary efficacy v
ent from Ba
tients who ac
in raw over
variable. 
t from Basel
n overall ocu
h patient: 
onth 6 -  OO
nt change  -
roportion of r
 
46 
 
aseline in Ov
chieved  1 g
e, change fro
variable. 
aseline in Ov
chieved  2 g
rall ocular di
line in Overa
ular discomf
ODS at baseli
-50% (ie, im
responders w
P
verall Ocula
grade impro
om baseline 
verall Ocula
grade impro
iscomfort sco
all Ocular D
fort score (O
ine)/OODS a
mprovement 
will be analy
Protocol 19526
GD
ar Discomfo
ovement in o
in raw score
ar Discomfo
ovement from
ore  -2) wil
Discomfort S
OODS) define
at baseline]x
50%) will b
yzed as a sec
63-009 Amendm
DD-TA-T-004 v2
ort Score 
overall ocular
e  -1) will b
ort Score 
m baseline (i
ll be analyze
Score 
ed as below 
x100 
be considere
condary effic
ment 2 
2015.10 
r 
be 
ie, 
ed as 
will 
ed as 
cacy 
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Protocol 195263-009 Amendment 2 
 
 
 
47 
GDD-TA-T-004 v2015.10 
 
 
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Approval Date: 	
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Protocol 195263-009 Amendment 2 
 
 
 
 
48 
GDD-TA-T-004 v2015.10 
 
 

 
7.3 
Hypothesis and Methods of Analysis 
In general, continuous data will be summarized with descriptive statistics (number of 
patients, mean, standard deviation, median, minimum, and maximum) and will be analyzed 
using an analysis of variance (ANOVA) model or 2-sample t-test for between-group 
comparisons and paired t-test for within-group analyses.  Categorical variables will be 
summarized by number of patients, frequency count, and percent, and will be analyzed using 
Pearson's chi-square or Fisher's exact test (if the expected cell count is less than 5 in 25% or 
more of the cells).  Ordinal variables will be analyzed using the Cochran-Mantel-Haenszel 
(CMH) test or the Wilcoxon rank-sum test for between-treatment comparisons and the 
signed-rank test for within-treatment comparisons. 
A 2-sided test with a p-value  0.05 will be considered statistically significant unless 
otherwise stated. 
SAT and Prohibited Treatments Impacting Efficacy Assessment  
Usage of SAT or prohibited treatments described below will be considered to impact the 
efficacy assessments for the visit immediately following the use of SAT or prohibited 
treatments.  The subsequent visits will not be impacted, unless the SAT or prohibited 
treatments are used again prior to any subsequent visits within the timeframe specified below.  
The efficacy data that are determined to be impacted by the usage of SAT or prohibited 
treatment will be considered as missing for the continuous variables with the missing data 
imputation method described below to be implemented.  For the analysis of complete 
response in ocular symptoms, patients will be analyzed as nonresponders for the visits 
impacted by SAT or prohibited treatments. 
 artificial tears (including SAT):  use within 24 hours before each scheduled visit 
(vehicle run-in visit to month 12 visit) 
 lid hygiene:  use at least 8 days out of the 30-day window preceding each scheduled 
visit or any use within 14 days before each office visit 
 any use during the study after the randomization visit of oral or topical macrolides, 
tetracyclines, tetracycline derivative drugs 
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Missi
ITT a
the m
 
 
 
 
7.3.1
The p
The n
respo
of pa
altern
who d
treatm
analy
disco
meth
inclu
strati
group
estim
gan Confidentia
ing Data Im
analyses of th
missing data: 
If the data
efficacy o
assessmen
o Re
su
o Ot
ca
If the data
than lack 
The interm
The missi
patients w
of treatme
 
Pr
1
primary effic
null hypothe
onse, is that 0
tients who a
native hypoth
discontinued
ments within
ysis.  Missing
ontinuation d
od.  The ach
ding the imp
fied by gend
p difference 
mated based o
al 
mputation 
he efficacy v
a is missing 
or use of SAT
nts, 
esponder ana
ubsequent vis
ther analyse
arried forwar
a is missing 
of efficacy, 
mittent miss
ing data at b
who had non-
ent group 
rimary Ef
cacy analyse
sis for the pr
0.1% AGN-1
are complete 
hesis is that 
d from the st
n the impact 
g data due to
due to reason
hievement of
puted data.  T
der and basel
in the respon
on the norma
variables des
because the 
T or other pr
alyses:  the p
sits 
s:  the missin
rd (LOCF) m
because the 
the missing 
ing data will
aseline visit 
-missing bas
fficacy An
es will be per
rimary effica
195263 is no
overall ocul
a between-g
tudy due to l
intervals spe
o other reaso
ns other than
f complete o
The null hyp
line overall o
nder rate wi
al approxima
 
49 
 
scribed below
patient disco
rohibited trea
patient will b
ng data will 
method 
patient disco
data will be
l be imputed
will be impu
seline assess
alyses 
rformed for 
acy variable
o different th
lar discomfo
group differe
lack of effica
ecified will b
ons including
n lack of effic
verall ocular
pothesis will
ocular disco
ll be reporte
ation for the
P
w will use th
ontinued the
atments that
be considere
be imputed 
ontinued the
 imputed usi
d using the L
uted by the m
sment of the
month 6 vis
e, complete o
han vehicle w
ort responder
ence exists. 
acy or used S
be counted a
g intermitten
cacy will be
r discomfort
l be tested us
omfort score 
ed with the c
e binary varia
Protocol 19526
GD
he following
e study due t
t impacts the
ed a non-resp
using the la
e study due t
ing the LOC
LOCF metho
mean value 
variable ana
sit using the I
overall ocula
with respect 
rs at month 6
As described
SAT or other
as non-respo
nt missing vi
e imputed by
t response w
sing the CM
(1 vs 2 to 3)
onfidence in
able. 
63-009 Amendm
DD-TA-T-004 v2
g rules to imp
to lack of 
e efficacy 
ponder at all
st observatio
to reasons ot
CF method. 
od. 
across all 
alyzed regar
ITT populat
ar discomfor
to the propo
6.  The 
d above, pat
r prohibited 
onders in the
isits, early 
y the LOCF 
will be determ
H method 
).  The betwe
ntervals 
ment 2 
2015.10 
pute 
l 
on 
ther 
dless 
ion.  
rt 
ortion 
tients 
e 
mined 
een-
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Allerg
 
 
 
 
7.3.2
There
Secti
treatm
basel
sodiu
using
corre
on th
score
basel
 1-g
impro
be an
score
gan Confidentia
 
Se
2
e are total 8 
on 7.2.2 wil
ment, gender
line TBUT v
um fluoresce
g the CMH m
sponding va
e overall ocu
e will be anal
line overall o
grade improv
ovement from
nalyzed by th
e (1 vs 2 to 3
al 
econdary E
secondary e
l be analyze
r, and baselin
value as a cov
ein staining r
method strati
ariable..  In a
ular discomf
lyzed by an A
ocular discom
vement from
m baseline i
he CMH met
). 
Efficacy A
fficacy varia
d using an a
ne overall oc
variate.  The
response, and
ified by gend
addition, ther
fort score.  C
ANCOVA m
mfort score a
m baseline,  
n overall ocu
thod stratifie
 
50 
 
Analyses 
ables.  Chang
analysis of co
cular discom
e complete b
d complete o
der and base
re are 4 seco
Change from
model with tr
as a covariat
2 grade imp
ular discomf
ed by gender
P
ge from base
ovariance (A
mfort score (
blurred vision
ocular burnin
eline score (1
ondary effica
m baseline in 
reatment and
te.  The prop
provement fr
fort score as
r and baselin
Protocol 19526
GD
eline in TBU
ANCOVA) m
1 vs 2 to 3) a
n response, c
ng response 
1 vs 2 to 3) o
acy variables
overall ocul
d gender as f
portion of pa
rom baseline
s defined in S
ne overall oc
63-009 Amendm
DD-TA-T-004 v2
UT described
model with 
as factors an
complete co
will be anal
of the 
s derived ba
lar discomfo
factors and 
atients with 
e and  50% 
Section 7.2.2
cular discom
ment 2 
2015.10 
d in 
nd the 
rneal 
lyzed 
sed 
ort 
2 will 
mfort 
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Allerg
 
 
 
7.3.4
Safet
Regu
treatm
phase
treatm
exten
comb
0.1%
gan Confidentia
 
Sa
4
ty measures w
ulatory Activ
ment-emerge
e.  In additio
ment will be 
nsion phase b
bined.  This a
% AGN-1952
al 
afety Anal
will be analy
vities (MedD
ent adverse e
on, treatment
summarized
by the treatm
analysis will
63 during th
lyses 
yzed using th
DRA) nomen
events will b
t emergent a
d for random
ment received
l be perform
he study.  Inc
 
51 
 
he safety pop
nclature will 
be summariz
dverse event
mized study t
d during the 
med for the su
cidence rates
P
pulation.  M
be used to c
zed for rando
ts attributed 
treatment ph
randomized
ubset of safe
s for each tre
Protocol 19526
GD
Medical Dicti
code adverse
omized study
to 0.1% AG
hase and ope
d study treatm
ety populatio
eatment-eme
63-009 Amendm
DD-TA-T-004 v2
ionary for 
e events.  The
y treatment 
GN-195263 
en-label treat
ment phase a
on who recei
ergent advers
ment 2 
2015.10 
e 
tment 
and 
ived 
se 
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Approval Date: 	
Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
52 
GDD-TA-T-004 v2015.10 
 
 
event will be summarized separately by (1) preferred term, (2) by primary system organ class 
and preferred term, and (3) by primary system organ class, preferred term and maximum 
severity.  Summary tables will be generated for all treatment-emergent adverse events 
regardless of causality as well as for those considered to be treatment-related. 
Detailed methods for the analyses of safety variables will be described in the AP. 
7.4 
Subgroup Analyses 
Subgroup analyses will be performed for the primary and secondary efficacy variables by 
baseline overall ocular discomfort score (1, 2 to 3), baseline TBUT( 2, > 2 to  4.5, > 4.5 to 
 7, and > 7),  age group, gender, and race. 
7.5 
Pharmacokinetic Analysis  
Pharmacokinetic analysis will be performed on AGN-195263 treated patients only for post 
drug treatment analysis.  To enable only bioanalysis of samples from patients who receive 
active AGN-195263 treatment, the randomization codes will be made available based on 
Allergan internal procedures.
 
 
 
 
  Serum concentrations of SHGB will be measured using 
a validated analytical method.  If the serum concentrations of a given analyte are measurable, 
pharmacokinetic parameters, including peak or maximum drug concentration (Cmax), time to 
achieve the peak concentration (Tmax), and the area under the concentration-time curve from 
time 0 (baseline, prior to study treatment administration) to time of last quantifiable 
concentration (AUC0-last), will be calculated for individual patient concentration and time 
profiles using standard model-independent techniques.  Descriptive statistics (eg, mean, 
standard deviation), if applicable, will be computed for all pharmacokinetic parameters 
calculated. 
7.6 
Sample Size Calculation 
The total number of patients planned for this study is 527 patients including an estimated 
10% attrition rate.  The sample size was estimated based on the primary efficacy analysis to 
compare the proportion of patients with complete overall ocular discomfort response (defined 
as overall ocular discomfort score equals 0) at Month 6. 
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Based
propo
is 20.
vehic
with 
of pa
the tw
527 p
7.7 
There
8. 
This 
6-mo
pharm
scree
(rand
the sc
8.1 
8.1.1
Prosp
criter
8.1.2
The s
inform
must 
only)
priva
treatm
gan Confidentia
d on the fina
ortion of pat
.0% vs 9.8%
cle, respectiv
type I error r
tients with c
wo-sided z-te
 
  A
patients at m
In
e will be no 
St
study will be
onth open lab
macokinetics
ning (day -5
domization, d
chedule of v
Pa
 
O
1
pective patie
ria) will be c
 
In
2
study will be
med consent
also give wr
), and other w
acy requirem
ment. 
al 
al analysis of
ients with co
% (between-g
vely.  A total 
rate of 0.05 
complete ove
est (pooled v
Accounting f
multiple sites 
nterim Ana
interim anal
tudy Visit 
e comprised
bel treatment
s of 0.1% AG
51), standard
day 1), mont
isits and pro
atient Entr
Overview o
ents as define
considered fo
nformed C
e discussed w
t prior to any
ritten author
written docu
ments (where 
f an Allergan
omplete over
group differe
of 237 patie
to detect a b
erall ocular d
variance with
 
for an anticip
is planned.
alyses 
lysis. 
Schedule 
d of a 6-mont
t extension p
GN-195263 
dization (day
ths 1, 3, 6, 9
ocedures and
ry Proced
of Entry Pr
ed by the cri
or entry into 
Consent an
with the pati
y study-relat
rization (US 
umentation in
applicable) 
 
53 
 
n phase 2 stu
rall ocular d
ence of 10.2%
ents per treat
between-grou
discomfort r
h continuity
 
pated attritio
and Proce
th double-m
phase evalua
in patients w
y -21), vehicl
, and 12/stud
d Figure 1 fo
dures 
rocedures
iteria in Sect
this study. 
nd Patient
ent and a pa
ted procedur
sites only), 
n accordance
prior to any 
P
udy (protoco
discomfort re
%) for 0.1% 
tment group
up difference
response at M
y correction),
 
on rate of 10
edures 
masked treatm
ating safety, 
with EDE.  T
le run-in (da
dy exit.  See
or schematic 
s 
tions 4.3 and
t Privacy
atient wishing
res or change
data protect
e with the re
y study-relate
Protocol 19526
GD
ol 195263-00
esponse over
 AGN-19526
p will achieve
e of 10.2% i
Month 6.  Th
, 
 
0%, enrollme
ment phase fo
efficacy, and
There will be
ay -14), base
e Table 1 for 
diagram of t
d 4.4 (inclusi
g to particip
e in treatmen
tion consent 
elevant count
ed procedure
63-009 Amendm
DD-TA-T-004 v2
06), the obse
r a 7-day ave
63 versus 
e 85% powe
in the propor
his is based o
 
 
ent of a total
followed by a
d systemic 
e 9 study vis
eline 
a schematic
the study de
ion/exclusio
pate must giv
nt.  The patie
(European s
try and local
es or change
ment 2 
2015.10 
erved 
erage 
er 
rtion 
on 
 
l of 
a 
sits:  
c of 
esign. 
on 
ve 
ent 
sites 
l 
 in 
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8.2 
Each 
and d
A pat
exclu
See S
8.3 
Evalu
possi
that e
discu
The f
inform
listed
shoul
perfo
study
8.3.1
The f
 
 
gan Confidentia
Pr
patient’s me
determined to
tient is consi
usion criteria
Section 5.5 f
Vi
uations shou
ible.  If it is n
evaluations s
uss findings f
following se
mation on th
d in this secti
ld be perform
ormed in the 
y visit, the re
 
Sc
1
following pr
Informed 
Demograp
al 
rocedures 
edical and op
o be accepta
idered to hav
a and are ass
for the metho
isits and A
uld be perform
not possible 
should overla
for at least 1
ction provid
he examinati
ion is presen
med on both 
order shown
emaining pro
creening V
ocedures and
consent/auth
phics (includ
for Final 
phthalmic hi
able to the in
ve entered th
igned a stud
od for assign
Associated 
med by the s
to use the sa
ap and the ev
 visit. 
des a list of p
ion procedur
nted in Sectio
eyes.  The p
n unless othe
ocedures for 
Visit (Day 
d assessmen
horization 
ding height, 
 
54 
 
Study Ent
istory as wel
nvestigator p
he study onc
dy enrollmen
nment to trea
Procedur
same evalua
ame evaluato
valuators wi
procedures fo
res, equipme
on 12.  Unle
procedures li
erwise speci
that visit sh
-51) 
nts will be pe
weight) 
P
try 
ll as medicat
rior to patien
e they have 
nt number at 
atment group
res 
ator througho
or to follow 
ill examine t
or each sche
ent, and tech
ess otherwise
isted below 
fied.  If the p
ould not be p
erformed dur
Protocol 19526
GD
tion usage w
nt enrollmen
met the incl
the enrollm
ps/randomiz
out the study
the patient, 
the patient to
eduled visit.  
hniques for th
e specified, p
are recomm
patient does 
performed. 
ring the scre
63-009 Amendm
DD-TA-T-004 v2
will be evalua
nt in the stud
usion and 
ent visit (day
ation. 
y whenever 
it is preferre
ogether and 
Additional 
he measures 
procedures 
mended to be 
not qualify 
eening visit:
ment 2 
2015.10 
ated 
dy. 
y 1).  
ed 
at a 
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Approval Date: 	
Allerg
 
 
 
 
 
 
 
 
 
8.3.2
The f
 
 
 
 
 
 
 
gan Confidentia
Inclusion/
Medical a
Medicatio
o Li
o An
o Or
Contact Ix
Adverse e
 
St
2
following pr
Inclusion/
and stand
Medical a
standardiz
Concomit
standardiz
o Li
o An
o Or
Vital sign
Hair evalu
removal p
Visual acu
Biomicro
al 
/exclusion cr
and ophthalm
on history/co
id hygiene (i
ny artificial 
ral or topica
xRS 
events 
tandardiza
ocedures and
/exclusion cr
dardization v
and ophthalm
zation visits 
tant medicat
zation visits 
id hygiene (w
ny artificial 
ral or topica
ns (pulse rate
uation (all pa
procedures) 
uity (manife
scopy (inclu
riteria review
mic history 
oncomitant m
ie, warm com
tear product
l macrolides
ation Visit
d assessmen
riteria review
isits are on s
mic history (
are on separ
tions (reasses
are on separ
warm compr
tear product
l macrolides
e, blood pres
atients asked
st refraction
udes upper an
 
55 
 
w 
medications.
mpress, lid m
ts  
s, tetracyclin
t (Day -21
nts will be pe
w (reassessm
separate day
reassessmen
rate days) 
ssment only 
rate days). E
ress, lid mas
ts 
s, tetracyclin
ssure) 
d to report an
n) 
nd lower lid 
P
 Ensure to q
massage, lid 
nes, tetracycl
 [±1 day])
erformed dur
ment only for
ys) 
nt only for pa
 for patients
Ensure to que
sage, lid scr
nes, tetracycl
ny use of ha
d margin app
Protocol 19526
GD
query use of:
scrub) 
line derivativ
) 
ring the stan
r patients wh
atients whos
 whose scree
ery use of: 
rub) 
line derivativ
air growth pr
earance eval
63-009 Amendm
DD-TA-T-004 v2
 
ve drugs 
ndardization
hose screeni
se screening 
ening and 
ve drugs 
roducts or ha
luation) 
ment 2 
2015.10 
visit: 
ing 
and 
air 
	






Approval Date: 	
Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
56 
GDD-TA-T-004 v2015.10 
 
 
 TBUT 
 Sodium fluorescein corneal staining (Oxford scheme) 
 Sodium fluorescein conjunctival staining (Oxford scheme) 
 At least 10-minute wait 
 Schirmer tear test with anesthesia 
 Lower lid margin meibomian gland secretion evaluation 
 IOP 
 Ophthalmoscopy (eyes should be dilated) 
 Contact IxRS 
 Blood and urine collection sample for hematology, blood chemistry, PSA 
measurement (males only), and urinalysis 
 Pre-dose blood sample collection for pharmacokinetic analysis 
 
 
 In-office administration of SAT 
 Post-dose blood sample collection for systemic pharmacokinetics (5 minutes ± 
1 minute, 10 minutes ± 1 minute, 30 minutes ± 5 minutes, 2 hours ± 15 minutes, 
4 hours ± 30 minutes, 6 hours ± 30 minutes and 12 hours ± 30 minutes) (at selected 
sites) (To facilitate the 12 hour time course of blood draws for pharmacokinetic 
analysis at the standardization (day -21) and month 1 visits, sites may “split” the visit, 
and perform the serial blood draws at a separate visit (the “split visit”).  The split visit 
must occur within 5 days from the scheduled visit.) 
 Adverse events 
 SAT dispensing 
	






Approval Date: 	
Allerg
 
 
 
 
8.3.3
Patien
study
each 
the st
The f
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.3.4
Patien
study
gan Confidentia
 
Ve
3
nts will be in
y visit.  In ad
study visit.  
tudy visit an
following pr
Concomit
o Li
o SA
o An
o Or
Ocular sy
Visual acu
Biomicro
TBUT 
Sodium fl
Sodium fl
IOP 
Contact Ix
In-office a
Adverse e
Study trea
SAT dispe
Collect un
 
B
4
nts will be in
y visit.  In ad
al 
Vehicle Run
nstructed to 
ddition, patie
One day pri
d continues 
ocedures and
tant medicat
id hygiene (i
AT 
ny artificial 
ral or topica
ymptoms que
uity 
scopy (inclu
luorescein co
luorescein co
xRS 
administratio
events 
atment dispe
ensing 
nused study 
aseline Vi
nstructed to 
ddition, patie
n-in Visit (
not adminis
ents will be a
ior to each st
until the end
d assessmen
tions. Ensure
ie, warm com
tear product
l macrolides
estions:  ove
udes upper an
orneal staini
onjunctival s
on of study t
ensing 
treatment  
sit (Rando
not adminis
ents will be a
 
57 
 
(Day -14 [
ter morning 
asked to refr
tudy visit be
d of the stud
nts will be pe
e to query us
mpress, lid m
ts other than 
s, tetracyclin
rall ocular d
nd lower lid 
ing (Oxford 
staining (Ox
treatment 
omization,
ter morning 
asked to refr
P
[+3 days])
dose of stud
rain from use
egins on the 
dy visit. 
erformed dur
se of: 
massage, lid 
 SAT 
nes, tetracycl
discomfort, b
d margin app
scheme) 
xford scheme
, Day 1) 
dose of stud
rain from use
Protocol 19526
GD
dy treatment
e of SAT for
morning of t
ring the vehi
scrub) 
line derivativ
blurred visio
earance eval
e) 
dy treatment
e of SAT for
63-009 Amendm
DD-TA-T-004 v2
t the day of a
r 1 day prior 
the day befo
icle run-in v
ve drugs 
n, ocular bur
luation) 
t the day of a
r 1 day prior 
ment 2 
2015.10 
a 
to 
ore 
visit: 
rning 
a 
to 
	



	


Approval Date: 	
Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
58 
GDD-TA-T-004 v2015.10 
 
 
each study visit.  One day prior to each study visit begins on the morning of the day before 
the study visit and continues until the end of the study visit. 
The following procedures and assessments will be performed during the baseline visit: 
 Inclusion/exclusion criteria review  
 Concomitant medications. Ensure to query use of: 
o Lid hygiene (warm compress, lid massage, lid scrub) 
o SAT 
o Any artificial tear products other than SAT 
o Oral or topical macrolides, tetracyclines, tetracycline derivative drugs 
 Vital signs (pulse rate, blood pressure) 
 Pregnancy test (female patients only) 
 Hair evaluation 
 
 
 
 
 
 
 Visual acuity 
 Biomicroscopy (includes upper and lower lid margin appearance evaluation) 
 TBUT 
 Sodium fluorescein corneal staining (Oxford scheme) 
 Sodium fluorescein conjunctival staining (Oxford scheme) 
 At least 10-minute wait 
 Schirmer tear test with anesthesia 
 Lower lid margin meibomian gland secretion evaluation 
 IOP 
 Ophthalmoscopy (during examination, eyes to be undilated) 
 Contact IxRS (randomization) 
	






Approval Date: 	
Allerg
 
 
 
 
 
 
 
 
 
8.3.5
Patien
study
each 
the st
The f
 
 
 
 
 
 
 
 
 
gan Confidentia
In-office a
Adverse e
Study trea
SAT dispe
Collect un
 
M
5
nts will be in
y visit.  In ad
study visit.  
tudy visit an
following pr
Concomit
o Li
o SA
o An
o Or
Hair evalu
Visual acu
Biomicro
TBUT 
Sodium fl
Sodium fl
At least 1
Schirmer’
al 
administratio
events 
atment dispe
ensing 
nused study 
Month 1 Vi
nstructed to 
ddition, patie
One day pri
d continues 
ocedures and
tant medicat
id hygiene (i
AT 
ny artificial 
ral or topica
uation 
uity 
scopy (inclu
luorescein co
luorescein co
0-minute wa
’s tear test w
on of study t
ensing 
treatment  
isit (± 5 da
not adminis
ents will be a
ior to each st
until the end
d assessmen
tions. Ensure
ie, warm com
tear product
l macrolides
udes upper an
orneal staini
onjunctival s
ait 
with anesthes
 
59 
 
treatment  
ays) 
ter morning 
asked to refr
tudy visit be
d of the stud
nts will be pe
e to query us
mpress, lid m
ts other than 
s, tetracyclin
nd lower lid 
ing (Oxford 
staining (Ox
sia 
P
dose of stud
rain from use
egins on the 
dy visit. 
erformed dur
se of: 
massage, lid 
 SAT 
nes, tetracycl
d margin app
scheme) 
xford scheme
Protocol 19526
GD
dy treatment
e of SAT for
morning of t
ring the mon
scrub) 
line derivativ
earance eval
e) 
63-009 Amendm
DD-TA-T-004 v2
t the day of a
r 1 day prior 
the day befo
nth 1 visit: 
ve drugs 
luation) 
ment 2 
2015.10 
a 
to 
ore 
	






Approval Date: 	
Allerg
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.3.6
Patien
study
each 
the st
The f
 
gan Confidentia
IOP 
Contact Ix
Blood and
measurem
Pre-dose b
SHBG) (p
to the pre
In-office a
pharmaco
align to th
participat
be admini
within 10
the curren
Post-dose
± 1 minut
4 hours ± 
patients)  
Adverse e
Study trea
SAT dispe
Collect un
 
M
6
nts will be in
y visit.  In ad
study visit.  
tudy visit an
following pr
Concomit
o Li
al 
xRS  
d urine samp
ment, and uri
blood sampl
performed fo
-dose collec
administratio
okinetic bloo
he baseline (
ing in blood
istered at app
 min after th
nt visit) 
e blood samp
te, 10 minute
30 minutes,
events 
atment dispe
ensing 
nused study 
Month 3 Vi
nstructed to 
ddition, patie
One day pri
d continues 
ocedures and
tant medicat
id hygiene (w
ple collection
inalysis 
le collection 
or selected p
tion perform
on of study t
od draws, tim
(day 1) admi
d sampling fo
proximately
he time the p
ple collection
es ± 1 minut
, 6 hours ± 3
ensing 
treatment  
isit (± 7 da
not adminis
ents will be a
ior to each st
until the end
d assessmen
tions. Ensure
warm compr
 
60 
 
n for hemato
for pharmac
patients); tim
med at the sta
treatment (If
me of in-offic
inistration tim
or pharmaco
y the same tim
pre-dose bloo
n for system
te, 30 minute
30 minutes an
ays) 
ter morning 
asked to refr
tudy visit be
d of the stud
nts will be pe
e to query us
ress, lid mas
P
ology, blood 
cokinetic an
me of the coll
andardizatio
f patient is n
ce administr
me of day  ±
okinetic analy
me of day du
od sample co
mic pharmaco
es ± 5 minut
nd 12 hours 
dose of stud
rain from use
egins on the 
dy visit. 
erformed dur
se of: 
sage, lid scr
Protocol 19526
GD
chemistry, P
alysis (testo
lection shoul
n (day -21) v
not participat
ration should
± 1 hour.  Fo
ysis, study tr
uring each o
ollection wa
okinetics (5 m
tes, 2 hours ±
± 30 minute
dy treatment
e of SAT for
morning of t
ring the mon
rub) 
63-009 Amendm
DD-TA-T-004 v2
PSA 
sterone, DH
ld align ± 1 
visit.  
ting in 
d be schedule
r all patients
reatment sho
office visit an
s performed
minutes 
± 15 minutes
es) (for selec
t the day of a
r 1 day prior 
the day befo
nth 3 visit: 
ment 2 
2015.10 
HT, 
hour 
ed to 
s 
ould 
nd 
d at 
s, 
cted 
a 
to 
ore 
	






Approval Date: 	
Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
61 
GDD-TA-T-004 v2015.10 
 
 
o SAT 
o Any artificial tear products other than SAT 
o Oral or topical macrolides, tetracyclines, tetracycline derivative drugs 
 Vital signs (pulse rate, blood pressure) 
 Hair evaluation 
 Visual acuity 
 Biomicroscopy (includes upper and lower lid margin appearance evaluation) 
 TBUT 
 Sodium fluorescein corneal staining (Oxford scheme) 
 Sodium fluorescein conjunctival staining (Oxford scheme) 
 At least 10-minute wait 
 Schirmer’s tear test with anesthesia 
 IOP 
 Contact IxRS  
 Blood and urine sample collection for hematology, blood chemistry, PSA 
measurement, and urinalysis 
 Pre-dose blood sample collection for pharmacokinetic analysis 
 
 (performed for selected patients); time of the collection should align ± 1 hour 
to the pre-dose collection performed at the standardization (day -21) visit.   
 In-office administration of study treatment (If patient is not participating in 
pharmacokinetic blood draws, time of in-office administration should be scheduled to 
align to the baseline (day 1) administration time of day  ± 1 hour.  For all patients 
participating in blood sampling for pharmacokinetic analysis, study treatment should 
be administered at approximately the same time of day during each office visit and 
within 10 min after the time the pre-dose blood sample collection was performed at 
the current visit) 
	






Approval Date: 	
Allerg
 
 
 
 
 
 
 
 
8.3.7
Patien
study
each 
the st
The f
 
 
 
 
 
 
 
 
 
 
gan Confidentia
Adverse e
Study trea
SAT dispe
Collect un
 
M
7
nts will be in
y visit.  In ad
study visit.  
tudy visit an
following pr
Concomit
o Li
o SA
o An
o Or
Vital sign
Hair evalu
Visual acu
Biomicro
TBUT 
Sodium fl
Sodium fl
At least 1
Schirmer’
al 
events 
atment dispe
ensing 
nused study 
Month 6 Vi
nstructed to 
ddition, patie
One day pri
d continues 
ocedures and
tant medicat
id hygiene (i
AT 
ny artificial 
ral or topica
ns (pulse rate
uation 
uity 
scopy (inclu
luorescein co
luorescein co
0-minute wa
’s tear test w
ensing 
treatment  
isit (± 7 da
not adminis
ents will be a
ior to each st
until the end
d assessmen
tions. Ensure
ie, warm com
tear product
l macrolides
e, blood pres
udes upper an
orneal staini
onjunctival s
ait 
with anesthes
 
62 
 
ays) 
ter morning 
asked to refr
tudy visit be
d of the stud
nts will be pe
e to query us
mpress, lid m
ts other than 
s, tetracyclin
ssure) 
nd lower lid 
ing (Oxford 
staining (Ox
sia 
P
dose of stud
rain from use
egins on the 
dy visit. 
erformed dur
se of: 
massage, lid 
 SAT 
nes, tetracycl
d margin app
scheme) 
xford scheme
Protocol 19526
GD
dy treatment
e of SAT for
morning of t
ring the mon
scrub) 
line derivativ
earance eval
e) 
63-009 Amendm
DD-TA-T-004 v2
t the day of a
r 1 day prior 
the day befo
nth 6 visit: 
ve drugs 
luation) 
ment 2 
2015.10 
a 
to 
ore 
	






Approval Date: 	
Allerg
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.3.8
Patien
study
each 
the st
The f
 
gan Confidentia
Lower lid
IOP 
Ophthalm
Contact Ix
Blood and
measurem
Pre-dose b
SHBG) (p
to the pre
In-office a
pharmaco
align to th
participat
be admini
within 10
the curren
Post-dose
patients); 
Adverse e
Study trea
SAT dispe
Collect un
 
M
8
nts will be in
y visit.  In ad
study visit.  
tudy visit an
following pr
Medicatio
al 
d margin mei
moscopy 
xRS 
d urine samp
ment, and uri
blood sampl
performed fo
-dose collec
administratio
okinetic bloo
he baseline (
ing in blood
istered at app
 min after th
nt visit) 
e blood samp
the sample c
events 
atment dispe
ensing 
nused study 
Month 9 Vi
nstructed to 
ddition, patie
One day pri
d continues 
ocedures and
on history/co
ibomian glan
ple collection
inalysis 
le collection 
or selected p
tion perform
on of study t
od draws, tim
(day 1) admi
d sampling fo
proximately
he time the p
ple collection
collection sh
ensing 
treatment  
isit (± 14 d
not adminis
ents will be a
ior to each st
until the end
d assessmen
oncomitant m
 
63 
 
nd secretion 
n for hemato
for pharmac
patients); tim
med at the sta
treatment(If 
me of in-offic
inistration tim
or pharmaco
y the same tim
pre-dose bloo
n for system
hould be per
days) 
ter morning 
asked to refr
tudy visit be
d of the stud
nts will be pe
medications.
P
evaluation
ology, blood 
cokinetic an
me of the coll
andardizatio
f patient is no
ce administr
me of day  ±
okinetic analy
me of day du
od sample co
mic pharmaco
rformed at 10
dose of stud
rain from use
egins on the 
dy visit. 
erformed dur
 Ensure to q
Protocol 19526
GD
chemistry, P
alysis (testo
lection shoul
n (day -21) v
ot participati
ration should
± 1 hour.  Fo
ysis, study tr
uring each o
ollection wa
okinetics (for
0 minutes ± 
dy treatment
e of SAT for
morning of t
ring the mon
query use of:
63-009 Amendm
DD-TA-T-004 v2
PSA 
sterone, DH
ld align ± 1 
visit. 
ing in 
d be schedule
r all patients
reatment sho
office visit an
s performed
r selected 
1 minute on
t the day of a
r 1 day prior 
the day befo
nth 9 visit: 
 
ment 2 
2015.10 
HT, 
hour 
ed to 
s 
ould 
nd 
d at 
nly 
a 
to 
ore 
	






Approval Date: 	
Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
64 
GDD-TA-T-004 v2015.10 
 
 
o Lid hygiene (warm compress, lid massage, lid scrub) 
o SAT 
o Any artificial tear products other than SAT 
o Oral or topical macrolides, tetracyclines, tetracycline derivative drugs 
 Vital signs (pulse rate, blood pressure) 
 Hair evaluation 
 Visual acuity 
 Biomicroscopy (includes upper and lower lid margin appearance evaluation) 
 TBUT 
 Sodium fluorescein corneal staining (Oxford scheme) 
 Sodium fluorescein conjunctival staining (Oxford scheme) 
 At least 10-minute wait 
 Schirmer’s tear test with anesthesia 
 IOP 
 Contact IxRS  
 Blood and urine sample collection for hematology, blood chemistry, PSA 
measurement, and urinalysis 
 Pre-dose blood sample collection for pharmacokinetic analysis 
 
 (performed for selected patients); time of the collection should align ± 1 hour 
to the pre-dose collection performed at the standardization (day -21) visit. 
	






Approval Date: 	
Allerg
 
 
 
 
 
 
 
 
 
8.3.9
Patien
study
each 
the st
Patien
proce
durin
 
 
 
gan Confidentia
In-office a
pharmaco
align to th
participat
be admini
within 10
the curren
Adverse e
Study trea
SAT dispe
Collect un
 
M
9
nts will be in
y visit.  In ad
study visit.  
tudy visit an
nts who exit
edures when
ng the month
Concomit
o Li
o SA
o An
o Or
Vital sign
Hair evalu
al 
administratio
okinetic bloo
he baseline (
ing in blood
istered at app
 min after th
nt visit) 
events 
atment dispe
ensing 
nused study 
Month 12/S
nstructed to 
ddition, patie
One day pri
d continues 
t early from 
possible.  T
h 12/study ex
tant medicat
id hygiene (w
AT 
ny artificial 
ral or topica
ns (pulse rate
uation 
on of study t
od draws, tim
(day 1) admi
d sampling fo
proximately
he time the p
ensing 
treatment 
Study Exit
not adminis
ents will be a
ior to each st
until the end
the study sh
The following
xit visit: 
tions. Ensure
warm compr
tear product
l macrolides
e, blood pres
 
65 
 
treatment (If
me of in-offic
inistration tim
or pharmaco
y the same tim
pre-dose bloo
t (Early Ex
ter morning 
asked to refr
tudy visit be
d of the stud
hould comple
g procedures
e to query us
ress, lid mas
ts other than 
s, tetracyclin
ssure) 
P
f patient is n
ce administr
me of day  ±
okinetic analy
me of day du
od sample co
xit) (± 14 d
dose of stud
rain from use
egins on the 
dy visit. 
ete the month
s and assessm
se of: 
sage, lid scr
 SAT 
nes, tetracycl
Protocol 19526
GD
not participat
ration should
± 1 hour.  Fo
ysis, study tr
uring each o
ollection wa
days) 
dy treatment
e of SAT for
morning of t
th 12/study e
ments will b
rub) 
line derivativ
63-009 Amendm
DD-TA-T-004 v2
ting in 
d be schedule
r all patient
reatment sho
office visit an
s performed
t the day of a
r 1 day prior 
the day befo
exit visit 
be performed
ves 
ment 2 
2015.10 
ed to 
ould 
nd 
d at 
a 
to 
ore 
d 
	






Approval Date: 	
Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
66 
GDD-TA-T-004 v2015.10 
 
 
 Visual acuity 
 Biomicroscopy (includes upper and lower lid margin appearance evaluation) 
 TBUT 
 Sodium fluorescein corneal staining (Oxford scheme) 
 Sodium fluorescein conjunctival staining (Oxford scheme) 
 At least 10-minute wait 
 Schirmer’s tear test with anesthesia 
 Lower lid margin meibomian gland secretion evaluation 
 IOP 
 Ophthalmoscopy 
 Contact IxRS (only for patients who are exiting early from the study) 
 Blood and urine sample collection for hematology, blood chemistry, PSA 
measurement, and urinalysis 
 Blood sample collection for pharmacokinetic analysis 
 
(performed for selected patients); time of the collection should align ± 1 hour to the 
pre-dose collection performed at the standardization (day -21) visit. 
 Adverse events 
 Collect unused study treatment 
8.4 
Instructions for the Patients 
 Non-PK patients: Return to the study site for study visits at days -21, -14, 1 and 
months 1, 3, 6, 9, and 12.  Visits should be scheduled so that in-office administration 
of study treatment at months 1, 3, 6, 9, and 12 will be ± 1 hour from the time of day 
established at baseline (day 1). 
 PK patients: Return to the study site for study visits at days -21, -14, 1, and months 1, 
3, 6, 9, and 12.  Visits should be scheduled so that the time of the pre-dose blood 
sample collection in the morning will be at approximately the same time of day 
during each office visit (± 1 hour from the pre dose blood sample collection time at 
the standardization (day -21) visit). 
	






Approval Date: 	
Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
67 
GDD-TA-T-004 v2015.10 
 
 
 Patients should remain at the site for the duration of the visit to complete the study-
related procedures as explained to them by the study site personnel. 
 If glasses are worn for vision correction, patients should remember to bring their 
glasses each time they visit the doctor’s office. 
 Follow the study visit schedule and to report all changes in their medical condition to 
the site. 
 Maintain a stable dose if any concomitant medication is taken. 
 Report any changes to their medication at their next study visit or report any new 
medication(s) initiated during the study.  Patients should also be reminded to contact 
the study site if they are experiencing any difficulties during their study participation. 
DOSING INFORMATION 
 Directions will be provided on proper dosing technique and storage of study 
treatment.  For study treatment dosing, patients will be instructed that each vial from 
their kit is for single-use dosing; 1 drop should be instilled in each eye from the first 
vial for the morning dose and a second (new) vial should be used to instill one-drop in 
each eye for the evening dose. 
 If SAT is required for intolerable symptoms, any use of SAT should be instilled at 
least 30 minutes before or 30 minutes after study treatment whenever both 
medications are used. 
 Patients are NOT to administer SAT or study treatment on the morning of study days  
-14, -1 and months 1, 3, 6, 9, and 12, as the first (morning) dose on these days will be 
administered by site staff. 
 To administer one drop of SAT in each eye on the evening of study day -21 and 
1 drop of study treatment in each eye on the evening of study days -14 and 1 and 
months 1, 3, 6, and 9. 
 Save all unused study treatment vials in their study treatment kit and to bring their 
study treatment kit(s) with them on day 1 and months 1, 3, 6, 9 and 12. 
 During the open label period beginning after the month 6 visit and through month 
12/study exit, patients may resume lid hygiene or artificial tears as needed, but use of 
artificial tears will continue to be prohibited within 24 hours of any study visit 
	
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

	


Approval Date: 	
Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
68 
GDD-TA-T-004 v2015.10 
 
 
8.5 
Unscheduled Visits 
Patients may experience adverse events that necessitate their returning to the study site for 
unscheduled visits.  The adverse event and all required information should be recorded on the 
appropriate eCRF and the patient’s record should include all relevant information. 
Unscheduled visits may be performed as necessary to ensure the safety and wellbeing of 
patients during the study period.  Unscheduled visit eCRFs should be completed for each 
unscheduled visit.  An assessment of any adverse event should be completed. 
8.6 
Compliance with Protocol 
Patients must be able to adhere to the study visit schedule, testing parameters, and 
appropriate inclusion, exclusion, and treatment criteria as described in the protocol. 
At each study visit, patients will be asked if they have used any concomitant 
medications/therapies or had any concurrent procedures since the previous visit. 
8.7 
Early Discontinuation of Patients 
Patients may voluntarily withdraw from the study at any time. 
Notification of early patient discontinuation from the study and the reason for discontinuation 
will be made to the sponsor and will be clearly documented on the appropriate case report 
form. 
8.8 
Withdrawal Criteria 
Patients may voluntarily withdraw from the study at any time.  Table 6 describes the 
applicable follow-up depending on whether an enrolled study patient decides to discontinue 
voluntarily, or is discontinued by the investigator or by Allergan. 
	






Approval Date: 	
Allerg
 
 
 
 
Table
Patie
Patie
enro
coho
Patie
enro
stud
not a
Patie
discr
Patie
 
Notif
disco
a coh
8.9 
The s
may s
9. 
Adve
form.
9.1 
9.1.1
An ad
patien
relati
unint
assoc
gan Confidentia
e 6 
Ea
Reason
ent elects to no
ent elects to di
ollment visit an
ort but before e
ent is discontin
ollment visit du
y cohort or coh
asked to return
ent discontinue
retion 
ent discontinue
fication of pa
ontinuation w
hort or if coh
St
study may be
stop the stud
Ad
erse events o
.  If adverse 
De
 
A
1
dverse event
nt administe
ionship with 
tended sign (
ciated with th
al 
arly Discont
n for Discontin
ot complete a fu
scontinue after
nd assignment i
exit visit is init
nued after comp
ue to patient no
hort is full (and
n for additional
ed at the invest
ed at Allergan’
atient’s early
will be made
hort enrollme
tudy Term
e stopped at 
dy (and/or th
dverse Ev
occurring dur
events occu
efinitions 
Adverse Ev
t is any unto
ered a pharm
this treatme
(including an
he use of a m
tinuation R
nuation 
full study visit
r completion of
into a study 
iated 
pletion of the 
ot qualifying fo
d thus patient i
 study visits) 
tigator’s 
s discretion 
y discontinua
 to Allergan 
ent goal is m
mination 
his/her stud
he study site)
vents 
ring the stud
ur, the first co
vent 
ward medica
maceutical pro
ent.  An adve
n abnormal l
medicinal (in
 
69 
 
Requirement
Stu
Early ex
be comp
possible
f 
No addi
or a 
s 
No addi
Early ex
be comp
possible
Early ex
be comp
possible
ation from th
or to the site
met, and will 
dy site at any
) for any rea
dy will be rec
oncern will b
al occurrenc
oduct and th
erse event ca
laboratory fi
nvestigationa
P
ts 
udy Procedure
xit procedures,
pleted before th
e. 
itional procedu
itional procedu
xit procedures,
pleted before th
e. 
xit procedures,
pleted before th
e. 
he study and
e in the case
be clearly d
y time by the
ason with app
corded on an
be the safety
ce in a patien
hat does not n
an therefore 
inding), sym
al) product, w
Protocol 19526
GD
es and Visits R
, as described i
he end of that 
ures or study vi
ures or study vi
, as described i
he end of that 
, as described i
he end of that 
d the reason 
e of patient n
documented o
e site investig
propriate not
n adverse ev
y of the study
nt or clinical
necessarily h
be any unfav
mptom, or dis
whether or n
63-009 Amendm
DD-TA-T-004 v2
Requirements
in Table 1, sho
visit, wheneve
isits are require
isits are require
in Table 1, sho
visit, wheneve
in Table 1, sho
visit, wheneve
for 
not qualifyin
on the eCRF
gator.  Allerg
tification. 
vent case rep
y participant
 investigatio
have a causa
vorable and 
sease tempor
not related to
ment 2 
2015.10 
  
uld 
er 
ed. 
ed. 
uld 
er 
uld 
er 
ng for 
F. 
gan 
ort 
ts. 
on 
al 
rally 
o the 
	






Approval Date: 	
Allerg
 
 
 
 
medi
will b
Note
of wh
Progr
or sym
assoc
adver
of the
Adve
(ie, a
query
“How
then b
appro
9.1.2
A ser
follow
prolo
conge
life-th
based
may r
defin
Aller
consi
Pre-p
patien
Any p
docum
gan Confidentia
cinal (invest
be assessed r
:  Adverse ev
hether or not
ression of tre
mptoms, wh
ciated with th
rse events un
e disease. 
erse events w
fter informe
ying for adve
w have you b
be done as a
opriate case r
 
Se
2
rious adverse
wing outcom
ongation of e
enital anoma
hreatening, o
d upon appro
require med
nition.  (See S
rgan conside
iders any abo
planned surg
nt requires h
pre-planned 
ments by the
al 
tigational) pr
regardless of
vents must b
t the patient 
eatment indi
hich are colle
he disease pr
nless the dise
will be assess
d consent ha
erse events b
been feeling 
appropriate.  
report form.
erious Adv
e event is an
mes:  death, a
existing hosp
aly/birth def
or require ho
opriate medi
ical or surgic
Section 9.3 f
rs all cancer
ortion (spont
eries or proc
hospitalizatio
surgery or p
e medically q
roduct.  In a
f the adminis
be collected o
has been adm
ication inclu
ected as clini
rogression a
ease progres
sed, docume
as been obtai
by asking ea
since the las
All reported
 
verse Even
ny adverse ev
a life-threate
pitalization, a
fect.  Importa
ospitalization
cal judgmen
cal intervent
for procedur
r adverse eve
taneous or n
cedures for p
on is not repo
procedure sh
qualified inv
 
70 
 
ddition, duri
stration of a 
once inform
ministered s
ding new or 
ical efficacy
and /or lack o
ssion is great
ented, and re
ined).  At ea
ch patient a 
st visit?”  Di
d adverse eve
nt 
vent occurrin
ening advers
a persistent o
ant medical 
n may be con
nt, they may 
tion to preve
res for report
ents as seriou
nonspontaneo
pre-existing, 
ortable as a 
hould be clea
vestigator at 
P
ing the scree
pharmaceut
med consent h
study drug. 
r worsening o
y variables an
of efficacy, s
ter than antic
ecorded in th
ach visit, the 
general, non
irected quest
ents will be 
ng at any do
se event, inpa
or significan
events that m
nsidered a se
jeopardize t
ent one of th
ting a seriou
us adverse e
ous) as a ser
 known med
serious adve
arly documen
the time of t
Protocol 19526
GD
ening period
tical product
has been obt
of anticipate
nd assessed 
should NOT 
cipated in th
he CRF throu
 investigator
n-directed qu
tioning and e
documented
se that result
atient hospit
nt disability/
may not resu
erious adver
the patient or
he outcomes 
us adverse ev
events.  In ad
rious adverse
dical conditio
erse event. 
nted in the s
the patient’s
63-009 Amendm
DD-TA-T-004 v2
d, adverse ev
t. 
tained, regar
ed clinical si
as unequivo
be reported 
he natural co
ughout the st
r will begin b
uestion such
examination
d on the 
ts in any of t
talization or 
incapacity, o
ult in death, b
rse event wh
r subject and
listed in this
vent.) 
ddition, Aller
e event. 
ons for whic
site source 
s entry into th
ment 2 
2015.10 
vents 
rdless 
gns 
ocally 
as 
ourse 
tudy 
by 
h as 
n will 
the 
or a 
be 
hen, 
d 
s 
rgan 
ch a 
he 
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

	


Approval Date: 	
Allerg
 
 
 
 
study
shoul
9.1.3
A clin
asses
guide
Mild 
Mode
Sever
 
9.1.4
A det
study
determ
been 
9.2 
Any a
All ad
curre
Board
regul
at the
9.3 
Any s
conse
repor
event
Study
seriou
gan Confidentia
y.  If it has no
ld be docum
 
Se
3
nical determ
sment for a 
elines: 
erate 
re 
 
R
4
termination w
y drug or stud
mination is m
caused by th
Pr
adverse even
dverse event
nt Investigat
d/Independe
lations, and t
e exit visit m
Pr
serious adve
ent) and for a
rted but no la
ts must be re
y Contacts P
us adverse e
al 
ot been docu
mented as a se
everity 
mination will 
clinical adve
Awarenes
Discomfo
Incapacit
Relationshi
will be made
dy procedur
made that th
he drug or st
rocedures 
nt must be re
ts that are dr
tor's Brochu
ent Ethics Co
the governin
must be follow
rocedures 
erse event oc
at least 28 d
ater than 24 
eported to Al
Page and reco
vent must be
umented at th
erious adver
be made of 
erse event m
ss of sign or 
ort enough to
tating with in
ip to Study
e of the relat
e, as applica
here is a reas
tudy procedu
for Repor
ecorded on t
rug-related a
ure) must be 
ommittee (IR
ng health aut
wed-up as ap
for Repor
ccurring duri
ays after the
hours after l
llergan (or A
orded on the
e followed u
 
71 
 
he time of th
se event and
the intensity
must be comp
symptom, b
o cause inter
nability to w
y Drug or 
tionship (if a
able.  A caus
onable possi
ure. 
rting Adve
the appropria
and unexpect
reported to t
RB/IEC) as r
horities.  An
ppropriate. 
rting a Ser
ing the study
e last dose of
learning of a
Agent of Alle
e serious adv
up and the ou
P
he patient’s e
d reported to
y of an adver
pleted using 
but easily tol
rference with
work or do us
Study Pro
any) between
al relationsh
ibility that th
erse Event
ate case repo
ted (not liste
the governin
required by t
ny adverse ev
rious Adve
y period (beg
f study drug 
a serious adv
ergan eg, CR
verse event f
utcomes repo
Protocol 19526
GD
entry into the
o Allergan. 
rse event.  T
the followin
lerated. 
h usual activ
sual activity.
ocedure 
n an adverse
hip is present
he adverse e
ts 
ort form. 
ed as treatme
ng Institution
the IRB/IEC
vent that is m
erse Event
ginning with
must be imm
verse event.  
RO as listed o
form.  All pa
orted.  The i
63-009 Amendm
DD-TA-T-004 v2
e study, then
The severity 
ng definition
vity. 
. 
e event and t
t if a 
event may ha
ent-related in
nal Review 
C, local 
marked ‘ong
t 
h informed 
mediately 
Serious adv
on the Allerg
atients with a
investigator m
ment 2 
2015.10 
n it 
ns as 
he 
ave 
n the 
going’ 
verse 
gan 
a  
must 
	



	


Approval Date: 	
Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
72 
GDD-TA-T-004 v2015.10 
 
 
supply the sponsor and the IRB/IEC with any additional requested information (eg, autopsy 
reports and discharge summaries). 
In the event of a serious adverse event, the investigator must: 
1. Notify Allergan immediately by fax or email using the serious adverse event form 
(contact details can be found on page 1 of the serious adverse event form); phone 
numbers and relevant Allergan personnel contacts are also on the front page of 
protocol and Study Contacts Page. 
2. Obtain and maintain in his/her files all pertinent medical records, information, and 
medical judgments from colleagues who assisted in the treatment and follow-up of 
the patient. 
3. Provide Allergan with a complete, written description of the adverse event(s) on the 
serious adverse event form describing the event chronologically, including any 
treatment given (eg, medications administered, procedures performed) for the adverse 
event(s).  Summarize relevant clinical information about the event:  signs, symptoms, 
diagnosis, clinical course and relevant clinical laboratory tests, etc.  Include any 
additional or alternative explanation(s) for the causality which includes a statement as 
to whether the event was or was not related to the use of the investigational drug. 
4. Promptly inform the governing IRB/IEC of the serious adverse event as required by 
the IRB/IEC, local regulations, and the governing health authorities. 
9.4 
Procedures for Unmasking of Study Medication 
When necessary for the safety and proper treatment of the patient, the investigator can 
unmask the patient’s treatment assignment to determine which treatment has been assigned 
and institute appropriate follow-up care.  When possible, the sponsor (Allergan Medical 
Safety Physician) should be notified prior to unmasking study medication.  The investigator 
should inform the sponsor (Allergan Medical Safety Physician) of the unmasking if there is 
no notification prior to the unmasking. 
The treatment assignment for the patient can be determined by designated site personnel 
calling into the IVRS or IWRS system via password protected access.  The reason for 
breaking the code must be recorded in the patient’s source documents. 
	
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

	


Approval Date: 	
Allerg
 
 
 
 
10. 
This 
(GCP
Guid
10.1
10.1
Writt
activi
repre
signe
local 
10.1
This 
or ap
const
Aller
proce
with 
10.1
This 
guide
10.1
This 
electr
10.2
The i
appro
gan Confidentia
Ad
protocol is t
P) regulation
eline on GC
 
Pr
 
C
.1
Pa
ten informed
ities or proce
sentative.  If
ed by the leg
regulatory r
 
C
.2
study is to b
plicable IEC
tituted IRB/I
rgan is to be 
eedings leadi
the investiga
 
C
.3
protocol is t
elines. 
 
C
.4
R
study is to b
ronic signatu
 
Ch
investigator m
oval by Aller
al 
dministra
to be conduc
ns and guidel
P. 
rotection o
ompliance
art 50) an
d consent is t
edures in the
f the patient 
ally authoriz
requirements
ompliance
be conducted
C regulations
IEC prior to 
notified imm
ing to disqua
ator should b
ompliance
to be conduc
ompliance
Regulations
be conducted
ure. 
hanges to 
must not imp
rgan and prio
tive Items
cted in accord
lines, eg, the
of Human 
e with Info
d Relevan
to be obtaine
e study, and/
is under the
zed represen
s. 
e With IR
d in accordan
s.  The inves
initiating th
mediately if 
alification ha
be provided
e With Go
cted in accord
e With Ele
s (US 21C
d in complian
the Proto
plement any
or review an
 
73 
 
s 
dance with t
e Internation
Patients
ormed Co
nt Country
ed from each
/or from the 
e legal age of
ntative in acc
B or IEC 
nce with IRB
stigator must
e study and 
the responsi
ave begun.  
to Allergan.
ood Clinica
dance with t
ectronic R
FR Part 1
nce with the 
col 
y deviation fr
nd document
P
the applicabl
nal Conferen
onsent Reg
y Regulati
h patient prio
patient's leg
f consent, th
cordance wit
Regulatio
B regulations
t obtain appr
re-approval 
ible IRB/IEC
Copies of al
 
al Practice
the applicabl
Records; E
11) 
 regulations 
from or chan
ted approval
Protocol 19526
GD
le Good Clin
nce on Harmo
gulations (
ions 
or to any stu
gally authoriz
he consent fo
th the releva
ons 
s (US 21 CF
roval from a
or review at
C has been d
ll IRB/IEC c
e 
le GCP regu
Electronic 
on electroni
nges of the pr
l/favorable o
63-009 Amendm
DD-TA-T-004 v2
nical Practic
onisation (IC
(US 21 CF
udy-related 
zed 
orm must be 
ant country a
FR Part 56.10
a properly 
t least annua
disqualified o
corresponden
ulations and 
Signature
ic records an
rotocol with
opinion from
ment 2 
2015.10 
ce 
CH) 
FR 
and 
03) 
ally.  
or if 
nce 
es 
nd 
out 
m the 
	



	


Approval Date: 	
Allerg
 
 
 
 
IRB/I
to stu
study
10.3
A rep
autho
patien
disclo
FDA 
confi
10.3
Writt
other
(wher
and/o
priva
for Pr
Prote
In acc
publi
10.4
10.4
Sourc
inves
labor
serve
The f
 
 
gan Confidentia
IEC of a pro
udy patients,
y (eg, change
 
Pa
port of the re
orities in any
nt’s name w
osed to the S
if they inspe
dentiality of
 
Pa
.1
ten authoriza
r documentat
re applicable
or from the p
acy requirem
rivacy of Ind
ection Direct
cordance wi
ishing of ano
 
Do
 
So
.1
ce document
stigator's pati
ratory tests, a
es as part of t
following inf
Patient’s n
Patient’s c
al 
otocol amend
 or when the
e in monitors
atient Con
esults of this 
y country in w
ill not be dis
Sponsor of th
ect the study
f medical rec
atient Priv
ation (US sit
tion in accor
e) is to be ob
patient's lega
ments (eg, the
dividually Id
tive 95/46/EC
th HIPAA re
onymous pat
ocumenta
ource Doc
ts may inclu
ient study fil
and electroca
the investiga
formation sh
name 
contact infor
dment, excep
e changes inv
s, change of 
nfidentialit
study may b
which the st
sclosed in th
he study, All
y records.  A
cords and pe
vacy 
tes only), dat
rdance with t
btained from
ally authorize
e Health Insu
dentifiable H
C [“EU Dire
equirements,
tient data fro
tion 
cuments 
ude a patient'
les, as well a
ardiograms. 
ator's record 
hould be ente
rmation 
 
74 
 
pt where nec
volve only lo
f telephone n
ty 
be published
tudy drug ma
hese documen
lergan, or the
Appropriate p
ersonal inform
ta protection
the relevant 
m each patien
ed represent
urance Porta
Health Inform
ective”]). 
, additional p
om the study
s medical re
as the results
 The investi
of a patient'
ered into the
P
cessary to eli
ogistical or a
numbers). 
d or sent to th
ay ultimately
nts.  The pat
e governing 
precautions w
mation. 
n consent (Eu
country and
nt prior to en
tative in acco
ability and A
mation (“HIP
purposes of 
y. 
ecords, hospi
s of diagnost
igator's copy
's study-rela
e patient’s m
Protocol 19526
GD
iminate imm
administrativ
he appropria
y be markete
tient's name 
health autho
will be taken
uropean site
d local privac
nrollment int
ordance with
Accountability
PAA”), Euro
this study m
ital charts, c
tic tests such
y of the case 
ated data. 
medical recor
63-009 Amendm
DD-TA-T-004 v2
mediate hazar
ve aspects o
ate health 
ed, but the 
may be 
orities or the
n to maintain
es only), and 
cy requireme
to the study, 
h the applica
y Act Standa
opean Union 
may include 
clinic charts, 
h as X-rays, 
report form
rd: 
ment 2 
2015.10 
rds 
of the 
e 
n 
ents 
able 
ards 
 Data 
the 
ms 
	


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	


Approval Date: 	
Allerg
 
 
 
 
 
 
 
 
 
 
 
 
 
Sourc
Cons
Cont
10.4
The i
case r
signa
repor
forms
timel
be ma
gan Confidentia
The date t
[or medic
The study
A stateme
written au
country an
obtained (
Dates of a
All concu
being take
medicatio
Occurrenc
The date t
completed
The result
tests) 
Key study
ce document
olidated Gui
emporaneou
 
C
.2
investigator 
report forms
ature page sh
rt forms) to e
s correctly a
ly manner at 
aintained in 
al 
that the patie
cation kit] nu
y title and/or
ent that infor
uthorization 
nd local pati
(including th
all patient vi
urrent medica
en at the tim
ons should be
ce and status
the patient e
d the study o
ts of laborato
y variables 
tation practic
idance and A
us, Original a
ase Repor
is responsibl
s and related
hould person
ensure that th
and complete
the complet
a central dat
ent entered t
umber 
r the protoco
rmed consen
(US sites on
ient privacy 
he date) 
isits 
ations (List a
me of enrollm
e recorded.)
s of any adve
exited the stu
or reason for
ory tests per
ces must fol
ALCOA, ie, 
and Accurat
rt Form C
le for ensuri
d documents.
nally sign for
he observati
ely.  The case
tion of the st
ta repository
 
75 
 
the study, pa
l number of 
nt was obtain
nly), data pro
required doc
all prescripti
ment.  At each
erse events
udy, and a no
r discontinua
rformed by th
low Section 
records mus
e. 
ompletion
ng that data 
.  An investig
r the case rep
ons and find
e report form
tudy, or as ot
y. 
P
atient numbe
f the study an
ned (includin
otection cons
cumentation
ion and non-
h subsequen
otation as to 
ation 
he site (eg, r
4.0 of ICH 
st be Attribu
n 
are properly
gator who ha
port forms (a
dings are rec
ms are to be 
therwise spe
Protocol 19526
GD
er, and patien
nd the name 
ng the date). 
sent (EU site
n for this stud
-prescription
nt visit, chan
whether the
results of uri
E6, Good C
utable, Legib
y recorded o
as signed the
as indicated 
corded on the
submitted to
ecified by Al
63-009 Amendm
DD-TA-T-004 v2
nt randomiza
of Allergan
 A statemen
es only), or o
dy has been 
n medication
nges to the lis
e patient 
ine pregnanc
Clinical Pract
ble, 
on each patie
e protocol 
in the case 
e case report
o Allergan in
llergan and w
ment 2 
2015.10 
ation 
nt that 
other 
ns 
st of 
cy 
tice: 
ent's 
t 
n a 
will 
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Approval Date: 	
Allerg
 
 
 
 
10.4
An in
comp
the re
10.4
All st
docum
of cas
For c
docum
appli
appli
disco
shoul
requi
In ad
requi
Aller
owne
owne
10.5
gan Confidentia
 
St
.3
nvestigator's 
pletion of the
esponsible IR
 
R
.4
tudy related 
mentation, r
se report for
countries fall
ments should
cation in an 
cations in an
ontinuation o
ld be retaine
irement(s) or
ddition, for co
irements sho
rgan requires
ership of the 
ership to a su
 
La
M
al 
tudy Summ
summary w
e study, or as
RB/IEC. 
Retention o
corresponde
ecords of the
rms should b
ling within th
d be retained
ICH region 
n ICH region
of clinical de
ed for a longe
r if needed b
ountries not 
ould be follow
s that it be no
data so that 
uitably quali
abeling, P
Medications
mary 
will be provid
s designated
of Docume
ence, patient
e distribution
be maintaine
he scope of t
d until at lea
and until the
n or at least 2
evelopment o
er period, ho
by the sponso
falling with
wed regardin
otified in wr
mutually ag
fied, respons
ackaging, 
s/Treatme
 
76 
 
ded to Allerg
d by Allergan
entation 
t records, con
n and use of
d on file. 
the ICH guid
ast 2 years af
ere are no pe
2 years have
of the investi
owever, if re
or. 
hin the scope
ng the retent
riting if the in
greed-upon a
sible person
and Retu
ents 
P
gan within a 
n.  A summar
nsent forms,
f all investig
delines, the 
fter the last a
ending or co
e elapsed sin
igational pro
quired by th
e of the ICH 
tion of clinic
nvestigator w
arrangement
. 
urn or Disp
Protocol 19526
GD
short time a
ry is also to 
, patient priv
ational prod
sponsor-spe
approval of a
ontemplated 
nce the forma
oduct.  These
he applicable
guidelines, l
cal study doc
wishes to rel
s can be mad
posal of St
63-009 Amendm
DD-TA-T-004 v2
after the 
be provided
vacy 
ducts, and co
cific essenti
a marketing 
marketing 
al 
e documents
e regulatory 
local regulat
cumentation
linquish 
de for transf
tudy 
ment 2 
2015.10 
d to 
opies 
al 
s 
tory 
n. 
fer of 
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Approval Date: 	
Allerg
 
 
 
 
10.5
The i
receiv
return
return
detail
dispe
The s
the di
10.5
All u
or Al
10.6
A rep
of the
purpo
Auth
on-sit
meet 
study
10.7
Blood
at the
shipm
Detai
Appe
gan Confidentia
 
C
.2
investigator m
ved from Al
ned to the in
ned to Allerg
led inventory
ensed or adm
study treatm
irect supervi
 
R
.3
Su
nused clinic
lergan desig
 
M
presentative 
e extent and 
ose, design, 
orized repre
te visits to re
with the inv
y-related data
 
H
d samples co
e clinical site
ment to a bio
ils of sample
endix 12.1 (A
al 
linical Sup
must keep an
lergan, dispe
nvestigator by
gan or Allerg
y must be co
ministered on
ent is to be u
ision of an in
Return or D
upplies 
al study med
gnee for destr
Monitoring 
of the spons
nature of m
complexity, 
sentatives of
eview, audit 
vestigator(s) 
a and questio
andling of
ollected for p
es, submitted
oanalytical la
e collection, 
Attachments
pply Inven
n accurate a
ensed or adm
y the patient
gan’s design
ompleted for
nly by an app
used in accor
nvestigator.
Disposal o
dications/tre
ruction. 
by the Sp
or will moni
onitoring wi
blinding, siz
f Allergan or
and copy stu
and appropr
ons. 
f Biologica
pharmacokin
d to a central
aboratory for
handling, st
) as well as t
 
77 
 
ntory 
ccounting of
ministered to
t (if applicab
ee during an
r the study m
propriately q
rdance with 
f Study M
eatments and
ponsor 
itor the study
ill be based o
ze, and endp
r regulatory 
udy-related 
riate staff at 
al Specime
netic analysi
l laboratory 
r analysis ut
torage, and s
the appropri
P
f the number
o the patients
ble), and the 
nd at the com
medication.  T
qualified per
the protocol
Medication
d/or supplies 
y on a period
on considera
points of the 
authority rep
documents. 
mutually co
ens 
is will be pro
for processi
tilizing a vali
shipping proc
iate Study Pr
Protocol 19526
GD
r of investig
s, the numbe
number of u
mpletion of th
The study tr
rson to patien
l for patients
s/Treatme
 will be retu
dic basis.  T
ations such a
study. 
presentative
 These repre
onvenient tim
ocessed into 
ing and/or st
idated metho
cedures are 
rocedure Ma
63-009 Amendm
DD-TA-T-004 v2
gational units
er of unused 
unused units
he study.  A 
reatment mu
nts in the stu
s who are un
ents and/o
urned to Alle
The determin
as the object
es will condu
esentatives w
mes to discus
serum samp
orage, prior 
od. 
found in 
anuals. 
ment 2 
2015.10 
s 
units 
s 
st be 
udy.  
nder 
r 
rgan 
nation 
tive, 
uct 
will 
ss 
ples 
to 
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Approval Date: 	
Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
78 
GDD-TA-T-004 v2015.10 
 
 
10.8 
Publications 
Allergan as the sponsor has proprietary interest in this study.  Authorship and manuscript 
composition will reflect joint cooperation between multiple investigators and sites and 
Allergan personnel.  Authorship will be established prior to the writing of the manuscript.  As 
this study involves multiple centers, no individual publications will be allowed prior to 
completion of the final report of the multicenter study except as agreed with Allergan. 
10.9 
Coordinating Investigator 
A signatory Coordinating Investigator will be designated prior to the writing of the Clinical 
Study Report. 
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Approval Date: 	
Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
79 
GDD-TA-T-004 v2015.10 
 
 
11. 
References 
Alves M, Fonseca EC, Alves MF, Malki LT, Arruda GV, Reinach PS, et al.  Dry eye disease 
treatment:  a systemic review of published trials and a critical appraisal of therapeutic 
strategies.  Ocul Surf.  2013;11:181-192. 
Azcarate PM, Venincasa VD, Feuer W, Stanczyk F, Schally AV, Galor A.  Androgen 
deficiency and dry eye syndrome in the aging male.  Invest Ophthalmol Vis Sci.  
2014;55:5046-5053. 
Baudouin C, Aragona P, Van Setten G, Rolando M, Irkec M, Benítez Del Castillo J, et al.  
Diagnosing the severity of dry eye:  a clear and practical algorithm.  Br J Ophthalmol.  
2014;98:1168-1176. 
Bron AJ, Tomlinson A, Foulks GN, Pepose JS, Baudouin C, Geerling G, et al.  Rethinking 
dry eye disease:  a perspective on clinical implications.  Ocul Surf.  2014;12(2 Suppl):S1-S3. 
Cuevas M, González-García MJ, Castellanos E, Quispaya R, del la Parra P, Fernández I, et al.  
Correlations among symptoms, signs, and clinical tests in evaporative-type dry eye disease 
caused by meibomian gland dysfunction (MGD).  Curr Eye Res.  2012;37:855-863. 
Dry Eye WorkShop (DEWS).  The definition and classification of dry eye disease:  report of 
the definition and classification subcommittee of the international dry eye workshop (2007).  
Ocul Surf.  2007;5:75-92. 
Ferriman DM, Gallwey JD. Clinical assessment of body hair growth in women. J Clin 
Endocrinol. 1961;21:1440-1447. 
 
 
 
 
Gayton JL.  Etiology, prevalence, and treatment of dry eye disease.  Clin Ophthalmol.  
2009;3:405-412. 
Hintze J. PASS (Power Analysis and Sample Size) 2008. Kaysville, Utah: NCSS, LLC; 2008. 
Available at: www.ncss.com. 
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Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
80 
GDD-TA-T-004 v2015.10 
 
 
Jabs DA, Nussenblatt RB, Rosenbaum JT; Standardization of Uveitis Nomenclature (SUN) 
Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results 
of the First International Workshop. Am J Ophthalmol 2005;140:509-516. 
Khandelwal P, Liu S, Sullivan DA.  Androgen regulation of gene expression in human 
meibomian gland and conjunctival epithelial cells.  Mol Vis.  2012;18:1055-1067. 
Krenzer KL, Dana MR, Ullman MD, Cermak JM, Tolls DB, Evans JE, et al.  Effect of 
androgen deficiency on the human meibomian gland and ocular surface.  J Clin Endocrinol 
Metab.  2000;85:4874-4882. 
Lemp MA, Nichols KK.  Blepharitis in the United States 2009:  a survey-based perspective 
on prevalence and treatment.  Ocul Surf.  2009;7(2 Suppl):S1-S14. 
Lemp MA, Crews LA, Bron AJ, Foulks GN, Sullivan BD.  Distribution of aqueous-deficient 
and evaporative dry eye in a clinic-based patient cohort:  a retrospective study.  Cornea.  
2012;31:472-478. 
Ludwig E. Classification of the types of androgenetic alopecia (common baldness) occurring 
in the female sex. Br J Dermatol. 1977;97(3):247-254. 
Mathers WD, Shields WJ, Sachdev MS, Petroll WM, Jester JV.  Meibomian gland 
morphology and tear osmolarity:  changes with Accutane therapy.  Cornea.  
1991;10:286-290. 
 
 
Nelson JD, Shimazaki J, Benitez-del-Castillo JM, Craig JP, McCulley JP, Den S, et al.  The 
international workshop on meibomian gland dysfunction:  report of the definition and 
classification subcommittee.  Invest Ophthalmol Vis Sci.  2011;52:1930-1937. 
Nien CJ, Massei S, Lin G, Nabavi C, Tao J, Brown D, et al.  Effects of age and dysfunction 
on human meibomian glands.  Arch Ophthalmol.  2011;129:462-469. 
Norwood OT. Male Pattern Baldness: Classification and Incidence. South Med J. 
1975;68(11):1359-1365. 
Rege A, Kulkarni V, Puthran N, Khandgave T.  A clinical study of subtype-based prevalence 
of dry eye.  J Clin Diagn Res.  2013;7:2207-2010. 
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Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
81 
GDD-TA-T-004 v2015.10 
 
 
Rocha EM, Wickham LA, da Silveira LA, Krenzer KL, Yu FS, Toda I, et al.  Identification of 
androgen receptor protein and 5alpha-reductase mRNA in human ocular tissues.  Br J 
Ophthalmol.  2000;84:76-84. 
Rolando M, Geerling G, Dua HS, Benítez-del-Castillo JM, Creuzot-Garcher C.  Emerging 
treatment paradigms of ocular surface disease:  proceedings of the Ocular Surface Workshop.  
Br J Ophthalmol.  2010;94(Suppl ):i1-i9. 
Rubin DB. Randomization-based evaluations. In: Multiple Imputation for Nonresponse in 
Surveys. New York, NY: John Wiley & Sons, Inc.; 1987. p. 114-115. 
Schiffman R, Christianson MD, Jacobsen G, Hirsch JD, Reis BL.  Reliability and validity of 
the ocular surface disease index.  Arch Ophthalmol.  2000;118:615-621. 
Schirra F, Suzuki T, Richards SM, Jensen RV, Liu M, Lombardi MJ, et al.  Androgen control 
of gene expression in the mouse meibomian gland.  Invest Ophthalmol Vis Sci.  
2005;46:3666-3675. 
Sullivan DA, Sullivan BD, Ullman MD, Rocha EM, Krenzer KL, Cermak JM, et al.  
Androgen influence on the meibomian gland.  Invest Ophthalmol Vis Sci.  
2000;41:3732-3742. 
Sullivan BD, Evans JE, Cermak JM, Krenzer KL, Dana MR, Sullivan DA.  Complete 
androgen insensitivity syndrome:  effect on human meibomian gland secretions.  Arch 
Ophthalmol.  2002a;120:1689-1699. 
Sullivan DA, Sullivan BD, Evans JE, Schirra F, Yamagami H, Liu M, et al.  Androgen 
deficiency, Meibomian gland dysfunction, and evaporative dry eye.  Ann N Y Acad Sci.  
2002b;966:211-222. 
Sullivan DA, Yamagami H, Liu M, Steagall RJ, Schirra F, Suzuki T, et al.  Sex steroids, the 
meibomian gland and evaporative dry eye.  Adv Exp Med Biol.  2002c;506:389-399. 
Sullivan BD, Evans JE, Dana MR, Sullivan DA.  Influence of aging on the polar and neutral 
lipid profiles in human meibomian gland secretions.  Arch Ophthalmol.  
2006;124:1286-1292. 
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Protocol 195263-009 Amendment 2 
 
 
 
 
82 
GDD-TA-T-004 v2015.10 
 
 
Sullivan DA, Jensen RV, Suzuki T, Richards SM.  Do sex steroids exert sex-specific and/or 
opposite effects on gene expression in lacrimal and meibomian glands?  Mol Vis.  
2009;15:1553-1572. 
Truong S, Cole N, Stapleton F, Golebiowski B.  Sex hormones and the dry eye.  Clin Exp 
Optom.  2014;97:324-336. 
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Approval Date: 	
Allerg
 
 
 
 
12. 
12.1
For e
appro
morn
study
collec
samp
stand
descr
12.1
All fe
Fema
postm
salpin
perm
exper
physi
Table
12.1
Pulse
be co
Systo
time 
5 min
gan Confidentia
At
 
Ex
each patient, 
oximately th
ning at appro
y administrat
ction of bloo
ple collection
dardization (d
ribed in Tabl
 
Pr
.1
emale patien
ales will be c
menopausal o
ngectomy, an
manent cessat
rienced 12 m
iological cau
e 1. 
 
V
.2
e rate:  The p
ounted for 30
olic and diast
using a sphy
nutes.  Blood
al 
ttachment
xaminatio
their visits f
e same time
oximately the
tion time at b
od samples f
n should be s
day -21) visi
le 1.  Below 
regnancy 
nts will have 
considered o
or permanen
nd/or bilater
tion of mens
months of am
use.  Howeve
Vital Signs 
patient shoul
0 seconds, m
tolic blood p
ygmomanom
d pressure w
ts 
n Procedu
for ophthalm
 of the day, s
e same time 
baseline).  In
for pharmaco
scheduled to
it ± 1 hour. 
is a brief de
Test 
a urine preg
of childbearin
ntly sterilized
ral oophorect
trual periods
menorrhea wi
er, all female
ld be in a res
multiplied by 
pressure:  blo
meter with th
will be record
 
83 
 
ures, Tests
mic examinat
such that stu
of day durin
n addition, fo
okinetic anal
o align to tim
Procedures s
scription of 
gnancy test p
ng potential 
d (ie, tubal o
tomy).  Natu
s, determine
ithout any ot
es in this stu
sting state (se
2, and recor
ood pressure
he patient in r
ded in millim
P
s, Equipm
tions should 
udy treatmen
ng each offic
for patients th
lysis,  the tim
me sample wa
should be pe
selected pro
performed at
unless they 
occlusion, hy
ural menopa
d retrospecti
ther obvious
udy will unde
eated) for at
rded in beats
e will be mea
resting state
meters of mer
Protocol 19526
GD
ent, and T
be schedule
nt can be adm
ce visit (± 1 h
hat participa
me of the pre
as collected 
erformed in 
ocedures. 
t the baseline
are naturally
ysterectomy,
ause is define
ively after a 
s pathologica
ergo a pregn
t least 5 minu
s per minute
asured in the
e (seated) for
rcury (mm H
63-009 Amendm
DD-TA-T-004 v2
Techniques
ed at 
ministered in
hour from th
ate in the 
e-dose blood
at the 
the order 
e (day 1) vis
y 
, bilateral 
ed as the 
woman has
al or 
nancy test as
utes.  Pulse w
e. 
e same arm e
r at least 
Hg). 
ment 2 
2015.10 
s 
n the 
he 
d 
sit.  
 
 per 
will 
each 
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Approval Date: 	
Allerg
 
 
 
gan Confidential 
 
84 
 
Protocol 19526
GD
63-009 Amendm
DD-TA-T-004 v2
ment 2 
2015.10 
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Approval Date: 	
Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
85 
GDD-TA-T-004 v2015.10 
 
 
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Approval Date: 	
Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
86 
GDD-TA-T-004 v2015.10 
 
 
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Approval Date: 	
Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
87 
GDD-TA-T-004 v2015.10 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Approval Date: 	
Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
88 
GDD-TA-T-004 v2015.10 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
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Approval Date: 	
Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
89 
GDD-TA-T-004 v2015.10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Approval Date: 	
Allerg
 
 
 
 
gan Confidential 
 
90 
 
Protocol 19526
GD
63-009 Amendm
DD-TA-T-004 v2
ment 2 
2015.10 
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Approval Date: 	
 
 
91 
 
GDD-TA-T-004 v2
 
2015.10 
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


Approval Date: 	
Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
92 
GDD-TA-T-004 v2015.10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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


Approval Date: 	
A
 
 
Allergan Confidential 
93 
Protocol 195263-009 A
GDD-TA-T
Amendment 2 
T-004 v2015.10 
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


Approval Date: 	
Allerg
 
 
 
gan Confidential 
 
94 
Protocol 19526
GD
63-009 Amendm
DD-TA-T-004 v2
ment 2 
2015.10 
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Approval Date: 	
Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
95 
GDD-TA-T-004 v2015.10 
 
 
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Approval Date: 	
Allerg
 
 
 
 
gan Confidential 
 
96 
Protocol 19526
GD
63-009 Amendm
DD-TA-T-004 v2
ment 2 
2015.10 
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Approval Date: 	
Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
97 
GDD-TA-T-004 v2015.10 
 
 
  
  
 
  
  
 
  
  
 
  
  
 
  
  
 
 
  
 
 
  
 
  
  
 
  
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
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	


Approval Date: 	
Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
98 
GDD-TA-T-004 v2015.10 
 
 
 
 
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
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Allerg
 
 
 
gan Confidential 
 
99 
Protocol 19526
GD
63-009 Amendm
DD-TA-T-004 v2
ment 2 
2015.10 
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Approval Date: 	
Allerg
 
 
 
gan Confidential 
 
100 
Protocol 19526
GD
63-009 Amendm
DD-TA-T-004 v2
ment 2 
2015.10 
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


Approval Date: 	
Allerg
 
 
 
 
12.1
Labo
count
certif
[CAP
using
labor
Aller
the st
gan Confidentia
 
B
.15
ratory specim
t with differe
fication from
P] or Clinica
g validated m
ratory follow
rgan shall ha
tudy.  The fo
al 
lood and U
mens for blo
ential, and u
m a recognize
al Laboratory
methods. All 
wing testing, 
ave full owne
ollowing ana
Urine Sam
ood chemistr
urinalysis wil
ed accreditat
y Improveme
blood and u
and will be 
ership rights
alyses will be
 
101 
mples for B
ry panel, hem
ll be sent to 
tion agency 
ent Amendm
urine samples
discarded af
to any biolo
e performed 
P
Blood Che
matology inc
a centralized
(eg, College
ments [CLIA
s will be sto
fter a time pe
ogical specim
by the centr
Protocol 19526
GD
emistry an
cluding com
d clinical lab
e of America
A] certificatio
ored at the ce
eriod indicat
mens/sample
ral laborator
63-009 Amendm
DD-TA-T-004 v2
nd Urinaly
mplete blood 
boratory with
an Pathology
on) to be ass
entralized cli
ted by Allerg
es derived fr
ry: 
ment 2 
2015.10 
ysis 
h 
y 
ayed 
inical 
gan. 
rom 
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Approval Date: 	
Allerg
 
 
 
 
 
 
 
 
12.1
Blood
and s
Prior 
availa
Pharm
For e
gan Confidentia
Hematolo
corpuscul
(MCHC),
RBC mor
bands, lym
Serum ch
aminotran
bicarbona
indirect b
cholestero
protein, u
Urine wil
bilirubin, 
casts, and
PSA for m
 
B
.16
d samples ob
stored frozen
to the start o
able for each
macokinetic 
each collectio
al 
ogy paramete
lar hemoglob
, mean corpu
rphology, tot
mphocytes, m
emistry para
nsferase, asp
ate, calcium,
ilirubin, mag
ol, high dens
urea nitrogen
l be analyze
and microsc
d crystals). 
male patient 
lood Samp
btained for s
n until shippe
of collection
h collection t
Analysis Pr
on timepoint
ers will inclu
bin (MCH), 
uscular volum
tal white blo
monocytes, b
ameters will 
partate amino
 chloride, cr
gnesium, ph
sity lipoprote
n, uric acid 
d for specifi
copic examin
samples onl
ple Collect
selected patie
ed to a facili
n, sites must 
timepoint as
ocedures Ma
t, the investi
 
102 
ude hematoc
mean corpu
me (MCV), 
od cell (WB
basophils, an
include albu
otransferase,
reatinine, cre
hosphorous, p
ein, low den
ic gravity, pH
nation (WBC
y 
tion for Ph
ents for phar
ity for analys
ensure that 
s described in
anual. 
igator will dr
P
crit, hemoglo
scular hemo
platelets, red
BC) count, an
nd eosinoph
umin, alkalin
, gamma-glu
eatine kinase
potassium, s
nsity lipoprot
H, color, pro
C, RBC, epit
harmacok
rmacokinetic
sis. 
all required 
n the Blood 
raw approxim
Protocol 19526
GD
obin (Hb), H
oglobin conc
d blood cell 
nd differenti
hils). 
ne phosphata
utamyl transf
e, direct bilir
sodium, total
tein, triglyce
otein, glucos
thelial cells,
kinetic Ana
c analysis w
pre-labeled 
Sample Col
mately 3 mL
63-009 Amendm
DD-TA-T-004 v2
HbA1c, mean
centration 
(RBC) coun
al (neutroph
ase, alanine 
ferase, 
rubin, glucos
l bilirubin, to
erides, total 
e, blood, 
, bacteria, mu
alysis 
will be proces
tubes are 
llection for 
L of blood. 
ment 2 
2015.10 
n 
nt, 
hils, 
se, 
otal 
ucus, 
ssed 
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Approval Date: 	
Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
103 
GDD-TA-T-004 v2015.10 
 
12.2 
Glossary of Abbreviations 
Term / Abbreviation 
Definition 
 
 
ADDE 
aqueous deficient dry eye 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
AP 
analysis plan 
BCVA 
best-corrected visual acuity 
BID 
twice-daily administration 
BMI 
body mass index 
CMH 
Cochran-Mantel-Haenszel 
DED 
dry eye disease 
 
 
eCRF 
electronic case report form 
EDE 
evaporative dry eye 
GnRH 
gonadotropin-releasing hormone 
IOP 
intraocular pressure 
ITT 
intent-to-treat 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
IxRS 
automated interactive (telephone or web) response system 
KCS 
keratoconjunctivitis sicca 
LC-MS/MS 
liquid chromatography with tandem mass spectrometry 
LOCF 
last observation carried forward 
LogMAR 
logarithm of the minimum angle of resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCH 
mean corpuscular hemoglobin  
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MGD 
meibomian gland dysfunction 
NE 
non-expressible 
NSAID 
nonsteroidal anti-inflammatory drug 
OSDI 
Ocular Surface Disease Index 
PP 
per-protocol 
PSA 
prostate-specific antigen 
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Approval Date: 	
Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
104 
GDD-TA-T-004 v2015.10 
 
Term / Abbreviation 
Definition 
RBC 
red blood cell 
SAT 
study artificial tears 
SHBG 
sex hormone-binding globulin 
TBUT 
tear film break-up time 
US(A) 
United States (of America) 
WBC 
white blood cell 
 
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Approval Date: 	
Allerg
 
 
 
 
12.3
12.3
Title:
Proto
Date 
Ame
This 
Follo
proto
revisi
Sectio
Protoc
Summ
Design
Protoc
Summ
Exclus
Criteri
Protoc
Summ
Exclus
Criteri
Table 
Sched
Proced
Sectio
Inclus
Criteri
Sectio
Permi
Medic
Sectio
Exclus
Criteri
gan Confidentia
 
Pr
 
A
.1
:  Topical Op
ocol 195263-
of Amendm
ndment Sum
summary in
owing is a su
ocol, and a br
ions have no
on 
R
col 
mary/Study 
n 
St
tw
st
col 
mary/Key 
sion 
ia 
H
pe
st
st
re
col 
mary/Key 
sion 
ia 
U
th
w
un
1 
dule of 
dures 
on 4.3/ 
ion 
ia 
In
in
di
on 4.5.1/ 
ssible 
cations 
In
fo
st
vi
w
on 4.4/ 
sion 
ia 
L
th
pr
st
al 
rotocol Am
Amendmen
phthalmic AG
-009 Amend
ment:  Octobe
mmary 
cludes chang
ummary of co
rief rationale
ot been summ
Revision 
tudy artificial t
wice daily for 6
tandardization 
Hormone replac
ermitted so lon
table for 90 day
tandardization 
emain stable th
Use of oral or to
he eyes or eyeli
within 60 days o
ntil the month 
nclusion criteri
nclude addition
isease or meibo
nhaled corticos
or at least 60 da
tandardization 
isit. Dermal an
will be permitte
Lifitegrast (Xiid
herapeutic treat
rohibited 60 da
tandardization 
mendment
nt 2 
GN-195263 
dment 2 
er 2016 
ges made to 
ontent-orien
e for these ch
marized. 
tears (SAT) wi
6 days followin
(day -21) vist
cement therapy
ng as dosing ha
ys prior to 
and is anticipa
hroughout the s
opical corticost
ids will be proh
of standardizat
6 visit. 
ion #11 expand
nal treatments f
omian gland di
steroids must b
ays prior to 
and until the m
nd nasal cortico
d as needed. 
dra) and any ot
tments for dry 
ays prior to 
through month
 
105 
t Summary
for the Trea
Protocol 19
nted changes 
hanges.  Min
R
ill be used 
ng the 
C
p
y will be 
as been 
ated to 
study. 
R
st
teroids in 
hibited 
tion and 
R
c
1
ded to 
for dry eye 
isease. 
T
p
m
be stable 
month 6 
osteroids 
R
c
c
p
ther 
eye 
h 6 visit. 
U
tr
tr
c
P
y 
atment of Ev
95263-009 A
that were m
nor editorial
Rationale 
Clarification of
prohibited 24 h
Revised to be c
tudy 195263-0
Revised from a
consistent with 
95263-006. 
To broaden crit
pharmacologic 
meibomian glan
Revised to acco
corticosteroid u
corticosteroids,
permitted as ne
Updated to excl
reatment for dr
reatments whic
course of the stu
Protocol 19526
GD
vaporative D
Amendment 1
made to each 
l and docume
f 6 days, not 7, 
hours prior to an
consistent with 
006. 
a window of 30
previous phas
teria to include
treatments for 
nd disease. 
ommodate chro
use, and clarifie
, in addition to 
eeded. 
lude this recen
ry eye, and any
ch may be appr
tudy. 
63-009 Amendm
DD-TA-T-004 v2
ry Eye 
1 (27 June 20
section of th
ent formattin
as SAT are 
ny study visit.
previous phas
0 days to be 
e 2 study  
e use of 
dry eye or 
onic inhaled 
ed that dermal 
nasal, will be 
ntly marketed 
y therapeutic 
roved during th
ment 2 
2015.10 
016).  
he 
ng 
e 2 
he 
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Approval Date: 	
Allergan Confidential 
Protocol 195263-009 Amendment 2 
 
 
 
 
106 
GDD-TA-T-004 v2015.10 
 
Section 
Revision 
Rationale 
Section 4.4/ 
Exclusion 
Criteria 
Exclusion criterion #29 added to 
exclude hair weaves and scalp hair 
transplants. 
To exclude procedures that may confound hair 
growth evaluations. 
Section 4.4/ 
Exclusion 
Criteria 
Exclusion criterion #30 added to outline 
prohibited female hair removal practices 
and windows around study visits. 
To exclude procedures that may confound hair 
growth evaluations. 
Section 7.2.3/ 
Other Efficacy 
Variables 
Expanded other efficacy variables to 
include change from baseline 
assessments of corneal and conjunctival 
staining scores, upper and lower lid 
margin appearance measures, global 
meibum quality scores, and ocular 
symptom scores 
Addition of exploratory analyses. 
 
 
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


Approval Date: 	
Allerg
 
 
 
 
12.3
Title:
Proto
Date 
Ame
This 
a sum
brief 
not b
Sectio
Invest
Signat
Table 
Sched
Visits 
Proced
Sectio
Tear F
Break
Evalua
Invest
 
gan Confidentia
 
A
.2
:  Topical Op
ocol 195263-
of Amendm
ndment Sum
summary in
mmary of con
rationale for
een summar
on 
R
tigator 
ture Page 
A
th
1 
dule of 
and 
dures 
La
ex
pe
ch
re
pe
on 12.1.5 
Film 
-up Time 
ated by 
tigator 
R
Pr
al 
Amendmen
phthalmic AG
-009 Amend
ment:  June 20
mmary 
cludes chang
ntent-oriente
r these chang
rized. 
Revision 
Added the inves
he protocol. 
anguage in tab
xaminations/pr
erformed in the
hanged to “It is
equired that the
erformed in the
eference to Tea
rocedures Man
nt 1 
GN-195263 
dment 1 
016 
ges made to 
ed changes th
ges.  Minor 
stigator signatu
le header statin
rocedures shou
e order listed b
s recommended
e procedures be
e order shown”
ar Film Break-
nual was remov
 
107 
for the Trea
Protocol 19
hat were ma
editorial and
R
ure page to 
T
re
ap
ng “All 
ld be 
below” 
d but not 
elow be 
” 
T
in
p
-up Time 
ved. 
P
atment of Ev
95263-009 ( 
ade to each s
d document f
Rationale 
The investigato
emoved from t
pproval. 
To comply with
nclusion in all 
protocols 
Protocol 19526
GD
vaporative D
19 May 201
section of the
formatting r
or signature pag
the original pro
h updated stand
ophthalmology
63-009 Amendm
DD-TA-T-004 v2
ry Eye 
6).  Followin
e protocol, a
revisions hav
ge was acciden
otocol prior to 
dard language 
y development
ment 2 
2015.10 
ng is 
and a 
ve 
ntally 
for 
t 
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	


Approval Date: 	
ALLERGAN
 
Date (DD/MMM/YYYY)/Time (PT)
Signed by:
Justification
            
           
            
           
            
           
           
            
           
            
           
            
           
            
           
            
           
            
      
            
      
            
      
            
      
            
      
            
      
            
      
            
      
            
      
            
      
            
      
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