The Efficacy and Safety of Bimatoprost SR in Patients With Open-angle Glaucoma or Ocular Hypertension
Phase: PHASE3
Conditions: Glaucoma, Open-Angle, Ocular Hypertension
Sponsor: Allergan

 
   
 
 
 
         NCT02250651 
 
Study ID: 192024-092 
 
 
Title: The Efficacy and Safety of Bimatoprost SR in Patients With Open-angle 
Glaucoma or Ocular Hypertension 
 
                                Protocol Date: June 5, 2018 

 
 
Approval Date: 
 
05-Jun-2018
Allergan Confidential 
Protocol 192024-092 Amendment 3 
 
 
1 
GDD-TA-T-004 v2013.9 
 
Title Page 
ALLERGAN – CONFIDENTIAL 
The following contains confidential, proprietary information  
which is the property of Allergan 
 
The Efficacy and Safety of Bimatoprost SR in Patients With Open-angle Glaucoma or 
Ocular Hypertension 
 
Protocol Number:   
192024-092 Amendment 3 
EudraCT Number: 
2014-003186-24  
Phase: 
3 
Name of Investigational Product: 
Bimatoprost SR 
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. 
Serious Adverse Event Reporting 
Fax Numbers: 
 
(Backup Fax No.: 
)   
 
Allergan Medical Safety Physician 
Contact Information: 
 
Tel (office):  
 
Tel (mobile):  
 
Fax:  
 
Email: 
 

 
 
Approval Date: 
 
05-Jun-2018
Allergan Confidential 
Protocol 192024-092 Amendment 3 
 
 
2 
GDD-TA-T-004 v2013.9 
 
Allergan Signatory: 
 
Vice President and  
Therapeutic Area Head 
Anterior Segment and Consumer Eye Care 
Allergan – Global Drug Development 
Refer to the final page of this protocol for electronic signature 
and date of approval. 
 
The following information can be found on FDA Form 1572 and/or study contacts page:  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 the research facilities to be used; name and 
address of each reviewing institutional review board (IRB); US 21 CFR 312.23 section 6(iii)b. 
 

 
 
Approval Date: 
 
05-Jun-2018
Allergan Confidential 
Protocol 192024-092 Amendment 3 
 
 
3 
GDD-TA-T-004 v2013.9 
 
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 
 
 

 
 
Approval Date: 
 
05-Jun-2018
Allergan Confidential 
Protocol 192024-092 Amendment 3 
 
 
4 
GDD-TA-T-004 v2013.9 
 
Table of Contents 
Table of Contents ...................................................................................................................... 4 
List of Tables ............................................................................................................................. 8 
List of Figures ........................................................................................................................... 9 
Protocol Summary .................................................................................................................. 10 
1. 
Background and Clinical Rationale ................................................................................. 24 
1.1 
Glaucoma Overview............................................................................................... 24 
1.2 
Bimatoprost (LUMIGAN®) ................................................................................... 25 
1.3 
Bimatoprost SR ...................................................................................................... 26 
1.3.1  Nonclinical Studies with Bimatoprost SR.................................................. 26 
1.3.2  Other Biodegradable Ocular Implants ....................................................... 28 
1.3.3  Clinical Study with Bimatoprost SR .......................................................... 28 
1.4 
Study Rationale ...................................................................................................... 28 
2. 
Study Objectives and Clinical Hypotheses ...................................................................... 29 
2.1 
Study Objectives .................................................................................................... 29 
2.2 
Clinical Hypotheses ............................................................................................... 29 
3. 
Study Design .................................................................................................................... 29 
4. 
Study Population and Entry Criteria ................................................................................ 31 
4.1 
Number of Patients ................................................................................................. 31 
4.2 
Study Population Characteristics ........................................................................... 31 
4.2.1  Patients With Sickle Cell Trait or Disease ................................................. 31 
4.3 
Inclusion Criteria .................................................................................................... 31 
4.4 
Exclusion Criteria................................................................................................... 33 
4.5 
Permissible and Prohibited Medications/Treatments ............................................. 37 
4.5.1  Permissible Medications/Treatments ......................................................... 37 
4.5.2  Prohibited Medications/Treatments ........................................................... 38 
4.5.3  Definition of Females of (Non-)Childbearing Potential and/or Acceptable 
Contraceptive Methods .............................................................................. 40 
5. 
Study Treatments ............................................................................................................. 41 
5.1 
Study Treatments and Formulations ...................................................................... 41 
5.2 
Control Treatments ................................................................................................. 41 
5.3 
Methods for Masking ............................................................................................. 41 
5.4 
Treatment Allocation Ratio and Stratification ....................................................... 43 

 
 
Approval Date: 
 
05-Jun-2018
Allerg
 
 
 
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Metho
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Treatm
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5.7 
Storag
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Prepar
5.9 
Treatm
5.9.1 
5.9.2 
5.9.3 
5.9.4 
5.10  Retrea
Response M
6.1 
Efficac
6.1.1 
6.2 
Safety 
6.3 
Other M
6.4 
Exami
6.4.1 
6.4.2 
6.4.3 
6.5 
Other S
6.6 
Summ
Statistical Pr
7.1 
Analys
7.2 
Collec
7.2.1 
7.2.2 
7.3 
Hypoth
7.3.1 
al 
d for Assign
ment Regime
Treatment R
e of Study M
ration of Stud
ment Admini
Patient Prep
Study Trea
Administra
Immediate 
atment .........
easures and 
cy Measures
Primary Ef
Measures ..
Measures (O
nation Proce
Medical Hi
 
M
6.4.1.1
 
P
6.4.1.2
 
V
6.4.1.3
Pregnancy 
Laboratory
 
H
6.4.3.1
 
S
6.4.3.2
 
U
6.4.3.3
Study Suppl
mary of Metho
rocedures ....
sis Populatio
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Primary Ef
Secondary 
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Primary Ef
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Regimen/Do
Medications/
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Posttreatme
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Summary of
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fficacy Meas
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istory, Physi
Medical Hist
Physical Exa
Vital Signs ...
Testing .......
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Hematology .
Serum Chem
Urinalysis ....
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ons ...............
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Efficacy Var
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Approval Date: 
 
05-Jun-2018
Allerg
 
 
 
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Subgro
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Interim
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Sample
Study Visit S
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Patient
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Efficacy An
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Cycle 1:  Day
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Cycle 2:  We
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Approval Date: 
 
05-Jun-2018
Allerg
 
 
 
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Adverse Eve
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9.4 
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Administrati
10.1  Protect
10.1.1 
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10.3  Patient
10.3.1 
10.4  Docum
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8.4.3.20
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8.4.3.22
Extended F
 
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8.4.4.1
 
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M
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M
8.4.4.4
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Cycle 3:  We
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Month 14 .....
Month 16 .....
Month 18 .....
Month 20/Ex
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Approval Date: 
 
05-Jun-2018
Allergan Confidential 
Protocol 192024-092 Amendment 3 
 
 
8 
GDD-TA-T-004 v2013.9 
 
10.4.1  Source Documents ..................................................................................... 91 
10.4.2  Case Report Form Completion................................................................... 92 
10.4.3  Study Summary .......................................................................................... 92 
10.4.4  Retention of Documentation ...................................................................... 92 
10.5  Labeling, Packaging, and Return or Disposal of Study Medications/Treatments . 93 
10.5.1  Labeling/Packaging .................................................................................... 93 
10.5.2  Clinical Supply Inventory .......................................................................... 93 
10.5.3  Return or Disposal of Study Medications/Treatments and/or Supplies ..... 93 
10.6  Monitoring by the Sponsor .................................................................................... 94 
10.7  Handling of Biological Specimens......................................................................... 94 
10.8  Publications ............................................................................................................ 94 
10.9  Coordinating Investigator ...................................................................................... 95 
 ................................................... 95 
11.  References ........................................................................................................................ 95 
12.  Attachments ..................................................................................................................... 98 
12.1  Package Insert ........................................................................................................ 98 
12.2  Glossary of Abbreviations ...................................................................................... 99 
12.3  Protocol Amendment Summary ........................................................................... 102 
12.3.1  Amendment 1 ........................................................................................... 102 
12.3.2  Amendment 2 ........................................................................................... 116 
12.3.3  Amendment 3 ........................................................................................... 127 
 
List of Tables 
Table 1 
Treatment Groups ........................................................................................... 10 
Table 2 
Screening through Treatment Day 1 ............................................................... 15 
Table 3 
Administration Cycle 1 Schedule of Visits and Procedures: Treatment Period 
Day 2 through Week 12 .................................................................................. 17 
Table 4 
Administration Cycle 2 Schedule of Visits and Procedures:  Treatment Period 
Week 15 Through Week 28 ............................................................................. 18 
Table 5 
Administration Cycle 3 Schedule of Visits and Procedures:  Treatment Period 
Week 31 Through Week 52 ............................................................................. 20 
Table 6 
Schedule of Visits and Procedures:  Extended Follow Up Months 14, 16, 18, 
and 20 .............................................................................................................. 22 

 
 
Approval Date: 
 
05-Jun-2018
Allergan Confidential 
Protocol 192024-092 Amendment 3 
 
 
9 
GDD-TA-T-004 v2013.9 
 
Table 7 
Treatment Groups ........................................................................................... 30 
Table 8 
Minimum Washout Period by Ophthalmic Medication Class ........................ 63 
 
List of Figures 
Figure 1 
Flowchart of Patient Participation .................................................................. 14 

 
 
Approval Date: 
 
05-Jun-2018
Allergan Confidential 
Protocol 192024-092 Amendment 3 
 
 
10 
GDD-TA-T-004 v2013.9 
 
Protocol Summary 
 
Study Compound: Bimatoprost sustained-release (SR) biodegradable implants containing preservative-free 
AGN-192024 (bimatoprost)  
Phase: 3 
Study Objectives:   
To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of 2 dose strengths of Bimatoprost SR 
in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT) after initial and repeated 
administrations  
Clinical Hypotheses:   
At least 1 dose strength (10 µg or 15 µg) of Bimatoprost SR will have an IOP-lowering effect that is noninferior 
to that of topically administered timolol maleate 0.5% (hereafter referred to as timolol) eye drops in patients 
with OAG or OHT following single and repeat administration. 
Bimatoprost SR administered intracamerally in dose strengths of 10 µg or 15 µg will have an acceptable safety 
profile in patients with OAG or OHT following single and repeat administration. 
Study Design 
Structure: Phase 3, multicenter, randomized, masked, parallel-group comparison (2 dose strengths of 
Bimatoprost SR versus active control), repeat administration 
Duration: Approximately 22 months, consisting of screening of up to 28 days before washout, washout period 
of up to 42 days before initial administration of study medication, 52-week treatment period, plus 8 months 
extended follow-up  
Study Treatment Groups: Bimatoprost SR dose groups:  10 µg and 15 µg 
Control: Timolol eye drops plus Sham needleless procedure (that involves touching the eye at the area of 
insertion with a needleless applicator). 
Dosage/Dose Regimen: Patients will receive 1 of 2 dose strengths of Bimatoprost SR or Control treatment in the 
study eye on Day 1 (with repeat administration of the same dose strength or Sham at Week 16 and Week 32). 
Bimatoprost SR-treated patients will receive intracameral administration of Bimatoprost SR in the study eye 
using a prefilled applicator.  Timolol vehicle eye drops will be used twice daily (BID; in the morning and 
evening) to mask the treatment of patients receiving Bimatoprost SR in the study eye.  The fellow eye will 
receive a Sham needleless procedure (hereafter called Sham administration or Sham administration procedure) 
plus topical timolol eye drops, BID.  Control group patients will receive a Sham administration plus timolol in 
both eyes. 
All patients will be masked to their treatment group.  Treatment groups are shown in Table 1. 
Table 1 
Treatment Groups 
Treatment 
Study Eye Treatment 
Fellow Eye Treatment 
Bimatoprost SR 10 µg  
Dose strength:  10 µg 
Eye drops:  Vehicle BID 
Sham administration procedure 
Eye drops:  Timolol BID 
Bimatoprost SR 15 µg 
Dose strength:  15 µg 
Eye drops:  Vehicle BID 
Sham administration procedure 
Eye drops:  Timolol BID 
Control 
Sham administration procedure 
Eye drops:  Timolol BID 
Sham administration procedure 
Eye drops:  Timolol BID 
BID = twice daily 

 
 
Approval Date: 
 
05-Jun-2018
Allergan Confidential 
Protocol 192024-092 Amendment 3 
 
 
11 
GDD-TA-T-004 v2013.9 
 
The patients will begin self-administration of the study-provided eye drops (vehicle or timolol) in both eyes, 
starting with the evening dose on the first administration (Bimatoprost SR or Sham administration) day visit.  
Patients will continue self-administration of the study-provided eye drops in the morning (08:00 ± 1 hour) and 
in the evening (20:00  ± 1 hour) approximately 12 hours apart throughout the study, with the exception of the 
morning of a subsequent visit, on which the morning eye drop administration will be performed at the study 
site. 
Randomization/Stratification: Randomization to treatment groups will use a 1:1:1 ratio (Bimatoprost SR 
10 µg:Bimatoprost SR 15 µg:Control).  Randomization will be stratified by baseline study eye Hour 0 IOP 
(≤ 25 mm Hg or > 25 mm Hg). 
Visit Schedule: Patients who complete the entire study without receiving nonstudy IOP-lowering medication in 
both eyes will have a minimum of 25 visits and 6 phone calls.  The schedule includes:  
• 
Screening (up to 28 days); Washout period of up to 42 days for both eyes (which may begin once 
screening procedures have been completed); Baseline (up to 3 days)  
• 
Treatment period  
o 
Cycle 1:  Day 1 Administration Day; Day 2; phone call on Days 4 and 8; and visits at 
Weeks 2, 6, 12, and 15 
o 
Cycle 2:  Week 16 Administration Day; Cycle 2 Day 2; phone call on Cycle 2 Days 4 and 8; 
and visits at Weeks 18, 22, 28, and 31 
o 
Cycle 3:  Week 32 Administration Day; Cycle 3 Day 2; phone call on Cycle 3 Days 4 and 8; 
and visits at Weeks 34, 38, 44, 48, and 52 
• 
Extended Follow-up 
o 
Visits at Months 14, 16, 18, and 20/Exit 
Intraocular pressure evaluations will occur at 2 timepoints:  Hour 0 (08:00 ± 1 hour) and Hour 2 
(Hour 0 + 2 hours [± 30 minutes]). 
Patients who have not received nonstudy IOP-lowering medication (prohibited prior to Week 52) in both eyes 
will receive a repeat administration of Bimatoprost SR (or Sham administration in Control group study eyes and 
all fellow eyes) at the Week 16 and Week 32 visits as indicated.  Administration should not occur if the 
investigator believes that there are any safety concerns.  Patients who have received nonstudy IOP-lowering 
medication  in both eyes will be followed for at least 12 months following the last administration of 
Bimatoprost SR or Sham, at which time they may exit early at the investigator’s discretion. 
Study Population Characteristics 
Number of Patients: Approximately 510 patients will be enrolled in the study. 
Condition/Disease: Patients with OAG (primary OAG, pseudoexfoliative glaucoma, or pigmentary glaucoma) 
or OHT who require IOP-lowering medications in both eyes.  The eye that meets the entry criteria will be 
selected as the study eye.  If both eyes meet the entry criteria, the eye with the higher IOP at baseline Hour 0 
will be selected as the study eye.  If both eyes have the same IOP at Hour 0, then the right eye will be 
designated as the study eye. 
Key Inclusion Criteria:  
• 
Written informed consent has been obtained 
• 
Diagnosis of either OAG (ie, primary, pseudoexfoliation, or pigmentary glaucoma) or OHT in each 
eye and both eyes require IOP-lowering treatment (Note:  diagnosis does not have to be the same in 
both eyes) 
• 
In the investigator’s opinion, either eye can be treated adequately with topical ophthalmic beta-blocker 
(eg, timolol) eye drops as the sole therapy 

 
 
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• 
In the investigator’s opinion, either eye can be treated adequately with topical prostamide, 
prostaglandin, or prostaglandin analog (eg, LUMIGAN, Xalatan, Travatan) eye drops as the sole 
therapy 
• 
The iridocorneal angle in the study eye must be independently confirmed as being qualified by 
2 ophthalmologists using the following criteria: 
a. 
Shaffer Grade ≥ 3 on clinical gonioscopy of the inferior angle 
b. Peripheral anterior chamber depth by Van Herick  examination ≥ 1/2 corneal thickness  
Note: The independent eligibility assessments must both agree that the Shaffer grade is ≥ 3 and the 
Van Herick grade is ≥ 1/2 corneal thickness. 
• 
At the Baseline visit: Hour 0 IOP in the study eye of ≥ 22 mm Hg and ≤ 32 mm Hg, and in the fellow 
eye of ≤ 32 mm Hg 
• 
At the Baseline visit: Hour 2 IOP in the study eye of ≥ 19 mm Hg and ≤ 32 mm Hg, and in the fellow 
eye of ≤ 32 mm Hg 
• 
By the Baseline visit, the final central endothelial cell density in both eyes must be confirmed as being 
qualified by Reading Center assessment, with at least one eye qualified for inclusion as the study eye 
Key Exclusion Criteria: 
• 
The following surgical history: 
a. 
History or evidence of complicated cataract surgery in the study eye: eg, surgery resulting in 
complicated lens placement (such as anterior chamber intraocular lens implant [IOL], sulcus 
IOL, aphakia, etc) or intraoperative complications (such as a posterior capsular tear [with or 
without vitreous loss], substantial iris trauma, etc) 
Note: history of uncomplicated cataract surgery is not an exclusion. 
b. History of phakic IOL insertion for refractive error correction in the study eye 
• 
In the investigator’s opinion, patient is nonresponsive to topical ophthalmic beta-blockers and/or 
topical prostamides, prostaglandins, or prostaglandin analogs (eg, LUMIGAN, Xalatan, Travatan) 
• 
Contraindications to beta-blocker therapy 
Response Measures 
Efficacy: Intraocular pressure measured by Goldmann applanation tonometry   
Safety: Adverse events; ocular parameters as determined through assessment of visual acuity and visual field; 
evaluation of macroscopic bulbar conjunctival hyperemia and iris color; assessment of endothelial cell density 
and corneal thickness; IOP measurement, biomicroscopic and ophthalmoscopic examinations (including 
gonioscopy with Bimatoprost SR implant assessment, optic disc examination, and dilated fundus examination); 
and optical coherence tomography (OCT) of the macula 
General Statistical Methods and Types of Analyses:   
The intent-to-treat population (ITT) is defined as all randomized patients and will be used for demographic and 
efficacy analyses. The per protocol (PP) population will consist of the subset of the ITT population with no 
protocol deviations affecting the primary efficacy analysis and will be used to confirm the primary efficacy 
analysis. A list of patients excluded from the PP population will be finalized prior to database lock. The safety 
population is defined as all patients who received study drug treatment and will be used for safety analyses. 
Analyses in the ITT population will be based on the treatment to which a patient was randomized, and analyses 
in both the PP and safety populations will be based on the actual treatment a patient received. 
Continuous variables will be summarized by descriptive statistics including sample size, mean, standard 
deviation, median, minimum, and maximum. Categorical variables will be summarized by frequency and 
percentage. 

 
 
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The primary efficacy variable is study eye time-matched IOP change from baseline. Mean IOP change from 
baseline will be compared between each Bimatoprost SR dose strength and timolol for each hour (Hours 0 
and 2) using the ITT population. The comparisons at Week 12 will be considered the primary analysis. 
Intraocular pressure change from baseline will be analyzed using a mixed-effects model repeated measures 
(MMRM) approach.  The model will include IOP time-matched change from baseline as the response variable 
and treatment, timepoint (Hours 0 and 2 at each visit of Weeks 2, 6, and 12), treatment-by-timepoint interaction, 
and baseline IOP stratification as fixed effects. Unstructured covariance matrix will be used for repeated 
measures on the same patient; if the model with unstructured covariance matrix fails to converge, multiple 
imputation (MI) will be implemented before MMRM. 
Within the framework of this model, the mean difference between each Bimatoprost SR dose strength and 
timolol (Bimatoprost SR minus timolol) and the corresponding 2-sided 95% confidence interval will be 
provided for each hour (Hours 0 and 2) at each visit. The formal noninferiority test will be performed at 
Week 12 for each Bimatoprost SR dose strength versus timolol using a noninferiority margin of 1.5 mm Hg. A 
gatekeeping procedure will be used to control the overall type I error rate at the 0.05 level for each hour at 
Week 12, testing Bimatoprost SR 15 µg against timolol first and followed by the comparison between 
Bimatoprost SR 10 µg and timolol. The test of Bimatoprost SR 10 µg versus timolol for a given hour at 
Week 12 is valid only if the noninferiority of Bimatoprost SR 15 µg to timolol is demonstrated for the same 
timepoint. Bimatoprost SR 15 µg (or 10 µg) will be declared noninferior to timolol if the upper limit of the 95% 
confidence interval is ≤ 1.5 mm Hg for both Hours 0 and 2 at Week 12.   
For the United States Food and Drug Administration (US FDA), the primary efficacy variable will be the study 
eye IOP. The primary analysis will be based on Weeks 2, 6, and 12 using the ITT population. Specifically, the 
following analysis will be performed: IOP will be analyzed using an MMRM approach based on the same 
model as described for the primary efficacy analysis of time-matched IOP change from baseline. Within the 
framework of this model, the mean difference between each Bimatoprost SR dose strength and timolol group 
and the corresponding 95% confidence interval will be provided for each hour (Hours 0 and 2) and each visit 
(Weeks 2, 6, and 12). A gatekeeping procedure will be used to control the overall type I error rate at the 
0.05 level for each timepoint, testing Bimatoprost SR 15 µg against timolol first and followed by the 
comparison between Bimatoprost SR 10 µg and timolol. The test for Bimatoprost SR 10 µg versus timolol for a 
given hour at a visit is valid only if the noninferiority of Bimatoprost SR 15 µg to timolol has been 
demonstrated for the given timepoint. Each Bimatoprost SR dose strength that shows noninferiority to timolol at 
all 6 timepoints with a 1.5 mm Hg margin (ie, the upper limit of the 95% confidence interval is ≤ 1.5 mm Hg) 
will be declared clinically noninferior to timolol if the upper limit of the 95% confidence interval is 
≤ 1.0 mm Hg for 3 or more timepoints.   
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and will be 
summarized for all events regardless of causality and for treatment-related adverse events. Ocular adverse 
events and safety variables will be tabulated by study eye and fellow eye within each treatment dose strength or 
group, and nonocular safety variables will be summarized by patient. 
Sample Size Calculation: The sample size calculation is based on the primary efficacy analysis of the IOP for 
US FDA review because the sample size based on the primary efficacy analysis for other regions is expected to 
be smaller. Based on simulations, a sample size of 486 patients (162 per group) will provide approximately 
95.1% and 83.5% power to show noninferiority (NI) of Bimatoprost SR 15 µg and Bimatoprost SR 10 µg, 
respectively, to timolol at all 6 scheduled timepoints based on an NI margin of 1.5 mm Hg and at 3 or more 
timepoints based on an NI margin of 1.0 mm Hg. Assuming a premature discontinuation rate of 5% within 
12 weeks (before the primary database lock), approximately 510 patients (170 per group) are to be enrolled into 
this study. 
 

 
 
 
 
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Figure 1 
Flowchart of Patient Participation 
 
 
 
 

 
 
 
 
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Table 2 
Screening through Treatment Day 1 

 
 
 
 
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Table 3 
Administration Cycle 1 Schedule of Visits and Procedures: Treatment Period Day 2 through Week 12 

 
 
 
 
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Table 4 
Administration Cycle 2 Schedule of Visits and Procedures:  Treatment Period Week 15 Through Week 28 

 
 
 
 
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Table 6 
Schedule of Visits and Procedures:  Extended Follow Up Months 14, 16, 18, and 20 

 
 
 
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1. 
Background and Clinical Rationale  
1.1 
Glaucoma Overview 
Glaucoma is a family of diseases commonly characterized by progressive optic neuropathy 
with associated visual field defects and is the leading cause of irreversible blindness in the 
world.  Glaucoma is classified by Becker-Shaffer into 3 broad types:  developmental, 
angle-closure, and open-angle glaucoma (OAG) (Stamper et al, 2009).  Open-angle glaucoma 
is further categorized into primary OAG (POAG, sometimes also referred to as chronic 
OAG) and secondary OAG (which includes pigmentary and pseudoexfoliation glaucoma), 
the former being the predominant form of OAG.  Primary OAG is characterized as a multi-
factorial optic neuropathy with a characteristic acquired atrophy of the optic nerve and loss of 
ganglion cells and their axons, developing in the presence of open anterior chamber (AC) 
angles, and manifesting characteristic visual field abnormalities (American Academy 
of Ophthalmology, 2010a).  It is estimated that 2.25 million people in the United States (US) 
over the age of 40 years have POAG, half of whom are unaware of their disease despite 
demonstrable visual field loss (Quigley, 1996).  Globally, over 60 million people are 
estimated to be affected by glaucoma (the majority of whom have open angle glaucoma) and 
these numbers are expected to increase over time (Quigley and Broman, 2006; 
Varma et al, 2011; Cook and Foster, 2012). 
Although many risk factors have been associated with OAG, elevated intraocular pressure 
(IOP) remains the most prominent factor and the only factor existing that ophthalmic 
intervention can reliably affect (Stamper et al, 2009).  A number of controlled trials have 
demonstrated that lowering IOP will slow or delay the appearance or progression of 
glaucomatous damage.  Large, randomized clinical trials such as the Ocular Hypertension 
Treatment Study (OHTS) (Kass et al, 2002) and the Early Manifest Glaucoma Trial (EMGT) 
(Heijl et al, 2002) addressed the value of early detection and lowering of elevated IOP in 
ocular hypertension (OHT) or POAG.  The effects and parameters of various interventions in 
eyes with established glaucomatous damage were addressed by the Collaborative Initial 
Glaucoma Treatment Study (CIGTS) (Lichter et al, 2001) and the Advanced Glaucoma 
Intervention Study (AGIS) (AGIS, 2000).  The currently available approaches to lowering 
IOP include pharmacological therapy, laser trabeculoplasty, incisional surgery, and 
cyclodestructive procedures.  Each of these approaches has its own risk-benefit ratio.  
Because the risk-benefit ratio with drug therapy appears to be lower than that of surgical 
procedures, both historical and contemporary practice has been to attempt pharmacological 
treatment before resorting to other more invasive alternatives. 

 
 
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Patient nonadherence to topical therapy is one of the major challenges to preventing vision 
loss due to glaucoma, as consistent IOP reduction is associated with reduced risks of the 
development and progression of optic nerve damage (Friedman, 2009; Tsai, 2009).  In 
patients that are nonadherent to medical therapy, guidelines are provided to clinicians for 
assisting patients with being adherent (Budenz, 2009).  Nevertheless, frequently, patients 
with OAG or OHT not taking their medications will require incisional surgery to control the 
IOP.  Some of the disadvantages of performing incisional surgery include the significant 
sight-threatening complications that can occur with surgery, such as the globe perforation, 
suprachoroidal hemorrhage, hypotony maculopathy, corneal decompensation, and cataract 
formation or progression that may occur with filtering surgery (Mosaed et al, 2009).  Given 
the risks associated with incisional surgery, sustained-release formulations of ocular 
antihypertensive drugs are in development as an alternative to surgery for the management of 
elevated IOP (Knight and Lawrence, 2014). 
1.2 
Bimatoprost (LUMIGAN®) 
Bimatoprost is a member of a series of unique prostanoid compounds that are potent and 
efficacious ocular antihypertensive agents (Woodward et al, 1994, 2001, and 2004).  
Bimatoprost appears to mimic the activity of biologically active prostamides 
(Study BIO-99-308; Matias et al, 2004).  Chemically, prostamides differ from prostaglandin 
analogs by being neutral because they lack carboxylic acids (Krauss and Woodward, 2004).  
Prostamides can be biosynthetically derived from anandamide, an endogenous membrane 
lipid (Kozak et al, 2002; Weber et al, 2004; Woodward et al, 2001; Yu et al, 1997).  The 
prostamide pathway leads to the biosynthesis of novel lipid amides that lower IOP. 
The IOP-lowering efficacy of LUMIGAN (bimatoprost ophthalmic solution) 0.03% is well 
established.  In phase 3 studies in patients with POAG or OHT, LUMIGAN administered 
once daily as monotherapy was superior to timolol at all timepoints (Higginbotham et al, 
2002).  This was further substantiated in the extension studies which followed patients in a 
masked manner for up to 4 years (Cohen et al, 2004; Williams et al, 2008; 
Study 192024-014).  In clinical studies of patients with OAG or OHT with a mean baseline 
IOP of 26 mm Hg, the IOP-lowering effect of LUMIGAN once daily in the evening was 7 to 
8 mm Hg (Cohen et al, 2004; LUMIGAN® Package Insert, 2012; Williams et al, 2008). 
LUMIGAN was approved by the US Food and Drug Administration (FDA) in 2001.  
Worldwide, LUMIGAN 0.03% is currently licensed and marketed in more than 80 countries 
and LUMIGAN 0.01% is licensed and marketed in more than 40 countries.  Preservative-free 

 
 
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bimatoprost ophthalmic solution 0.03% has been approved since November 2012 for 
lowering IOP, and is currently marketed in 10 countries. 
1.3 
Bimatoprost SR 
A sustained-release formulation of bimatoprost was developed at Allergan, Inc. to evaluate 
ocular antihypertensive therapies that do not require patient self-administration.  Bimatoprost 
SR refers to the biodegradable, sustained-release, preservative-free bimatoprost implant 
which is preloaded in an applicator for administration; together they comprise the 
Bimatoprost Sustained Release product (and will henceforth be referred to as 
Bimatoprost SR).  The Bimatoprost SR implant is injected into the AC via the corneal limbus 
using the prefilled applicator.  The biodegradable polymer matrix gradually degrades to 
carbon dioxide and water so that there is no need to remove the Bimatoprost SR implant once 
the drug has been released.  The Bimatoprost SR implant used in this study contains total 
preservative-free bimatoprost loads of 10 µg or 15 µg, to provide average daily release (as 
determined by in vitro studies) of approximately 110 ng or 170 ng, respectively, over an 
approximate 3-month duration in the AC.  In contrast, a typical 35 µL drop of LUMIGAN 
0.03% contains approximately 10 µg of bimatoprost.  Thus, with topical therapy, a patient 
would have drug exposure to the ocular surface totaling approximately 900 µg over 
3 months.  Substantially reducing the total daily drug exposure to the eye and delivering the 
drug directly to the aqueous humor may reduce the adverse effects that occur with topical 
therapy.  The Bimatoprost SR implant is expected to release drug over approximately 3 to 
4 months, and > 75% polymer matrix degradation is expected within approximately 
12 months.  Although the biodegradation process of the Bimatoprost SR implant exceeds the 
drug release duration, experience from preclinical studies, the phase 1/2 clinical study 
192024-041D, and approved intravitreal implants composed of similar biodegradable 
polymers provide support for the anticipated safety in a phase 3 clinical trial with repeated 
administration. 
1.3.1 
Nonclinical Studies with Bimatoprost SR 
Pharmacology, toxicology, and pharmacokinetic studies with multiple dose strengths, implant 
sizes and formulations (Generation 1 and Generation 2) of Bimatoprost SR were done in 
2 species (Beagle dog, Cynomolgus monkeys) with a range of anterior chamber angle sizes 
in order to support the clinical program.  These studies build on the already considerable 
amount of nonclinical and clinical information available for topical bimatoprost (see 
Investigator’s Brochure for additional details). 

 
 
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Nonclinical studies with pharmacology endpoints (Reports BIO-09-803, BIO-11-920, 
PK09109-PK, BIO-09-785) showed dose-related reductions in IOP in normotensive 
Cynomolgus monkeys and Beagle dogs, as well as in laser-induced ocular hypertensive 
Cynomolgus monkeys following single doses.  Toxicology studies, of at least 6 to 12 months 
duration and including single and repeat Bimatoprost SR administration, were conducted in 
Cynomolgus monkeys and Beagle dogs (TX09051-TX, TX09066-TX, TX10016-TX, 
TX11076-TX, TX12012-TX, TX12018-TX, and TX12102-TX).  Monkeys, which have a 
characteristically small anterior chamber angle compared to both dogs and humans, did not 
tolerate Bimatoprost SR dose strengths tested (≥ 10 µg Bimatoprost SR) due to chronic 
contact of the implant with corneal endothelium.  Single and repeat ocular toxicity studies 
with Generation 2 Bimatoprost SR in dogs with varying AC angle sizes demonstrated 
acceptable safety and ocular tolerability with single doses ≤ 20 µg (TX11076-TX, 
TX12012-TX, TX12018-TX) and with repeat doses of ≤ 15 µg (TX12012-TX, 
TX12018-TX).  Furthermore, no adverse drug- or implant-related ocular findings have been 
seen following three intracameral injections of up to 20 µg (two 10 µg implants) Bimatoprost 
SR in the 18-month repeat dose Good Laboratory Practice (GLP) study in dogs 
(Report TX12102-TX). 
Pharmacokinetic studies (PK09109-PK, PK11086-PK) in Beagle dogs demonstrated that 
systemic exposure of bimatoprost and bimatoprost acid was below the limit of quantitation 
(BLQ) with doses ≤ 60 µg.  Aqueous humor concentrations generally peaked by 10 weeks 
postdose for doses ≤ 30 µg (Generation 1 and Generation 2), then declined to low levels 
suggestive of near-complete drug release from the device at 3 months for doses ≤ 20 µg.  By 
14 weeks following a 20 µg (Generation 2) dose, ocular tissues samples were collected for 
analysis, which demonstrated that drug and metabolite concentrations were BLQ in aqueous 
humor, vitreous humor, retina, and the remnant implants, but detected in cornea, choroid, and 
iris-ciliary body.  A pharmacokinetic study (PK14025-PK) was conducted in Beagle dogs 
comparing the ocular distribution of topical bimatoprost 0.03% solution or a single 
Generation 2 Bimatoprost SR implant (15 µg).  Following topical administration, 
bimatoprost and bimatoprost acid distributed into the iris-ciliary body as well as other (off 
target) tissues with concentrations in the bulbar conjunctiva, eyelid margin, and periorbital 
fat significantly higher than those observed in the iris-ciliary body. In contrast, following 
administration of a single Generation 2 Bimatoprost SR implant at 15 µg, bimatoprost and 
bimatoprost acid concentrations were either below the limit of quantitation (BLQ) or near the 
detection limit in bulbar conjunctiva, eyelid margin, and periorbital fat while the highest 
bimatoprost and bimatoprost acid concentrations were observed in the target tissue, the iris 
ciliary body. Retinal concentrations were BLQ following both topical and Bimatoprost SR 
administration. 

 
 
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1.3.2 
Other Biodegradable Ocular Implants 
A number of sustained-release drug delivery implants using the Allergan biodegradable 
polylactic acid (PLA) and/or polylactic-co-glycolic acid (PLGA) NOVADUR® drug delivery 
system  preceded the development of the Bimatoprost SR implant.  The extensive clinical 
experience with previous intraocular implants demonstrates the safety and tolerability of an 
intraocular biodegradable implant administered into the eye via an applicator system.  For 
example, late phase clinical trials of sustained-release implants have been completed for the 
OZURDEX® dexamethasone intravitreal implant using the NOVADUR drug delivery system 
for intraocular injections.  Because Bimatoprost SR is similar to OZURDEX in a number of 
aspects and uses the NOVADUR drug delivery system for intraocular injections, these data 
may be supportive of the safety and tolerability of Bimatoprost SR in humans. 
1.3.3 
Clinical Study with Bimatoprost SR 
Study 192024-041D was a Phase 1/2, paired-eye comparison evaluating the safety and 
efficacy of 4 dose strengths of Bimatoprost SR (6 µg, 10 µg, 15 µg, or 20 µg [2 × 10 µg 
implants]), as single or repeat administration in one eye (study eye), versus the use of topical 
LUMIGAN® 0.03% in the fellow eye (nonstudy eye).  The objective of this study was to 
evaluate the safety and IOP-lowering efficacy of Bimatoprost SR in patients with OAG. 
A total of 109 patients received a single administration and 24 patients received a repeat 
administration of Bimatoprost SR.  A trend in dose-response was observed across the 4 dose 
strengths that were tested.  Data suggest that the implant may provide topical prostaglandin 
analog-like efficacy up to 3 to 4 months post-implantation in the majority of patients.  Data 
following the second administration in the redosed patients showed similar IOP lowering to 
that observed following the first administration of Bimatoprost SR.  
Bimatoprost SR showed an acceptable safety profile with single and repeat administrations in 
Study 192024-041D.  Most adverse events were ocular, mild or moderate in severity, 
occurred within the first 2 days after Bimatoprost SR administration, and were considered 
related to the study drug administration procedure.  There were no reports of serious study 
drug-related adverse events, and no new safety concerns were observed after the second 
treatment.  Please refer to the Investigator’s Brochure for details on reported safety findings. 
1.4 
Study Rationale 
In the 192024-041D Phase 1/2 clinical study, results suggest that Bimatoprost SR provides 
IOP-lowering efficacy similar to topical prostaglandin analogs in the dose strengths proposed 

 
 
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for this Phase 3 investigation.  Additionally, the safety profile of Bimatoprost SR at dose 
strengths of 20 µg (2 × 10 µg) or less in the Phase 1/2 study was acceptable, and supports 
additional clinical study in man.  Study 192024-092 is a randomized, patient and efficacy 
evaluator-masked, parallel-group comparison to evaluate the safety and IOP-lowering effects 
of repeated administrations of 10 µg or 15 µg Bimatoprost SR in patients with OAG or OHT 
and open iridocorneal angles inferiorly in the study eye by clinical gonioscopy. 
The 2 dose strengths of Bimatoprost SR will be compared versus a control group treated with 
the active comparator, topically applied timolol 0.5%.  Timolol is a well-established 
treatment for IOP lowering in glaucoma and OHT, and has been used as a comparator in 
other IOP-lowering studies (Weinreb and Kaufman, 2009). 
2. 
Study Objectives and Clinical Hypotheses  
2.1 
Study Objectives 
• To evaluate the IOP-lowering efficacy and safety of 2 dose strengths of Bimatoprost 
SR in patients with OAG or OHT after initial and repeated administrations 
2.2 
Clinical Hypotheses 
• At least 1 dose strength (10 µg or 15 µg) of Bimatoprost SR will have an 
IOP-lowering effect that is noninferior to that of topically administered timolol 
maleate 0.5% (hereafter referred to as timolol) eye drops in patients with OAG or 
OHT following single and repeat administrations. 
• Bimatoprost SR administered intracamerally in dose strengths of 10 µg or 15 µg will 
have an acceptable safety profile in patients with OAG or OHT, following single and 
repeat administrations. 
3. 
Study Design 
This study is a multicenter, dose-ranging, randomized, parallel-group, patient and 
efficacy-evaluator masked 52-week evaluation (52-week treatment period with 8 months 
extended follow-up) of the safety and efficacy of Bimatoprost SR compared to timolol twice 
daily (BID) in patients with OAG or OHT.  The patients and the evaluators of the primary 
endpoint (IOP) will be masked to the treatment received.  The site coordinator and designated 
staff will not be masked to whether the patient received 1 of the two dose strengths of 
Bimatoprost SR or the Sham administration, but will be masked to the specific dose strength 
that the patient receives.  Vehicle eye drops will be used BID to mask the treatment of 

 
 
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patients receiving Bimatoprost SR in the study eye.  The fellow eye will receive a Sham 
administration plus topical timolol eye drops BID.  Control group patients will receive a 
Sham administration plus timolol in both eyes (see Table 7).  The study will be conducted at 
approximately 180 sites globally. 
Two Bimatoprost SR dose strengths (10 µg or 15 µg) will be tested in this study.  Patients 
will receive a scheduled second administration of Bimatoprost SR at 16 weeks following the 
first administration and a third scheduled administration at 16 weeks following the second 
administration (ie, 32 weeks after the initial administration).  Control group patients will 
receive Sham administrations at all administration visits. 
Table 7 
Treatment Groups 
Treatment 
Study Eye Treatment 
Fellow Eye Treatment 
Bimatoprost SR 10 µg 
Dose strength: 10 µg 
Sham administration procedure 
Eye drops:  Vehicle BID 
Eye drops:  Timolol BID 
Bimatoprost SR 15 µg 
Dose strength: 15 µg 
Sham administration procedure 
Eye drops:  Vehicle BID 
Eye drops:  Timolol BID 
Control 
Sham administration procedure 
Sham administration procedure 
Eyedrops:  Timolol BID 
Eyedrops:  Timolol  BID 
BID = twice daily 
 
Patients will begin self-administration of the study-provided eye drops in both eyes starting 
with the evening dose on the first administration (Day 1) visit (at which they will receive 
Bimatoprost SR administration or Sham administration).  Patients will continue 
self-administration of study-provided eye drops in the morning (at 08:00 ± 1 hour) and in the 
evening (at 20:00 ± 1 hour), which is approximately 12 hours apart.  Patients will be 
instructed not to administer their drops on the morning of a study visit.  Drops will be 
administered immediately after the Hour 0 IOP measurement. 
The duration of the study for each patient is approximately 22 months (screening duration of 
up to 28 days before washout, plus washout of up to 42 days before the first administration, 
plus the 52-week treatment period, plus 8 months extended follow-up).  Patients will be 
followed for at least 12 months after their last Bimatoprost SR (or Sham) administration, and 
may exit early at or after the twelfth month following the last administration if there are no 
safety concerns in the opinion of the investigator. 

 
 
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4. 
Study Population and Entry Criteria 
4.1 
Number of Patients  
Enrollment of approximately 510 patients in total at approximately 180 sites, with 
approximately 170 patients per group, is planned to ensure 162 completed patients per group, 
assuming a premature discontinuation rate of 5%. 
4.2 
Study Population Characteristics 
The study population consists of patients with OAG or OHT and an open iridocorneal angle 
inferiorly by clinical gonioscopy in the study eye, and OAG or OHT in the fellow eye, where 
both eyes require IOP-lowering medication.  The eye that meets the entry criteria 
(Sections 4.3 and 4.4) will be selected as the study eye.  If both eyes meet the entry criteria, 
the eye with the higher IOP at Baseline Hour 0 will be selected as the study eye.  If both eyes 
have the same IOP, then the right eye will be designated as the study eye. 
Angle qualification will be independently confirmed as being qualified by 
2 ophthalmologists, and endothelial cell density qualification for study entry will be 
determined by the Reading Center based on specular microscopy assessment (see Protocol 
Procedure Manual for details). 
4.2.1 
Patients With Sickle Cell Trait or Disease 
Patients with sickle cell trait or disease (or other hemoglobinopathies) may be enrolled at the 
discretion of the investigator based on an individual risk-benefit assessment.  Because of a 
slightly higher risk of IOP elevation and intraocular complications in the setting of a 
microhyphema, patients with these disorders may undergo optional additional biomicroscopy 
and IOP measurements after injection/Sham injection at the investigator’s discretion (see 
Section 8.4).  Additional information about the Bimatoprost SR experience in patients with 
sickle trait is provided in the Investigator’s Brochure. 
4.3 
Inclusion Criteria 
The following are requirements for entry into the study: 
1. Male or female, ≥ 18 years of age 
2. Written informed consent has been obtained 

 
 
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3. Written documentation has been obtained in accordance with the relevant country and 
local privacy requirements, where applicable (eg, Written Authorization for Use and 
Release of Health and Research Study Information [US sites] and written Data Protection 
consent [EU sites]) 
4. Patient is willing to withhold his/her IOP-lowering treatments according to the study 
requirements, and in the opinion of the investigator can do so without significant risk.  
5. Patient has the ability to understand and willingness to follow study instructions and is 
likely to complete all required visits and procedures 
6. A negative pregnancy test result for females of childbearing potential at Baseline  
7. Diagnosis of either OAG (ie, primary, pseudoexfoliation, or pigmentary glaucoma) or 
OHT in each eye and both eyes require IOP-lowering treatment (Note:  diagnosis does 
not have to be the same in both eyes) 
8. In the investigator’s opinion, either eye can be treated adequately with topical ophthalmic 
beta-blocker (eg, timolol) eye drops as the sole therapy   
9. In the investigator’s opinion, either eye can be treated adequately with topical 
prostamide, prostaglandin, or prostaglandin analog (eg, LUMIGAN, Xalatan, Travatan) 
eye drops as the sole therapy   
10. The iridocorneal angle in the study eye must be independently confirmed as being 
qualified by 2 ophthalmologists using the following criteria: 
a. Shaffer Grade ≥ 3 on clinical gonioscopy of the inferior angle 
b. Peripheral anterior chamber depth by Van Herick examination ≥ 1/2 corneal 
thickness  
Note: The independent eligibility assessments must both agree that the Shaffer grade is 
≥ 3 and the Van Herick grade is ≥ 1/2 corneal thickness.  
11. At the Baseline visit, patient has been appropriately washed out of all IOP-lowering 
medications  

 
 
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12. At the Baseline visit:   
a. Hour 0 IOP in the study eye of ≥ 22 mm Hg and ≤ 32 mm Hg, and in the fellow eye 
of ≤ 32 mm Hg 
b. Hour 2 IOP in the study eye of ≥ 19 mm Hg and ≤ 32 mm Hg, and in the fellow eye 
of ≤ 32 mm Hg  
13. Central corneal endothelial cell density by specular microscopy: 
b. By Baseline:  final central endothelial cell density in both eyes must be confirmed as 
being qualified by Reading Center assessment, with at least one eye qualified for 
inclusion as the study eye 
4.4 
Exclusion Criteria 
The following are criteria for exclusion from participating in the study: 
Non-ocular Criteria for Exclusion 
1. Uncontrolled systemic disease 
2. Female patients who are pregnant, nursing, or planning a pregnancy, or who are of 
childbearing potential and not using a reliable means of contraception during the study 
(see Section 4.5.3) 
3. Known allergy or sensitivity to any study medication or its components, any component 
of the delivery vehicle, procedure-related materials, or diagnostic agents used during the 
study (eg, topical anesthetic, dilating drops, fluorescein) 
4. Contraindications to beta-blocker therapy

 
 
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5. Any condition which would preclude the patient’s ability to comply with study 
requirements, including completion of the study 
6. Patients who have a condition or are in a situation which, in the investigator’s opinion, 
may put the patient at significant risk, may confound the study results, or may interfere 
significantly with the patient’s participation in the study 
7. Anticipated use of oral, intramuscular, or intravenous corticosteroids from 2 months prior 
to the Baseline visit through Week 52 
8. Concurrent or anticipated enrollment in an investigational drug or device study or 
participation in such a study within 2 months prior to the Baseline visit through the final 
study visit  
9. Previous enrollment in another Allergan Bimatoprost SR study 
Ocular Criteria for Exclusion 
11. In the investigator’s opinion, patient is nonresponsive to topical ophthalmic beta-blockers 
and/or topical prostamides, prostaglandins, or prostaglandin analogs (eg, LUMIGAN, 
Xalatan, Travatan) 
12. History or evidence of clinically relevant, substantial ocular trauma (eg, a traumatic 
cataract, traumatic angle recession, etc) in the study eye  
13. The following surgical history: 
a. History or evidence of complicated cataract surgery in the study eye: eg, surgery 
resulting in complicated lens placement (such as anterior chamber intraocular lens 
implant [IOL], sulcus IOL, aphakia, etc) or intraoperative complications (such as 
a posterior capsular tear [with or without vitreous loss], substantial iris trauma, 
etc). Note: history of uncomplicated cataract surgery is not an exclusion. 

 
 
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b. History of phakic IOL insertion for refractive error correction in the study eye 
14. Intraocular surgery (including cataract surgery) and/or any ocular laser surgery within the 
6 months prior to treatment (Day 1) in the study eye 
16. Incisional refractive surgery (eg, radial keratotomy), other than astigmatic keratotomy or 
limbal relaxing incisions in the study eye  

 
 
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25. Anticipated need for any incisional or laser ocular surgery in either eye within the first 
52 weeks of the study duration 

 
 
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4.5 
Permissible and Prohibited Medications/Treatments 
4.5.1 
Permissible Medications/Treatments 
The fellow eyes of patients randomized to the Bimatoprost SR or Control groups will receive 
timolol BID for IOP lowering. 
Intermittent use of artificial tear products is allowed if they are not taken ≤ 15 minutes before 
any study procedure or ≤ 15 minutes before or after topical administration of study 
medication.  Intermittent use of ocular decongestants or antihistamines is allowed if not taken 
within 2 days prior to a scheduled visit and/or ≤ 15 minutes before or after topical 
administration of study medication.  Use of artificial tear products and ocular decongestants 
or antihistamines may be restarted 3 days after any Bimatoprost SR (or Sham) administration 
procedure. 

 
 
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Use of postoperative topical ocular antibiotics, corticosteroids, and non-steroidal 
anti-inflammatory drugs (NSAIDs) from the Administration Day (on Day 1, Week 16, and 
Week 32) to Day 7 following administration is allowed. 
Systemic beta-blocker containing medications are permitted, provided that the dose/dosing 
regimen has remained stable for at least 2 months prior to Screening, and is not anticipated to 
change during the duration of the study. 
Required surgical procedures may be performed in the fellow eye only after completion of 
Week 52. 
In addition, therapy considered necessary for the patient’s welfare may be given at the 
discretion of the investigator.  If concurrent medications may have an effect on study 
outcomes, these medications should be administered in dosages that remain constant 
throughout the entire duration of the study.  If the permissibility of a specific 
medication/treatment is in question, please contact Allergan. 
The use of systemic NSAIDs is also permitted. 
In the unlikely event that the Bimatoprost SR implant requires removal for significant safety 
reasons, this may be performed at the discretion of the investigator following a discussion 
with the medical safety physician at Allergan (see Protocol Procedure Manual for details).   
Note that in the event that the investigator performs an unanticipated incisional surgical 
procedure on the study eye during which ocular fluid is to be removed, ocular fluid/implant 
samples may be collected for analysis (see Protocol Procedure Manual for further details) at 
the investigator’s discretion.   
4.5.2 
Prohibited Medications/Treatments 
The decision to administer a prohibited medication and/or treatment is done with the safety 
of the study participant as the primary consideration.  When possible, Allergan should be 
notified before the prohibited medication/treatment is administered. 
During the study, patients should not participate in other investigational drug or device 
studies. 
Nonstudy IOP-lowering Medications 

 
 
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Use of any topical ophthalmic medication containing an ocular antihypertensive, other than 
use of study medication (timolol) in Control group or fellow eyes, is prohibited as concurrent 
therapy in either eye, unless necessary for the safety of the patient due to inadequate control 
of IOP as determined by the investigator.  Inadequate control of IOP should be confirmed at a 
subsequent visit (scheduled or unscheduled visit).  Prior to Week 52, the investigator will be 
expected to attest to the need for additional nonstudy IOP- lowering medication for safety 
reasons.  After the Week 52 visit, nonstudy topical IOP-lowering medications will be 
permitted if in the investigator’s clinical judgment the IOP is not adequately controlled at two 
consecutive visits.  Initiation of medication in one eye should not automatically lead to 
initiation of medication in the other eye.  Each eye should be evaluated on an individual basis 
when determining the need for additional nonstudy IOP-lowering medications.  If nonstudy 
IOP-lowering medication is initiated prior to Week 52, the investigator will be expected to 
attest to the need for additional nonstudy IOP-lowering medication for safety reasons for 
each eye individually.  
Contact Lenses 
Use of soft contact lenses within 3 days and use of rigid gas permeable or hard contact lenses 
within 1 week prior to a scheduled study visit or Administration Day, or use of contact lenses 
of any kind within 1 week following any Bimatoprost SR (or Sham) administration in either 
eye is prohibited.  
Contact lenses should be removed prior to instilling any study-provided eye drops and 
patients should wait at least 15 minutes before putting contact lenses back in the eyes after 
instilling topical drops. 
Other Medications 
The following medications (or classes of medications) and treatment procedures are not 
permitted as concurrent therapy during the study through 12 months after the last 
Bimatoprost SR or Sham administration unless the patient has already been treated with 
nonstudy IOP-lowering medication in both eyes: 
• Subconjunctival, sub-Tenon’s, intravitreal, or other ophthalmic injections of any 
medications in either eye  
• Surgical procedures that are not related to Bimatoprost SR (or sham) administration 
procedures in the study eye (surgical procedures are allowed in the fellow eye after 
Week 52 as described in Section 4.5.1) 

 
 
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• Use of any topical ophthalmic medications (except as described above and in 
Section 4.5.1) in either eye. 
• Use of any ophthalmic (including topical, intravitreal, sub-Tenon’s, subconjunctival) 
corticosteroids in either eye from 2 months prior to the baseline visit through 
12 months after the last administration, except for use of postoperative topical ocular 
coritcosteroids after administration as described in Section 4.5.1. 
• Oral, intramuscular, or intravenous corticosteroids from 2 months prior to the 
baseline visit through the twelfth month after the last injection. 
• Use of LATISSE® (bimatoprost for hypotrichosis) during the study period in either 
eye  
• Systemic use of carbonic anhydrase inhibitors (eg, Diamox®)   
• Any initiation of or alterations in systemic regimen of beta-blocker containing 
medications from 2 months prior to Screening through the final study visit 
4.5.3 
Definition of Females of (Non-)Childbearing Potential and/or 
Acceptable Contraceptive Methods 
For purposes of this study, women will be considered of childbearing potential unless they 
are naturally postmenopausal or permanently sterilized (ie, hysterectomy).  Natural 
menopause is defined as the permanent cessation of menstrual periods, determined 
retrospectively after a woman has experienced 12 months of amenorrhea without any other 
obvious pathological or physiological cause.  For women of childbearing potential who may 
participate in the study, the following methods of contraception, if properly used, are 
generally considered reliable:  hormonal contraceptives (ie, oral, patch, injection, implant), 
male condom with intravaginal spermicide, diaphragm or cervical cap with spermicide, 
vaginal contraceptive ring, intrauterine device, surgical sterilization (bilateral tubal ligation, 
bilateral salpingectomy), vasectomized partner, or true sexual abstinence (when this is in line 
with the preferred and usual lifestyle of the subject). 
The investigator and each patient will determine the appropriate method of contraception for 
the patient during the participation in the study. 

 
 
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5. 
Study Treatments  
5.1 
Study Treatments and Formulations 
5.2 
Control Treatments  
For Sham administration, a needleless applicator is provided. 
The following topical eye drops are also used as controls: 
• Timolol 0.5% ophthalmic solution 
 
 
 
 
• Timolol vehicle 
 is identical in appearance to the 
timolol 0.5% ophthalmic solution 
 
 
5.3 
Methods for Masking 
Patients in the Control group will receive timolol eye drops BID plus Sham administration in 
both eyes.  Vehicle eye drops will be used BID to mask the treatment of patients receiving 
Bimatoprost SR in the study eye.  Treatment for fellow eyes of patients assigned to 1 of the 
2 Bimatoprost SR dose groups will be a Sham administration procedure + timolol eye drops 
BID. 
The site coordinator and designated staff will not be masked to whether the patient received 
1 of the 2 dose strengths of Bimatoprost SR or the Sham administration procedure, but will 
be masked to the specific implant dose strength.  The patient and the remaining staff will be 
masked to the patient’s treatment assignment.  Efficacy IOP measurements will be masked by 
using a 2-person reading method as described in Section 6.1.1 (for optional postoperative 

 
 
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IOP measurements for patients with sickle cell disease or trait [or other hemoglobinopathies], 
see Section 8.4). 
The site staff who perform IOP readings will be masked regarding the study eye (which eye 
received Bimatoprost SR or the Sham administration procedure), Bimatoprost SR dose 
strength, and the study treatments that are delivered in bottles.  Site personnel and patients 
will be instructed and reminded throughout the study not to discuss study medication 
assignments to ensure maintenance of the masking. 

 
 
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5.4 
Treatment Allocation Ratio and Stratification 
Randomization to treatment groups will use a 1:1:1 ratio.  Patients will be randomized to 
receive Bimatoprost SR (either 10 µg or 15 µg) plus vehicle eye drops, or a Sham 
administration procedure plus timolol eye drops, in the study eye.  Randomization will be 
stratified by Baseline study eye Hour 0 IOP (≤ 25 mm Hg or > 25 mm Hg). 
5.5 
Method for Assignment to Treatment Groups/Randomization 
Prior to initiation of any study procedures, each patient who provides informed consent will 
be assigned a subject number that will serve as the patient’s identification number on all 
study documents. 
Eligible patients will be randomly assigned to 1 of 3 treatment groups in a 1:1:1 ratio to 
receive study Bimatoprost SR 10 µg, Bimatoprost SR 15 µg, or timolol.  The randomization 
will be stratified by Baseline Hour 0 IOP (baseline study eye IOP ≤ 25 mm Hg or 
> 25 mm Hg). 

 
 
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5.6 
Treatment Regimen and Dosing 
The treatment groups are shown in Table 7.  Patients randomized to 1 of the Bimatoprost SR 
dose groups will receive an intracameral administration of Bimatoprost SR in the study eye 
on Day 1, Week 16, and Week 32, in addition to using topical vehicle eye drops (1 drop 
BID).  They will receive timolol eye drops (1 drop BID) plus Sham administration in the 
fellow eye.  Patients randomized to the Control group will receive a Sham administration in 
both eyes on Day 1, Week 16, and Week 32, in addition to timolol eye drops (1 drop BID) in 
both eyes. 
5.6.1 
Treatment Regimen/Dosage Adjustments  
Patients who have received nonstudy topical IOP-lowering medication (prohibited before 
Week 52 unless required for safety reasons due to inadequate IOP control and attested to by 
the investigator) in a Bimatoprost SR study eye will receive Sham administration in that eye 
on the Bimatoprost SR repeat administration day(s).  Patients who have received nonstudy 
topical IOP-lowering medication in a fellow eye or a Control Group study eye will continue 
to receive Sham administration in that eye on the administration day(s). 
Patients who have received nonstudy IOP-lowering medication in both eyes will not undergo 
Bimatoprost SR administration or Sham administration in either eye. 

 
 
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Patients who use nonstudy IOP-lowering medication (prohibited before Week 52 unless 
required for safety reasons due to inadequate IOP control and attested to by the investigator) 
in only one eye will be followed for the duration of the study.  If used in both eyes, patients 
will be followed at minimum for 12 months after the last administration of Bimatoprost SR 
or Sham.  Patients using nonstudy IOP-lowering medications in both eyes prior to the 
Week 16 or Week 32 Administration Day will not attend the administration visit(s), nor will 
they attend the Day 2, Days 4 and 8 (phone call), or 2-week visits (ie, Weeks 2, 18, and 34) 
following an administration.  They would continue the schedule at Week 22 or Week 38, as 
appropriate for the administration cycle. 
5.7 
Storage of Study Medications/Treatments 
The study medication must be stored in a secure area 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.  Only assigned study personnel, authorized by the investigator, 
may have access to study medication.  
 
 
 
 
 
 
 

 
 
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5.8 
Preparation of Study Medications/Treatments  
Bimatoprost SR is loaded into the single use applicator during manufacturing and is provided 
within the applicator as a sterile, finished product.  Study site personnel should notify 
Allergan or its designee immediately to advise of any situation in which the study medication 
is defective. 
5.9 
Treatment Administration  
Study medication must only be administered to patients who meet the eligibility criteria in 
accordance with the conditions specified in this protocol.  
 
 
 
 
5.9.1 
Patient Preparation 
5.9.2 
Study Treatment Location 
At the discretion of the investigator, Bimatoprost SR (or Sham) administration may be 
performed at an Ambulatory Surgical Center (ASC; free standing or hospital based) or in the 
office setting (eg, in a procedure room with an operating microscope).  
 
 
 
 
  A separate standard consent to have the 
procedure at an Ambulatory Surgical Center may be required per the standard operating 
procedures at the facility. 
Sterile technique will be practiced at all times. 

 
 
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5.9.3 
Administration Technique 
Intracameral administration of Bimatoprost SR must be performed by an ophthalmologist 
who has had adequate training and has been approved by Allergan to perform the procedure.  
The principal investigator at a site may designate a subinvestigator to perform the procedure, 
subject to Allergan approval and training.  The study medication kit should be readily 
available during the procedure. 
5.9.4 
Immediate Posttreatment Observation 
Following study treatment administration, the patient is allowed to sit upright and is kept for 
a minimum of 1 hour of observation.  The surgeon will examine each of the patient’s eyes to 
ensure that the anterior chamber is formed prior to the patient being released. 
 
 
 
Prior to leaving the site, patients should be instructed to contact the study site immediately if 
they experience any adverse events after treatment.  If the patient reports having experienced 
adverse events, these should be recorded on the appropriate eCRF. 

 
 
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The same posttreatment observation requirements apply after the second and third 
administrations of Bimatoprost SR or Sham administration. 
Note:  Patients with sickle cell disease or trait (or other hemoglobinopathies) may undergo 
optional biomicroscopy and IOP examination in both eyes 4 hours after each Bimatoprost SR 
administration (or Sham administration).  This optional IOP examination is for postoperative 
purposes only, and as such does not require a masked, 2-person reading method.  The IOP 
should be taken only once to avoid excessive postadministration (or Sham administration) 
manipulation of the eye, and should be taken by the investigator (or other unmasked, 
qualified personnel).  This postadministration (or Sham administration) examination may be 
performed using a Goldmann applanation tonometer or a hand-held tonometer.  (See the 
Study Procedure Manual for details.) 
5.10 
Retreatment  
Administration of Bimatoprost SR will occur at fixed intervals of 16 weeks, up to a total of 
3 administrations.  Patients will be readministered the Bimatoprost SR dose strength to which 
they were randomized unless in the investigator’s opinion it would not be in the best interest 
of the patient to readminister Bimatoprost SR based on previous adverse events or safety 
concerns.  
 
 
 
 
 
 
 
 
6. 
Response Measures and Summary of Data Collection Methods 
 
 
6.1 
Efficacy Measures 
6.1.1 
Primary Efficacy Measure 
The primary efficacy measure, IOP, will be measured using a Goldmann applanation 
tonometer.  Examiners masked to the treatment assignment should perform all efficacy IOP 

 
 
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measurements at approximately the same time of day for a given patient throughout the study 
whenever possible. 
A 2-person reading method will be used for all efficacy IOP measurements, wherein 1 person 
adjusts the dial in a masked fashion and a second person reads and records the value.  The 
right eye is to be measured first and the left eye measured second.  Two consecutive 
measurements will be taken of each eye.  If the first 2 measurements differ by > 1 mm Hg, a 
third measurement will be taken.  If the first 2 measurements differ by 1 mm Hg or less, the 
IOP for the given eye will be the average of the 2 readings.  If the difference between the first 
2 measurements is > 1 mm Hg, the IOP for the given eye will be the median of the 
3 readings. 
All Hour 0 IOP examinations should be scheduled at 08:00 ± 1 hour.  As scheduling permits, 
the patient should have approximately the same Hour 0 time of day throughout the study.  
Hour 2 IOP examinations should occur 2 hours after the Hour 0 IOP exam.  The acceptable 
window for the Hour 2 IOP examination is ± 30 minutes. 
6.2 
Safety Measures 
The following will be collected and recorded on the appropriate eCRF page(s):  
Adverse Events:  All adverse events, from the moment the patient signs the informed 
consent form, will be monitored and recorded in the patient’s source documents.  All events 
will be reported to Allergan on an adverse event eCRF, including seriousness, severity, action 
taken and relationship to study drug.  If adverse events occur, the first concern will be the 
safety of the study patient. 
Weight and Height:  Weight will be measured in pounds (lb) or kilograms (kg) using a 
scale.  Height will be measured in inches (in) or centimeters (cm).  Height and weight will be 
measured at screening as part of the demographic data; historical patient information and/or 
patient reports should not be used for either measurement. 
Vital signs:  Systolic and diastolic blood pressure and pulse rate will be measured after 
patients have been at rest (seated) for at least 5 minutes.  Body temperature will be measured 
orally (or with an infrared forehead thermometer) and recorded as °F or °C. 
Hematology, blood chemistry, and urinalysis:  Blood and urine samples will be collected 
for blood chemistry and hematology panels and urinalysis.   

 
 
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Pregnancy:  Females of childbearing potential will have pregnancy tests performed.  
Pregnancy test kits will be provided by Covance Central Laboratory Services or a designated 
regional laboratory and will be administered according to the instructions provided with the 
tests. 
Measures of ocular safety include: 
Visual Acuity:  Visual acuity tests will be performed at all scheduled visits except on any of 
the 3 administration days.  Manifest refraction using Snellen equivalent with a logMar chart 
(see Protocol Procedure Manual) will be performed at Screening, Baseline, Weeks 12 and 52, 
and Month 20/Exit.  At all other visits, the visual acuity technician will use the last manifest 
refraction performed and determine the Snellen equivalent visual acuity using the logMar 
chart.  If there is a 2-line or more reduction in visual acuity from the last BCVA performed, a 
repeat manifest refraction in both eyes and BCVA will be performed. 
Macroscopic Iris Color Assessment:  Iris color will be assessed visually at each designated 
visit using the appropriate assessment guide (see the Protocol Procedure Manual for further 
details).  Macroscopic, binocular color photography will be performed at baseline to 
document iris color.  The baseline photograph printout from each patient will be used as a 
comparator to assess any change in iris color at subsequent visits.  A suspected change in iris 
color will be documented with a binocular color photograph at that visit.  A binocular color 
photograph will also be obtained at Week 52 and a final binocular color photograph will be 
obtained during the Month 20/Exit visit in all patients. 
Progressive changes in iris color will be photographed and compared to the last photograph 
taken. 
Macroscopic Conjunctival Hyperemia Assessment:  Macroscopic conjunctival hyperemia 
will be assessed using the appropriate Assessment Guide (see the Protocol Procedure Manual 
for further details). 
Bimatoprost SR Implant Assessment:  Using gonioscopy, the investigator will evaluate the 
Bimatoprost SR implant and the inferior iridocorneal angle. 
Biomicroscopic Examination:  Biomicroscopic examinations will be performed using a slit 
lamp.  The examinations will include evaluation of the condition of the eyelids, conjunctiva, 
cornea, AC, iris/pupil, and lens.   

 
 
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Lens Assessment:  Biomicroscopic findings will be evaluated for the presence and severity 
of nuclear, cortical, and posterior subcapsular lens opacities.  See the Protocol Procedure 
Manual for further details. 
Gonioscopy: Gonioscopic examination for eligibility at Screening (only) will be 
independently performed by 2 ophthalmologists as described in the Protocol Procedure 
Manual. The independent eligibility assessors should not share their assessments with each 
other until the assessment is recorded. The 2 ophthalmologists’ independent eligibility 
assessments must confirm patient eligibility for participation in the study. Subsequent 
gonioscopic examinations will be performed by the study investigator. 
Optic Disc Examination:  The cup/disc ratio and presence of optic disc pathology will be 
determined using stereoscopic evaluation. 
Dilated Ophthalmoscopic Examination:  The stereoscopic fundus assessments should be 
conducted through a dilated pupil.  The examinations will include evaluation of the macula, 
vitreous, and retina. 
Optical Coherence Tomography (OCT):  OCT of the macula will be performed to assess 
macular edema.  The same instrument should be used throughout the study for a given 
patient.  See the Protocol Procedure Manual for further details. 
Specular Microscopy:  Endothelial cell density will be assessed using specular microscopy 
performed on the central cornea at all sites.  The final qualification of central endothelial cell 
density for study entry will be determined by the Reading Center.  Qualification will remain 
valid for 1 year after Screening in patients who are not enrolled at the time of Screening, if in 
the investigator’s opinion there have been no clinically significant changes occurring in the 
eye (eg, ocular surgery) during that time.  All additional specular microscopy images taken 
during the study will be assessed by the Reading Center.  See the Protocol Procedure Manual 
for further details.  The same instrument should be used throughout the study for a given 
patient. 
Pachymetry:  Corneal thickness using ultrasound (contact) pachymetry will be performed on 
the central cornea.  The same instrument should be used throughout the study for a given 
patient.  Contact pachymetry may be performed any time after the Hour 2 IOP measurement.  
See the Protocol Procedure Manual for further details. 
Anterior Segment Optical Coherence Tomography (AS-OCT):  AS-OCT measurements 
will be performed at all sites and a Reading Center will be used to examine angle size for 

 
 
Approval Date: 
 
05-Jun-2018
Allerg
 
 
 
inves
for fu
manu
desig
study
Visua
perim
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6.3 
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by Allergan 
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Approval Date: 
 
05-Jun-2018
Allerg
 
 
 
or OH
docum
6.4.1
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heart/
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ast 3 months 
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be examined
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kin.  The pat
ital Signs 
signs will be
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imum of 5 m
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essure (mm H
m of 5 minute
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ssure measu
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an infrared fo
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The urine te
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females of c
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will analyze 
Blood and ur
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53 
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at all patient 
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xtremities; ba
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ment.  Pulse
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be resting in
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potential fo
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esting may b
urine specim
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Protocol 19202
GDD-TA
d on the app
any physica
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propriate sou
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ment 3 
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ty of 
visit 
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ition 
er 
will 
ated 
orally 
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urine 
ding 
f

 
 
Approval Date: 
 
05-Jun-2018
Allerg
 
 
 
Refer
collec
Labo
Aller
labor
event
Evalu
local 
6.4.3
Hema
(HbA
conce
count
bands
6.4.3
Serum
aspar
direct
total 
6.4.3
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ratory test re
rgan or its de
ratory results
ts should be 
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3.1
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reflected on
management 
e. 
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be measured
corpuscular h
MCHC), mean
phology, tota
ytes, monocy
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minase (AST)
glucose, indi
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pH, protein, 
asts, bacteri
ther Study
ory Manual f
edures. 
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verse events.
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of abnormal
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specific grav
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54 
for further de
from the ce
or or qualifie
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event eCRF
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(MCH), mea
ar volume (M
od cell (WBC
ils, and eosin
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results shou
rit, hemoglob
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MCV), platel
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nophils). 
sphatase, alan
chloride, cre
um, phosphor
trogen, and u
ood, glucose
nogen, and m
al cells). 
Protocol 19202
GDD-TA
ding central l
tory to the st
nnel must re
s that represe
uld be conduc
bin, glycated
ular hemoglo
lets, red bloo
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microscopic 
24-092 Amendm
A-T-004 v2013
laboratory 
tudy site and
eview all 
ent adverse 
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ment 3 
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ing to 
in, 
C) 
ls, 
T), 
, 
m, 

 
 
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55 
GDD-TA-T-004 v2013.9 
 
6.6 
Summary of Methods of Data Collection 
7. 
Statistical Procedures 
Three database locks are planned.  The first database lock will take place after all patients 
have completed or prematurely discontinued before the Week 12 visit.  Similarly, the 
database will be locked after all patients have completed or prematurely discontinued before 
Week 52 and Month 20/Exit.  Analyses will be performed after each lock.  Prior to the first 
database lock a detailed analysis plan will be finalized.  To maintain the integrity of the 
ongoing study, Allergan study personnel who are directly involved in data handling and 
supporting the trial (such as the clinical study team) will remain masked to treatment 
assignment of individual patients during the study. To avoid potential data unmasking 
between locks and to protect trial integrity, study statistical personnel who have been 
unmasked after each lock will no longer be involved directly in any ongoing masked study 
conduct. Another statistician, who is still masked to study treatment, will assume these 

 
 
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56 
GDD-TA-T-004 v2013.9 
 
responsibilities until the next lock. Unmasked data handling and appropriate data and results 
access will be specified prior to each lock. 
Efficacy analyses specific for the US FDA (Division of Transplant and Ophthalmology 
Products) review are described in Section 7.6. 
The details of all analyses will be provided in the analysis plan. 
7.1 
Analysis Populations 
The intent-to-treat population (ITT) is defined as all randomized patients and will be used for 
demographic and efficacy analyses.  The per protocol (PP) population will consist of the 
subset of the ITT population with no protocol deviations affecting the primary efficacy 
analysis and will be used to confirm the primary efficacy analysis.  A list of patients excluded 
from the PP population will be finalized prior to database lock.  The safety population is 
defined as all patients who received study drug treatment and will be used for safety 
analyses.  Analyses in the ITT population will be based on the treatment to which a patient 
was randomized, and analyses in both PP and safety populations will be based on the actual 
treatment a patient received. 
7.2 
Collection and Derivation of Primary and Secondary Efficacy 
Assessments 
The primary efficacy measurement is IOP, which will be measured in each eye using the 
Goldmann applanation tonometer.  Two consecutive measurements will be taken for each 
eye.  If these 2 measurements differ by > 1 mm Hg then a third measurement will be 
performed.  If the first 2 measurements differ by 1 mm Hg or less, or a third measurement is 
required but only 2 measurements are obtained, then the IOP value for a given eye is the 
average of the 2 measurements.  If 3 measurements are required (ie, the first 2 measurements 
differ by > 1 mm Hg) and obtained, then the IOP value for the given eye is the median of the 
3 measurements.  If, for any reason, only a single measurement is obtained, then this 
measurement will be used as the IOP value. 
To avoid confounding of efficacy data, IOP measurements obtained after initiating the use of 
nonstudy IOP-lowering medication in an eye will be excluded from the calculation of the 
summary statistics and the statistical analyses for that eye but raw values will be presented in 
the listings. 

 
 
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7.2.1 
Primary Efficacy Variable 
The primary efficacy variable is the study eye time-matched IOP change from baseline 
(follow-up minus time-matched baseline) at each hour evaluated (Hours 0 and 2). 
7.2.2 
Secondary Efficacy Variable 
The secondary efficacy variable is time-matched IOP. 
7.3 
Hypothesis and Methods of Analysis 
In general, continuous variables will be summarized by descriptive statistics including 
sample size, mean, standard deviation, median, minimum, and maximum.  Categorical 
variables will be summarized by frequency and percentage. 
7.3.1 
Primary Efficacy Analyses 
The primary efficacy variable is the study eye time-matched IOP change from baseline.  
Mean IOP change will be compared between each Bimatoprost SR dose strength and the 
timolol group for each hour (Hours 0 and 2) using the ITT population.  The comparisons at 
Week 12 will be considered the primary analysis. 
The null and alternative hypotheses for the comparison between a given Bimatoprost SR 
dose strength and timolol at each hour of Week 12 are: 
• Null hypothesis:  the difference in mean IOP change from baseline between the given 
Bimatoprost SR dose strength and timolol (Bimatoprost SR minus timolol) is 
> 1.5 mm Hg. 
• Alternative hypothesis:  the difference (Bimatoprost SR minus timolol) in mean IOP 
change from baseline between the given Bimatoprost SR dose strength and timolol is 
≤ 1.5 mm Hg. 
Intraocular pressure change from baseline will be analyzed using a mixed-effects model 
repeated measures (MMRM) approach.  The model will include IOP time-matched change 
from baseline as the response variable and treatment, timepoint (Hours 0 and 2 at each visit 
of Weeks 2, 6, and 12), treatment-by-timepoint interaction, and baseline IOP stratification as 
fixed effects. Unstructured covariance matrix will be used for repeated measures on the same 
patient; if the model with unstructured covariance matrix fails to converge, multiple 
imputation (MI) will be implemented before MMRM.  The details of the model 
specifications will be provided in the analysis plan. 

 
 
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Within the framework of this model, the mean difference between each Bimatoprost SR dose 
strength and timolol (Bimatoprost SR minus timolol) and the corresponding 2-sided 95% 
confidence interval will be provided for each hour (Hours 0 and 2) at each visit.  The formal 
noninferiority test will be performed at Week 12 for each Bimatoprost SR dose strength 
versus timolol using a noninferiority margin of 1.5 mm Hg.  A gatekeeping procedure will be 
used to control the overall type I error rate at the 0.05 level for each hour at Week 12, testing 
Bimatoprost SR 15 µg against timolol first and followed by the comparison between 
Bimatoprost SR 10 µg and timolol.  The test of Bimatoprost SR 10 µg versus timolol for a 
given hour at Week 12 is valid only if the noninferiority of Bimatoprost SR 15 µg to timolol 
is demonstrated for the same timepoint.  Bimatoprost SR 15 µg (or 10 µg) will be declared 
noninferior to timolol if the upper limit of the 95% confidence interval is ≤ 1.5 mm Hg for 
both Hours 0 and 2 at Week 12.   
Sensitivity analyses of handling missing data will be performed using multiple imputation. 
7.3.2 
Secondary Efficacy Analyses  
Secondary efficacy analyses comparing each Bimatoprost SR dose strength and timolol to 
test the no-difference null hypothesis will be performed at scheduled visits (Weeks 2, 6, and 
12) and hours for (1) IOP and (2) time-matched IOP change from baseline. 
The analysis of time-matched IOP change from baseline utilizes the identical model as that 
described for the primary analysis in Section 7.3.1 with the same 2-sided 95% confidence 
intervals constructed at each hour and each visit for the mean difference between each 
Bimatoprost SR dose strength and timolol (Bimatoprost SR minus timolol).  An upper 95% 
confidence limit of the mean difference that is less than zero corresponds to a significant 
difference in favor of the given Bimatoprost SR dose strength for the given timepoint. 
Each Bimatoprost SR dose strength that demonstrates the following at all scheduled 
timepoints within the 12-week period (at Hours 0 and 2 at Weeks 2, 6, and 12) will be 
considered superior to timolol: 
• The upper 95% confidence limit of the mean difference is less than zero (ie, a 
significant difference in favor of the given Bimatoprost SR dose strength) 
The analysis of IOP will be similarly performed as described above with IOP replacing time-
matched IOP change from baseline in the analysis model. 

 
 
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59 
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7.3.3 
Other Efficacy Analyses 
7.3.4 
Safety Analyses 
The Medical Dictionary for Regulatory Activities (MedDRA) nomenclature will be used to 
code adverse events.  Adverse events will be coded from the verbatim text into preferred term 
and system organ class (SOC).  The number and percent of patients reporting treatment 
emergent adverse events will be tabulated based on the primary SOC and preferred terms.  
Summary tables will be generated for all adverse events regardless of causality as well as 
treatment-related adverse events for the entire study and by treatment cycle. 
Other safety variables include vital signs (blood pressure, pulse rate, and temperature) and 
pregnancy test results.  Ocular safety will be evaluated through assessment of visual acuity 
and visual field; evaluation of macroscopic bulbar conjunctival hyperemia and iris color; 
assessment of endothelial cell density and corneal thickness; IOP measurement, 
biomicroscopic and ophthalmoscopic examinations (including gonioscopy with Bimatoprost 
SR implant assessment, optic disc examination and dilated fundus examination); and OCT of 
the macula.  
Ocular adverse events and safety variables will be tabulated by study eye and fellow eye 
within each treatment dose strength, and nonocular safety variables will be summarized by 
patient.  A separate summary will be provided for safety events occurring after nonstudy 
IOP-lowering medication has been initiated. 
7.4 
Subgroup Analyses 
Subgroup analyses for the primary variable will be performed  
7.5 
Interim Analyses 
No interim analysis is planned for this study.  Each database lock will correspond to a 
milestone and statistical analysis when all randomized patients have either completed or 
exited from the targeted visit. 

 
 
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60 
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7.6 
Analyses for US FDA  
Primary Efficacy Analyses 
For the US FDA review, the primary efficacy variable will be the study eye IOP.  The 
primary analysis will be based on Weeks 2, 6, and 12 using the ITT population.  Mean IOP 
will be compared between each Bimatoprost SR dose strength and timolol for each hour 
(Hours 0 and 2) at Weeks 2, 6, and 12. 
The null and alternative hypotheses for the comparison between a given Bimatoprost SR 
dose strength and timolol for each hour at each visit are: 
• The null hypothesis is that the difference in mean IOP between the given Bimatoprost 
SR dose strength and timolol (Bimatoprost SR minus timolol) is > 1.5 mm Hg. 
• The alternative hypothesis is that the difference (Bimatoprost SR minus timolol) in 
mean IOP between the given Bimatoprost SR dose strength and timolol is 
≤ 1.5 mm Hg. 
IOP will be analyzed using an MMRM approach based on the same model as described in 
Section 7.3.1.  Within the framework of this model, the mean difference between each 
Bimatoprost SR dose strength and timolol and the corresponding 2-sided 95% confidence 
interval will be provided for each hour (Hours 0 and 2) and each visit (Weeks 2, 6, and 12).  
A gatekeeping procedure will be used to control the overall type I error rate at the 0.05 level 
at each timepoint, testing Bimatoprost SR 15 µg against timolol first and followed by the 
comparison between Bimatoprost SR 10 µg and timolol.  The test for Bimatoprost SR 10 µg 
versus timolol for a given hour at a visit is valid only if the noninferiority of Bimatoprost SR 
15 µg to timolol has been demonstrated for the given timepoint. 
Each Bimatoprost SR dose strength that shows noninferiority to timolol at all 6 timepoints 
with a 1.5 mm Hg margin (ie, the upper limit of the 95% confidence interval is ≤ 1.5 mm Hg) 
will be declared clinically noninferior to timolol if the upper limit of the 95% confidence 
interval is ≤ 1.0 mm Hg for 3 or more timepoints. 
Sensitivity analyses of handling missing data will be performed using multiple imputation. 
Secondary Efficacy Analyses 
For each Bimatoprost SR dose strength which demonstrates efficacy (clinical noninferiority) 
as described in the primary efficacy analyses, secondary efficacy analyses comparing the 
Bimatoprost SR dose strength and timolol to test the no-difference null hypothesis will be 

 
 
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61 
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performed at scheduled visits (Weeks 2, 6, and 12) and hours for IOP.  A gatekeeping 
procedure will be used to control the overall type I error rate at the 0.05 level within each 
dose strength; the specific sequence of the tests will be provided in the analysis plan. 
Other Efficacy Analyses 
7.7 
Sample Size Calculation 
The sample size calculation is based on the primary efficacy analysis of the IOP for US FDA 
review since the sample size based on the primary efficacy analysis for other regions is 
expected to be smaller. 
The initial sample size was estimated based on a 2-sided t-test with α = 0.05 at each 
timepoint and the assumption that the mean IOP difference between Bimatoprost SR 10 µg 
and timolol is -0.25 mm Hg (ie, Bimatoprost SR 10 µg is 0.25 mm Hg better in IOP-lowering 
than timolol) at Weeks 2 and 6 and 0 mm Hg at Week 12, with a common standard deviation 
of 4.0 mm Hg and a common within-subject correlation of 0.6.  It was also assumed that the 
efficacy (IOP-lowering effect) of Bimatoprost SR 15 µg is better than that of Bimatoprost SR 
10 µg by 0.25 mm Hg at each timepoint (Hours 0 and 2).  These assumptions were made at 
the study design phase based on the data obtained from the ongoing clinical study 
192024-041D.  Based on simulations, a sample size of 540 patients (180 per group) would 
provide approximately 95% and 81% power to show noninferiority (NI) of Bimatoprost SR 
15 µg and Bimatoprost SR 10 µg, respectively, to timolol at all 6 scheduled timepoints based 
on an NI margin of 1.5 mm Hg and at 3 or more timepoints based on an NI margin of 
1.0 mm Hg.  Assuming a premature discontinuation rate of 10% within 12 weeks (before 
primary database lock), approximately 600 patients (200 per group) were to be enrolled into 
this study. 
As part of ongoing centralized data monitoring of masked study data, some of the initial 
assumptions used for sample size calculation have been revisited. The rate of discontinued or 
rescued patients in the first 12 weeks is approximately 5%, which was less than the rate of 
10% assumed at the study design phase. Furthermore, the masked common IOP variability 
(pooled standard deviation across treatments and timepoints) is approximately 3.8 mm Hg, 
which was also less than the assumed 4.0 mm Hg at the study design phase. With the updated 

 
 
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62 
GDD-TA-T-004 v2013.9 
 
assumption on the common IOP standard deviation of 3.8 mm Hg, a sample size of 
486 patients (162 per group) would provide approximately 95.1% and 83.5% power to show 
NI of Bimatoprost SR 15 µg and Bimatoprost SR 10 µg, respectively, to timolol at all 
6 scheduled timepoints based on an NI margin of 1.5 mm Hg; and at 3 or more timepoints 
based on an NI margin of 1.0 mm Hg. With the updated premature discontinuation or rescue 
rate of 5% within 12 weeks, approximately 510 patients (170 per group) are to be enrolled 
into this study. 
8. 
Study Visit Schedule and Procedures 
Patients who complete the entire study without receiving nonstudy IOP-lowering medication 
will have a minimum of 25 visits and 6 phone calls.  The schedule begins with Screening, 
followed by a Washout period of up to 42 days for both eyes, and then Baseline.  These visits 
are followed by 3 cycles of Bimatoprost SR or Sham administration.  Each administration 
cycle includes Bimatoprost SR or Sham administration (Day 1), visit on Day 2, phone calls 
on Days 4 and 8, and visits on Weeks 2, 6, 12, and 15 (which is the visit prior to the next 
administration day).  Additional treatment period visits occur through Week 52 and extended 
follow-up continues into Months 14, 16, 18, and 20/exit. 
The study visits should adhere as closely as possible to the schedule shown in Table 2 
through Table 6.  See Figure 1 for a flowchart of patient participation. 
8.1 
Patient Entry Procedures  
8.1.1 
Overview of Entry Procedures 
Prospective patients as defined by the criteria in Sections 4.3 and 4.4 (inclusion/exclusion 
criteria) will be considered for entry into this study.   
8.1.2 
Informed Consent and Patient Privacy 
The study will be discussed with the patient and a patient wishing to participate must give 
informed consent prior to any study-related procedures or change in treatment.  The patient 
must also give authorization (US only), data protection consent (Europe only), and other 
written documentation in accordance with the relevant country and local privacy 
requirements (where applicable) prior to any study-related procedures or change in treatment. 
Each patient who provides informed consent will be assigned a subject number that will be 
used on patient documentation throughout the study. 

 
 
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8.2 
Washout Intervals 
All patients must provide informed consent prior to beginning any drug washout for the 
purposes of inclusion in this study.  Patients currently being treated with IOP-lowering 
medication(s) in either eye will begin washout of these medication(s) following completion 
of the screening procedures.  The Screening and Washout periods may not be concurrent.  
The Washout period will be up to 42 days depending on the minimum washout period 
schedule below. 
If, after initial washout, the IOP does not meet entry criteria and the investigator believes this 
is due to inadequate washout, if time remains in the Washout period, he/she may perform 
additional washout, as long as the total Washout period does not exceed 42 days. 
For patients undergoing a washout, interim safety evaluation(s) of IOP at some time during 
the washout period may be performed at the discretion of the investigator. 

 
 
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Note:  Medications should only be discontinued (washed out) if the investigator feels that it 
is safe and appropriate, and if the patient is willing to discontinue the medication for the 
duration of the study.  If the medication cannot be discontinued, then the patient will not be 
eligible for study entry. 
8.3 
Procedures for Final Study Entry 
The results from the screening ocular and physical examinations, and laboratory tests 
(hematology/blood chemistry/urinalysis) must be evaluated and determined to be acceptable 
to the investigator prior to the patient’s entry into the study.  If repeat laboratory tests are 
done, the results must be reviewed prior to study treatment initiation on Day 1.  Reading 
Center qualification of endothelial cell density must be confirmed by the Baseline visit.  
After confirmation of eligibility on Day 1, IV/WRS is contacted for randomization.  
However, this contact for randomization may take place at the end of the Baseline visit if 
needed.  See Section 5.5 for the method for assignment to treatment groups/randomization. 
A patient is considered to have enrolled in the study at the time of the first study treatment 
administration (or Sham). 
8.4 
Visits and Associated Procedures  
The following sections provide a list of procedures for each scheduled visit.  
 
 
 

 
 
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8.4.1 
Screening Visit 
After informed consent and other documentation have been obtained (as described in 
Section 8.1.2), the procedures listed below are done.  Intraocular pressure measurements 
must be performed in one day; however, other procedures (eg, postdilation and imaging 
procedures) may be performed on a different day as long as the screening procedures are 
completed within a 28-day period.  Perform pupil dilation/diagnostic procedures after the 
completion of the final IOP measurement of the day or on a different day. 
• Collection of demographic data 
• Collection of medical and ophthalmic history 
• Collection of adverse events 
• Collection of concomitant medications and procedures 
• Physical examination 
• Vital signs 
• Collection of blood and urine samples 
 

 
 
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Washout may begin after screening procedures have been completed. 
8.4.2 
Baseline Visit 
The Baseline visit occurs after the Washout period has been completed.  Final Reading 
Center confirmation of central endothelial cell density should be received by the site by the 
Baseline visit.  Baseline visit procedures, excluding IOP measurements (which must be 
performed in 1 day), can be performed over a 3-day period; all must be completed by the day 
before the Administration Day.  Perform pupil dilation/diagnostic procedures after the 
completion of the final IOP measurement of the day or on a different day. 
• Collection of medical and ophthalmic history (changes since the Screening visit) 
• Collection of adverse events 
• Collection of concomitant medications and procedures 
• Vital signs  
• Pregnancy test for females of childbearing potential (as defined in Section 4.5.3) 

 
Approval Date: 
 
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Allerg
 
 
 
8.4.3
8.4.3
The f
• 
• 
• 
• 
• 
gan Confidentia
3 
Tr
 
Cy
3.1
following pr
Collection
Collection
Vital sign
Confirm e
Administe
al 
reatment P
ycle 1:  Da
ocedures are
n of adverse 
n of concom
ns  
eligibility 
er assigned s
Period 
ay 1 Admi
e performed 
events 
mitant medica
study treatm
67 
inistration
on the day o
ations and pr
ment 
P
n Day 
of study trea
rocedures 
Protocol 19202
GDD-TA
atment admin
24-092 Amendm
A-T-004 v2013
nistration: 
ment 3 
.9 

 
 
Approval Date: 
 
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Allerg
 
 
 
8.4.3
On D
• 
• 
• 
gan Confidentia
 
Cy
3.2
Day 2 after st
Collection
Collection
Vital sign
al 
ycle 1:  Da
tudy treatme
n of adverse 
n of concom
ns 
ay 2  
ent administr
events 
mitant medica
68 
ration, the fo
ations and pr
P
ollowing pro
rocedures 
Protocol 19202
GDD-TA
ocedures are 
24-092 Amendm
A-T-004 v2013
performed:
ment 3 
.9 

 
 
Approval Date: 
 
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Allerg
 
 
 
8.4.3
The f
• 
• 
• 
gan Confidentia
 
Cy
3.5
following pr
Collection
Collection
Vital sign
al 
ycle 1:  W
ocedures are
n of adverse 
n of concom
ns 
Week 6  
e performed 
events 
mitant medica
69 
at Week 6 (±
ations and pr
P
±4 days): 
rocedures 
Protocol 19202
GDD-TA
24-092 Amendm
A-T-004 v2013
ment 3 
.9 

 
 
Approval Date: 
 
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Allerg
 
 
 
8.4.3
The f
• 
• 
• 
8.4.3
The f
• 
• 
• 
gan Confidentia
 
Cy
3.6
following pr
Collection
Collection
Vital sign
 
Cy
3.7
following pr
Collection
Collection
Vital sign
al 
ycle 1:  W
ocedures are
n of adverse 
n of concom
ns 
ycle 1:  W
ocedures are
n of adverse 
n of concom
ns 
Week 12  
e performed 
events 
mitant medica
Week 15  
e performed 
events 
mitant medica
70 
at Week 12 
ations and pr
at Week 15 
ations and pr
P
(± 4 days):
rocedures 
(± 4 days):
rocedures 
Protocol 19202
GDD-TA
24-092 Amendm
A-T-004 v2013
ment 3 
.9 

 
 
Approval Date: 
 
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Allerg
 
 
 
8.4.3
The f
• 
• 
• 
• 
gan Confidentia
 
Cy
3.8
following pr
Collection
Collection
Vital sign
Administe
al 
ycle 2:  W
ocedures are
n of adverse 
n of concom
ns  
er assigned s
Week 16 Ad
e performed 
events 
mitant medica
study treatm
71 
dministrati
at Week 16 
ations and pr
ment 
P
ion Day 
(-2 to +4 da
rocedures 
Protocol 19202
GDD-TA
ays): 
24-092 Amendm
A-T-004 v2013
ment 3 
.9 

 
 
Approval Date: 
 
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8.4.3
On D
perfo
• 
• 
• 
8.4.3
On D
conta
• 
• 
8.4.3
The f
• 
• 
• 
gan Confidentia
 
Cy
3.9
Day 2 after th
ormed: 
Collection
Collection
Vital sign
 
Cy
3.10
Day 4 and Da
acted by telep
Collection
Collection
 
Cy
3.11
following pr
Collection
Collection
Vital sign
al 
ycle 2:  Da
he second stu
n of adverse 
n of concom
ns 
ycle 2:  Da
ay 8 after the
phone to col
n of adverse 
n of concom
ycle 2:  W
ocedures are
n of adverse 
n of concom
ns 
ay 2 
udy treatmen
events 
mitant medica
ay 4 and D
e second cyc
llect the follo
events 
mitant medica
Week 18  
e performed 
events 
mitant medica
72 
nt administra
ations and pr
Day 8 (Pho
cle administr
owing: 
ations and pr
at Week 18 
ations and pr
P
ation, the fol
rocedures 
one Calls)
ration proced
rocedures 
(±4 days): 
rocedures 
Protocol 19202
GDD-TA
llowing proc
dure, the pat
24-092 Amendm
A-T-004 v2013
cedures are 
tient will be 
ment 3 
.9 

 
 
Approval Date: 
 
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8.4.3
The f
• 
• 
• 
8.4.3
The f
• 
gan Confidentia
 
Cy
3.12
following pr
Collection
Collection
Vital sign
 
Cy
3.13
following pr
Collection
al 
ycle 2:  W
ocedures are
n of adverse 
n of concom
ns 
ycle 2:  W
ocedures are
n of adverse 
Week 22  
e performed 
events 
mitant medica
Week 28  
e performed 
events 
73 
at Week 22 
ations and pr
at Week 28 
P
(±4 days): 
rocedures 
(±4 days): 
Protocol 19202
GDD-TA
24-092 Amendm
A-T-004 v2013
ment 3 
.9 

 
 
Approval Date: 
 
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Allerg
 
 
 
• 
• 
8.4.3
The f
• 
• 
• 
gan Confidentia
Collection
Vital sign
 
Cy
3.14
following pr
Collection
Collection
Vital sign
al 
n of concom
ns 
ycle 2:  W
ocedures are
n of adverse 
n of concom
ns 
mitant medica
Week 31  
e performed 
events 
mitant medica
74 
ations and pr
at Week 31 
ations and pr
P
rocedures 
(± 4 days):
rocedures 
Protocol 19202
GDD-TA
24-092 Amendm
A-T-004 v2013
ment 3 
.9 

 
 
Approval Date: 
 
05-Jun-2018
Allerg
 
 
 
8.4.3
The f
• 
• 
• 
• 
gan Confidentia
 
Cy
3.15
following pr
Collection
Collection
Vital sign
Administe
al 
ycle 3:  W
ocedures are
n of adverse 
n of concom
ns  
er assigned s
Week 32 Ad
e performed 
events 
mitant medica
study treatm
75 
dministrati
at Week 32 
ations and pr
ment 
P
ion Day 
(-2 to + 4 da
rocedures 
Protocol 19202
GDD-TA
ays): 
24-092 Amendm
A-T-004 v2013
ment 3 
.9 

 
 
Approval Date: 
 
05-Jun-2018
Allerg
 
 
 
8.4.3
On D
perfo
• 
• 
• 
8.4.3
On D
conta
• 
• 
8.4.3
The f
• 
• 
• 
gan Confidentia
 
Cy
3.16
Day 2 after th
ormed: 
Collection
Collection
Vital sign
 
Cy
3.17
Day 4 and Da
acted by telep
Collection
Collection
 
Cy
3.18
following pr
Collection
Collection
Vital sign
al 
ycle 3:  Da
he third study
n of adverse 
n of concom
ns 
ycle 3:  Da
ay 8 after the
phone to col
n of adverse 
n of concom
ycle 3:  W
ocedures are
n of adverse 
n of concom
ns 
ay 2 
y treatment a
events 
mitant medica
ay 4 and D
e third cycle 
llect the follo
events 
mitant medica
Week 34  
e performed 
events 
mitant medica
76 
administratio
ations and pr
Day 8 (Pho
administrati
owing: 
ations and pr
at Week 34 
ations and pr
P
on, the follo
rocedures 
one Calls)
ion procedur
rocedures 
(± 4 days):
rocedures 
Protocol 19202
GDD-TA
owing proced
re, the patien
24-092 Amendm
A-T-004 v2013
dures are 
nt will be 
ment 3 
.9 

 
 
Approval Date: 
 
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Allerg
 
 
 
8.4.3
The f
• 
• 
• 
8.4.3
The f
• 
gan Confidentia
 
Cy
3.19
following pr
Collection
Collection
Vital sign
 
Cy
3.20
following pr
Collection
al 
ycle 3:  W
ocedures are
n of adverse 
n of concom
ns 
ycle 3:  W
ocedures are
n of adverse 
Week 38  
e performed 
events 
mitant medica
Week 44  
e performed 
events 
77 
at Week 38 
ations and pr
at Week 44 
P
(±4 days): 
rocedures 
(± 4 days):
Protocol 19202
GDD-TA
24-092 Amendm
A-T-004 v2013
ment 3 
.9 

 
 
Approval Date: 
 
05-Jun-2018
Allerg
 
 
 
• 
• 
8.4.3
The f
• 
• 
• 
gan Confidentia
Collection
Vital sign
 
Cy
3.21
following pr
Collection
Collection
Vital sign
al 
n of concom
ns 
ycle 3:  W
ocedures are
n of adverse 
n of concom
ns 
mitant medica
Week 48  
e performed 
events 
mitant medica
78 
ations and pr
at Week 48 
ations and pr
P
rocedures 
(± 4 days):
rocedures 
Protocol 19202
GDD-TA
24-092 Amendm
A-T-004 v2013
ment 3 
.9 

 
 
Approval Date: 
 
05-Jun-2018
Allerg
 
 
 
8.4.3
The f
• 
• 
• 
gan Confidentia
 
Cy
3.22
following pr
Collection
Collection
Vital sign
al 
ycle 3:  W
ocedures are
n of adverse 
n of concom
ns 
Week 52  
e performed 
events 
mitant medica
79 
at Week 52 
ations and pr
P
(± 7 days):
rocedures 
Protocol 19202
GDD-TA
24-092 Amendm
A-T-004 v2013
ment 3 
.9 

 
 
Approval Date: 
 
05-Jun-2018
Allerg
 
 
 
8.4.4
8.4.4
The f
• 
• 
• 
8.4.4
The f
• 
• 
• 
gan Confidentia
4 
E
 
M
4.1
following pr
Collection
Collection
Vital sign
 
M
4.2
following pr
Collection
Collection
Vital sign
al 
xtended F
Month 14  
ocedures are
n of adverse 
n of concom
ns 
Month 16  
ocedures are
n of adverse 
n of concom
ns 
Follow Up
e performed 
events 
mitant medica
e performed 
events 
mitant medica
80 
 
at the Month
ations and pr
at the Month
ations and pr
P
h 14 (± 14 d
rocedures 
h 16 (± 14 d
rocedures 
Protocol 19202
GDD-TA
days) visit: 
days) visit: 
24-092 Amendm
A-T-004 v2013
ment 3 
.9 

 
 
Approval Date: 
 
05-Jun-2018
Allerg
 
 
 
8.4.4
The f
• 
• 
• 
8.4.4
The f
gan Confidentia
 
M
4.3
following pr
Collection
Collection
Vital sign
 
M
4.4
following pr
al 
Month 18  
ocedures are
n of adverse 
n of concom
ns 
Month 20/E
ocedures are
e performed 
events 
mitant medica
Exit 
e performed 
81 
at the Month
ations and pr
at the Month
P
h 18 (± 14 d
rocedures 
h 20 (± 14 d
Protocol 19202
GDD-TA
days) visit: 
days) visit or
24-092 Amendm
A-T-004 v2013
r at early exi
ment 3 
.9 
it: 

 
 
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• Collection of adverse events 
• Collection of concomitant medications and procedures 
• Vital signs 
• Pregnancy test for females of childbearing potential 
8.5 
Instructions for the Patients 
Patients should be instructed to strictly follow the study visit schedule and to report all 
changes in their condition to the investigative site. 

 
 
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Instruction should be given to the patient to maintain a stable dose of any concomitant 
medication used chronically, or any new medications initiated during the study whenever 
possible.  Patients should be instructed to communicate any changes to their medication at 
their next study visit.  Patients should also be reminded to contact the study site if they are 
experiencing any difficulties during their study participation. 
Patients should keep the study medication bottles in the original kit that was provided and 
return the bottles to the designated (unmasked) site staff.  Patients should be instructed that 
bottles of provided medications should only be used for 28 days each. 
8.6 
Unscheduled Visits 
Additional examinations 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. 
8.7 
Compliance with Protocol 
Patients must be able to adhere to the study visit schedule; appropriate inclusion, exclusion, 
and treatment criteria; permitted and prohibited medication criteria; and testing parameters as 
described in the protocol.  At each study visit, patients will be asked if they have used their 
study-provided eye drops as instructed and whether they have used any concomitant 
medications/therapies or had any concurrent procedures since the previous visit. 
Patients should be scheduled for study visits as closely to the day specified in the visit 
schedule as possible. 

 
 
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8.8 
Early Discontinuation of Patients 
Patients may voluntarily withdraw from the study at any time. 
Patients who have received nonstudy IOP-lowering medication in only one eye will be 
followed for the duration of the study through the Month 20 visit. 
Patients who have received nonstudy IOP-lowering medication in both eyes, or who do not 
complete an Administration Day visit, may discontinue the study 12 months after the last 
Bimatoprost SR or Sham administration at which time they should complete the 
Month 20/Exit visit procedures. 
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 eCRF. 
When patients exit before Month 20, the site should complete all procedures for the 
Month 20/Exit visit at the patient’s last visit. 
8.9 
Withdrawal Criteria 
After the first administration (or Sham), failure to undergo an Administration Day visit does 
not indicate total withdrawal from the study.  Patients who have received nonstudy 
IOP-lowering medication in only one eye will continue through the duration of the study.  
Patients who have received nonstudy IOP-lowering medication in both eyes, or patients who 
do not undergo Cycle 2 or 3 (or both) Administration Visits, will still be followed for 
12 months after the last Bimatoprost SR or Sham administration for safety reasons.  These 
patients are eligible for Early Discontinuation (Early Exit) as described in Section 8.8, above.  
The investigator should consider withdrawing a patient from the study early if any of the 
following criteria are met: 
• Patient develops (or has an exacerbation of) a medical condition that, in the opinion 
of the investigator, compromises the patient’s ability to participate in the study 
• Patient develops (or has an exacerbation of) a medical condition that, in the opinion 
of the investigator, compromises the patient’s ability to participate in the study 
• Patient is unwilling or unable to continue to comply with study procedures 
• Patient is unwilling or unable to continue in the study 

 
 
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If a patient develops (or has an exacerbation of) a medical condition that, in the opinion of 
the investigator, would put the patient at an unacceptable medical risk by continuing study 
participation, the patient will be withdrawn from the study. 
Whenever possible, the decision to withdraw a patient from the study or study treatment 
should be discussed with Allergan. 
8.10 
Study Termination 
The study may be stopped at his/her study site at any time by the site investigator.  Allergan 
may stop the study (and/or the study site) for any reason with appropriate notification. 
9. 
Adverse Events  
Adverse events occurring during the study will be recorded on an adverse event eCRF.  If 
adverse events occur, the first concern will be the safety of the study participants. 
9.1 
Definitions 
9.1.1 
Adverse Event 
An adverse event is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product.  In addition, during the screening period, adverse events 
will be assessed regardless of the administration of a pharmaceutical product. 
Note:  Adverse events must be collected once informed consent has been obtained, regardless 
of whether or not the patient has been administered study drug. 
Progression of treatment indication including new or worsening of anticipated clinical signs 
or symptoms, which are collected as clinical efficacy variables and assessed as unequivocally 
associated with the disease progression and /or lack of efficacy, should NOT be reported as 
adverse events unless the disease progression is greater than anticipated in the natural course 
of the disease. 
Adverse events will be assessed, documented, and recorded in the CRF throughout the study 
(ie, after informed consent has been obtained).  At each visit, the investigator will begin by 

 
 
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querying for adverse events by asking each patient a general, nondirected question such as 
“How have you been feeling since the last visit?”  Directed questioning and examination will 
then be done as appropriate.  All reported adverse events will be documented on the 
appropriate case report form. 
9.1.2 
Serious Adverse Event 
A serious adverse event is any adverse event occurring at any dose that results in any of the 
following outcomes:  death, a life-threatening adverse event, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a 
congenital anomaly/birth defect.  Important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, they may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  (See Section 9.3 for procedures for reporting a serious adverse event.) 
Allergan considers all cancer adverse events as serious adverse events.  In addition, Allergan 
considers any abortion (spontaneous or nonspontaneous) as a serious adverse event. 
Preplanned surgeries or procedures for pre-existing, known medical conditions for which a 
patient requires hospitalization is not reportable as a serious adverse event. 
Any preplanned surgery or procedure should be clearly documented in the site source 
documents by the medically qualified investigator at the time of the patient’s entry into the 
study.  If it has not been documented at the time of the patient’s entry into the study, then it 
should be documented as a serious adverse event and reported to Allergan. 

 
 
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9.1.3 
Severity 
A clinical determination will be made of the intensity of an adverse event.  The severity 
assessment for a clinical adverse event must be completed using the following definitions as 
guidelines: 
Mild 
Awareness of sign or symptom, but easily tolerated. 
Moderate 
Discomfort enough to cause interference with usual activity. 
Severe 
Incapacitating with inability to work or do usual activity. 
Not applicable 
In some cases, an adverse event may be an ‘all or nothing’ finding 
which cannot be graded. 
 
9.1.4 
Relationship to Study Drug or Study Procedure 
A determination will be made of the relationship (if any) between an adverse event and the 
study drug or study procedure, as applicable.  A causal relationship is present if a 
determination is made that there is a reasonable possibility that the adverse event may have 
been caused by the drug or study procedure. 
If an adverse event is deemed related to study treatment, the investigator will be asked to 
further delineate whether the adverse event was related to the administration procedure 
(versus the study medication). 
Note:  A study procedure occurring during the Screening/Baseline period can include a 
washout of medication or introduction of a run-in medication or study required diagnostic 
procedure. 
9.2 
Procedures for Reporting Adverse Events 
Any adverse event must be recorded on the appropriate case report form. 
All adverse events that are drug-related and unexpected (not listed as treatment-related in the 
current Investigator's Brochure) must be reported to the governing Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) as required by the IRB/IEC, local 
regulations, and the governing health authorities.  Any adverse event that is marked 
“ongoing” at the exit visit must be followed up as appropriate. 

 
 
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9.3 
Procedures for Reporting a Serious Adverse Event 
Any serious adverse event occurring during the study period (beginning with informed 
consent) and for at least 4 months after the last dose of study drug must be immediately 
reported but no later than 24 hours after learning of a serious adverse event.  Serious adverse 
events must be reported to Allergan (or Agent of Allergan)
 
  All patients with a serious 
adverse event must be followed up and the outcomes reported.  The investigator must 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 
 
 
 
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.  
 
 
 
 

 
 
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10. 
Administrative Items 
This protocol is to be conducted in accordance with the applicable Good Clinical Practice 
(GCP) regulations and guidelines, eg, the International Conference on Harmonisation (ICH) 
Guideline on GCP. 
10.1 
Protection of Human Subjects 
10.1.1 
Compliance with Informed Consent Regulations (US 21 CFR 
Part 50) and Relevant Country Regulations 
Written informed consent is to be obtained from each patient prior to any study-related 
activities or procedures in the study, and/or from the patient's legally authorized 
representative.  If the patient is under the legal age of consent, the consent form must be 
signed by the legally authorized representative in accordance with the relevant country and 
local regulatory requirements. 
There are special situations in which oral informed consent may be taken.  Approval to utilize 
oral consent procedures and instructions on how to properly obtain oral informed consent 
must be obtained from Allergan personnel. 
10.1.2 
Compliance With IRB or IEC Regulations 
This study is to be conducted in accordance with IRB regulations (US 21 CFR Part 56.103) 
or applicable IEC regulations.  The investigator must obtain approval from a properly 
constituted IRB/IEC prior to initiating the study and reapproval or review at least annually.  
Allergan is to be notified immediately if the responsible IRB/IEC has been disqualified or if 
proceedings leading to disqualification have begun.  Copies of all IRB/IEC correspondence 
with the investigator should be provided to Allergan. 
10.1.3 
Compliance With Good Clinical Practice 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines. 

 
 
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10.1.4 
Compliance With Electronic Records; Electronic Signatures 
Regulations (US 21 CFR Part 11) 
This study is to be conducted in compliance with the regulations on electronic records and 
electronic signature. 
10.2 
Changes to the Protocol 
The investigator must not implement any deviation from or changes of the protocol without 
approval by Allergan and prior review and documented approval/favorable opinion from the 
IRB/IEC of a protocol amendment, except where necessary to eliminate immediate hazards 
to study patients, or when the changes involve only logistical or administrative aspects of the 
study (eg, change in monitors, change of telephone numbers). 
10.3 
Patient Confidentiality 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study drug may ultimately be marketed, but the 
patient’s name will not be disclosed in these documents.  The patient's name may be 
disclosed to the Sponsor of the study, Allergan, or the governing health authorities or the 
FDA if they inspect the study records.  Appropriate precautions will be taken to maintain 
confidentiality of medical records and personal information. 
10.3.1 
Patient Privacy 
Written authorization (US sites only), data protection consent (European sites only), and 
other documentation in accordance with the relevant country and local privacy requirements 
(where applicable) is to be obtained from each patient prior to enrollment into the study, 
and/or from the patient's legally authorized representative in accordance with the applicable 
privacy requirements (eg, the Health Insurance Portability and Accountability Act Standards 
for Privacy of Individually Identifiable Health Information (“HIPAA”), European Union Data 
Protection Directive 95/46/EC [“EU Directive”]). 
In accordance with HIPAA requirements, additional purposes of this study may include 
publishing of anonymous patient data from the study. 

 
 
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10.4 
Documentation 
10.4.1 
Source Documents 

 
 
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10.4.2 
Case Report Form Completion 
The investigator is responsible for ensuring that data are properly recorded on each patient's 
case report forms and related documents.  
 
 
 
 
 
 
10.4.3 
Study Summary 
An investigator's summary will be provided to Allergan within a short time after the 
completion of the study, or as designated by Allergan.  A summary is also to be provided to 
the responsible IRB/IEC. 
10.4.4 
Retention of Documentation 
All study related correspondence, patient records, consent forms, patient privacy 
documentation, records of the distribution and use of all investigational products, and copies 
of case report forms should be maintained on file. 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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10.5 
Labeling, Packaging, and Return or Disposal of Study 
Medications/Treatments 
10.5.1 
Labeling/Packaging 
Packaged and labeled study medication will be supplied by Allergan. 
10.5.2 
Clinical Supply Inventory 
The investigator must keep an accurate accounting of the number of investigational units 
received from Allergan, dispensed to the patients, the number of units returned to the 
investigator by the patient, and the number of units returned to Allergan during and at the 
completion of the study.  A detailed inventory must be completed for the study medication.  
The study medication must be dispensed only by an appropriately qualified person to patients 
in the study.  The medication is to be used in accordance with the protocol by patients who 
are under the direct supervision of an investigator. 
10.5.3 
Return or Disposal of Study Medications/Treatments and/or 
Supplies 
All clinical study medications/treatments and/or supplies will be returned to Allergan or 
Allergan designee for destruction.  
 
 

 
 
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Any malfunctioning applicators should be returned to Allergan or designee.  Written 
instructions provided by Allergan should be followed when returning a malfunctioning 
applicator to Allergan or its representative. 
10.6 
Monitoring by the Sponsor 
A representative of the sponsor will monitor the study on a periodic basis.  The determination 
of the extent and nature of monitoring will be based on considerations such as the objective, 
purpose, design, complexity, blinding, size, and endpoints of the study. 
Authorized representatives of Allergan or regulatory authority representatives will conduct 
on-site visits to review, audit and copy study-related documents.  These representatives will 
meet with the investigator(s) and appropriate staff at mutually convenient times to discuss 
study-related data and questions. 
10.7 
Handling of Biological Specimens  
Laboratory specimens for blood chemistry panel, hematology including complete blood 
count with differential, and urinalysis will be sent to a centralized clinical laboratory 
(
 
) with certification from a recognized accreditation agency 
 
) to 
be assayed using validated methods.
 
 
 
 
 
 
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. 

 
 
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10.9 
Coordinating Investigator 
A signatory Coordinating Investigator will be designated prior to the writing of the Clinical 
Study Report. 
11. 
References 
AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship 
between control of intraocular pressure and visual field deterioration. Am J Ophthalmol. 
2000;130:429-440. 
American Academy of Ophthalmology Glaucoma Panel. Preferred Practice Pattern® 
Guidelines. Primary open-angle glaucoma. San Francisco, CA: American Academy of 
Ophthalmology; 2010a. 27 p. 
Budenz DL. A clinician's guide to the assessment and management of nonadherence in 
glaucoma. Ophthalmology. 2009;116:S43-S47. 
Cohen JS, Gross RL, Cheetham JK, VanDenburgh AM, Bernstein P, Whitcup SM. Two-year 
double-masked comparison of bimatoprost with timolol in patients with glaucoma or ocular 
hypertension. Surv Ophthalmol. 2004;49 (Suppl 1):S45-S52. 
Cook C, Foster P. Epidemiology of glaucoma:  What’s new?  Can J Ophthalmol. 
2012;47:223-226. 
Friedman DS. Introduction: new insights on enhancing adherence to topical glaucoma 
medications. Ophthalmology. 2009;116:S29. 

 
 
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Heijl A, Leske MC, Bengtsson B, Hyman L, Bengtsson B, Hussein M. Reduction of 
intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma 
Trial. Arch Ophthalmol. 2002;120:1268-1279. 
Higginbotham EJ, Schuman JS, Goldberg I, Gross RL, VanDenburgh AM, Chen K, et al. 
One-year, randomized study comparing bimatoprost and timolol in glaucoma and ocular 
hypertension. Arch Ophthalmol. 2002;120:1286-1293. 
Kass MA, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JL, Miller JP, et al. The Ocular 
Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive 
medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 
2002;120:701-713. 
Knight O’RJ, Lawrence SD. Sustained drug delivery in glaucoma. Current Opinion in 
Ophthalmology 2014;25(2):112-117. 
Kozak KR, Crews BC, Morrow JD, Wang L-H, Ma YH, Weinander R, et al. Metabolism of 
the endocannabinoids, 2-arachidonylglycerol and anandamide, into prostaglandin, 
thromboxane, and prostacyclin glycerol esters and ethanolamides. J Biol Chem. 
2002;277:44877-44885. 
Krauss AH, Woodward DF. Update on the mechanism of action of bimatoprost: a review and 
discussion of new evidence. Surv Ophthalmol. 2004;49(Suppl 1):S5-11. 
Lichter PR, Musch DC, Gillespie BW, Guire KE, Janz NK, Wren PA, et al. Interim clinical 
outcomes in the Collaborative Initial Glaucoma Treatment Study comparing initial treatment 
randomized to medications or surgery. Ophthalmology. 2001;108:1943-1953. 
LUMIGAN® [Package Insert]. Irvine, CA: Allergan, Inc. 2012. 
Matias I, Chen J, De Petrocellis L, Bisogno T, Ligresti A, Fezza F, et al. Prostaglandin 
ethanolamides (prostamides): in vitro pharmacology and metabolism. J Pharmacol Exp Ther. 
2004;309:745-757. 
Mosaed S, Dustin L, Minckler DS. Comparative outcomes between newer and older 
surgeries for glaucoma. Trans Am Ophthalmol Soc. 2009;107:127-33. 
Quigley HA. Number of people with glaucoma worldwide. Br J Ophthalmol. 
1996;80:389-393. 

 
 
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Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. 
Br J Ophthalmol. 2006;90:262-267. Doi: 10.1136/bjo.2005.081224. Downloaded from 
bjo.bm.com, April 9, 2014. 
Stamper RL, Lieberman MF, Drake MV, eds. Introduction and Classification of the 
Glaucomas. In: Stamper RL, Lieberman MF, Drake MV, editors. Becker-Shaffer's Diagnosis 
and Therapy of the Glaucomas, 8th ed. Amsterdam, Netherlands: Mosby Elsevier; 2009;Chap 
1:1-7. 
Tsai JC. A comprehensive perspective on patient adherence to topical glaucoma therapy. 
Ophthalmology. 2009;116:S30-S36. 
Varma R, Lee PP, Goldberg I, Kotak S. An assessment of the health and economic burdens of 
glaucoma. Am J Ophthalmol. 2011;152:515-522. 
Weber A, Ni J, Ling KH, Acheampong A, Tang-Liu DD, Burk R, et al. Formation of 
prostamides from anandamide in FAAH knockout mice analyzed by HPLC with tandem 
mass spectrometry. J Lipid Res. 2004;45:757-763. 
Weinreb RN, Kaufman PL. The Glaucoma Research Community and FDA look to the future:  
a report from the NEI/FDA CDER Glaucoma Clinical Trial Design and Endpoints 
Symposium. Inv Ophthalomol & Vis Sci. 2009;50(4):1497-1505. 
Williams RD, Cohen JS, Gross RL, Liu CC, Safyan E, Batoosingh AL. Long-term efficacy 
and safety of bimatoprost for intraocular pressure lowering in glaucoma and ocular 
hypertension: year 4. Br J Ophthalmol. 2008;92:1387-1392. 
Woodward DF, Chan MF, Burke JA, Cheng-Bennett A, Chen G, Fairbairn CE, et al. Studies 
on the ocular hypotensive effects of prostaglandin F2 alpha ester prodrugs and receptor 
selective prostaglandin analogs. J Ocul Pharmacol. 1994;10:177-193. 
Woodward DF, Krauss AH, Chen J, Lai RK, Spada CS, Burk RM. The pharmacology of 
bimatoprost (Lumigan). Surv Ophthalmol. 2001;45(Suppl 4):S337-S345. 
Woodward DF, Phelps RL, Krauss AH, Weber A, Short B, Chen J, et al. Bimatoprost: A novel 
antiglaucoma agent. Cardiovasc Drug Rev. 2004;22:103-120. 
Yu M, Ives D, Ramesha CS. Synthesis of prostaglandin E2 ethanolamide from anandamide 
by cyclooxygenase-2. J Biol Chem. 1997;272:21181-21186. 
 

 
 
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12. 
Attachments 
12.1 
Package Insert 
The appropriate package insert or Summary of Product Characteristics will be supplied to 
investigators in countries where timolol (study-provided eye drops) is marketed. 

 
 
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12.2 
Glossary of Abbreviations 
Term/Abbreviation 
Definition 
ABMD 
Anterior Basement Membrane Disease 
AC 
Anterior chamber 
ARMD 
Age-related Macular Degeneration 
ASC 
Ambulatory Surgical Center 
AS-OCT 
Anterior segment optical coherence tomography 
BCVA 
Best-corrected visual acuity 
BID 
Twice daily 
BLQ 
Below the limit of quantitation 
CRF 
Case report form 
DMEK 
Descemet’s Membrane Endothelial Keratoplasty 
DSEK 
Descemet’s Stripping Endothelial Keratoplasty 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
GLP 
Good Laboratory Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IOL 
Intraocular lens implant 
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IV/WRS 
Interactive voice/web response system 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effects model repeated measures 
NI 
Noninferiority 
NSAID 
Non-steroidal anti-inflammatory drug 
OAG 
Open-angle glaucoma 
OCT 
Optical coherence tomography 
OHT 
Ocular hypertension 
OU 
Both eyes 

 
 
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Term/Abbreviation 
Definition 
PAS 
Peripheral anterior synechiae 
PLA 
Polylactic acid 
PLGA 
Polylactic-co-glycolic acid 
POAG 
Primary open-angle glaucoma 
PP 
Per protocol 
RBC 
Red blood cell 
SC/T 
Patients with sickle cell disease or trait or other 
hemoglobinopathies 
SOC 
System Organ Class (MedDRA) 
SR 
Sustained release 
US 
United States 
WBC 
White blood cell 
 
 

 
 
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12.3 
Protocol Amendment Summary 
12.3.1 
Amendment 1 
Title:  The Efficacy and Safety of Bimatoprost SR in Patients With Open-angle Glaucoma or 
Ocular Hypertension 
Protocol 192024-092 Amendment 1 
Date of Amendment:  August 2015 
Amendment Summary 
This summary includes changes made to Protocol 192024-092 (approved September 2014).  
This protocol was amended to clarify some sections and to modify the inclusion/exclusion 
criteria. 
Following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes.  Minor editorial and document formatting 
revisions have not been summarized. 
 

 
 
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Section 
Revision 
Rationale 
Title 
Page 
Updated Allergan Medical Safety Physician and Allergan 
Signatory information. 
 
Protocol 
Summary 
Updated and reordered the following key inclusion criteria 
as follows: 
• 
Diagnosis of either OAG (ie, primary OAG, 
pseudoexfoliation glaucoma, or pigmentary glaucoma) 
or OHT in each eye, and both eyes require 
IOP-lowering treatment (Note:  diagnosis does not have 
to be the same in both eyes) 
• 
In the investigator’s opinion, either eye can be treated 
adequately with timolol topical ophthalmic 
beta-blocker (eg, timolol) eye drops as the sole therapy 
• 
In the opinion of the investigator’s opinion, based on 
prior use or on IOP rebound (elevation) during the 
washout period, patient is a responder to IOP lowering 
by topical prostamides, prostaglandins, or 
prostaglandin analogs  either eye can be treated 
adequately with topical prostamide, prostaglandin, or 
prostaglandin analog (eg, LUMIGAN, Xalatan, 
Travatan) eye drops as the sole therapy 
• 
The iridocorneal angle inferiorly in the study eye must 
be confirmed as being qualified by Reading Center 
AS-OCT assessment 
• 
In both eyes, aAt the Baseline visit:  Hour 0 IOP in the 
study eye of ≥ 22 mm Hg and ≤ 32 mm Hg, and in the 
fellow eye of  ≥ 17 mm Hg and ≤ 32 mm Hg, with 
difference between eyes of ≤ 5 mm Hg 
• 
In both eyes At Hour 2 at the Baseline visit:  Hour 2 
IOP in the study eye of ≥ 19 mm Hg and ≤ 32 mm Hg, 
and in the fellow eye of ≥ 14 mm Hg and ≤ 32 mm Hg  
Updated the following key exclusion criterion: 
• 
In the investigator’s opinion, patient is nonresponsive 
to topical ophthalmic beta-blockers and/or topical 
prostamides, prostaglandins, or prostaglandin analogs 
(eg, LUMIGAN, Xalatan, Travatan) 
Revised key entry criteria based on 
the updated inclusion and exclusion 
criteria in the body of the protocol. 
 
 

 
 
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Section 
Revision 
Rationale 
Section 
1.3.3 
The objective of this stage of the study is to evaluate the 
safety and intraocular pressure (IOP)-lowering efficacy of 
Bimatoprost SR in patients with OAG. 
As of March 2015April, 2014, a total of 87 109 patients had 
received a single administration; and of those as of June 
2015, 12 24 had received a repeat administration of 
Bimatoprost SR.  Based on a review of the efficacy data as 
of March 2015,  a trend in dose-response has been observed 
across the 4 dose strengths that were tested.  Available data 
suggest that the implant may provide topical prostaglandin 
analog-like efficacy up to 3 to 4 months post-implantation 
in the majority of patients.   from the 10 µg and 15 µg 
single administrations show comparable IOP pressure 
lowering between the study eye and the nonstudy eye 
during the first 12 to 16 weeks after dosing.  Of the 67 
patients across all dose groups who had reached the Week 
16 visit, 62 (92.5%) had not required the use of additional 
intraocular pressure-lowering topical medication by that 
visit.  A total of 12 patients had received a repeat 
administration of Bimatoprost SR (2 at 6 µg, 5 at 10 µg, and 
5 at 15 µg), providing up to 20 weeks of data following the 
second administration.  The timing of the second 
administration ranged from 20 weeks after the first dose in 
the 6 µg group, 14 to 33 weeks (14, 16, 19, 24, and 33 
weeks) in the 10 µg group, and 17 to 37 weeks (17, 19, 19, 
26, and 37 weeks) in the 15 µg group.  Data for up to 16 
weeks of follow up afterfollowing the second 
administration in the redosed patients showed similar IOP 
lowering to that observed following the first administration 
of Bimatoprost SR. 
As of AprilMarch, 20142015, Bimatoprost SR has shown 
an acceptable safety profile with single and repeat 
Updated the summary of data from 
Study 192024-041D with more 
current results. 

 
 
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Section 
Revision 
Rationale 
administrations in ongoing study 192024-041D.  The most 
frequently reported adverse events (> 10% of patients) for 
the study eye have been conjunctival hyperaemia, 
conjunctival haemorrhage, eye pain, foreign body sensation, 
and lacrimation increased.  Most of these adverse events 
were ocular, mild in severity, occurred within the first 
8 days after Bimatoprost SR administration, and were 
considered related to the study drug administration 
procedure.  There have been no reports of serious study 
drug-related adverse events, and no new safety concerns 
have been observed after the second treatment.  Please refer 
to the Investigator’s Brochure for details on reported safety 
findings. 
Sections 
3 and 4.1 
Updated the number of study sites from 170 to 180. 
Updated the number of study sites 
based on a revised estimate of 
global participating sites. 
Section 
4.3 
Updated the following inclusion criteria: 
4.  Patient is willing to withhold his/her IOP-lowering 
treatments according to the study requirements, and in the 
opinion of the investigator can do so without significant 
risk.  
 
 
 
 
 
7.  Diagnosis of either OAG (ie, primary pseudoexfoliation, 
or pigmentary glaucoma) or OHT in each eye and both eyes 
require IOP-lowering treatment.  (Note:  diagnosis does not 
have to be the same in both eyes) 
8.  In the investigator’s opinion, either eye can be treated 
adequately with topical ophthalmic beta-blocker (eg, 
timolol) eye drops as the sole therapy. 
Updated inclusion criteria 4, 7, and 
8 for better clarity.   
 
Added the following inclusion criterion: 
9.  In the investigator’s opinion, either eye can be treated 
adequately with topical prostamide, prostaglandin, or 
prostaglandin analog (eg, LUMIGAN, Xalatan, Travatan) 
eye drops as the sole therapy.  
Removed the following original inclusion criterion:  
11.  In the opinion of the investigator based on prior use or 
on IOP rebound (elevation) during the Washout period, 
patient is a responder to IOP lowering by topical 
prostamides, prostaglandins, or prostaglandin analogs (eg, 
LUMIGAN, Xalatan, Travatan)  
 
Replaced original inclusion criterion 
11 with new inclusion criterion 9 for 
consistency in requirements related 
to the study medication and the 
control treatment groups of the 
study, avoiding potential bias, 
which is consistent with previous 
bimatoprost studies.  Data from the 
ongoing 192024-041D study 
support this change. There have 
been no safety concerns for the  
patients who have been re-
implanted based on the 
“investigator’s opinion” for getting 
the injection. 

 
 
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Section 
Revision 
Rationale 
 
Updated the following inclusion criteria: 
13.  At the Baseline visit: 
a. 
Hour 0 IOP in the study eye of ≥ 22 mm Hg 
and ≤ 32 mm Hg, and in the fellow eye 
of  ≥ 17 mm Hg and ≤ 32 mm Hg, with 
difference between eyes of ≤ 5 mm Hg 
b. Hour 2 IOP in the study eye of ≥ 19 mm Hg 
and ≤ 32 mm Hg, and in the fellow eye of 
≥ 14 mm Hg and ≤ 32 mm Hg 
14.  Central Corneal Endothelial Cell Density by specular 
microscopy:  
Updated criteria 13 and 15 because 
the study design is not paired eye 
comparison and to ease entry 
criteria related to nonstudy eye. 
 
Updated criterion 14 to make the 
automated specular microscopy 
count consistent with the Reading 
Center manual count. 
Section 
4.4 
Updated the following exclusion criterion: 
3.  Known allergy or sensitivity to theany study medication 
or its components, any component of the delivery vehicle, 
procedure-related materials, or diagnostic agents used 
during the study (eg, topical anesthetic, dilating drops, 
fluorescein)  
Revised exclusion criterion 3 for 
clarity.   
 
 
 
Removed the following original exclusion criterion: 
6.  Patients who plan for an extended absence away from 
the area of the study center that would preclude them from 
returning for all protocol-specified study visits 
Exclusion criterion 6 was deleted to 
allow flexibility when possible. 
 
Updated the following inclusion criteria: 
7.  Anticipated use of oral, intramuscular, or intravenous 
(IV) corticosteroids from 2 months prior to the Baseline 
visit through the 12th month after the last Bimatroprost SR 
or Sham administration Week 52 
 
For exclusion criterion 7, decreased 
the time to 52 weeks because it is 
difficult to predict more than 1 year 
in advance.   
 
11.  In the investigator’s opinion, patient is nonresponsive 
to topical ophthalmic beta-blockers and/or topical 
prostamides, prostaglandins, or prostaglandin analogs (eg, 
LUMIGAN, Xalatan, Travatan) 
Revised exclusion criterion 11 for 
consistency with inclusion criteria.   
 
12.  History of traumatic cataract and/or traumatic angle 
recession in either the study eye 
Revised exclusion criteria12,
 
and 16 because this is not a paired 
eye comparison design; therefore, 
history only needs to be from the 
study eye.   

 
 
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Section 
Revision 
Rationale 

 
 
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Section 
Revision 
Rationale 
Section 
4.5.1 
Revised the following:  Intermittent use of ocular 
decongestants or antihistamines is allowed if not taken 
within 2 weeksdays prior to a scheduled visit and/or ≤ 15 
minutes before or after topical administration of study 
medication. 
Added the following: Required surgical procedures may be 
performed in the fellow eye only after completion of Week 
52. 
Updated as follows: Note that in the event that the 
investigator performs an unanticipated incisional surgical 
procedure on the study eye during which ocular fluid is to 
be removed, ocular fluid/implant samples may be collected 
for analysis (see Protocol Procedure Manual for further 
details).) at the investigator’s discretion. 
Decreased to 2 days in order to 
reduce limitations on patients in a 
2-year study. 
 
Because this is not a paired eye 
comparison, the fellow eye may 
have required surgery after the 
treatment period has been 
completed.   
 
Revised  the description of ocular 
fluid collection for clarity. 
Section 
4.5.2 
Nonstudy IOP-lowering Medications 
Use of any topical ophthalmic medication containing an 
ocular antihypertensive, other than use of study medication 
(timolol) in Control group or fellow eyes, is prohibited as 
concurrent therapy in either eye during the study through 
Week 52, unless necessary for the safety of the patient due 
to inadequate control of IOP as determined by the 
investigator.  NonstudyInadequate control of IOP should be 
confirmed at a subsequent visit (scheduled or unscheduled 
visit).  Prior to Week 52 the investigator will be expected to 
attest to the need for additional nonstudy IOP -lowering 
medication for safety reasons.  After the Week 52 visit, 
nonstudy topical IOP-lowering medications will be 
permitted after the Week 52 visit, if in the investigator’s 
clinical judgment the IOP is not adequately controlled at 
two consecutive visits at least 1 week apart.  Initiation of 
medication in one eye should not automatically lead to 
initiation of medication in the other eye.  Each eye should 
be evaluated on an individual basis when determining the 
need for additional non-study IOP-lowering medications.  If 
nonstudy IOP lowering medication is initiated prior to 
Week 52, the investigator will be expected to attest to the 
need for additional non-study IOP- lowering medication for 
safety reasons for each eye individually.  
Contact Lenses 
Use of soft contact lenses within 3 days and use of rigid gas 
permeable or hard contact lenses within 1 week prior to a 
scheduled study visit or Administration Day, or use of 
contact lenses of any kind within 1 week following any 
Bimatoprost SR (or Sham) administration in either eye is 
prohibited. 
Contact lenses should be removed prior to instilling any 
study-provided eye drops and patients should wait at least 
15 minutes before putting contact lenses back in the eyes 
Updated text for clarity. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Updated text for clarity and to 
reduce limitations for patients who 
use contact lenses.   
 

 
 
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Section 
Revision 
Rationale 
after instilling topical drops. 
Other Medications 
• 
Surgical procedures that are not related to Bimatoprost 
SR (or sham) administration procedures in either eye 
the study eye.  (Surgical procedures are allowed in the 
fellow eye after Week 52 as described in Section 4.5.1) 
• 
Use of any nonstudy topical ophthalmic medications 
(except as described above and in Section 4.5.1) in 
either eye 
• 
Use of soft contact lenses within 1 week and use of 
rigid gase permeable or hard contact lenses within 2 
weeks prior to a scheduled study visit, or use of contact 
lenses of any kind within 2 weeks following any 
Bimatroprost SR (or Sham) administration in either eye 
Section 
4.5.3 
For women of childbearing potential who may participate in 
the study, the following methods of contraception, if 
properly used, are generally considered reliable:  hormonal 
contraceptives (ie, oral, patch, injection, implant), male 
condom with intravaginal spermicide, diaphragm or 
cervical cap with spermicide, vaginal contraceptive ring, 
intrauterine device, surgical sterilization (bilateral tubal 
ligation, bilateral salpingectomy), vasectomized partner, or 
true sexual abstinence, when this is in line with the 
preferred and usual lifestyle of the subject. 
 
Updated text for clarity. 

 
 
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Section 
5.6.1 
Patients who have received nonstudy topical IOP- lowering 
medication (prohibited before Week 52 unless required for 
safety reasons due to inadequate IOP control and attested to 
by the investigator) in a Bimatoprost SR study eye will 
receive Sham administration in that eye on the Bimatoprost 
SR repeat administration day(s). 
 
Patients who use nonstudy IOP-lowering medication 
(prohibited before Week 52 unless required for safety 
reasons due to inadequate IOP control and attested to by the 
investigator) in only one eye will be followed for the 
duration of the study. 
 
Updated text for clarity.   
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Section 
6.2 
Biomicroscopic Examination:  Biomicroscopic 
examinations will be performed using a slit lamp.  The 
examinations will include evaluation of the condition of the 
eyelids, conjunctiva, cornea, AC, iris/pupil, and lens 
(through a dilated pupil). 
Lens Assessment (Phakic Eyes Only):  Biomicroscopic 
findings will be evaluated for the presence and severity of 
nuclear, cortical, and posterior subcapsular lens opacities.  
See the Protocol Procedure Manual for further details. 
Specular Microscopy:  Endothelial cell density will be 
assessed using specular microscopy performed on the 
central cornea at all sites.  The final qualification of central 
endothelial cell density for study entry will be determined 
by the Reading Center based on manual specular 
microscopy analysis..  Qualification will remain valid for 
1 year after Screening in patients who are not enrolled at the 
time of Screening, if in the investigator’s opinion there have 
been no clinically significant changes occurring in the eye 
(eg, ocular surgery) during that time.  All additional 
specular microscopy images taken during the study will be 
assessed by the Reading Center.  See the Protocol 
Procedure Manual for further details.  The same instrument 
should be used throughout the study for a given patient. 
Anterior Segment Optical Coherence Tomography 
(AS-OCT):  AS-OCT measurements will be performed at 
all sites as a criterion for inclusion and a Reading Center 
will be used to confirm patient iridocorneal angle size and 
determine eligibility.  Each patient’s iridocorneal angle 
eligibility is valid for the duration of the study; however, if 
in the investigator’s opinion the patient’s angle size may 
have changed, an unscheduled AS-OCT may be performed 
prior to retreatment.  Qualification will remain valid for 
1 year after Screening in patients who are not enrolled at the 
Updated text for clarity.  Defined a 
time frame and requirements for the 
validity of the qualifications 
provided by the Reading Center. 

 
 
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time of Screening, if in the investigator’s opinion there have 
been no clinically significant changes occurring in the eye).  
See the OCT Image Acquisition manuals from the Reading 
Center for further details on the use of OCT.  In the event 
that the AS-OCT type as specified in the manuals is not 
available, a suitable alternative may be approved by 
Allergan and the designated Reading Center for use.  The 
same instrument should be used throughout the study for a 
given patient. 
Section 
8.3 
Reading Center qualification of angle must be confirmed by 
the completion of Screening and endothelial cell density 
must be confirmed by the Baseline visit.  
Updated text for clarity. 
Section 
8.4 
Ocular examination procedures should be performed in the 
order listed at each visit.  Some flexibility in procedure 
order is allowed.  However, the general flow of 
examinations set forth in the schedule starting with  
noncontact examinations, followed by IOP, followed by 
contact examinations, and followed by dilation and post-
dilation activities should be maintained.  Intraocular 
pressure should be measured at approximately the same 
time of day at each visit.  Hour 0 (H0) is 8 AM ± 1 hour and 
Hour 2 (H2) is 2 hours after Hour  0  (± 30  minutes).  
Study-provided eye drop medications should be 
administered immediately after performing the Hour 0 IOP 
measurements.  All IOP measurements for a given visit day 
must be completed prior to performing any examination 
procedures that require pupil dilation. 
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Section 
8.8 
Patients who have received nonstudy IOP-lowering 
medication in both eyes, or who do not complete an 
Administration Day visit, may discontinue the study 12 
months after the last Bimatoprost SR or Sham 
administration. at which time they should complete the 
Month 20/Exit visit procedures. 
Updated text for clarity. 
Section 
8.9 
After the first administration (or Sham), failure to undergo 
an Administration visit does not indicate total withdrawal 
from the study.  Patients who have received nonstudy 
IOP-lowering medication in only one eye will be followed 
for the duration of the study.  Patients who have received 
nonstudy IOP-lowering medication in both eyes, or patients 
who do not undergo Cycle 2 or 3 (or both) administrations 
(or Sham administrations), will still be followed for 12 
months after the last Bimatoprost SR or Sham 
administration for safety reasons.  These patients are 
eligible for Early Discontinuation (Early Exit) as described 
in Section 8.8, above. 
•Patient develops (or has an exacerbation of) a medical 
condition that, in the opinion of the investigator, would 
putcompromises the patient at an unacceptable medical risk 
by continuingpatient’s ability to participate in the study 
participation 
If a patient develops (or has an exacerbation of) a medical 
condition that, in the opinion of the investigator, would put 
the patient at an unacceptable medical risk by continuing 
study participation, the patient will be withdrawn from the 
study. 
Updated text for clarity, as in this 
study design, patients are followed 
for 12 months after their last 
injection (or Sham) for safety 
purposes, and cessation of injection 
does not constitute study 
withdrawal. 

 
 
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12.3.2 
Amendment 2 
Title: The Efficacy and Safety of Bimatoprost SR in Patients With Open-angle Glaucoma or 
Ocular Hypertension 
Protocol 192024-092 Amendment 2 
Date of Amendment: March 2017 
Amendment Summary 
This summary includes changes made to Protocol 192024-092 Amendment 1 (approved 
August 2015). This protocol was amended to change the screening requirement for angle 
eligibility confirmation in the study eye, modify/clarify the inclusion/exclusion criteria, 
clarify the statistical analyses, and change additional procedures for patients with sickle cell 
disease from required to optional. 
Following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes. Minor editorial and document formatting 
revisions have not been summarized. 
Section 
Revision 
Rationale 
Protocol 
Summary 
Removed text from the visit schedule section referring to 
reading center confirmation of iridocorneal angle: 
• 
Screening (up to 28 days); Washout period of up to 
42 days for both eyes (which may begin once 
screening procedures have been completed and the site 
has obtained confirmation of anterior segment optical 
coherence tomography [AS-OCT] iridocorneal angle 
qualification from the Reading Center); Baseline 
(Days -3 to -1 up to 3 days) 
Updated the following key inclusion criteria: 
• 
The iridocorneal angle in the study eye must be 
independently confirmed as being qualified by 
Reading Center AS-OCT assessment 
2 ophthalmologists using the following criteria: 
a. 
Shaffer Grade ≥ 3 on clinical gonioscopy of 
the inferior angle 
b. Peripheral anterior chamber depth by Van 
Herick examination ≥ 1/2 corneal thickness 
Note: The independent eligibility assessments must 
both agree that the Shaffer grade is ≥ 3 and the Van 
Herick grade is ≥ 1/2 corneal thickness. 
• 
At the Baseline visit: Hour 0 IOP in the study eye of 
≥ 22 mm Hg and ≤ 32 mm Hg, and in the fellow eye of 
Updated to reflect changes in the 
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≥ 17 mm Hg and ≤ 32 mm Hg, with difference 
between eyes of ≤ 5 mm Hg 
• 
At the Baseline visit: Hour 2 IOP in the study eye of 
≥ 19 mm Hg and ≤ 32 mm Hg, and in the fellow eye of 
≥ 14 mm Hg and ≤ 32 mm Hg 
• 
By the Baseline visit, the final central endothelial cell 
density in both eyes must be confirmed as being 
qualified by Reading Center assessment, with at least 
one eye qualified for inclusion as the study eye 
Updated the following key exclusion criterion: 
• 
The following surgical history: 
a. 
History or evidence of complicated cataract 
surgery in the study eye: eg, surgery resulting in 
complicated lens placement (such as anterior 
chamber intraocular lens implant (IOL); phakic 
IOL; sulcus IOL; aphakia, etc) or intraoperative 
complications (eg such as a posterior capsular tear 
[with or without vitreous loss], substantial iris 
trauma, etc) 
Note: history of uncomplicated cataract surgery is 
not an exclusion. 
b. History of phakic IOL insertion for refractive 
error correction in the study eye 
Updated the statistical analyses as follows: 
• 
Intraocular pressure change from baseline will be 
analyzed using a mixed-effects model repeated 
measures (MMRM) approach. The model will include 
the fixed effects of treatment; IOP time-matched 
change from baseline IOP stratification; visit ( as the 
response variable and treatment, timepoint (Hours 0 
and 2 at each visit of Weeks 2, 6, and 12), hour; the 
two-way interaction between treatment and each of 
hour and visit; and the three-way treatment-by-
timepoint interaction between treatment, hour, and 
visit and baseline IOP stratification as fixed effects. 
Unstructured covariance matrix will be used for 
repeated measures on the same patient; if the model 
with unstructured covariance matrix fails to converge, 
multiple imputation (MI) will be implemented before 
MMRM. 
• 
For the United States Food and Drug Administration 
(US FDA), the primary efficacy variable will be the 
study eye time-matched IOP.  The primary analysis 
will be based on Weeks 2, 6, and 12 using the ITT 
population.  Specifically, the following analysis will be 
performed:  time-matched IOP will be analyzed using 
an MMRM approach based on the same model as 
described for the primary efficacy analysis of time-
matched IOP change from baseline.   
• 
Sample Size Calculation:  The sample size calculation 
is based on the primary efficacy analysis of the 

 
 
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time-matched IOP for US FDA review because the 
sample size based on the primary efficacy analysis for 
other regions is expected to be smaller. 
Section 
1.3.1 
Nonclinical studies with pharmacology endpoints (Reports 
BIO-09-803, BIO-11-920, PK09109-PK, BIO-09-785) 
showed dose-related reductions in IOP in normotensive 
Cynomolgus monkeys and Beagle dogs, as well as in laser-
induced ocular hypertensive Cynomolgus monkeys 
following single doses.  Toxicology studies, of at least 6 to 
12 months duration and including single and repeat 
Bimatoprost SR administration, were conducted in 
Cynomolgus monkeys and Beagle dogs (TX09051-TX, 
TX09066-TX, TX10016-TX, TX11076-TX, TX12012-TX, 
TX12018-TX, and TX12102-TX-I1 [ongoing]).  Monkeys, 
which have a characteristically small anterior chamber 
angle compared to both dogs and humans, did not tolerate 
Bimatoprost SR dose strengths tested (≥ 10 µg Bimatoprost 
SR) due to chronic contact of the implant with corneal 
endothelium.  Single and repeat ocular toxicity studies with 
Generation 2 Bimatoprost SR in dogs with varying AC 
angle sizes demonstrated acceptable safety and ocular 
Updated information from 
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tolerability with single doses ≤ 20 µg (TX11076 TX, 
TX12012-TX, TX12018-TX) and with repeat doses of 
≤ 15 µg (TX12012 TX, TX12018-TX).  Furthermore, no 
adverse drug- or implant-related ocular findings have been 
seen following three intracameral injections of up to 20 µg 
(two 10 µg implants) Bimatoprost SR (9 month timepoint 
including histopathology) in the ongoing 18-month repeat 
dose Good Laboratory Practice (GLP) study in dogs 
(Report TX12102 TX). 
Pharmacokinetic studies (PK09109 PK, PK11086-PK) in 
Beagle dogs demonstrated that systemic exposure of 
bimatoprost and bimatoprost acid was below the limit of 
quantitation (BLQ) with doses ≤ 60 µg.  Aqueous humor 
concentrations generally peaked by 10 weeks postdose for 
doses ≤ 30 µg (Generation 1 and Generation 2), then 
declined to low levels suggestive of near-complete drug 
release from the device at 3 months for doses ≤ 20 µg.  By 
14 weeks following a 20 µg (Generation 2) dose, ocular 
tissues samples were collected for analysis, which 
demonstrated that drug and metabolite concentrations were 
BLQ in aqueous humor, vitreous humor, retina, and the 
remnant implants, but detected in cornea, choroid, and iris-
ciliary body. A pharmacokinetic study (PK14025-PK) was 
conducted in Beagle dogs comparing the ocular distribution 
of topical bimatoprost 0.03% solution or a single 
Generation 2 Bimatoprost SR implant (15 µg).  Following 
topical administration, bimatoprost and bimatoprost acid 
distributed into the iris-ciliary body as well as other (off 
target) tissues with concentrations in the bulbar 
conjunctiva, eyelid margin, and periorbital fat significantly 
higher than those observed in the iris-ciliary body. In 
contrast, following administration of a single Generation 2 
Bimatoprost SR implant at 15 µg, bimatoprost and 
bimatoprost acid concentrations were either below the limit 
of quantitation (BLQ) or near the detection limit in bulbar 
conjunctiva, eyelid margin, and periorbital fat while the 
highest bimatoprost and bimatoprost acid concentrations 
were observed in the target tissue, the iris ciliary body. 
Retinal concentrations were BLQ following both topical 
and Bimatoprost SR administration. 
Section 
1.3.3 
Study 192024-041D is an ongoing was a Phase 1/2, paired-
eye comparison evaluating the safety and efficacy of 4 dose 
strengths of Bimatoprost SR (6 µg, 10 µg, 15 µg, or 20 µg 
[2 × 10 µg implants]), as single or repeat administration in 
one eye (study eye), versus the use of topical LUMIGAN® 
0.03% in the fellow eye (nonstudy eye).  The objective of 
this study is was to evaluate the safety and IOP-lowering 
efficacy of Bimatoprost SR in patients with OAG. 
As of March 2015, a total of 109 patients had received a 
single administration; and as of June 2015, 24 patients had 
received a repeat administration of Bimatoprost SR.  Based 
on a review of the efficacy data as of March 2015, a A 
trend in dose response has been was observed across the 4 
Updated information from recently 
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dose strengths that were tested.  Available d Data suggest 
that the implant may provide topical prostaglandin analog-
like efficacy up to 3 to 4 months post-implantation in the 
majority of patients.  Data following the second 
administration in the redosed patients showed similar IOP 
lowering to that observed following the first administration 
of Bimatoprost SR.  
As of March 2015, Bimatoprost SR has shown showed an 
acceptable safety profile with single and repeat 
administrations in ongoing s Study 192024-041D.  Most 
adverse events were ocular, mild or moderate in severity, 
occurred within the first 8 2 days after Bimatoprost SR 
administration, and were considered related to the study 
drug administration procedure.  There have been were no 
reports of serious study drug-related adverse events, and no 
new safety concerns have been were observed after the 
second treatment.  Please refer to the Investigator’s 
Brochure for details on reported safety findings. 
Section 
4.2 
The study population consists of patients with OAG or 
OHT and an open iridocorneal angle inferiorly by clinical 
gonioscopy in the study eye, and OAG or OHT in the 
fellow eye, where both eyes require IOP-lowering 
medication.  The eye that meets the entry criteria 
(Sections 4.3 and 4.4) will be selected as the study eye.  If 
both eyes meet the entry criteria (including iridocorneal 
angles that have been confirmed as qualified by the 
Reading Center anterior segment optical coherence 
tomography [AS-OCT assessment]), the eye with the 
higher IOP at Baseline Hour 0 will be selected as the study 
eye.  If both eyes have the same IOP, then the right eye will 
be designated as the study eye. 
Angle qualification will be independently confirmed as 
being qualified by 2 ophthalmologists, and endothelial cell 
density qualification for study entry will be determined by 
the Reading Center based on AS-OCT and specular 
microscopy assessment respectively (see Protocol 
Procedure Manual for details). 
Revised for consistency with 
updated inclusion criteria 
Section 
4.2.1 
4.2.1 
Patients With Sickle Cell Trait or Disease 
At screening all patients will be tested for sickle cell trait or 
disease.  Patients with sickle cell trait or disease (or other 
hemoglobinopathies) may be enrolled at the discretion of 
the investigator based on an individual risk-benefit 
assessment.  Because of a slightly higher risk of IOP 
elevation and intraocular complications in the setting of a 
microhyphema, patients with these disorders must may 
undergo optional additional safety monitoring 
(biomicroscopy and IOP measurements) after 
injection/Sham injection at the investigator’s discretion (as 
outlined in see Section 8.4).  Additional information about 
the Bimatoprost SR experience in patients with sickle trait 
is provided in the Investigator’s Brochure. 
Based on the ongoing safety 
monitoring of the 192024-091 and 
192024-092 studies, no increased 
risk of hyphema or microhyphema 
with sickle cell traits or sickle cell 
disease is confirmed. There are 
400+ patients had at least one 
Bimatoprost SR injection in the 
2 studies (estimated based on 1:1:1 
ratio), there is only one report of 
microhyphema in a NON-sickle cell 
patient. No anterior chamber safety 
concerns reported in the 14 sickle 
cell or traits patients. 
Section 
10. The iridocorneal angle in the study eye inferiorly in 
Inclusion criterion for angle 

 
 
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4.3 
both eyes must be open based on clinical gonioscopic 
examination independently confirmed as being qualified by 
2 ophthalmologists using the following criteria: 
a. Shaffer Grade ≥ 3 on clinical gonioscopy of the inferior 
angle 
b. Peripheral anterior chamber depth by Van Herick 
examination ≥ 1/2 corneal thickness 
Note: The independent eligibility assessments must both 
agree that the Shaffer grade is ≥ 3 and the Van Herick 
grade is ≥ 1/2 corneal thickness. 
11. Iridocorneal angle in the study eye must be confirmed 
as being qualified by Reading Center AS-OCT assessment 
13 12a. Hour 0 IOP in the study eye of ≥ 22 mm Hg and 
≤ 32 mm Hg, and in the fellow eye of ≥ 17 mm Hg and 
≤ 32 mm Hg, with difference between eyes of ≤ 5 mm Hg 
13 12b. Hour 2 IOP in the study eye of ≥ 19 mm Hg and 
≤ 32 mm Hg, and in the fellow eye of ≥ 14 mm Hg and 
≤ 32 mm Hg 
14 13b. By Baseline:  final central endothelial cell density 
in both eyes must be confirmed as being qualified by 
Reading Center assessment, with at least one eye qualified 
for inclusion as the study eye 
assessment revised to use clinical 
measures in order to develop a 
more “real-life” measure of angle 
openness.  
 
 
 
 
 
 
 
Lower limit of IOP in fellow eye 
removed to allow for flexibility in 
enrollment. Fellow eye IOP upper 
limit is required for safety purposes, 
but lower limit is not included in 
analysis. 
 
Revised for clarity; at least one eye 
needs to be qualified as study eye 
for patient to be included in the 
study. 
Section 
4.4 
9. Previous enrollment in another Allergan Bimatoprost SR 
Study 192024-041D 
12. History or evidence of a clinically relevant, substantial 
ocular trauma (eg, a traumatic cataract, and/or traumatic 
angle recession, etc) in the study eye 
13. The following surgical history: 
a. History or evidence of complicated cataract surgery in 
the study eye: eg, surgery resulting in complicated lens 
placement (such as anterior chamber intraocular lens 
implant ([IOL]);, phakic IOL;, sulcus IOL;, aphakia;, etc) 
or intraoperative complications (eg, such as a posterior 
capsular tear [with or without vitreous loss], iris trauma, 
etc). Note: history of uncomplicated cataract surgery is not 
an exclusion. 
b. History of phakic IOL insertion for refractive error 
correction in the study eye 
Revised because multiple studies 
are ongoing. 
Revised for clarity. 
 
 
Revised for clarity 
 
 
 
 
 
 
 

 
 
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Section 
5.3 
The site coordinator and designated staff will not be 
masked to whether the patient received 1 of the 2 dose 
strengths of Bimatoprost SR or the Sham administration 
procedure, but will be masked to the specific implant dose 
strength.  The patient and the remaining staff will be 
masked to the patient’s treatment assignment.  Efficacy 
IOP measurements will be masked by using a 2-person 
reading method as described in Section 6.1.1 (for optional 
postoperative IOP measurements for patients with sickle 
cell disease or trait [or other hemoglobinopathies], see 
Section 8.4). 
Based on the ongoing safety 
monitoring of the 192024-091 and 
192024-092 studies, no increased 
risk of hyphema or microhyphema 
with sickle cell traits or sickle cell 
disease is confirmed. There are 
400+ patients had at least one 
Bimatoprost SR injection in the 
2 studies (estimated based on 1:1:1 
ratio), there is only one report of 
microhyphema in a NON-sickle cell 
patient. No anterior chamber safety 
concerns reported in the 14 sickle 
cell or traits patients. 
Section 
5.9.4 
Note:  Patients with sickle cell disease or trait (or other 
hemoglobinopathies) will be expected to may undergo 
optional biomicroscopy and IOP examination in both eyes 
4 hours after each Bimatoprost SR administration (or Sham 
administration).  This optional IOP examination is for 
postoperative purposes only, and as such does not require a 
masked, 2-person reading method.  The IOP should be 
taken only once to avoid excessive postadministration (or 
Sham administration) manipulation of the eye, and should 
be taken by the investigator (or other unmasked, qualified 
personnel).  This postadministration (or Sham 
administration) examination may be performed using a 
Goldmann applanation tonometer or a hand-held 
tonometer.  (See the Study Procedure Manual for details.) 
Based on the ongoing safety 
monitoring of the 192024-091 and 
192024-092 studies, no increased 
risk of hyphema or microhyphema 
with sickle cell traits or sickle cell 
disease is confirmed. There are 
400+ patients had at least one 
Bimatoprost SR injection in the 
2 studies (estimated based on 1:1:1 
ratio), there is only one report of 
microhyphema in a NON-sickle cell 
patient. No anterior chamber safety 
concerns reported in the 14 sickle 
cell or traits patients. 
Section 
6.2 
Hematology, blood chemistry, and urinalysis:  Blood and 
urine samples will be collected for blood chemistry and 
hematology panels (including sickle cell testing by local 
laboratories) and urinalysis. 
Based on the ongoing safety 
monitoring of the 192024-091 and 
192024-092 studies, no increased 
risk of hyphema or microhyphema 
with sickle cell traits or sickle cell 
disease is confirmed. There are 
400+ patients had at least one 
Bimatoprost SR injection in the 
2 studies (estimated based on 1:1:1 
ratio), there is only one report of 
microhyphema in a NON-sickle cell 
patient. No anterior chamber safety 
concerns reported in the 14 sickle 
cell or traits patients. 
 
Visual Acuity:  Visual acuity tests will be performed at all 
scheduled visits except on any of the 3 administration days.  
Manifest refraction using Snellen equivalent with a logMar 
Revised for consistency with 
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chart (see Protocol Procedure Manual) will be performed at 
Screening;, Baseline;, Weeks 12, 28, 44, and 52;, and 
Month 20/Exit. 
Gonioscopy: Gonioscopic examination for eligibility at 
Screening (only) will be independently performed by 
2 ophthalmologists as described in the Protocol Procedure 
Manual. The independent eligibility assessors should not 
share their assessments with each other until the assessment 
is recorded. The 2 ophthalmologists’ independent 
eligibility assessments must confirm patient eligibility for 
participation in the study. Subsequent gonioscopic 
examinations will be performed by the study investigator. 
Pachymetry:  Corneal thickness using ultrasound (contact) 
pachymetry will be performed on the central cornea at all 
sites..  The same instrument should be used throughout the 
study for a given patient.  Contact pachymetry willmay be 
performed any time after the Hour 2 IOP Measurement and 
before gonioscopymeasurement.  See the Protocol 
Procedure Manual for further details. 
Anterior Segment Optical Coherence Tomography 
(AS-OCT):  AS-OCT measurements will be performed at 
all sites as a criterion for inclusion and a Reading Center 
will be used to confirm patient iridocorneal angle size and 
determine eligibility.  Each patient’s iridocorneal angle 
eligibility is valid for the duration of the study; however, if 
in the investigator’s opinion the patient’s angle size may 
have changed, an unscheduled AS-OCT may be performed 
prior to retreatment.  Qualification will remain valid for 1 
year after Screening in patients who are not enrolled at the 
time of Screening, if in the investigator’s opinion there 
have been no clinically significant changes occurring in the 
eye) and a Reading Center will be used to examine angle 
size for investigational purposes.  See the OCT Image 
Acquisition manuals from the Reading Center for further 
details on the use of OCT.  In the event that the AS-OCT 
type as specified in the manuals is not available, a suitable 
alternative may be approved by Allergan and the 
designated Reading Center for use.  The same instrument 
should be used throughout the study for a given patient. 
 
 
Revised for consistency with 
revised eligibility criteria 
 
 
 
 
 
Revised for consistency with visit 
schedule 
 
 
 
 
Revised for consistency with 
updated eligibility criteria 
Section 
6.4.3.1 
The blood tests performed at the screening visit will 
include testing for sickle cell disease or trait by a site-
selected and qualified local laboratory, as outlined in the 
Protocol Procedure Manual. 
Based on the ongoing safety 
monitoring of the 192024-091 and 
192024-092 studies, no increased 
risk of hyphema or microhyphema 
with sickle cell traits or sickle cell 
disease is confirmed. There are 
400+ patients had at least one 
Bimatoprost SR injection in the 
2 studies (estimated based on 1:1:1 
ratio), there is only one report of 
microhyphema in a NON-sickle cell 
patient. No anterior chamber safety 
concerns reported in the 14 sickle 
cell or traits patients. 

 
 
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Section 7 
Three database locks are planned.  The first database lock 
will take place after all patients have completed or 
prematurely discontinued before the Week 12 visit.  
Similarly, the database will be locked after all patients have 
completed or prematurely discontinued before Week 52 
and Month 20/Exit.  Analyses will be performed after each 
lock.  Prior to the first database lock a detailed analysis 
plan will be finalized.  To maintain the integrity of the 
ongoing study, Allergan study personnel who are directly 
involved in data handling and supporting the trial (such as 
the clinical study team) will remain masked to treatment 
assignment of individual patients until during the study 
completion. To avoid potential data unmasking between 
locks and to protect trial integrity, study statistical 
personnel who have been unmasked after each lock will no 
longer be involved directly in any ongoing masked study 
conduct. Another statistician, who is still masked to study 
treatment, will assume these responsibilities until the next 
lock. Unmasked data handling and appropriate data and 
results access will be specified prior to each lock. 
Updated text for clarity. 
Section 
7.2 
To avoid confounding of efficacy data, IOP measurements 
obtained after initiating the use of nonstudy IOP-lowering 
medication in an eye will be treated as missing for that eye 
excluded from the calculation of the summary statistics and 
the statistical analyses for that eye but raw values will be 
presented in the listings. 
Updated text for clarity. 
Section 
7.3.1 
Intraocular pressure change from baseline will be analyzed 
using a mixed-effects model repeated measures (MMRM) 
approach.  The model will include the fixed effects of 
treatment; IOP time-matched change from baseline IOP 
stratification; visit (as the response variable and treatment, 
timepoint (Hours 0 and 2 at each visit of Weeks 2, 6, and 
12); hour; the two-way, treatment-by-timepoint interaction, 
between treatment and each of hour and visit; and the 
three-way interaction between treatment, hour, and visit 
baseline IOP stratification as fixed effects. Unstructured 
covariance matrix will be used for repeated measures on 
the same patient; if the model with unstructured covariance 
matrix fails to converge, multiple imputation (MI) will be 
implemented before MMRM.  The details of the model 
specifications will be provided in the analysis plan. 
Updated text for clarity. 
Section 
7.3.2 
Secondary efficacy analyses comparing each Bimatoprost 
SR dose strength and timolol to test the no-difference null 
hypothesis will be performed at scheduled visits (Weeks 2, 
6, and 12) and hours for (1) time-matched IOP and (2) 
time-matched IOP change from baseline. 
The analysis of time-matched IOP will be similarly 
performed as described above with time matched IOP 
replacing time-matched IOP change from baseline in the 
analysis model. 
Updated text for clarity. 

 
 
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Section 
Revision 
Rationale 
Section 
7.6 
For the US FDA review, the primary efficacy variable will 
be the study eye time-matched IOP. 
For each Bimatoprost SR dose strength which demonstrates 
efficacy (clinical noninferiority) as described in the 
primary efficacy analyses, secondary efficacy analyses 
comparing the Bimatoprost SR dose strength and timolol to 
test the no-difference null hypothesis will be performed at 
scheduled visits (Weeks 2, 6, and 12) and hours for time-
matched IOP. 
Updated text for clarity. 
Section 
7.7 
The sample size calculation is based on the primary 
efficacy analysis of the time-matched IOP for US FDA 
review since the sample size based on the primary efficacy 
analysis for other regions is expected to be smaller. 
Updated text for clarity. 
Section 
8.2 
Patients currently being treated with IOP-lowering 
medication(s) in either eye will begin washout of these 
medication(s) following completion of the screening 
procedures and Reading Center confirmation of AS-OCT 
iridocorneal angle qualification. 
Revised for consistency with 
revised inclusion criterion 
 
 
Section 
8.3 
Reading Center qualification of angle must be confirmed 
by the completion of Screening and endothelial cell density 
must be confirmed by the Baseline visit. 
Revised for consistency with 
revised inclusion criterion 
 

 
 
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Section 
Revision 
Rationale 

 
 
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12.3.3 
Amendment 3 
Title: The Efficacy and Safety of Bimatoprost SR in Patients With Open-angle Glaucoma or 
Ocular Hypertension 
Protocol 192024-092 Amendment 3 
Date of Amendment: June 2018 
Amendment Summary 
This summary includes changes made to Protocol 192024-092 Amendment 2 (approved 
March 2017). This protocol was amended to reduce the sample size. 
Following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes. Minor editorial and document formatting 
revisions have not been summarized. 
Section 
Revision 
Rationale 
Title Page 
Change in Allergan signatory 
Personnel change 
Protocol 
Summary 
Number of Patients: Approximately 600 510 patients 
will be enrolled in the study. 
Sample Size Calculation: The sample size calculation 
is based on the primary efficacy analysis of the IOP for 
US FDA review because the sample size based on the 
primary efficacy analysis for other regions is expected 
to be smaller. Based on simulations, a sample size of 
540 486 patients (180 162 per group) will provide 
approximately 95 95.1% and 81 83.5% power to show 
noninferiority (NI) of Bimatoprost SR 15 µg and 
Bimatoprost SR 10 µg, respectively, to timolol at all 6 
scheduled timepoints based on an NI margin of 1.5 
mm Hg and at 3 or more timepoints based on an NI 
margin of 1.0 mm Hg. Assuming a premature 
discontinuation rate of 10 5% within 12 weeks (before 
the primary database lock), approximately 600 510 
patients (200 170 per group) are to be enrolled into this 
study. 
Updated to reflect changes in the 
body of the protocol. 
Section 
4.1 
Enrollment of approximately 600 510 patients in total 
at approximately 180 sites, with approximately 200 
170 patients per group, is planned to ensure 180 
162 completed patients per group, assuming a 
premature discontinuation rate of 10 5%. 
Revised based on new sample size 
calculation 

 
 
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Section 
Revision 
Rationale 
Section 
7.7 
The initial sample size is was estimated based on a 
2-sided t-test with α = 0.05 at each timepoint and the 
assumption that the mean IOP difference between 
Bimatoprost SR 10 µg and timolol is -0.25 mm Hg (ie, 
Bimatoprost SR 10 µg is 0.25 mm Hg better in IOP-
lowering than timolol) at Weeks 2 and 6 and 0 mm Hg 
at Week 12, with a common standard deviation of 4.0 
mm Hg and a common within-subject correlation of 
0.6.  It is was also assumed that the efficacy 
(IOP-lowering effect) of Bimatoprost SR 15 µg is 
better than that of Bimatoprost SR 10 µg by 0.25 mm 
Hg at each timepoint (Hours 0 and 2).  These 
assumptions are were made at the study design phase 
based on the data obtained from the ongoing clinical 
study 192024-041D. Based on simulations, a sample 
size of 540 patients (180 per group) will would provide 
approximately 95% and 81% power to show 
noninferiority (NI) of Bimatoprost SR 15 µg and 
Bimatoprost SR 10 µg, respectively, to timolol at all 6 
scheduled timepoints based on an NI margin of 1.5 
mm Hg and at 3 or more timepoints based on an NI 
margin of 1.0 mm Hg.  Assuming a premature 
discontinuation rate of 10% within 12 weeks (before 
primary database lock), approximately 600 patients 
(200 per group) are were to be enrolled into this study. 
As part of ongoing centralized data monitoring of 
masked study data, some of the initial assumptions 
used for sample size calculation have been revisited. 
The rate of discontinued or rescued patients in the first 
12 weeks is approximately 5%, which was less than 
the rate of 10% assumed at the study design phase. 
Furthermore, the masked common IOP variability 
(pooled standard deviation across treatments and 
timepoints) is approximately 3.8 mm Hg, which was 
also less than the assumed 4.0 mm Hg at the study 
design phase. With the updated assumption on the 
common IOP standard deviation of 3.8 mm Hg, a 
sample size of 486 patients (162 per group) would 
provide approximately 95.1% and 83.5% power to 
show NI of Bimatoprost SR 15 µg and Bimatoprost SR 
10 µg, respectively, to timolol at all 6 scheduled 
timepoints based on an NI margin of 1.5 mm Hg; and 
at 3 or more timepoints based on an NI margin of 1.0 
mm Hg. With the updated premature discontinuation 
or rescue rate of 5% within 12 weeks, approximately 
510 patients (170 per group) are to be enrolled into this 
study. 
Revised because the observed 
discontinuation rate and IOP 
variability are lower than initially 
assumed 
 

 
 
Approval Date: 
 
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ALLERGAN 
 
 
 
 
 
 
 
 
 
Date (DD/MMM/YYYY)/Time (PT) 
Signed by: 
Justification 
  
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
     
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
 
Protocol 192024-092 Amd 3
05-Jun-2018 11:22 GMT-070
Clinical Development Approval