Clinical trial NCT02636946
Conditions: Glaucoma Open-Angle Ocular Hypertension
Sponsor: Allergan
Start date: 2016-02-24; Completion date: 2021-01-26
Enrollment: 144 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the intraocular pressure (IOP)-lowering effect and safety of Bimatoprost SR compared with selective laser trabeculoplasty in participants with open-angle glaucoma or ocular hypertension who are not adequately managed with topical IOP-lowering medication for reasons other than medication efficacy (e.g., due to intolerance or nonadherence).

Detailed description:

Arms: arm 1: Primary Eye: Selective Laser Trabeculoplasty (SLT) administered on Day 1 followed by up to three Sham Bimatoprost sustained release (Bim SR) administrations at Day 4 (Cycle 1), Weeks 16 (Cycle 2) and 32 (Cycle 3) or two Sham Bimatoprost SR administrations at Day 4 (Cycle 1) and Week 16 (Cycle 2) for participants who were enrolled under Protocol Amendment 2 or later.

Contralateral (Other) Eye: Sham SLT administered on Day 1 followed by up to three Bimatoprost SR 15 μg administrations at Day 4 (Cycle 1), Weeks 16 (Cycle 2) and 32 (Cycle 3) or two Bimatoprost SR 15 μg administrations at Day 4 (Cycle 1) and Week 16 (Cycle 2) for participants enrolled under Protocol Amendment 2 or later. arm 2: Primary Eye: Sham SLT administered on Day 1 followed by up to three Bimatoprost SR 15 μg administrations at Day 4 (Cycle 1), Weeks 16 (Cycle 2) and 32 (Cycle 3) or two Bimatoprost SR 15 μg administrations at Day 4 (Cycle 1) and Week 16 (Cycle 2) for participants who were enrolled under Protocol Amendment 2 or later.

Contralateral (Other) Eye: SLT administered on Day 1 followed by up to three Sham Bimatoprost SR administrations at Day 4 (Cycle 1), Weeks 16 (Cycle 2) and 32 (Cycle 3) or two Sham Bimatoprost SR administrations at Day 4 (Cycle 1) and Week 16 (Cycle 2) for participants who were enrolled under Protocol Amendment 2 or later.
Interventions: intervention 1: Bimatoprost SR intervention 2: Sham Bimatoprost SR intervention 3: Selective Laser Trabeculoplasty intervention 4: Sham Selective Laser Trabeculoplasty
Intervention descriptions: intervention 1: Up to three Bimatoprost SR 15 micrograms (μg) administrations at Day 4, Weeks 16 and 32 (Stage 1) or two Bimatoprost SR 15 μg administrations at Day 4 and Week 16 (Stage 2). intervention 2: Up to three Sham Bimatoprost SR administrations at Day 4, Weeks 16 and 32 (Stage 1) or two Sham Bimatoprost SR administrations at Day 4 and Week 16 (Stage 2). intervention 3: Selective Laser Trabeculoplasty administered on Day 1. intervention 4: Sham Selective Laser Trabeculoplasty administered on Day 1.

Protocol documents:
Prot_000.pdf: 
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Allergan Signatory: 
Ophthalmology 
Allergan, Inc. 
 
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 IRB; US 21 CFR 312.23 
section 6(iii)b. 
 
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INVESTIGATOR SIGNATURE PAGE 
INVESTIGATOR: 
 
 
 
 
I agree to: 
• Implement and conduct this study diligently and in strict compliance with the protocol, 
good clinical practices and all applicable laws and regulations. 
• Maintain all information supplied by Allergan in confidence and, when this information 
is submitted to an Institutional Review Board (IRB), Independent Ethics Committee 
(IEC) or another group, it will be submitted with a designation that the material is 
confidential. 
• Ensure that all persons assisting with the trial are adequately informed about the protocol, 
the investigational product(s), and their trial-related duties and functions. 
I have read this protocol in its entirety and I agree to all aspects.  
 
 
 
 
 
Investigator Printed Name 
 
Signature 
 
Date 
 
 
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Table of Contents 
Table of Contents ...................................................................................................................... 4 
List of Tables ............................................................................................................................. 7 
Protocol Summary .................................................................................................................... 8 
1. 
Background and Clinical Rationale ................................................................................. 23 
1.1 
Glaucoma and Treatment ....................................................................................... 23 
1.2 
Bimatoprost (LUMIGAN®) ................................................................................... 24 
1.2.1 Nonclinical Studies with Bimatoprost SR.................................................. 25 
1.2.2 Other Biodegradable Ocular Implants ....................................................... 27 
1.2.3 Clinical Studies with Bimatoprost SR ....................................................... 27 
1.3 
Study Rationale ...................................................................................................... 28 
2. 
Study Objectives and Clinical Hypotheses ...................................................................... 29 
2.1 
Study Objectives .................................................................................................... 29 
2.2 
Clinical Hypotheses ............................................................................................... 29 
3. 
Study Design .................................................................................................................... 30 
4. 
Study Population and Entry Criteria ................................................................................ 30 
4.1 
Number of Patients ................................................................................................. 30 
4.2 
Study Population Characteristics ........................................................................... 31 
4.2.1 Patients with Sickle Cell Trait/Disease or Other Hemoglobinopathies ..... 31 
4.3 
Inclusion Criteria .................................................................................................... 31 
4.4 
Exclusion Criteria................................................................................................... 33 
4.5 
Permissible and Prohibited Medications/Treatments ............................................. 36 
4.5.1 Permissible Medications/Treatments ......................................................... 36 
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 Treatment .................................................................................................. 41 
5.3 
Methods for Masking ............................................................................................. 41 
5.4 
Treatment Allocation Ratio and Stratification ....................................................... 42 
5.5 
Method for Assignment to Treatment Groups/Randomization .............................. 42 
5.6 
Treatment Regimen ................................................................................................ 42 
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5.7 
Storage of Study Medications ................................................................................ 43 
5.8 
Preparation of Study Medications/Treatments ....................................................... 43 
5.9 
Study Treatment Administration ............................................................................ 43 
5.9.1 Bimatoprost SR Administration ................................................................. 44 
5.9.2 SLT Administration .................................................................................... 46 
6. 
Response Measures and Summary of Data Collection Methods ..................................... 47 
6.1 
Efficacy Measures .................................................................................................. 47 
6.1.1 Primary Efficacy Measure .......................................................................... 47 
6.2 
Safety Measures ..................................................................................................... 48 
6.3 
Other Measures ...................................................................................................... 50 
6.3.1 Medical History, Physical Examination, and Vital Signs........................... 51 
6.3.2 Pregnancy Testing ...................................................................................... 52 
6.3.3 Laboratory Procedures ............................................................................... 52 
6.4 
Other Study Supplies ............................................................................................. 53 
6.5 
Summary of Methods of Data Collection .............................................................. 54 
7. 
Statistical Procedures ....................................................................................................... 54 
7.1 
Analysis Populations .............................................................................................. 55 
7.2 
Collection and Derivation of Primary and Secondary Efficacy Assessments ........ 55 
7.2.1 Primary Efficacy Variable .......................................................................... 55 
7.2.2 Secondary Efficacy Variables ..................................................................... 56 
7.2.3 Other Efficacy Variables ............................................................................ 56 
7.3 
Hypothesis and Methods of Analysis ..................................................................... 56 
7.3.1 Primary Efficacy Analyses ......................................................................... 56 
7.3.2 Secondary Efficacy Analyses ..................................................................... 58 
7.3.3 Other Efficacy Analyses ............................................................................. 58 
7.3.4 Safety Analyses .......................................................................................... 59 
7.4 
Subgroup Analyses ................................................................................................. 59 
7.5 
Sample Size Calculation ........................................................................................ 59 
7.6 
Interim Analyses..................................................................................................... 60 
8. 
Study Visit Schedule and Procedures .............................................................................. 60 
8.1 
Patient Entry Procedures ........................................................................................ 61 
8.1.1 Overview of Entry Procedures ................................................................... 61 
8.1.2 Informed Consent and Patient Privacy ....................................................... 61 
8.2 
Washout Intervals ................................................................................................... 61 
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8.3 
Procedures for Final Study Entry ........................................................................... 62 
8.4 
Visits and Associated Procedures ........................................................................... 63 
8.4.1 Screening Visit ........................................................................................... 63 
8.4.2 Baseline Visit ............................................................................................. 65 
8.4.3 Treatment Period ........................................................................................ 66 
8.5 
End of Study ........................................................................................................... 76 
8.6 
Instructions for the Patients .................................................................................... 77 
8.7 
Unscheduled Visits ................................................................................................. 77 
8.8 
Compliance with Protocol ...................................................................................... 77 
8.9 
Early Discontinuation of Patients .......................................................................... 77 
8.10 Withdrawal Criteria ................................................................................................ 78 
8.11 Study Termination .................................................................................................. 78 
9. 
Adverse Events ................................................................................................................ 79 
9.1 
Definitions .............................................................................................................. 79 
9.1.1 Adverse Event ............................................................................................ 79 
9.1.2 Serious Adverse Event ............................................................................... 80 
9.1.3 Severity ...................................................................................................... 80 
9.1.4 Relationship to Study Drug, Device, or Procedure .................................... 81 
9.2 
Procedures for Reporting Adverse Events ............................................................. 81 
9.3 
Procedures for Reporting a Serious Adverse Event ............................................... 81 
9.4 
Procedures for Unmasking of Study Treatment ..................................................... 82 
10. Administrative Items ....................................................................................................... 82 
10.1 Protection of Human Patients ................................................................................ 83 
10.1.1 Compliance With Informed Consent Regulations (US 21 CFR Part 50) and 
Relevant Country Regulations ................................................................... 83 
10.1.2 Compliance With IRB or IEC Regulations ................................................ 83 
10.1.3 Compliance With Good Clinical Practice .................................................. 83 
10.1.4 Quality Assurance ...................................................................................... 83 
10.1.5 Compliance With Electronic Records; Electronic Signatures Regulations 
(US 21 CFR Part 11) .................................................................................. 84 
10.2 Changes to the Protocol ......................................................................................... 84 
10.3 Patient Confidentiality ........................................................................................... 84 
10.3.1 Patient Privacy ........................................................................................... 84 
10.4 Documentation ....................................................................................................... 85 
10.4.1 Source Documents ..................................................................................... 85 
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10.4.2 Case Report Form Completion................................................................... 86 
10.4.3 Study Summary .......................................................................................... 86 
10.4.4 Retention of Documentation ...................................................................... 87 
10.5 Labeling, Packaging, and Return or Disposal of Study Medications/Treatments . 87 
10.5.1 Labeling/Packaging .................................................................................... 87 
10.5.2 Clinical Supply Inventory .......................................................................... 87 
10.5.3 Return or Disposal of Study Medications/Treatments and/or Supplies ..... 88 
10.6 Monitoring by the Sponsor .................................................................................... 88 
10.7 Handling of Biological Specimens......................................................................... 88 
10.8 Publications ............................................................................................................ 89 
10.9 Coordinating Investigator ...................................................................................... 89 
10.10
...... 89 
11. References ........................................................................................................................ 90 
12. Attachments ..................................................................................................................... 94 
12.1 Glossary of Abbreviations ...................................................................................... 94 
12.2 Protocol Amendment Summary ............................................................................. 96 
12.2.1 Amendment 1 ............................................................................................. 96 
12.2.2 Amendment 2 ........................................................................................... 108 
12.2.3 Amendment 3 ........................................................................................... 117 
 
List of Tables 
Table 1 
Treatment Schedule by Eye .............................................................................. 9 
Table 2 
Administration Cycle 1 Schedule of Visits and Procedures:  Screening through 
Day 2 ............................................................................................................... 13 
Table 3 
Administration Cycle 1 Schedule of Visits and Procedures: Day 4 through 
Week 15........................................................................................................... 15 
Table 4 
Administration Cycle 2 Schedule of Visits and Procedures:  Week 16 through 
Week 31........................................................................................................... 17 
Table 5 
Administration Cycle 3 Schedule of Visits and Procedures (Stage 1 Patients 
Only) ............................................................................................................... 19 
Table 6 
Schedule of Visits and Procedures:  Week 36 through Week 52/Exit ............. 21 
Table 7 
Minimum Washout Period by Ophthalmic Medication Class ........................ 62 
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Protocol Summary 
 
Study Compound:  Bimatoprost sustained release (SR) implants containing preservative-free bimatoprost 
(AGN-192024) 
Phase:  3 
Study Objective:  To evaluate the intraocular pressure (IOP)-lowering effect and safety of Bimatoprost SR 
compared with selective laser trabeculoplasty (SLT) in patients with open-angle glaucoma (OAG) or ocular 
hypertension (OHT) who are not adequately managed with topical IOP-lowering medication for reasons other 
than medication efficacy (eg, due to intolerance or nonadherence)  
Clinical Hypotheses:   
Bimatoprost SR will have an IOP-lowering effect that is noninferior to that of SLT in patients with OAG or 
OHT who are not adequately managed with topical IOP-lowering medication for reasons other than medication 
efficacy (eg, due to intolerance or nonadherence). 
Bimatoprost SR administered intracamerally will have an acceptable safety profile in patients with OAG or 
OHT who are not adequately managed with topical IOP-lowering medication for reasons other than medication 
efficacy (eg, due to intolerance or nonadherence). 
Study Design 
Structure:  multicenter, paired eye, randomized, masked, conducted in 2 stages: 
• 
Stage 1:  Bimatoprost SR 15 μg vs SLT; 3 administration cycles for patients who were enrolled and 
reached the Week 32 visit prior to implementation of Amendment 2  
• 
Stage 2:  Bimatoprost SR 15 μg vs SLT; 2 administration cycles for patients who had not reached Week 32 
prior to implementation of Amendment 2; and all patients enrolled under Amendment 2. 
With implementation of Amendment 3, no new patients can be enrolled into the study and study 
treatment/retreatment of enrolled patients will not be permitted. 
Duration:  up to approximately 14 months, including screening period of up to 28 days before washout, washout 
period of up to 42 days before initial study treatment, plus 52 weeks of follow-up after initial Bimatoprost SR 
and SLT administration 
Study Treatment:  Bimatoprost SR 15 μg  
Controls:  360° SLT administration  
Dosage/Dose Regimen:   
Patients will receive a 360° administration of SLT in 1 eye on Day 1 and an administration of Bimatoprost SR 
in the contralateral eye on Day 4, with a repeat administration of Bimatoprost SR at Week 16.  Patients who 
were enrolled and reached the Week 32 visit prior to implementation of Amendment 2 received a third 
administration of Bimatoprost SR at Week 32 (Stage 1 patients).  In order to mask the patient to the treatment 
assigned to each eye, on Day 1, a sham SLT procedure will be performed in the eye that will receive 
Bimatoprost SR administrations (hereafter referred to as the “Bimatoprost SR eye”).  Similarly, a sham 
needleless Bimatoprost SR administration (hereafter referred to as the “Sham Bimatoprost SR administration”) 
that involves touching the eye at the area of insertion with a needleless applicator that does not deliver an 
implant into the anterior chamber, will be performed on the SLT-treated eye (hereafter referred to as the “SLT 
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eye”) on Bimatoprost SR administration visits.  With the implementation of Amendment 3, no further study 
treatments will be allowed. 
Treatment schedule by eye is shown in Table 1. 
Table 1 
Treatment Schedule by Eye 
Treatment Visit 
Bimatoprost SR Eye 
SLT Eye 
SLT administration 
(Day 1) 
Sham SLT 
360° SLT 
Bimatoprost SR Cycle 1 
administration 
(Day 4) 
Bimatoprost SR 
Sham Bimatoprost SR 
Bimatoprost SR Cycle 2a 
administration  
(Week 16) 
Bimatoprost SR 
Sham Bimatoprost SR 
SLT = selective laser trabeculoplasty; SR = sustained release 
aCycle 2 treatment will not be available once Amendment 3 is implemented. 
Note:  Patients who were enrolled and reached the Week 32 visit prior to implementation of Amendment 2 received a third 
administration of Bimatoprost SR at Week 32. 
 
Randomization/Stratification:  The eye with the higher IOP at Baseline will be assigned to be the primary eye.  
If baseline IOP is the same in both eyes, the right eye will be the primary eye.  The primary eye will be 
randomized to receive either Bimatoprost SR or SLT using a 1:1 ratio, stratified by primary eye baseline IOP 
( 25 or > 25 mm Hg) 
.  If the 
primary eye receives Bimatoprost SR, the contralateral eye will receive SLT.  If the primary eye receives SLT, 
the contralateral eye will receive Bimatoprost SR. 
Visit Schedule:  Patients who complete all study treatments will have a minimum of 20 visits and 5 phone calls.  
The schedule includes the following: 
• 
Screening (up to 28 days); Washout period of up to 42 days for both eyes; and Baseline visit (up to 3 days) 
• 
SLT treatment (Day 1) and phone call (Day 2)  
• 
Bimatoprost SR Cycle 1 administration (Day 4); Cycle 1 Day 2 safety visit; Cycle 1 Day 4 and Week 2 
phone calls; and follow-up study visits at Weeks 4, 8, 12, and 15 
• 
Bimatoprost SR Cycle 2 administration at Week 16; Cycle 2 Day 2 safety visit; Cycle 2 Day 4 and Week 2 
phone calls; and follow-up study visits at Weeks 20, 24, 28, and 31 (With the implementation of 
Amendment 3, patients who are enrolled and have not yet reached Week 16 will not receive Cycle 2 
administration and will continue to be followed at the scheduled follow-up visits through Week 52/Exit. 
Therefore, the Week 16 will not be required for these patients.). 
• 
Follow-up visits at Weeks 36, 40, 44, 47, and 52/Exit 
Patients who were enrolled and reached the Week 32 visit prior to implementation of Amendment 2 (Stage 1 
patients) had an additional 2 visits and 2 phone calls as follows: 
• 
Bimatoprost SR Cycle 3 administration at Week 32; Cycle 3 Day 2 safety visit; Cycle 3 Day 4 and Week 2 
phone calls   
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Intraocular pressure evaluations will occur at Hour 0 (08:00 AM ± 1 hour).  Selected patients at selected sites 
will have additional IOP measurements performed at Hour 2 (Hour 0 + 2 hours [± 30 minutes]) and Hour 8 
(Hour 0 + 8 hours [± 30 minutes]).  
 
Study Population Characteristics 
Number of Patients:  Stage 1:  approximately 40 patients; Stage 2:  approximately 120 patients 
Condition/Disease:  patients with OAG or OHT who require IOP-lowering medications in both eyes 
 
Key Inclusion Criteria:   
• 
Male or female, 18 years of age or older 
• 
Written informed consent and authorization for use and release of personal health information are 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 [United States (US) sites] 
and written Data Protection consent [European Union (EU) sites]) 
• 
In the investigator’s opinion, patient’s IOP is not adequately managed with topical medication for reasons 
other than medication efficacy (eg, due to intolerance or nonadherence) 
Ocular 
• 
In the investigator’s opinion, both eyes can be treated adequately with topical prostamide, prostaglandin, or 
prostaglandin analog (eg, LUMIGAN, Xalatan®, Travatan®) eye drops as the sole therapy if medication 
was taken as directed  
• 
In the investigator’s opinion, patient’s IOP can be adequately managed with SLT monotherapy 
• 
In the investigator’s opinion, patient is a suitable candidate for SLT 
• 
Diagnosis of either OAG (ie, primary OAG,  pseudoexfoliation glaucoma, pigmentary glaucoma) or OHT 
in each eye, requiring bilateral IOP-lowering treatment (Note:  diagnosis does not have to be the same in 
both eyes) 
• 
Central endothelial cell density by specular microscopy confirmed as being qualified by Reading Center 
assessment prior to beginning Washout  
• 
The iridocorneal angle must be independently confirmed as being qualified by 2 ophthalmologists using the 
following criteria: 
o 
Shaffer Grade  3 on clinical gonioscopy of the inferior angle 
o 
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 (8:00 AM ± 1 hour), IOP of  22 and  34 mm Hg, with difference between eyes of  
 5 mm Hg   
Key Exclusion Criteria:   
Ocular 
• 
History of previous laser trabeculoplasty  
• 
The following surgical history: 
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showing noninferiority for 2 out of 3 timepoints with a noninferiority margin of 1.0 mm Hg, assuming that both 
the between-eyes and the within-patient correlation coefficients are 0.5.  Assuming a premature discontinuation 
rate of 10%, approximately 160 patients are to be enrolled into this study (including approximately 40 patients 
in Stage 1 and 120 patients in Stage 2). 
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Table 2 
Administration Cycle 1 Schedule of Visits and Procedures:  Screening through Day 2 
Visit 
Screening 
 
Baselineb 
Day 1  
(SLT Administration) 
Day 2 
Phone Callc 
Visit Windows 
Up to 28 days 
 
Up to 3 days 
 
 
Informed Consent/Authorization 
X 
Washouta 
Up to 42 days 
 
 
 
Demographic Data 
X 
 
 
 
Medical/Ophthalmic History 
X 
X 
 
 
Adverse Events 
X 
X 
X 
X 
Concomitant Medications/ Procedures 
X 
X 
X 
X 
Visual Function Questionnaire-25 
 
X 
 
 
Physical Examination  
X 
 
 
 
Vital Signs (at rest  5 minutes) 
X 
X 
X 
 
Pregnancy Testd 
 
X 
 
 
Blood and Urine Sample Collectione 
Xe 
 
 
 
Ocular Examinations in bold should be performed in the order shown  
Pre-Hour 0 Exam (perform before Hour 0 IOP): 
 
 
 
 
 
  Macroscopic Conjunctival Hyperemia Assessmentf 
OU 
Washouta 
Up to 42 days 
OU 
 
 
Manifest Refractiong 
OU 
OU 
 
 
Best-Corrected Visual Acuity 
OU 
OU 
 
 
Intraocular Pressure Measurement Hour 0 
OU 
OU 
 
 
Non-contact Exams (may perform in any order at any time before gonioscopy [before Hour 8 at Baselineh]) 
 
 
 
  Macroscopic Iris Color Assessment  
 
OU 
 
 
  Visual Fieldi 
OU 
OU 
 
 
  Specular Microscopy 
OU 
 
 
 
  Anterior Segment Optical Coherence Tomography 
OU 
 
 
 
OU 
 
 
 
  Biomicroscopyf  
OU 
OU 
OUk 
 
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Table 6 
Schedule of Visits and Procedures:  Week 36 through Week 52/Exit 
Visits 
Week 36 
Week 40 
Week 44 
Week 47 
Week 52/ Exit 
Visit Windows 
±4 days 
±4 days 
±4 days 
±4 days 
±7 days 
Adverse Events 
X 
X 
X 
X 
X 
Concomitant Medications/Procedures 
X 
X 
X 
X 
X 
Vital Signs (at rest  5 minutes) 
X 
X 
X 
X 
X 
Pregnancy Test  
 
 
 
 
X 
Ocular Examinations in bold should be performed in the order shown  
Pre-Hour 0 Exams (may perform in any order before Hour 0 IOP) 
Macroscopic Conjunctival Hyperemia 
Assessmenta 
OU 
OU 
OU 
OU 
OU 
Best-Corrected Visual Acuityb 
OU 
OU 
OU 
OU 
OU 
Intraocular Pressure H0  
OU 
OU 
OU 
OU 
OU 
Non-contact Exams (may perform in any order at any time before gonioscopy) 
Macroscopic Iris Color Assessment 
 
 
 
 
OU 
Manifest Refractionb 
 
 
 
 
OU 
Visual Fieldc 
 
 
 
 
OU 
Specular Microscopy 
 
OU 
 
 
OU 
 
 
 
 
OU 
Biomicroscopya  
OU 
OU 
OU 
OU 
OU 
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Visits 
Week 36 
Week 40 
Week 44 
Week 47 
Week 52/ Exit 
Visit Windows 
±4 days 
±4 days 
±4 days 
±4 days 
±7 days 
Gonioscopy/Angle Assessment  
OUe 
OU 
OU 
OU 
OUe 
Pachymetry (may be done any time after 
gonioscopy) 
 
OU 
 
 
OU 
Pupil Dilation (perform post-dilation eye 
exams in any order) 
 
OU 
 
 
OU 
Dilated Ophthalmoscopy  
 
OU 
 
 
OU 
Optic Disc Examination  
 
OU 
 
 
OU 
Contact Interactive Response Systemf  
 
 
 
 
X 
H = Hour; Hour 0 = 08:00 ± 1 hour; IOP = intraocular pressure; OU = both eyes; X = perform procedure  
a 
 
 See Procedure Manual for details. 
b 
Manifest refraction will be used to provide a correction for best-corrected visual acuity testing.  At all study visits, if there is a 2-line or more reduction in visual acuity from 
the last best-corrected visual acuity performed, a repeat manifest refraction in both eyes and best-corrected visual acuity will be performed. 
c 
For a given patient, the same test methodology must be used for historical fields and all fields performed throughout the study.  
d 
  Assessment will be performed at Week 52/Exit in 
patients who underwent assessment at Screening.  Perform any contact assessments following completion of IOP measurements.  See Procedure Manual for details.  
e 
 See Procedure Manual for details. 
f 
Contact at Week 52/Exit to report patient’s exit status.
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1. 
Background and Clinical Rationale 
1.1 
Glaucoma and Treatment 
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 
multifactorial 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).  Globally, over 60 million people are 
estimated to be affected by glaucoma (the majority of whom have OAG) and these numbers 
are expected to increase over time (Quigley and Broman, 2006; Varma et al, 2011; 
Cook and Foster, 2012).  Approximately 10% of eyes with elevated intraocular pressure 
(IOP) will progress to OAG over the course of a decade (Quigley et al, 1994). 
Although many risk factors have been associated with OAG, elevated 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 
(Kass et al, 2002) and the Early Manifest Glaucoma Trial (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 (Lichter et al, 2001) and the Advanced Glaucoma Intervention Study (AGIS) 
(AGIS, 2000).  The currently available approaches to lowering IOP include topical 
pharmacological therapy, laser trabeculoplasty (LT), 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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Although a variety of effective topical ocular antihypertensive medications (including 
bimatoprost) are available, 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).  One literature review found that up to 80% of patients 
deviated from their prescribed medication regimen (Olthoff et al, 2005).  In addition, most 
patients with OAG or OHT are elderly, and many have inherent difficulties applying daily 
antihypertensive eye drops due to physical and/or cognitive disabilities such as arthritis and 
poor memory (European Glaucoma Society guidelines, 2014; Tsai, 2009).  Guidelines have 
been developed and provided to clinicians for assisting patients with being adherent 
(Budenz, 2009).  In addition, surgical interventions, both laser based (eg, LT) and incisional, 
are recommended as treatment options for patients with OAG and OHT who have challenges 
with topical medication adherence or tolerance (European Glaucoma Society guidelines, 
2014).  Laser trabeculoplasty is a safe and noninvasive procedure; however, repeatability of 
LT is controversial (Realini, 2008).  Patients will often require adjunctive therapy after LT, 
and may eventually require incisional surgery to control their IOP (Francis et al, 2005; 
Koucheki and Hashemi, 2012).  Incisional surgery presents the risk of significant 
sight-threatening complications, 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).  As a result, Allergan has developed a 
sustained-release (SR) bimatoprost implant as an ocular antihypertensive therapy for patients 
with OAG and OHT who are not adequately managed by topical medication due to 
medication adherence or tolerability issues. 
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 
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(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 administered 
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 
United States (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 bimatoprost ophthalmic 
solution 0.03% has been approved since November 2012 for lowering IOP, and is currently 
marketed in 10 countries.   
A sustained-release (SR) 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 SR product.  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 a 
total preservative-free bimatoprost load of 15 ȝg, and intracameral administration of this dose 
strength is expected to reduce the total daily drug exposure to the eye by approximately 
80-fold compared with topical LUMIGAN 0.03% application over 4 months, as well as 
possibly reducing the adverse effects observed with topical glaucoma medications.  The 
Bimatoprost SR implant is expected to release drug over approximately 4 months, and 
% 
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 (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.   
1.2.1 
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 completed 
in 2 species (Beagle dogs and Cynomolgus monkeys) with a range of AC angle sizes in order 
to support the clinical program.  These studies build on the already considerable amount of 
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nonclinical and clinical information available for topical bimatoprost (see Investigator’s 
Brochure [IB] for additional details). 
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 (Studies TX09051-TX, TX09066-TX, TX10016-TX, 
TX11076-TX, TX12012-TX, TX12018-TX, and TX12102-TX).  Monkeys, which have a 
characteristically small AC angle compared to both dogs and humans, did not tolerate 
Bimatoprost SR dose strengths tested ( 10 ȝg 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 ȝg (Studies TX11076-TX, TX12012-TX, 
TX12018-TX) and with repeat doses of  15 ȝg (Studies TX12012-TX and TX12018-TX).  
Furthermore, no adverse drug- or implant-related ocular findings have been seen following 
3 intracameral injections of up to 20 ȝg (two 10 ȝg implants) Bimatoprost SR in the 
18-month repeat-dose Good Laboratory Practice (GLP) study in dogs (Study TX12102-TX).  
Pharmacokinetic studies of Bimatoprost SR (Studies PK09109-PK and PK11086-PK) in 
Beagle dogs demonstrated that systemic exposure of bimatoprost and bimatoprost acid was 
below the limit of quantitation (BLQ) with doses  60 ȝg.  Aqueous humor concentrations 
generally peaked by 10 weeks postdose for doses 
 ȝg (Generation 1 and Generation 2), 
then declined to low levels suggestive of near-complete drug release from the device at  
months for doses 
 ȝg.  By 14 weeks following a 20 ȝg (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 ȝg, 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 
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observed in the target tissue, the iris ciliary body. Retinal concentrations were BLQ 
following both topical and Bimatoprost SR administration. 
1.2.2 
Other Biodegradable Ocular Implants 
A number of SR drug delivery implants using the Allergan polylactic acid (PLA) and/or 
polylactic-co-glycolic acid (PLGA) biodegradable platform 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 
SR 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. 
1.2.3 
Clinical Studies with Bimatoprost SR 
Study 192024-041D was a phase 1/2 paired-eye comparison study evaluating the safety and 
efficacy of 4 dose strengths of Bimatoprost SR (6, 10, 15, or 20 ȝg [2 x10 ȝg implants]), as 
single or repeat administrations in 1 eye (study eye), versus the use of topical LUMIGAN 
0.03% once daily in the contralateral 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 at least a single administration of Bimatoprost SR, 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 retreated patients showed similar IOP lowering efficacy to that observed 
following the first administration of Bimatoprost SR.  In addition, efficacy was maintained 
longer than the expected 4-month duration in many patients in this completed study.  By 
Month 6, most patients (68%) were still maintained on monotherapy with the initial 
Bimatoprost SR implant administered.  Among all Generation 2 dose strengths, 40% of 
patients had not received rescue or a second Bimatoprost SR treatment by Month 12.  At 
Month 24, 28% of patients had not received rescue or a second treatment. 
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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. 
Two identical global phase 3 studies (Completed study  192024-091 and ongoing study 
192024-092) were initiated in late 2014.  These studies are assessing the safety and efficacy 
of Bimatoprost SR in multicenter, randomized, masked, parallel-group comparison studies of 
2 dose strengths of Bimatoprost SR (10 and 15 μg) to an active control (timolol maleate 
0.5%). 
1.3 
Study Rationale 
Results of the completed phase 1/2 study, 192024-041D, showed that Bimatoprost SR 
provides a prostaglandin analog-like IOP-lowering efficacy when used at the dose strengths 
being used in this phase 3 investigation.  Additionally, the safety profile of Bimatoprost SR 
at dose strengths of 20 ȝg (2 × 10 ȝg) or less in the phase 1/2 study was acceptable and 
supports additional clinical studies in humans.  Study 192024-095 was designed as a 
randomized, patient and efficacy evaluator-masked, paired-eye comparison evaluating the 
safety and IOP-lowering effects of repeated administrations of 15 ȝg Bimatoprost SR in 
patients with OAG or OHT who are not adequately managed with topical medication (eg, 
due to intolerance or nonadherence).   
Bimatoprost SR is being compared with SLT in 2 phase 3 studies (192024-093 and 
192024-095). Based on the interim data from the phase 1/2 study 192024-041D, the higher of 
the 2 dose strengths being evaluated in the other global phase 3 studies, 15 μg, was selected 
for this study.  Now that additional data from later-stage studies has become available, the 
number of administration cycles in this study was reduced from 3 to 2 (eliminating Week 32 
administration for newly enrolled patients and ongoing patients who have not yet received 
the Week 32 administration).  The number of administration cycles was reduced based on the 
duration of effect observed in the completed 24-month Study 192024-041D as well as the 
preliminary analysis of data from the first 3 months of treatment (primary analysis) in 
Study 192024-091, which suggested that the majority of patients do not require rescue 
treatment for an extended duration following their last Bimatoprost SR administration.  The 
results of both studies suggest that efficacy may be maintained with fewer administration 
cycles.  The change from 3 to 2 administration cycles will have no impact on the primary 
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efficacy analysis, and allows for assessment of the duration of effect of 2 Bimatoprost SR 
administration cycles throughout the study.   With the implementation of Amendment 3, 
Allergan is discontinuing the administration of the Bimatoprost SR 15 μg dose strength to 
patients based on a thorough review of the long-term Bimatoprost SR safety data from the 
recently completed and ongoing studies. The discontinuation is based on the conclusion that 
corneal adverse events associated with repeat administrations of the 15 μg dose strength are 
no longer supported by a favorable benefit:risk consideration. 
The comparator that is to be administered in the contralateral eye is selective laser 
trabeculoplasty (SLT), which is also indicated for this patient population.  SLT, one of the 
most frequently used LT modalities, is commonly used as an intermediate step between 
topical medications and incisional glaucoma surgery and is comparable in efficacy and 
durability to argon laser trabeculoplasty (ALT) (Damji et al, 1999; Damji et al, 2006; 
Martinez-de-la-casa et al, 2004; Rolim de Moura et al, 2007; Wang et al, 2013).  SLT causes 
minimal tissue destruction compared with ALT and is increasingly being adopted as the LT 
standard of care (Realini, 2008).  SLT has been reported to reduce IOP effectively in eyes 
with OHT and OAG, as reports often suggest IOP reduction to be similar to topical 
prostaglandin analogues (Katz et al, 2012; Nagar et al, 2009; McAlinden 2014).  This study 
is 1 of 2 phase 3 studies that will compare the IOP-lowering effects and safety profiles of 
Bimatoprost SR and SLT. 
2. 
Study Objectives and Clinical Hypotheses  
2.1 
Study Objectives 
To evaluate the IOP-lowering effect and safety of Bimatoprost SR compared with SLT in 
patients with OAG or OHT, who are not adequately managed with topical IOP-lowering 
medication for reasons other than medication efficacy (eg, due to intolerance or 
nonadherence). 
2.2 
Clinical Hypotheses 
Bimatoprost SR will have an IOP-lowering effect that is noninferior to that of SLT in patients 
with OAG or OHT who are not adequately managed with topical IOP-lowering medication 
for reasons other than medication efficacy (eg, due to intolerance or nonadherence). 
Bimatoprost SR administered intracamerally will have an acceptable safety profile in patients 
with OAG or OHT who are not adequately managed with topical IOP-lowering medication 
for reasons other than medication efficacy (eg, due to intolerance or nonadherence). 
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3. 
Study Design 
This study is a multicenter, paired-eye, randomized, efficacy evaluator-masked 14-month 
study conducted in 2 stages (Stage 1 and 2).  The safety and IOP-lowering effect of 
Bimatoprost SR will be compared with SLT in OAG and OHT patients who are not 
adequately managed with topical medication for reasons other than medication efficacy (eg, 
due to intolerance or nonadherence).    
The study is being conducted in 2 stages because the protocol is being amended 
(Amendment 2) to reduce the number of administration cycles performed, in order to allow 
for longer duration of efficacy follow up after the second administration. With the 
implementation of Amendment 3, no new patients will be enrolled into the study and study 
treatment/retreatment of enrolled patients will not be permitted.  All patients will be followed 
for the duration of the study through the Week 52/Exit visit.  Therefore, the Week 16 will not 
be required for these patients.  The eye with the higher IOP at Baseline will be assigned as 
the primary eye.  If baseline IOP is the same in both eyes, the right eye will be the primary 
eye.  The primary eye will be randomized to receive either Bimatoprost SR or SLT using a 
1:1 ratio, stratified by primary eye baseline IOP (  25  versus > 25 mm Hg) 
 
.  If the primary eye receives 
Bimatoprost SR, the contralateral eye will receive SLT.  If the primary eye receives SLT, the 
contralateral eye will receive Bimatoprost SR. 
Patients will receive a 360° administration of SLT in 1 eye on Day 1, and administration of 
Bimatoprost SR in the contralateral eye on Day 4, with a repeat administration of 
Bimatoprost SR at Week 16.  Stage 1 patients (who enrolled and reached the Week 32 visit 
prior to implementation of Amendment 2) received a third administration of Bimatoprost SR 
at Week 32.  In order to mask the patient to the treatment assigned to each eye, on Day 1 a 
Sham SLT procedure will be performed in the eye to be administered Bimatoprost SR 
(hereafter refer to as the “Bimatoprost SR eye”).  A Sham Bimatoprost SR administration 
will be performed in the eye that underwent SLT (hereafter referred to as the “SLT eye”) on 
each Bimatoprost SR administration visit (Day 4 and Week 16) (see Table 1).   
4. 
Study Population and Entry Criteria 
4.1 
Number of Patients  
Approximately 160 patients (including approximately 40 patients in Stage 1 and 120 patients 
in Stage 2) will be enrolled at approximately 68 sites, in order to have an estimated 
144 patients complete the study based on a premature discontinuation rate of 10%.  
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4.2 
Study Population Characteristics 
The study population consists of patients with bilateral OAG or OHT who are not adequately 
managed with topical medication for reasons other than medication efficacy (eg, due to 
intolerance or nonadherence).  Both eyes must require IOP-lowering treatment, must be able 
to be adequately managed on SLT monotherapy, and must meet study entry criteria. 
4.2.1 
Patients with Sickle Cell Trait/Disease or Other 
Hemoglobinopathies 
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 safety 
monitoring (biomicroscopy and IOP measurement) after Bimatoprost SR administration at 
the investigator’s discretion.  Additional information about the previous experience with the 
use of Bimatoprost SR in patients with sickle cell trait is provided in the IB.    
4.3 
Inclusion Criteria 
The following are requirements for entry into the study:  
1. Male or female, 18 years of age or older  
2. Written informed consent and authorization for use and release of personal health 
information are 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 [Unites States (US) sites] and written Data 
Protection consent [European Union (EU) sites]) 
3. Patient is willing to withhold his/her IOP treatments according to the study 
requirements, and in the opinion of the investigator, can do so without significant risk.  
Note:  If patients cannot discontinue their currently prescribed therapy for up to 6 
weeks to meet the Washout period for study entry, the investigator may switch the 
patient’s medication to one that requires a shorter washout interval during the washout 
of the original medication (see Section 8.2 and Table 7) 
4. Patient has the ability to understand and the willingness to follow study instructions 
and requirements and is likely to complete all required visits and procedures 
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5. In the investigator’s opinion, patient’s IOP is not adequately managed with topical 
medication for reasons other than medication efficacy (eg, due to intolerance or 
nonadherence) 
6. Negative pregnancy test at Baseline for females of childbearing potential 
Ocular Inclusion Criteria for Both Eyes: 
7. In the investigator’s opinion, both eyes can be treated adequately with topical 
prostamide, prostaglandin, or prostaglandin analog (eg, LUMIGAN, Xalatan, 
Travatan) eye drops as the sole therapy if medication was taken as directed   
8. In the investigator’s opinion, patient’s IOP can be adequately managed with SLT 
monotherapy 
9. In the investigator’s opinion, patient is a suitable candidate for SLT 
10. Diagnosis of either OAG (ie, primary OAG, pseudoexfoliation glaucoma, pigmentary 
glaucoma) or OHT in each eye, requiring bilateral IOP-lowering treatment. (Note:  
diagnosis does not have to be the same in both eyes) 
11. Central endothelial cell density by specular microscopy confirmed as being qualified 
by Reading Center assessment prior to beginning Washout  
12. The iridocorneal angle 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   
13. At the Baseline visit, patient has been appropriately washed out of all IOP-lowering 
medications 
14. At the Baseline visit (8:00 AM ± 1 hour), IOP of  22 and  34 mm Hg, with difference 
between eyes of  5 mm Hg   
15. At the Screening and Baseline (Day -3 to -1) visits, Best-Corrected Visual Acuity 
(Snellen equivalent, by manifest refraction) of 20/50 or better in each eye 
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4.4 
Exclusion Criteria 
The following are criteria for exclusion from participating in the study: 
1. Uncontrolled systemic disease 
2. Females 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 the study medication or its components, any 
component of the delivery vehicle, or any diagnostic or surgical prep agents used 
during the study (eg, topical anesthetic, dilating drops, fluorescein, povidone-iodine) 
4. Any condition which would preclude the patient’s ability to comply with study 
requirements (including completion of the study) 
5. 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 
6. Concurrent or anticipated enrollment in an investigational drug or device study or 
participation in such a study from 2 months prior to the Baseline visit through the final 
study visit 
7. Previous or concurrent enrollment in another Allergan Bimatoprost SR study  
8. Known history of bleeding disorder or prolonged bleeding after surgery (in the 
opinion of the investigator).  Note:  Patients receiving pharmacologic blood thinners 
(eg, aspirin, Coumadin) may be enrolled at the investigator’s discretion. 
Ocular Exclusion Criteria for Both Eyes: 
9. History of previous laser trabeculoplasty 
10. History or evidence of clinically relevant, substantial ocular trauma (eg, a traumatic 
cataract, traumatic angle recession, etc) 
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11. The following surgical history: 
a. History or evidence of complicated cataract surgery: 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  
12. Intraocular surgery (including cataract surgery) and/or any ocular laser surgery within 
the 6 months prior to treatment (Day 1)  
13. Any history of corneal graft, including partial grafts (eg, Descemet’s Stripping 
Endothelial Keratoplasty [DSEK], Descemet’s Membrane Endothelial Keratoplasty 
[DMEK]); or incisional refractive surgery (eg, radial keratotomy), other than 
astigmatic keratotomy or limbal relaxing incisions 
14. Corneal or other ocular abnormalities that would preclude accurate readings with an 
applanation tonometer, anterior segment-optical coherence tomography, specular 
microscope, and/or a contact pachymeter, or could confound study results, eg, 
moderate to severe corneal dystrophy, including Anterior Basement Membrane 
Disease (ABMD; ie, Map-Dot-Fingerprint [MDF]) and guttata.  Mild ABMD or mild 
guttata are not exclusionary by clinical examination if, in the opinion of the 
investigator, the condition is stable and not likely to cause corneal changes during the 
course of the study.   
15. Active or recurrent ocular disease (eg, uveitis, ocular infection, chronic moderate to 
severe blepharitis or severe dry eye, severe ocular seasonal allergies) or sight 
threatening diseases (eg, neovascular age-related macular degeneration [ARMD], 
diabetic macular edema) that, in the opinion of the investigator, would put the patient 
at a significant risk or would interfere with the interpretation of the study data.  
Patients with slowly progressive eye diseases (ie, mild cataracts, nonneovascular 
ARMD) can be enrolled at the discretion of the investigator. 
16. Any history of external ocular or intraocular malignancy, and/or any history of benign 
ocular neoplasia that in the investigator’s opinion resulted in clinically significant 
ocular morbidity  
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17. History of herpetic ocular diseases (including herpes simplex virus and varicella zoster 
virus) 
18. The following ocular surface findings: 
a. Bulbar conjunctival hyperemia, on either macroscopic or slit-lamp 
examination, > +1 (mild) at baseline 
b. Active ocular surface findings other than bulbar conjunctival 
hyperemia, on either macroscopic or slit-lamp examination, > +1 
(mild) at Baseline 
19. History of moderate or worse ( +2) bulbar conjunctival hyperemia due to marketed 
prostaglandin, prostamide, or prostaglandin analog use 
20. The anticipated wearing of contact lenses during the study that deviates from the 
following (contact lens wear is allowed during the study, but is to be temporarily 
discontinued before study visits, and before and after an Administration Day according 
to the following): 
a. Use of soft lenses should be discontinued at least 3 days prior to 
Baseline, and use of rigid gas permeable or hard contact lenses should 
be discontinued at least 1 week prior to Baseline  
b. Use of soft lenses should be discontinued at least 3 days and use of 
rigid gas permeable or hard contact lenses should be discontinued at 
least 1 week prior to a scheduled study visit or Administration Day 
visit 
c. Use of contact lenses of any kind should be discontinued for 1 week 
following any Bimatoprost SR (or Sham) administration 
21. Central corneal thickness of < 480 or > 620 micrometers  
22. Anticipated need for any incisional or laser ocular surgery during the study 
23. History of anatomically narrow angle resulting in evidence of angle changes or any 
history of closed angle glaucoma.  Note: historically narrow angled patients whose 
angle has been opened by cataract surgery or peripheral iridotomy may be eligible for 
enrollment if they have no evidence of angle abnormalities. 
24. History or evidence of a peripheral iridotomy/iridectomy in the inferior iris  
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25. Any history of trabeculectomy or other types of glaucoma surgery, including a 
glaucoma seton or aqueous bypass stents 
26. Peripheral anterior synechiae (PAS) in the inferior iridocorneal angle on gonioscopic 
examination at Screening 
27. Visual field loss that, in the opinion of the investigator, is functionally significant (eg, 
split fixation, field defect within the central 10 degrees that is visually significant or 
likely to cause central visual impairment upon progression) or shows evidence of 
progressive visual field loss within the year prior to baseline (Note:  Two visual fields 
are required for qualification, 1 performed within the 10 months prior to or at 
Screening, and 1 performed at baseline or during the washout period using the 
protocol-required testing method [see Procedure Manual].  The same test methodology 
should be used for all historical and study-related examination for a given patient.) 
28. Evidence of macular edema during screening or in patient’s medical history  
29. Anticipated use of corticosteroids in either eye (except as described in Section 4.5.1 
[Permissible Medications/Treatments]) or systemically during the study, or historical 
use prior to Baseline within: 
• 3 years:  intraocular fluocinolone acetonide 
• 6 months:  intraocular corticosteroid(s) other than fluocinolone; any injectable 
periocular or sub-Tenon’s/subconjunctival corticosteroid 
• 2 months:  systemic (eg, oral, intramuscular, intravenous) or topical ocular 
corticosteroids  
• 2 weeks:  dermal corticosteroids applied to skin of the eyelid(s), around the eye, 
or adnexa  
30. Anticipated use of other topical ocular medications except as described in 
Section 4.5.1 (Permissible Medications/Treatments) 
4.5 
Permissible and Prohibited Medications/Treatments 
4.5.1 
Permissible Medications/Treatments 
Ophthalmic Medications/Treatments 
Intermittent use of artificial tear products is allowed if they are taken > 15 minutes before any 
study procedure or if they are required for a study procedure.  Intermittent use of ocular 
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decongestants or antihistamines is allowed if not taken within 2 days prior to a scheduled 
visit.   
Use of artificial tear products and ocular decongestants or antihistamines may be restarted 3 
days after any study administration (Bimatoprost SR, Sham Bimatoprost SR, SLT, or Sham 
SLT) procedure.  
Note: post-procedural use of artificial tear products following SLT/Sham SLT 
administration is allowed at the investigator’s discretion; patients should be instructed 
to wait at least 15-20 minutes after instilling required medication (eg, NSAID) drops 
before instilling artificial tear products. Use of artificial tears is not allowed following 
Bimatoprost SR/Sham Bimatoprost SR administration except as described above 
(restart 3 days after). 
Use of post-Bimatoprost SR administration topical ocular antibiotics for 3 days, and 
corticosteroids or nonsteroidal anti-inflammatory drugs (NSAIDs) for up to 7 days following 
the administration days is permissible. 
Use of immediate pre- and post-SLT topical ocular antihypertensive medication (ie, 
brimonidine or apraclonidine) is permissible.  Post-SLT topical NSAIDS are also permissible 
for 3 days following the procedure.  The medications instructed for use pre- and post-SLT are 
described in detail in Section 5.9.2. 
Systemic Medications 
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. 
The use of systemic NSAIDS is also permitted. 
In addition, therapy considered necessary for the patient’s welfare may be given at the 
discretion of the investigator.  If possible, the concurrent therapy (ocular and systemic) 
administered should not have an effect on study outcomes.  However, if concurrent 
medications may have an effect on study outcomes, these medications should be 
administered in dosages that remain constant throughout the duration of the study.  If the 
permissibility of a specific medication/treatment is in question, please contact Allergan. 
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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 as needed (see Procedure Manual for details). 
Note that in the event that the investigator performs an unanticipated incisional surgical 
procedure on the Bimatoprost SR implanted eye during which ocular fluid is to be removed, 
ocular fluid/implant samples may be collected for analysis at the investigator’s discretion  
(see Procedure Manual for details). 
4.5.2 
Prohibited Medications/Treatments 
The decision to administer a prohibited medication/treatment is taken 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 must not participate in other investigational drug or device studies. 
Nonstudy IOP-lowering Treatments 
Any concurrent nonstudy IOP-lowering treatment (eg, topical ophthalmic medication 
containing an ocular antihypertensive, LT) is prohibited 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.  Inadequate control of IOP should be confirmed at a 
subsequent visit (scheduled or unscheduled visit).  Initiation of treatment in one eye should 
not automatically lead to initiation of treatment in the contralateral eye.  Each eye should be 
evaluated on an individual basis when determining the need for additional nonstudy IOP-
lowering treatments.  If nonstudy IOP-lowering treatment is initiated, the investigator will be 
expected to attest to the need for additional nonstudy IOP-lowering treatment for safety 
reasons for each eye individually. Use of any concurrent nonstudy IOP-lowering treatment 
with any known effect on study outcomes (eg, crossover effect on the contralateral eye) is 
prohibited during the study.   
In order to maintain patient masking to treatments assigned to each eye, patients who have 
received nonstudy topical IOP-lowering treatment in a Bimatoprost SR eye will receive 
Sham Bimatoprost SR administration in that eye on the Bimatoprost SR Cycle 2 (and Cycle 3 
for Stage 1 patients) administration day(s).  If nonstudy topical IOP-lowering medication is 
initiated in an SLT eye, the patient will continue to receive Sham Bimatoprost SR 
administration in the SLT eye on the administration day(s).  In all cases, the contralateral eye 
that does not require nonstudy topical IOP-lowering medication will maintain the same 
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treatment regimen assigned at randomization.  Patients who have received nonstudy 
IOP-lowering treatment in both eyes will not receive Bimatoprost SR administration or Sham 
Bimatoprost SR administration in either eye, and therefore do not need to attend the 
Bimatoprost SR (or Sham Bimatoprost SR) administration visits and immediate 
postadministration visits (ie, Bimatoprost SR Cycle 2 administration [Week 16], Cycle 2 
Day 2 safety visit, and Cycle 2 Day 4 and Week 2 phone calls, and for Stage 1 patients only, 
Bimatoprost SR Cycle 3 administration [Week 32], Cycle 3 Day 2 safety visit, and Cycle 3 
Day 4 and Week 2 phone calls). 
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.  
Other Medications 
The following medications (or classes of medications) and treatment procedures are not 
permitted as concurrent therapy during the study unless the patient has already received 
nonstudy IOP-lowering medication or treatment in both eyes: 
• Subconjunctival, sub-Tenon’s, intravitreal, or other ophthalmic injections of any 
medications in either eye 
• Use of any topical ophthalmic medications (except as described above and in 
Section 4.5.1) in either eye 
• Surgical (incisional and laser) procedures that are not related to study-specific 
Bimatoprost SR (or Sham) and SLT administration procedures in either eye; patients may 
exit the study early if an ophthalmic incisional procedure is required   
• Oral, intramuscular, or intravenous corticosteroids from 2 months prior to the Baseline 
visit through study exit  
• Use of bimatoprost for hypotrichosis during the study period in either eye 
• Use of cyclosporine ophthalmic solution during the study period in either eye 
• Systemic use of carbonic anhydrase inhibitor  
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• Any initiation of or alterations in systemic regimen of beta-blocker containing 
medications from 2 months prior to screening through the study exit 
• Use of corticosteroids in either eye (except as described in Section 4.5.1 for postoperative 
use) or systemically during the study or historical use prior to Baseline within: 
• 3 years:  intraocular fluocinolone acetonide 
• 6 months:  intraocular corticosteroid(s) other than fluocinolone; any injectable 
periocular or sub-Tenon’s/subconjunctival corticosteroid 
• 2 months:  systemic (eg, oral, intramuscular, intravenous) or topical ocular 
corticosteroids  
• 2 weeks: dermal corticosteroid applied to skin of the eyelid(s), around the eye, or 
adnexa 
4.5.3 
Definition of Females of (Non-)Childbearing Potential and/or 
Acceptable Contraceptive Methods 
For purposes of this study, females 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. 
If a female becomes pregnant during the study, the investigator will notify Allergan 
immediately after the pregnancy is confirmed and the patient will be exited from the study 
after appropriate safety follow up.  The investigator will (1) notify the patient’s physician that 
the patient was being treated with an investigational drug (and unmask the study treatment as 
needed for pregnancy monitoring), and (2) follow the progress of the pregnancy.  The 
investigator must document the outcome of the pregnancy and provide a copy of the 
documentation to Allergan. 
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5. 
Study Treatments  
5.1 
Study Treatments and Formulations 
The clinical formulation of Bimatoprost SR contains preservative-free bimatoprost dispersed 
in a biodegradable polymer matrix (including PLA and PLGA).  The biodegradable implants 
are preloaded in the applicator.  The formulation used in this study is Bimatoprost SR 15 μg 
(11048X). 
5.2 
Control Treatment  
The control treatment is a 360° administration of SLT. 
5.3 
Methods for Masking 
A sham SLT procedure will be performed in the Bimatoprost SR eye and a sham Bimatoprost 
SR administration will be performed in the SLT eye to ensure masking of the study 
treatments.  The Sham Bimatoprost SR administration involves touching of the eye at the 
area of insertion with an Allergan-provided needleless applicator that does not deliver an 
implant into the AC.  
The patient and the site staff will be masked to the treatment assignment for each eye.  Only 
the site coordinator and designated staff will be unmasked to the patient’s treatment 
assignment for each eye.  Efficacy IOP measurements will be masked using a 2-person 
reading method as described in Section 6.1.1.  
The site staff who perform IOP readings will be masked to the treatment assignment for each 
eye.  Site personnel and patients will be instructed and reminded throughout the study not to 
discuss study medication assignments to ensure masking is maintained.   
In the event that the patient requires postoperative topical eyedrops in only 1 eye following a 
Bimatoprost SR administration (eg, topical corticosteroids or anti-inflammatory eyedrops) or 
SLT administration (eg, treatment of acute post-SLT IOP spike), in order to maintain masking 
of the eye receiving study treatment, the investigator will be instructed to dispense the 
required medication without disclosing which eye is the Bimatoprost SR or SLT eye or the 
etiology of the signs/symptoms that require the medication. 
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5.4 
Treatment Allocation Ratio and Stratification  
The eye with the higher IOP at baseline will be assigned as primary eye and randomized to 
receive either Bimatoprost SR or SLT using a 1:1 ratio, stratified by the primary eye baseline 
IOP ( 25 or > 25 mm Hg) 
 
.  If the primary eye receives Bimatoprost SR, the contralateral eye will receive 
SLT.  If the primary eye receives SLT, the contralateral eye will receive Bimatoprost SR.  If 
baseline IOP is the same in both eyes, the right eye will be the primary eye. 
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 patient number that will serve as the patient’s identification number on all 
study documents. 
For determination of stratification group assignment for the primary eye for each patient, 
sites will be required to enter Baseline IOP (at Hour 0) data for both eyes into an automated 
interactive response system. 
At the time of randomization (Day 1 SLT Administration Day), an automated interactive 
response system will be used to manage the randomization and treatment assignment for the 
Bimatoprost SR and SLT.  A randomization number will be assigned to a patient according to 
the order of enrollment within each IOP stratum (Baseline primary eye hour 0 IOP  25 or 
> 25 mm Hg) 
 
across the study.  That is, the interactive response system will assign the next available 
randomization number to the patient at the time when the investigator requests 
randomization.   
The interactive response system will provide the site with the specific treatment assignment 
for each randomized patient/eye at the time of randomization (Day 1 SLT Administration 
Day).  Sites will contact the interactive response system at subsequent visits to obtain a study 
medication kit number for dispensing study medication (Bimatoprost SR and Sham).  Study 
medication kits for Bimatoprost SR and Sham administration will be labeled with medication 
kit numbers.  Sites will receive interactive response system confirmation notifications for 
each transaction.  All notifications are to be maintained with the study source documents. 
5.6 
Treatment Regimen  
The treatment assignments are summarized in Table 1.  The eye randomized to receive 
Bimatoprost SR will receive an intracameral administration of Bimatoprost SR on Day 4 and 
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Week 16 (and Week 32 for Stage 1 patients only), plus Sham SLT administration on Day 1 
only.  The contralateral eye will receive one 360° SLT administration on Day 1 only, plus 
Sham Bimatoprost SR administration on Day 4 and Week 16 (and Week 32 for Stage 1 
patients).  With the implementation of Amendment 3, patients who are enrolled and have not 
yet reached Week 16 will not receive Cycle 2 administration. 
For patients who still have any visible Bimatoprost SR implants or have not received 
nonstudy IOP-lowering medications by the time of study discontinuation or completion, 
poststudy evaluations including the need for IOP-lowering medications should be conducted 
according to the treating physician’s clinical opinion.  Further patient follow-up will be 
determined by the treating physician’s clinical opinion. 
5.7 
Storage of Study Medications 
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.  Bimatoprost SR and Sham needleless applicators must be 
stored in the original sealed foil pouch.  Investigational medicinal product must be stored as 
described in the Investigator’s Brochure.  Sites must report any temperature excursions as 
described in the Procedure Manual or contact Allergan or its designee for further instructions. 
For further details on storage, including requirements for study-provided eye drops, please 
refer to the Procedure Manual and/or contact Allergan. 
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 
Study Treatment Administration  
Study medication must only be administered to patients who meet the eligibility criteria in 
accordance with the conditions specified in this protocol.  Medication will be labeled with 
either a single panel label or booklet label.  Records of use of medication kit numbers for 
each patient will be maintained by the site and recorded in the electronic case report form 
(eCRF) as appropriate. 
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5.9.1 
Bimatoprost SR Administration 
5.9.1.1 
Patient Preparation 
Administration day assessments (including vital signs and query for concomitant medications 
and adverse events) should be completed.  At least 3 administrations of a broad spectrum 
topical ophthalmic antibiotic drop and topical anesthetic drop should be administered to each 
eye approximately every 5 minutes beginning approximately 15 minutes prior to the 
procedure.  With the patient in a supine position, the eye and conjunctival fornices should be 
irrigated with 5% ophthalmic povidone-iodine solution and the lids and surrounding orbital 
area should be prepped and draped according to the standard protocol detailed in the 
Procedure Manual. 
5.9.1.2 
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).  As a standard ASC 
technique an intravenous catheter may be placed and intravenous sedatives may be used at 
the discretion of the investigator and/or anesthesiologist.  The ASC may have standard 
operating procedures (SOPs) that require an electrocardiogram and/or a chest radiograph 
performed prior to the procedure.  A separate standard consent to have the procedure at an 
ASC may be required per the SOPs at the facility. 
Sterile technique should be practiced at all times. 
5.9.1.3 
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. 
The procedure is described in detail in the Procedure Manual.  In brief, following the sterile 
preparation and sterile field setup, an appropriately sized sterile lid speculum should be 
placed between the eyelids of the patient.  The entrance site for the applicator needle is just 
anterior to the insertion of the conjunctiva through the clear cornea in the superior or 
temporal quadrant.  The trajectory of the needle should be parallel to the iris plane.  The eye 
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is stabilized by either counter traction with a sterile toothed forceps or counter pressure with 
a cotton tipped applicator as the needle is advanced through the cornea.  The actuator button 
is depressed until an audible and/or palpable click is heard.  The Bimatoprost SR implant 
should be visible exiting the needle bevel into the aqueous humor.  The needle is then 
immediately removed from the AC, and the wound is checked for aqueous leakage.  
Following removal of the lid speculum and sterile drape, additional drops of broad spectrum 
antibiotics should be applied. 
The procedure for the second (and third for Stage 1 patients) administration(s) of 
Bimatoprost SR is the same. 
The preparation and procedure for all sham administrations is the same; however, the sham 
applicator will not have a needle and thus will not enter the AC (but should touch the eye at 
the area of recommended insertion). 
5.9.1.4 
Immediate Posttreatment Observation 
Following Bimatoprost SR 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 AC is formed prior to the patient being released. 
The patient will be supplied a bottle of topical ophthalmic antibiotic drops and instructions to 
use them for the next 3 days (including the day of the administration) in both eyes and to 
follow up as per protocol. 
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 must be recorded on the appropriate eCRF. 
The same posttreatment observation and antibiotic requirements apply after the second (and 
third for Stage 1 patients) administration(s) of Bimatoprost SR or Sham. 
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 use of the 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) 
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examination may be performed using a Goldmann applanation tonometer or a hand-held 
tonometer (see the Procedure Manual for details). 
5.9.1.5 
Retreatment with Bimatoprost SR 
With the implementation of Amendment 3, patients who are enrolled and have not yet 
reached Week 16 will not receive Cycle 2 administration.  All patients will be followed for 
the duration of the study through the Week 52/Exit visit.  Therefore, the Week 16 will not be 
required for these patients.   
5.9.2 
SLT Administration 
5.9.2.1 
Pre-SLT Patient Preparation 
Measure the IOP in both eyes and record the result.  Because this is a preoperative 
measurement and not used for efficacy analyses, this measurement does not need to be 
masked and only 1 measurement needs to be performed.  
Instill 1 drop of apraclonidine or brimonidine  (see Procedure Manual) into each eye 
30 minutes to 1 hour prior to SLT (or Sham SLT).  Topical anesthetic drop (eg, proparacaine 
hydrochloride or equivalent) should be administered to each eye approximately every 
5 minutes beginning approximately 15 minutes prior to the procedure.   
5.9.2.2 
SLT and Sham SLT Procedure 
SLT must be performed by an ophthalmologist who has had adequate training and has been 
approved by Allergan.  The investigator will perform 360 degrees of SLT using the 
standardized method that is detailed in the Procedure Manual.  Sham SLT will then be 
performed on the contralateral eye using the same method, with the exception that the laser is 
not switched to the active state.  
5.9.2.3 
Post-SLT 
Administer 1 drop of apraclonidine or brimonidine into each eye and recheck the IOP 1 hour 
after SLT and Sham SLT administration; because this is a postoperative measurement and not 
used for efficacy analyses, this measurement does not need to be masked and only 
1 measurement needs to be performed.  If an IOP spike is observed, the investigator should 
treat using his/her standard of practice. 
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The patient will be supplied a bottle of topical NSAID eyedrops and instructions to use them 
as directed for the next 3 days (including the day of the administration) in both eyes and to 
follow up as per protocol. 
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. 
6. 
Response Measures and Summary of Data Collection Methods 
Detailed information on equipment and methodology to be used is provided in the Procedure 
Manual. 
Study evaluations should be performed by the same investigator/subinvestigator throughout 
the study whenever possible.  If it is not possible to use the same individual to follow the 
patient, then an attempt should be made to have investigators overlap (examine the patient 
together and discuss findings) for at least 1 visit. 
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 
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, 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 AM ± 1 hour.  As scheduling 
permits, the patient should have approximately the same Hour 0 time of day throughout the 
study.  At selected sites in consenting patients, additional IOP measurements will be 
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performed at Hour 2 (Hour 0 + 2 hours [± 30 minutes]) and Hour 8 (Hour 0 + 8 hours 
[± 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. 
Blood and Urine Sample Collection:  Blood and urine samples will be collected for blood 
chemistry, hematology panels, and urinalysis by a central laboratory or designated regional 
facility.   
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: 
Best Corrected Visual Acuity:  Visual acuity tests will be performed at all scheduled visits 
except on any of the Bimatoprost SR administration days or SLT Administration Day.  
Manifest refraction using Snellen equivalent with a logMar chart (see Procedure Manual) 
will be performed at Screening, Baseline, and Weeks 12, 24, and 52/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 
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in visual acuity from the last best-corrected visual acuity performed, a repeat manifest 
refraction in both eyes and best-corrected visual acuity will be performed. 
Macroscopic Iris Color Assessment:  Iris color will be assessed visually at each designated 
visit using the appropriate assessment guide (see the Procedure Manual for further details).   
Macroscopic Conjunctival Hyperemia Assessment:  Macroscopic conjunctival hyperemia 
will be assessed using the appropriate assessment guide (see the Procedure Manual for 
further details). 
Gonioscopy/Angle Assessment:  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. Using 
gonioscopy, the investigator will evaluate the inferior iridocorneal angle and the Bimatoprost 
SR implant. 
Biomicroscopy:  Biomicroscopic examinations will be performed using a slit lamp.  The 
examinations will include evaluation of the condition of the eyelids, conjunctiva, cornea, AC 
(with Van Herick anterior chamber depth assessment at Screening only), iris/pupil, and lens 
(Lens assessment is performed using the modified AREDS procedure and is collected on 
dilated examination days through a dilated pupil, using the slit lamp biomicroscope. Please 
see the Procedure Manual for details).   
Lens Assessment:  Biomicroscopic findings will be evaluated for the presence and severity 
of nuclear, cortical, and posterior subcapsular lens opacities.  See the Procedure Manual for 
further details. 
Optic Disc Examination:  The cup/disc ratio and presence of optic disc pathology will be 
determined using stereoscopic evaluation. 
Dilated Ophthalmoscopy:  The stereoscopic fundus assessments should be conducted 
through a dilated pupil.  The examinations will include evaluation of the macula, vitreous, 
and retina. 
Specular Microscopy:  Endothelial cell density will be assessed using specular microscopy 
performed on the central cornea at all sites.  The determination of central endothelial cell 
density for study entry as well as study visit measures will be determined by the Reading 
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Center.  See the Procedure Manual for further details.  The same instrument should be used 
throughout the study for a given patient.  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 eyes (eg, ocular 
surgery) during that time. 
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 gonioscopy .  See the 
Procedure Manual for further details. 
Anterior Segment-Optical Coherence Tomography:  Anterior segment-optical coherence 
tomography measurements will be performed at all sites and a Reading Center will be used to 
examine angle size for investigational purposes.  See the Anterior Segment Optical 
Coherence Tomography Image Acquisition manuals from the Reading Center for further 
details on the use of optical coherence tomography.  In the event that the anterior 
segment-optical coherence tomography 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. 
Visual Field:  Visual field examinations will be assessed using automated perimetry (using 
either Humphrey 24-2 full threshold program or 24-2 Swedish Interactive Thresholding 
Algorithm (SITA) Standard, or Octopus G1 or 24-2 and dynamic or normal strategy).  The 
same test methodology must be used throughout the entire study for a given patient. 
6.3 
Other Measures 
 
 
  See the 
Procedure Manual for details. 
 
 
  See the Procedure Manual for 
details. 
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.  See the Procedure Manual for details. 
 
 
 
 
  
See the Procedure Manual for details. 
6.3.1 
Medical History, Physical Examination, and Vital Signs  
6.3.1.1 
Medical History  
A standard medical history (including all relevant conditions that the patient has had in the 
past or currently has) will be captured in the patient source documents.  All surgical 
procedures should have an associated medical history entry.  Current medications as well as 
those stopped within 60 days prior to the Screening visit and procedures within 90 days prior 
to the Screening visit will be recorded.  In addition, all previous medications taken for OAG 
or OHT for at least 3 months prior to study entry will be recorded on the appropriate source 
document and/or eCRF page. 
6.3.1.2 
Physical Examination 
The patient will be examined by qualified medical personnel for any physical abnormality of 
the following systems:  general appearance; head, eyes, ears, nose, and throat; 
heart/cardiovascular; lungs; abdomen; neurologic; extremities; back; musculoskeletal; 
lymphatic; and skin.  The patient’s height and weight will be recorded at the Screening visit 
only. 
6.3.1.3 
Vital Signs 
The below vital signs will be measured at all patient visits and should be recorded prior to 
any invasive procedures. 
• Pulse rate (beats per minute [bpm]):  the patient should be resting in a seated position for 
a minimum of 5 minutes prior to measurement.  Pulse rate is then counted over 
30 seconds (and multiplied by 2 to obtain bpm). 
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• Blood pressure (mm Hg):  the patient should be resting in a seated position for a 
minimum of 5 minutes prior to measurement.  Systolic/diastolic blood pressure will be 
measured with a sphygmomanometer (manual sphygmomanometer or automated blood 
pressure measuring device). 
• Temperature (°C/°F):  the patient should be seated and the body temperature taken orally 
(or with an infrared forehead thermometer). 
6.3.2 
Pregnancy Testing 
Urine will be collected from females of childbearing potential for pregnancy testing (urine 
pregnancy test).  The urine test for pregnancy will be performed at the site utilizing the 
dipstick method at all specified timepoints.  Serum testing may be performed instead of urine 
testing if required by the local institution.  
Further, in countries/institutions where required by local institution or health authority, an 
additional serum test may be done any time between Baseline and Bimatoprost SR (or Sham) 
administration.  Negative results for all pregnancy tests are required to be confirmed prior to 
the time of Bimatoprost SR (or Sham) administration.  
6.3.3 
Laboratory Procedures 
A central laboratory or designated regional facility will analyze blood and urine specimens 
for this study; including any repeat laboratory tests.  Blood and urine samples will be 
obtained for the analysis of blood chemistry, hematology, and urinalysis. 
Refer to the Central Laboratory Manual for further details regarding central laboratory 
collection and shipment procedures. 
Laboratory test results will be forwarded from the central laboratory or designated regional 
facility to the study site and to Allergan or its designee.  The investigator or qualified site 
personnel must review all laboratory results for any adverse events.  Laboratory test results 
that represent adverse events should be reflected on an adverse event eCRF page. 
Evaluation and management of abnormal laboratory results should be conducted according to 
local site practice. 
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6.3.3.1 
Hematology  
Hematology will be measured and includes hematocrit, hemoglobin, glycated hemoglobin, 
mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean 
corpuscular volume, platelets, red blood cell (RBC) count, RBC morphology, total white 
blood cell (WBC) count and differential (neutrophils, bands, lymphocytes, monocytes, 
basophils, and eosinophils).  
6.3.3.2 
Serum Chemistry  
Serum chemistry will include albumin, alkaline phosphatase, alanine transaminase, aspartate 
transaminase, bicarbonate, calcium, chloride, creatinine, creatine kinase, direct bilirubin, 
glucose, indirect bilirubin, magnesium, phosphorous, potassium, sodium, total bilirubin, total 
cholesterol, total protein, urea nitrogen, and uric acid. 
6.3.3.3 
Urinalysis  
Urine will be analyzed for clarity, color, bilirubin, blood, glucose, ketones, leukocyte 
esterase, nitrite, pH, protein, specific gravity, urobilinogen, and microscopic sediment 
(WBCs, RBCs, casts, bacteria, crystals, and epithelial cells). 
6.4 
Other Study Supplies 
The following will be provided by Allergan or designated suppliers: 
• All supplies needed for central laboratory blood and urine sampling (urinalysis, blood 
chemistry, and hematology), urine pregnancy test kits, and ocular fluid collection kits 
• Shipping materials for shipment of laboratory samples to central laboratory  
• 
  
• As needed:  anterior segment-optical coherence tomography, anterior segment-optical 
coherence tomography software and/or module, Specular Microscope, contact 
(ultrasound) pachymetry equipment 
• 
 
 
• 
 
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• Ancillary administration procedure supplies and postoperative topical ophthalmic 
antibiotics may be supplied 
Sites that are not able to receive supplies from Allergan due to country regulations will need 
to provide their own supplies. 
Allergan will not provide any nonstudy IOP-lowering medications. 
6.5 
Summary of Methods of Data Collection 
This study will use eCRFs using remote electronic data capture through a qualified third 
party vendor.  The data will be entered on the eCRFs in a timely manner on an ongoing basis.  
The investigator is responsible for ensuring that data are properly recorded on each patient’s 
eCRFs and related documents.  An investigator who has signed the protocol signature page 
should personally sign for the case report forms (as indicated in the eCRFs) to ensure that the 
observations and findings are recorded on the eCRFs correctly and completely.  A certified 
electronic copy of the eCRF including data corrections will be provided to the site for 
archiving at the end of the study. 
A central laboratory or designated regional facility will be used for analysis of blood 
chemistry and hematology, urinalysis, and ocular fluid sample analysis (if ocular fluid is 
obtained).  Laboratory data will be transferred to Allergan on a periodic basis throughout the 
study. 
7. 
Statistical Procedures 
Two database locks will be performed:  1) when patients included in the primary analysis 
have completed the Week 24 visit or have prematurely discontinued before the Week 24 visit, 
and 2) when all patients complete the Week 52 visit or exit the study.  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 responsibilities until the next lock.  Unmasked data handling and 
appropriate data and results access will be specified prior to each lock. 
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7.1 
Analysis Populations 
The intent-to-treat (ITT) population is defined as all randomized patients, and will be used 
for efficacy analyses.   
The modified intent-to-treat (mITT) population is defined based on ITT population, but will 
exclude patients who did not receive the second implant after the implementation of 
Amendment 3. The mITT population will be used for the primary analysis.   
The per-protocol (PP) population is defined as all patients in the ITT population who have no 
protocol deviations affecting the data for primary efficacy analysis for all visits (Week 4, 
Week 12, and Week 24) in both eyes.  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 treatment and will be used for 
safety analyses.   
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 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 included in the study database but will 
be excluded from efficacy analysis. 
7.2.1 
Primary Efficacy Variable  
The primary efficacy variable is IOP change from baseline (follow up value minus baseline 
value) and the primary time period is 24 weeks (measurements for the primary analysis are 
designated for the following timepoints:  Weeks 4, 12, and 24).  
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7.2.2 
Secondary Efficacy Variables 
Secondary efficacy variables include:   
• Time to initial use of nonstudy IOP-lowering treatment (as determined by the 
investigator) 
• Percentage of Bimatoprost SR and SLT eyes achieving   20%  reduction in IOP from 
baseline  
• IOP changes from baseline at Weeks 8, 15, and 20 
7.2.3 
Other Efficacy Variables 
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 analysis will be performed for patients in the mITT population.  The 
primary efficacy variable is IOP change from baseline and Weeks 4, 12, and 24 are the 
primary analysis timepoints. 
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The null and alternative hypotheses for the comparison between Bimatoprost SR 15 ȝg 
treated eyes and SLT treated eyes at each visit of Weeks 4, 12, and 24 are: 
• Null hypothesis:  the difference in mean IOP change from baseline between the 
Bimatoprost SR 15 ȝg and SLT eye (Bimatoprost SR minus SLT) is > 1.5 mm Hg. 
• Alternative hypothesis:  the difference in mean IOP change from baseline between the 
Bimatoprost SR 15 ȝg eye and SLT eye (Bimatoprost SR minus SLT) is  1.5 mm Hg. 
IOP change from baseline will be analyzed using a mixed effect model for repeated measures 
(MMRM). The model will include IOP change from baseline as the response variable and 
treatment, visit, eye, baseline IOP, treatment-by-visit, treatment-by-baseline, 
treatment-by-eye, and visit-by-eyes interactions as covariates. Unstructured correlation for 
study visits and compound symmetry correlation for eyes will be used for repeated measures 
on the same patient; if the model fails to converge, multiple imputation (MI) will be 
implemented before MMRM. 
The mean difference between the Bimatoprost SR 15 ȝg eyes and SLT eyes (Bimatoprost SR 
15 ȝg minus SLT) in the mITT population and the corresponding 95% confidence interval 
(CI) will be constructed at each visit from MMRM analysis.  The noninferiority comparison 
for Bimatoprost SR 15 ȝg versus SLT at Weeks 4, 12, and 24 is the primary analysis.  If the 
upper limit of the 95% CI is  1.5 mm Hg at all 3 visits Bimatoprost SR 15 ȝg statistical 
noninferiority to SLT is considered demonstrated. In addition, Bimatoprost SR 15 ȝg is 
considered clinically noninferior to SLT if the upper limit of the 95% CI is  1.0 mm Hg at 2 
out of the 3 visits of Weeks 4, 12, and 24. 
As part of the sensitivity analysis for the primary efficacy analysis, a PP analysis using the 
same MMRM model as the one used in the primary efficacy analysis will be performed. The 
PP analysis will be based on the data from PP population. 
Additionally, a by-visit analysis using an ANCOVA model will be conducted using the data 
from ITT population, where the between-eye correlation will be included in the same way as 
the MMRM model used for the primary analysis. 
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7.3.2 
Secondary Efficacy Analyses   
Superiority Test of Bimatoprost SR 15 μg Versus SLT  
A superiority test of Bimatoprost SR versus SLT will be performed once noninferiority is 
demonstrated in the primary efficacy analysis.  Superiority of Bimatoprost SR versus SLT is 
considered achieved if the upper limit of the 95% CI is < 0 mm Hg at Weeks 4, 12, and 24.  
The mITT population will be used. 
Time to Initial Use of Nonstudy IOP-lowering Treatment (As Determined by the 
Investigator) 
Time to initial use of nonstudy IOP-lowering treatment from the date of first treatment 
(Bimatoprost SR and SLT) associated with each eye will be estimated. 
Additionally, for Bimatoprost SR, the time to initial use of nonstudy IOP-lowering treatment 
from the last injection and the time to initial use of nonstudy IOP-lowering treatment from 
the second injection will be analyzed similarly. 
Percentage of Bimatoprost SR and SLT Eyes Achieving  20% Reduction in IOP  
Number and percent of Bimatoprost SR and SLT eyes that have achieved a  20% reduction 
in IOP by visit in each eye will be summarized.  
IOP Change from Baseline at Weeks 8, 15, and 20 
Summary statistics will be tabulated for IOP change from baseline at Weeks 8, 15 and 20; 
     
7.3.3 
Other Efficacy Analyses 
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7.3.4 
Safety Analyses 
Safety analyses will be performed for patients in Stage 1 and in Stage 2 safety populations.  
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, and biomicroscopic and 
ophthalmoscopic examinations (including gonioscopy with Bimatoprost SR implant 
assessment, optic disc examination, and dilated fundus examination). 
Ocular adverse events and safety variables will be summarized by Bimatoprost SR or SLT 
eye, 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 will be detailed in the Statistical Analysis Plan. 
7.5 
Sample Size Calculation 
The sample size calculation is based on paired-eye differences using a normal approximation 
with a 2-sided significance level of 0.05, assuming that there is no difference in mean IOP 
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change from baseline between Bimatoprost SR eyes and SLT eyes and that change from 
baseline in IOP has a standard deviation of 4 mm Hg.  A sample size of 144 patients will 
provide approximately 98% power in showing noninferiority in 3 out of 3 timepoints with a 
noninferiority margin of 1.5 mm Hg, and 90% power in showing noninferiority in 2 out of 
3 timepoints with a noninferiority margin of 1.0 mm Hg, assuming that both the 
between-eyes and the within-patient correlation coefficients are 0.5. 
Assuming a premature discontinuation rate of 10%, approximately 160 patients are to be 
enrolled into this study (including approximately 40 patients in Stage 1 and 120 patients in 
Stage 2). 
7.6 
Interim Analyses 
No interim analyses are planned.  
8. 
Study Visit Schedule and Procedures 
Patients who complete all study treatments will have a minimum of 20 visits and 5 phone 
calls.  The schedule includes the following:  
• Screening (up to 28 days); Washout period of up to 42 days for both eyes; and Baseline 
visit (up to 3 days) 
• SLT treatment (Day 1) and phone call (Day 2)  
• Bimatoprost SR Cycle 1 administration (Day 4); Cycle 1 Day 2 safety visit; Cycle 1 
Day 4 and Week 2 phone calls; and follow-up study visits at Weeks 4, 8, 12, and 15 
• Bimatoprost SR Cycle 2 administration at Week 16; Cycle 2 Day 2 safety visit; Cycle 2 
Day 4 and Week 2 phone calls; and follow-up study visits at Weeks 20, 24, 28, and 31 
With implementation of Amendment 3, no new patients can be enrolled into the study and 
study treatment/retreatment of enrolled patients will not be permitted. 
• Follow-up visits at Weeks 36, 40, 44, 47, and 52/Exit 
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Stage 1 patients had an additional 2 visits and 2 phone calls as follows: 
• Bimatoprost SR Cycle 3 administration at Week 32; Cycle 3 Day 2 safety visit; Cycle 3 
Day 4 and Week 2 phone calls 
IOP evaluations will occur at Hour 0 (08:00 AM ± 1 hour) in all patients.  Selected patients at 
selected sites will have additional IOP measurements performed at Hour 2 (Hour 0 + 2 hours 
[± 30 minutes]) and Hour 8 (Hour 0 + 8 hours [± 30 minutes]). 
The study visits should adhere as closely as possible to the schedule shown in Table 2 
through Table 6. 
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 (EU 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 patient number that will be 
used on patient documentation throughout the study.   
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 and Reading Center confirmation of endothelial cell density by 
specular microscopy.   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. 
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If patients cannot discontinue their prescribed therapy for up to 6 weeks to meet the washout 
period for study entry, the investigator may switch the patient’s medication to one that 
requires a shorter washout interval during the washout of the original medication (Table 7).  
Nonetheless, the investigator should adhere to the minimum washout period for all 
IOP-lowering medications as indicated in Table 7. 
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. 
Table 7 
Minimum Washout Period by Ophthalmic Medication Class 
Ophthalmic Medications 
Minimum 
Washout Period 
Parasympathomimetics (eg, PILAGAN®, Carbachol, Pilocar®) 
4 days 
Carbonic Anhydrase Inhibitors (topical or systemic) (eg, Diamox®, Trusopt®, 
Azopt®) 
4 days 
Sympathomimetics (eg, PROPINE®, Epifrin®) 
14 days 
Alpha-agonists (eg, ALPHAGAN P, Iopidine®) 
14 days 
Beta-adrenergic blocking agents (eg, Timoptic®, BETAGAN®, Betoptic®, 
Betoptic-S®, Opti-Pranolol®, Ocupress®, Timoptic XE®) 
28 days 
Rho kinase inhibitors (eg, Rhopressa®, Glanatec®) 
28 days 
Prostamides, prostaglandins and prostaglandin analogues, as well as combination 
products that include these medications (eg, LUMIGAN, Xalatan, Travatan, 
Rescula®, GANFORT®) 
28 days 
Combination therapy (for example, COMBIGAN® [28 days], Cosopt® [28 days], 
GANFORT® [28 days], Simbrinza® [14 days], Azarga® [28 days], etc) 
longest minimum 
duration of any 
component based 
on medication class 
 
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. 
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 
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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 prior to beginning 
Washout.  After confirmation of eligibility on Day 1, the interactive response system is 
contacted for randomization.  However, this contact for randomization may take place at the 
end of the baseline day 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 (SLT or Sham SLT). 
8.4 
Visits and Associated Procedures  
With implementation of Amendment 3, no new patients can be enrolled into the study and 
study treatment/retreatment of enrolled patients will not be permitted. 
The following sections provide a list of procedures for each scheduled visit.  Additional 
information on the examination procedures, equipment, and techniques for the measures 
listed in this section is presented in the Procedure Manual. 
Ocular examination procedures should be performed in the order listed at each visit.  
Flexibility in procedure order is allowed, as indicated in the tables (Table 2 to Table 5). 
Noncontact examinations may be performed at any time prior to gonioscopy (including 
before or after Hour 0 IOP).   Intraocular pressure should be measured at approximately the 
same time of day at each visit.  Hour 0 is defined as 8:00 AM ± 1 hour.  All IOP 
measurements for a given visit day must be completed prior to performing any examination 
procedures that require pupil dilation. 
Examiners performing IOP measurements should be masked to the patient’s treatment group.  
Effort should be made to keep IOP examiners masked to the patient’s other evaluation 
results. 
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 carried out.  Intraocular pressure 
measurements must be performed in 1 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 
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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 (at rest  5 minutes) 
• Collection of blood and urine samples 
The following procedures should be performed in both eyes in the order below (procedures in 
bold should be done in the order shown): 
• Pre-Hour 0 examination (perform before Hour 0 IOP): 
• Macroscopic conjunctival hyperemia assessment  
• Manifest refraction (Manifest refraction will be used to provide a correction for 
best-corrected visual acuity testing.  At all study visits, if there is a 2-line or more 
reduction in visual acuity from the last best-corrected visual acuity performed, a 
repeat manifest refraction in both eyes and best-corrected visual acuity will be 
performed.) 
• Best-corrected visual acuity 
• Intraocular pressure measurement at Hour 0 
• Non-contact examinations: The following may be performed in any order, at any 
time before gonioscopy (including prior to Hour 0 IOP): 
• Visual field (Two visual field tests are required prior to the administration 
procedure.  The first can be performed up to 10 months prior to or at Screening, 
and the second during the washout period or at the Baseline visit.  For a given 
patient, the same test methodology must be used for fields that are historical as 
well as fields performed throughout the study.) 
• Specular microscopy 
• Anterior segment-optical coherence tomography  
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• 
 
  Assessment will be 
repeated at Week 52/Exit and may be performed at any interim study visit at the 
discretion of the investigator.) 
• Biomicroscopy  
• Gonioscopy/angle assessment (The examination at Screening will be independently 
performed by 2 ophthalmologists for eligibility purposes. Examination will also 
include, 
 
) 
• Pachymetry (may be performed at any time after gonioscopy) 
• Pupil dilation (Post-dilation examinations below may be performed in any order) 
• Dilated ophthalmoscopy 
• Optic disc examination 
Eligibility is then determined and the interactive response system is contacted. 
Washout may begin after Screening visit procedures have been completed and the Reading 
Center has confirmed central endothelial cell density (see Section 8.2 for a description of 
washout).   
8.4.2 
Baseline Visit 
The Baseline visit occurs after the washout period has been completed.  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 or on a different day. 
• Collection of medical and ophthalmic history (confirmation) 
• Collection of adverse events 
• Collection of concomitant medications and procedures 
• Completion of Visual Field Questionnaire-25 (VFQ-25) 
• Vital signs (at rest  5 minutes) 
• Pregnancy test for females of childbearing potential (as defined in Section 4.5.3) 
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The following procedures should be performed in both eyes (procedures in bold should be 
done in the order shown): 
• Pre-Hour 0 examination (perform before Hour 0 IOP): 
• Macroscopic conjunctival hyperemia assessment (The examination may also 
include, 
 
 
• Manifest refraction (Manifest refraction will be used to provide a correction for 
best-corrected visual acuity testing.  At all study visits, if there is a 2-line or more 
reduction in visual acuity from the last best-corrected visual acuity performed, a 
repeat manifest refraction in both eyes and best-corrected visual acuity will be 
performed.) 
• Best-corrected visual acuity 
• Intraocular pressure measurement at Hour 0  
• Non-contact examinations: The following may be performed in any order, at any 
time before Hour 8 IOP (including prior to Hour 0 IOP): 
• Macroscopic iris color assessment 
• Visual field (If dilation is required to perform this test, then the visual field test 
should be performed after the last IOP measurement of the day.) 
• Biomicroscopy (The examination may also include, 
 
 
• Intraocular pressure measurements at Hours 2 and 8 (at selected sites in 
consenting patients) 
• Pupil dilation (post-dilation examinations below may be performed in any order) 
• Dilated ophthalmoscopy 
• Optic disc examination 
Determine eligibility and enter Hour 0 IOP into the interactive response system.  
8.4.3 
Treatment Period 
8.4.3.1 
Day 1 SLT Administration 
The following procedures are performed on the day of SLT or Sham SLT administration: 
• Collection of adverse events 
• Collection of concomitant medications and procedures 
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• Vital signs (at rest  5 minutes) 
• Confirm eligibility 
• Contact interactive response system for randomization (this contact may take place 1 day 
prior to the administration day, if needed)   
• Preoperative IOP measurement (measurement does not need to be masked and only 
1 measurement needs to be performed) 
• Administer assigned study treatment (360  or Sham SLT; see details in Section 5.9.2) 
• Postoperative biomicroscopy 
• Postoperative IOP measurement (measurement does not need to be masked and only 1 
measurement needs to be performed)  
All patients must remain at the surgical facility for at least 1 hour for bilateral eye 
examination after 360  or Sham SLT administration.   
Each patient will be supplied a bottle of topical NSAID eyedrops and instructions to use 
them 4 times daily for the next 3 days (including the day of the administration) in both eyes 
and to follow up as per protocol. 
8.4.3.2 
Day 2 (Phone Call) 
On the day after study treatment administration, the patient will be contacted by telephone to 
collect the following: 
• Collection of adverse events 
• Collection of concomitant medications and procedures 
If the patient reports symptoms or findings of concern in the Day 2 phone call (including but 
not limited to photophobia, blurred vision, eye pain, vitreous floaters), the investigator must 
bring the patient in for ophthalmic examination 
8.4.3.3 
Day 4 (Bimatoprost SR Cycle 1 Administration) 
With implementation of Amendment 3, no new patients can be enrolled into the study and 
study treatment/retreatment of enrolled patients will not be permitted. 
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Only for those patients enrolled prior to Amendment 3, the following procedures are 
performed on the day of Bimatoprost SR administration: 
• Collection of adverse events 
• Collection of concomitant medications and procedures 
• Vital signs (at rest  5 minutes) 
• Contact interactive response system for kit allocation    
• Administer assigned study treatment (Bimatoprost SR or Sham Bimatoprost SR; see 
details in Section 5.9) 
• Contact interactive response system to confirm kit assignment if applicable 
All patients must remain at the surgical facility for bilateral eye examination at least 1 hour 
after Bimatoprost SR administration or sham administration procedure.  For patients with 
sickle cell disease or trait (or other hemoglobinopathies), the investigator may perform 
optional biomicroscopy and measure IOP in both eyes 4 hours after the administration 
procedure as desired.  This 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 full procedure instructions 
in the Procedure Manual. 
Each patient will be supplied a bottle of topical ophthalmic antibiotic drops and instructions 
to use them for the next 3 days (including the day of the administration) in both eyes and to 
follow up as per protocol. 
8.4.3.4 
Cycle 1:  Day 2 (Cycle 1 Safety Visit) 
The following procedures are performed on Cycle 1 Day 2: 
• Collection of adverse events 
• Collection of concomitant medications and procedures 
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• Vital signs (at rest  5 minutes) 
The following procedures should be performed in both eyes (procedures in bold should be 
done in the order shown): 
• Pre-Hour 0 examinations (may perform in any order before Hour 0 IOP):  
• Macroscopic conjunctival hyperemia assessment (The examination may also 
include, 
 
.) 
• Best-corrected visual acuity 
• Intraocular pressure measurement at Hour 0 
• Non-contact examination: The following may be performed at any time after the 
pre-Hour 0 examinations (including prior to Hour 0 IOP):  
• Biomicroscopy (The examination may also include, 
 
 
 
8.4.3.5 
Cycle 1:  Day 4 and Week 2 (Cycle 1 Phone Calls) 
On Cycle 1 Day 4 and Cycle 1 Week 2, the patient will be contacted by telephone to collect 
the following: 
• Collection of adverse events 
• Collection of concomitant medications and procedures 
If the patient reports symptoms or findings of concern in the Day 4 or Week 2 phone call 
(including but not limited to photophobia, blurred vision, eye pain, vitreous floaters), the 
investigator must bring the patient in for ophthalmic examination. 
8.4.3.6 
Cycle 1:  Weeks 4, 8, 12, and 15 
The following procedures are performed at Weeks 4 (±4 days), 8 (± 4 days), 12 (±4 days), 
and 15 (±4 days): 
• Collection of adverse events 
• Collection of concomitant medications and procedures 
• Vital signs (at rest  5 minutes) 
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The following procedures should be performed in both eyes (procedures in bold should be 
done in the order shown): 
• Pre-Hour 0 examinations (may be performed in any order before Hour 0 IOP): 
• Macroscopic conjunctival hyperemia assessment (The examination may also 
include, 
 
 
• Best-corrected visual acuity 
• Intraocular pressure measurement at Hour 0  
• Non-contact examinations: The following may be performed in any order, at any 
time before gonioscopy (including prior to Hour 0 IOP): 
• Macroscopic iris color assessment (Weeks 4 and 12 only) 
• Manifest refraction (Week 12 only) 
• Specular microscopy (Weeks 4 and 12 only) 
• Biomicroscopy (The examination may also include, 
 
 
 
• Intraocular pressure measurement at Hours 2 and 8 (at selected sites in 
consenting patients; Week 12 only) 
• Gonioscopy/angle assessment (The examination will also include, 
 
. Perform 
gonioscopy at least 2 hours prior to H8 IOP measurement at Week 12.) 
• Pachymetry (may be done any time after gonioscopy; Weeks 4 and 12 only) 
• Pupil dilation (Week 12 only) (post dilation examinations below may be performed 
in any order) 
• Dilated ophthalmoscopy (Week 12 only) 
• Optic disc examination (Week 12 only) 
8.4.3.7 
Week 16 (Bimatoprost SR Cycle 2 Day 1 Administration) 
With the implementation of Amendment 3, patients who are enrolled and have not yet 
reached Week 16 will not receive Cycle 2 administration and will be followed for the 
duration of the study through the Week 52/Exit visit.  Therefore, the Week 16 will not be 
required for these patients.   
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The following procedures are performed at Week 16 (-2/+4 days): 
• Collection of adverse events 
• Collection of concomitant medications and procedures 
• Vital signs (at rest  5 minutes) 
• Contact interactive response system for kit allocation (this contact may take place 1 day 
prior to the Cycle 2 administration day, if needed) 
• Administer assigned study treatment 
• Contact interactive response system to confirm kit assignment if applicable 
All patients must remain at the surgical facility for bilateral eye examination at least 1 hour 
after Bimatoprost SR administration or sham administration procedure.  For patients with 
sickle cell disease or trait (or other hemoglobinopathies), the investigator may perform 
optional biomicroscopy and measure IOP in both eyes 4 hours after the administration 
procedure as desired.  This 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 full procedure instructions 
in the Procedure Manual. 
8.4.3.8 
Cycle 2:  Day 2 (Cycle 2 Safety Visit) 
This visit is not required if Cycle 2 is not received.   
The following procedures are performed on Cycle 2 Day 2: 
• Collection of adverse events 
• Collection of concomitant medications and procedures 
• Vital signs (at rest  5 minutes) 
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The following procedures should be performed in both eyes (procedures in bold should be 
done in the order shown): 
• Pre-Hour 0 examinations: 
• Macroscopic conjunctival hyperemia assessment (The examination may also 
include, 
 
.) 
• Best-corrected visual acuity 
• Intraocular pressure measurement at Hour 0 
• Non-contact examination: The following may be performed at any time after the 
pre-Hour 0 examinations (including prior to Hour 0 IOP): 
• Biomicroscopy (The examination may also include, 
 
 
 
8.4.3.9 
Cycle 2:  Day 4 and Week 2 (Cycle 2 Phone Calls) 
These phone calls are not required if Cycle 2 is not received.   
On Cycle 2 Day 4 and Cycle 2 Week 2, the patient will be contacted by telephone to collect 
the following: 
• Collection of adverse events 
• Collection of concomitant medications and procedures 
If the patient reports symptoms or findings of concern in the Day 4 or Week 2 phone call 
(including but not limited to photophobia, blurred vision, eye pain, vitreous floaters), the 
investigator must bring the patient in for ophthalmic examination. 
8.4.3.10 
Cycle 2:  Weeks 20, 24, 28, and 31 
The following procedures are performed at Weeks 20 (± 4 days), 24 (±4 days), 28 (± 4 days), 
and 31 (± 4 days): 
• Collection of adverse events 
• Collection of concomitant medications and procedures 
• Vital signs (at rest  5 minutes) 
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The following procedures should be performed in both eyes (procedures in bold should be 
done in the order shown): 
• Pre-Hour 0 examinations: 
• Macroscopic conjunctival hyperemia assessment (The examination may also 
include, 
 
 
• Best-corrected visual acuity 
• Intraocular pressure measurement at Hour 0  
• Non-contact examinations: The following may be performed in any order, at any 
time before gonioscopy (including prior to Hour 0 IOP): 
• Macroscopic iris color assessment (Week 24 only) 
• Manifest refraction (Week 24 only) 
• Visual field (If dilation is required to perform this test, then the visual field test 
should be performed after the last IOP measurement of the day.) (Week 24 only) 
• Specular microscopy (Week 24 only) 
• Biomicroscopy (The examination may also include, 
 
 
) 
• Intraocular pressure measurement at Hours 2 and 8 (at selected sites in 
consenting patients; Week 24 only) 
• Gonioscopy/angle assessment (The examination will also include, 
 
) 
• Pachymetry (Week 24 only) (may be done any time after gonioscopy) 
• Pupil dilation (may perform post-dilation eye exams in any order; Week 24 only) 
• Dilated ophthalmoscopy (Week 24 only) 
• Optic disc examination (Week 24 only) 
8.4.3.11 
For Stage 1 Patients Only:  Week 32 (Bimatoprost SR Cycle 3 
Day 1 Administration) 
The following procedures are performed at Week 32 (-2/+4 days): 
• Collection of adverse events 
• Collection of concomitant medications and procedures 
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• Vital signs (at rest  5 minutes) 
• Contact interactive response system for kit allocation (this contact may take place 1 day 
prior to the Cycle 2 administration day, if needed) 
• Administer assigned study treatment 
• Contact interactive response system to confirm kit assignment if applicable 
All patients must remain at the surgical facility for bilateral eye examination at least 1 hour 
after Bimatoprost SR administration or Sham administration procedure.  For patients with 
sickle cell disease or trait (or other hemoglobinopathies), the investigator may perform 
optional biomicroscopy and measure IOP in both eyes 4 hours after the administration 
procedure as desired.  This 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 full procedure instructions 
in the Procedure Manual. 
8.4.3.12 
For Stage 1 Patients Only:  Cycle 3:  Day 2 (Cycle 3 Safety 
Visit) 
The following procedures are performed on Cycle 3 Day 2: 
• Collection of adverse events 
• Collection of concomitant medications and procedures 
• Vital signs (at rest  5 minutes) 
The following procedures should be performed in both eyes in the order below: 
• Pre-Hour 0 examinations: 
• Macroscopic conjunctival hyperemia assessment (The examination may also 
include, 
 
 
• Best-corrected visual acuity 
• Intraocular pressure measurement at Hour 0 
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• Non-contact examination: The following may be performed at any time after the 
pre-Hour 0 examinations (including prior to Hour 0 IOP): 
• Biomicroscopy (The examination may also include, 
 
 
) 
8.4.3.13 
For Stage 1 Patients Only:  Cycle 3:  Day 4 and Week 2 
(Cycle 3 Phone Calls) 
On Cycle 3 Day 4 and Cycle 3 Week 2, the patient will be contacted by telephone to collect 
the following: 
• Collection of adverse events 
• Collection of concomitant medications and procedures 
If the patient reports symptoms or findings of concern in the Day 4 or Week 2 phone call 
(including but not limited to photophobia, blurred vision, eye pain, vitreous floaters), the 
investigator must bring the patient in for ophthalmic examination 
8.4.3.14 
Weeks  36, 40, 44, 47, and 52/Exit 
The following procedures are performed at Weeks 36 (± 4 days), 40 (± 4 days), 44 (± 4 days), 
47 (± 4 days), and 52/Exit (± 7 days): 
• Collection of adverse events 
• Collection of concomitant medications and procedures 
• Vital signs (at rest  5 minutes) 
• Pregnancy test for females of childbearing potential (as defined in Section 4.5.3) (Week 
52/Exit only) 
The following procedures should be performed in both eyes (procedures in bold should be 
done in the order shown): 
• Pre-Hour 0 examinations (may perform in any order before Hour 0 IOP): 
• Macroscopic conjunctival hyperemia assessment (The examination will also 
include, 
 
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 may be 
performed at interim visits for appearance of or increase/decrease in hyperemia.) 
• Best-corrected visual acuity 
• Intraocular pressure measurement at Hour 0 
• Non-contact examinations: The following may be performed in any order, at any 
time before gonioscopy (including prior to Hour 0 IOP): 
• Macroscopic iris color assessment (Week 52/Exit only) 
• Manifest refraction (Week 52/Exit only) 
• Visual field  (If dilation is required to perform this test, then the visual field test 
should be performed after the last IOP measurement of the day.) (Week 52/Exit 
only) 
• Specular microscopy (Weeks 40 and 52/Exit only) 
• 
 (at Week 52/Exit at selected sites in 
both eyes of all consenting patients who underwent assessment at Screening; may 
be done at interim visits at the discretion of the investigator.  Perform any contact 
assessments following IOP measurements.) 
• Biomicroscopy (The examination will also include, 
 
 
 may be performed at interim visits for appearance of 
or increase/decrease in hyperemia.)  
• Gonioscopy/angle assessment (The examination will also include, 
 
.)  
• Pachymetry (Weeks 40 and 52/Exit only) (may be done any time after gonioscopy) 
• Pupil dilation (Weeks 40 and 52/Exit only) (post dilation exams below may be 
performed in any order) 
• Dilated ophthalmoscopy (Weeks 40 and 52/Exit only) 
• Optic disc examination (Weeks 40 and 52/Exit only) 
• Contact interactive response system at Week 52/Exit to report patient’s exit status 
8.5 
End of Study 
The end of the clinical phase of the study will be considered achieved when last patient has 
completed his or her last study visit. 
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8.6 
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. 
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 be instructed to remove their contact lenses before instillation of any topical 
ophthalmic medication, and to keep contact lenses out for at least 15 minutes after instillation 
of eye drops. 
8.7 
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. 
8.8 
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. 
8.9 
Early Discontinuation of Patients 
Patients may voluntarily withdraw from the study at any time. 
Patients who have received nonstudy IOP-lowering medication in one or both eyes, or who 
do not undergo Cycle 2 (or Cycle 3, for Stage 1 patients) administration, will be followed for 
the duration of the study through the Week 52/Exit visit. 
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If the implant has been removed, the patient may discontinue the study if based on 
investigator assessment the eye is in stable condition, at which time they should complete the 
Week 52/Exit visit procedures. 
Notification of early patient discontinuation from the study and the reason for discontinuation 
will be made to Allergan and will be clearly documented on the appropriate case report form. 
When patients discontinue before Week 52/Exit, the site should complete all procedures for 
the Week 52/Exit visit at the patient’s last visit. 
8.10 
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 treatment in one or both eyes, or who do not undergo Cycle 2 (or Cycle 3, for 
Stage 1 patients ) administration will continue through the duration of the study. 
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 is unwilling or unable to continue to comply with study procedures 
• Patient is unwilling or unable to continue in the study 
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. 
8.11 
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. In the 
event that the study is stopped, patients will be followed for 16 weeks after their last 
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Bimatoprost SR (or Sham) administration, after which they will return to standard of care as 
per the investigator’s discretion.  
9. 
Adverse Events  
Adverse events occurring during the study will be recorded on an adverse event case report 
form.  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 
patient administered a pharmaceutical product and that does not necessarily have a causal 
relationship with the 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.  This definition includes events related to the medical 
(investigational) product (Bimatoprost SR implant and applicator combination) or 
comparator medical device (SLT), and events related to the procedures involved, and also 
includes any malfunction or deterioration in the characteristics and/or performance of a 
device.  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 treatment. 
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. 
IOP return to baseline following the cessation of the Bimatoprost SR treatment effect should 
not be considered an adverse event. 
Adverse events will be assessed, documented, and recorded in the eCRF throughout the study 
(ie, after informed consent has been obtained).  At each visit, the investigator will begin by 
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 
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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. 
Pre-planned surgeries or procedures for pre-existing, known medical conditions for which a 
patient requires hospitalization is not reportable as a serious adverse event. 
Any pre-planned 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. 
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. 
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9.1.4 
Relationship to Study Drug, Device, or Procedure 
A determination will be made of the relationship (if any) between an adverse event and the 
study drug, device, or 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 study drug, device, or procedure.   
If an adverse event is deemed related to study drug or device, the investigator will be asked 
to further delineate whether the adverse event was related to the administration procedure 
(versus the study drug or device). 
Note:  A study procedure occurring during the screening/baseline period can include a 
washout of 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 study drug or device-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. 
9.3 
Procedures for Reporting a Serious Adverse Event 
Any serious adverse event occurring during the study period (beginning with informed 
consent and continuing through the final study visit) 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) as listed on the Allergan Study Contacts Page and recorded on the serious adverse 
event form.  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 by fax or email using the serious adverse event form 
(contact details can be found on page 1 of the serious adverse event form); phone 
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numbers and relevant Allergan personnel contacts are also on the front page of 
protocol and Study Contacts Page. 
2. Obtain and maintain in his/her files all pertinent medical records, information, and 
medical judgments from colleagues who assisted in the treatment and follow-up of 
the patient. 
3. Provide Allergan with a complete, written description of the adverse event(s) on the 
serious adverse event form describing the event chronologically, including any 
treatment given (eg, medications administered, procedures performed) for the adverse 
event(s).  Summarize relevant clinical information about the event:  signs, symptoms, 
diagnosis, clinical course and relevant clinical laboratory tests, etc.  Include any 
additional or alternative explanation(s) for the causality which includes a statement as 
to whether the event was or was not related to the use of the study drug, device, or 
procedure. 
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 Treatment 
The primary investigator and select site staff (eg, study coordinator) are unmasked. When 
necessary for the safety and proper treatment of the patient, the investigator can unmask the 
patient and/or other site personnel.   
When possible, the sponsor (Allergan Medical Safety Physician) should be notified prior to 
unmasking the patient and/or other site personnel. In instances where this is not possible, the 
sponsor should be notified as soon as possible thereafter.    
The reason for unmasking the patient and/or other site personnel must be recorded in the 
patient’s source documents. 
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, Allergan SOPs, and the applicable regulatory requirements. 
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10.1 
Protection of Human Patients 
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 re-approval 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.  
10.1.4 
Quality Assurance 
Compliance with the ethical and scientific ICH GCP quality standard, along with Allergan 
SOPs, on the design, conduct, recording, and reporting of clinical trials provides protection 
for the wellbeing and rights of patients as well as assuring the quality and credibility of the 
clinical trial data.  Quality Control activities will be undertaken within the quality assurance 
system to verify that the requirements for the quality of trial-related activities have been 
fulfilled. 
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10.1.5 
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 
Source documents may include a patient's medical records, hospital charts, clinic charts, the 
investigator's patient study files, as well as the results of diagnostic tests such as X-rays, 
laboratory tests, and electrocardiograms.  The investigator's copy of the case report forms 
serves as part of the investigator's record of a patient's study-related data.   
The following information should be entered into the patient's medical record: 
• Patient’s name 
• Patient’s contact information 
• The date that the patient entered the study, patient number, and patient medication kit 
number.  
• The study title and/or the protocol number of the study and the name of Allergan. 
• A statement that informed consent was obtained (including the date).  A statement that 
written authorization (US sites only), data protection consent (EU sites only), or other 
country and local patient privacy required documentation for this study has been obtained 
(including the date). 
• Dates of all patient visits 
• All concurrent medications (List all prescription and non-prescription medications being 
taken at the time of enrollment.  At each subsequent visit, changes to the list of 
medications should be recorded.) 
• Occurrence and status of any adverse events (including any procedure-related adverse 
events due to complications) 
• The date the patient exited the study, and a notation as to whether the patient completed 
the study or reason for discontinuation. 
• The results of laboratory tests performed by the site (eg, blood chemistry and 
hematology, urinalysis, and pregnancy tests) 
• Key study variables 
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o Documentation of the patient's medical history 
o Vital signs, physical examination findings 
o IOP and ophthalmic examination findings 
o Dates of SLT or Sham SLT administration procedure 
o Dates of Bimatoprost SR or Sham administration procedure 
o Documentation of whether any procedure including study treatment 
administration was performed according to the protocol, noting any deviations 
(if applicable) 
o 
Source documentation practices must follow Section 4.0 of ICH E6, Good Clinical Practice: 
Consolidated Guidance and ALCOA, ie, records must be Attributable, Legible, 
Contemporaneous, Original, and Accurate. 
10.4.2 
Case Report Form Completion 
The investigator is responsible for ensuring that data are properly recorded on each patient's 
eCRFs and related documents.  An investigator who has signed the protocol signature page 
should personally sign for the eCRFs (as indicated in the eCRFs) to ensure that the 
observations and findings are recorded on the eCRFs correctly and completely.  The eCRFs 
are to be submitted to Allergan in a timely manner at the completion of the study, or as 
otherwise specified by Allergan and will be maintained in a central data repository. 
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. 
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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. 
For countries falling within the scope of the ICH guidelines, Allergan-specific essential 
documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirement(s) or if needed by Allergan. 
In addition, for countries not falling within the scope of the ICH guidelines, local regulatory 
requirements should be followed regarding the retention of clinical study documentation. 
Allergan requires that it be notified in writing if the investigator wishes to relinquish 
ownership of the data so that mutually agreed-upon arrangements can be made for transfer of 
ownership to a suitably qualified, responsible person. 
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. 
The assembled Bimatoprost SR (or Sham applicator) is individually packaged into a 
laminated foil pouch with desiccant and sealed.  The entire foil pouch package is terminally 
sterilized.  Each pouch will be placed into its own carton.  The medication will be identified 
as an investigational product.  The study number and medication kit number will be 
identified on the medication labels. 
The study medication contents are described in Sections 5.1 and 5.2. 
10.5.2 
Clinical Supply Inventory 
The investigator must keep an accurate accounting of the number of investigational units 
received from Allergan, dispensed or administered to the patients, the number of units 
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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 or administered 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.  Used applicators will be disposed of immediately in a 
sharps container. 
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 Allergan 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 or a 
designated regional facility with certification from a recognized accreditation agency (eg, 
College of American Pathology or Clinical Laboratory Improvement Amendments 
certification) to be assayed using validated methods.  All blood and urine samples will be 
stored at the centralized clinical laboratory following testing, and will be discarded after a 
time period indicated by Allergan.  Allergan shall have full ownership rights to any biological 
specimens/samples derived from the study. 
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See the Covance Laboratory Manual and the Procedure Manual for procedural details. 
10.8 
Publications 
Allergan as the sponsor, has proprietary interest in this study.  Authorship and manuscript 
composition will reflect joint cooperation between multiple investigators and sites and 
Allergan personnel.  Authorship will be established prior to the writing of the manuscript.  As 
this study involves multiple centers, no individual publications will be allowed prior to 
completion of the final report of the multicenter study except as agreed with Allergan.   
10.9 
Coordinating Investigator 
A signatory Coordinating Investigator will be designated prior to the writing of the Clinical 
Study Report. 
10.10 
 
 
 
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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. 
Damji KF, Bovell AM, Hodge WG, Rock W, Shah K, Buhrmann R, et al. Selective laser 
trabeculoplasty versus argon laser trabeculoplasty: results from a 1Ǧyear randomised clinical 
trial. Br J Ophthalmol. 2006;90(12):1490-1494. Epub 09 Aug 2006. 
Damji KF, Shah KC, Rock WJ, Bains HS, Hodge WG. Selective laser trabeculoplasty v 
argon laser trabeculoplasty: a prospective randomised clinical trial. Br J Ophthalmol. 
1999;83(6):718-22. 
European Glaucoma Society (EUGS). Terminology and Guidelines for Glaucoma. 4th ed. 
PubliComm: Italy; 2014. 187p.  
Francis BA, Ianchulev T, Schofield JK, Minckler DS. Selective laser trabeculoplasty as a 
replacement for medical therapy in open-angle glaucoma. Am J Ophthalmol. 
2005;140(3)524-525. 
Friedman DS. Introduction: new insights on enhancing adherence to topical glaucoma 
medications. Ophthalmology. 2009;116:S29. 
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. 
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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(6):701-713; discussion 829-830. 
Katz LJ, Steinmann WC, Kabir A, Molineaux J, Wizov SS, Marcellino G, et al. Selective 
laser trabeculoplasty versus medical therapy as initial treatment of glaucoma: a prospective, 
randomized trial. J Glaucoma. 2012;21(7):460-468. 
Koucheki B, Hashemi H. Selective laser trabeculoplasty in the treatment of open-angle 
glaucoma. J Glaucoma. 2012;21(1):65-70. 
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-S11. 
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. 
Martinez-de-la-Casa JM, Garcia-Feijoo J, Castillo A, Matilla M, Macias JM, Benitez-del-
Castillo JM, et al. Selective vs argon laser trabeculoplasty: hypotensive efficacy, anterior 
chamber inflammation, and postoperative pain. Eye (Lond). 2004;18(5):498-502. 
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. 
McAlinden C. Selective laser trabeculoplasty (SLT) vs other treatment modalities for 
glaucoma: systematic review. Eye (Lond). 2014;28(3):249-258. 
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Mosaed S, Dustin L, Minckler DS. Comparative outcomes between newer and older 
surgeries for glaucoma. Trans Am Ophthalmol Soc. 2009;107:127-133; discussion 134-135. 
Nagar M, Luhishi E, Shah N. Intraocular pressure control and fluctuation: the effect of 
treatment with selective laser trabeculoplasty. Br J Ophthalmol. 2009;93(4):497-501. 
Olthoff CM, Schouten JS, van de Borne BW, Webers CA. Noncompliance with ocular 
hypotensive treatment in patients with glaucoma or ocular hypertension an evidence-based 
review. Ophthalmology. 2005;112(6):953-961. 
Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. 
Br J Ophthalmol. 2006;90(3):262-267. 
Quigley HA, Enger C, Katz J, Sommer A, Scott R, Gilbert D.  Risk factors for the 
development of glaucomatous visual field loss in ocular hypertension.  Arch Ophthalmol. 
1994;112:644-649. 
Realini T. Selective laser trabeculoplasty: a review. J Glaucoma. 2008;17(6):497-502. 
Rolim de Moura CR, Paranhos Jr A, Wormald R. Laser trabeculoplasty for open angle 
glaucoma. Cochrane Database Syst Rev. 2007;17(4):CD003919. 47 p. 
Stamper RL, Lieberman MF, Drake MV. Introduction and classification of the glaucomas. In: 
Becker-Shaffer’s Diagnosis and Therapy of the Glaucomas. 8th ed. Amsterdam: Mosby 
Elsevier; 2009. p. 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. 
Wang H, Cheng JW, Wei RL, Cai JP, Li Y, Ma XY. Meta-analysis of selective laser 
trabeculoplasty with argon laser trabeculoplasty in the treatment of open-angle glaucoma. 
Can J Ophthalmol. 2013;48(3):186-192. 
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. 
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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 
Not applicable 
12.1 
Glossary of Abbreviations 
Term/Abbreviation 
Definition 
ABMD 
Anterior Basement Membrane Disease 
AC 
anterior chamber 
AGIS 
Advanced Glaucoma Intervention Study 
ALT 
argon laser trabeculoplasty 
ARMD 
Age-related macular degeneration 
ASC 
Ambulatory Surgical Center 
BLQ 
below the limit of quantitation 
CI 
confidence interval 
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 Practice 
GLP 
Good Laboratory Practice 
H 
hour 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
IOL 
intraocular lens  
IOP 
intraocular pressure 
IRB 
institutional review board 
ITT 
intent-to-treat 
LOCF 
last observation carried forward  
LT 
laser trabeculoplasty 
MDF 
Map-Dot-Fingerprint 
MedDRA 
Medical Dictionary for Regulatory Activities 
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Term/Abbreviation 
Definition 
NSAID 
nonsteroidal anti-inflammatory drug 
OAG 
open-angle glaucoma 
OHT 
ocular hypertension 
OU 
both eyes 
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 
SLT 
selective laser trabeculoplasty 
SOC 
system organ class 
SOP 
standard operating procedures 
SR 
sustained release 
US 
United States 
WBC 
white blood cell 
WOCF 
worst (postrandomization) observation carried forward 
X  
perform procedure  
 
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Section 
Revision 
Rationale 
o 
Peripheral anterior segment optical coherence 
tomography assessment prior to beginning Washout 
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. 
Under key exclusion criteria, revised the subheading from 
“Both Eyes” to “Ocular.” 
Revised the following key exclusion criterion: 
• 
The following surgical history: 
a. 
History or evidence of complicated cataract 
 
surgery: eg, surgery resulting in complicated lens 
 
placement (such as anterior chamber (AC) 
 
intraocular lens (IOL) implant, 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 
Table 2 
Changed visit window for the Baseline visit from Day -3 to 
-1 to up to 3 days 
Visit window text revised for clarity. 
Baseline is a period of up to 3 days. 
Table 2 
Changed footnote “a” for Table 2 to reflect change in 
procedure for confirming angle eligibility: 
Washout may begin after all screening procedures have 
been completed and the Reading Center has confirmed 
angle eligibility and central endothelial cell density.  
Minimum washout period for each medication class is 
detailed in Section 8.2. 
Changed for consistency with 
protocol revision 
Tables 2 
to 5 
Reordered some procedures and clarified which procedures 
must be performed in the order shown 
Reordered to provide additional 
flexibility to sites and patients 
Tables 3 
to 5 
Changed requirement for additional biomicroscopy and 
IOP measurements on Day 1 for patients with sickle-cell 
disease to be optional 
Based on the ongoing safety 
monitoring of the 192024-091 and 
192024-092 studies, no increased 
risk of hyphema or microhyphema 
with sickle cell trait or sickle cell 
disease is confirmed. There are 400+ 
patients who have had at least one 
Bimatoprost SR injection in the 
2 studies (estimated based on 
1:1:1 ratio), however there is only 
one report of microhyphema in a 
NON-sickle cell patient. No anterior 
chamber safety concerns have been 
reported in the 14 sickle cell disease 
or sickle cell trait patients. 
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Revision 
Rationale 
Section 
1.2 
Although the biodegradation process of the Bimatoprost 
SR implant exceeds the drug release duration, experience 
from preclinical studies, the ongoing phase 1/2 
(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. 
Updated study status 
Section 
1.2.1 
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 AC 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 (9 month timepoint including 
histopathology) in the ongoing 18-month repeat dose Good 
Laboratory Practice (GLP) study in dogs (Report 
TX12102-TX I1). 
Pharmacokinetic studies of Bimatoprost SR (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 
 μg (Generation 1 and 
Generation 2), then declined to low levels suggestive of 
near-complete drug release from the device at  months for 
doses
 μg.  By 14 weeks following a 20 ȝg (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-
Updated information from 
completed studies 
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Revision 
Rationale 
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 ȝg, 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 
1.2.3 
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, 10, 15, or 20 μg [2 × 10 μg 
implants]), as single or repeat administration in 1 eye 
(study eye), versus the use of topical LUMIGAN® 0.03% 
once daily in the contralateral 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. 
Based on available data at the time of writing, aA total of 
109 patients have received at least a single administration 
of Bimatoprost SR, and 24 havepatients received a repeat 
administration of Bimatoprost SR.  A trend in dose 
response has beenwas observed across the 4 dose strengths 
that were tested.  The 15 ȝg dose was selected for this 
study as it provided the best option to maximize efficacy 
and minimize polymer accumulation within the eye.  
Available dataData 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 efficacy to that observed 
following the first administration of Bimatoprost SR. 
Bimatoprost SR has shownshowed an acceptable safety 
profile with single and repeat administrations in ongoing 
study 192024-041D.  Most adverse events were ocular, 
mild or moderate in severity, occurred within the first 82 
days after Bimatoprost SR administration, and were 
considered related to the study drug administration 
procedure.  There have beenwere no reports of serious 
study drug-related adverse events, and no new safety 
concerns have beenwere observed after the second 
treatment.  Please refer to the Investigator’s Brochure for 
details on reported safety findings. 
Updated information from recently 
completed study 
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Revision 
Rationale 
Section 
1.3 
Preliminary resultsResults of the ongoing phase 1/2 study, 
192024-041D, suggest that Bimatoprost SR provides a 
prostaglandin analog-like IOP-lowering efficacy when used 
in the dose strength proposed for this phase 3 investigation.  
Additionally, the safety profile of Bimatoprost SR at dose 
strengths of 20 ȝg (2 × 10 ȝg) or less in the phase 1/2 study 
has beenwas acceptable and supports additional clinical 
studies in humans. 
Updated information from recently 
completed study 
Section 3 
Patients will receive a 360° administration of SLT in 1 eye 
on Day 1, and administration of Bimatoprost SR in the 
contralateral eye on Day 4, with repeat administrations of 
Bimatoprost SR at Weeks 16 and 32.  In order to mask the 
patient to the treatment assigned to each eye, on Day 1 a 
sham SLT procedure will be performed in the eye  to be 
administered Bimatoprost SR (hereafter refer to as the 
“Bimatoprost SR eye”) on Day 1 and a”).  A Sham 
Bimatoprost SR administration will be performed in the 
eye that underwent SLT (hereafter refer to as the “SLT 
eye”) on each Bimatoprost SR administration visitsvisit 
(Day 4 and Weeks 16 and 32).) (see Table 1). 
For clarification 
Section 
4.1 
Approximately 160 patients will be enrolled at 
approximately 35 68 sites in order to have an estimated 144 
patients complete the study based on a premature 
discontinuation rate of 10%. 
Revised to update the approximate 
number of sites 
Section 
4.2.1 
At screening all patients will be tested for sickle cell trait, 
sickle celldisease, and other hemoglobinopathies.  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 Bimatoprost SR administration. at the investigator’s 
discretion.  Additional information about the previous 
experience with the use of Bimatoprost SR in patients with 
sickle cell trait is provided in the IB. 
Based on the ongoing safety 
monitoring of the 192024-091 and 
192024-092 studies, no increased 
risk of hyphema or microhyphema 
with sickle cell trait 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 disease or trait patients. 
Section 
4.3 
12. The iridocorneal angle in the study eye inferiorly must 
be independently confirmed as being qualified by Reading 
Center2 ophthalmologists using the following criteria: 
a. Shaffer Grade  3 on clinical gonioscopy of the inferior 
angle 
b. Peripheral anterior segment optical coherence 
tomography assessment prior to beginning 
Washoutchamber 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. 
Based on additional information 
summarized in the Investigator’s 
Brochure, Edition 10,inclusion 
criterion for angle assessment 
revised to use clinical measures in 
order to develop a more “real-life” 
measure of angle openness.  
 
 
 
 
 
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Section 
4.4 
7. Previous or concurrent enrollment in Allergan Studies 
192024 041D, 192024 091, 192024 092, and/or 192024
095another Allergan Bimatoprost SR study 
10. History or evidence of a clinically relevant, substantial 
ocular trauma (eg, a traumatic cataract, and/or traumatic 
angle recession, etc)  
11. The following surgical history: 
a. History or evidence of complicated cataract surgery: eg, 
surgery resulting in AC complicated lens placement (such 
as anterior chamber intraocular lens (IOL) implant, 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 
15. Any history of iris color changes associated with use of 
topical prostaglandins or prostamides  
21.20. 
The anticipated wearing of contact lenses during 
the study that deviates from the following (contact lens 
wear is allowed during the study, but is to be 
temporarily discontinued before study visits, and 
before and after an Administration Day according to 
the following): 
 
a. Use of soft lenses should be discontinued at 
least   
3 days prior to Baseline (Day  3 to 1),, and use of 
 
rigid gas permeable or hard contact lenses should 
 
be discontinued at least 1 week prior to Baseline 
24.23. History of anatomically narrow angle resulting in 
evidence of angle changes or any history of closed angle 
glaucoma.  Note: historically narrow angled patients whose 
angle has been opened by cataract surgery or peripheral 
iridotomy may be eligible for enrollment if they have no 
evidence of angle abnormalities. 
25.24. History or evidence of a peripheral 
iridotomy/iridectomy in the inferior 180° of the iris  (Note:  
patients with a history of a peripheral iridotomy/ 
iridectomy in the superior 180° of the iris are eligible for 
study entry) 
Revised because multiple studies are 
ongoing. 
 
Revised for clarity. 
 
Revised for clarity. 
 
 
 
 
 
 
 
 
 
Revised for consistency. 
 
 
 
 
 
 
Revised to correct the omission of 
peripheral iridotomy. 
 
Revised for clarity. Measurement of 
degrees is not required. Note 
removed as it is unnecessary. 
Section 
4.5.1 
Note: post-procedural use of artificial tear products 
following SLT/Sham SLT administration is allowed at the 
investigator’s discretion; patients should be instructed to 
wait at least 15-20 minutes after instilling required 
medication (eg, NSAID) drops before instilling artificial 
tear products. Use of artificial tears is not allowed 
following Bimatoprost SR/Sham Bimatoprost SR 
administration except as described above (restart 3 days 
after). 
Revised to allow use of artificial 
tears following SLT administration 
at the investigator’s discretion 
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Rationale 
Section 
4.5.2 
• 
Use of LATISSE® (bimatoprost for hypotrichosis) 
during the study period in either eye 
• 
Use of RESTASIS®cyclosporine ophthalmic solution 
during the study period in either eye 
• 
Systemic use of carbonic anhydrase inhibitor (eg, 
Diamox®) 
For clarification purposes, revised to 
use generic terminology rather than 
brand names, which may not be 
identical in all study locations. 
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Rationale 
Section 
5.7 
Investigational medicinal product must be stored at a room 
temperature representing a usual and customary working 
environment, as described in the Procedure 
ManualInvestigator’s Brochure. 
With the product being under 
development, the current details on 
the storage conditions will be 
reflected in the Investigator’s 
Brochure. 
Section 
5.9.1.4 
Note:  Patients with sickle cell disease or trait (or other 
hemoglobinopathies) will be expected tomay 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 
use of the masked, 2-person reading method. 
Based on the ongoing safety 
monitoring of the 192024-091 and 
192024-092 studies, no increased 
risk of hyphema or microhyphema 
with sickle cell trait or sickle cell 
disease is confirmed. There are 400+ 
patients who have had at least one 
Bimatoprost SR injection in the 
2 studies (estimated based on 
1:1:1 ratio), however there is only 
one report of microhyphema in a 
NON-sickle cell patient. No anterior 
chamber safety concerns have been 
reported in the 14 sickle cell disease 
or sickle cell trait patients. 
Section 
5.9.1.5 
Patients who have been treated with nonstudy IOP-
lowering medication in both eyes will not attend the 
administration day visits, nor will they attend the Day 2, 
Day 84 (phone call), and Week 2 (phone call) visits 
following an administration. 
Corrected error in original protocol. 
Section 
5.9.2.1 
Instill 1 drop of apraclonidine (Iopidine) or brimonidine 
(eg, ALPHAGAN®, ALPHAGAN P) (see Procedure 
Manual) into each eye 30  minutes to 1 hour prior to SLT 
(or Sham SLT). 
For clarification purposes, revised to 
use generic terminology rather than 
brand names, which may not be 
identical in all study locations. 
Section 
6.2 
Blood and Urine Sample Collection:  Blood and urine 
samples will be collected for blood chemistry, hematology 
panels (including sickle cell testing),, and urinalysis by a 
central laboratory or designated regional facility. 
Based on the ongoing safety 
monitoring of the 192024-091 and 
192024-092 studies, no increased 
risk of hyphema or microhyphema 
with sickle cell trait or sickle cell 
disease is confirmed. There are 400+ 
patients who have had at least one 
Bimatoprost SR injection in the 
2 studies (estimated based on 
1:1:1 ratio), however there is only 
one report of microhyphema in a 
NON-sickle cell patient. No anterior 
chamber safety concerns have been 
reported in the 14 sickle cell disease 
or sickle cell trait patients. 
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Section 
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Rationale 
Section 
6.2 
Gonioscopy/Angle Assessment:  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. 
Using gonioscopy, the investigator will evaluate the 
inferior iridocorneal angle and the Bimatoprost SR implant. 
Revised for consistency with revised 
eligibility criteria. Based on 
additional information summarized 
in the Investigator’s Brochure, 
Edition 10, inclusion criterion for 
angle assessment revised to use 
clinical measures in order to develop 
a more “real-life” measure of angle 
openness 
 
Section 
6.2 
Biomicroscopy:  Biomicroscopic examinations will be 
performed using a slit lamp.  The examinations will include 
evaluation of the condition of the eyelids, conjunctiva, 
cornea, AC, (with Van Herick anterior chamber depth 
assessment at Screening only), iris/pupil, and lens (Lens 
assessment is performed using the modified AREDS 
procedure and is collected on dilated examination days 
through a dilated pupil, using the slit lamp biomicroscope. 
Please see the Procedure Manual for details). 
Revised for consistency with revised 
eligibility criteria 
 
Section 
6.2 
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 IOP Measurement and before 
gonioscopy .  See the Procedure Manual for further details. 
Revised for consistency with 
updated visit schedule 
 
Section 
6.2 
Anterior Segment-Optical Coherence Tomography:  
Anterior segment-optical coherence tomography 
measurements will be performed at all sites on all patients 
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 
analysis 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 anterior segment optical 
coherence tomography 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 eyes (eg, 
ocular surgery) during that time.and a Reading Center will 
be used to examine angle size for investigational purposes.  
Revised for consistency with revised 
eligibility criteria 
 
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Section 
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Rationale 
Section 
6.3.2 
Further, in countries/institutions where required by local 
institution or health authority, an additional serum test may 
be done any time between Baseline and Bimatoprost SR (or 
Sham) administration.  Negative results for all pregnancy 
tests are required to be confirmed prior to the time of 
Bimatoprost SR (or Sham) administration. 
Changes made to support local 
institutional and regulatory 
requirements 
Section 
6.3.3.1 
The blood tests performed at the Screening visit will 
include testing for sickle cell disease or trait by a central 
laboratory or designated regional facility, as outlined in the 
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 trait 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 disease or trait patients. 
Section 8 
• 
Screening (up to 28 days); Washout period of up to 42 
days for both eyes; and Baseline visit (Day 3up 
to 13 days) 
IOP evaluations will occur at Hour 0 (08:00 AM ± 1 
hour).) in all patients.   
Visit window text revised for clarity. 
Baseline is a period of up to 3 days. 
For clarification. 
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 anterior 
segment optical coherence tomography iridocorneal angle 
qualification.endothelial cell density by specular 
microscopy. 
Table 6: 
Combination therapy (for example, COMBIGAN® [28 
days], Cosopt® [28 days], GANFORT® [28 days], 
Simbrinza® [14 days], Azarga® [28 days], etc) longest 
minimum duration of any component based on medication 
class 
Revised for consistency with revised 
inclusion criterion 
 
 
 
 
Revised to reflect availability of new 
combination topical medications 
Section 
8.3 
Reading Center qualification of iridocorneal angle and 
endothelial cell density must be confirmed prior to 
beginning Washout. 
Revised for consistency with revised 
inclusion criterion 
 
Section 
8.4 
Ocular examination procedures should be performed in the 
order listed at each visit.  Some flexibilityFlexibility in 
procedure order is allowed.  However, the general flow of, 
as indicated in the tables (Table 2 to Table 5). Noncontact 
examinations set forth in the schedule starting with 
noncontact examinations, followed bymay be performed at 
any time prior to gonioscopy (including before or after 
Hour 0 IOP, followed by contact examinations, and 
followed by dilation and post dilation activities should be 
maintained.).    
Revised for clarity and consistency 
with tables. 
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Revision 
Rationale 
Section 
8.4.3.3, 
8.4.3.7, 
8.4.3.11 
For patients with sickle cell disease or trait (or other 
hemoglobinopathies), the investigator may perform 
optional biomicroscopy and measure IOP in both eyes 4 
hours after the administration procedure as welldesired. 
Based on the ongoing safety 
monitoring of the 192024-091 and 
192024-092 studies, no increased 
risk of hyphema or microhyphema 
with sickle cell trait 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 disease or trait patients. 
Section 
8.4.3.6 
The following procedures are performed at Weeks 4  
( (±4days), 8 (± 4 days), 12 ( (±4 days), and  
15 (+(±4 days): 
Revised for consistency with visit 
schedule 
Section 
8.4.3.7 
The following procedures are performed at Week 16  
(-2/+4 days) 
Revised for consistency with visit 
schedule 
Section 
8.4.3.10 
The following procedures are performed at Weeks 20  
(± 4 days), 24 ( (±4 days), 28 (± 4 days), and  
31 (+(± 4 days) 
Revised for consistency with visit 
schedule 
Section 
8.4.3.11 
The following procedures are performed at Week 32  
(-2/+4 days) 
Revised for consistency with visit 
schedule 
Section 
8.11 
In the event that the study is stopped, patients will be 
followed for 16 weeks after their last Bimatoprost SR (or 
Sham) administration, after which they will return to 
standard of care as per the investigator’s discretion. 
Corrected text in original protocol 
Section 
9.3 
Any serious adverse event occurring during the study 
period (beginning with informed consent and continuing 
through the final study visit) and for at least 28 days 
4 months after the last dose of study treatmentdrug must be 
immediately reported but no later than 24 hours after 
learning of a serious adverse event. 
For clarification and correction 
Section 
9.4 
The primary investigator and select site staff (eg, study 
coordinator) are unmasked. 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.  patient and/or other site personnel.   
When possible, the sponsor (Allergan Medical Safety 
Physician) should be notified prior to unmasking study 
treatment.  The investigator should inform the sponsor 
(Allergan Medical Safety Physician) of the unmasking if 
there is no notification prior to the unmasking.the patient 
and/or other site personnel. In instances where this is not 
possible, the sponsor should be notified as soon as possible 
thereafter.    
The reason for breakingunmasking the codepatient and/or 
other site personnel must be recorded in the patient’s 
source documents. 
For clarification 
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12.2.2 
Amendment 2 
Title: A Comparison of Bimatoprost SR to Selective Laser Trabeculoplasty in Patients with 
Open-Angle Glaucoma or Ocular Hypertension 
Protocol 192024-095 Amendment 2 
Date of Amendment: September 2018 
Amendment Summary 
This summary includes changes made to Protocol 192024-095 Amendment 1 (approved 
April 2017). This protocol was amended to reduce the number of administration cycles from 
3 to 2. 
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 
 
Tel (office):  
Tel (mobile): 
Email
 
Updated medical safety physician 
and Allergan signatory 
Protocol 
Summary 
Structure: multicenter, paired eye, randomized, masked, 
conducted in 2 stages: 
Stage 1:  Bimatoprost SR 15 μg vs SLT; 3 administration 
cycles for patients who were enrolled and reached the Week 
32 visit prior to implementation of Amendment 2 
Stage 2:  Bimatoprost SR 15 μg vs SLT; 2 administration 
cycles for patients who had not reached Week 32 prior to 
implementation of Amendment 2; and all patients enrolled 
under Amendment 2 
Study Treatment: Bimatoprost SR 15 μg  
Dosage/Dose Regimen: Patients will receive a 360° 
administration of SLT in 1 eye on Day 1 and an 
administration of Bimatoprost SR in the contralateral eye on 
Day 4, with a repeat administrations of Bimatoprost SR at 
Weeks 16 and 32.  Patients who were enrolled and reached 
the Week 32 visit prior to implementation of Amendment 2 
Reduced the number of 
administration cycles from 3 to 2 
across the 2 sister studies of 
Bimatoprost SR vs SLT  
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received a third administration of Bimatoprost SR at Week 
32 (Stage 1 patients). 
Table 1 
Treatment Schedule by Eye 
Treatment Visit 
Bimatoprost SR 
Eye 
SLT Eye 
SLT 
administration 
(Day 1) 
Sham SLT 
360° SLT 
Bimatoprost SR 
Cycle 1 
administration 
(Day 4) 
Bimatoprost SR 
Sham 
Bimatoprost SR 
Bimatoprost SR 
Cycle 2 
administration  
(Week 16) 
Bimatoprost SR 
Sham 
Bimatoprost SR 
Bimatoprost SR 
Cycle 3 
administration  
(Week 32) 
Bimatoprost SR 
Sham 
Bimatoprost SR 
Note:  Patients who were enrolled and reached the Week 32 visit 
prior to implementation of Amendment 2 received a third 
administration of Bimatoprost SR at Week 32. 
Visit Schedule: 
Patients who complete all study treatments will have a 
minimum of 22 20 visits and 7 5 phone calls. 
Bimatoprost SR Cycle 3 administration at Week 32; Cycle 3 
Day 2 safety visit; Cycle 3 Day 4 and Week 2 phone calls; 
and f Follow-up visits at Weeks 36, 40, 44, 47, and 52/Exit 
Patients who were enrolled and reached the Week 32 visit 
prior to implementation of Amendment 2 (Stage 1 patients) 
had an additional 2 visits and 2 phone calls as follows: 
Bimatoprost SR Cycle 3 administration at Week 32; Cycle 3 
Day 2 safety visit; Cycle 3 Day 4 and Week 2 phone calls 
Number of Patients:  Stage 1:  approximately 40 patients; 
Stage 2:  approximately 120 patients 
General Statistical Methods and Types of Analyses: 
Efficacy:  The primary efficacy analysis will be performed 
for patients in the Stage 1 and Stage 2 intent-to-treat (ITT) 
populations combined.  The primary efficacy variable is IOP 
change from baseline and the primary time period is 24 
weeks (measurements for the primary analysis are designated 
for the following timepoints:  Weeks 4, 12, and 24). 
IOP change from baseline will be analyzed using a paired t-
test.  The mean difference between the Bimatoprost SR 15 
ȝg eyes and SLT eyes (Bimatoprost SR 15 ȝg minus SLT) in 
the intent to treat (Stage 1 and Stage 2 ITT) populations 
combined and the corresponding 95% confidence interval 
(CI) will be constructed at each visit.  The noninferiority 
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Section 
1.3 
Results of the completed phase 1/2 study, 192024-041D, 
suggest showed that Bimatoprost SR provides a 
prostaglandin analog-like IOP-lowering efficacy when used 
in at the dose strengths proposed for being used in this phase 
3 investigation.  Study 192024-095 is was designed as a 
randomized, patient and efficacy evaluator-masked, paired-
eye comparison evaluating the safety and IOP-lowering 
effects of repeated administrations of 15 ȝg Bimatoprost SR 
in patients with OAG or OHT who are not adequately 
managed with topical medication (eg, due to intolerance or 
nonadherence).   
Bimatoprost SR is being compared with SLT in 2 phase 3 
studies (192024-093 and 192024-095). Based on the interim 
data from the phase 1/2 study 192024-041D, the higher of 
the 2 dose strengths being evaluated in the other global phase 
3 studies, 15 μg, was selected for this study.  Now that 
additional data from later-stage studies has become 
available, the number of administration cycles in this study 
was reduced from 3 to 2 (eliminating Week 32 
administration for newly enrolled patients and ongoing 
patients who have not yet received the Week 32 
administration).  The number of administration cycles was 
reduced based on the duration of effect observed in the 
completed 24-month Study 192024-041D as well as the 
preliminary analysis of data from the first 3 months of 
treatment (primary analysis) in ongoing Study 192024-091, 
which suggested that the majority of patients do not require 
rescue treatment for an extended duration following their last 
Bimatoprost SR administration.  The results of both studies 
suggest that efficacy may be maintained with fewer 
administration cycles.  The change from 3 to 2 
administration cycles will have no impact on the primary 
efficacy analysis, and allows for assessment of the duration 
of effect of 2 Bimatoprost SR administration cycles 
throughout the study. 
Specified number of administration 
cycles for patients enrolled in each 
stage and provided rationale for the 
changes 
Section 3 
This study is a multicenter, paired-eye, randomized, efficacy 
evaluator-masked 14-month study conducted in 2 stages 
(Stage 1 and 2). 
The study is being conducted in 2 stages because the 
protocol is being amended (Amendment 2) to reduce the 
number of administration cycles performed, in order to allow 
for longer duration of efficacy follow up after the second 
administration. 
Patients will receive a 360° administration of SLT in 1 eye 
on Day 1, and administration of Bimatoprost SR in the 
contralateral eye on Day 4, with a repeat administrations of 
Bimatoprost SR at Weeks 16 and 32. Stage 1 patients 
(enrolled and reached the Week 32 visit prior to 
implementation of Amendment 2) received a third 
administration of Bimatoprost SR at Week 32. 
Specified the number of 
administration cycles for patients 
enrolled in each stage 
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Section 
4.1 
Approximately 160 patients (including approximately 
40 patients in Stage 1 and 120 patients in Stage 2) will be 
enrolled at approximately 68 sites, in order to have an 
estimated 144 patients complete the study based on a 
premature discontinuation rate of 10%.  
Clarified enrollment of 
approximately 160 patients in the 
study (approximately 40 in Stage 1 
and approximately 120 in Stage 2) 
Section 
4.5.1 
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 as 
needed (see Procedure Manual for details). 
For clarity 
Section 
4.5.2 
In order to maintain patient masking to treatments assigned 
to each eye, patients who have received nonstudy topical 
IOP-lowering treatment in a Bimatoprost SR eye will receive 
Sham Bimatoprost SR administration in that eye on the 
Bimatoprost SR Cycles 2 (and Cycle 3 for Stage 1 patients) 
administration day(s). Patients who have received nonstudy 
IOP-lowering treatment in both eyes will not receive 
Bimatoprost SR administration or Sham Bimatoprost SR 
administration in either eye, and therefore do not need to 
attend the Bimatoprost SR (or Sham Bimatoprost SR) 
administration visits and immediate postadministration visits 
(eg ie, Bimatoprost SR Cycle 2 administration [Week 16], 
Cycle 2 Day 2 safety visit, and Cycle 2 Day 4 and Week 2 
phone calls,; and for Stage 1 patients only, Bimatoprost SR 
Cycle 3 administration [Week 32], Cycle 3 Day 2 safety 
visit, and Cycle 3 Day 4 and Week 2 phone calls). 
Specified that visits associated with 
the third treatment cycle are for 
patients who reached Week 32 prior 
to implementation of Amendment 2 
only 
Section 
5.6 
The eye randomized to receive Bimatoprost SR will receive 
an intracameral administration of Bimatoprost SR on Day 4, 
and Week 16, (and Week 32 for Stage 1 patients only) plus 
Sham SLT administration on Day 1 only.  The contralateral 
eye will receive one 360° SLT administration on Day 1 only, 
plus Sham Bimatoprost SR administration on Day 4, and 
Week 16, (and Week 32 for Stage 1 patients).   
Specified that visits associated with 
the third treatment cycle are for 
patients who reached Week 32 prior 
to implementation of Amendment 2 
only 
Section 
5.9.1.3 
The procedure for the second (and third administrations for 
Stage 1 patients) administration(s) of Bimatoprost SR is the 
same. 
Specified that visits associated with 
the third treatment cycle are for 
patients who reached Week 32 prior 
to implementation of Amendment 2 
only 
Section 
5.9.1.4 
The same posttreatment observation and antibiotic 
requirements apply after the second (and third 
administrations for Stage 1 patients) administration(s) of 
Bimatoprost SR or Sham. 
Specified that visits associated with 
the third treatment cycle are for 
patients who reached Week 32 prior 
to implementation of Amendment 2 
only 
Section 
5.9.1.5 
Administration of Bimatoprost SR will occur at fixed 
intervals of 16 weeks, up to a total of 3 2 administrations (or 
3 for Stage 1 patients) unless in the investigator’s opinion it 
would not be in the best interest of the patient to re-
administer Bimatoprost SR based on previous adverse events 
or safety concerns. 
Patients who have been treated with nonstudy IOP-lowering 
medication in both eyes will not attend the administration 
day visits, nor will they attend the Day 2, Day 4 (phone call), 
Specified that visits associated with 
the third treatment cycle are for 
patients who reached Week 32 prior 
to implementation of Amendment 2 
only and extended safety follow-up 
period for patients who received 
nonstudy IOP-lowering medication 
in both eyes or did not complete an 
administration visit 
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and Week 2 (phone call) visits following an administration.  
Patients who have received nonstudy IOP-lowering 
medication in only 1 one or both eyes will be followed for 
the duration of the study through the Week 52/Exit visit.  
Patients who have received nonstudy IOP lowering 
medication in both eyes, or who do not complete an 
Administration Day visit, as described in Section 5.9 will 
still remain in the study and will be followed for 16 weeks 
after the last Bimatoprost SR or Sham administration. 
Section 
6.2 
Best Corrected Visual Acuity:  Visual acuity tests will be 
performed at all scheduled visits except on any of the 
3 Bimatoprost SR administration days or SLT 
Administration Day. 
Removed number of administration 
visits 
Section 7 
Two database locks will be performed:  1) when all patients 
complete the Week 24 visit or have prematurely 
discontinued before the Week 24 visit, and 2) when all 
patients complete the Week 52 visit or exit the study.  
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 responsibilities until the next 
lock.  Unmasked data handling and appropriate data and 
results access will be specified prior to each lock. 
Added language about maintaining 
the integrity of the masking after 
the first database lock 
Section 
7.1 
The Stage 1 and Stage 2 intent-to-treat (ITT) populations 
(ITT) is are defined as all randomized patients in Stage 1 and 
Stage 2, respectively, and will be used for all efficacy 
analyses. 
The Stage 1 and Stage 2 per-protocol (PP) populations (PP) 
is are defined as all ITT patients in the Stage 1 and Stage 2 
ITT populations who have no major protocol deviations, 
respectively, and will be used for selected efficacy analyses 
to confirm the primary efficacy analysis.  A list of patients 
excluded from the Stage 1 and Stage 2 PP populations will 
be finalized prior to database lock. 
The Stage 1 and Stage 2 safety populations, are defined as all 
patients who received randomized treatment in Stage 1 and 
Stage 2, respectively, and will be used for safety analyses. 
Specified analysis populations for 
Stages 1 and 2 
Section 
7.3.1 
As described in Section 7.2.1, t The primary efficacy 
analysis will be performed for patients in the Stage 1 and 
Stage 2 ITT populations combined.  The primary efficacy 
variable is IOP change from baseline and Weeks 4, 12, and 
24 are the primary analysis timepoints. 
The null and alternative hypotheses for the comparison 
between Bimatoprost SR 15 ȝg treated eyes and SLT treated 
Specified analyses for Stages 1 and 
2 
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medication in both eyes, or who do not complete an 
Administration Day visit, may discontinue the study 16 
weeks after the last Bimatoprost SR or Sham 
administrationIf the implant has been removed, the patient 
may discontinue the study if based on investigator 
assessment the eye is in stable condition, at which time they 
should complete the Week 52/Exit visit procedures. 
When patients exit discontinue before Week 52/Exit, the site 
should complete all procedures for the Week 52/Exit visit at 
the patient’s last visit. 
Section 
8.10 
Patients who have received nonstudy IOP lowering treatment 
in only one eye will continue through the duration of the 
study.  Patients who have received nonstudy IOP lowering 
treatment in one or both eyes, or patients who do not 
undergo Cycle 2 or 3 (or both) Administration Visits, will 
still be followedCycle 3, for 16 weeks after the last 
Bimatoprost SR or ShamStage 1 patients) administration for 
safety reasons.  These patients are eligible for Early 
Discontinuation (Early Exit) as described in Section 8.9, 
abovewill continue through the duration of the study. 
Increased duration of safety 
follow-up for patients who received 
nonstudy IOP-lowering medication 
in both eyes or did not complete an 
administration visit  
 
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12.2.3 
Amendment 3 
Title: A Comparison of Bimatoprost SR to Selective Laser Trabeculoplasty in Patients with 
Open-Angle Glaucoma or Ocular Hypertension 
Protocol 192024-095 Amendment 3 
Date of Amendment: March 2020 
Amendment Summary 
This summary includes changes made to Protocol 192024-095 Amendment 2 (approved 
May 2018). This protocol was amended to reflect the discontinuation of treatment with 
Bimatoprost SR 15 μg dose strength, an update to the list of medications requiring washout, 
and to revise the statistical methods. 
This amendment is considered to be substantial in accordance to Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union due to the 
significant impact on the safety of study participants. 
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 
General 
note for 
entire 
protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
With the implementation of Amendment 3, patients who 
are enrolled and have not yet reached Week 16 will not 
receive Cycle 2 administration and no additional 
administrations of the Bimatoprost SR 15 μg dose will be 
given.  Therefore, the Week 16 will not be required for 
these patients and they will continue to be followed at the 
scheduled follow-up visits through Week 52/Exit. 
Based on these revisions, the following statistical areas 
have been updated:   
-The first database lock will be when patients included in 
the primary analysis have completed the Week 24 visit or 
have prematurely discontinued before the Week 24 visit; 
-The ITT and safety population definitions were updated to 
delete ‘in Stages 1 and 2’ 
-An mITT population has been added and is defined based 
on ITT population, but will exclude patients who did not 
receive the second implant after the implementation of 
Amendment 3.  
-The mITT population will be used for the primary 
analysis and for the secondary efficacy analyses for the 
Based on a thorough review of the 
long-term Bimatoprost SR safety 
data from the recently completed 
and ongoing studies, the 
discontinuation of the 
administration of the 
Bimatoprost SR 15 μg dose strength 
is based on the conclusion that 
corneal adverse events associated 
with repeat administrations of the 
15 μg dose strength are no longer 
supported by a favorable 
benefit:risk consideration 
 
 
 
 
 
 
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Section 
5.9.1.5 
Administration of Bimatoprost SR will occur at fixed 
intervals of 16 weeks, up to a total of 2 administrations (or 
3 for Stage 1 patients) unless in the investigator’s opinion 
it would not be in the best interest of the patient to re-
administer Bimatoprost SR based on previous adverse 
events or safety concerns, such as clinically significant 
corneal endothelial cell density loss.   
For clarification. 
Section 
7.1 
The Stage 1 and Stage 2 intent-to-treat (ITT) populations 
arepopulation is defined as all randomized patients in 
Stages 1 and Stage 2, respectively, and will be used for 
efficacy analyses.   
The Stage 1 and Stage 2 per-protocol (PP) populations 
arepopulation is defined as all patients in the Stage 1 and 
Stage 2 ITT populations who have no major protocol 
deviations, respectively, and will be used affecting the data 
for selectedprimary efficacy analyses.analysis for all visits 
(Week 4, Week 12, and Week 24) in both eyes.  A list of 
patients excluded from the Stage 1 and Stage 2 PP 
populations will be finalized prior to database lock.   
The Stage 1 and Stage 2 safety populations arepopulation 
is defined as all patients who received randomized 
treatment in Stage 1 and Stage 2, respectively, and will be 
used for safety analyses. 
For clarification. 
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 
included in the study database but will be excluded from 
efficacy analysis. 
Missing IOP values will be imputed using a combination 
of worst (highest IOP value; postrandomization) 
observation carried forward (WOCF) and last observation 
carried forward (LOCF) methods for the primary analysis.  
Specifically, missing IOP values after the use of nonstudy 
IOP lowering treatment or early withdrawal due to lack of 
efficacy will be imputed with WOCF using the worst 
postrandomization IOP of the patient.  All other missing 
IOP values will be imputed with LOCF, including 
intermittent missing IOP values.  Handling of missing data 
will be supplemented by sensitivity analyses using 
methods such as multiple imputations and/or a mixed
effects model repeated measures approach. 
To revise the planned statistical 
methods. 
Section 
7.2.2 
Secondary efficacy variables to compare include:   
• 
Time to initial use of nonstudy IOP-lowering 
treatment (as determined by the investigator) 
• 
Percentage of Bimatoprost SR eyes and SLT eyes 
achieving   20%  reduction in IOP from baseline  
• 
IOP changes from baseline at Weeks 8, 15, and 20 
To revise the planned statistical 
methods. 
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Section 
7.2.3 
7.2.3 
Other Efficacy Variables 
To revise the planned statistical 
methods. 
Section 
7.3.1 
The primary efficacy analysis will be performed for 
patients in the Stage 1 and Stage 2 ITT populations 
combined.ITT population.  The primary efficacy variable 
is IOP change from baseline and Weeks 4, 12, and 24 are 
the primary analysis timepoints. 
The null and alternative hypotheses for the comparison 
between Bimatoprost SR 15 ȝg treated eyes and SLT 
treated eyes at each visit of Weeks 4, 12, and 24 are: 
• 
Null hypothesis:  the difference in mean IOP change 
from baseline between the Bimatoprost SR 15 ȝg and 
SLT eye (Bimatoprost SR minus SLT) is > 1.5 mm 
Hg. 
• 
Alternative hypothesis:  the difference in mean IOP 
change from baseline between the Bimatoprost SR 15 
ȝg eye and SLT eye (Bimatoprost SR minus SLT) is  
1.5 mm Hg. 
Intraocular pressure change from baseline will be analyzed 
using a paired t test.    IOP change from baseline will be 
analyzed using a mixed effect model for repeated measures 
(MMRM). The model will include IOP change from 
baseline as the response variable and treatment, visit, eye, 
baseline IOP, treatment-by-visit, treatment-by-baseline, 
treatment by eye, and visit-by-eyes interactions as 
covariates. Unstructured correlation for study visits and 
compound symmetry correlation for eyes will be used for 
repeated measures on the same patient; if the model fails to 
converge, multiple imputation (MI) will be implemented 
before MMRM. 
The mean difference between the Bimatoprost SR 15 ȝg 
eyes and SLT eyes (Bimatoprost SR 15 ȝg minus SLT) in 
the Stage 1 and Stage 2 ITT populations 
combinedpopulation and the corresponding 95% 
confidence interval (CI) will be constructed at each visit 
from MMRM analysis.  The noninferiority comparison for 
Bimatoprost SR 15 ȝg versus SLT at Weeks 4, 12, and 24 
is the primary analysis.  If the upper limit of the 95% CI is 
 1.5 mm Hg at all 3 visits and is  1.0 mm Hg at 2 out of 
To revise the planned statistical 
methods. 
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the 3 visits of Weeks 4, 12, and 24, Bimatoprost SR 15 ȝg 
statistical noninferiority to SLT is considered 
demonstrated.  The noninferiority comparison using the 
Stage 1 and Stage 2 PP populations combined will be 
performed as a sensitivity analysis.  In addition, 
Bimatoprost SR 15 ȝg is considered clinically noninferior 
to SLT if the upper limit of the 95% CI is  1.0 mm Hg at 
2 out of the 3 visits of Weeks 4, 12, and 24. 
As part of the sensitivity analysis for the primary efficacy 
analysis, a PP analysis using the same MMRM model as 
the one used in the primary efficacy analysis will be 
performed. The PP analysis will be based on the data from 
PP population. 
Additionally, a by-visit analysis using an ANCOVA model 
will be conducted using the data from ITT population, 
where the between-eye correlation will be included in the 
same way as the MMRM model used for the primary 
analysis. 
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SAP_001.pdf: 
Allergan PLC
Page 1
Bimatoprost SR
192024-095 Statistical Analysis Plan Amendment (v 1.0)
2 Oct 2020
1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
A Comparison of Bimatoprost SR to Selective Laser Trabeculoplasty in 
Patients with Open-Angle Glaucoma or Ocular Hypertension
Amendment Version 1.0: 2020-10-02
Protocol Number:
192024-095
Development Phase: Phase 3
Name of Investigational Product:
Bimatoprost sustained release (SR)
Study Statistician:
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
Confidentiality Statement
This document is the property of Allergan, Inc. and may not, in full or part, be passed on, 
reproduced, published, distributed to any person, or submitted to any regulatory authority 
without the express written permission of Allergan, Inc.
31AUG2021 CSR 192024-095 Final
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Allergan PLC
Page 2
Bimatoprost SR
192024-095 Statistical Analysis Plan Amendment (v 1.0)
2 Oct 2020
2.0
TABLE OF CONTENTS
1.0
Title Page ..........................................................................................................................................1
2.0
Table of Contents..............................................................................................................................2
2.1
List of Tables......................................................................................................................3
3.0
List of Abbreviations ........................................................................................................................4
4.0
Introduction.......................................................................................................................................6
5.0
Study Objectives and Clinical Hypotheses .....................................................................................18
5.1
Study Objectives...............................................................................................................18
5.2
Clinical Hypotheses..........................................................................................................18
6.0
Analysis Populations.......................................................................................................................18
6.1
Intent-to-Treat Population.................................................................................................18
6.2
Per-Protocol Population....................................................................................................19
6.3
Safety Population..............................................................................................................20
6.4
Data Collected but not analyzed .......................................................................................20
7.0
Patient Enrollment, Disposition and Compliance ...........................................................................20
8.0
Demographics and Other Baseline Data .........................................................................................20
8.1
Demographics...................................................................................................................21
8.2
Baseline Characteristics....................................................................................................21
8.3
Medical and surgical History............................................................................................21
8.4
Prior and Concomitant Medications .................................................................................21
8.4.1
General Medications...........................................................................................22
8.4.2
Ocular Medications ............................................................................................22
9.0
Study Duration................................................................................................................................22
10.0
Efficacy Assessments......................................................................................................................22
10.1
Primary Efficacy Analysis................................................................................................22
10.2
Secondary Analysis ..........................................................................................................24
10.3
Other Efficacy Analyses ...................................................................................................25
10.4
Sensitivity Analyses..........................................................................................................27
11.0
Safety Analyses...............................................................................................................................29
11.1
Adverse Events .................................................................................................................31
11.2
Vital Signs ........................................................................................................................33
11.3
Other Safety Parameters ...................................................................................................33
11.3.1
Pregnancy...........................................................................................................33
11.3.2
Best Corrected Visual Acuity.............................................................................33
11.3.3
Visual Field ........................................................................................................34
11.3.4
Macroscopic Conjunctival Hyperemia ...............................................................35
11.3.5
Specular Microscopy..........................................................................................35
11.3.6
Pachymetry.........................................................................................................36
11.3.7
Biomicroscopy and Dilated Ophthalmoscopy....................................................36
11.3.8
Lens Status and Opacification ............................................................................38
11.3.9
Gonioscopy and Bim SR Implant Assessment ...................................................38
12.0
Visual Function Questionnaire........................................................................................................39
13.0
Interim Analyses .............................................................................................................................39
14.0
Determination of Sample Size ........................................................................................................39
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192024-095 Statistical Analysis Plan Amendment (v 1.0)
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15.0
Statistical Software .........................................................................................................................40
16.0
Data Handling Conventions ............................................................................................................40
16.1
Efficacy Data ....................................................................................................................40
16.2
Visit Time Windows.........................................................................................................40
16.3
Derived Variables .............................................................................................................43
16.4
Repeated or Unscheduled Assessments of Safety Parameters..........................................44
16.5
Missing Severity Assessment for Adverse Events............................................................44
16.6
Missing Causal Relationship to Bim SR Implant for Adverse Events..............................44
16.7
Missing Date Information for Adverse Events .................................................................44
16.8
Missing Date Information for Prior or Concomitant Medications....................................45
16.8.1
Incomplete Start Date.........................................................................................45
16.8.2
Incomplete Stop Date .........................................................................................46
17.0
Changes to Analyses Specified in Protocol.....................................................................................47
18.0
References.......................................................................................................................................47
19.0
Amendments ...................................................................................................................................47
19.1
Amendment 1....................................................................................................................47
2.1
LIST OF TABLES
Table 4-1
Treatment Schedule by Eye.........................................................................................7
Table 4-2
Administration Cycle 1 Schedule of Visits and Procedures:  Screening through 
Day 2 ...........................................................................................................................8
Table 4-3
Administration Cycle 1 Schedule of Visits and Procedures: Day 4 through 
Week 15.....................................................................................................................10
Table 4-4
Administration Cycle 2 Schedule of Visits and Procedures:  Week 16 through 
Week 31.....................................................................................................................12
Table 4-5
Administration Cycle 3 Schedule of Visits and Procedures (Stage 1 Patients 
Only)..........................................................................................................................14
Table 4-6
Schedule of Visits and Procedures:  Week 36 through Week 52/Exit.......................16
Table 16-1
Visit Windows for Patients who only had Bim SR Cycle 1 Implant.........................41
Table 16-2
Visit windows for patients who only had Bim SR Cycles 1 and 2 implants..............42
Table 16-3
Visit windows for patients who had Bim SR Cycle 1, 2 and 3 implants ...................43
2.2
LIST OF FIGURES
Figure 11-1
Analysis Cycle Illustration ........................................................................................30
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3.0
LIST OF ABBREVIATIONS
AC
anterior chamber
ACG
angle closure glaucoma
AE
adverse event
AREDS
age-related eye disease study
ATC
anatomical therapeutic chemical
BCVA
best-corrected visual acuity
Bim SR
Bimatoprost SR
CCT
central corneal thickness
CI
confidence interval
CV
coefficient of variation
dB
decibels
ECD
endothelial cell density
eCRF
electronic case report form
IOP
intraocular pressure
ITT
intent-to-treat
K-M
Kaplan-Meier
MedDRA
medical dictionary for regulatory activities 
MI
multiple imputation
mITT
modified intent-to-treat
MMRM
mixed effect model for repeated measurement
NA
not applicable
OAG
open-angle glaucoma
OD
right eye
OHT
ocular hypertension
OS
left eye
OU
both eyes
PAS
peripheral anterior synechiae
PID
patient identification
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PP
per protocol
PT
preferred term
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SI
Le Système International d’Unités (International System of Units)
SLT
selective laser trabeculoplasty
SMQ
standard MedDRA query 
SOC
system organ class
SR
sustained release
SUN
standardization of the uveitis nomenclature
TEAE
treatment-emergent adverse event
TFLs
tables, figures and data listings
VA
visual acuity
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4.0
INTRODUCTION
This statistical analysis plan (SAP) provides a more technical and detailed elaboration of 
the statistical analyses of the efficacy and safety data as outlined and/or specified in the 
Study Protocol 192024-095 (Amendment 3). Specifications of tables, figures, and data 
listings (TFLs) are contained in a separate document. Additionally, if data are to be 
excluded from per-protocol analyses, a separate document will provide detailed rules for 
the data exclusion. 
Study 192024-095 is a multicenter, paired-eye, randomized, efficacy evaluator-masked 
14-month study conducted in 2 stages (Stage 1 and 2). The safety and intraocular 
pressure (IOP)-lowering effect of Bimatoprost SR (Bim SR) will be compared with 
selective laser trabeculoplasty (SLT) in open-angle glaucoma (OAG) or ocular 
hypertension (OHT) patients who are not adequately managed with topical medication 
for reasons other than medication efficacy (e.g., due to intolerance or nonadherence).
After the screening visit procedures, patients currently being treated with IOP-lowering 
medication(s) in either eye will begin washout of these medication(s) for a medication-
dependent minimum washout period. The maximum washout period is 42 days. Baseline 
visit occurs after the washout period has been completed. To be eligible to participate in 
the study, at the Baseline visit, patients must have an Hour 0 IOP of ≥22 and ≤ 34 mmHg
in each eye with a difference between the eyes of ≤5 mmHg. The eye with the higher 
IOP at Baseline will be assigned as the primary eye. If baseline IOP is the same in both 
eyes, the right eye will be the primary eye. The primary eye will be randomized to 
receive either Bim SR or SLT using a 1:1 ratio, stratified by:
!
primary eye baseline IOP (≤ 25 versus > 25 mmHg) 
and 
!
 
If the primary eye receives Bim SR, the contralateral eye will receive SLT. If the primary 
eye receives SLT, the contralateral eye will receive Bim SR.
The study is being conducted in 2 stages because the protocol was amended 
(Amendment 2) to reduce the number from 3 to 2 cycles of Bim SR administration, 
which allows for longer duration of efficacy follow up after the second administration:
!
Stage 1: Bim SR 15 μg vs SLT; 3 administration cycles for patients who were 
enrolled and reached the Week 32 administration visit prior to implementation of 
Protocol Amendment 2
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!
Stage 2: Bim SR 15 μg vs SLT; 2 administration cycles for patients who had not 
reached Week 32 prior to implementation of Amendment 2; and all patients 
enrolled under Protocol Amendment 2
Patients will receive a 360° administration of SLT in 1 eye on Day 1, and administration 
of Bim SR in the contralateral eye on Day 4 (Bim SR Cycle 1 Day 1), with a repeat 
administration of Bim SR at Week 16 (Bim SR Cycle 2 Day 1). Patients who were 
enrolled and reached Week 32 prior to implementation of Protocol Amendment 2
received a third administration of Bim SR at Week 32 (Bim SR Cycle 3 Day 1).
Therefore, the planned number of treatment cycles for Stage 1 patients is 3, and the 
planned treatment cycles for Stage 2 patients is 2.
To mask the patient to the treatment assigned to each eye, on Day 1 a Sham SLT 
procedure will be performed in the eye to be administered Bim SR. A Sham Bim SR 
administration will be performed in the eye that underwent SLT on each Bim SR 
administration visit (Day 4 [Bim SR Cycle 1 Day 1] and Week 16 [Bim SR Cycle 2 
Day 1]) (see Table 4-1). For brevity, the eye administered Bim SR will be referred to as 
the “Bim SR eye”, and the eye that underwent SLT will be referred to as the “SLT eye”.
Due to the paired-eye design of the study, the experimental units for treatment effects are 
individual eyes of each patient. Therefore, data summaries will primarily be done by
randomized treatment (Bim SR and SLT). Where appropriate, data summaries at patient 
level will be provided.
Table 4-1
Treatment Schedule by Eye
Treatment Visit
Bim SR Eye
SLT Eye
SLT administration
(Day 1)
Sham SLT
360° SLT
Bim SR Cycle 1 administration
(Day 4)
Bim SR
Sham Bim SR
Bim SR Cycle 2 administration 
(Week 16)
Bim SR
Sham Bim SR
SLT = selective laser trabeculoplasty; SR = sustained release
Note: Patients who were enrolled and reached the Week 32 administration visit prior to implementation of Protocol 
Amendment 2 received a third administration of Bim SR at Week 32.
Schedule of visits and procedures to be performed on randomized patients are presented 
in Tables 4-2 to 4-6. 
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Table 4-2
Administration Cycle 1 Schedule of Visits and Procedures:  Screening through Day 2
Visit
Screening
Baselineb
Day 1
(SLT Administration)
Day 2
Phone Callc
Visit Windows
Up to 28 days
Up to 3 days
Informed Consent/Authorization
X
Washouta
Up to 42 days
Demographic Data
X
Medical/Ophthalmic History
X
X
Adverse Events
X
X
X
X
Concomitant Medications/ Procedures
X
X
X
X
Visual Function Questionnaire-25
X
Physical Examination 
X
Vital Signs (at rest ≥5 minutes)
X
X
X
Pregnancy Testd
X
Blood and Urine Sample Collectione
Xe
Ocular Examinations in bold should be performed in the order shown
Pre-Hour 0 Exam (perform before Hour 0 IOP):
  Macroscopic Conjunctival Hyperemia Assessmentf
OU
Washout
Up to 42 
days
OU
Manifest Refractiong
OU
OU
Best-Corrected Visual Acuity
OU
OU
Intraocular Pressure Measurement Hour 0
OU
OU
Non-contact Exams (may perform in any order at any time before gonioscopy [before Hour 8 at 
Baselineh])
  Macroscopic Iris Color Assessment 
OU
  Visual Fieldi
OU
OU
  Specular Microscopy
OU
  Anterior Segment Optical Coherence Tomography
OU
  
OU
  Biomicroscopyf
OU
OU
OUk
Gonioscopy/Angle Assessment 
OUl
Pachymetry: (may be done any time after gonioscopy)
OU
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Table 4-6
Schedule of Visits and Procedures:  Week 36 through Week 52/Exit
Visits
Week 36
Week 40
Week 44
Week 47
Week 52/ Exit
Visit Windows
±4 days
±4 days
±4 days
±4 days
±7 days
Adverse Events
X
X
X
X
X
Concomitant Medications/Procedures
X
X
X
X
X
Vital Signs (at rest ≥5 minutes)
X
X
X
X
X
Pregnancy Test 
X
Ocular Examinations in bold should be performed in the order shown 
Pre-Hour 0 Exams (may perform in any order before Hour 0 IOP)
Macroscopic Conjunctival Hyperemia Assessmenta
OU
OU
OU
OU
OU
Best-Corrected Visual Acuityb
OU
OU
OU
OU
OU
Intraocular Pressure H0 
OU
OU
OU
OU
OU
Non-contact Exams (may perform in any order at any time before gonioscopy)
Macroscopic Iris Color Assessment
OU
Manifest Refractionb
OU
Visual Fieldc
OU
Specular Microscopy
OU
OU
OU
Biomicroscopya
OU
OU
OU
OU
OU
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5.0
STUDY OBJECTIVES AND CLINICAL HYPOTHESES
5.1
STUDY OBJECTIVES
To evaluate the IOP-lowering effect and safety of Bim SR compared with SLT in patients 
with OAG or OHT who are not adequately managed with topical IOP-lowering 
medication for reasons other than medication efficacy (e.g., due to intolerance or 
nonadherence).
Two database locks will occur at the following two timepoints:  1) when all patients in 
Stage 2 complete the Week 24 visit or have prematurely discontinued before the Week 24 
visit (primary analysis), and 2) when all patients in Stage 2 complete the Week 52 visit or 
exit the study (final analysis).  Analyses will be performed after each lock on unmasked 
data. The analysis based on the first database lock will be considered as the primary
analysis of the study. The analyses based on the second database lock will provide further 
efficacy and safety information.
5.2
CLINICAL HYPOTHESES
Bim SR will have an IOP-lowering effect that is noninferior to that of SLT in patients 
with OAG or OHT who are not adequately managed with topical IOP-lowering 
medication for reasons other than medication efficacy (e.g., due to intolerance or 
nonadherence). Bim SR administered intracamerally will have an acceptable safety 
profile in patients with OAG or OHT who are not adequately managed with topical IOP-
lowering medication for reasons other than medication efficacy (e.g., due to intolerance 
or nonadherence).
6.0
ANALYSIS POPULATIONS
The primary eye of each patient will be randomized to receive either Bim SR or SLT
treatment. Based on treatment randomization, the contralateral eye will receive SLT if the 
primary eye receives Bim SR (or vice versa). Per study design, each eye of every patient
will provide data for the two study treatments separately, and the experimental units for 
treatment effect are individual eyes. 
6.1
INTENT-TO-TREAT POPULATION
Patients whose primary eyes were randomized to receive either Bim SR or SLT treatment 
will be referred to as randomized patients. The intent-to-treat (ITT) population is defined 
as all randomized patients, and will be referred to as “ITT population” in this SAP and 
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TFLs. Analyses using the ITT population will be based on the randomized treatment 
assigned to each eye.
The modified intent-to-treat (mITT) population is defined based on ITT population, but 
will exclude patients who could not receive the second implant due to the discontinuation 
for the Bim SR 15μg dose strength implemented in protocol Amendment 3. The 
exclusion algorithm is as follows:
!
If a patient had a missing Cycle 2 Day 1 Bim SR administration date with study 
exit date after March 19, 2020 (IWRS deactivation date), unless the patient had 
AE leading to drug withdrawn or received a rescue medication before March 19, 
2020 in planned Bim SR eye, then the patients will be excluded from the mITT.
The reason for a missing Cycle 2 Day 1 Bim SR administration date is only due to the 
discontinuation for the Bim SR 15μg dose strength in protocol Amendment 3, not due to 
AE leading to drug withdrawn or rescue medications. 
The mITT population will be used for the primary analysis.
6.2
PER-PROTOCOL POPULATION
The per-protocol (PP) population is defined as all patients in ITT population who have no 
protocol deviations affecting the data for the primary efficacy analysis for all visits 
(Week 4, Week 12, and Week 24) in both eyes, and will be referred to as the “PP 
population” in this SAP and TFLs. 
Since the primary eye and contralateral eye of a patient will contribute data separately for 
the two different treatments in the study, the data from one eye can be excluded from PP 
analysis due to a protocol deviation, but the patient can still be included in PP population 
because of valid data from the other eye.
Examples of protocol deviations that will result in removal of data from PP analysis 
include but are not limited to the following cases:
!
For eyes with no study treatment, post-baseline data will be excluded from PP 
analysis, and
!
For eyes that received both study treatments, data after the wrong treatment will 
be excluded from PP analysis.
A separate document will be prepared to describe data exclusion algorithm for PP 
analysis. All patients with data excluded from the PP analysis will be identified and
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finalized prior to each database lock and will be displayed in a data listing with reason(s) 
for exclusion.
6.3
SAFETY POPULATION
The safety population is defined as all patients who had received at least one treatment
regardless of whether it was the planned treatment or not, and will be used for the safety 
analyses. Both eyes in the safety population are included in the ocular safety analyses. 
Ocular safety assessments will be based on the treatment received in each eye at the first 
administration. However, one patient received both SLT and Bim SR in the same eye. 
Safety assessment for the patient will be summarized under the Bim SR treatment group.
6.4
DATA COLLECTED BUT NOT ANALYZED
Clinical lab test data, vital signs, pregnancy test, national eye institute visual functioning 
questionnaire, and general (non-ophthalmic) physical examination are collected only at 
Screening and will not be analyzed. Other data collected but not analyzed, will be 
described in the clinical study report.
7.0
PATIENT ENROLLMENT, DISPOSITION AND COMPLIANCE
The number of patients in analysis populations (ITT, mITT, Safety, and PP) will be 
summarized for the overall study. The numbers and percentages of patients randomized 
by county and site will be presented. The numbers and percentages of patients who 
complete the study and the numbers and percentages of patients who prematurely 
discontinue the study will be presented overall and by analysis cycle defined in 
Figure 11-1.
The study completers will be defined as the patients who received at least one study 
treatment and marked as completed in the eCRF disposition page. A patient who received 
study treatment in the relevant cycle will be considered to have completed the analysis 
cycle, if (a) the patient is a study completer or (b) the patient received the subsequent
study treatment (Bim SR).
The categories of premature discontinuation reasons and the number of patients who 
prematurely discontinued during the study will be summarized.
8.0
DEMOGRAPHICS AND OTHER BASELINE DATA
Demographics and other baseline characteristics will be summarized descriptively for the 
ITT population.
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8.1
DEMOGRAPHICS
Demographic parameters including age, age group, race, race group, ethnicity, sex as 
well as baseline characteristics such as weight (kg) and height (cm) will be summarized 
descriptively. Patient’s age at Baseline (years) will be presented in categories of less than 
45 years; between 45 years and 65 years, inclusive; and greater than 65 years. In addition, 
race will be further grouped as White versus non-White and Hispanic versus non-
Hispanic (Ethnicity).
8.2
BASELINE CHARACTERISTICS
Baseline characteristics for each eye will be descriptively summarized by treatment of the 
eye for the following categories: iris color, diagnosis of either OAG (primary OAG, 
pseudoexfoliation glaucoma, pigmentary glaucoma) or OHT, baseline Hour 0 IOP 
(≤25 mm Hg or > 25 mmHg), iridocorneal angle Shaffer grade, and central endothelial 
cell density, will be summarized descriptively by treatment group for the ITT population. 
Study eye iris color will be summarized by color for each of the following categories: 
monochromic, heterochromic peripupillary, and heterochromic diffuse.
8.3
MEDICAL AND SURGICAL HISTORY
Abnormalities in patients’ medical and surgical histories will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA), 21.0 or newer. The number and 
percentage of patients with non-ophthalmic medical and surgical histories at the time of 
randomization will be summarized separately by system organ class (SOC) and preferred 
term (PT) for the ITT population. Ophthalmic medical and surgical histories associated 
with Bim SR eye and SLT eye at randomization will also be summarized separately for 
the Safety Population by SOC and PT.
8.4
PRIOR AND CONCOMITANT MEDICATIONS
Medications will be coded using the current version of World Health Organization Drug 
Global Dictionary and anatomical therapeutic chemical (ATC) classification system.
Prior medications are defined as medications with administration date or start date before 
the date of randomization. Concomitant medications are defined as those medications 
with administration date or start date on or after the date of the initial treatment. If a 
medication started prior to the date of randomization and continued past the date of 
randomization, it will be considered ongoing at randomization (i.e., study start) and will 
be presented as both a prior medication and a concomitant medication.
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8.4.1
General Medications
Prior and concomitant non-ocular medications will be summarized by drug class and 
preferred name in the ITT population.
8.4.2
Ocular Medications
Prior ocular medications, washout ocular medications, concomitant ocular medications,
and non-study IOP lowering medications will be summarized by eye identified by 
randomized treatment, drug class, and preferred name separately. A non-study IOP-
lowering medication will be defined by the information provided by the investigator on 
electronic case report form (eCRF).
9.0
STUDY DURATION
Patients’ study duration will be summarized using descriptive statistics for each treatment 
group using safety population. Duration of time on study (days) for each patient will be
calculated as the last visit date available or study exit date– Day 1 SLT administration 
date + 1.
10.0
EFFICACY ASSESSMENTS
The primary efficacy measurement is IOP at Hour 0, which will be measured in each eye 
using the Goldmann applanation tonometer. Two consecutive measurements will be
taken for each eye. If the first 2 measurements differ by > 1 mm Hg, a third measurement 
will be taken.  The IOP value for a given eye will be the median of all measurements, and 
this is consistent with the protocol IOP description in Study Protocol Section 6.1.1 (If the 
first 2 measurements differ by ≤ 1 mm Hg, 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). For consenting patients at 
selected sites, additional IOP data will be collected at Hour 2 and 8, and these data will 
be included in
.
10.1
PRIMARY EFFICACY ANALYSIS
The primary efficacy variable is Hour 0 IOP change from baseline (follow-up value 
minus baseline value, thus negative values reflect IOP reduction from baseline) assessed 
at Weeks 4, 12, and 24. Intraocular pressure values at Hour 0 at Baseline visit is 
considered as the baseline values.
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Baseline and Weeks 4, 12 and 24 Hour 0 IOP measurements with their changes from 
baseline will be descriptively summarized.
Primary efficacy analysis will be performed for patients in the mITT population. The null 
and alternative hypotheses for the comparison between Bim SR treated eyes and SLT 
treated eyes at Weeks 4, 12, and 24 are:
!
Null hypothesis: the difference in mean IOP change from baseline between the 
Bim SR and SLT eye (Bim SR minus SLT) is > 1.5 mmHg.
!
Alternative hypothesis: the difference in mean IOP change from baseline between 
the Bim SR eye and SLT eye (Bim SR minus SLT) is ≤ 1.5 mmHg.
Hour 0 IOP change from baseline will be analyzed using a mixed effect model for 
repeated measurement (MMRM). The model will include Hour 0 IOP change from 
baseline as the response variable and treatment, visit, eye, baseline Hour 0 IOP, 
treatment-by-visit, treatment-by-baseline Hour 0 IOP, treatment-by-eye, visit-by-eye
interactions as covariates. Unstructured covariance matrix for study visit and compound 
symmetry correlation for eyes will be used for repeated measures on the same patient. If 
the model fails to converge, alternative covariance structures may be used in the MMRM
analysis. If the model fails to converge with alternative covariance structures, multiple 
imputation (MI) will be implemented before MMRM.
The mean difference in the Hour 0 IOP change from baseline between the Bim SR eyes 
and SLT eyes (Bim SR minus SLT) in the mITT population and the corresponding 95% 
confidence intervals (CI) will be constructed at each visit from MMRM analysis. The 
noninferiority comparison for Bim SR versus SLT at Weeks 4, 12, and 24 is the primary 
analysis. If the upper limit of the 95% CI is ≤ 1.5 mmHg at all 3 visits, Bim SR 15 μg
statistical noninferiority to SLT is considered demonstrated.
For additional clinical consideration, Bim SR is considered clinically noninferior to SLT 
if the upper limit of the 95% CI is ≤ 1.0 mmHg at 2 out of the 3 visits of Weeks 4, 12, 
and 24.
Sample SAS® code for primary analysis is shown as below:
proc mixed data=iop4;
    where avisitn >1;
    class subjid eye trt avisitn; 
     model chg=trt avisitn eye base trt*avisitn  
               trt*base trt*eye avisitn*eye/ddfm=kr;
    repeated avisitn*eye/type=un@cs subject=subjid rcorr;
    lsmeans trt*avisitn/diff;
run;
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The definitions of variables are:
chg = Hour 0 IOP percentage change from baseline at the primary analysis time points of 
Week 4, Week 12, and Week 24
avisitn = Programming derived analysis visits at Week 4, Week 12, and Week 24
subjid = Subject ID
eye = Variable to indicate primary eye or contralateral eye
trt = Variable to indicate Bim SR treatment or SLT treatment
base = Baseline IOP
10.2
SECONDARY ANALYSIS
Superiority test of Bim SR 15 μg versus SLT
As the secondary efficacy analysis, a superiority test of Bim SR 15 μg versus SLT will be 
performed if noninferiority is demonstrated in the primary efficacy analysis. Superiority 
of Bim SR versus SLT is considered achieved if the upper limit of the 95% CI is < 0 mm 
Hg at Weeks 4, 12, and 24. The mITT population will be used.
Time to initial use of non-study IOP-lowering treatment (as determined by the 
investigator)
Time to the event of the initial use of non-study IOP-lowering treatment from the Date of 
the First Treatment will be estimated using Kaplan-Meier (KM) method with graphical 
displays. 
Time to initial use of non-study IOP-lowering treatment = (Date of initial use of non-
study IOP-lowering treatment – Date of the First Treatment) +1,
where the Date of the First Treatment for SLT is the SLT Treatment date (study Day 1), 
and the Date of First Treatment for Bim SR is Bim SR Cycle 1 Day 1 administration date
(study Day 4).
Additionally, for Bim SR, the time to non-study IOP-lowering treatment from the second 
injection and the time to non-study IOP-lowering treatment from the third injection will 
be summarized:
Time to initial use of non-study IOP-lowering treatment from the second Bim SR implant
= (Date of initial use of non-study IOP-lowering treatment after the second Bim SR 
implant – Date of the second Bim SR implant) +1
Time to initial use of non-study IOP-lowering treatment from the third Bim SR treatment 
= (Date of initial use of non-study IOP after the third Bim SR implant -lowering 
treatment – Date of the third Bim SR implant) +1
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In the calculation of time to initial use of non-study IOP-lowering treatment, if a patient
did not use any non-study IOP-lowering medications in an eye, then the event (initial use 
of non-study IOP-lowering treatment) time will be censored at the study exit date or the 
last visit date if the study exit date is not available.
In the calculation for the time to the event of non-study IOP-lowering treatment from the 
second Bim SR implant, patients with at least two Bim SR implants will be used, and the 
event will be censored at the third Bim SR implant if the patients didn’t use any non-
study IOP-lowering medications up-to the third implant.
Percentage of Bim SR and SLT eyes achieving ≥ 20% reduction by visit
Number and percent of Bim SR and SLT eyes that have achieved a ≥ 20% reduction in 
IOP by each post-baseline visit in each eye will be summarized.
IOP changes from baseline in raw IOP at Weeks 8, 15, and 20
Week 8, 15 and 20 raw IOP values and their changes from baseline will be descriptively 
summarized for Bim SR eye and SLT eye at each timepoint.
10.3
OTHER EFFICACY ANALYSES
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10.4
SENSITIVITY ANALYSES
As part of the sensitivity analyses, the mean difference and 95% CI in the IOP change 
from baseline between the Bim SR eyes and SLT eyes (Bim SR minus SLT) will be 
constructed for each analysis visit for the Per Protocol (PP) population using the same 
MMRM model as the one used in the primary analysis.
To simplify the interpretation of treatment effect, and to allow flexible adjustment for 
baseline effect and the between-eye correlation across different visits, the following 
MMRM model will be used in sensitivity analysis using mITT population: (1) the
MMRM model will include Hour 0 IOP change from baseline as the response variable 
and treatment, visit, eye, baseline Hour 0 IOP, treatment-by-visit, visit-by-baseline Hour 
0 IOP, and visit-by-eye interactions as covariates; (2) an unstructured covariance matrix 
(6×6 matrix) will be used for measurements across 3 primary visits (Weeks 4, 12, and 24)
and 2 eyes for the same patients. The same MMRM model will be used in the tipping-
point sensitivity analysis described in the later part of the section.
Sample SAS® code for the sensitivity analysis is shown as below:
proc mixed data=iop4;
    where avisitn >1;
    class subjid eye trt avisitn repid; 
     model chg=trt avisitn eye base trt*avisitn  
               avisitn*base avisitn*eye/ddfm=kr;
    repeated repid/type=un subject=subjid rcorr;
   lsmeans trt*avisitn/diff;
run;
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The definitions of variables are:
chg = Hour 0 IOP percentage change from baseline at the primary analysis time points of 
Week 4, Week 12, and Week 24
avisitn = Programming derived analysis visits at Week 4, Week 12, and Week 24
subjid = Subject ID
eye = Variable to indicate primary eye or contralateral eye
trt = Variable to indicate Bim SR treatment or SLT treatment
base = Baseline IOP
repid=Variable created to identify the repeated measures cross each eye and each visit 
within a given subject for the unstructured covariance matrix (6 × 6).
Additionally, ANCOVA including within-subject correlation at each visit will be 
conducted using the observed values of ITT population, where IOP measurements 
obtained after initiating the use of non-study IOP-lowering medication will be set to 
missing. At each visit, the model for IOP change from baseline is specified as: IOP 
Change from Baseline = Treatment + Eye + Baseline IOP, where Eye is primary eye or 
contralateral eye. A compound symmetric covariance matrix will be used for between eye 
correlation.
The tipping-point sensitivity analysis will also be used to assess the robustness of the 
analysis results. A multiple imputation (MI) will be performed to the missing data as the 
first step; then different shifts using various assumptions on the missing IOP CFB will be 
applied to the imputed missing values in Bim SR treated eyes separately (note: shift will 
not be applied to SLT treated eyes); finally MMRM analyses will be conducted based on 
the imputed data with shifts and the corresponding tipping region of the shifts will be 
used to evaluate the robustness of the noninferiority conclusion.
In the MI procedures, a two-step method will be used to impute the missing values at 
Weeks 4, 8, 12, 15, 20, and 24 for each eye. During Step 1, missing intermittent data will 
be imputed to obtain a monotone missing pattern and during Step 2 linear regression will 
be used to impute the remaining missing values. Note that baseline IOP values associated 
with each eye must not be missing in any of the patients; otherwise they will be excluded 
from this analysis. At least twenty-five (25) sets of imputed datasets will be created using 
SAS proc MI procedure. A sample code is shown below for Hour 0 IOP measurements 
associated with each eye:
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proc mi data=iop nimpute=25 seed=123451 out=_miint;
    var baseline week4_hr0 week8_hr0 week12_hr0 week15_hr0 week20_hr0 week24_hr0;
  by treatment;
  mcmc chain=single impute=monotone;
run;
proc mi data=_miint nimpute=1 seed=123457 out=mifull;
  class race_group sex lens;
  var race_group sex lens age baseline week4_hr0 week8_hr0 week12_hr0 week15_hr0 week20_hr0
week24_hr0;
  monotone regression (week4= race_group sex lens age baseline/details);
  monotone regression (week8= race_group sex lens age baseline week4/details);
  monotone regression (week12= race_group sex lens age baseline week4 week8/details);
  monotone regression (week15= race_group sex lens age baseline week4 week8 week12/details);
  monotone regression (week20= race_group sex lens age baseline week4 week8 week12 week15/details);
  monotone regression (week24= race_group sex lens age baseline week4 week8 week12 week15
week20/details);
by _imputation_ treatment;
run;
MMRM method will be used to analyze each imputation dataset obtained from the above. 
PROC MIANALYZE will then be used to pool the analyses results across the imputation 
datasets and produce final parameter estimates.  
Additional sensitivity analyses may be conducted to further evaluate the robustness of 
primary analysis results.
11.0
SAFETY ANALYSES
All safety analyses will be performed using the Safety Population. As indicated in 
Section 6.5, safety data collected at Screening for eligibility assessment will not be 
analyzed.
Non-ocular safety assessments include: non-ocular adverse events (AEs), clinical 
laboratory, vital signs (blood pressure, pulse rate and temperature), and pregnancy test. 
Ocular safety will be evaluated through: ocular AEs, best corrected visual acuity, visual 
field examination, specular microscopy, macroscopic iris color assessment, macroscopic 
conjunctival hyperemia assessment, gonioscopy / angle assessment, biomicroscopy 
(using a slit lamp), lens assessment, optic disc examination, dilated ophthalmoscopy, 
pachymetry, and anterior segment-optical coherence tomography.
 
 
 
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11.1
ADVERSE EVENTS
Adverse events will be coded by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities, version 21.0 or newer. An AE with the same PT 
may have two different worst severities associated with two eyes separately or could be 
associated with only one eye. For summary by severity of each PT, the highest severity 
will be counted for each eye separately. Therefore, the comparison of AE incidence rates 
will be conducted at the same treatment exposure across Bim SR eye and SLT eye.  
An AE will be considered a treatment-emergent adverse event (TEAE) for the study 
treatment period if the AE meets one of the following criteria:
•
The onset date is on or after the first study treatment date.
•
The onset date is before the first study treatment date and either:
o
The severity of the event worsened on or after the first treatment date.
o
The event became serious on or after the first study treatment date.
An AE will be considered as a TEAE for a treatment cycle if the AE meets one of the 
following criteria:
•
The onset date is on or after the treatment administration of the cycle but prior to 
the next cycle administration.
•
The onset date is before the treatment administration of the cycle and either:
o
The severity of the event worsened on or after the treatment administration 
of the cycle.
o
The event became serious on or after the treatment administration of the 
cycle.
An ocular AE will be defined by the location information on the adverse event page in 
eCRF. Additionally, questions about adverse event relationships to study treatment and 
study procedure will be asked in eCRF, and the answers to these questions will be used 
together to derive the treatment related TEAE.
An overall summary of patient incidences of TEAEs will be presented by event type and
event category (ocular or non-ocular). These summaries will include the following:
! All TEAE
! Treatment-related TEAE
! TEAE related to study procedure:
o Related to study drug
o Related to study drug administration procedure
o Related to SLT laser
! All serious TEAE
! Treatment-related serious TEAE
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! Serious TEAE related to study procedure:
o Related to study drug
o Related to study drug administration procedure
o Related to SLT laser
! Any TEAE leading to Bim SR implant removal
! Any TEAE leading to study discontinuation
The following non-ocular adverse events will be summarized by SOC and PT:
!
Any non-ocular TEAEs,
!
Any treatment related non-ocular TEAEs,
!
Any serious non-ocular TEAEs, and
!
Any non-ocular TEAEs leading to study discontinuation.
Additionally, a summary by SOC, PT, and severity will be provided for non-ocular 
TEAEs.
For patient eye incidences of treatment emergent ocular adverse events, overall and by 
period summaries will be provided for the following categories:
!
Any ocular TEAEs by SOC and PT
!
Any ocular TEAEs by SOC, PT, and severity
!
Any treatment related ocular TEAEs by SOC and PT
!
Any serious ocular TEAEs by SOC and PT
!
Any ocular TEAEs leading to study discontinuation by SOC and PT
!
Any ocular TEAEs within two days of study treatment by SOC and PT
i.e, Ocular TEAEs that occur within two days from the Bim SR treatment 
or Bim SR sham
!
Any ocular TEAEs after two days of study treatment by SOC and PT
i.e, Ocular TEAEs that occur after two days from the Bim SR treatment or
Bim SR sham to next Bim SR treatment or Bim SR sham
!
SLT procedure related ocular TEAEs by SOC and PT 
i.e, Ocular TEAEs that occur starting from Day 1, but before the first Bim 
SR treatment will be summarized.
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!
Any corneal TEAEs of interest by SOC and PT (Corneal AEs of interest will be
identified separately prior to database lock.)
!
Any anterior segment inflammation TEAEs of interest by SOC and PT (Anterior 
segment inflammation AEs will be identified separately prior to database lock.)
11.2
VITAL SIGNS
Vital signs (systolic and diastolic blood pressures [mmHg], pulse rate [bpm], and 
temperature [Celsius]) will be collected at baseline, but will not be analyzed. 
11.3
OTHER SAFETY PARAMETERS
Blood and urine samples obtained for the analysis of blood chemistry, hematology, and 
urinalysis will be reviewed by the investigator or qualified site personnel for any adverse 
events. Any safety laboratory test results that represent adverse events will be reflected 
on adverse event eCRF page, and thus will be part of the suggested analyses of AEs. 
Therefore, laboratory data collected will not be analyzed. 
11.3.1
Pregnancy
Pregnancy test results for female patients of childbearing potential will be collected, but 
will not be analyzed or listed.
11.3.2
Best Corrected Visual Acuity
Best-corrected visual acuity (BCVA) at an assessment timepoint is recorded in Snellen 
equivalent units on eCRF as 20/8, 20/10, 20/12.5, 20/16, …, or 20/800. An increase in the 
second number (denominator) in Snellen equivalent unit indicates worsening of VA and a 
decrease indicates an improvement. For example, change from 20/32 to 20/40 is a 
worsening of VA by one line, 20/32 to 20/20 (note that 20/25 is in between) is an 
improvement by 2 lines.
The line change from baseline at each post-baseline evaluation can be calculated using 
the formula:
Line change = 10×[log10(dBL/dPBL)]
where dBL = denominator of the Snellen equivalent unit at baseline,
           dPBL = denominator of the Snellen equivalent unit at post-baseline
The logarithmic value in the formula above needs to be rounded to the nearest tenth 
before proceeding to the calculation of the line change. A positive value indicates an 
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improvement, a negative value indicates a worsening, and a zero indicates no change. For 
example, the line change for a Snellen equivalent unit at baseline of 20/25 followed by a 
Snellen equivalent unit of 20/80 at a post-baseline visit would be:
Line change = 10×[log10(25/80)] = 10×(−0.5) (rounded to nearest tenth) = −5
representing a worsening of 5 lines in VA. Note that there are 4 Snellen equivalent units 
(20/32, 20/40, 20/50 and 20/63) between 20/25 and 20/80, thus moving from 20/25 to 
20/80 is a worsening by 5 lines in VA because the denominator has increased.
The greatest line change in best corrected visual acuity (BCVA) from baseline will be 
summarized for each eye with respect to number of line change categories by study 
period. Categories will be summarized as worsening VA of 2 lines or more, worsening of
one line, no change, improvement of one line, and improvement of 2 lines or more. 
11.3.3
Visual Field
Visual field examinations will be assessed by automated perimetry with either Humphrey
Field Analyzer (using 24-2 full threshold or 24-2 [SITA] Standard program) or Octopus
Perimeter (using G1 Dynamic or Normal strategy or 24-2 Dynamic or Normal strategy 
program) at Screening, Baseline, Week 24, and Week 52/Exit by test methods. The same 
test methodology should be used throughout the entire study for a given patient. Visual 
field overall results will be recorded on the eCRF as normal or abnormal. Abnormal 
findings include enlargement of blind spot, superior arcuate scotoma, interior arcuate 
scotoma, paracentral scotoma, nasal step, central scotoma, generalized depression, and 
temporal scotoma and other. An eye may exhibit multiple abnormalities. In addition, 
mean deviation or mean defect (MD) and change from baseline will also be recorded in 
decibels (dB), and will be analyzed by visit and by machine type (Humphrey and 
Octopus respectively). If the machine type is different between baseline and post baseline 
visit, no change from baseline will be derived and machine type will not be imputed. For 
patients whose visual fields were assessed by one machine type as recorded, the mean 
deviation or mean defect assessments with missing machine type will be imputed as 
assessments by the corresponding unique machine type. 
Any post-baseline abnormal findings on visual field will be summarized by eye using 
number and percentage format to calculate patient incidences overall and by analysis 
cycle. 
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11.3.4
Macroscopic Conjunctival Hyperemia
Severity assessment of hyperemia of both eyes is performed at Screening, Baseline, 
during Analysis Cycle 1 and during Analysis Cycle 2 for all patients and during Analysis 
Cycle 3. Conjunctival hyperemia severity in each eye is assessed as 0 (None), +0.5 
(Trace), +1 (Mild), +2 (Moderate), +3 (Severe) or ‘Not Evaluable’. These data will be 
summarized by eye using the worst severity of hyperemia observed by study period.
In addition, worst severity grade increase greater than 1 (worsening, i.e, a change from 0 
to 2 and above, from 0.5 to 2 and above, or from 1 to 3 and above) in hyperemia from 
baseline will also be summarized for each eye by study period. If the worst severity grade 
during a period is less severe compared to baseline, it will be considered as ‘no increase’. 
11.3.5
Specular Microscopy 
Endothelial Cell Density:  Endothelial cell density average (cells/mm2) will be assessed 
using specular microscopy performed on the central cornea of each eye at Screening, 
Week 4, Week 12, Week 24, Week 40, and Week 52/Exit.
Endothelial cell density at baseline (Screening) and raw values and their changes from 
baseline will be summarized descriptively by visit for each eye. 
In addition, the number and percentage of patient-eyes that showed following
!
beyond 200 cells/mm2 increase
!
within 200 cells/mm2 increase
!
within 200 cells/mm2 decrease
!
≥10% loss
!
≥20% loss
!
≥30% loss
!
≥40% loss
!
≥ 50% loss
!
≥10% and < 20% loss
!
≥20% and < 30% loss
!
≥30% and < 40% loss
!
≥40% and < 50% loss
in endothelial cell density change from baseline will be summarized by visit for each eye. 
Percent change from baseline is defined as: 100 × (At Visit ECD – Baseline 
ECD)/(Baseline ECD) where ECD = endothelial cell density. For the ECD decrease, the 
worst ECD assessment within the given analysis visit window (or analysis cycle) 
including unscheduled visits will be summarized by visit and by analysis cycle. For the 
ECD increase, the maximum ECD assessment will be summarized by visit and by 
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analysis cycle.  Listings for patients with 20% or more central corneal endothelia cell 
density (CECD) loss at any visit will be provided. 
Coefficient of Variation Average (CVAVE): Coefficient of variation average of raw data 
and changes from baseline will be summarized descriptively by visit for each eye.
Pleomorphism Average (HEXAVE): Pleomorphism average of raw data and their
changes from baseline will be summarized descriptively by visit for each eye.
11.3.6
Pachymetry
Corneal thickness using ultrasound (contact) pachymetry is performed on the central 
cornea for each eye at Screening, Week 4, Week 12, Week 24, and Week 52/Exit visits. 
At each examination, 3 measurements of central corneal thickness (CCT) and associated 
standard deviation is reported, and the average of the 3 measurements will be calculated 
and used for analysis. CCT raw values and their changes from baseline at each post-
Baseline visit will be summarized descriptively by visit for each eye.
11.3.7
Biomicroscopy and Dilated Ophthalmoscopy
Biomicroscopy will be performed in each eye by slit-lamp examination at Screening, 
Baseline, and during Cycle 1, Cycle 2, Follow-up, and during Cycle 3 for Stage 1 
patients.
At these exams, any findings noted on the following will be recorded for each eye on the 
eCRF as follows:
!
Eyelids/Eyelid Margins/Lashes
o
Erythema
o
Edema
o
Other
!
Conjunctiva (Bulbar or Palpebral)
o
Hyperemia
o
Edema
o
Subconjunctival Hemorrhage
o
Pterygium, encroaching on visual axis
o
Pterygium, not encroaching on visual axis
o
Other
!
Cornea
o
Punctate Epithelial Staining
o
Infiltrates
o
Edema
o
Corneal Guttata
o
Endothelial Pigment
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o
Keratic Precipitates
o
Neovascularization
o
Opacity(ies)
o
Stromal Haze
o
Other
!
Anterior Chamber
o
Cells
o
Flare
o
Hypopyon
o
Hyphema
o
Other
!
Iris/Pupil
o
Afferent Pupillary Defect (APD)
o
Posterior Synechiae
o
Transillumination Defect(s)
o
Pseudoexfoliative Material
o
Peripheral Iridectomy
o
Laser Peripheral Iridotomy
!
Other
Severity of findings in the categories of Eyelids/Eyelid Margins/Lashes, Conjunctiva
(Bulbar or Palpebral) and Cornea will be recorded as +0.5 (Trace), +1 (Mild), +2 
(Moderate), +3 (Severe) or Not Applicable. Severity of Anterior Chamber findings will 
be recorded as +0.5, +1, +2, +3, +4, or Not Applicable using the Standardization of the 
Uveitis Nomenclature (SUN) Working Group criteria. No severity grade will be assigned 
for Iris/Pupil findings, and only findings noted will be recorded.
Biomicroscopy findings will be coded using MedDRA. Number and percentage of patient
eyes with findings showing more than one grade increase from baseline will be presented 
by coded PT (more than 1 severity grade increase means a change from 0 to 2 and above, 
from 0.5 to 2 and above, or from 1 to 3 and above from baseline at any of the follow-up 
visits). Number and percentage of patient eyes with findings present at post-baseline 
which did not present at baseline will be summarized (i.e., findings not associated with a 
severity grade). The analysis results will be presented by study periods and analysis 
cycle. 
Dilated ophthalmoscopy and lens status and opacity assessments will be performed in
each eye at Screening, Baseline, Week 12, Week 24, Week 40, and Week 52/Exit. At 
ophthalmoscopy exams, any findings noted on the following areas will be recorded for 
each eye:
!
Vitreous (each finding will be entered as free text field)
!
Macula (Intraretinal Fluid or Other (other is entered as free-text))
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!
Retina Periphery (each finding will be entered as free text)
!
Optic Nerve Exam – Cup/Disc Ratio Disc examination findings will be recorded 
under 2 sub-categories; Disk Hemorrhage, and Other Disc Pathology (other 
pathology is entered as a free text)
Dilated ophthalmoscopy findings will be coded using MedDRA. Similar analysis from 
Biomicroscopy will be performed for opthalmoscopy findings. 
Optic Nerve cup/disc ratio is evaluated using a 0.0 to 1.0 scale, with larger values 
indicating glaucoma or other pathologies, thus a reduction from baseline is considered an 
improvement. Categorical changes in cup/disc ratio from baseline will be summarized by 
each post-Baseline assessment visit. Change from baseline at each follow-up visit (visit 
value – baseline values) will be categorized as an improvement of 0.2 or more (≤ - 0.2), 
no change - between 0.2 and -0.2 (> -0.2 to < 0.2), or a worsening if the ratio increases by
0.2 or more (i.e., change ≥ 0.2). The number and percentage of patients in each category 
will be provided for each eye by assessment visit.
11.3.8
Lens Status and Opacification
Lens status and lens opacity assessments are performed through a dilated pupil in each 
eye at Screening, Baseline, Week 12, Week 24, Week 40, and Week 52/Exit. Lens status 
is assessed as phakic, pseudophakic, or aphakic and recorded on the eCRF. 
Lens opacity is assessed by the Age-Related Eye Disease Study (AREDS) as:
!
Nuclear cataract
!
Cortical cataract
!
Posterior subcapsular cataract
!
Posterior capsular opacification with location central or peripheral
!
Capsular bag not intact, due to central laser/surgical capsulotomy
!
Capsular bag not intact, due to capsular tear with location central or peripheral
!
Other
At post-Baseline visits, for eyes evaluated as phakic at Baseline, the severity of nuclear, 
cortical, and posterior subcapsular cataract lens opacities will be summarized (< standard 
photo #2, and ≥ standard photo #2) in number and percentage format by visit and eye.
11.3.9
Gonioscopy and Bim SR Implant Assessment
Gonioscopy is performed to assess the inferior iridocorneal angle and the Bim SR 
implant in study visits during Cycle 1 and Cycle 2 for all patients, and during Cycle 3. 
Patients presenting with peripheral anterior synechiae (PAS) on gonioscopy at any time 
during the study will be presented in a listing with the time period in which it occurred.
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If an implant is visible, visible implant size is to be recorded on eCRF as a percentage of 
the original material (0-25, 26-50, 51-75, 76-100, 101-125, 126-150, 151-200, >200).
Number and percentage of patients with any implant visible during the study will be 
summarized in a tabular format. In addition, number and percentage of implants visible 
will also be summarized during each study period for Bim SR eye further breaking down 
by the categorical percentage visible of each implant. Also, the number and percentage of 
patients who have any implant(s) in contact with corneal endothelium at any visit within 
a cycle will be summarized by analysis cycle. Implant assessment will be presented as 
data listings displaying the location of implant (12 zones), status of contact with other 
implant(s), and status of contact with corneal endothelium for each patient.
12.0
VISUAL FUNCTION QUESTIONNAIRE
National Eye Institute Visual Function Questionnaire responses collected at Baseline will 
not be summarized as part of this SAP.
13.0
INTERIM ANALYSES
No interim analysis is currently planned for the study.
Two database locks are planned for this study as described in Section 5.1: 
1) When all patients have completed Week 24 visit or have prematurely discontinued 
before Week 24 visit (primary lock), and
2) When all patients have completed the Week 52 visit or exited the study.
The analysis results based on the first database lock is considered as the primary analysis. 
The analyses based on the second database lock will provide further efficacy and safety 
information. Two CSRs will be written, one following each lock.
14.0
DETERMINATION OF SAMPLE SIZE
The sample size calculation is based on paired-eye differences using a normal 
approximation with a 2-sided significance level of 0.05, assuming that there is no 
difference in mean IOP change from baseline between Bim SR eyes and SLT eyes, and 
that change from baseline in IOP has a standard deviation of 4 mmHg. A sample size of 
144 patients will provide approximately 98% power in showing noninferiority in 3 out of 
3 timepoints with a noninferiority margin of 1.5 mmHg, and 90% power in showing 
noninferiority in 2 out of 3 timepoints with a noninferiority margin of 1.0 mmHg, 
assuming that both the between-eyes and the within-patient correlation coefficients are 
0.5.
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Assuming a premature discontinuation rate of 10%, approximately 160 patients are to be 
enrolled into this study.
15.0
STATISTICAL SOFTWARE
Statistical analyses will be performed using version 9.3 (or newer) of SAS software.
16.0
DATA HANDLING CONVENTIONS
16.1
EFFICACY DATA
As stated in protocol Section 5.9.1.5 Retreatment with Bim SR, when eye(s) received 
non-study IOP lowering medication or procedure, to avoid confounding of efficacy data, 
IOP measurements obtained after initiating the use of non-study IOP-lowering 
medication or procedure in an eye will be treated as missing for that eye. 
Additionally, handling of missing data will be supplemented by sensitivity analyses using 
multiple imputation and tipping point (adding different penalties on the imputed values)
approach.
16.2
VISIT TIME WINDOWS
Table 16-1, Table 16-2, and Table 16-3 present respectively, the analysis visits assigned 
for efficacy and safety assessments for patients who received only Cycle 1 implant, 
Cycles 1 and 2 implants and Cycles 1, 2, and 3 implants. If multiple assessments were 
taken within an analysis window, the assessment obtained on the day closest to the target 
day will be used; in the case of a tie, the assessment obtained on the later day will be used 
in the analysis. Please be noted, IOP values will be measured for safety, and these safety 
IOP values should not be included in efficacy analysis of IOP. IOP values for safety are 
often recorded on unscheduled IOP eCRF page with assessment reason provided in free 
text, which cannot be programmed straightforwardly. For simplicity, an unscheduled IOP 
values in an analysis windows will not be used, unless the IOP value is the only one in 
the window.
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Table 16-1
Visit Windows for Patients who only had Bim SR Cycle 1 Implant
Derived Visit
Target Visit Day
Visit Window
Baseline a
-1
≤ (SLT Date -1)
SLT/Sham SLT Administration
Day 1
1
SLT Date
Bim SR Cycle 1 Day 1b
Bim SR Cycle 1 Day 1
Bim SR Cycle 1 Day 1
Bim SR Cycle 1 Day 2 b
Bim SR Cycle 1 Day 1 + 1
Bim SR Cycle 1 Day 1 + 1
Week 4/Cycle 1 Week 4 b
25
[Bim SR Cycle 1 Day 1+ 2, 38]
Week 8/Cycle 1 Week 8 b
53
[39, 66]
Week 12/Cycle 1 Week 12 b
81
[67, 91]
Week 15/Cycle 1 Week 15 b
102
[92, 105] 
Week 16/Cycle 1 Week 16 b
109
[106, 122]
Week 20/Cycle 1 Week 20 b
137
[123, 150]
Week 24/Cycle 1 Week 24 b
165
[151, 178]
Week 28/Cycle 1 Week 28 b
193
[179, 203] 
Week 31/Cycle 1 Week 31 b
214
[204, 217]
Week 32/Cycle 1 Week 32 b
221
[218, 234]
Week 36/Cycle 1 Week 36 b
249
[235, 262]
Week 40/Cycle 1 Week 40 b
277
[263, 290]
Week 44/Cycle 1 Week 44 b
305
[291, 315]
Week 47/Cycle 1 Week 47 b
326
[316, 343] 
Week 52/Cycle 1 Week 52 b
361
>=344
a
Relative to the date of the SLT treatment.
b
Relative to the date of Bim SR 1st implant. If a patient did not receive the first Bim SR cycle, but treated in SLT at 
Day 1, Bim SR cycle 1 Day 1 will be determined as SLT+ 3 days. 
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Table 16-2
Visit windows for patients who only had Bim SR Cycles 1 and 2 implants
Derived Visit
Target Visit Day
Visit Window
Baseline a
-1
≤ (SLT Date -1)
SLT/Sham SLT Administration
Day 1
1
SLT Date
Bim SR Cycle 1 Day 1b
Bim SR Cycle 1 
Day 1
Bim SR Cycle 1 Day 1
Bim SR Cycle 1 Day 2b
Bim SR Cycle 1 
Day 1 + 1
Bim SR Cycle 1 Day 1 + 1
Week 4/Cycle 1 Week 4b
25
[Bim SR Cycle 1 Day 1+ 2, 38]
Week 8/Cycle 1 Week 8b
53
[39, 66]
Week 12/Cycle 1 Week 12b
81
[67, 91]
Week 15/Cycle 1 Week 15b
102
[92, 
Bim SR Cycle 2 Day1-Bim SR Cycle 1 Day 1]
Week 16/Bim SR Cycle 2 Day 1c
1
Bim SR Cycle 2 Day 1
Cycle 2 Day 2c
2
Bim SR Cycle 2 Day 1 + 1
Week 20/Cycle 2 Week 4c
29
[Bim SR Cycle 2 Day 1+ 2, 42]
Week 24/Cycle 2 Week 8c
57
[43, 70]
Week 28/Cycle 2 Week 12c
85
[71, 95]
Week 31/Cycle 2 Week 15c
106
[96, 109] 
Week 32/Cycle 2 Week 16c
113
[110, 126]
Week 36/Cycle 2 Week 20c
141
[127, 154]
Week 40/Cycle 2 Week 24c
169
[155, 182]
Week 44/Cycle 2 Week 28c
197
[183, 207] 
Week 47/Cycle 2 Week 31c
218
[208, 235]
Week 52/Cycle 2 Week 36c
253
>=236
a
Relative to the date of the SLT treatment.
b
Relative to the date of Bim SR 1st implant. If a patient did not receive the first Bim SR cycle, but treated in SLT at 
Day 1, Bim SR cycle 1 Day 1 will be determined as SLT+ 3 days.
c
Relative to the date of Bim SR 2rd implant.
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Table 16-3
Visit windows for patients who had Bim SR Cycle 1, 2 and 3 implants
Derived Visit
Target Visit Day
Visit Window
Baseline a
-1
≤ (SLT Date -1)
SLT/Sham SLT Administration
Day 1
1
SLT Date
Bim SR Cycle 1 Day 1b
Bim SR Cycle 1 
Day 1
Bim SR Cycle 1 Day 1
Bim SR Cycle 1 Day 2b
Bim SR Cycle 1 
Day 1 + 1
Bim SR Cycle 1 Day 1 + 1
Week 4/Cycle 1 Week 4b
25
[Bim SR Cycle 1 Day 1+ 2, 38]
Week 8/Cycle 1 Week 8b
53
[39, 66]
Week 12/Cycle 1 Week 12b
81
[67, 91]
Week 15/Cycle 1 Week 15b
102
[92, 
Bim SR Cycle 2 Day 1- Bim SR Cycle 1 Day 1] 
Week 16/Bim SR Cycle 2 Day 1c
1
Bim SR Cycle 2 Day 1
Cycle 2 Day 2c
2
Bim SR Cycle 2 Day 1 + 1
Week 20/Cycle 2 Week 4c
29
[Bim SR Cycle 2 Day 1+ 2, 42]
Week 24/Cycle 2 Week 8c
57
[43, 70]
Week 28/Cycle 2 Week 12c
85
[71, 95]
Week 31/Cycle 2 Week 15c
106
[96, Bim SR Cycle 3 Day 1- Bim SR Cycle 2 
Day1]
Week 32/Bim SR Cycle 3 Day 1d
1
Bim SR Cycle 3 Day 1
Cycle 3 Day 2d
2
Bim SR Cycle 3 Day 1 + 1
Week 36/Cycle 3 Week 4d
29
[Bim SR Cycle 3 Day 1+ 2, 42]
Week 40/Cycle 3 Week 8d
57
[43, 70]
Week 44/Cycle 3 Week 12d
85
[71, 95]
Week 47/Cycle 3 Week 15d
106
[96, 123]
Week 52/Cycle 3 Week 20d
141
>=124
a
Relative to the date of the SLT treatment.
b      Relative to the date of Bim SR 1st implant. If a patient did not receive the first Bim SR cycle, but treated in SLT at
     Day 1, Bim SR cycle 1 Day 1 will be determined as SLT+ 3 days.
c
Relative to the date of Bim SR 2rd implant.
d   Relative to the date of Bim SR 3rd implant.
16.3
DERIVED VARIABLES
Not applicable.
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192024-095 Statistical Analysis Plan Amendment (v 1.0)
2 Oct 2020
16.4
REPEATED OR UNSCHEDULED ASSESSMENTS OF SAFETY 
PARAMETERS
For safety parameters, if a patient has repeated assessments before the SLT treatment, 
unless otherwise stated, the results from the latest non-missing assessment made prior to 
the SLT treatment will be used as baseline. If end-of-study assessments are repeated or if 
unscheduled visits occur, the last non-missing postbaseline assessment will be used as the 
end-of-study assessment for generating summary statistics. However, all postbaseline 
assessments will be used for safety evaluation, and all assessments will be presented in
the data listings.
16.5
MISSING SEVERITY ASSESSMENT FOR ADVERSE EVENTS
If severity is missing for an AE that started before the date of study treatment, severity of 
mild will be assigned. If severity is missing for an AE that started on or after the date of 
study treatment, severity of ‘severe’ will be assigned. The imputed values for severity
assessment will be used for the incidence summaries; the values will be shown as missing
in the data listings.
16.6
MISSING CAUSAL RELATIONSHIP TO BIM SR IMPLANT FOR 
ADVERSE EVENTS
If the causal relationship to a study treatment is missing for an AE that started on or after 
the date of the study treatment, a causality of ‘yes’ will be assigned. The imputed values 
for causal relationship will be used for the incidence summaries; the values will be shown 
as missing in the data listings.
16.7
MISSING DATE INFORMATION FOR ADVERSE EVENTS
Per database design, only the day part of an AE start or stop date could be set to 
‘unknown’, month and year cannot be set to ‘unknown’. If the day part is missing, it will 
be imputed as follows:
!
If the month and year of the incomplete start date are the same as the month and year 
of the SLT Date or Bim SR Cycle 1 Date or Bim SR Cycle 2 Date or Bim SR Cycle 3 
date, the day part of the earliest of the above matching dates will be used to impute 
the missing day.
!
If either the year of the incomplete start date is before the year of the date of the SLT 
treatment or if both years are the same, but the month of the incomplete start date is 
before the month of the date of the SLT treatment, the last day of the month will be 
assigned to the missing day.
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!
If either the year of the incomplete start date is after the year of the date of SLT 
treatment or if both years are the same, but the month of the incomplete start date is 
after the month of the date of the SLT treatment, the first day of the month will be 
assigned to the missing day.
!
If the month and year of the incomplete stop date are the same as the month and year 
of the SLT Date or Bim SR Cycle 1 Date or Bim SR Cycle 2 Date or Bim SR Cycle 3 
date, the day part of the latest of the above matching dates will be used to impute the 
missing day.
!
If either the year of the incomplete stop date is before the year of the date of the SLT 
treatment or if both years are the same, but the month of the incomplete stop date is 
before the month of the date of the SLT treatment, the last day of the month will be 
assigned to the missing day.
!
If either the year of the incomplete stop date is after the year of the date of SLT 
treatment or if both years are the same, but the month of the incomplete stop date is 
after the month of the date of the SLT treatment, the last day of the month will be 
assigned to the missing day.
However, after the imputation if the stop date appears to be before the start date, start 
date will be set to stop date if the stop date was complete (non-missing) and stop date will 
be set to start date if the start date was complete (non-missing).
16.8
MISSING DATE INFORMATION FOR PRIOR OR 
CONCOMITANT MEDICATIONS
For prior or concomitant medications, including medications of interest, incomplete (i.e., 
partly missing) start dates and/or stop dates will be imputed. Per database design, year 
part of a medication start or stop date cannot be set to ‘unknown’ and if the medication 
started after informed consent form is signed, start date must be a complete date. If a 
medication stopped during the course of the study, then the medication stop date must be 
complete. When the start date and the stop date are both incomplete for a patient, the start 
date will be imputed first.
16.8.1
Incomplete Start Date
The following rules will be applied to impute the missing numeric fields for an 
incomplete prior or concomitant medication start date. If the stop date is complete (or 
imputed) and the imputed start date is after the stop date, the start date will be imputed 
using the stop date.
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2 Oct 2020
Missing month and day
!
If the year of the incomplete start date is same as the year of the informed consent 
date, January 1 will be assigned to the missing fields.
!
If the year of the incomplete start date is before the year of the informed consent date, 
December 31 will be assigned to the missing fields
Missing month only
!
If only the month is missing, the day will be treated as missing and both the month 
and the day will be replaced according to rules described above.
Missing day only
!
If the month and year of the incomplete start date are the same as the month and year 
of the informed consent date, first day of the month will be assigned to the missing 
day
!
If either the year of the incomplete start date is before the year of the informed 
consent date or if both years are the same, but the month of the incomplete start date 
is before the month of the informed consent date, the last day of the month will be 
assigned to the missing day.
16.8.2
Incomplete Stop Date
The following rules will be applied to impute the missing numeric fields for an 
incomplete prior or concomitant medication stop date. If the imputed stop date is before 
the start date (imputed or non-imputed start date), the imputed stop date will be set equal 
to the start date.
Missing month and day
!
If the year of the incomplete stop date is the same as the year of the informed consent
date, the month and day of the informed consent date will be assigned to the missing
fields.
!
If the year of the incomplete stop date is before the year of informed consent date, 
December 31 will be assigned to the missing fields.
Missing month only
!
If only the month is missing, the day will be treated as missing and both the month 
and the day will be replaced according to the rules described above.
Missing day only
!
If the month and year of the incomplete stop date are the same as the month and year 
of the informed consent date, the day of the informed consent date will be assigned to 
the missing day.
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IOP and the interaction between treatment and eye will be removed from 
the primary analysis model An unstructured covariance matrix (6×6 
matrix) will be used for measurements across 3 primary visits (Weeks 4, 
12, and 24) and between eye correlation. 
6. In Section 11.0, definition of Bim SR cycle is updated to Analysis Cycle.
!
SLT Cycle: SLT date through Cycle 1 Bim SR implant date -1
!
Analysis Bim SR Cycle1: Cycle 1 Bim SR implant SLT Treatment date
(Day 1) through the second Cycle 2 Bim SR implant date – 1. If the 
second Bim SR implant was not given to a patient, all safety assessments 
through Week52/Exit visit/last study visit available will be included in 
analysis cycle1. 
!
Analysis Bim SR Cycle 2: Second Cycle 2 Bim SR implant date through 
the third Cycle 3 Bim SR implant date – 1. If the third Bim SR implant 
was not given to a patient, all safety assessments through Week52/Exit 
visit/last study visit available will be included in analysis cycle 2. 
!
Analysis Bim SR Cycle 3: Third Cycle 3 Bim SR implant date through 
Week 52/Exit visit/last study visit available. Note that only Stage 1 
patients were eligible to receive third Bim SR implant.
7. In Section 11.1, analysis of SLT procedure related ocular TEAEs by SOC and PT 
is added.  
8. In Section 16.1, delete the statement below since mITT is covered excluding 
patients who had one Bim SR implant. Details for mITT is described in 
Section 6.1.
!
Additionally, for patients treated with Bim SR in Cycle 2, Week 24 data in 
primary analysis will be treated as missing if Bim SR treatment was not 
done in Cycle 2.
31AUG2021 CSR 192024-095 Final
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Electronic Signatures
User
Date
Justification
02-Oct-2020
23:27:42
(GMT)
Document Originator Approval
02-Oct-2020
21:17:52
(GMT)
Subject Matter Expert Approval
02-Oct-2020
23:24:21
(GMT)
Manager Approval
02-Oct-2020
22:14:27
(GMT)
Subject Matter Expert Approval
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