Clinical trial NCT02507687
Conditions: Glaucoma, Open-Angle Ocular Hypertension
Sponsor: AbbVie
Start date: 2015-08-27; Completion date: 2023-05-31
Enrollment: 240 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 patients 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: Participants enrolled prior to implementation of Protocol Amendment 3 receive the following treatment in each eye:

Assigned Primary Eye: Selective laser trabeculoplasty (SLT) administered on Day 1 followed by up to three sham bimatoprost SR administrations.

Contralateral Eye: Sham SLT administered on Day 1 followed by up to three bimatoprost SR 15 µg administrations.

Bimatoprost SR/sham bimatoprost SR is administered on Day 4 (Cycle 1) and at Week 16 (Cycle 2) and Week 32 (Cycle 3; participants who reach Week 32 prior to implementation of Protocol Amendment 3 only). arm 2: Participants enrolled prior to implementation of Protocol Amendment 3 receive the following treatment in each eye:

Assigned Primary Eye: Sham SLT administered on Day 1 followed by up to three bimatoprost SR 15 µg administrations.

Contralateral Eye: SLT administered on Day 1 followed by up to three sham bimatoprost SR administrations.

Bimatoprost SR/sham bimatoprost SR is administered on Day 4 (Cycle 1) and at Week 16 (Cycle 2) and Week 32 (Cycle 3; participants who reach Week 32 prior to implementation of Protocol Amendment 3 only). arm 3: Participants enrolled after implementation of Protocol Amendment 3 receive the following treatment in each eye:

Assigned Primary Eye: SLT administered on Day 1 followed by up to two sham bimatoprost SR administrations.

Contralateral Eye: Sham SLT administered on Day 1 followed by up to two bimatoprost SR 10 µg administrations.

Bimatoprost SR/sham bimatoprost SR is administered on Day 4 (Cycle 1) and at Week 16 (Cycle 2). After implementation of Protocol Amendment 6, Cycle 2 retreatment could occur after Week 16 and prior to Month 12 based on when retreatment criteria are met. arm 4: Participants enrolled after implementation of Protocol Amendment 3 receive the following treatment in each eye:

Assigned Primary Eye: Sham SLT administered on Day 1 followed by up to two bimatoprost SR 10 µg administrations.

Contralateral Eye: SLT administered on Day 1 followed by up to two sham bimatoprost SR administrations.

Bimatoprost SR/sham bimatoprost SR is administered on Day 4 (Cycle 1) and at Week 16 (Cycle 2). After implementation of Protocol Amendment 6, Cycle 2 retreatment could occur after Week 16 and prior to Month 12 based on when retreatment criteria were met.
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: Bimatoprost SR is a biodegradable, sustained-release, preservative-free bimatoprost implant, preloaded in an applicator for administration. The Bimatoprost SR implant is injected into the anterior chamber via the corneal limbus using the prefilled applicator. intervention 2: Sham bimatoprost SR performed using the same procedure as for Bimatoprost SR using an needleless applicator that touches the eye at the area of insertion but does not deliver an implant into the anterior chamber. intervention 3: SLT is a laser procedure that targets the melanin, or pigment, in specific cells of the eye.

An ophthalmologist performed 360 degrees of SLT using a standardized method. intervention 4: Sham SLT is performed on the contralateral eye using the same method as for SLT, with the exception that the laser is not switched to the active state.

Protocol documents:
Prot_000.pdf: 


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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 .................................................................................................................... 9
1.
Background and Clinical Rationale................................................................................. 25
1.1
Glaucoma and Treatment ....................................................................................... 25
1.2
Bimatoprost (LUMIGAN®) ................................................................................... 26
1.2.1
Nonclinical Studies with Bimatoprost SR.................................................. 27
1.2.2
Other Biodegradable Ocular Implants ....................................................... 29
1.2.3
Clinical Studies with Bimatoprost SR........................................................ 29
1.3
Study Rationale ...................................................................................................... 30
2.
Study Objectives and Clinical Hypotheses...................................................................... 31
2.1
Study Objectives .................................................................................................... 31
2.2
Clinical Hypotheses ............................................................................................... 31
3.
Study Design.................................................................................................................... 32
4.
Study Population and Entry Criteria................................................................................ 33
4.1
Number of Patients................................................................................................. 33
4.2
Study Population Characteristics ........................................................................... 33
4.2.1
Patients with Sickle Cell Trait/Disease or Other Hemoglobinopathies ..... 33
4.3
Inclusion Criteria.................................................................................................... 33
4.4
Exclusion Criteria................................................................................................... 35
4.5
Permissible and Prohibited Medications/Treatments............................................. 38
4.5.1
Permissible Medications/Treatments ......................................................... 38
4.5.2
Prohibited Medications/Treatments ........................................................... 40
4.5.3
Definition of Females of (Non-)Childbearing Potential and/or Acceptable 
Contraceptive Methods .............................................................................. 42
5.
Study Treatments ............................................................................................................. 43
5.1
Study Treatments and Formulations....................................................................... 43
5.2
Control Treatment .................................................................................................. 43
5.3
Methods for Masking............................................................................................. 43
5.4
Treatment Allocation Ratio and Stratification........................................................ 44
5.5
Method for Assignment to Treatment Groups/Randomization.............................. 44
5.6
Treatment Regimen................................................................................................ 44


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5.7
Storage of Study Medications ................................................................................ 45
5.8
Preparation of Study Medications/Treatments....................................................... 45
5.9
Study Treatment Administration ............................................................................ 46
5.9.1
Bimatoprost SR Administration................................................................. 46
5.9.2
SLT Administration.................................................................................... 49
6.
Response Measures and Summary of Data Collection Methods..................................... 50
6.1
Efficacy Measures.................................................................................................. 50
6.1.1
Primary Efficacy Measure.......................................................................... 50
6.2
Safety Measures ..................................................................................................... 51
6.3
Other Measures ...................................................................................................... 54
6.3.1
Medical History, Physical Examination, and Vital Signs........................... 54
6.3.2
Pregnancy Testing ...................................................................................... 55
6.3.3
Laboratory Procedures ............................................................................... 55
6.4
Other Study Supplies.............................................................................................. 56
6.5
Summary of Methods of Data Collection .............................................................. 57
7.
Statistical Procedures....................................................................................................... 57
7.1
Analysis Populations.............................................................................................. 58
7.2
Collection and Derivation of Primary and Secondary Efficacy Assessments........ 58
7.2.1
Primary Efficacy Variable.......................................................................... 59
7.2.2
Secondary Efficacy Variables..................................................................... 59
7.2.3
Other Efficacy Variables ............................................................................ 59
7.3
Hypothesis and Methods of Analysis..................................................................... 59
7.3.1
Primary Efficacy Analyses......................................................................... 60
7.3.2
Secondary Efficacy Analyses..................................................................... 61
7.3.3
Other Efficacy Analyses............................................................................. 62
7.3.4
Safety Analyses.......................................................................................... 62
7.4
Subgroup Analyses................................................................................................. 63
7.5
Sample Size Calculation ........................................................................................ 63
7.6
Interim Analyses..................................................................................................... 63
8.
Study Visit Schedule and Procedures .............................................................................. 63
8.1
Patient Entry Procedures........................................................................................ 65
8.1.1
Overview of Entry Procedures................................................................... 65
8.1.2
Informed Consent and Patient Privacy....................................................... 65
8.2
Washout Intervals................................................................................................... 65


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8.3
Procedures for Final Study Entry........................................................................... 66
8.4
Visits and Associated Procedures........................................................................... 67
8.4.1
Screening Visit ........................................................................................... 67
8.4.2
Baseline Visit ............................................................................................. 69
8.4.3
Treatment Period........................................................................................ 70
8.5
End of Study........................................................................................................... 78
8.6
Instructions for the Patients.................................................................................... 78
8.7
Unscheduled Visits................................................................................................. 79
8.8
Compliance with Protocol...................................................................................... 79
8.9
Early Discontinuation (Early Exit) of Patients....................................................... 79
8.10 Withdrawal Criteria................................................................................................ 80
8.11 Study Termination.................................................................................................. 80
9.
Adverse Events ................................................................................................................ 80
9.1
Definitions.............................................................................................................. 81
9.1.1
Adverse Event............................................................................................ 81
9.1.2
Serious Adverse Event ............................................................................... 81
9.1.3
Severity ...................................................................................................... 82
9.1.4
Relationship to Study Drug, Device, or Procedure.................................... 82
9.2
Procedures for Reporting Adverse Events ............................................................. 83
9.3
Procedures for Reporting a Serious Adverse Event............................................... 83
9.4
Procedures for Unmasking of Study Treatment..................................................... 84
10. Administrative Items ....................................................................................................... 84
10.1 Protection of Human Patients................................................................................. 84
10.1.1 Compliance With Informed Consent Regulations (US 21 CFR Part 50) and 
Relevant Country Regulations ................................................................... 84
10.1.2 Compliance With IRB or IEC Regulations ................................................ 85
10.1.3 Compliance With Good Clinical Practice .................................................. 85
10.1.4 Quality Assurance ...................................................................................... 85
10.1.5 Compliance With Electronic Records; Electronic Signatures Regulations 
(US 21 CFR Part 11).................................................................................. 85
10.2 Changes to the Protocol ......................................................................................... 85
10.3 Patient Confidentiality ........................................................................................... 86
10.3.1 Patient Privacy ........................................................................................... 86
10.4 Documentation....................................................................................................... 86
10.4.1 Source Documents ..................................................................................... 86




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Table 6
Schedule of Visits and Procedures:  Month 13 through Month 24/Exit ......... 23
Table 7
Minimum Washout Period by Ophthalmic Medication Class ........................ 66
Table 8
Administration Cycle 3 Schedule of Visits and Procedures (only for patients 
who reached Week 32 prior to implementation of Amendment 3)............... 157


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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; 2 administration cycles for patients who had not received a 
third administration cycle before implementation of Amendment 3

Stage 2:  Bimatoprost SR 10 µg vs SLT; 2 administration cycles
Duration:  approximately 26 months, including screening period of up to 28 days before washout, washout 
period of up to 56 days before initial study treatment, plus 24 months of follow-up after initial Bimatoprost SR 
and SLT administration.
Study Treatment:  Bimatoprost SR 15 µg (Stage 1) or 10 µg (Stage 2)
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 if the patient 
meets the retreatment criteria.  For those patients not meeting retreatment criteria at Week 16, Cycle 2 may be 
performed at the investigator’s discretion during an unscheduled visit after Week 16 and prior to the Month 12
visit if the retreatment criteria are met.  (Note that for all patients who were enrolled and reached the Week 16 
visit prior to implementation of Amendment 6, retreatment with Bimatoprost SR was fixed at Week 16.) 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 eye”) on Bimatoprost SR administration visits.  
Treatment schedule by eye is shown in 
Table 1.


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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)a
Bimatoprost SR
Sham Bimatoprost SR
SLT = selective laser trabeculoplasty; SR = sustained release
a
Cycle 2 administration of Bimatoprost SR is performed at Week 16 for all patients who meet retreatment criteria.  For 
those patients not meeting retreatment criteria at Week 16, Cycle 2 may be performed at the investigator’s discretion 
during an unscheduled visit after Week 16 and prior to the Month 12 visit if the retreatment criteria are met.  
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 up to 28 visits and 5 phone calls.  The 
schedule includes the following:

Screening (up to 28 days); Washout period of up to 56 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 (to occur at Week 16 for all patients who meet retreatment
criteria); Cycle 2 Day 2 safety visit; and Cycle 2 Day 4 and Week 2 phone calls
o
Patients who do not receive Cycle 2 administration at Week 16 will not attend the Cycle 2 
Administration Day visit on Week 16, or the Day 2 Safety or Day 4 and Week 2 phone calls 
associated with administration at Week 16.  For these patients, Cycle 2 may be performed at 
the investigator’s discretion during an unscheduled visit after Week 16 and prior to the 
Month 12 visit if the retreatment criteria are met; in this case, inadequate control of IOP 
should be confirmed at another scheduled or unscheduled visit prior to initiation of Cycle 2.  
All Cycle 2 visits will apply at the time of the Cycle 2 administration.

Follow-up visits at Weeks 20, 24, 28, 31, 36, 40, 44, 47, and 52; and Months 13, 14, 15, 16, 18, 20, 22, 
and 24/Exit
o
Regardless of the timing of Cycle 2 administration, all regularly scheduled visits should be 
completed.  Cycle 2 visits should be scheduled such that the Administration Day and the 
Day 2 Safety Visit do not occur on the day of a regularly scheduled study visit.  However, if 
the Cycle 2 Day 4 or Week 2 Phone Calls overlap with a regularly scheduled visit, perform
the regularly scheduled visit.  
o
Patients who receive the second administration of Bimatoprost SR at Week 16 and patients 
who never receive a second administration may, at the investigator’s discretion, skip the 


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visits at Months 13, 15 and 22 if the patient has received nonstudy IOP lowering medication 
in both eyes; has ≤ 25% of each implant remaining in the eye; and in the investigator’s 
clinical judgment, has no safety or other concern that would require the patient to attend these 
visits.  Please note: each eye should be evaluated on an individual basis when determining 
the need for additional nonstudy IOP-lowering treatments; initiation of treatment in one eye 
should not automatically lead to initiation of treatment in the contralateral eye.

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 50 patients
Stage 2:  approximately 160 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:

Shaffer Grade ≥ 3 on clinical gonioscopy of the inferior angle

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.




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Regulatory Activities (MedDRA) nomenclature.  The number and percentage of patients reporting 
treatment-emergent adverse events will be tabulated based on the system organ class and preferred term.  
Ocular safety variables attributable to each eye will be tabulated by Bimatoprost SR or SLT eye. Nonocular 
safety variables will be summarized.
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
change from baseline between Bimatoprost SR 10 µg 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 for 3 out of 3 timepoints with a noninferiority margin of 1.5 mm Hg, and 90% power in 
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 and treated with 
Bimatoprost SR 10 µg.  Additionally, there are approximately 50 patients who were enrolled before 
implementation of Amendment 3.


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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 56 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 56 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






















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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.


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The IOP-lowering efficacy of LUMIGAN (bimatoprost ophthalmic solution) 0.03% is well 
established.  In phase 3 studies in patients with POAG or OHT, LUMIGAN administered 
once daily as monotherapy was superior to timolol at all timepoints 
(Higginbotham et al, 2002).  This was further substantiated in the extension studies which 
followed patients in a masked manner for up to 4 years (Cohen et al, 2004; 
Williams et al, 2008; Study 192024-014).  In clinical studies of patients with OAG or OHT 
with a mean baseline IOP of 26 mm Hg, the IOP-lowering effect of LUMIGAN 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 10 μg, and intracameral administration of this dose 
strength is expected to reduce the total daily drug exposure to the eye by approximately 
126-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 


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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 
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 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 (Studies TX11076-TX, TX12012-TX, 
TX12018-TX) and with repeat doses of ≤ 15 μg (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 μg (two 10 μg 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 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 μg (Generation 2) dose, ocular 
tissues samples were collected for analysis, which demonstrated that drug and metabolite 
concentrations were BLQ in aqueous humor, vitreous humor, retina, and the remnant 
implants, but detected in cornea, choroid, and iris-ciliary body.  A pharmacokinetic study 
(PK14025-PK) was conducted in Beagle dogs comparing the ocular distribution of topical 
bimatoprost 0.03% solution or a single Generation 2 Bimatoprost SR implant (15 µg).  
Following topical administration, bimatoprost and bimatoprost acid distributed into the 
iris-ciliary body as well as other (off target) tissues with concentrations in the bulbar 
conjunctiva, eyelid margin, and periorbital fat significantly higher than those observed in the 
iris-ciliary body.  In contrast, following administration of a single Generation 2 Bimatoprost 
SR implant at 15 μg, bimatoprost and bimatoprost acid concentrations were either below the 


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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.
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 μg [2 x10 μg 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 3- to 4-month duration in many patients in this completed study.  By 
Month 6, most patients (> 66%) were still maintained on monotherapy with the initial 
Bimatoprost SR implant administered.  Among all Generation 2 dose strengths, at least 33% 
of patients had not received rescue or a second Bimatoprost SR treatment by Month 12.  At 
Month 24, at least 23% 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 (Studies 192024-091 and 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 μg (2 × 10 μg) or less in the phase 1/2 study was acceptable and 
supports additional clinical studies in humans.  Study 192024-093 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 μg Bimatoprost SR in 
patients with OAG or OHT who are not adequately managed with topical medication (eg, 
due to intolerance or nonadherence).  
Based on the interim data from phase 1/2 study 192024-041D, the higher of the two dose 
strengths being evaluated in the other global phase 3 studies, 15 µg, was selected for the 
2 phase 3 studies against an SLT comparator (192024-093 and 192024-095).  After
additional data from later-stage studies became available, the protocol in one of these studies 
(192024-093) was amended (Amendment 3) to reduce the dose strength for newly enrolled 
patients to 10 µg, in order to broaden the range of dose strengths evaluated in the 2 phase 3 
studies with the SLT comparator arm.  In addition, the number of administration cycles was 
reduced from 3 to 2 (eliminating Week 32 administration for newly enrolled patients and 
ongoing patients who had not yet received the Week 32 administration).  The number of 
administration cycles was reduced based on the duration of effect observed in completed 
24-month Study 192024-041D as well as the 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 


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maintained with fewer administration cycles.  In Amendment 6, an IOP-based retreatment 
criterion was added as a requirement for the second administration of Bimatoprost SR at 
Week 16 (patients not meeting retreatment criteria at Week 16 may receive the second 
administration of Bimatoprost SR at the investigator’s discretion during an unscheduled visit 
after Week 16 and prior to the Month 12 visit if the retreatment criteria are met).  The change 
from 3 to 2 administration cycles and the addition of the IOP-based retreatment criterion will 
not change the primary efficacy analysis, which is planned to occur after all patients treated 
with Bimatoprost SR 10 µg complete the Week 24 visit or discontinue the study and allows 
for assessment of the duration of effect of 2 Bimatoprost SR administration cycles 
throughout the study.
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).


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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).
3.
Study Design
This study is a multicenter, paired-eye, randomized, efficacy evaluator-masked 26-month 
study conducted in 2 stages and evaluating 2 different dose strengths of Bimatoprost SR 
(Stage 1:  15 µg; Stage 2:  10 µg).  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 was amended (Amendment 3)
to reduce the dose strength for newly enrolled patients to 10 µg in order to broaden the range 
of dose strengths evaluated in the 2 phase 3 studies with the SLT comparator arm.  The 
primary efficacy analysis will be performed for patients in Stage 2 only.
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 for all patients who meet retreatment criteria.  For those patients 
not meeting retreatment criteria at Week 16, Cycle 2 may be performed at the investigator’s 
discretion during an unscheduled visit after Week 16 and prior to the Month 12 visit if the 
retreatment criteria are met.  (Note that for all patients who were enrolled and reached the 
Week 16 visit prior to implementation of Amendment 6, retreatment with Bimatoprost SR 
was fixed at Week 16.) 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 


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Table 1).
4.
Study Population and Entry Criteria
4.1
Number of Patients 
Approximately 160 patients will be enrolled and treated with Bimatoprost SR 10 µg at 
approximately 70 sites, in order to have an estimated 144 patients treated with Bimatoprost 
SR 10 µg complete the study based on a premature discontinuation rate of 10%.  
Approximately 50 patients enrolled before implementation of Amendment 3 and received 
Bimatoprost SR 15 µg.
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 


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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 
8 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
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 


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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
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 use of commercially available Bimatoprost SR; concurrent enrollment in 
another Allergan Bimatoprost SR study; or previous enrollment in which an implant 
was received.  Patients enrolled in the 192024-091/092 studies who were randomized 
to the control treatment and never received an implant may be considered for 
enrollment at the investigator’s discretion.  
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.


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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)
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.


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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 
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 
decongestants or antihistamines is allowed if not taken within 2 days prior to a scheduled 
visit.  


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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.      
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).


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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 Month 24), 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 
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 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 


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administration [Week 16], Cycle 2 Day 2 safety visit, and Cycle 2 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 

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:


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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 formulations used in this study are Bimatoprost SR 
15 µg (11048X, for Stage 1) and 10 µg (11047X, for Stage 2).
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 


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Table 1.  The eye randomized to receive Bimatoprost SR will receive an intracameral 
administration of Bimatoprost SR on Day 4 and at Week 16 (if retreatment criteria are met),
plus Sham SLT administration on Day 1 only.  For those patients who do not meet 
retreatment criteria at Week 16, the second Bimatoprost SR administration may be performed 
at the investigator’s discretion during an unscheduled visit after Week 16 and prior to the 
Month 12 visit if the retreatment criteria are met.  The contralateral eye will receive one 360° 
SLT administration on Day 1 only, plus Sham Bimatoprost SR administration on Day 4 and
Week 16 (or at the time of the second Bimatoprost SR administration for patients who 
receive it later than Week 16).  Patients will receive the same dose strength throughout the 
study (ie, patients in Stage 1 received 15 µg and patients in Stage 2 will receive 10 µg).
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.


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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.
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, 


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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 
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 administration 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 
administration of Bimatoprost SR or Sham.


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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) 
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
For all patients who meet retreatment criteria at Week 16, Cycle 2 Bimatoprost SR
administration will occur at Week 16.  
For patients who do not meet retreatment criteria at Week 16, Cycle 2 Bimatoprost SR
administration may occur at the investigator’s discretion during an unscheduled visit after 
Week 16 and prior to the Month 12 visit based on the investigator’s clinical judgment 
regarding the patient’s IOP control and if the retreatment criteria are met.  Note:  beyond 
Week 16, Cycle 2 administration is not mandatory even if the retreatment criteria are met.
Patients who have received nonstudy IOP-lowering treatment (prohibited during the study 
except for pre- and post-SLT administration, Section 4.5.1) in only 1 eye will still attend 
administration visits regardless of whether the eye receiving additional medication is the 
Bimatoprost SR eye or the SLT eye.  If the eye treated with additional nonstudy IOP lowering 
medication is the Bimatoprost SR eye, the eye will receive Sham Bimatoprost SR 
administrations at the administration visits.  If the eye treated with additional nonstudy IOP 
lowering medication is the SLT eye, that eye will continue to receive Sham Bimatoprost SR 
administrations.  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), and Week 2 (phone call) visits following an administration.  Patients who have 
received nonstudy IOP-lowering medication in one or both eyes will be followed for the 
duration of the study through the Month 24/Exit visit.  
Retreatment of an eligible implanted eye is permitted if the following criteria are met in that 
eye:

IOP > 17 mm Hg

There is no evidence of any of the following:


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o
Significant corneal findings related to presence of the implant (including corneal 
edema, peripherally adjacent to the implant location and/or central) at any visit
o
Endothelial cell density less than 1800 cells/mm2 by specular microscopy, 
confirmed at 2 consecutive visits on separate days
o
Persistent and progressive corneal endothelial cell density decrease ≥15% from 
baseline confirmed at 2 consecutive visits on separate days (scheduled or 
unscheduled)
o
Remaining implant size or position from prior administration that, based on the 
investigator’s evaluation, precludes placement of another implant (eg, may cause 
chronic contact of the implants with the corneal endothelium)
o
Clinically significant intraocular inflammatory findings (eg, PAS, uveitis, 
iridocyclitis, macular edema, etc) at any visit.  Note:  mild AC cells/iritis related 
to the administration procedure itself that resolves rapidly (with or without 
NSAIDs or steroids) is not prohibitive

In the investigator’s opinion, it is safe for the study eye to receive an additional 
administration of Bimatoprost SR
Signs or symptoms will be documented in the eCRF.
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.  


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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.
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 


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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 
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.  


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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; Weeks 12, 24, and 52; and Months 18 and 24/Exit.  
At all other visits, the visual acuity technician will use the last manifest refraction performed 
and determine the Snellen equivalent visual acuity using the logMar chart.  If there is a 2-line 
or more reduction in visual acuity from the last 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.


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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 
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. Visual
field data may also be submitted to an Allergan designated vendor for additional evaluation.


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6.3
Other Measures
 
 
 
 
 
 
 
 
 
 
 
  
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; 


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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).

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.


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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.
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 

 


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
As needed:  anterior segment-optical coherence tomography, anterior segment-optical 
coherence tomography software and/or module, Specular Microscope, contact 
(ultrasound) pachymetry equipment

 

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
The study is being conducted in 2 stages.  In Stage 1, patients are treated with 
Bimatoprost SR 15 µg and SLT.  In Stage 2, patients are treated with Bimatoprost SR 10 µg 
and SLT.  
Three database locks will be performed:  1) when all patients treated with Bimatoprost SR 10
µg complete the Week 24 visit or have prematurely discontinued before the Week 24 visit, 
2) when all patients treated with Bimatoprost SR 10 µg have completed the Month 12 visit or 


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prematurely discontinued before the Month 12 visit, and 3) when all patients treated with 
Bimatoprost SR 10 µg have completed the Month 24 visit or prematurely discontinued before 
the Month 24 visit.  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.
7.1
Analysis Populations
The intent-to-treat (ITT) population is defined as all patients randomized to receive 
Bimatoprost SR 15 µg, Bimatoprost SR 10 µg, or SLT.  
The per-protocol (PP) population is defined as all patients in the Bimatoprost SR 10 µg ITT
population who have no protocol deviations affecting the data for primary efficacy analysis
for all visits (Week 4, Week 12, and Week 24).  The PP population will be used for selected 
efficacy analyses.  A list of patients with data excluded from the PP population will be 
finalized prior to database lock.
The Bimatoprost SR 15 µg, Bimatoprost SR 10 µg, and SLT safety populations are defined 
as all patients who received any study treatments 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.


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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 analyses.
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). 
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. 


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Data collected from patients treated with Bimatoprost SR 10 µg and Bimatoprost SR 15 µg
will be analyzed separately. Specifically, efficacy analysis for patients treated with 
Bimatoprost SR 15 µg will be limited to Hour 0 IOP descriptive summary statistics. Safety 
summaries will be generated for Bimatoprost SR 10 µg and Bimatoprost SR 15 µg using the 
same analysis methods, but will be presented separately.
7.3.1
Primary Efficacy Analyses
The primary efficacy analysis will be performed for patients treated with Bimatoprost SR 
10 µg in the 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 10 µg-
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 10 µg eye and SLT eye (Bimatoprost SR 10 µg minus SLT) is 
> 1.5 mm Hg.
Alternative hypothesis:  the difference in mean IOP change from baseline between the 
Bimatoprost SR 10 µg eye and SLT eye (Bimatoprost SR 10 µg 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, visit-by-baseline, and visit-by-eyes 
interactions as covariates.  Unstructured correlation for study visits and eyes will be used for
repeated measures on the same patient.  
The mean difference between the Bimatoprost SR 10 µg eyes and SLT eyes (Bimatoprost SR
10 µg minus SLT) and the corresponding 95% confidence interval (CI) will be constructed at 
each visit from MMRM analysis. The noninferiority comparison for Bimatoprost SR 10 µg
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 10 µg statistical noninferiority to SLT is 
demonstrated.  In addition, Bimatoprost SR 10 µg 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.


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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 Bimatoprost SR 10 µg ITT population, where the between-eye correlation will be 
included in the same way as the MMRM model used for the primary analysis.
Finally, handling of missing data will be supplemented by sensitivity analyses using multiple 
imputation and tipping point (adding different penalties to the imputed values) approach.
7.3.2
Secondary Efficacy Analyses 
Secondary efficacy analyses will be performed for patients treated with Bimatoprost SR 
10 µg in the ITT populations.  
Superiority Test of Bimatoprost SR 10 μg Versus SLT
A superiority test of Bimatoprost SR 10 µg versus SLT will be performed once noninferiority 
is demonstrated in the primary efficacy analysis.  Superiority of Bimatoprost SR 10 µg
versus SLT is considered achieved if the upper limit of the 95% CI is < 0 mm Hg at Weeks 4, 
12, and 24.
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 the first study 
treatment will be estimated separately for Bimatoprost SR 10 µg and SLT .
Additionally, time to initial use of nonstudy IOP-lowering treatment from the second
injection, will be analyzed similarly for Bimatoprost SR 10 µg.
Percentage of Bimatoprost SR and SLT Eyes Achieving ≥ 20% Reduction in IOP
Number and percent of Bimatoprost SR 10 µg 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 for Bimatoprost SR 10 µg and SLT eyes will be tabulated for IOP change 
from baseline at Weeks 8, 15 and 20;


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7.3.3
Other Efficacy Analyses
 
 
 
 
 
 
7.3.4
Safety Analyses
Safety analyses will be performed separately for patients in the Bimatoprost SR 15 µg and 
Bimatoprost SR 10 µg safety populations.  The Medical Dictionary for Regulatory Activities 
(MedDRA) nomenclature will be used to code adverse events and medical history.  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 attributable to each eye will be summarized by 
Bimatoprost SR or SLT eye, and nonocular safety variables will be summarized by patient.


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7.4
Subgroup Analyses
A subgroup analysis will be conducted for patients who received Bimatoprost SR 10 µg
administration under the flexible dosing regimen as specified in the protocol. This will
include patients enrolled under Amendment 6 and patients who were reconsented to 
Amendment 6 before receiving the second Bimatoprost SR administration. 
The details of this subgroup analysis will be provided 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 
change from baseline between Bimatoprost SR 10 µg 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 
treated with Bimatoprost SR 10 µg 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 and treated with Bimatoprost SR 10 µg.  Additionally, there are 
approximately 50 patients who were enrolled before implementation of Amendment 3.
7.6
Interim Analyses
No interim analyses are planned.  
8.
Study Visit Schedule and Procedures
Patients who complete all study treatments will have up to 28 visits and 5 phone calls.  The 
schedule includes the following:  

Screening (up to 28 days); Washout period of up to 56 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


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
Bimatoprost SR Cycle 2 administration (to occur at Week 16 for all patients who 
meet retreatment criteria); Cycle 2 Day 2 safety visit; and Cycle 2 Day 4 and Week 2 
phone calls
o Patients who do not receive Cycle 2 administration at Week 16 will not attend 
the Cycle 2 Administration Day visit on Week 16, or the Day 2 Safety or Day 
4 and Week 2 phone calls associated with administration at Week 16. For 
these patients, Cycle 2 may be performed at the investigator’s discretion 
during an unscheduled visit after Week 16 and prior to the Month 12 visit if 
the retreatment criteria are met; in this case, inadequate control of IOP should 
be confirmed at another scheduled or unscheduled visit prior to initiation of 
Cycle 2.  All Cycle 2 visits will apply at the time of the Cycle 2 
administration.

Follow-up visits at Weeks 20, 24, 28, 31, 36, 40, 44, 47, and 52; and Months 13, 14, 
15, 16, 18, 20, 22, and 24/Exit

Regardless of the timing of Cycle 2 administration, all regularly scheduled 
visits should be completed.  Cycle 2 visits should be scheduled such that the 
Administration Day and the Day 2 Safety Visit do not occur on the day of a 
regularly scheduled study visit.  However, if the Cycle 2 Day 4 or Week 2 
Phone Calls overlap with a regularly scheduled visit, perform the regularly 
scheduled visit.

Patients who receive the second administration of Bimatoprost SR at Week 16 
and patients who never receive a second administration may, at the 
investigator’s discretion, skip the visits at Months 13, 15 and 22 if the patient 
has received nonstudy IOP lowering medication in both eyes; has ≤25% of
each implant remaining in the eye; and in the investigator’s clinical judgment, 
has no safety or other concern that would require the patient to attend these 
visits.  Please note:  as described in Section 4.5.2, each eye should be 
evaluated on an individual basis when determining the need for additional
nonstudy IOP-lowering treatments; initiation of treatment in one eye should 
not automatically lead to initiation of treatment in the contralateral eye.
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]).


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The study visits should adhere as closely as possible to the schedule shown in Table 2,
Table 3, Table 4, Table 5, and Table 6.
8.1
Patient Entry Procedures 
8.1.1
Overview of Entry Procedures
Prospective patients as defined by the criteria in Section 4.3 and Section 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 56 days depending on the minimum washout period schedule 
below.
If patients cannot discontinue their prescribed therapy for up to 8 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 56 days.


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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 
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).


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8.4
Visits and Associated Procedures
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, Table 3, Table 4, 
Table 5, and Table 6).  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 
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


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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):
o
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):
o
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.)
o
Specular microscopy
o
Anterior segment-optical coherence tomography 
o
  
  Assessment 
will be repeated at Week 52 and Month 24/Exit and may be performed at any 
interim study visit at the discretion of the investigator.)
o
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)
o
Dilated ophthalmoscopy
o
Optic disc examination
Eligibility is then determined and the interactive response system is contacted.


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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)
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):
o
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):
o
Macroscopic iris color assessment
o
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.)


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o
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)
o
Dilated ophthalmoscopy
o
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

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.


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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)
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 (this contact may take place 
1 day prior to the administration day, if needed)    

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.


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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

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):  
o
Macroscopic conjunctival hyperemia assessment (The examination may also 
include, 
 
)
o
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):  
o
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.


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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)
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):
o
Macroscopic conjunctival hyperemia assessment (The examination may also 
include, 
 
.)
o
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):
o
Macroscopic iris color assessment (Weeks 4 and 12 only)
o
Manifest refraction (Week 12 only)
o
Specular microscopy (Weeks 4 and 12 only)
o
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)
o
Dilated ophthalmoscopy (Week 12 only)
o
Optic disc examination (Week 12 only)


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8.4.3.7
Bimatoprost SR Cycle 2 Day 1 Administration
The following procedures are performed at Week 16 (-2/+4 days) for all patients who meet 
retreatment criteria.  
Patients who do not receive Cycle 2 administration at Week 16 will not attend the Cycle 2 
Administration Day visit on Week 16, or the Day 2 Safety or Day 4 and Week 2 phone calls 
associated with administration at Week 16.  For those patients not meeting retreatment 
criteria at Week 16, Cycle 2 may be performed at the investigator’s discretion during an 
unscheduled visit after Week 16 and prior to the Month 12 visit if the retreatment criteria are 
met; in this case, inadequate control of IOP should be confirmed at another scheduled or 
unscheduled visit prior to initiation of Cycle 2.  For patients who begin Cycle 2 after Week 
16 and before Month 12, the Cycle 2 visits (Administration Day, Day 2 Safety Visit, and Day 
4 and Week 2 Phone Calls) will apply at the time that Cycle 2 occurs.  Regardless of the 
timing of Cycle 2, all regularly scheduled visits should be completed.  Cycle 2 should be 
scheduled such that the Administration Day and the Day 2 Safety Visit do not occur on the 
day of a regularly scheduled study visit.  However, if the Cycle 2 Day 4 or Week 2 Phone 
Calls overlap with a regularly scheduled visit, perform the regularly scheduled visit.

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.


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8.4.3.8
Cycle 2:  Day 2 (Cycle 2 Safety Visit)
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)
The following procedures should be performed in both eyes (procedures in bold should be 
done in the order shown):

Pre-Hour 0 examinations:
o
Macroscopic conjunctival hyperemia assessment (The examination may also 
include, 
 
)
o
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):
o
Biomicroscopy (The examination may also include, 
 
 
)
8.4.3.9
Cycle 2:  Day 4 and Week 2 (Cycle 2 Phone Calls)
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
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):


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
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 (procedures in bold should be 
done in the order shown):

Pre-Hour 0 examinations:
o
Macroscopic conjunctival hyperemia assessment (The examination may also 
include, 
 
)
o
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):
o
Macroscopic iris color assessment (Week 24 only)
o
Manifest refraction (Week 24 only)
o
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)
o
Specular microscopy (Week 24 only)
o
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)
o
Dilated ophthalmoscopy (Week 24 only)
o
Optic disc examination (Week 24 only)


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8.4.3.11
Weeks 36, 40, 44, 47, and 52; and Months 13, 14, 15, 16, 18, 20, 
22, and 24/Exit
The following procedures are performed at Weeks 36 (± 4 days), 40 (± 4 days), 44 (± 4 days), 
47 (± 4 days), and 52 (± 4 days) and Months 13 (± 4 days), 14 (± 4 days), 15 (± 4 days), 
16 (± 4 days), 18 (± 7 days), 20 (± 7 days)¸ 22 (± 7 days)¸ and 24/Exit (± 7 days).
Patients who receive the second administration of Bimatoprost SR at Week 16 and patients 
who never receive a second administration may, at the investigator’s discretion, skip the 
visits at Months 13, 15 and 22 if the patient has received nonstudy IOP lowering medication 
in both eyes; has ≤25% of each implant remaining in the eye; and in the investigator’s 
clinical judgment, has no safety or other concern that would require the patient to attend 
these visits.  Please note:  as described in Section 4.5.2, each eye should be evaluated on an 
individual basis when determining the need for additional nonstudy IOP-lowering treatments; 
initiation of treatment in one eye should not automatically lead to initiation of treatment in 
the contralateral eye.

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) 
(Month 24/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):
o
Macroscopic conjunctival hyperemia assessment (The examination will also
include,
 
 
 may be performed at interim visits for appearance of or 
increase/decrease in hyperemia.)
o
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):
o
Macroscopic iris color assessment (Week 52 and Months 18 and 24/Exit only)
o
Manifest refraction (Week 52 and Months 18 and 24/Exit only)


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o
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
and Months 18 and 24/Exit only)
o
Specular microscopy (Weeks 40 and 52 and Months 16, 20, and 24/Exit only)
o
(at Week 52 and Month 24/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.)
o
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 and Months 16, 20, and 24/Exit only) (may be done 
any time after gonioscopy)

Pupil dilation (Weeks 40 and 52 and Months 16, 20, and 24/Exit only) (post dilation 
exams below may be performed in any order)
o
Dilated ophthalmoscopy (Weeks 40 and 52 and Months 16, 20, and 24/Exit 
only)
o
Optic disc examination (Weeks 40 and 52 and Months 16, 20, and 24/Exit 
only)

Contact interactive response system at Month 24/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.
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 


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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 (Early Exit) 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 administration, will be followed for the duration of the study through 
the Month 24/Exit visit.  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 Month 24/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 Month 24/Exit, the site should complete all procedures for 
the Month 24/Exit visit at the patient’s last visit.


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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 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 
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.  


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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 
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 


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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.
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.  


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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 
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.


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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.
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 


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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.
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 


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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.  
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


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
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
Documentation of the patient's medical history
Vital signs, physical examination findings
IOP and ophthalmic examination findings
Dates of SLT or Sham SLT administration procedure
Dates of Bimatoprost SR or Sham administration procedure
Documentation of whether any procedure including study treatment
administration was performed according to the protocol, noting any deviations (if 
applicable)
 
 


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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.
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.


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10.5
Labeling, Packaging, and Return or Disposal of Study 
Medications/Treatments
10.5.1
Labeling/Packaging
Packaged and labeled study medication will be supplied by Allergan.
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 Section 5.1 and Section 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
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.


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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.
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.


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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 1-year 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):718-722.
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.


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Heijl A, Leske MC, Bengtsson B, Hyman L, Bengtsson B, Hussein M.  Reduction of 
intraocular pressure and glaucoma progression:  results from the early manifest glaucoma 
trial.  Arch Ophthalmol.  2002;120:1268-1279.
Higginbotham EJ, Schuman JS, Goldberg I, Gross RL, VanDenburgh AM, Chen K, et al.  
One-year, randomized study comparing bimatoprost and timolol in glaucoma and ocular 
hypertension.  Arch Ophthalmol.  2002;120:1286-1293.
Kass MA, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JL, Miller JP, et al.  The 
Ocular Hypertension Treatment Study:  a randomized trial determines that topical ocular 
hypotensive medication delays or prevents the onset of primary open-angle glaucoma.  Arch 
Ophthalmol. 2002;120(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.


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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.
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.


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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.
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
ANCOVA
analysis of covariance
ARMD
Age-related macular degeneration
ASC
Ambulatory Surgical Center
BLQ
below the limit of quantitation
bpm
beats per minute
CFR
Code of Federal Regulations
CI
confidence interval
DMEK
Descemet’s Membrane Endothelial Keratoplasty
DSEK
Descemet’s Stripping Endothelial Keratoplasty
eCRF
electronic case report form
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


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Term/Abbreviation
Definition
MDF
Map-Dot-Fingerprint
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple imputation
MMRM
mixed effect model for repeated measures
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 

SAP_001.pdf: 




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Statistical Analysis Plan for 192024-093 CSR (Amendment 1.1)                                     
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............................................................ 34
11.3.5
Specular Microscopy ..................................................................................... 35
11.3.6
Pachymetry.................................................................................................... 37
11.3.7
Biomicroscopy and Dilated Ophthalmoscopy ................................................. 37
11.3.8
Optic Disc Examination................................................................................. 37
11.3.9
Lens Status and Opacification ........................................................................ 37
11.3.10 Gonioscopy and Bim SR Implant Assessment ................................................ 38
12.0
Subgroup Analyses ................................................................................................................... 38
12.1
IOP Change from Baseline .......................................................................................... 38
12.2
Time to Second Bim SR Administration ...................................................................... 38
12.3
ECL Analyses by Fixed and Flexible administration .................................................... 39
12.4
Ocular Adverse Event by Fixed and Flexible administration......................................... 39
13.0
Visual Function Questionnaire................................................................................................... 39
14.0
Interim Analyses....................................................................................................................... 39
15.0
Determination of Sample Size................................................................................................... 39
16.0
Statistical Software ................................................................................................................... 40
17.0
Data Handling Conventions....................................................................................................... 40
17.1
Efficacy Data .............................................................................................................. 40
17.2
Missing Data Handling for Sensitivity Analyses........................................................... 40
17.2.1
Last Observation Carried Forward (LOCF)..................................................... 40
17.2.2
Multiple Imputation....................................................................................... 40
17.3
Analysis Windows....................................................................................................... 41
17.4
Derived Variables........................................................................................................ 46
17.5
Repeated or Unscheduled Assessments of Safety Parameters........................................ 46
17.6
Missing Severity Assessment for Adverse Events......................................................... 46
17.7
Missing Causal Relationship to Bim SR Implant for Adverse Events............................ 47
17.8
Missing Date Information for Adverse Events.............................................................. 47
17.9
Missing Date Information for Prior or Concomitant Medications.................................. 48
17.9.1
Incomplete Start Date .................................................................................... 48
17.9.2
Incomplete Stop Date..................................................................................... 48
18.0
References ................................................................................................................................ 49
19.0
Amendments............................................................................................................................. 49
19.1
Amendment 1.............................................................................................................. 49
19.2
Amendment 1.1........................................................................................................... 50
2.1
LIST OF TABLES
Table 4-1
Summary of Protocol Amendments with Revisions related to Statistical Analysis.... 8
Table 4-2
Treatment Schedule by Eye..................................................................................... 8
Table 4-3
Administration Cycle 1 Schedule of Visits and Procedures:  Screening through 
Day 2 ................................................................................................................... 10


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Statistical Analysis Plan for 192024-093 CSR (Amendment 1.1)                                     
Table 4-4
Administration Cycle 1 Schedule of Visits and Procedures: Day 4 through 
Week 15............................................................................................................... 12
Table 4-5
Administration Cycle 2 Schedule of Visits and Procedures:  Week 16 through 
Week 31............................................................................................................... 14
Table 4-6
Schedule of Visits and Procedures: Week 36 through Week 52.............................. 16
Table 4-7
Schedule of Visits and Procedures:  Month 13 through Month 24/Exit................... 18
Table 17-1
Visit Schedule, Visit Windows and By-Cycle Analysis for Efficacy and Safety 
Assessments ......................................................................................................... 42
Table 17-2
Visit Windows for By Visit Analysis for Assessments Occurring Every 4 weeks ... 43
Table 17-3
Visit windows for By Visit and Analysis Cycle for Assessments Occurring Every
3- 4 Months.......................................................................................................... 45
Table 17-4
Visit windows for By Visit Analysis for Assessments Occurring Every 6 Months.. 46
2.2
LIST OF FIGURES
Figure 11-1
Analysis Cycle Illustration.................................................................................... 30


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Statistical Analysis Plan for 192024-093 CSR (Amendment 1.1)                                     
3.0
LIST OF ABBREVIATIONS
AE
adverse event
ATC
anatomical therapeutic chemical
ANCOVA
analysis of covariance
BCVA
best-corrected visual acuity
Bim SR
Bimatoprost SR
CCT
central corneal thickness
CECD
corneal endothelial cell density
CI
confidence interval
CV
coefficient of variation
CVAVE
coefficient of variation average
dB
decibels
DBL
database lock
ECD
endothelial cell density
eCRF
electronic case report form
HEXAVE
pleomorphism average
IOP
intraocular pressure
ITT
intent-to-treat
KM
Kaplan-Meier
LOCF
last observations carried forward
MAR
missing at random
MCMC
Markov Chain Monte Carlo
MD
mean defect
MedDRA
medical dictionary for regulatory activities 
MI
multiple imputation
MMRM
mixed effect model for repeated measurement
MNAR
missing not at random
NA
not applicable
OAG
open-angle glaucoma
OD
right eye
OHT
ocular hypertension
OS
left eye
OU
both eyes
PP
per protocol
PT
preferred term
SAE
serious adverse event


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Statistical Analysis Plan for 192024-093 CSR (Amendment 1.1)                                     
SAP
statistical analysis plan
SD
standard deviation
SI
Le Système International d’Unités (International System of Units)
SLT
selective laser trabeculoplasty
SOC
system organ class
SR
sustained release
TEAE
treatment-emergent adverse event
TFLs
tables, figures and data listings
VA
visual acuity


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Statistical Analysis Plan for 192024-093 CSR (Amendment 1.1)                                     
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 192024-093. Specifications of tables, figures, and data listings (TFLs) are 
contained in a separate document.
Study 192024-093 is a multicenter, paired-eye, randomized, efficacy evaluator-masked
26- 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).
The study duration is approximately 26 months, including screening period of up to 28 
days before washout; a washout period of up to 56 days before initial study treatment;
and 24 months of follow-up after the initial Bim SR and SLT administration. 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. 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 key changes made in study protocol amendments that would impact the analysis
dataset are summarized in Table 4-1.


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Table 4-1
Summary of Protocol Amendments with Revisions related to Statistical Analysis 
Protocol Amendment
Summary
Amendment 3

2 Bim SR administrations given at Day 4 and Week 16.

Discontinuation of Bim SR 15 µg dose strength for newly 
enrolled patients under Amendment 3.

Bim SR 10 µg dose strength was started to treat newly enrolled 
patients.
(Stage 1: Bim SR 15 µg with 2 administration cycles; Stage 2: 
Bim SR 10 µg with 2 administration cycles).
Amendment 6

For patients who do not meet retreatment criteria at Week 16, the
second administration of Bim SR 10 µg may be performed at the 
investigator’s discretion during an unscheduled visit after Week 
16 and prior to the Month 12 visit if the retreatment criteria are 
met. 
(Note that for all patients who were enrolled and reached the 
Week 16 visit prior to implementation of Amendment 6, 
retreatment with Bim SR was fixed at Week16). 
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 Bim SR administrations 
(hereafter referred to as the Bim SR eye). Similarly, a sham, needleless Bim SR 
administration (hereafter referred to as the Sham Bim SR administration and 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 eye) at the Bim SR administration visits. 
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 at eye 
level by randomized treatment (Bim SR and SLT). Where appropriate, data summaries at 
patient level will be provided.
Table 4-2
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 )a
Bim SR
Sham Bim SR
SLT = selective laser trabeculoplasty; SR = sustained release
a   Cycle 2 administration of Bim SR is performed at Week 16 for all patients who meet retreatment criteria. For those 
patients not meeting retreatment criteria at Week 16, Cycle 2 may be performed at the investigator’s discretion during 
an unscheduled visit after Week 16 and prior to the Month 12 visit if the retreatment criteria are met.  


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Three database locks will be performed: 
1) when all patients treated with Bim SR 10 µg have completed the Week 24 visit or have 
prematurely discontinued before the Week 24 visit (referred to as the primary DBL);
2) when all patients treated with Bim SR 10 µg have completed the Month 12 visit or 
have exited the study prior to Month 12 (referred to as the Month 12 DBL). To provide 
sufficient safety follow-up data after the repeat administrations, the second database lock 
will occur when all patients have completed a minimum of 3 months of follow-up after 
the second administration or reached Month 12 without the need for the second 
administration; and 
3) when all patients treated with Bim SR 10 µg have completed the Month 24 visit or 
have prematurely discontinued before Month 24 (referred to as the final DBL).
Analyses will be performed on unmasked data after each lock. The analysis based on the 
primary database lock will be considered as the primary analysis of the study. The 
analysis plan will support each of DBLs, but some analyses will be reduced for the final 
DBL (e.g, the primary efficacy analysis will not be re-produced at the final DBL). 
Additional unmasked analyses based on accumulated data may be conducted after the 
initial Week 24 DBL (primary DBL) to support health authority submissions (e.g, 120 
Day Safety Update and responses to questions). These analyses will be consisted of 
available data that are deemed suitable for regulatory submissions, although may not be 
of the quality standard used for formal, prespecified database locks. 
Schedule of visits and procedures to be performed on randomized patients are presented 
in Table 4-3 to Table 4-7. 


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Table 4-3
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 56 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 56 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




















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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).
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 the “ITT population”. Analyses using 
the ITT population will be based on the randomized treatment assigned to each eye.
6.2
PER-PROTOCOL POPULATION
The per-protocol (PP) population is defined as all patients in the ITT population who 
have no protocol deviations affecting the data for the primary efficacy analysis for all 
primary analysis visits (Week 4, Week 12, and Week 24), and will be referred to as the 
“PP population”. 
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.


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Examples of protocol deviations that will result in removal of data from PP analysis 
include but are not limited to the following cases:

Eyes with no study treatment will be excluded from PP analysis, and

For eyes that received both study treatments or swapped treatments, data after the 
wrong treatment will be excluded from PP analysis.
A separate document will be prepared to describe the data exclusion criteria and 
algorithm for PP analysis. Additional considerations for PP exclusion from the IOP 
analysis may include situations where out of time window for Hour 0 IOP data; 
concomitant medication (or procedure) that potentially affects IOP data but is not 
identified as a non-study IOP lowering medication (or procedure) in the eCRF; or, 
implant removal, etc. 
All patients with data excluded from the PP analysis will be identified and finalized prior 
to the primary 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 study 
treatment (regardless of whether it was the randomized 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. If a patient received both SLT and Bim SR in the same
eye, safety assessment for this 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, Safety, and PP) will be summarized 
for the overall study. The numbers and percentages of patients randomized by country
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 as defined in Figure 11-1, with categories 
of premature discontinuation reasons included.


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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).
8.0
DEMOGRAPHICS AND OTHER BASELINE DATA
Demographics and other baseline characteristics will be summarized descriptively for the 
ITT population.
8.1
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
Demographic parameters (including age, age group, race, race group, ethnicity, sex) and
baseline characteristics (weight [kg], height [cm], and iris color) 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). The iris color will be summarized by color for each of the following 
categories: monochromic, heterochromic peripupillary, and heterochromic diffuse. In 
addition, the reason for not being adequately managed with topical IOP-lowering 
medications (memory loss, physical inability to administer medication, tolerability, and 
other) will be summarized at patient level.
8.2
BASELINE DISEASE CHARACTERISTICS
Baseline disease characteristics for each eye will be descriptively summarized by 
treatment of the eye for the following variables for the ITT population: diagnosis of either 
Open-Angle Glaucoma (OAG); primary, pseudoexfoliation , pigmentary, or Ocular 
Hypertension (OHT), baseline Hour 0 IOP (≤25 mm Hg or > 25 mmHg), iridocorneal 
angle Shaffer grade, and central endothelial cell density.
8.3
MEDICAL AND SURGICAL HISTORY
Abnormalities in patients’ medical and surgical histories will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA), 23.1 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 the Bim SR eye and/or SLT eye at randomization will also be summarized 
separately for the ITT population by SOC and PT
8.4
PRIOR AND CONCOMITANT MEDICATIONS
Medications will be coded using the current version of the World Health Organization
Drug Global Dictionary and the anatomical therapeutic chemical (ATC) classification 
system.


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Prior medications are defined as medications taken before the date of the first 
administration of study treatment. Concomitant medications are defined as those 
medications taken on or after the date of the first administration of study treatment. If a 
medication is taken before the date of the first administration of study treatment and 
continues after initiation of study treatment, it will be considered as both a prior 
medication and concomitant medication.
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 for the ITT population. 
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 days from the SLT administration date to the last visit date as shown below. 

Study duration = 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 diurnal IOP analyses.
Unless specified otherwise, the IOP measurements obtained after initiating the use of 
non-study IOP-lowering treatment (medications or procedures or both) in an eye will be 
excluded from the efficacy analysis. 


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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.
Hour 0 IOP measurements at baseline, Weeks 4, 12 and 24 and changes from baseline 
will be descriptively summarized.
Primary efficacy analysis will be performed for patients treated with Bim SR 10 µg in the 
ITT population. The null and alternative hypotheses for the comparisons of IOP-lowering 
effect between Bim SR 10 µg and SLT at Weeks 4, 12, and 24 are:

Null hypothesis: the difference in mean IOP change from baseline between the 
Bim SR 10 µg and SLT (Bim SR 10 µg minus SLT) is > 1.5 mmHg.

Alternative hypothesis: the difference in mean IOP change from baseline between 
the Bim SR 10 µg and SLT (Bim SR 10 µg 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, visit-by-baseline Hour 0 IOP, visit-by-eye interactions as fixed effects. 
Unstructured covariance matrix for study visits and eyes will be used for repeated 
measures on the same patient. IOP measurements obtained after initiating the use of non-
study IOP-lowering medication or procedure in an eye will be treated as missing. This 
will correspond to the hypothetical strategy defined in ICH E9 addendum (Section 18.0). 
If the model fails to converge, multiple imputation (MI) will be implemented for missing 
data before applying MMRM.
The mean difference in the Hour 0 IOP change from baseline between the Bim SR 10 µg 
and SLT (Bim SR 10 µg minus SLT) in the ITT population and the corresponding 95% 
confidence intervals (CI) will be constructed at each visit of Weeks 4, 12, and 24 from 
MMRM analysis. If the upper limit of the 95% CI is ≤ 1.5 mmHg at all 3 visits, the 
statistical noninferiority of Bim SR 10 μg to SLT is demonstrated.
For additional clinical consideration, Bim SR 10 µg 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.
Sample SAS® code for primary analysis is shown as below:
proc mixed data=iop;
where avisitn >1;
class subjid eye trt avisitn; 
model chg=trt avisitn eye base trt*avisitn  
               avisitn*base avisitn*eye/ddfm=kr;


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repeated avisitn*eye/type=un subject=subjid rcorr;
lsmeans trt*avisitn/diff;
run;
The definitions of variables are:
chg = Hour 0 IOP change from baseline at the primary analysis time points of 
           Week 4, Week 12, and Week 24
avisitn = 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
10.2.1
Superiority Test of Bim SR 10 μg versus SLT
As the secondary efficacy analysis, a superiority test of Bim SR 10 μg versus SLT will be 
performed if the statistical noninferiority is demonstrated in the primary efficacy analysis
for the ITT population as the gatekeeping procedure to control overall type I error rate at 
the 0.05 level. Superiority of Bim SR 10 µg versus SLT is considered achieved if the 
upper limit of the 95% CI is < 0 mmHg at Weeks 4, 12, and 24.
10.2.2
Time to Initial Use of Non-study IOP-lowering Treatment 
Time to the initial use of non-study IOP-lowering treatment from the Date of the First 
Treatment as defined below will be analyzed 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 (Day 1), and the 
Date of First Treatment for Bim SR 10 µg is Bim SR 10 µg administration date (Day 4).
Additionally, for Bim SR 10 µg, the time to non-study IOP-lowering treatment from the 
second injection will be summarized:

Time to initial use of non-study IOP-lowering treatment from the second Bim SR 10 
µg administration = (Date of initial use of non-study IOP-lowering treatment after the 
second Bim SR 10 µg implant – Date of the second Bim SR 10 µg administration) +1
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 treatment 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.


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In the calculation for the time to the event of non-study IOP-lowering treatment from the 
second Bim SR 10 µg administration, patients with at least two Bim SR 10 µg 
administrations will be used, and the event will be censored at the last available visit date 
or exit date if the patients did not use any non-study IOP-lowering treatment.
10.2.3
Percentage of Bim SR and SLT Eyes Achieving ≥ 20% Reduction by 
Visit
Number and percent of eyes that have achieved a ≥ 20% reduction in IOP at each post-
baseline visit will be summarized by treatment.
10.2.4
IOP Changes from Baseline at Weeks 8, 15, and 20
IOP values at Week 8, 15 and 20 and the changes from baseline will be descriptively 
summarized for Bim SR 10 µg and SLT at each timepoint for the ITT population.
10.3
OTHER EFFICACY ANALYSES
Other efficacy analyses comparing Bim SR 10 µg and SLT include:

IOP change from baseline as time-weighted average through Week 24

Post-baseline IOP as time-weighted average through Week 24 

Time to first achieving ≥20% IOP reduction

Percentage of eyes achieving ≥ 15% and ≥ 30% reductions from baseline IOP by 
visit

Diurnal IOP 
Analyses will be performed for the ITT population. KM method will be used for time to 
event analysis. 
For patients treated with Bim SR 15 µg, descriptive statistics for baseline and change 
from baseline IOP will be summarized for each eye (SLT and Bim SR 15 µg) and visits 
in the ITT population. 
10.3.1
IOP Change from Baseline (and Post-baseline IOP) Time-weighted 
Average through Week 24
Time-weighted average change in IOP from baseline is calculated as described below:
Let y0, y1, …, yn represent IOP measurements taken on calendar dates d0, d1, …, dn
respectively, where y0 is the measurement taken on calendar date d0, representing 
baseline IOP value, and let Δyi=yi- y0, representing the change in IOP from baseline to 
date di for i=0, 1,…, n. Then the time-weighted average change, denoted by S1 is: 


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S1 =
1
(	 −) ( + ) × ( −)
2
	

In this analysis, IOP measurements taken at Baseline (at d0), Week 4, Week 8, Week 12, 
Week 15, Week 20, and Week 24 will be considered, thus n = 6. The analysis visit with 
missing value will be skipped from the calculation. S1 will be calculated for each patient
and each eye by using the actual dates of the IOP measurements. The time-weighted 
average change from baseline will be summarized descriptively by Bim SR 10 µg eye 
and SLT eye. Similar equation will be applied for the time-weighted average post-
baseline IOP.
10.3.2
Time to Onset of Effect (Time to First Achieving ≥20% IOP 
Reduction)
Percentage reduction in Hour 0 IOP from baseline will be calculated for all available 
post-baseline IOP measurement visits for each eye using the formula:

Percentage Reduction = 100 x (Baseline IOP – Visit IOP)/Baseline IOP
Time in days to onset of effect will be calculated using the Date of First Treatment and 
the date of the earliest observation of ≥20% reduction in IOP using the formula:

Time to onset of effect = (Date of the earliest observation of ≥20% reduction – Date 
of First Treatment) +1
where the Date of First Treatment for SLT is SLT treatment date (Day 1), and the Date of 
First Treatment for Bim SR 10 µg is the first administration date (Day 4).
For eyes that did not achieve ≥20% reduction in IOP at any post-baseline visit, ‘Time to 
onset of effect’ will be censored at the date of the latest IOP measurement. Due to large 
IOP drop on the day immediately after treatment, the IOP values within two days after 
SLT or Bim SR 10 µg treatment will not be considered for this analysis. Time to onset of 
effect associated with each eye will be analyzed using Kaplan-Meier method with 
graphical displays. 
10.3.3
Percentage of Bim SR and SLT Eyes Achieving ≥ 15% and ≥ 30% 
Reductions in IOP by Visit
Number and percent of eyes that have achieved a ≥ 15% reduction in IOP will be 
summarized by visit and by treatment. Similar summaries for patients achieved ≥30%
reductions in IOP will be provided.


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10.3.4
Diurnal IOP Analyses
For consenting patients at selected sites, diurnal IOP measurements will be conducted at 
Hour 0, 2, and 8. The diurnal IOP measurements will be summarized by hour and by 
visit. Additionally, descriptive statistics for the mean IOP across Hours 0, 2, and 8 will be 
summarized by visit for patients who had least 2 IOP measurements available out of 3 
timepoints. Similarly, descriptive statistics of the IOP range (max IOP – min IOP among 
three timepoints) will be summarized by visit. 
10.3.5
Baseline Hour 0 IOP and Change from Baseline in Bim SR 15 µg
For patients treated with Bim SR 15 µg, descriptive statistics for baseline and change 
from baseline in Hour 0 IOP will be summarized for Bim SR 15 µg and SLT separately at 
each visit. 
10.4
SENSITIVITY ANALYSES
10.4.1
Per Protocol Analysis
As part of the sensitivity analyses, the mean difference and 95% CI in the IOP change 
from baseline between the Bim SR 10 µg and SLT (Bim SR 10 µg minus SLT) will be 
constructed for Week 4, 12, and 24 visits for the Per Protocol (PP) population using the 
same MMRM model as specified for the primary analysis.
10.4.2
Analysis of Covariance (ANCOVA)
Analysis of Covariance (ANCOVA) including within-patient correlation at each visit will
be conducted for IOP change from baseline at Weeks 4, 12, and 24 in the ITT population. 
In this analysis, missing data will be imputed using the last observation carried forward.
At each visit, the model for IOP change from baseline is specified as: IOP Change from 
Baseline = Treatment + Eye + Baseline IOP, where Eye is a primary eye or a 
contralateral eye. Unstructured covariance matrix will be used for between eye 
correlation.
10.4.3
Treatment Effect Regardless of Non-Study IOP Treatment Use
To evaluate the treatment effect regardless of whether there is any use of non-study IOP 
lowering treatment, the MMRM analysis for primary analysis in Section 10.1 will be 
performed in the ITT population using all available Hour 0 IOP data. In this analysis, 
data after the use of non-study IOP lowering treatment will not be excluded.
10.4.4
Tipping Point Analysis
A tipping-point analysis will be used to assess the robustness of the primary efficacy 
analysis with respect to possible deviations from missing at random (MAR) assumption
in MMRM model. This analysis will evaluate the sensitivity of study results under the 
missing not at random (MNAR) assumption.


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Tipping point analysis will be based on multiple imputed (MI) datasets for IOP data as 
described in Section 17.2 while applying a shift parameter to imputed IOP data for Bim 
SR 10 µg treated eyes. Specifically, missing IOP data will be calculated by adding a 
positive shift value to the imputed data to discount the treatment effect for Bim SR 10 µg. 
This shift will essentially make the IOP data higher than imputed for Bim SR 10 µg
treated eyes. Note that there will be no shift applied to SLT treated eyes. With each shift, 
the MMRM analysis as specified for the primary efficacy will be performed based on the
MI-based but shifted IOP data. SAS PROC MIANALYZE procedure will be used to 
aggregate the analysis results by using the parameter estimates from each imputed 
dataset. 
Starting from a shift of 0 mmHg (ie, no shift), the above procedures will be repeated with 
incremental shift values of 1 mmHg. The shift values will be adjusted with unmasked 
data. The tipping point is reached when the analysis result being switched from positive 
(ie, Bim SR 10 µg is non-inferior to SLT) to negative (ie, Bim SR 10 µg is no longer 
non-inferior to SLT). The corresponding shift value is defined as the tipping point. If the 
IOP value at the tipping point is clinically implausible, the primary analysis results will 
be considered as robust.
The scientific plausibility, clinical relevance, as well as the interpretations of the different 
shift values will be discussed in the clinical study report. 
10.4.5
Impact of Receiving the 2nd Bim SR After Week 16 and Prior to 
Week 24
Some patients may receive the second Bim SR 10 µg administration after Week 16 and 
prior to Week 24, thus the time interval between the second Bim SR 10 µg administration 
and the primary analysis endpoint at Week 24 will be shorter for these patients as 
compared with patients who received the second Bim SR 10 µg at Week 16. To evaluate
any potential impact of this difference in timing of the second administration on Week 24 
IOP data from these patients in the primary analysis, additional sensitivity analysis will 
be conducted by excluding the IOP data at Week 24 for these patients. More specifically, 
for patients who received flexible administration of the second Bim SR 10 µg beyond the
Week 16 visit, the Week 24 IOP assessment will be excluded from the current sensitivity 
analysis if the second administration date is in the analysis windows for Week 20 or
Week 24 and prior to the Week 24 IOP assessment. The MMRM model for the primary 
efficacy analysis as described in Section 10.1 will be used. 
11.0
SAFETY ANALYSES
All safety analyses will be performed using the safety population. Unless otherwise
stated, the last non-missing safety assessment before the SLT treatment (Day 1) will be 
used as the baseline for all analyses of that safety parameter. As indicated in Section 6.4, 
safety data collected at Screening for eligibility assessment will not be analyzed.


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All safety analyses described in the section 11.0 will be performed both Bim SR 10 µg
and Bim SR 15 µg. 
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.
Non-ocular safety analysis includes non-ocular adverse events (AEs), clinical laboratory
results, vital signs (blood pressure, pulse rate and temperature), and pregnancy test
results. 
Safety analyses will be summarized by study periods. Analysis study periods are defined 
as follows:

During the study: Date of SLT treatment through Month 24/Exit visit/last study 
visit available.

Analysis Cycle 1: SLT Treatment date (Day 1) through the second Bim SR
administration date – 1. If the second Bim SR administration was not given to a 
patient, all safety assessments through Month 24/Exit visit/last study visit 
available will be included in analysis cycle1. 

Analysis Cycle 2: Second Bim SR administration date through Month 24/Exit 
visit – 1. 

Analysis Cycle 3: Third Bim SR administration date through Month 24/Exit visit 
– 1, valid for only Bim SR 15 µg. 
All summaries will be based on the first treatment received in each eye (Bim SR or SLT). 
If a patient who received both SLT and Bim SR in the same eye, safety assessments will 
be summarized in Bim SR. For non-ocular safety measures, overall summaries will be 
presented regardless of study treatment. For ocular safety assessments, summaries will be 
presented for the periods of during the study, Analysis Cycle 1 and Analysis Cycle 2 as 
shown in Figure 11-1 below.
Figure 11-1
Analysis Cycle Illustration
Cycles for Safety Data Analyses
Treatment Schedule
SLT eye
BIM SR eye
Day 1, SLT administration
Analysis Cycle 1
Analysis Cycle 1
Day 4,  Bim SR 1st administration
Analysis Cycle 1
Analysis Cycle 1
Week 16a, Bim SR 2nd administration
Analysis Cycle 2
Analysis Cycle 2


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Week 32b, Bim SR 3rd administration
Analysis Cycle 3
Analysis Cycle 3
a     The second administration of Bim SR 10 µg is performed at Week 16 for all patients who meet retreatment criteria. 
For those patients not meeting retreatment criteria at Week 16, the second administration may be performed during 
an unscheduled visit after Week 16 and prior to the Month 12 visit if the retreatment criteria are met.
b     Analysis cycle 3 is valid only for Bim SR 15 µg.
11.1
ADVERSE EVENTS
Adverse events will be coded by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities, version 22.0 or newer.
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. 
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 TEAEs
o
Ocular
o
Non-ocular

Treatment-related TEAEs:
o
Ocular

Related to study drug

Related to study drug administration procedure

Related to SLT laser
o
Non-ocular

Treatment-related serious TEAEs:


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o
Ocular

Related to study drug

Related to study drug administration procedure

Related to SLT laser
o
Non-ocular

Any TEAEs leading to Bim SR implant removal

Any TEAEs leading to study discontinuation

Deaths
The following non-ocular TEAEs 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.
Ocular TEAEs will be summarized by analysis cycle and by treatment eye as described 
below:

Any ocular TEAEs by 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 
for the Bim SR eye and/or (Bim SR sham for the SLT eye)

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
for the Bim SR eye and/or (Bim SR sham for the SLT eye) to next Bim 
SR/ Sham Bim SR treatment (Bim SR sham for SLT eye)

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 
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:


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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.
Summary statistics for the line change from baseline will be presented by visits in each of 
the following categories: worsening (< -2), no change (≥ -2 and ≤ 2), and improvement
(> 2). The data for the largest line change from baseline across follow-up will be 
summarized for the entire study period (overall) and analysis cycle. The largest line 
change is defined as the greatest decrease from baseline in the number of lines read
during the entire study period for overall summary or within analysis cycle for by-cycle 
summary. 
11.3.3
Visual Field
Visual field examinations will be assessed by automated perimetry with either the
Humphrey Field Analyzer (using a 24-2 full threshold or 24-2 [SITA] Standard program)
or the Octopus Perimeter (using a G1 Dynamic or Normal strategy or 24-2 Dynamic or 
Normal strategy program) at Screening, Baseline, Week 24, Week 52, Month 18, and 
Month 24/Exit. The same machine type (Humphrey vs. Octopus) 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. Number and percentage of any post-baseline 
abnormal findings compared with baseline normal findings on visual field will be 
summarized by eye and by visit regardless of the machine type. 
In addition, mean deviation or mean defect (MD) and change from baseline recorded in 
decibels (dB) 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. For patients, whose visual fields were assessed by 
one machine type as recorded, but there is a missing machine type at a post-baseline visit, 
the missing machine type will be assumed as the same machine type and the mean 
deviation or mean defect assessments will be derived. 
11.3.4
Macroscopic Conjunctival Hyperemia
Severity assessment of hyperemia of each eye is performed at all scheduled visits except 
on any of the study treatment administration days using the following severity scale: 0 
(None), +0.5 (Trace), +1 (Mild), +2 (Moderate), +3 (Severe) or ‘Not Evaluable’. 


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The frequency distribution for the severity grade at each scheduled visit will be 
summarized by eyes. In addition, patients who had at least 2-grade increase from baseline 
in severity (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) will also be summarized for each eye by visits and analysis cycle.
If the severity grade during an analysis cycle decreases from baseline, it will be 
considered as ‘no increase’. 
11.3.5
Specular Microscopy 
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, Week 52, Month 16, Month 20, and Month 24/Exit. Baseline endothelial cell 
density (measured at Screening), raw values, and change from baseline as well as percent
changes from baseline will be summarized descriptively by visit and analysis cycle for 
each eye. 
The number and percentage of patients will be tabulated by various thresholds (including 
but not limited to endothelial cell count change; e.g, >=10% gain, >=10% loss, >=15% 
loss, etc.) for the percent change from baseline at each visit and at the last visit (i.e., last 
visit assessment). Overall summary during the entire study and within analysis cycle will 
be summarized based on the greatest decrease from baseline. 
Kaplan-Meier Analysis for Time to ECL Event
To further investigate the endothelial cell loss (ECL), time to event analyses will be 
performed on the ECL event using Kaplan-Meier (KM) method with graphical displays. 
The ECL event is defined as post-baseline percent loss in central corneal endothelial cell 
density (CECD) meeting a specified threshold. The analyses of ECL events will be 
performed for threshold values of ≥15% and ≥20%. For each threshold value, First 
Observed ECL and First Confirmed ECL are defined as following:
1. First Observed ECL: The first observed ECL meeting the threshold is considered the
initial ECL event.
2. First Confirmed ECL: 
The first confirmed ECL event is defined as the first of two ECLs meeting the same
threshold at two consecutive visits (scheduled or unscheduled) with CECD 
assessment done on different days. 
For discontinued or completed patients, if the first ECL event meeting the 
threshold occurs at the patient’s final CECD assessment before 
discontinuing/exiting the study, the loss will be counted as a confirmed loss at 
that date. 
For analyses performed prior to the final database lock, if a patient is 
continuing in the study and the first ECL meeting the threshold occurs at the


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most recent CECD assessment visit before data cutoff, the loss will NOT be 
counted as a confirmed loss.
The KM analyses will be performed for each of the first confirmed ECL and the first 
observed ECL. Compelling evidence of intra-eye variability of CECD has been observed 
in global, well-controlled, randomized, multicenter studies despite methodological 
measures in place to control for CECD variability. Therefore, the key analysis for Time 
to ECL Event will based on the confirmed ECL values. For each analysis, Time (days) is 
calculated as follows:

Time to the First Confirmed ECL event = (Date of the First Confirmed ECL event 
– Date of the First Study Treatment) + 1, 

Time to the First Observed ECL event = (Date of the First Observed ECL event –
Date of the First Study Treatment) + 1, 
where the Date of First Study Treatment is the first date of Bimatoprost SR 10 µg or SLT 
administration. For eyes that did not have any observed ECL events, time to the first ECL 
event will be right-censored at the last available CECD assessment date. 
For each scheduled visit, the tabulation will display the number of eyes at risk, 
cumulative number of eyes with events, and the cumulative probability of event and the 
associated 95% confidence interval.
Exposure Adjusted Analysis for ECL Rate
Additionally, to take into account the differences in follow up time, an exposure-adjusted 
analysis for ECL rate over the entire study period will be performed by treatment for 
Bimatoprost SR 10 µg and SLT treated eyes. Exposure time will be calculated for each 
treated eye. For eyes that experienced an ECL event during the study, exposure time is 
the number of days from the first study treatment administration to the date when the first 
ECL event occurred. For eyes without an ECL event, exposure time is the number of 
days from the first study treatment administration to the last assessment for CECD. 
Exposure time in person-years is calculated as (exposure time in days)/365.25. Exposure 
adjusted ECL rate will be calculated per 100 person-years as:

100 ×(number of eyes that experienced the ECL event)/total exposure time in 
person-years for the treatment group.
Listings for patients with ≥20% 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 and analysis cycle 
for each eye.


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Pleomorphism Average (HEXAVE): Pleomorphism average of raw data and their
changes from baseline will be summarized descriptively by visit and analysis cycle 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, Week 52, Month 16, 
Month 20, Month 24/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 and 
analysis cycle 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 post-baseline visits. Dilated ophthalmoscopy examination of the vitreous, 
macula, and retina periphery will be performed at the Screening, Baseline, Week 12, 
Week 24, Week 40, Week 52, Month 16, Month 20, Month 24/Exit visits. 
All findings will be coded using the MedDRA dictionary.
The Number and percentage of patient eyes with findings at least 2-grade increase in 
severity from baseline, or a status change from absence at baseline to presence at follow-
up visit for findings which is not associated with a severity grade, at 1 or more post-
baseline visits, will be summarized by preferred term in descending order of incidence 
rate. For findings that are associated with a severity grade, at least 2-grade increase in 
severity from baseline is defined as a change from no finding to 2 and above, from 0.5 to 
2 and above, or from 1 to 3 and above from baseline at any of the follow-up visits. 
11.3.8
Optic Disc Examination
Optic nerve cup/disc ratio will be evaluated using a 0.0 to 1.0 scale, with larger values
indicating more advanced optic nerve damage, thus a reduction from baseline is a 
considered an improvement. Categorial changes in cup/disc ratio from baseline will be 
summarized for post-baseline visits. Change from baseline at the follow-up visit (visit 
value – baseline values) will be categorized as an improvement of 0.2 or more (≤ -0.2), 
no change (> -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 
summarized by visit and analysis cycle. 
11.3.9
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, Week 52, Month 16, Month 20, 
and Month 24/Exit. Lens status is assessed as phakic, pseudophakic, or aphakic and 
recorded on the eCRF. 


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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 analysis 
cycle.
11.3.10
Gonioscopy and Bim SR Implant Assessment
Gonioscopy is performed to assess the inferior iridocorneal angle and the Bim SR 
implant in all study visits except SLT and Bim SR administration days for all patients. 
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. 
12.0
SUBGROUP ANALYSES
Subgroup analyses will be conducted for patients who received the Bim SR 10 µg
administration under the flexible dosing regimen as specified in the protocol amendment 
6 regardless of the visit at which patients received the second Bim SR 10 µg
administration. It will include patients enrolled under amendment 6 or patients 
reconsented to amendment 6 before receiving the second Bim SR 10 µg administration.
Otherwise, patients will be classified in the fixed dosing regimen subgroup.
In addition, subgroup analysis by the disease diagnosis, open-angle glaucoma (OAG) or
ocular hypertension (OHT) at screening, will be performed on IOP data.   
12.1
IOP CHANGE FROM BASELINE
The primary efficacy analysis in Section 10.1 will be performed for the ITT and PP 
populations for the flexible administration regimen.
For the OAG and OHT subgroups, baseline IOP and IOP change from baseline will be 
summarized for the ITT population.
12.2
TIME TO SECOND BIM SR ADMINISTRATION
For patients who received 2 Bim SR 10 µg administrations under the flexible dosing 
regimen, the time from the first to the second administration will be analyzed using 
Kaplan-Meier (KM) method with graphical displays:


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
Time to the second administration of Bim SR= (Date of the second administration of 
Bim SR 10 µg – Date of the First Bim SR 10 µg) +1.
In the calculation, if a patient did not receive the second Bim SR by Month 12 as 
specified in the study protocol, then the patient will be censored at Month 12 unless the 
patient withdrew early or received non-study IOP treatment prior to Month 12 visit which 
ever occurred first.
12.3
ECL ANALYSES BY FIXED AND FLEXIBLE ADMINISTRATION 
Analyses of time to ECL events and exposure-adjusted ECL rate as well as the number 
and percentage of patients by various thresholds as described in Section 11.3.5 will be 
performed separately for the subgroups of patients treated under the fixed and flexible 
administration regimens. 
12.4
OCULAR ADVERSE EVENT BY FIXED AND FLEXIBLE 
ADMINISTRATION
Overall and by-cycle ocular adverse event, corneal adverse events, and ocular adverse 
events leading to implant removal will be analyzed by flexible or fixed dosing regimen 
subgroup. Other ocular adverse events by the subgroup may be performed on as-needed 
basis. 
13.0
VISUAL FUNCTION QUESTIONNAIRE
National Eye Institute Visual Function Questionnaire-25 responses collected at Baseline 
will not be summarized as part of this SAP.
14.0
INTERIM ANALYSES
No interim analysis is planned for the study. Three database locks are planned for this 
study as described in Section 4.0. The analysis results based on the first database lock is 
considered as the primary analysis. The analyses based on the Month 12 and/or final
database locks will provide further efficacy and safety information. Three CSRs will be 
written, one following each lock.
15.0
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 10 µg eyes and SLT eyes,
and that change from baseline in IOP has a standard deviation of 4 mmHg. A sample size 
of 144 patients with eyes treated with Bim SR 10 µg and SLT 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 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 and treated with Bim SR 10 µg. Additionally, there are 55 Bim 
SR 15 µg treated patients who were enrolled before implementation of Amendment 3 and 
treated with the 15 µg Bim SR dose strength.
16.0
STATISTICAL SOFTWARE
Statistical analyses will be performed using version 9.4 (or newer) of SAS software.
17.0
DATA HANDLING CONVENTIONS
17.1
EFFICACY DATA
As stated in protocol Section 4.5.2 Prohibited Medications/Treatments, eye(s) may 
receive 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 unless 
specified otherwise. 
For sensitivity analyses, missing data will be imputed using the last observation carried 
forward (LOCF) and multiple imputation method as detailed in Section 17.2.
17.2
MISSING DATA HANDLING FOR SENSITIVITY ANALYSES
17.2.1
Last Observation Carried Forward (LOCF)
Last observations carried forward method will be used to impute missing IOP data up to 
Week 24. In this approach, IOP data after the rescue treatment will be replaced by LOCF.
17.2.2
Multiple Imputation
Multiple imputation will be utilized to impute missing IOP values. The primary efficacy 
variable is Hour 0 IOP change from baseline assessed at Weeks 4, 12, and 24. However, 
to gain additional imputation efficiency, multiple imputation with a 2-step approach will 
be used for imputing missing IOP at Weeks 4, 8, 12, 15, 20, and 24 separately for each 
treatment group. The first step of multiple imputation will use the Markov Chain Monte 
Carlo (MCMC) method to impute intermittent missing data to achieve a monotone 
missing pattern. The second step will be based on a linear regression to impute the 
missing data. 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. Covariates to 
be included in the regression will be baseline Hour 0 IOP, race, sex, lens status, and age. 
The planned number of MIs is 25 and a prespecified seed of “123451” will be used for 
MCMC and a seed of “123457” for the regression part. 
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;
17.3
ANALYSIS WINDOWS
Table 17-1 provides an overview of efficacy and safety assessments with visit schedule
and analysis window table for by-visit and by-cycle analysis.  


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Table 17-1
Visit Schedule, Visit Windows and By-Cycle Analysis for Efficacy and Safety 
Assessments
Efficacy/Safety
Assessments
Visit Schedule
Visit Window for by-visit and 
Analysis Cycle Analysis
Hour 0 IOP
Baseline, Day 2, W4, W8, W12,W15,
W20,W24,W28,W31,W36,W40,W44,
W47,W52, M13, M14,M15,M16,M18,
M20,M22, M24/EXIT
Table 17-2
Macroscopic 
conjunctival 
hyperemia
Baseline, Day2,W4,W8,W12,W15,
W20,W24,W28,W31,W36,W40,W44,W47
,W52,M13,M14,M15,M16,M18,M20,M22
, M24/EXIT
Table 17-2
BCVA
Baseline, Day 2, W4, W8, W12, W15, 
w20,W24,W28,W31,W36,W40,W44,
W47,W52,M13,M14,M15,M16,M18,M20,
M22,M24/EXIT
Table 17-2
Visual field
Baseline, W24,W52,M18,M24/exit
Table 17-4
Specular 
microscopy
Baseline, W4, W12, W24, W40, 
W52,M16,M20, M24/Exit
Table 17-3
Biomicroscopy
Baseline, Day2, W4, W8,W12,W15, 
W20,W24,W28,W31,W36,W40,W44,
W47,W52, M13,M14,M15,M16,M18,
M20,M22, M24/EXIT
Overall by-cycle summary 
Gonioscopy/
Angle assessment
Baseline,W4(optional),W8,W12(optional),
W15,W20,W24(optional),W28,W31,W36,
W40,W44,W47,W52,M13,M14,M15,M16,
M18,M20,M22,M24/EXIT
Table 17-2
Pachymetry
Baseline, W4, W12, W24, W40, W52, 
M16, M20, M24/EXIT
Table 17-3
Optic disc/
Ophthalmoscopy/
Lens assessment
Baseline, W12, W24, W40, W52, M16, 
M20, M24/EXIT
Table 17-3
Table 17-2 presents the visits assigned for by- visit and analysis cycle analyses of the 
efficacy (Hour 0 IOP), and safety assessments that occur every month (or 2 months after 
1-year of follow-up after the first Bim SR administration), including of macroscopic 
conjunctival hyperemia, best-corrected visual acuity, biomicroscopy, and 
gonioscopy/angle assessment. Table 17-3 presents the visit assigned for by-visit and 
analysis cycle that occur every 3 or 4 months, including of specular microscopy, 
pachymetry and optic disc assessments which occur every 3 or 4 months. Table 17-4
presents the visits assigned for by-visit and analysis cycle analyses of visual filed, 
ophthalmoscopy, optic disc, and lens assessments which occur every 6 months.
If both scheduled and unscheduled visit occur within a single window, the scheduled visit 
will be used; and unscheduled visits will be used only if there are no scheduled values 
available in that window. If multiple visits are eligible for windowing within a single visit 
window, the scheduled visit closest to target day will be used in the analysis.
If 2 visits are equidistant to the target day, the later visit will be used. 


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Table 17-2
Visit Windows for By Visit Analysis for Assessments Occurring Every 4 weeks 
Derived Visit
Target Visit Day*
Visit Window*
Baselinea
-1
≤ (SLT Date -1)
Analysis Cycle 1
     Cycle 1 SLT Day 1
1
SLT Date
     Cycle 1 Bim SR Day 1b
Bim SR 1st administration, 
Day 1
Bim SR 1st administration, Day 1
     Cycle 1 Bim SR  Day 2 b
Bim SR 1st administration,
Day 1 + 1
Bim SR 1st administration Day 1 + 1
     Cycle 1 Week 4
25
[Bim SR 1st administration, Day 1+2, 
38]
     Cycle 1 Week 8
53
[39, 66]
     Cycle 1 Week 12
81
[67, 91]
     Cycle 1 Week 15
102
[92,119] 
    Cycle 1Week 20
137
[120, 150]
    Cycle 1Week 24
165
[151, 178]
   Cycle 1Week 28
193
[179, 203] 
   Cycle 1Week 31
214
[204, 231]
   Cycle 1Week 36
249
[232, 262]
    Cycle 1Week 40
277
[263, 290]
    Cycle 1Week 44
305
[291, 315]
    Cycle 1Week 47
326
[316, 343] 
    Cycle 1Week 52
361
[344,373]
    Cycle 1 Month 13c
387
[374,401]
    Cycle 1 Month 14
417
[402,431]
    Cycle 1 Month 15c
447
[432,461]
    Cycle 1 Month 16
477
[462,506]
    Cycle 1 Month 18
537
[507,566]
     Cycle 1 Month 20
597
[567,626]
     Cycle 1 Month 22c
657
[627,686]
  Cycle 1 Month 24
717
>686
Analysis Cycle 2d
    Cycle 2 Bim SR Day 1
1
Bim SR 2nd administration, Day 1
    Cycle 2 Bim SR Day 2
2
Bim SR 2nd Administration Day 1 + 1
    Cycle 2 Week 4
29
[Bim SR 2nd administration, Day 1+2, 
42]
    Cycle 2 Week 8
57
[43, 70]
    Cycle 2 Week 12
85
[71, 98]
    Cycle 2 Week 16
113
[99,126] 
    Cycle 2 Week 20
141
[127,154]
    Cycle 2 Week 24
169
[155, 182]
    Cycle 2 Week 28
197
[183,210]
    Cycle 2 Week 32
225
[211, 238]
    Cycle 2 Week 36
253
[239, 266]


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    Cycle 2 Week 40
281
[267, 294]
   Cycle 2 Week 44
309
[295, 322]
   Cycle 2 Week 48
337
[323,350]
   Cycle 2 Week 52
365
[351, 377]
   Cycle 2 Month 13
391
[378, 405]
   Cycle 2 Month 14
421
[406,435]
   Cycle 2 Month 15
451
[436,465]
   Cycle 2 Month 16
481
[466,495]
  Cycle 2 Month 17
511
[496, 525]
  Cycle 2 Month 18
541
[526,555]
  Cycle 2 Month 19
571
[556,585]
  Cycle 2 Month 20
601
> 585
Analysis Cycle 3e
    Cycle 3 Bim SR Day 1
Bim SR 3rd administration, 
Day 1
Bim SR 3rd administration, Day 1
    Cycle 3 Bim SR Day 2
Bim SR 3rd administration 
Day 1 + 1
Bim SR 3rd administration Day 1 + 1
    Cycle 3 Week 4
29
[Bim SR 3rd administration, Day 1+2, 
42]
    Cycle 3 Week 8
57
[43, 70]
    Cycle 3 Week 12
85
[71, 98]
    Cycle 3 Week 16
113
[99,126] 
    Cycle 3 Week 20
141
[127,154]
    Cycle 3 Week 24
169
[155, 182]
    Cycle 3 Week 28
197
[183,210]
    Cycle 3 Week 32
225
[211, 238]
    Cycle 3 Week 36
253
[239, 266]
    Cycle 3 Week 40
281
[267, 294]
    Cycle 3 Week 44
309
[295, 322]
    Cycle 3 Week 48
337
[323,350]
    Cycle 3 Week 52
365
[351, 377]
    Cycle 3 Month 13
391
[378, 405]
    Cycle 3 Month 14
421
[406,435]
    Cycle 3 Month 15
451
[436,465]
    Cycle 3 Month 16
481
> 465
*     Target days and window definitions from Week 4 and onward are based on the relative days from the date of the 
Bim SR administration for each cycle.
a
Relative to the date of the SLT administration. 
b    Relative to the date of Bim SR 1st administration. If a patient did not receive the first Bim SR, but treated in SLT at 
Day 1, Bim SR 1st administration, Day 1 will be determined as SLT+ 3 days. 
c    Patients who received the second administration of Bim SR at W16 and patients who never received a second 
    administration may skip the visits.
d   Relative to the date of the second Bim SR administration.
e   Relative to the date of the third Bim SR administration and valid for Bim SR 15 µg.


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Table 17-3
Visit windows for By Visit and Analysis Cycle for Assessments Occurring Every 
3- 4 Months 
Derived Visit
Target Visit Day*
Visit Window*
Baseline a
-1
≤ (SLT Date -1)
Analysis Cycle 1
    Cycle 1 SLT
Day 1
1
SLT Date
    Cycle 1Bim SR 1st Day 1b
Bim SR 1st administration,
Day 1
Bim SR 1st administration, Day 1
    Cycle 1 Week 4c
25
[Bim SR 1st administration, Day 1+ 1, 
52]
    Cycle 1 Week 12
81
[53, 122]
    Cycle 1 Week 24
165
[123, 220]
    Cycle 1 Week 40
277
[221,318]
    Cycle 1 Week 52
361
[319,418] 
    Cycle 1 Month 16
477
[419, 536]
    Cycle 1 Month 20
597
[537, 656]
    Cycle 1 Month 24
717
>656
Analysis Cycle 2d
  Cycle 2 Bim SR Day 1
1
Bim SR 2nd administration, Day 1
  Cycle 2 Week 4
29
[Bim SR 2nd administration, Day 1+1, 
42]
  Cycle 2 Week 8
57
[43, 70]
  Cycle 2 Week 12
85
[71, 98]
  Cycle 2 Week 16
113
[99,126] 
Analysis Cycle 3e
  Cycle 3 Bim SR Day 1
1
Bim SR 3rd administration, Day 1
  Cycle 3 Week 4
29
[Bim SR 3rd administration, Day 1+1, 
42]
  Cycle 3 Week 8
57
[43, 70]
  Cycle 3 Week 12
85
[71, 98]
  Cycle 3 Week 16
113
[99,126] 
*     Target days and window definitions from Week 4 and onward are based on the relative days from the date of the 
Bim SR administration for each cycle.
a
Relative to the date of the SLT administration.
b
Relative to the date of Bim SR 1st administration. If a patient did not receive the first Bim SR, but treated in SLT at 
Day 1, Bim SR 1st administration Day 1 will be determined as SLT+ 3 days.
c
Optic disc assessment will not occur at Week 4. The lower bound of visit window at Week 12 will be Bim SR 1st
administration, Day 1+2.
d
Relative to the date of the second Bim SR administration. The visits for Cycle 2 will continue all the way to Month 
20. Use the same target day and window as in Table 17-2. 
e
Relative to the date of the third Bim SR administration and valid for Bim SR 15 µg. The visits for Cycle 3 will 
continue all the way to Month 16. Use the same target day and window as in Table 17-2.


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Table 17-4
Visit windows for By Visit Analysis for Assessments Occurring Every 6 Months
Derived Visit
Target Visit Day
Visit Window
Baseline a
-1
≤ (SLT Date -1)
SLT/Sham SLT Administration
Day 1
1
SLT Date
    Cycle 1Bim SR 1st Day 1b
Bim SR 1st
administration, Day 1
Bim SR 1st administration, Day 1
Week 24
165
[Bim SR 1st administration, Day 1+1, 267]
Week 52
361
[268, 451]
Month 18
537
[448, 627]
Month 24
717
>627
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, but treated in SLT at Day 1, 
Bim SR 1st administration, Day 1 will be determined as SLT+ 3 days. 
17.4
DERIVED VARIABLES
Not applicable.
17.5
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.
17.6
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.


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17.7
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.
17.8
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 Analysis Cycle 1 Date, Bim SR Analysis 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.

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 Analysis Cycle 1 Date,  Bim SR Analysis 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).


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Statistical Analysis Plan for 192024-093 CSR (Amendment 1.1)
17.9
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.
17.9.1
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.
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.
17.9.2
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.


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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.

If either the year of the incomplete stop date is before the year of the date informed
consent date or if both years are the same, but the month of the incomplete stop date
is before the month of the informed consent date, the last day of the month will be
assigned to the missing day
18.0
REFERENCES
[1] E9 (R1) Statistical Principles for Clinical Trials: Addendum: Estimands and
Sensitivity Analysis in Clinical Trials; Guidance for Industry, by the Food and Drug
Administration.
19.0
AMENDMENTS
19.1
AMENDMENT 1
1. In Section 10.4.5, clarified the planned analysis.
2. In Section 11.3.5, added new analyses for ECL events including Kaplan-Meier and
exposure adjusted analysis for ECL rate.
3. In Section 12.0, added the subgroup analysis by the disease diagnosis, open-angle
glaucoma (OAG) or ocular hypertension (OHT) as well as ocular AEs.
4. In Section 12.3, added new ECL analyses by fixed and flexible dosing subgroup.
5. In Section 12.4, added new ocular adverse events by fixed and flexible dosing
subgroup.


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19.2
AMENDMENT 1.1
1. In Section 4.0, added the clarification of the Month 12 DBL to include 3-month
follow-up data after the second Bim SR administration.
2. In Section 10.1, added the clarification for the primary analysis model terms.
3. In Section 10.2.1, added the clarification for the superiority testing after meeting the
statistical non-inferiority to control type I error.