Clinical trial NCT04285580
Conditions: Open-Angle Glaucoma Ocular Hypertension
Sponsor: AbbVie
Start date: 2020-06-11; Completion date: 2022-05-14
Enrollment: 37 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the 24-hour intraocular pressure lowering effect and safety after a single administration of Bimatoprost SR in patients with Open-Angle Glaucoma or Ocular Hypertension

Detailed description:

Arms: arm 1: Participants will receive Bimatoprost SR 10 μg implant in the study eye on Day 1 and standard of care treatment in the fellow eye for the duration of the study. arm 2: Participants will receive topical LUMIGAN 0.01% in the study eye once daily starting evening Dose on Day 1 and standard of care treatment in the fellow eye for the duration of the study.
Interventions: intervention 1: Bimatoprost SR intervention 2: LUMIGAN
Intervention descriptions: intervention 1: Consists of 1 Bimatoprost SR administration in the study eye. intervention 2: Treatment with LUMIGAN 0.01% begins on Day 1. The drop will be instilled once daily in the evening to the study eye throughout the duration of the study.

Protocol documents:
Prot_000.pdf: 
 
 
Approval Date: 
 
20-Dec-2019
 
CONFIDENTIAL  
Protocol 1698-304-007 
Bimatoprost SR 
1 
GRD-CLN-T-01-01 v3.0 
Title Page 
Protocol Title: An Evaluation of the 24-Hour IOP-lowering Effect of Bimatoprost SR in 
Participants with Open-Angle Glaucoma or Ocular Hypertension 
Protocol Number: 1698-304-007 
Product: Bimatoprost SR 
Brief Protocol Title: 24-Hour IOP-lowering Effect of Bimatoprost SR 
Study Phase: 3b 
Sponsor Name and Legal Registered Address: Allergan Sales LLC, 5 Giralda Farms, 
Madison, NJ 07940, USA 
Emergency Telephone Number: 
 
Refer to the study contacts page 
SAE Reporting Fax Number/Email: 
 
Business Unit 
Email 
Phone 
Fax 
Allergan 
IR-Clinical-SAE@allergan.com 
Not applicable 
+1-714-796-9504 
Backup:  
+1-714-246-5295 
 
Sponsor Signatory: 
 MD 
Vice President, Therapeutic Area Head 
Ophthalmology 
Refer to the final page of this protocol for electronic signature and date of approval. 
 
 
 
 
 
 
 
 
 
NCT04285580


 
 
Approval Date: 
 
20-Dec-2019
 
CONFIDENTIAL  
Protocol 1698-304-007 
Bimatoprost SR 
2 
GRD-CLN-T-01-01 v3.0 
Table of Contents 
Title Page .........................................................................................................................................1 
Table of Contents .............................................................................................................................2 
List of Tables ...................................................................................................................................6 
List of Figures ..................................................................................................................................6 
1. 
Protocol Summary ..................................................................................................................7 
1.1. 
Synopsis ......................................................................................................................7 
1.2. 
Schema ........................................................................................................................9 
1.3. 
Schedule of Activities (SoA) ....................................................................................10 
2. 
Introduction ...........................................................................................................................13 
2.1. 
Study Rationale .........................................................................................................13 
2.2. 
Background ...............................................................................................................13 
2.2.1. 
Glaucoma and Treatment ...........................................................................13 
2.2.2. 
Bimatoprost (LUMIGAN) .........................................................................14 
2.2.3. 
Other Biodegradable Ocular Implants .......................................................14 
2.2.4. 
Clinical Studies with Bimatoprost SR .......................................................15 
2.3. 
Benefit/Risk Assessment ..........................................................................................16 
3. 
Objectives and Endpoints .....................................................................................................18 
4. 
Study Design .........................................................................................................................19 
4.1. 
Overall Design ..........................................................................................................19 
4.2. 
Scientific Rationale for Study Design .......................................................................19 
4.3. 
Justification for Dose ................................................................................................19 
4.4. 
End of Study Definition ............................................................................................20 
5. 
Study Population ...................................................................................................................21 
5.1. 
Inclusion Criteria ......................................................................................................21 
5.2. 
Exclusion Criteria .....................................................................................................23 
5.3. 
Lifestyle Considerations ...........................................................................................26 
5.3.1. 
Caffeine, Alcohol, Tobacco, and Sleep .....................................................26 
5.4. 
Screen Failures ..........................................................................................................26 
6. 
Study Treatment ....................................................................................................................27 
6.1. 
Study Treatment Administered .................................................................................27 
6.1.1. 
Instructions for Use and Administration of 
Bimatoprost SR ..........................................................................................28 
6.1.1.1. 
Participant Preparation .............................................................28 
6.1.1.2. 
Study Treatment Location........................................................28 
6.1.1.3. 
Administration Technique .......................................................28 
6.1.1.4. 
Immediate Posttreatment Observation .....................................29 
6.2. 
Preparation/Handling/Storage/Accountability ..........................................................29 
 
 
 
 


 
 
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6.3. 
Measures to Minimize Bias: Randomization and Blinding ......................................30 
6.4. 
Study Treatment Compliance ...................................................................................31 
6.5. 
Concomitant Therapy................................................................................................31 
6.5.1. 
Prohibited Interventions and Washout Before the 
Study ..........................................................................................................31 
6.5.2. 
Permitted Treatments .................................................................................32 
6.5.3. 
Rescue Medicine ........................................................................................33 
6.5.4. 
Prohibited Interventions During the Study ................................................34 
6.6. 
Dose Modification ....................................................................................................35 
6.7. 
Treatment after the End of the Study ........................................................................35 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal .................................................................................................35 
7.1. 
Discontinuation of Study Intervention ......................................................................36 
7.2. 
Participant Discontinuation/Withdrawal from the Study ..........................................36 
7.3. 
Lost to Follow Up .....................................................................................................37 
8. 
Study Assessments and Procedures ......................................................................................38 
8.1. 
Efficacy Assessments ................................................................................................38 
8.2. 
Safety Assessments ...................................................................................................39 
8.2.1. 
Physical Examinations ...............................................................................39 
8.2.2. 
Vital Signs ..................................................................................................39 
8.2.3. 
Pregnancy Testing ......................................................................................40 
8.2.4. 
Clinical Safety Laboratory Assessments ...................................................40 
8.2.5. 
Ocular Safety Assessments ........................................................................40 
8.2.5.1. 
Macroscopic Conjunctival Hyperemia 
Assessment ...............................................................................40 
8.2.5.2. 
Best-corrected Visual Acuity ...................................................40 
8.2.5.3. 
Visual Field ..............................................................................40 
8.2.5.4. 
Specular Microscopy ...............................................................40 
8.2.5.5. 
Biomicroscopy .........................................................................41 
8.2.5.6. 
Gonioscopy/Angle Assessment ...............................................41 
8.2.5.7. 
Pachymetry ..............................................................................41 
8.2.5.8. 
Dilated Ophthalmoscopy .........................................................41 
8.2.5.9. 
Optic Disc Examination ...........................................................41 
8.3. 
Adverse Events and Serious Adverse Events ...........................................................41 
8.3.1. 
Time Period and Frequency for Collecting Adverse 
Event and Serious Adverse Event Information ..........................................42 
8.3.2. 
Method of Detecting Adverse Events and Serious 
Adverse Events ..........................................................................................42 
8.3.3. 
Follow Up of Adverse Events and Serious Adverse 
Events .........................................................................................................42 
8.3.4. 
Regulatory Reporting Requirements for Serious 
Adverse Events ..........................................................................................43 
8.3.5. 
Pregnancy ...................................................................................................43 
 
 
 
 


 
 
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8.3.6. 
Medication Errors ......................................................................................43 
8.4. 
Treatment of Overdose .............................................................................................44 
8.5. 
Pharmacokinetics ......................................................................................................44 
8.6. 
Pharmacodynamics ...................................................................................................44 
8.7. 
Genetics.....................................................................................................................44 
8.8. 
Biomarkers and Other Assessments..........................................................................44 
8.8.1. 
Anterior Segment Imaging .........................................................................44 
8.9. 
Health Economics .....................................................................................................44 
9. 
Statistical Considerations ......................................................................................................44 
9.1. 
Statistical Hypotheses ...............................................................................................44 
9.2. 
Sample Size Determination .......................................................................................45 
9.3. 
Populations for Analyses ..........................................................................................45 
9.4. 
Statistical Analyses ...................................................................................................45 
9.4.1. 
Efficacy Analyses ......................................................................................45 
9.4.1.1. 
Analysis Endpoints ..................................................................45 
9.4.1.2. 
Primary Efficacy Analyses ......................................................46 
9.4.1.3. 
Secondary Efficacy Analyses ..................................................46 
9.4.1.4. 
Other Efficacy Analyses ..........................................................46 
9.4.2. 
Safety Analyses ..........................................................................................46 
9.4.2.1. 
Adverse Events ........................................................................46 
9.4.2.2. 
Vital Signs ................................................................................47 
9.5. 
Interim Analyses .......................................................................................................47 
10. Supporting Documentation and Operational Considerations ...............................................48 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations...........................................................................................................48 
10.1.1. Regulatory and Ethical Considerations ......................................................48 
10.1.2. Financial Disclosure ...................................................................................48 
10.1.3. Informed Consent Process .........................................................................49 
10.1.4. Data Protection...........................................................................................49 
10.1.5. Posting Clinical Study Data .......................................................................49 
10.1.6. Data Quality Assurance .............................................................................50 
10.1.7. Source Documents .....................................................................................50 
10.1.8. Study and Site Closure ...............................................................................50 
10.1.9. Publication Policy ......................................................................................51 
10.1.10. Compliance with Protocol..........................................................................51 
10.2. Appendix 2: Clinical Laboratory Tests .....................................................................52 
10.3. Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ...................................................54 
Definition of AE .......................................................................................................54 
Definition of SAE .....................................................................................................55 
Recording and Follow Up of AEs and/or SAEs .......................................................56 
Reporting of SAEs ....................................................................................................58 
10.4. Appendix 4: Abbreviations .......................................................................................59 
 
 
 
 


 
 
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10.5. Appendix 5: Standard Discontinuation Criteria ........................................................61 
10.6. Appendix 6: Study Tabular Summary ......................................................................63 
10.7. Appendix 7: Contraceptive Guidance and Collection of 
Pregnancy Information..............................................................................................65 
Definitions: ...............................................................................................................65 
Contraception Guidance: ..........................................................................................65 
Pregnancy Testing: ....................................................................................................66 
Collection of Pregnancy Information: ......................................................................67 
10.8. Appendix 8: Study Schedule Supplement.................................................................68 
10.8.1. Screening....................................................................................................68 
10.8.2. Baseline ......................................................................................................69 
10.8.2.1. Office Visit...............................................................................69 
10.8.2.2. Sleep Lab Visit .........................................................................70 
10.8.3. Day 1 ..........................................................................................................71 
10.8.4. Day 2 Safety Visit ......................................................................................72 
10.8.5. Day 8 Phone Call .......................................................................................72 
10.8.6. Week 8 Visits .............................................................................................72 
10.8.6.1. Office Visit...............................................................................72 
10.8.6.2. Sleep Lab Visit .........................................................................73 
10.8.7. Week 16 and Months 6, 9, and 12/Study Exit Visits .................................74 
11. References .............................................................................................................................76 
 
 
 
 


 
 
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List of Tables 
Table 1-1 
Schedule of Activities – Screening through Week 8 ............................................ 10 
Table 1-2 
Schedule of Activities – Week 16 through Month 12/Study Exit ........................ 12 
Table 6-1 
Study Treatment Administered ............................................................................. 27 
Table 6–2 
Minimum Washout Period by Ophthalmic Medication Class .............................. 32 
Table 10-1 
Protocol Required Safety Laboratory Assessments .............................................. 53 
Table 10-2 
Highly Effective and Acceptable Contraception Methods ................................... 66 
 
List of Figures 
Figure 1-1 
Study Schema.......................................................................................................... 9 
 
 
 
 
 
 


 
 
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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title: An Evaluation of the 24-Hour IOP-lowering Effect of Bimatoprost SR in 
Participants with Open-Angle Glaucoma or Ocular Hypertension 
Protocol Number: 1698-304-007 
Brief Title: 24-Hour IOP-lowering Effect of Bimatoprost SR 
Study Phase: 3b 
Study Rationale: Results of the completed 24-month Phase 1/2 Study 192024-041D indicated 
that Bimatoprost SR provides prostaglandin analog-like IOP-lowering efficacy. Additionally, the 
safety profile of Bimatoprost SR at dose strengths of 20 µg (2 × 10 µg) or less (15, 10, and 6 µg) 
in the Phase 1/2 study was acceptable, and supports additional clinical studies in humans. Four 
global Phase 3 studies with up to 3 administrations of Bimatoprost SR at fixed 16 week intervals, 
1 global extension study, and 1 global Phase 3b study with initial scheduled and subsequent “as 
needed” repeat administration(s) of Bimatoprost SR 
 
are ongoing. The current study (1698-304-007) is a multicenter, open-label Phase 3b study to 
evaluate the IOP-lowering effect over 24 hours of a single administration of Bimatoprost SR in 
participants with OAG or OHT. The purpose of this study is to obtain data on the 24-hour 
IOP-lowering effect at Week 8 of Bimatoprost SR treatment, with safety assessed through Month 
12. 
Objectives and Endpoints: 
Objectives 
Endpoints/Measures 
Efficacy: 
Primary 
• 
To evaluate the 24-hour IOP-lowering effect of 
Bimatoprost SR in participants with OAG or 
OHT  
 
Secondary 
• 
To evaluate the change in diurnal variation of 
IOP in eyes treated with Bimatoprost SR  
 
Other 
• 
To evaluate the IOP-lowering effect of 
Bimatoprost SR 
 
 
• 
Time-matched IOP change from Baseline Sleep 
Lab visit at Week 8 Sleep Lab visit in Bimatoprost 
SR-treated eyes  
 
 
• 
Change from baseline in range of IOP in eyes 
treated with Bimatoprost SR at Week 8 Sleep Lab 
visit  
 
 
• 
Hour 0 IOP change from baseline through 
Month 12 
• 
Time to initial use of nonstudy IOP-lowering 
treatment 
 
 
 


 
 
Approval Date: 
 
20-Dec-2019
 
CONFIDENTIAL  
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Objectives 
Endpoints/Measures 
Safety: 
• 
To evaluate the safety of Bimatoprost SR in 
participants with OAG or OHT 
 
• 
AEs, visual fields, visual acuity, macroscopic 
bulbar conjunctival hyperemia, slit-lamp 
biomicroscopic assessments, dilated 
ophthalmoscopic assessments (including optic disc 
assessment), contact ultrasound pachymetry, 
gonioscopy, specular microscopy 
 
Overall Study Design:  This is a multicenter, open-label, Phase 3b study in participants with 
OAG or OHT.  
Number of Participants:  Approximately 35 participants will be enrolled: 25 to 30 in the 
Bimatoprost SR cohort (to achieve a minimum total of 20 evaluable participants at baseline and 
Week 8 to evaluate the 24-hour IOP-lowering effect of Bimatoprost SR, assuming a premature 
discontinuation rate of up to 33%), and 5 in the LUMIGAN® 0.01% (bimatoprost ophthalmic 
solution) cohort. Participants who prematurely discontinue from the study will not be replaced. 
Number of Sites: Approximately 3 sites in the United States 
Intervention Group and Study Duration:   
Participants in the Bimatoprost SR cohort will receive a 10 µg implant in the study eye on Day 1, 
and the fellow eye will receive standard of care treatment (provided that there is no known 
crossover effect of the fellow eye’s standard of care treatment to the study eye) for the duration 
of the study. At selected site(s) an additional cohort of participants will be enrolled and assigned 
to receive topical LUMIGAN 0.01% in the study eye (once daily, at 20:00 ± 1 hour, starting with 
the evening dose on Day 1), and standard of care treatment in the fellow eye (provided that there 
is no known crossover effect of the fellow eye’s standard of care treatment to the study eye) for 
the duration of the study. Participants will be assigned to the Bimatoprost SR cohort or 
LUMIGAN 0.01% cohort by the investigator. 
The participant and investigator will not be masked to the study treatment assignment for the 
duration of the study. Site staff collecting 24-hour IOP measurements at Sleep Lab visits will be 
masked to the study treatment and study eye. 
Study Eye Treatment 
Fellow Eye Treatment 
Bimatoprost SR 10 µg or LUMIGAN 0.01%a  
(at selected site[s]) 
Standard of Care  
a 
Participants will begin self-administration of LUMIGAN 0.01% in the study eye once daily in the evening (20:00 ± 1 hour)  
starting with the evening dose on Day 1, and will continue self-administration daily through the duration of the study. 
The duration of the study for each participant is approximately 15 months, consisting of a 
screening period of up to 60 days before washout, washout period of up to 42 days before 
Baseline, and 12 months of follow-up. 
Data Monitoring Committee: No 
 
 
 








 
 
 
 
Approval Date: 
 
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Table 1-2 
Schedule of Activities – Week 16 through Month 12/Study Exit 
Visit 
Week 16 
Month 6 
Month 9 
Month 12/ Study 
Exit 
Visit Windows 
± 4 days 
± 14 days 
± 14 days 
± 14 days 
Adverse Events 
X 
X 
X 
X 
Concomitant Medications/ Procedures 
X 
X 
X 
X 
Vital Signs (at rest ≥ 5 minutes) 
X 
X 
X 
X 
Pregnancy Test 
 
 
 
X 
Ocular Examinations in bold should be performed in the order shown 
Pre-Hour 0 Exams (perform before Hour 0 IOP): 
Macroscopic Conjunctival Hyperemia Assessment 
OU 
OU 
OU 
OU 
Best-Corrected Visual Acuity  
OU 
OU 
OU 
OU 
Intraocular Pressure Measurement Hour 0 
OU 
OU 
OU 
OU 
Anterior Segment Imaginga (may perform any time after Hour 0 IOP)
 
OU 
 
OU 
Non-contact Exams (may perform in any order at any time before gonioscopy, including prior to H0 IOP) 
Visual Fieldb 
 
OU 
 
OU 
Manifest Refractionc 
 
 
 
OU 
Specular Microscopyd 
OU 
OU 
OU 
OU 
Biomicroscopy 
OU 
OU 
OU 
OU 
Gonioscopy/Angle Assessment  
OU 
OU
OU 
OU 
Pachymetry: (may be performed any time after non-contact exams) 
OU 
OU 
OU 
OU 
Pupil Dilation  (may perform exams in any order) 
 
 
 
OU 
Dilated Ophthalmoscopy  
 
 
 
OU 
Optic Disc Examination 
 
 
 
OU 
Contact IWRSe 
 
 
 
X 
Hour 0 = 08:00 ± 1 hour assessed with a Goldmann applanation tonometer 
a 
At selected sites/selected participants only, anterior segment imaging may be performed in both eyes of consenting participants using Allergan-approved instruments. 
b 
For a given participant, the same test methodology must be used for all visual fields performed at Screening, Baseline, and throughout the study. 
c 
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. 
d 
For a given participant, the same specular microscope model and analysis methodology must be used at Screening, Baseline, and throughout the study. 
e       Contact IWRS for study completion or participant discontinuation/withdrawal. 
 
 
 
 


 
 
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2. 
Introduction 
In an effort to develop ocular antihypertensive therapies that do not require patient 
self-administration, an SR formulation of bimatoprost was developed at Allergan, Inc. 
Bimatoprost SR refers to a biodegradable, sustained-release, preservative-free bimatoprost 
implant that is preloaded in an applicator for administration; together they comprise the 
Bimatoprost SR product. The Bimatoprost SR implant is injected into the AC through clear 
cornea adjacent to the corneoscleral limbus using the 28-gauge needle of the prefilled applicator. 
The biodegradable polymer matrix of the implant gradually degrades to carbon dioxide and 
water so that there is no need to remove the 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. Intracameral administration of the 10 µg implant is expected to reduce the total daily drug 
exposure to the eye by approximately 120-fold compared with daily topical LUMIGAN® 0.03% 
(bimatoprost ophthalmic solution) application over 4 to 6 months, as well as possibly reduce the 
adverse effects observed with topical glaucoma medications. To date, 24-hour (diurnal and 
nocturnal) IOP data collection in participants administered with Bimatoprost SR has not been 
performed. 
2.1. 
Study Rationale 
Results of the completed 24-month Phase 1/2 Study 192024-041D indicated that Bimatoprost SR 
provides prostaglandin analog-like IOP-lowering efficacy. Additionally, the safety profile of 
Bimatoprost SR at dose strengths of 20 µg (2 × 10 µg) or less (15, 10, and 6 µg) in the Phase 1/2 
study was acceptable, and supports additional clinical studies in humans. Four global Phase 3 
studies with up to 3 administrations of Bimatoprost SR at fixed 16 week intervals, 1 global 
extension study, and 1 global Phase 3b study with initial scheduled and subsequent “as needed” 
repeat administration(s) of Bimatoprost SR 
 are all 
ongoing. The current study (1698-304-007) is a multicenter, open-label Phase 3b study to 
evaluate the IOP-lowering effect over 24 hours of a single administration of Bimatoprost SR in 
participants with OAG or OHT. The purpose of this study is to obtain data on the 24-hour IOP 
lowering effect at Week 8 of Bimatoprost SR treatment, with safety assessed until Month 12. 
2.2. 
Background 
2.2.1. 
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 (Stamper 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), with POAG being the predominant form of OAG. 
POAG 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 
 
 
 
 


 
 
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AC angles, and manifesting characteristic visual field abnormalities (American Academy of 
Ophthalmology 2010a, Skuta 2008). 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 2006, Varma 2011, Cook 2012). Approximately 10% of eyes with 
elevated IOP will progress to OAG over the course of a decade (Quigley 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 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 2002) and the Early Manifest Glaucoma 
Trial (Heijl 2002) addressed the value of early detection and lowering of elevated IOP in ocular 
hypertension 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 2001) and the Advanced Glaucoma Intervention Study (AGIS 2000). 
2.2.2. 
Bimatoprost (LUMIGAN) 
Bimatoprost is a member of a series of unique prostanoid compounds that are potent and 
efficacious ocular antihypertensive agents (Woodward 1994, 2001, and 2004). Bimatoprost 
appears to mimic the activity of biologically active prostamides (Study BIO 99 308, 
Matias 2004). Chemically, prostamides differ from prostaglandin analogs by being neutral 
because they lack carboxylic acids (Krauss 2004). Prostamides can be biosynthetically derived 
from anandamide, an endogenous membrane lipid (Kozak 2002, Weber 2004, Woodward 2001, 
Yu 1997). The prostamide pathway leads to the biosynthesis of novel lipid amides that lower 
IOP. 
The IOP-lowering efficacy of LUMIGAN 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 through 12 months (Higginbotham 2002). This was further 
substantiated in the extension studies which followed patients in a masked manner for up to 4 
years (Cohen 2004, Williams 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 2004, LUMIGAN Package 
Insert 2017, Williams 2008). LUMIGAN 0.03% was approved by the US 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. 
2.2.3. 
Other Biodegradable Ocular Implants 
Formulation of a number of SR drug delivery implants using the Allergan PLA and/or PLGA 
biodegradable platform preceded the development of the Bimatoprost SR implant. The extensive 
clinical experience with the OZURDEX® implant (first approved in 2009 and is registered 
globally in over 70 countries), which also uses the NOVADUR® drug delivery system for 
 
 
 
 


 
 
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intraocular administration, demonstrates the safety and tolerability of an intraocular 
biodegradable implant administered into the eye via an applicator system. Because 
Bimatoprost SR is similar to OZURDEX in a number of aspects and uses the NOVADUR drug 
delivery system for intraocular injections, these data are considered supportive of the safety and 
tolerability of Bimatoprost SR in humans. 
2.2.4. 
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 the study was to evaluate the 
safety and IOP-lowering efficacy of Bimatoprost SR in participants with OAG.  
A total of 109 participants received at least a single administration of Bimatoprost SR, and 
24 participants received a repeat administration of their initial Bimatoprost SR dose strength. A 
trend in dose response was observed across the 4 dose strengths that were tested. Data collected 
in this study suggested that the implant would provide topical prostaglandin analog-like efficacy 
up to 3 to 4 months after implantation in the majority of participants. Data following the second 
administration in the retreated participants showed similar IOP-lowering efficacy to that 
observed following the first administration of Bimatoprost SR. 
There have been 2 generations of the Bimatoprost SR implant: the original Generation 1 
formulation, and Generation 2, which is the formulation currently used in the Phase 3 studies.  
Among all Generation 2 dose strengths, most participants (> 66%) were still maintained on 
monotherapy with the initial Bimatoprost SR implant by Month 6. Additionally, at least 33% of 
participants had not received rescue topical IOP-lowering medication or a second Bimatoprost 
SR administration by Month 12. At Month 24, at least 23% of participants had not received 
rescue IOP-lowering  treatment or a second administration of Bimatoprost SR. 
Bimatoprost SR showed an acceptable safety profile with single and repeat administrations in 
Study 192024-041D. Most AEs 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 AEs, and no new 
safety concerns were observed after the second treatment that were not already known from the 
initial administration of Bimatoprost SR. Please refer to the investigator’s brochure for details on 
reported safety findings. 
The implant is being investigated in Phase 3 studies to evaluate efficacy and safety following a 
fixed administration schedule of every 16 weeks for up to 3 administrations. Two identical 
global Phase 3 studies (Studies 192024-091 [NCT02247804] and 192024-092 [NCT02250651]) 
were initiated in late 2014. These studies are assessing the safety and efficacy of Bimatoprost SR 
in multicenter, randomized, masked, parallel-group comparisons of 2 dose strengths of 
Bimatoprost SR (10 and 15 µg) to an active control (topical ophthalmic timolol maleate 0.5%). 
Two additional global Phase 3 studies (Studies 192024-093 [NCT02507687] and 192024-095 
[NCT02636946]) were initiated in late 2015. These studies are assessing the safety and efficacy 
 
 
 
 


 
 
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of Bimatoprost SR in multicenter, randomized, masked, paired eye comparisons of 2 dose 
strengths of Bimatoprost SR (10 µg or 15 µg) to an active control (360° SLT).  Participants from 
all 4 Phase 3 studies will have the opportunity to participate in a long-term safety and efficacy 
extension study (Study 1698-302-007 [NCT03891446]), with potential repeat “as needed” 
administration(s) of Bimatoprost SR 10 or 15 µg if they qualify; this extension study was 
initiated in early 2019. Additionally, the implant is also being investigated in a global Phase 3b 
study (1698-301-007 [NCT03850782]) initiated in early 2019 to evaluate the duration of effect 
and safety of up to 3 “as needed” administrations of Bimatoprost SR.   
2.3. 
Benefit/Risk Assessment 
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 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 for clinicians to assist patients with being adherent have been developed 
and are available (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 inconsistent (Realini 2008). Repeat ALT procedures are limited due to 
tissue fibrosis and scarring of the trabecular meshwork (Kramer 2001). While the SLT procedure 
is repeatable, mean IOP reductions following repeat SLT appears to be smaller (Garg 2018). 
Patients will often require adjunctive therapy after LT, and may eventually require incisional 
surgery to control their IOP (Francis 2005, Koucheki 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 2009). Allergan has developed the 
Bimatoprost SR implant as an additional therapeutic option for lowering IOP in patients with 
OAG and OHT. 
IOP is a dynamic parameter that has circadian and postural variations, with IOP typically 
elevated at night when an individual is in a supine position (Liu 1999). The magnitude and 
timing of peak IOP values may be an independent contributor to glaucoma progression 
(Konstas 2012). Due to the fluctuating nature of IOP, affected by physiological and 
environmental conditions, uniform reduction throughout a 24 hour period is a desired therapeutic 
target (Liu 2005). Patients typically visit the physician’s office during the day, which are usually 
limited to typical “business hours.” Measuring a single IOP value at a single timepoint in this 
limited window may fail to capture the breadth of variation of an individual’s IOP over the full 
24 hours in a day. For patients with OAG and/or OHT, Bimatoprost SR offers ocular 
antihypertensive therapy that is not dependent on daily patient self-administration, potentially 
 
 
 
 


 
 
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improving both treatment adherence and continuous IOP control. Based on data from a 
completed Phase 1/2 study, plus the ongoing monitoring of 4 long-duration masked Phase 3 
studies, continued development and understanding of the 24-hour IOP-lowering effect of 
Bimatoprost SR is warranted. 
More detailed information about the known and expected benefits and risks, and the reasonably 
expected AEs of Bimatoprost SR, may be found in the investigator’s brochure. 
 
 
 
 


 
 
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3. 
Objectives and Endpoints 
Objectives 
Endpoints/Measures 
Efficacy: 
Primary 
• 
To evaluate the 24-hour IOP-lowering effect of 
Bimatoprost SR in participants with OAG or 
OHT  
 
Secondary 
• 
To evaluate the change in diurnal variation of 
IOP in eyes treated with Bimatoprost SR  
 
Other 
• 
To evaluate the IOP-lowering effect of 
Bimatoprost SR 
 
 
• 
Time-matched IOP change from Baseline Sleep 
Lab visit at Week 8 Sleep Lab visit in Bimatoprost 
SR-treated eyes 
 
 
• 
Change from baseline in range of IOP in eyes 
treated with Bimatoprost SR at Week 8 Sleep Lab 
visit 
 
 
• 
Hour 0 IOP change from baseline through 
Month 12 
• 
Time to initial use of nonstudy IOP-lowering 
treatment 
Safety: 
• 
To evaluate the safety of Bimatoprost SR in 
participants with OAG or OHT 
 
• 
AEs, visual fields, visual acuity, macroscopic 
bulbar conjunctival hyperemia, slit-lamp 
biomicroscopic assessments, dilated 
ophthalmoscopic assessments (including optic disc 
assessment), contact ultrasound pachymetry, 
gonioscopy, specular microscopy 
 
 
 
 


 
 
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4. 
Study Design 
4.1. 
Overall Design 
This is a multicenter, open-label, Phase 3b study in participants with OAG or OHT. 
Approximately 35 participants will be enrolled: 25 to 30 in the Bimatoprost SR cohort (to 
achieve a minimum total of 20 evaluable participants at baseline and Week 8 to evaluate the 
24-hour IOP-lowering effect of Bimatoprost SR, assuming a premature discontinuation rate of up 
to 33%), and 5 in the LUMIGAN 0.01% cohort. Participants who prematurely discontinue from 
the study will not be replaced. 
Participants in the Bimatoprost SR cohort will receive a 10 µg implant in the study eye on Day 1, 
and the fellow eye will receive standard of care treatment (provided that there is no known 
crossover effect of the fellow eye’s standard of care treatment to the study eye) for the duration 
of the study (see Sections 6.5.2 and 6.5.4 for additional details). At selected site(s) an additional 
cohort of participants will be enrolled and assigned to receive topical LUMIGAN 0.01% in the 
study eye (once daily, at 20:00 ± 1 hour, starting with the evening dose on Day 1), and standard 
of care treatment in the fellow eye (provided that there is no known crossover effect of the fellow 
eye’s standard of care treatment to the study eye) for the duration of the study. Participants will 
be assigned to the Bimatoprost SR cohort or LUMIGAN 0.01% cohort 
.  
The participant and investigator will not be masked to the study treatment assignment for the 
duration of the study. Site staff collecting 24-hour IOP measurements at Sleep Lab visits will be 
masked to the study treatment and study eye. 
Study Eye Treatment 
Fellow Eye Treatment 
Bimatoprost SR 10 µg or LUMIGAN 0.01%a  
(at selected site[s]) 
Standard of Care  
a 
Participants will begin self-administration of LUMIGAN 0.01% in the study eye once daily in the evening (20:00 ± 1 hour)  
starting with the evening dose on Day 1, and will continue self-administration daily through the duration of the study. 
The duration of the study for each participant is approximately 15 months, consisting of a 
screening period of up to 60 days before washout; washout period of up to 42 days before 
Baseline; and 12 months of follow-up. 
4.2. 
Scientific Rationale for Study Design 
With IOP being a dynamic measure subject to fluctuations over the course of a 24-hour period, 
this Phase 3b study is designed to collect information on the 24-hour (diurnal and nocturnal) IOP 
profile after a single administration of Bimatoprost SR.  
4.3. 
Justification for Dose 
The 10 µg dose strength of Bimatoprost SR is 1 of 2 dose strengths currently being evaluated in 
ongoing Phase 3 studies. Based on data from the completed Phase 1/2 Study 192024-041D, the 
 
 
 


 
 
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10 µg dose strength has an acceptable safety and efficacy profile and was selected for this 
Phase 3b study to provide information on the 24-hour IOP lowering effect of Bimatoprost SR. 
4.4. 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in the SoA for the last participant in the study. 
A participant assigned and treated with Bimatoprost SR is considered to have completed the 
study if he/she has completed all visits of the study to Month 12. At the Month 12/Study Exit 
visit, if the investigator determines that any safety concerns warrant participant follow-up, the 
participant may be followed post exit until safety concerns are resolved based on the 
investigator’s discretion. Participants assigned and treated with LUMIGAN 0.01% may early 
exit the study after completion of the Week 8 Sleep Lab visit, if there are no safety concerns in 
the opinion of the investigator, and at which time all assessments performed at the 
Month 12/Study Exit visit should be performed. 
 
 
 
 


 
 
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5. 
Study Population 
The study population consists of participants with OAG or OHT in at least 1 eye that requires 
IOP lowering treatment and has an open iridocorneal angle inferiorly by clinical gonioscopy. The 
eye that meets the entry criteria (Sections 5.1 and 5.2) will be selected as the study eye. If both 
eyes meet the entry criteria, the eye with the higher IOP at Baseline Hour 0 will be selected as 
the study eye. If both eyes have the same IOP, then the right eye will be designated as the study 
eye.   
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. 
Age 
1.01 
Participant must be at least 18 years of age at the time of signing the informed 
consent 
2. 
Sex 
2.01 
Male or female 
3. 
Informed Consent 
3.01 
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 [US sites] and written Data Protection 
consent [EU sites]) 
4. 
Contraceptives 
4.01 
Female participants willing to minimize the risk of inducing pregnancy for the 
duration of the clinical study and follow-up period 
4.02 
A female participant is eligible to participate if she is not pregnant (ie, has a negative 
urine pregnancy result at Baseline; see Appendix 7), not breastfeeding, and at least 1 
of the following conditions applies: 
a. Not a WOCBP as defined in Appendix 7 
OR 
b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 7 
during the study period 
 
 
 


 
 
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5. 
Other General Criteria 
5.01 
Participant is willing to withhold his/her IOP treatments in both eyes according to 
the study requirements, and in the opinion of the investigator, can do so without 
significant risk 
Note: If participants cannot discontinue their currently prescribed therapy in both 
eyes for up to 6 weeks to meet the Washout period for study entry, the investigator 
may switch the participant’s medication to one that requires a shorter washout 
interval during the washout of the original medication. 
 
5.02 
Participant has the ability to understand and willingness to follow study instructions 
and is likely to complete all required visits and procedures 
 
5.03 
Participant is currently a nonsmoker and has not smoked any nicotine-containing 
products within the previous 6 months 
6. 
Ocular Inclusion Criteria 
6.01 
Diagnosis of either OAG (ie, primary OAG, pseudoexfoliation glaucoma, 
pigmentary glaucoma) or OHT in the study eye, requiring IOP-lowering treatment 
6.02 
In the investigator’s opinion, the study eye could be treated adequately with topical 
prostamide, prostaglandin, or prostaglandin analog (eg, LUMIGAN, Xalatan, 
Travatan) eye drops as the sole therapy  
6.03 
The iridocorneal angle in the study eye must be, in the opinion of the investigator, 
able to safely receive the Bimatoprost SR implant 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 
6.04 
At the Baseline visit, participant has been appropriately washed out of all 
IOP-lowering medications 
6.05 
At the Baseline visit (08:00 ± 1 hour), IOP of ≥ 22 and ≤ 34 mm Hg in the study eye 
using a Goldmann applanation tonometer 
6.06 
Central corneal endothelial cell density by specular microscopy deemed acceptable, 
in the opinion of the investigator (at Screening, and a minimum endothelial cell 
density of 1800 cells/mm2 in the study eye by automated analysis) 
6.07 
At the Baseline visit: best-corrected visual acuity (Snellen equivalent, by manifest 
refraction) of 20/50 or better in the study eye and 20/100 or better in the fellow eye 
 
 
 
 




 
 
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2.04 
The following surgical history in the study eye: 
a. History or evidence of complicated cataract/lens surgery: eg, surgery resulting in 
complicated lens placement (such as anterior chamber 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 
2.05 
Intraocular surgery (including cataract surgery) in the study eye within the 6 months 
prior to Bimatoprost SR administration  
2.06 
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 in the study eye 
2.07 
Corneal or other ocular abnormalities that would preclude accurate readings with an 
applanation tonometer, specular microscope, and/or a contact pachymeter, or could 
confound study results in either eye, eg, moderate to severe corneal dystrophy, including 
Anterior Basement Membrane Disease (ABMD; ie, Map-Dot-Fingerprint) 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 
2.08 
Active or recurrent ocular disease in the study eye (eg, uveitis, ocular infection, chronic 
moderate to severe blepharitis or severe dry eye, ocular seasonal allergies) or sight 
threatening diseases (eg, neovascular age-related macular degeneration [AMD], diabetic 
macular edema) that, in the opinion of the investigator, would put the participant at a 
significant risk or would interfere with the interpretation of the study data 
Note: Participants with slowly progressive eye diseases (ie, mild cataracts, 
non-neovascular AMD) can be enrolled at the discretion of the investigator. If a 
participant has a potentially exclusionary condition or disease in one eye that tends to be 
bilateral or is likely to affect both eyes, the investigator should consider excluding that 
participant 
2.09 
Any history of external ocular or intraocular malignancy, and/or any history of benign 
ocular neoplasia in the study eye that in the investigator’s opinion resulted in clinically 
significant ocular morbidity 
2.10 
History of herpetic ocular diseases in the study eye (including herpes simplex virus and 
varicella zoster virus) 
2.11 
Active ocular surface findings other than bulbar conjunctival hyperemia, on either 
macroscopic or slit-lamp examination, > +1 (mild) at Baseline in the study eye 
 
 
 


 
 
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2.12 
The anticipated wearing of contact lenses in the study eye 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 Bimatoprost SR 
administration 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 Bimatoprost SR administration visit 
c. Use of contact lenses of any kind should be discontinued for 1 week following 
any Bimatoprost SR administration 
d. Use of contact lenses of any kind from 08:00 ± 30 minutes through completion of 
last IOP measurement of Sleep Lab visits ending at 06:00 ± 30 minutes 
2.13 
Central corneal thickness of < 480 or > 620 micrometers in the study eye 
2.14 
Anticipated need for any incisional or laser ocular surgery in the study eye during the 
study 
2.15 
History of anatomically narrow angle resulting in evidence of angle changes, and/or any 
history of acute angle closure glaucoma, in the study eye 
Note: historically narrow-angled participants who have not experienced an acute attack 
of angle closure and whose angle has been opened by cataract surgery or peripheral 
iridotomy may be eligible for enrollment if they have no evidence of angle abnormalities 
2.16 
History or evidence of a peripheral iridotomy/iridectomy in the inferior iris in the study 
eye 
2.17 
Any history of trabeculectomy or other types of glaucoma surgery, including a glaucoma 
seton or aqueous bypass stents (including MIGS) in the study eye 
2.18 
Any history of intracameral implants or intracameral device administration in the study 
eye 
2.19 
Peripheral anterior synechiae in the inferior iridocorneal angle on gonioscopic 
examination at Screening in the study eye 
2.20 
Visual field loss in either eye 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: The same test methodology should be used for all study-related examinations for a 
given participant 
2.21 
Evidence of macular edema in either eye during screening or in participant’s medical 
 
 
 


 
 
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history 
2.22 
Anticipated use of corticosteroids in either eye (except as described in Section 6.5.2) or 
systemically during the study, or historical use prior to Baseline within: 
a. 3 years: intraocular fluocinolone acetonide 
b. 6 months: intraocular corticosteroid(s) other than fluocinolone; any injectable 
periocular or sub-Tenon’s/subconjunctival corticosteroid 
c. 2 months: systemic (eg, oral, intramuscular, intravenous) or topical ocular 
corticosteroids  
d. 2 weeks: dermal corticosteroids applied to skin of the eyelid(s), around the eye, or 
adnexa 
2.23 
Anticipated use of other topical ocular medications in either eye except as described in 
Section 6.5.2. 
 
5.3. 
Lifestyle Considerations 
5.3.1. 
Caffeine, Alcohol, Tobacco, and Sleep 
1. Though not required, participants should be encouraged to maintain a consistent 
8-hour sleep schedule for 7 days prior to Sleep Lab visits. Participants’ sleep 
schedules in the 7 days prior to each Sleep Lab will be recorded at the 
corresponding Sleep Lab visit. 
2. Though not required, participants should be encouraged to abstain from ingesting 
caffeine- or xanthine-containing products (eg, coffee, tea, cola drinks, and 
chocolate) for 24 hours prior to first IOP measurement of Sleep Lab visit 
beginning at 08:00 ± 30 min. From 08:00 ± 30 minutes through completion of last 
IOP measurement of Sleep Lab visit ending at 06:00 ± 30 minutes, participants 
will not have access to caffeine or xanthine-containing products. 
3. Though not required, participants should be encouraged to abstain from drinking 
alcohol from 72 hours prior to first IOP measurement of Sleep Lab visit beginning 
at 08:00 ± 30 minutes. From 08:00 ± 30 minutes through completion of last IOP 
measurement of Sleep Lab visit ending at 06:00 ± 30 minutes,  participants will 
not have access to alcohol. 
4. Participants must currently be nonsmokers and have not smoked any 
nicotine-containing products within the previous 6 months. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. A minimal set of screen failure information is required to 
 
 
 


 
 
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ensure transparent reporting of screen failure participants to meet the CONSORT publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes indicating screen failure as reason for ending the study, demography, screen failure 
details, eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failures) may not 
be rescreened unless the participant’s condition has changed, in the investigator’s opinion.  
6. 
Study Treatment 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol. 
6.1. 
Study Treatment Administered 
Details regarding the study treatment administered is summarized in Table 6-1. 
Table 6-1 
Study Treatment Administered 
Study Treatment 
Name 
Bimatoprost SR 
At Selected Site(s) 
LUMIGAN 0.01% (Bimatoprost 
Ophthalmic Solution) 
Dosage Formulation 
Bimatoprost SR is an intraocular implant that 
contains preservative-free bimatoprost 
dispersed in a biodegradable polymer matrix 
(including PLA and/or PLGA). Implants are 
preloaded into an applicator to facilitate 
insertion of the implant into the AC of the 
eye. 
LUMIGAN 0.01% contains 
bimatoprost 0.01%, benzalkonium 
chloride, sodium chloride, sodium 
phosphate, dibasic, citric acid, and 
purified water. 
Unit Dose Strength/ 
Dosage Level 
A dose strength of 10 µg (formula number 
11047X) bimatoprost will be administered. 
A dose strength of 0.01% bimatoprost 
ophthalmic solution will be 
administered. 
Route of 
Administration  
Intracameral 
Topical 
Administration 
Instructions 
Bimatoprost SR is administered directly into 
the AC of the study eye using the prefilled 
applicator. 
LUMIGAN 0.01% is instilled 
topically to the study eye once daily 
in the evening (20:00 ± 1 hour). 
Packaging and 
Labeling 
Study treatment will be provided in a sterile, 
laminated foil pouch in an individual carton. 
Each package will be labeled as required per 
country requirement. 
Licensed and approved LUMIGAN 
0.01% will be acquired by the site in a 
multidose bottle. 
Manufacturer 
Allergan 
Allergan 
 
 
 


 
 
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Study Treatment 
Name 
Bimatoprost SR 
At Selected Site(s) 
LUMIGAN 0.01% (Bimatoprost 
Ophthalmic Solution) 
Number and Timing 
of Treatments 
This study consists of 1 Bimatoprost SR 
administration in the study eye: 
 
On Day 1, participants will receive an 
intracameral administration of Bimatoprost 
SR 10 µg in the study eye and begin standard 
of care treatment in the fellow eye (provided 
that there is no known potential crossover 
effect of the fellow eye’s standard of care 
treatment to the study eye).  
On Day 1, the participant will begin 
treatment with LUMIGAN 0.01%. 
The drop will be instilled once daily 
in the evening (20:00 ± 1 hour) to the 
study eye throughout the duration of 
the study. Standard of care treatment 
will be used in the fellow eye 
(provided that there is no known 
potential crossover effect of the 
fellow eye’s standard of care 
treatment to the study eye).  
 
6.1.1. 
Instructions for Use and Administration of Bimatoprost SR 
Study treatment must only be administered to participants who meet the eligibility criteria in 
accordance with conditions specified in this protocol. 
6.1.1.1. 
Participant 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 will be administered to the study eye 
approximately every 5 minutes beginning approximately 15 minutes prior to the procedure. With 
the participant 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. 
6.1.1.2. 
Study Treatment Location 
At the discretion of the investigator, Bimatoprost SR 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 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. 
6.1.1.3. 
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 an ophthalmologist subinvestigator to perform the 
 
 
 


 
 
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procedure, subject to Allergan approval and training. The study medication kit should be readily 
available during the procedure. 
The procedure is described in detail in the Procedure Manual. In brief, following the sterile 
preparation and sterile field setup, an appropriately sized sterile lid speculum should be placed 
between the eyelids of the participant. 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. 
6.1.1.4. 
Immediate Posttreatment Observation 
Following Bimatoprost SR administration, the participant is expected to sit upright and is kept 
for a minimum of 1 hour of observation. The surgeon will examine the Bimatoprost SR treated 
eye to ensure that the AC is formed prior to the participant being released. 
The participant 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 the Bimatoprost SR 
treated eye and to follow up as per protocol. 
Prior to leaving the site, participants should be instructed to contact the study site immediately if 
they experience any adverse events after treatment. If the participant reports having experienced 
adverse events, these must be recorded on the appropriate eCRF. 
6.2. 
Preparation/Handling/Storage/Accountability 
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 
immediately to advise or any situation in which the Bimatoprost SR applicator is defective. 
At selected site(s), licensed and marketed LUMIGAN 0.01% will be acquired in a multidose 
bottle by the site and be stored per manufacturer’s instructions prior to dispensing to the 
participant. 
The study medications must be stored in a secure area and administered/dispensed only to 
participants entered into the clinical study, at no cost to the participant, in accordance with the 
conditions specified in this protocol. Only assigned study personnel authorized by the 
investigator may have access to medications. Bimatoprost SR must be stored in the original 
sealed foil pouch.  
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study medications received and any discrepancies are reported 
and resolved before use of the study medications. 
 
 
 
 


 
 
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Only participants enrolled in the study may receive study medications, and only authorized site 
staff may supply or administer study medications. All study medications must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized site 
staff. More details regarding storage conditions of study medications are available in the 
Procedure Manual. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study medication accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
All used Bimatoprost SR applicators should be properly disposed of into a sharps container 
following the site's standard procedure and not physically returned to the depot. Malfunctioning 
applicators may be returned to the sponsor at the sponsor’s request. All unused Bimatoprost SR 
kits must be returned to the sponsor at the termination of the study. Unit counts will be 
performed when Bimatoprost SR kits are returned, and all Bimatoprost SR kits must be 
accounted for.  
At selected site(s) for participants assigned to LUMIGAN 0.01%, sites must ensure appropriate 
dispensing and documentation in source for the duration of the study. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
Prior to initiation of study treatment, each participant who provides informed consent will be 
assigned a participant number that will serve as the participant identification number on all study 
documents. 
This is an open-label study, and neither the investigator nor the participant will be masked to the 
assigned study treatment.    
The IWRS will dispense the appropriate Bimatoprost SR medication kit(s) on Day 1. Study 
medication kits for Bimatoprost SR will be labeled with medication kit numbers. Sites will 
receive IWRS confirmation notifications for each transaction. All notifications are to be 
maintained with the study source documents.  
The participant and the investigator will not be masked to the study treatment assignment for the 
duration of the study. However, delegated site staff collecting 24-hour IOP measurements will be 
masked to the study treatment and study eye. Participants and unmasked site staff should be 
discouraged from discussing treatment assignments with 24-hour IOP assessors. Hour 0 IOP 
measurements will be performed using a 2-person reading method.  
The study site will keep an accurate drug disposition record that specifies the kit number of the 
IP administered to each participant, the eye receiving the treatment, and the date of 
administration. 
At selected site(s), participants will be assigned to either Bimatoprost SR or LUMIGAN 0.01% 
in the study eye on Day 1 
. Sites will provide 
LUMIGAN 0.01% to assigned participants on Day 1 and keep an accurate drug disposition 
record that specifies the eye receiving treatment, and the start date of treatment. 
 
 
 
 


 
 
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6.4. 
Study Treatment Compliance 
On Day 1, participants assigned to Bimatoprost SR will receive an intracameral administration of 
Bimatoprost SR 10 µg in the study eye. Study treatment compliance will be assumed to be 100% 
when administration has been recorded in the eCRF. 
The study center will keep an accurate drug disposition record that specifies the amount of study 
treatment administered to each participant and the date of administration. 
Participants assigned to LUMIGAN 0.01% will begin self-administration of LUMIGAN 0.01% 
once daily in the evening (at 20:00 ± 1 hour) starting with the evening dose on Day 1 and will 
continue self-administration through the duration of the study. Study treatment compliance will 
be discussed with these participant at scheduled study visits and documented in source. At the 
Week 8 Sleep Lab visit, these participants must use their evening dose of LUMIGAN 0.01% at 
20:00 ± 1 hour, which will be documented in source. Please see the Procedure Manual for 
details. 
6.5. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter and/or prescription medicines; vitamins; 
herbal supplements, and/or cannabis or other specific categories of interest) that the participant is 
receiving at the time of enrollment or receives during the study must be recorded along with: 
• Indication 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
6.5.1. 
Prohibited Interventions and Washout Before the Study 
All participants must provide informed consent prior to beginning any drug washout for the 
purposes of inclusion in this study. Participants currently being treated with IOP-lowering 
medication(s) in either eye will begin washout of these medication(s) following completion of 
screening procedures. The screening and washout periods may not be concurrent. The washout 
period will be up to 42 days depending on the minimum washout period schedule below. 
If participants cannot discontinue their prescribed therapy for up to 6 weeks to meet the washout 
period for study entry, the investigator may switch the participant’s medication to one that 
requires a shorter washout interval during the washout of the original medication (Table 6–2). 
Nonetheless, the investigator should adhere to the minimum washout period for all IOP-lowering 
medications used, as indicated in Table 6–2. 
If, after initial washout, the IOP does not meet entry criteria and the investigator believes this is 
due to inadequate washout, if time remains in the washout period he/she may perform additional 
washout, as long as the total washout period does not exceed 42 days. 
 
 
 
 


 
 
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Table 6–2 
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 analogs, 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], Roclatan® [28 days], etc) 
Longest minimum 
duration of any 
component based on 
medication class 
For participants undergoing a washout, interim safety evaluation(s) of IOP at any 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 participant is willing to discontinue the medication for the 
duration of the study. If the medication cannot be discontinued, then the participant will not be 
eligible for study entry. 
6.5.2. 
Permitted Treatments 
Ophthalmic Treatments 
The fellow eye will receive standard of care for IOP lowering, provided there is no known 
potential crossover effect to the study eye (eg, prostaglandin analogues, carbonic anhydrase 
inhibitors, laser or surgical procedures, etc) (see Section 6.5.4 for details on prohibited 
treatments). If the fellow eye requires laser or surgical treatment, it must be performed not less 
than 3 days after Bimatoprost SR administration in the study eye.  
Intermittent use of artificial tear products is allowed if they are not taken ≤ 15 minutes before 
any study procedure or examination in either eye. Use of cyclosporine ophthalmic solution, 
lifitegrast ophthalmic solution, and intermittent use of ocular decongestants or antihistamines is 
allowed if not taken: 
• Within 2 days prior to the Baseline visit, through 3 days after Bimatoprost SR 
administration procedure 
• Within 2 days prior to the Week 8 visit, through the completion of the 24-hour lab 
assessments  
 
 
 


 
 
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Use of artificial tear products, cyclosporine ophthalmic solution, lifitegrast ophthalmic solution,  
and ocular decongestants or antihistamines may be restarted in the study eye 3 days after the 
Bimatoprost SR administration procedure. 
For participants assigned to LUMIGAN 0.01%, if the participant uses any other additional, 
permitted, topical ophthalmic medications, the topical ophthalmic medication(s) must be 
administered at least 5 minutes apart from the LUMIGAN 0.01% in the study eye. 
Use of postinjection topical ocular antibiotics is expected following the Bimatoprost SR 
administration procedure (see Procedure Manual). Use of topical ophthalmic corticosteroids and 
NSAIDs from Day 1 through Day 7 following administration is allowed at the investigator’s 
discretion. 
Implant Removal 
In the event that the Bimatoprost SR implant requires removal for significant safety reasons, this 
may be performed at the discretion of the investigator (see Procedure Manual for details). The 
investigator may contact the medical safety physician at Allergan for further discussion as 
needed. 
Note that in the event that the investigator performs an 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). 
Systemic Medications 
The use of systemic NSAIDs is permitted. 
In addition, therapy considered necessary for the participant’s welfare may be given at the 
discretion of the investigator. If concurrent medications may have an effect on study outcomes, 
these medications should be administered in dosages that remain constant throughout the entire 
duration of the study. If the permissibility of a specific medication/treatment is in question, 
please contact Allergan. 
6.5.3. 
Rescue Medicine 
In the event that the study eye IOP does not meet or does not maintain IOP-lowering 
expectations, rescue IOP-lowering treatment (medication[s] or procedure[s] or both) can be 
initiated at the investigator’s discretion. Inadequate control of IOP should be confirmed at a 
subsequent visit (scheduled or unscheduled visit) not on the same day. Rescue treatment can be 
initiated at the investigator’s discretion at any time during the study if it is in the best interest of 
the participant. Prior to completion of the Month 12/Study Exit visit, the investigator will be 
expected to attest to the need for additional nonstudy IOP-lowering (rescue) treatment in the 
study eye for safety reasons. 
 
 
 


 
 
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6.5.4. 
Prohibited Interventions During the Study 
The decision to administer a prohibited medication and/or treatment is done with the safety of 
the study participant as the primary consideration. When possible, Allergan should be notified 
before the prohibited medication/treatment is administered. 
During the study, participants should not participate in other investigational drug or device 
studies. 
Nonstudy IOP-lowering Treatments 
The fellow eyes of participants will receive standard of care for IOP lowering, provided there is 
no crossover effect on the study eye. Use of any concurrent nonstudy IOP-lowering treatment in 
the fellow eye with a known potential effect on outcomes (ie, alpha agonists and beta-adrenergic 
blocking agents) in the study eye is prohibited during the study.   
Contact Lenses 
Use of soft contact lenses within 3 days and/or use of rigid gas permeable or hard contact lenses 
within 1 week prior to a scheduled study visit or Day 1, and/or use of contact lenses of any kind 
within 1 week following Bimatoprost SR administration in the study eye, is prohibited. From 
08:00 ± 30 minutes through completion of last IOP measurement of Sleep Lab visits ending at 
06:00 ± 30 minutes,  participants will not be permitted to wear contact lenses. For participants 
assigned to LUMIGAN 0.01%, contact lenses must be removed prior to instillation and may be 
reinserted 15 minutes following administration of LUMIGAN 0.01%. 
Other Treatments 
The following medications (or classes of medications) and treatment procedures are not 
permitted as concurrent therapy during the study through completion of the Month 12/Study Exit 
visit, unless the participant has already been treated with rescue IOP-lowering medication in the 
study eye: 
• Subconjunctival, sub-Tenon’s, intravitreal, or other ophthalmic injections of any 
medications in either eye 
• Use of any topical ophthalmic medications (except as described in Section 6.5.2) in the 
study eye 
• Surgical procedures in the study eye that are not related to the Bimatoprost SR 
administration procedure  
• Use of bimatoprost for hypotrichosis during the study period in the study eye 
• Systemic use of carbonic anhydrase inhibitors  
• Any systemic regimen of beta-blocker containing medications  
 
 
 


 
 
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• Use of corticosteroids in the study eye (except as described in Section 6.5.2 for 
postinjection use) or systemically during the study or historical use prior to Baseline 
within: 
o 3 years: intraocular fluocinolone acetonide 
o 6 months: intraocular corticosteroid(s) other than fluocinolone; any injectable 
periocular or sub-Tenon’s/subconjunctival corticosteroid 
o 2 months: systemic (eg, oral, intramuscular, intravenous) or topical ocular 
corticosteroids  
o 2 weeks: dermal corticosteroid applied to skin of the eyelid(s), around the eye, 
or adnexa 
6.6. 
Dose Modification 
Dose modification is not applicable. 
6.7. 
Treatment after the End of the Study 
No interventions after the end of the study are planned; participants will be treated per standard 
of care by their health care provider. 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
A premature discontinuation from study treatment will occur if a participant who signs the ICF 
and receives study treatment ceases participation in the study, regardless of circumstances, 
before the completion of the protocol-defined study procedures. 
Notification of early participant discontinuation from the study and the reason for 
discontinuation will be made to the sponsor and will be clearly documented on the appropriate 
eCRF. 
Reasons for discontinuation from the study treatment and/or the study may include the following 
commonly used or other acceptable terms:  
 
 
 
 


 
 
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Commonly Used Terms 
Other Acceptable Terms 
Adverse event 
Death 
Completed 
Failure to meet enrollment criteria 
Lack of efficacy 
Progressive disease 
Lost to follow-up 
Technical problems 
Noncompliance with study drug 
 
Other 
 
Physician decision 
 
Pregnancy 
 
Protocol deviation 
 
Screen failure 
 
Site terminated by sponsor 
 
Study terminated by sponsor 
 
Withdrawal by subject 
 
 
7.1. 
Discontinuation of Study Intervention 
The Bimatoprost SR implant is designed to bioerode in the AC of the eye and is not meant to be 
removed. In the event that the Bimatoprost SR implant requires removal for significant safety 
reasons, please see Section 6.5.2 for guidance on implant removal and Section 7.2 for follow up 
requirements for participant discontinuation in the event the implant is removed. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
• A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. 
• If a participant develops (or has an exacerbation of) a medical condition that, in the 
opinion of the investigator, would put the participant at an unacceptable medical risk by 
continuing study participation, the participant will be withdrawn from the study. 
• If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records. 
 
 
 


 
 
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• Participants assigned to and treated with Bimatoprost SR who have received nonstudy 
IOP-lowering treatment (rescue) in the study eye, will be followed for the duration of the 
study through the Month 12/Exit visit. If the implant has been removed, the participant 
may discontinue the study if based on investigator assessment the eye is in stable 
condition, at which time they should complete the Month 12/Exit visit procedures. 
Notification of early participant 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. If participants discontinue before Month 12/Exit, the site 
should complete all procedures for the Month 12/Exit visit at the participant’s last visit. 
The investigator should consider withdrawing a participant from the study early if any of the 
following criteria are met: 
• Participant develops (or has an exacerbation of) a medical condition that, in the opinion of 
the investigator, compromises the participant’s ability to participate in the study 
• Participant is unwilling or unable to continue to comply with study procedures 
• Participant is unwilling or unable to continue in the study 
Whenever possible, the decision to withdraw a participant from the study or study treatment 
should be discussed with Allergan. 
7.3. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether the participant wishes to and/or should continue in the 
study. 
• Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls, and if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts will be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
 
 
 
 


 
 
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8. 
Study Assessments and Procedures 
• A detailed listing of study assessments by day is provided in Appendix 8. 
• Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol waivers 
or exemptions are not allowed. 
• Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
treatment. 
• Adherence to the study design requirements, including those specified in the SoA 
(Section 1.3), is essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
Participants who complete all regularly scheduled study visits should have 9 study office visits, 
2 sleep lab visits, and 1 phone call. The schedule includes the following: 
• Screening (up to 60 days); Washout Period of up to 42 days; and Baseline (Office visit and 
Sleep Lab visit) 
• Day 1; Day 2 Safety visit  
• Day 8 phone call 
• Weeks 8 (Office and Sleep Lab visit) and 16; and Months 6, 9, and 12/Study Exit visits  
8.1. 
Efficacy Assessments 
Efficacy assessments are to be completed as outlined in the SoA (Section 1.3). 
The primary and secondary efficacy measures of IOP collected over 24 hours at the Baseline 
Sleep Lab visit and Week 8 Sleep Lab visit will be measured using an Allergan-specified 
tonometer. The right eye is to be measured first and the left eye measured second. Two 
consecutive IOP measurements will be taken of each eye. If the first 2 measurements differ by > 
1 mm Hg, a third measurement will be taken. If the first 2 measurements differ by ≤ 1 mm Hg, 
the IOP for the given eye will be the average of the 2 readings. If the difference between the first 
2 measurements is > 1 mm Hg, the IOP for the given eye will be the median of the 3 readings. 
The 24-hour IOP values collected at the Baseline Sleep Lab visit and Week 8 Sleep Lab visit will 
be performed at 08:00 ± 30 minutes, 10:00 ± 30  minutes, 12:00 ± 30 minutes, 
14:00 ± 30 minutes, 16:00 ± 30 minutes, 18:00 ± 30 minutes, 20:00 ± 30 minutes, 
22:00 ± 30 minutes, 00:00 ± 30 minutes, 02:00 ± 30 minutes, 04:00 ± 30 minutes, and 
06:00 ± 30 minutes. Diurnal IOP measurements are defined as the IOP values collected between 
08:00 ± 30 minutes to 22:00 ± 30 minutes and nocturnal IOP measurements are defined as the 
 
 
 
 


 
 
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IOP values collected between 00:00 ± 30 minutes to 06:00 ± 30 minutes. For all 24-hour IOP 
measurements collected at the Sleep Lab visits, sites should attempt to collect IOP at least 
90 minutes after the previous time point. Diurnal IOP measurements performed at Baseline Sleep 
Lab visit and Week 8 Sleep Lab visit will be performed with the participants in a supine position 
≥ 5 minutes at rest then sitting  ≥ 5 minutes at rest. Nocturnal IOP measurements will be 
collected with the participants ≥ 5 minutes at rest in a supine position only. Lights in individual 
sleep rooms will be turned off at 23:00 and nocturnal IOP measurements will be performed 
under dim lighting with monitoring of the participant’s sleep status. At least 2 individuals, one 
being of the same sex as the participant, will be present in individual participant rooms for 
nocturnal assessments. At the Week 8 Sleep Lab visit, participants assigned to LUMIGAN 
0.01% must continue their evening dose of LUMIGAN 0.01% at 20:00 ± 1 hour. Caution must 
be taken not to unmask the IOP assessor. Please see Procedure Manual for additional details.  
Other efficacy measures assess Hour 0 IOP and time to initial use of nonstudy IOP-lowering 
treatment. All Hour 0 IOP examinations will be scheduled at 08:00 ± 1 hour and will be 
measured using a Goldmann applanation tonometer. As scheduling permits, the participant 
should have approximately the same Hour 0 time of day throughout the study. The right eye is to 
be measured first and the left eye measured second. Two consecutive IOP measurements will be 
taken of each eye. If the first 2 measurements differ by > 1 mm Hg, a third measurement will be 
taken. If the first 2 measurements differ by ≤ 1 mm Hg, the IOP for the given eye will be the 
average of the 2 readings, corresponding to the median. 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 will be performed with the participants in a sitting position. 
8.2. 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the Schedule of Activities 
(Section 1.3). 
8.2.1. 
Physical Examinations 
The participant will be examined by qualified medical personnel performing a modified physical 
examination, which may include assessments of: general appearance; head, eyes, ears, nose, and 
throat; heart/cardiovascular; lungs; abdomen; neurologic; extremities; back; musculoskeletal; 
lymphatic; and skin. Height and weight will also be measured and recorded. 
8.2.2. 
Vital Signs 
Vital signs will be assessed as follows: 
• Temperature, pulse rate, and BP will be assessed. 
• BP and pulse measurements will be assessed with participants in a seated position with a 
completely automated device. Manual techniques will be used only if an automated device is 
not available. 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest in a 
seated position. 
 
 
 
 


 
 
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8.2.3. 
Pregnancy Testing 
Pregnancy testing will be conducted at the Baseline Office visit. Urine pregnancy tests will be 
used unless the study site requires the use of serum testing, in which case serum testing will be 
used. WOCBP must have a negative test result before receiving study treatment. This test may 
also be performed at any other visit, at the investigator’s discretion. At each visit, the investigator 
should discuss contraceptive use compliance with WOCBP females of childbearing potential 
(see Appendix 7 for more details). 
8.2.4. 
Clinical Safety Laboratory Assessments 
See Appendix 2 for the list of clinical laboratory tests to be performed and the Schedule of 
Activities (Section 1.3) for the timing and frequency. 
At Screening, the investigator or qualified subinvestigator will assess the clinical significance of 
any values outside the reference ranges provided by the laboratory, and participants with 
abnormalities judged to be clinically significant will be excluded from the study. 
8.2.5. 
Ocular Safety Assessments 
8.2.5.1. 
Macroscopic Conjunctival Hyperemia Assessment 
Macroscopic conjunctival hyperemia will be assessed using the appropriate assessment guide 
(see the Procedure Manual for further details). 
8.2.5.2. 
Best-corrected Visual Acuity 
Visual acuity tests will be performed at all visits except on Day 1 and at the Sleep Lab visits. 
Manifest refraction using Snellen equivalent with a logMar chart (see Procedure Manual) will be 
performed at Screening, Baseline (Office visit), and Month 12/Study 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 BCVA will be performed. See the Procedure Manual for further details. 
8.2.5.3. 
Visual Field 
Visual field examinations will be assessed using automated perimetry (using either Humphrey 
24-2 full threshold program or 24-2 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 participant. If dilation is required to perform this test, then the visual field test should be 
performed after gonioscopy/angle assessment or with the scheduled dilated exams, if applicable. 
See the Procedure Manual for further details.  
8.2.5.4. 
Specular Microscopy 
Endothelial cell density will be assessed using specular microscopy performed on the central 
cornea. The determination of central endothelial cell density for study entry as well as study visit 
 
 
 
 


 
 
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measures will be by the study investigator using automated analysis. See the Procedure Manual 
for further details. The same instrument and analysis methodology must be used throughout the 
study for a given participant.  
8.2.5.5. 
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). 
8.2.5.6. 
Gonioscopy/Angle Assessment 
Gonioscopic examinations will be performed by the study investigator as described in the 
Procedure Manual. At Screening and the Baseline Office visits, the investigator’s eligibility 
assessments must confirm participant eligibility for participation in the study. In subsequent 
gonioscopic examinations during the study, the investigator will evaluate the inferior 
iridocorneal angle and the Bimatoprost SR implant. 
8.2.5.7. 
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 participant. Pachymetry 
may be performed any time after non-contact exams. See the Procedure Manual for further 
details. 
8.2.5.8. 
Dilated Ophthalmoscopy 
The stereoscopic fundus assessments should be conducted through a dilated pupil. The 
examinations will include evaluation of the macula, vitreous, and retina. 
8.2.5.9. 
Optic Disc Examination 
The cup/disc ratio and presence of optic disc pathology will be determined using stereoscopic 
evaluation. 
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Appendix 3.  
AEs may be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative). 
Additionally, the investigator and any qualified designees are responsible for detecting, 
documenting, and recording events that meet the definition of an AE or SAE and remain 
responsible for following up AEs that are serious, considered related to the study treatment or 
study procedures, or that caused the participant to discontinue the study treatment or the study 
(see Section 7). 
 
 
 
 


 
 
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8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information 
All AEs and SAEs from the signing of the ICF until the study exit visit will be collected at the 
timepoints specified in the SoA (Section 1.3), and as observed or reported spontaneously by 
study participants. 
Medical occurrences that begin before the start of study treatment, but after obtaining informed 
consent will be recorded in the AE section of the eCRF. 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as indicated 
in Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE information after conclusion of the 
study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must promptly 
notify the sponsor. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3. 
Follow Up of Adverse Events and Serious Adverse Events 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All AEs/SAEs will be followed until resolution, stabilization, the 
event is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
If a participant dies during participation in the study or during a recognized follow-up period, the 
investigator will provide Allergan with a copy of any postmortem findings including 
histopathology. 
New or updated information will be recorded in the originally completed eCRF. 
The investigator will submit any updated SAE data to sponsor or designee within 24 hours of 
receipt of the information. 
 
 
 
 


 
 
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8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events 
• Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.  
• The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/ IECs, and investigators.  
• Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary. 
• An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the investigator’s brochure and will notify the IRB/IEC, if 
appropriate according to local requirements. 
8.3.5. 
Pregnancy 
• If a pregnancy is confirmed after the participant has received the study treatment, the 
participant may choose to exit the study after appropriate safety follow-up or to remain in 
the study for all safety and efficacy follow up assessments through the study exit visit. 
• Details of all pregnancies in female participants will be collected from the signing of the 
ICF and through the duration of the pregnancy. 
• If a pregnancy is reported, the investigator should inform Allergan within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 7. 
• Abnormal pregnancy outcomes (eg, spontaneous or elective abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6. 
Medication Errors 
Medication error refers to any unintended error in the dose strength and/or administration of the 
study treatment as per instructions in the protocol and/or the Procedure Manual. Medication 
errors generally fall into the categories as follows: 
• Wrong study drug 
• Wrong dose strength 
• Wrong route of administration 
• Wrong participant (ie, not administered to the intended participant) or wrong eye 
• Study medication expired 
 
 
 
 


 
 
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8.4. 
Treatment of Overdose 
Not applicable. 
8.5. 
Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this study. 
8.6. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.7. 
 Genetics 
Genetics are not evaluated in this study. 
8.8. 
Biomarkers and Other Assessments 
8.8.1. 
Anterior Segment Imaging 
At selected sites/selected participants only, anterior segment imaging may be performed using 
Allergan-approved instruments. Please see the Procedure Manual for further details. The 
participant’s decision about whether to allow anterior segment imaging will not affect their 
eligibility for participation in the study. 
8.9. 
Health Economics 
Health economics are not evaluated in this study. 
9. 
Statistical Considerations 
Two database locks are planned for this study. The first database lock, for the primary and 
secondary efficacy endpoint analysis, will occur when 100% of participants have completed the 
primary visit (ie, Week 8 Sleep Lab visit) or prematurely discontinued prior to the Week 8 Sleep 
Lab visit. Similarly, the second database lock for the full study database will occur after all 
participants have completed the study at Month 12 or prematurely discontinued from the study. 
Analyses will be performed after each lock: the primary and secondary efficacy analysis results 
are based on the first database lock, and the analyses based on the second database lock provides 
further efficacy and safety information. Prior to the first database lock a detailed analysis plan 
will be finalized.  
9.1. 
Statistical Hypotheses 
There are no statistical hypotheses for this study. 
 
 
 
 


 
 
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9.2. 
Sample Size Determination 
The sample size is based on practical considerations. Approximately 35 participants will be 
enrolled: 25 to 30 in the Bimatoprost SR cohort and 5 in the LUMIGAN 0.01% cohort. 
Twenty-five to 30 participants will be enrolled in the Bimatoprost SR cohort to achieve a  
minimum total of 20 evaluable participants, defined as participants with sufficient data at 
baseline and Week 8 to evaluate the 24-hour IOP-lowering effect of Bimatoprost SR. This 
assumes a premature discontinuation rate of up to 33%. Participants who prematurely 
discontinue from the study will not be replaced. 
Participants will be assigned to the Bimatoprost SR or LUMIGAN 0.01% cohort by the 
investigator. 
9.3. 
Populations for Analyses 
Safety Analysis Set (SAF): All participants who have received study intervention (ie, 
Bimatoprost SR administration or LUMIGAN 0.01%) will contribute to the SAF. All safety data 
collected from these participants will be included in the SAF.  
Full Analysis Set (FAS): All participants who have received study intervention (ie, Bimatoprost 
SR administration or LUMIGAN 0.01%) with at least 1 postbaseline IOP assessment will 
contribute to the FAS. All efficacy data collected from these participants will be included in the 
FAS with the following exception:  
• To avoid confounding of efficacy data, IOP measurements obtained after initiating the use 
of nonstudy rescue IOP-lowering treatment (medication[s] or procedure[s] or both) in an 
eye will be excluded from FAS.   
9.4. 
Statistical Analyses 
In general, continuous variables will be summarized by cohort (Bimatoprost SR or LUMIGAN 
0.01%) for number of participants, mean, standard deviation, median, first quartile, third quartile, 
minimum, and maximum values. Categorical variables will be summarized by number and 
percentage of participants. 
An SAP will be developed and finalized before the first database lock. The details of the planned 
statistical analyses will be provided in the SAP. This section is a summary of the planned 
statistical analyses. 
9.4.1. 
Efficacy Analyses 
The efficacy analyses will be based on the FAS.  
9.4.1.1. 
Analysis Endpoints 
The primary efficacy endpoint is the time-matched IOP change from baseline at the Week 8 
Sleep Lab visit from the 24-hour IOP data collected at the Baseline Sleep Lab visit in the study 
eye for the Bimatoprost SR cohort.   
 
 
 
 


 
 
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As described in Section 8.1, the median of the IOP measurements at each timepoint will be the 
value used for analysis for the study eye.  
9.4.1.2. 
Primary Efficacy Analyses 
Sleep Lab visit collected IOP raw values and the corresponding time-matched change from 
baseline in IOP will be summarized descriptively by timepoint for the study eye in the 
Bimatoprost SR cohort. Ninety-five percent CIs based on a paired t-test will be provided for the 
mean time-matched IOP change from baseline. Mean IOP and mean time-matched IOP change 
from baseline across time during diurnal/wake period and nocturnal/sleep period will be 
presented graphically for the study eye in the Bimatoprost SR cohort.  
9.4.1.3. 
Secondary Efficacy Analyses 
IOP fluctuation will be evaluated by the range of IOP collected from the Sleep Lab visit during 
diurnal/wake period and nocturnal/sleep period, as well as over a 24-hour period in the 
Bimatoprost SR cohort. The range of IOP at baseline and Week 8, as well as the change from 
baseline to Week 8 in IOP range will be summarized descriptively.   
9.4.1.4. 
Other Efficacy Analyses 
Other efficacy analyses will include descriptive summary for IOP (Hour 0) values at baseline 
with corresponding change from baseline by visit through Month 12/Study Exit. In addition,  
time from Day 1 to initial use of nonstudy rescue IOP-lowering treatment (medication[s] or 
procedure[s] or both) in the study eye will be analyzed using Kaplan-Meier methods.   
Summary statistics calculating change from baseline in IOP will also be presented for the 
LUMIGAN 0.01% cohort. 
9.4.2. 
Safety Analyses 
The safety analyses will be performed using the safety analysis set and will be fully defined in 
the SAP. General safety parameters will include AEs (including pregnancy) and vital signs. 
Ocular safety parameters will include visual fields, best-corrected visual acuity, conjunctival 
hyperemia, biomicroscopy, dilated ophthalmoscopy (including optic disc assessment), 
pachymetry, gonioscopy, and specular microscopy. 
Ocular AEs and safety variables will be tabulated by cohort for the study eye and fellow eye, and 
nonocular safety variables will be summarized at the participant level.  
9.4.2.1. 
Adverse Events 
An AE will be considered a TEAE if the AE began or worsened (increased in severity or became 
serious) on or after the date (and time, if known) of the first administration of study treatment.  
An AE will be considered a treatment-emergent SAE if it is a TEAE that additionally meets any 
SAE criterion. 
 
 
 
 


 
 
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MedDRA nomenclature will be used to code AEs. Adverse events will be coded from the 
verbatim text into PT and SOC. AEs will be collected for both eyes and will be displayed 
separately where appropriate. Ocular AEs and safety variables will be summarized by cohort for 
the study eye or fellow eye, and nonocular safety variables will be summarized by participant. 
The number and percentage of participants reporting AEs will be tabulated by cohort based on 
primary SOC and PTs. Participants with multiple occurrences of a PT will be counted once in the 
calculation of the rate for that PT. Similarly, participants with multiple events within an SOC 
will be counted once in the incidence rate for that SOC.  
Summary tables will be generated for all AEs regardless of causality as well as treatment-related 
AEs for the entire study. Related AEs will be displayed as those related to study treatment or 
procedures. Summaries will also be displayed by severity. 
9.4.2.2. 
Vital Signs 
Descriptive statistics for vital signs (systolic and diastolic blood pressure, pulse rate, and 
temperature) at Baseline and changes from Baseline at each assessment will be presented by 
cohort.  
9.5. 
Interim Analyses 
Two database locks will occur as described under Section 9. Analyses will be performed after 
each lock. The primary and secondary efficacy analysis based on the first database lock will be 
considered as final analysis. The analyses based on the second database lock provide further 
efficacy and safety information. 
Additional safety analyses may be periodically performed based on relevant data snapshots.  
 
 
 
 


 
 
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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
CIOMS International Ethical Guidelines 
o Applicable ICH/ISO GCP guidelines 
o Applicable laws and regulations 
• The protocol, protocol amendments, ICF, investigator’s brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.  
• The investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o Providing oversight of the overall conduct of the study at the site and adherence to 
requirements of applicable local regulations, for example 21 CFR, ICH guidelines, 
the IRB/IEC, and European regulation 536/2014 for clinical studies (if applicable) 
10.1.2. 
Financial Disclosure 
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
 
 
 
 


 
 
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10.1.3. 
Informed Consent Process 
• The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study.  
• Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 
50, local regulations, ICH guidelines, HIPAA requirements, where applicable, and the 
IRB/IEC or study center.  
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
• A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.  
10.1.4. 
Data Protection 
• Participants will be assigned a unique identifier. Any participant records or datasets that 
are transferred to the sponsor will contain the identifier only; participant names or any 
information that would make the participant identifiable will not be transferred.  
• The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the participant.  
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5. 
Posting Clinical Study Data 
• Study data and information may be published in nonpromotional, peer-reviewed publications 
either by or on behalf of the sponsor with sponsor permission.  
• Clinical study reports, safety updates, and annual reports will be provided to regulatory 
authorities as required. 
• Company-sponsored study information and tabular study results will be posted on the US 
National Institutes of Health's website www.ClinicalTrials.gov and other publicly accessible 
sites. 
 
 
 
 


 
 
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10.1.6. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or eCRFs unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator 
is responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.  
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.  
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator as stated in the clinical trial agreement. No records 
may be destroyed during the retention period without the written approval of the sponsor. 
No records may be transferred to another location or party without written notification to 
the sponsor.  
10.1.7. 
Source Documents 
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study.  
• Definition of what constitutes source data can be found in Section 4.0 of ICH E6, Good 
Clinical Practice: Consolidated Guidance and must follow ALCOA, ie, records must be 
attributable, legible, contemporaneous, original, and accurate. 
10.1.8. 
Study and Site Closure 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
 
 
 
 


 
 
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The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor’s procedures, or GCP guidelines 
• Inadequate recruitment of participants by the investigator 
• Discontinuation of further study intervention development 
10.1.9. 
Publication Policy 
• 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. 
• The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.1.10. 
Compliance with Protocol 
The investigator is responsible for compliance with the protocol at the investigational site. A 
representative of the sponsor will make frequent contact with the investigator and his/her 
research staff and will conduct regular monitoring visits at the site to review participant and 
study treatment accountability records for compliance with the protocol. Protocol deviations will 
be discussed with the investigator upon identification. The use of the data collected for the 
participant will be discussed to determine if the data are to be included in the analysis. The 
investigator will enter data that may be excluded from analysis as defined by the protocol 
deviation specifications. Significant protocol deviations will be reported to the IRB/IEC 
according to the IRB/IEC’s reporting requirements. 
 
 
 
 


 
 
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10.2. 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in Table 10-1 will be performed by a central laboratory or designated regional 
facility, including any repeat laboratory tests. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 5 
of the protocol. Refer to the Central Laboratory Manual for further details regarding central 
laboratory collection and shipment procedures. 
Local laboratory results are only required in the event that the central laboratory results are not 
available in time for either study treatment administration and/or response evaluation. If a local 
sample is required, it is important that the sample for central analysis is obtained at the same 
time. Additionally, if the local laboratory results are used to make either a study treatment 
decision or response evaluation, the results must be entered into the eCRF. 
Laboratory test results will be forwarded from the central laboratory or designated regional 
facility to the study site and to Allergan or its designee. Additional tests may be performed at any 
time during the study as determined necessary by the investigator or required by local regulations. 
The investigator or qualified site personnel must review all laboratory results for any adverse 
events. Laboratory test results that represent adverse events should be reflected on an adverse 
event eCRF page. 
Evaluation and management of abnormal laboratory results should be conducted according to 
local site practice. 
 
 
 
 
 


 
 
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Table 10-1 
Protocol Required Safety Laboratory Assessments 
Laboratory 
Assessmentsa 
Parameters 
Hematology 
Platelets  
RBC indices: 
MCV 
MCH 
MCHC 
Morphology 
WBC count with differential 
(absolute): 
Neutrophils 
Bands 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC count 
Hemoglobin 
Glycated hemoglobin 
Hematocrit 
Serum Chemistry 
BUN, uric acid 
Potassium 
AST 
Total, direct, and 
indirect bilirubin 
 
Creatinine 
Sodium 
ALT 
Total protein 
 
Creatinine kinase 
Magnesium, 
phosphorus 
Bicarbonate 
Total cholesterol 
 
Glucose 
Calcium 
Alkaline 
phosphatase 
Chloride, albumin 
Routine 
Urinalysis 
• Specific gravity 
• pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase 
• Clarity, color, presence of blood 
• Microscopic examination (WBCs, RBCs, casts, bacteria, crystals, epithelial cells) 
a 
No laboratory assessments require fasting. 
 
 
 
 












 
 
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10.4. 
Appendix 4: Abbreviations 
 
Abbreviation/Term 
Definition 
ABMD 
Anterior Basement Membrane Disease 
AC 
anterior chamber 
AE 
adverse event 
AGIS 
Advanced Glaucoma Intervention Study 
ALT 
Alanine aminotransferase  
AMD 
age-related macular degeneration 
AREDS 
Age-related Eye Disease Study 
ASC 
ambulatory surgical center 
AST 
Aspartate aminotransferase  
BP 
blood pressure 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations  
CI  
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
eCRF 
electronic case report form 
EU 
European Union 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FSH 
follical stimulating hormone 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HRT 
hormone replacement therapy 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IOL 
intraocular lens implant 
IOP 
intraocular pressure 
IP 
investigational product 
IRB  
institutional review board 
ISO 
International Organization for Standardization 
IWRS 
interactive web response system 
LT 
laser trabeculoplasty 
MCHC 
mean corpuscular hemoglobin concentration 
MCH 
mean corpuscular hemoglobin 
 
 
 


 
 
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Abbreviation/Term 
Definition 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities  
MIGS 
minimally invasive glaucoma surgery 
NSAID 
nonsteroidal anti-inflammatory drugs 
OAG 
open-angle glaucoma 
OHT 
ocular hypertension 
OU 
both eyes 
PLA 
polylactic acid 
PLGA 
polylactic-co-glycolic acid  
POAG 
primary open-angle glaucoma 
PT 
preferred term 
RBC 
red blood cell 
SAE 
serious adverse event 
SAF 
safety analysis set 
SAP 
statistical analysis plan 
SLT 
selective laser trabeculoplasty  
SoA 
schedule of activities 
SOC 
system organ class 
SOP 
standard operating procedure 
SR 
sustained release 
SUSARS 
suspected unexpected serious adverse reactions  
TEAE 
treatment-emergent adverse event 
US/USA 
United States 
WBC 
white blood cell 
WHO 
World Health Organization 
WOCBP 
woman of childbearing potential 
 
 
 
 


 
 
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10.5. 
Appendix 5: Standard Discontinuation Criteria 
This table provides participant discontinuation criteria for this protocol. CDISC terminology is 
used, and thus subject or patient is used instead of participant (as used elsewhere in this 
protocol). These terms are interchangeable.   
CDISC Submission Value 
CDISC Definition 
Adverse event 
Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and 
which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, 
whether or not related to the medicinal (investigational) product. 
For further information, see the ICH Guideline for Clinical Safety 
Data Management: Definitions and Standards for Expedited 
Reporting (modified from ICH E2A) Synonyms: side effect, 
adverse experience. See also serious adverse event, serious adverse 
experience. (CDISC glossary) 
Completed 
To possess every necessary or normal part or component or step; 
having come or been brought to a conclusion (NCI) 
Death 
The absence of life or state of being dead (NCI) 
Disease relapse 
The return of a disease after a period of remission 
Failure to meet randomization criteria 
An indication that the subject has been unable to fulfill/satisfy the 
criteria required for assignment into a randomized group 
Lack of efficacy 
The lack of expected or desired effect related to a therapy (NCI) 
Lost to follow-up 
The loss or lack of continuation of a subject to follow-up 
Non-compliance with study drug 
An indication that a subject has not agreed with or followed the 
instructions related to the study medication (NCI) 
Other 
Different than the one(s) previously specified or mentioned (NCI) 
Physician decision 
A position, opinion, or judgment reached after consideration by a 
physician with reference to subject (NCI) 
Pregnancy 
Pregnancy is the state or condition of having a developing embryo 
or fetus in the body (uterus), after union of an ovum and 
spermatozoon, during the period from conception to birth. (NCI) 
Progressive disease 
A disease process that is increasing in extent or severity (NCI) 
Protocol deviation 
An event or decision that stands in contrast to the guidelines set out 
by the protocol (NCI) 
Recovery 
A healing process and/or an outcome implying relative health. The 
term is typically used in the context of direct and indirect effects of 
sickness or injury. (NCI) 
Screen failure 
The potential subject who does not meet one or more criteria 
required for participation in a trial 
Site terminated by sponsor 
An indication that a clinical study was stopped at a particular site 
by its sponsor (NCI) 
 
 
 


 
 
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CDISC Submission Value 
CDISC Definition 
Study terminated by sponsor 
An indication that a clinical study was stopped by its sponsor 
(NCI) 
Technical problems 
A problem with some technical aspect of a clinical study, usually 
related to an instrument (NCI) 
Withdrawal by subject 
An indication that a study participant has removed itself from the 
study (NCI) 
 
 
 
 


 
 
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10.6. 
Appendix 6: Study Tabular Summary 
This table is intended for use in posting study information to registries (eg, ClinicalTrials.gov).   
Parameter 
Group 
Parameter 
Value 
Trial 
information 
Trial Title 
An Evaluation of the 24-Hour IOP-lowering Effect of 
Bimatoprost SR in Participants with Open-Angle 
Glaucoma or Ocular Hypertension 
 
Clinical Study Sponsor 
Allergan Sales LLC 
 
Trial Phase Classification 
Phase 3b Trial 
 
Trial Indication 
Open-angle glaucoma or ocular hypertension 
 
Trial Indication Type 
Treatment 
 
Trial Type 
Efficacy 
Safety 
 
Trial Length 
15 months 
 
Planned Country of 
Investigational Sites 
United States 
 
Planned Number of Subjects 
30 
 
FDA-regulated Device Study 
No 
 
FDA-regulated Drug Study 
Yes 
 
Pediatric Study 
No 
Subject 
information 
Diagnosis Group 
Open-angle glaucoma or ocular hypertension 
 
Healthy Subject Indicator 
No 
 
Planned Minimum Age of 
Subjects 
18 
 
Planned Maximum Age of 
Subjects 
Not specified 
 
Sex of Participants 
Both 
 
Stable Disease Minimum 
Duration 
Not specified 
 
 
 


 
 
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Parameter 
Group 
Parameter 
Value 
Treatments 
Investigational Therapy or 
Treatment 
Bimatoprost SR   
LUMIGAN 0.01% 
 
Intervention Type 
Drug 
Drug 
 
Pharmacological Class of 
Investigational Therapy 
Prostaglandin analog 
Prostaglandin analog 
 
Dose Strength per Administration 
10 µg 
0.01% 
 
Dose Units 
1 implant 
Drop 
 
Dosing Frequency 
Single dose 
Once daily in the evening 
 
Route of Administration 
Intracameral 
Topical ophthalmic 
 
Current Therapy or Treatment 
No 
No 
 
Added on to Existing Treatments 
No 
No 
 
Control Type 
None 
None 
 
Comparative Treatment Name 
N/A 
N/A 
Trial design 
Study Type 
Interventional 
 
Intervention Model 
2 arm 
 
Planned Number of Arms 
2 
 
Trial is Randomized 
No 
 
Randomization Quotient 
N/A 
 
Trial Blinding Schema 
Open-label 
 
Stratification Factor 
N/A 
 
Adaptive Design 
No 
 
Study Stop Rules 
None 
 
 
 
 


 
 
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10.7. 
Appendix 7: Contraceptive Guidance and Collection of Pregnancy 
Information  
Definitions: 
WOCBP 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. However, in 
the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.  
• Females on HRT and whose menopausal status is in doubt will be required to use one of 
the nonestrogen hormonal highly effective contraception methods or acceptable 
contraception methods if they wish to continue their HRT during the study. Otherwise, 
they must discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment. 
Contraception Guidance: 
Female Participants 
WOCBP are eligible to participate if they agree to use a highly effective or acceptable method of 
contraception consistently and correctly as described in Table 10-2. 
 
 
 
 


 
 
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Table 10-2 
Highly Effective and Acceptable Contraception Methods 
Highly Effective Contraceptive Methods That Are User Dependenta  
Failure rate of < 1% per year when used consistently and correctly  
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation 
• 
Oral  
• 
Intravaginal  
• 
Transdermal  
Progestogen-only hormonal contraception associated with inhibition of ovulation 
• 
Oral  
• 
Injectable  
Highly Effective Methods That Are User Independenta  
Implantable progestogen-only hormonal contraception associated with inhibition of ovulation 
• 
IUD 
• 
IUS 
• 
Etonogestrel implant (ie, Nexplanon®) 
Bilateral tubal occlusion 
Intrauterine copper contraceptive (ie, ParaGard®) 
Vasectomized Partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male 
sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used.  
Sexual Abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatment. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the participant.  
Acceptable Methods  
Acceptable birth control methods that result in a failure of more than 1% per year include: 
• 
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of 
action 
• 
Male or female condom with or without spermicide 
• 
Cap, diaphragm, or sponge with spermicide 
• 
Nonhormonal intrauterine device 
A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-barrier methods) 
are also considered acceptable, but not highly effective, birth control methods. 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical 
studies.  
 
Pregnancy Testing: 
• 
WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive pregnancy test at Baseline. 
• 
Additional pregnancy testing should be performed at study exit, and as required locally. 
 
 
 


 
 
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• 
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected.  
• 
Urine pregnancy testing will be used unless the study site requires the use of serum testing, 
in which case serum testing will be used. 
Collection of Pregnancy Information: 
Female Participants Who Become Pregnant  
• 
The investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to Allergan within 24 hours of learning of a participant’s pregnancy. 
The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on the participant and the neonate, and the 
information will be forwarded to Allergan. Generally, follow up will not be required for 
longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of pregnancy 
will be reported, regardless of fetal status (presence or absence of anomalies) or indication 
for the procedure. 
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
will be reported as an AE or SAE. A spontaneous or elective abortion is always considered 
to be an SAE and will be reported as such. Any poststudy pregnancy-related SAE 
considered reasonably related to the study treatment by the investigator will be reported to 
Allergan as described in Section 8.3.4. While the investigator is not obligated to actively 
seek this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.  
• 
If a pregnancy is confirmed after the participant has received study treatment, the participant 
may choose to exit the study after appropriate safety follow up or to remain in the study for 
all safety and efficacy follow up assessments through study exit visit. 
 
 
 
 
 


 
 
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10.8. 
Appendix 8: Study Schedule Supplement  
10.8.1. 
Screening  
After informed consent and other documentation have been obtained, the procedures listed below 
are carried out. IOP measurements must be performed in 1 day; however, other procedures (eg, 
post dilation procedures) may be performed on a different day as long as the screening 
procedures are completed within a 60-day period, and procedures completed on the same day 
follow the schedule as set out in the protocol. Pupil dilation/diagnostic procedures are to be 
performed after the completion of the final IOP measurement of the day or on a different day. 
Screening procedures may be repeated for eligibility confirmation at any time prior to and during 
washout, at the discretion of the investigator 
• Collection of demographic data 
• Collection of medical and ophthalmic history 
• Collection of AEs 
• Collection of concomitant medications and procedures 
• Collection of alcohol/caffeine/smoking consumption and sleep habits 
• Physical examination 
• Vital signs (at rest ≥ 5 minutes) 
• Collection of blood and urine samples 
The following procedures should be performed in both eyes in the order below (procedures in 
bold should be done in the order shown): 
• Pre-Hour 0 examination (perform before Hour 0 IOP): 
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.) 
• BCVA 
• IOP measurement at Hour 0  
• Anterior segment imaging (perform any time after Hour 0 IOP; select sites/participants 
only) 
 
 
 
 


 
 
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• Non-contact examinations: The following may be performed in any order, at any time 
before gonioscopy: 
o Visual field (If dilation is required to perform this test, then the visual field 
test should be performed after gonioscopy/angle assessment with the 
scheduled dilated exams.) 
o Specular microscopy 
o Biomicroscopy 
• Gonioscopy/angle assessment  
• Pachymetry (may be performed at any time after non-contact exams) 
• 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 IWRS is contacted. 
10.8.2. 
Baseline  
10.8.2.1. Office Visit 
The Baseline Office visit occurs after the washout period has been completed. Baseline Office 
visit procedures must be performed in 1 day with the exception of anterior segment imaging, 
which may be performed on a different day. Pupil dilation/diagnostic procedures are to be 
performed after the completion of the final Hour 0 IOP measurement. The following procedures 
are performed at the Baseline Office visit:  
• Collection of medical and ophthalmic history 
• Collection of AEs 
• Collection of concomitant medications and procedures 
• Vital signs (at rest ≥ 5 minutes) 
• Pregnancy test for WOCBP 
The following procedures should be performed in both eyes (procedures in bold should be done 
in the order shown): 
 
 
 
 


 
 
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• 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.) 
• BCVA 
• IOP measurement at Hour 0  
• Anterior segment imaging (perform any time after Hour 0 IOP; select sites/participants 
only) 
• Non-contact examinations: The following may be performed at any time after IOP at 
Hour 0: 
o Visual field (If dilation is required to perform this test, then the visual field 
test should be performed after gonioscopy/angle assessment with the 
scheduled dilated exams.) 
o Specular microscopy 
o Biomicroscopy 
• Gonioscopy/angle assessment  
• Pachymetry (may be performed at any time after non-contact exams) 
• Pupil Dilation  (post dilation examinations below may be performed in any order) 
o Dilated ophthalmoscopy 
o Optic disc examination 
Eligibility is then determined and Hour 0 IOP is entered into the IWRS. 
10.8.2.2. Sleep Lab Visit 
Sleep Lab visit procedures must be performed on a different day from Baseline Office visit 
procedures. The following procedures are performed at the Baseline Sleep Lab visit: 
• Collection of AEs  
• Collection of concomitant medications and procedures 
• Collection of alcohol/caffeine/smoking consumption and sleep habits 
• Vital signs (at rest ≥ 5 minutes) 
 
 
 
 


 
 
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• Perform 24-hour Sleep Lab visit on a different day from all other Baseline Office visit study 
procedures.     
All 24-hour Sleep Lab visit IOP exams will be performed with an Allergan-specified tonometer. 
Diurnal IOP measurements will be taken supine ≥ 5 minutes at rest then sitting  ≥ 5 minutes at 
rest at 08:00 ± 30 min, 10:00 ± 30 min, 12:00 ± 30 min, 14:00 ± 30 min, 16:00 ± 30 min, 
18:00 ± 30 min, 20:00 ± 30 min, and 22:00 ± 30 min. Nocturnal IOP measurements will be taken 
supine only ≥ 5 minutes at rest 00:00 ± 30 min, 02:00 ± 30 min, 04:00 ± 30min, and 06:00 ± 30 
min. Lights in individual sleep rooms will be turned off at 23:00 and nocturnal IOP 
measurements will be performed under a dim lighting with monitoring of the participant’s sleep 
status. Please see Procedure Manual for details. 
10.8.3. 
Day 1 
The following procedures are performed on Day 1: 
• Collection of AEs 
• Collection of concomitant medications and procedures 
• Vital signs (at rest ≥ 5 minutes) 
• Contact IWRS for kit allocation (this contact may take place one day prior to Bimatoprost 
SR Administration [Day 1], if needed) 
• Administer study treatment (Bimatoprost SR 10 µg) in study eye or at selected 
sites/patients, begin LUMIGAN 0.01% in the study eye 
All participants must remain in the surgical facility for bilateral eye examination at least 1 hour 
after the Bimatoprost SR administration procedure. 
Each participant 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 the Bimatoprost SR 
treated eye and to follow up with the study site as per protocol. 
Participants assigned to LUMIGAN 0.01% will begin self-administration in the study eye once 
daily in the evening (at 20:00 ± 1 hour) starting with the evening dose on Day 1, and will 
continue daily self-administration through the duration of the study. 
 
 
 
 


 
 
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10.8.4. 
Day 2 Safety Visit 
The following procedures are performed on the Day 2 Safety visit: 
• Collection of AEs 
• 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  
• BCVA 
• IOP measurement at Hour 0  
• Non-contact examination: The following may be performed at any time after IOP at 
Hour 0:  
o Biomicroscopy 
10.8.5. 
Day 8 Phone Call 
On Day 8, the participant will be contacted by telephone to collect the following: 
• Collection of AEs 
• Collection of concomitant medications and procedures 
10.8.6. 
Week 8 Visits 
10.8.6.1. Office Visit 
Week 8 Office visit procedures must be performed in 1 day with the exception of anterior 
segment imaging, which may be performed on a different day. The following procedures are 
performed at the Week 8 Office visit:  
• Collection of AEs 
• Collection of concomitant medications and procedures 
• Vital signs (at rest ≥ 5 minutes) 
 
 
 
 


 
 
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The following procedures should be performed in both eyes (procedures in bold should be done 
in the order shown): 
• Pre-Hour 0 examinations (may be performed in any order before Hour 0 IOP): 
o Macroscopic conjunctival hyperemia assessment  
• BCVA 
• IOP measurement at Hour 0  
• Anterior segment imaging (perform any time after Hour 0 IOP; select sites/participants 
only) 
• Non-contact examinations: The following may be performed in any order, at any time 
before gonioscopy: 
o Biomicroscopy  
• Gonioscopy/angle assessment  
10.8.6.2. Sleep Lab Visit 
Sleep Lab visit procedures must be performed on a different day from Week 8 Office visit 
procedures. The following procedures are performed at the Week 8 Sleep Lab visit: 
• 
Collection of AEs 
• 
Collection of concomitant medications and procedures 
• 
Collection of alcohol/caffeine/smoking consumption and sleep habits 
• 
Vital signs (at rest ≥ 5 minutes) 
• 
Perform 24-hour Sleep Lab visit on a different day from all other Week 8 Office visit 
study procedures.   
All 24-hour Sleep Lab visit IOP exams will be performed with an Allergan-specified tonometer. 
Diurnal IOP measurements will be taken supine ≥ 5 minutes at rest then sitting  ≥ 5 minutes at 
rest at 8:00 ± 30 min, 10:00 ± 30 min, 12:00 ± 30 min, 14:00 ± 30 min, 16:00 ± 30 min, 18:00 ± 
30 min, 20:00 ± 30 min, and 22:00 ± 30 min. Nocturnal IOP measurements will be taken supine 
only ≥ 5 minutes at rest 00:00 ± 30 min, 02:00 ± 30 min, 04:00 ± 30min, and 06:00 ± 30 min. 
Lights in individual sleep rooms will be turned off at 23:00 and nocturnal IOP measurements 
will be performed under a dim lighting with monitoring of the participant’s sleep status. At the 
Week 8 Sleep Lab visit, participants assigned to LUMIGAN 0.01% must take their evening dose 
at 20:00 ± 1 hour. Caution must be taken not to unmask the IOP assessor. Please see Procedure 
Manual for details. 
 
 
 
 


 
 
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10.8.7. 
Week 16 and Months 6, 9, and 12/Study Exit Visits 
At all visits, procedures must be performed in 1 day with the exception of anterior segment 
imaging, which may be performed on a different day at applicable visits.  The following 
procedures are performed at Week 16 and Months 6, 9, and 12/Study Exit:   
• Collection of AEs 
• Collection of concomitant medications and procedures 
• Vital signs (at rest ≥ 5 minutes) 
• Pregnancy test for WOCBP (Month 12/Study Exit only) 
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  
o BCVA 
• IOP measurement at Hour 0  
• Anterior segment imaging (perform any time after Hour 0 IOP; select sites/participants 
only; Months 6 and 12/Study Exit only) 
• Non-contact examinations: The following may be performed in any order, at any time 
before gonioscopy: 
o Visual field (If dilation is required to perform this test, then the visual field 
test should be performed after gonioscopy/angle assessment with the 
scheduled dilated exams; Months 6 and 12/Study Exit only) 
o 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; Month 12/Study Exit only) 
o Specular microscopy  
o Biomicroscopy  
• Gonioscopy/angle assessment  
• Pachymetry (may be performed at any time after non-contact exams) 
 
 
 
 


 
 
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• Pupil Dilation  (post dilation examinations below may be performed in any order; 
Month 12/Study Exit only) 
o Dilated ophthalmoscopy 
o Optic disc examination 
IWRS is contacted to register early termination or study completion (Month 12/Study Exit 
only) 
 
 
 
 


 
 
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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. 
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. 
Garg A, Gazzard G. Selective laser trabeculoplasty: past, present, and future. Eye (Lond). 
2018;32(5):863-876. 
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. 
Konstas AG, Quaranta L, Mikropoulos DG, et al. Peak intraocular pressure and glaucomatous 
progression in primary open-angle glaucoma. J Ocul Pharmacol Ther. 2012;28(1):26-32. 
Koucheki B, Hashemi H. Selective laser trabeculoplasty in the treatment of open-angle glaucoma. 
J Glaucoma. 2012;21(1):65-70. 
 
 
 
 


 
 
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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. 
Kramer TR, Noecker RJ. Comparison of the morphologic changes after selective laser 
trabeculoplasty and argon laser trabeculoplasty in human eye bank eyes. Ophthalmology. 
2001;108(4):773-9. 
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. 
Liu JH, Kripke DF, Twa MD, et al. Twenty-four-hour pattern of intraocular pressure in the aging 
population. Invest Ophthalmol Vis Sci. 1999;40(12):2912-7. 
Liu JH, Sit AJ, Weinreb RN. Variation of 24-hour intraocular pressure in healthy individuals: 
right eye versus left eye. Ophthalmology. 2005;112(10):1670-5. 
LUMIGAN 0.01% [package insert]. Irvine, VA: Allergan; 2017. 
Matias I, Chen J, De Petrocellis L, Bisogno T, Ligresti A, Fezza F, et al. Prostaglandin 
ethanolamides (prostamides): in vitro pharmacology and metabolism. J Pharmacol Exp Ther. 
2004;309:745-757. 
Mosaed S, Dustin L, Minckler DS. Comparative outcomes between newer and older surgeries for 
glaucoma. Trans Am Ophthalmol Soc. 2009;107:127-133; discussion 134-135. 
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. 
Skuta GL, Cantor LB, and Weiss JS, eds. Basic and clinical science course. In: Glaucoma 
(Section 10, 2008-2009). San Francisco, California: American Academy of Ophthalmology; 
2008:1-17. 
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. 
 
 
 
 


 
 
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Varma R, Lee PP, Goldberg I, Kotak S. An assessment of the health and economic burdens of 
glaucoma. Am J Ophthalmol. 2011;152:515-522. 
Weber A, Ni J, Ling KH, Acheampong A, Tang-Liu DD, Burk R, et al. Formation of 
prostamides from anandamide in FAAH knockout mice analyzed by HPLC with tandem mass 
spectrometry. J Lipid Res. 2004;45:757-763. 
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. 
 
 
 
 

SAP_001.pdf: 
C O N FI D E N TI A L
Bi mat o pr ost S R
Statistical A nal y sis Pla n v 1. 0 1 6 9 8- 3 0 4- 0 0 7
Pa ge 1 of 3 1
Title P a ge
Pr ot oc ol Title: A n E val uati o n of t he 2 4 -H o ur I OP- l o weri n g Effect of Bi mat o pr ost S R i n 
Partici pa nts wit h O pe n -A n gle Gla uc o ma or Oc ular H y perte nsi o n
Pr ot oc ol N u m ber: 1 6 9 8 - 3 0 4- 0 0 7
Pr o d uct: Bi mat o pr ost S R
S h ort Title: 2 4 -H o ur I O P -l o weri n g Effect of Bi mat o pr ost S R
St u d y P h ase: 3 b
S p o ns or N a me: Aller ga n ( N ort h A merica),
Le g al Re gistere d A d dress: 2 5 2 5 D u p o nt Dri ve , Ir vi ne, Calif or nia, U S A
C o nfi de nti alit y St ate me nt
T his d oc u me nt is t he pr o pert y  of Aller ga n . a n d ma y n ot, i n f ull or part, be passe d o n,
re pr o d uce d, p u blis he d, distri b ute d t o a n y pers o n, or s u b mitte d t o a n y re g ulat or y a ut h orit y
wit h o ut t he e x press writte n per missi o n of Aller ga n .
Date: 3 0 Marc h 2 0 2 1
N C T 0 4 2 8 5 5 8 0


C O N FI D E N TI A L
Bi mat o pr ost S R
Statistical A nal y sis Pla n v 1. 0 1 6 9 8- 3 0 4- 0 0 7
Pa ge 2 of 3 1
Ta ble of C o nte nts
Title P a ge ....................................................................................................................................... 1
T a ble of C o nte nts .......................................................................................................................... 2
List of T a bles ................................................................................................................................. 3
List of Fi g ures ................................................................................................................................ 4
S A P Versi o n Hist or y ..................................................................................................................... 5
1.
I ntr o d ucti o n.................................................................................................................... 6
1. 1.
St u d y  O bjecti ves.............................................................................................................. 6
1. 2.
St u d y  Desi g n.................................................................................................................... 7
1. 2. 1.
I nter ve nti o n Gr o u p a n d St u d y D urati o n .......................................................................... 7
1. 2. 2.
Sc he ma ............................................................................................................................. 8
1. 2. 3.
Sc he d ule of Acti vities ( S o A) ........................................................................................... 9
1. 2. 4.
E n d of St u d y  Defi niti o n................................................................................................. 1 1
2.
St atistic al H y p ot heses .................................................................................................. 1 2
3.
S a m ple Size Deter mi n ati o n ......................................................................................... 1 2
4.
P o p ul ati o ns f or A n al ysis .............................................................................................. 1 2
4. 1.
Safet y  A nalys is Set ( S A F)............................................................................................. 1 2
4. 2.
F ull A nal ys is Set ( F A S)................................................................................................. 1 2
5. 
St atistic al A n al yses ...................................................................................................... 1 3
5. 1.
Ge neral C o nsi derati o ns .................................................................................................. 1 3
5. 1. 1.
Statistical N otati o n a n d Prese ntati o n ............................................................................. 1 3
5. 2.
Partici pa nt Dis p ositi o n ................................................................................................... 1 3
5. 3.
Efficac y  A nalys is........................................................................................................... 1 3
5. 3. 1.
A nal y sis E n d p oi nt(s)...................................................................................................... 1 4
5. 3. 2.
Pri mar y  Efficac y A nalys es ............................................................................................ 1 4
5. 3. 3.
Sec o n dar y  Efficac y  A nal yses ........................................................................................ 1 4
5. 3. 4.
Ot her Efficac y  A nalys es ................................................................................................ 1 5
5. 3. 4. 1.
I O P A nalys is b y B o d y P ositi o ns....................................................................... 1 5
5. 3. 4. 2.
Ti me -t o-E ve nt A nal ys is .................................................................................... 1 5
5. 3. 4. 3.
H o ur 0 I O P A nal ys es ......................................................................................... 1 5
5. 4.
Safet y  A nalys is.............................................................................................................. 1 5
5. 4. 1.
St u d y  D urati o n............................................................................................................... 1 6
5. 4. 2.
A d verse E ve nts ( A Es) .................................................................................................... 1 6
5. 4. 3.
Vital Si g ns ...................................................................................................................... 1 7
5. 4. 4.
Cli nical Safet y  La b orat or y Assess me nt......................................................................... 1 7
5. 4. 5.
Pre g na nc y  Test............................................................................................................... 1 7
5. 4. 6.
A d diti o nal Safet y  Assess me nts...................................................................................... 1 7
5. 4. 6. 1.
Best C orrect Vis ual Ac uit y ............................................................................... 1 7
5. 4. 6. 2.
Vis ual Fiel d ....................................................................................................... 1 8


C O N FI D E N TI A L
Bi mat o pr ost S R
Statistical A nal y sis Pla n v 1. 0 1 6 9 8- 3 0 4- 0 0 7
Pa ge 3 of 3 1
5. 4. 6. 3.
Macr osc o pic C o nj u ncti val H y pere mia .............................................................. 1 9
5. 4. 6. 4.
S pec ular Micr osc o p y......................................................................................... 1 9
5. 4. 6. 5.
Pac h y m etr y ........................................................................................................ 2 0
5. 4. 6. 6.
Bi o mi cr osc o p y a n d Dilate d O p ht hal m osc o p y ................................................... 2 0
5. 4. 6. 6. 1.
O ptic Disc E xa mi nati o n ............................................................................. 2 0
5. 4. 6. 6. 2.
Le ns Stat us a n d O pacificati o n .................................................................... 2 0
5. 4. 6. 7.
G o ni osc o p y  a n d Bi mat o pr ost S R Im pla nt Assess me nt ..................................... 2 1
5. 5.
I nteri m A nalys es ............................................................................................................ 2 1
5. 5. 1.
Data M o nit ori n g C o m mittee .......................................................................................... 2 1
6.
S u p p orti n g D oc u me nt ati o n ......................................................................................... 2 2
6. 1.
A p pe n di x 1: L ist of A b bre viati o ns ................................................................................ 2 2
6. 2.
A p pe n di x 2: S u p p orti n g St u d y  Inf or mati o n .................................................................. 2 4
6. 2. 1.
De m o gra p hics ................................................................................................................ 2 4
6. 2. 2.
Baseli n e a n d Disease C haracteristics ............................................................................. 2 4
6. 2. 3.
Pr ot oc ol De viati o ns ........................................................................................................ 2 4
6. 2. 4.
Me dical Hist or y
............................................................................................................. 2 4
6. 2. 5.
Pri or/ C o nc o mita nt Me dicati o ns..................................................................................... 2 4
6. 3.
A p pe n di x 3: Data Ha n dli n g C o n ve nti o n ....................................................................... 2 5
6. 3. 1.
Visit Ti me p oi nts ............................................................................................................. 2 5
6. 3. 2.
Re peate d or U nsc he d ule d Assess me nts of Safet y Para meters ....................................... 2 7
6. 3. 3.
Missi n g Date of t he Last D ose of St u d y  Inter ve nti o n .................................................... 2 7
6. 3. 4.
Missi n g Se verit y Assess me nt f or A d verse E ve nts ......................................................... 2 7
6. 3. 5.
Missi n g Ca usal Relati o ns hi p t o St u d y  Inter ve nti o n f or A d verse 
E ve nts ............................................................................................................................. 2 8
6. 3. 6.
Missi n g Date I nf or mati o n f or A d verse E ve nts .............................................................. 2 8
6. 3. 7.
Missi n g Date I nf or mati o n f or Pri or or C o nc o mita nt Me dicati o ns ................................. 2 9
6. 3. 7. 1.
I nc o m plete Start Date ........................................................................................ 2 9
6. 3. 7. 2.
I nc o m plete St o p Date ........................................................................................ 2 9
6. 3. 8.
C haracter Val ues of Cli nical La b orat or y  Para meters .................................................... 3 0
6. 4.
A p pe n di x 4: C ha n ges t o Pr ot oc ol -pla n ne d A nal ys es .................................................... 3 1
List of Ta bles
Ta ble 1 - 1
St u d y  O bjecti ves a n d C orres p o n di n g E n d p oi nts................................................. 6
Ta ble 1 - 2
Sc he d ule of Acti vities – Scree ni n g t hr o u g h Wee k 8........................................... 9
Ta ble 1 - 3
Sc he d ule of Acti vities – Wee k 1 6 t hr o u g h M o nt h 1 2/ St u d y  E xit..................... 1 1
Ta ble 6 - 1
Efficac y  Visit Ti me Wi n d o ws/ Safet y Visit Wi n d o w....................................... 2 5
Ta ble 6 - 2
Safet y  Visit Wi n d o ws........................................................................................ 2 6
Ta ble 6 - 3 
I O P Meas ure me nt Ti me Wi n d o ws.................................................................... 2 7


C O N FI D E N TI A L
Bi mat o pr ost S R
Statistical A nal y sis Pla n v 1. 0 1 6 9 8- 3 0 4- 0 0 7
Pa ge 4 of 3 1
Ta ble 6 - 4
I m p uti n g R ule f or Partiall y Missi n g A E Start Dates......................................... 2 8
Ta ble 6 - 5 
I m p uti n g R ule f or Missi n g Pri or or C o nc o mita nt Me dicati o ns Start Date....... 2 9
Ta ble 6 - 6
I m p uti n g R ule f or Missi n g Pri or or C o nc o mita nt Me dicati o ns St o p Date ....... 3 0
List of Fi g ur es
Fi g ure 1 – 1
St u d y  Sc he ma...................................................................................................... 8


C O N FI D E N TI A L
Bi mat o pr ost S R
Statistical A nal y sis Pla n v 1. 0 1 6 9 8- 3 0 4- 0 0 7
Pa ge 5 of 3 1
S A P Versi o n H ist or y
T his Statistical A nal y sis Pla n ( S A P) f or st u d y 1 6 9 8 -3 0 4- 0 0 7 is base d o n t he pr ot oc ol date d 
2 0 D E C 2 0 1 9.
S A P Versi o n Hist or y S u m m ar y
S A P 
Versi o n
A p pr o v al 
D ate
C h a n ge
R ati o n ale
1
Ori gi nal versi o n


C O N FI D E N TI A L
Bi mat o pr ost S R
Statistical A nal y sis Pla n v 1. 0 1 6 9 8- 3 0 4- 0 0 7
Pa ge 6 of 3 1
1.
I ntr o d ucti o n
T his S A P pr o vi des a tec h nical a n d detaile d ela b orati o n of t he statistical a nal y ses of t he efficac y 
a n d safet y data as o utli ne d a n d s pecifie d i n t he st u d y pr ot oc ol 1 6 9 8- 3 0 4-0 0 7 of t he P hase 3 b 
st u d y of t he 2 4- H o ur I O P -l o weri n g effect of Bi mat o pr ost S R i n partici pa nts wit h ope n -an gle 
gla uc o ma ( O A G) or o c ular h y perte nsi o n ( O H T).
1. 1.
St u d y O bjecti ves 
T he p ur p ose of t his st u d y is t o o btai n data o n t he 2 4 -h o ur I O P l o weri n g effect at Wee k 8 of 
Bi mat o pr ost S R treat me nt, wit h safet y  assesse d u ntil M o nt h 1 2. Eac h st u d y o bject i ve is 
prese nte d bel o w wit h ass o ciate d i nf or mati o n.
T a ble 1 - 1
St u d y O bjecti ves a n d C orres p o n di n g E n d p oi nts
O bjecti ves
E n d p oi nts / Me as ures
Effic acy :
Pri mar y

T o e val uate t he 2 4 -h o ur I O P -l o weri n g effect of 
Bi m at o pr ost S R i n partici pa nts wit h O A G or 
O H T 
Sec o n dar y

T o e val uate t he c ha n ge i n di ur nal variati o n of 
I O P i n e yes treate d wit h Bi mat o pr ost S R
Ot her

T o e val uate t he I O P -l o weri n g effect of 
Bi m at o pr ost S R

Ti m e-ma tc he d I O P c ha n ge fr o m Baseli ne Slee p 
La b visit at W ee k 8 Slee p La b visit i n 
Bi m at o pr ost S R -treate d e yes

C ha n ge fr o m baseli ne i n r a n ge of I O P i n e yes 
treate d wit h Bi m at o pr ost S R at Wee k 8 Slee p La b 
visit

H o ur 0 I O P c h a n ge fr o m baseli ne t hr o u g h 
M o nt h
1 2

Ti m e t o i nitial use of n o nst u d y I O P -l o weri n g 
treat me nt
S afety :

T o e val uate t he safet y of Bi mat o pr ost S R i n 
partici pa nts wit h O A G or O H T

A E s, vis ual fiel ds, vis ual ac uit y, macr osc o pic 
b ul bar c o nj u ncti val h y pere mia, slit -la m p 
bi o micr osc o pic assess me nts, dilate d 
o p ht hal m osc o pic assess me nts (i ncl u di n g o ptic 
disc assess me nt), c o ntact ultras o u n d pac h y metr y, 
g o ni osc o p y, s pec ular micr osc o p y


C O N FI D E N TI A L
Bi mat o pr ost S R
Statistical A nal y sis Pla n v 1. 0 1 6 9 8- 3 0 4- 0 0 7
Pa ge 7 of 3 1
1. 2.
St u d y Desi g n
T his st u d y  is a m ultice nter, o pe n -la bel, P hase 3 b st u d y i n partici pa nts wit h O A G or O H T. 
A p pr o xi matel y  3 5 partici pa nts will be e nr olle d: 2 5 t o 3 0 i n t he Bi mat o pr ost S R c o h ort (t o 
ac hie ve a mi ni m u m t otal of 2 0 e val ua ble partici pa nts at baseli ne a n d Wee k 8 t o e val uate t he 
2 4- h o ur I O P -lo weri n g effect of Bi mat o pr ost S R , ass u mi n g a pre mat ure disc o nti n uati o n rate of u p 
t o 3 3%), a n d 5 i n t he L U MI G A N ® 0. 0 1 % ( bi mat o pr ost o p ht hal mic s ol uti o n) c o h ort . Partici pa nts 
w h o pre mat urel y  disc o nti n ue fr o m t he st u d y will n ot be re place d.
1. 2. 1.
I nter ve nti o n Gr ou p a n d St u d y D ur ati o n
Partici pa nts i n t he Bi mat o pr ost S R c o h ort will recei ve a 1 0 µ g i m pla nt i n t he st u d y  e ye o n D a y  1, 
a n d t he fell o w e ye will recei ve sta n dar d of care treat me nt ( pr o vi de d t hat t here is n o k n o w n 
cr oss o ver effect of t he fell o w e y e’s sta n dard of care treat me nt t o t he st u d y  e ye) f or t he d urati o n 
of t he st u d y . At selecte d site(s) a n a d diti o nal c o h ort of partici pa nts will be e nr olle d a n d assi g ne d 
t o recei ve t o pical L U MI G A N 0. 0 1 % i n t he st u dy e ye ( o nce dail y, at 2 0: 0 0 ± 1 h o ur, starti n g wit h 
t he e ve ni n g d ose o n Da y 1), a n d sta n dar d of care treat me nt i n t he fell o w e ye ( pr o vi de d t hat t here 
is n o k n o w n cr oss o ver effect of t he fell o w e ye’s sta n dar d of care treat me nt t o t he st u d y e ye) f or 
t he d urati o n of t he st u dy. Pa rtici pa nts will be assi g ne d t o t he Bi mat o pr ost S R c o h ort or
L U M I G A N 0. 0 1 % c o h ort 
.
T he partici pa nt a n d i n vesti gat or will n ot be mas ke d t o t he st u d y treat me nt assi g n me nt f or t he 
d urati o n of t he st u d y . Site staff c ollecti n g 2 4 -h o ur I O P meas ure me nts at Slee p La b visits will be 
mas ke d t o t he st u d y  treat me nt a n d st u d y e ye.
St u d y E ye Tre at me nt
Fell o w E ye Tre at m e nt
Bi m at o pr ost S R 1 0 µ g or L U MI G A N 0. 0 1 % a
(at selecte d site[s])
Sta n dar d of Care
a
Partici pa nts will be gi n self -a d mi nistrati o n of L U MI G A N 0. 0 1 % i n t he st u d y e ye o nce dail y i n t he e ve ni n g ( 2 0: 0 0 ± 1 h o ur) 
starti n g wit h t he e ve ni n g d ose o n Da y 1, a n d will c o nti n ue self-a d mi nistrati o n dail y t hr o u g h t he d urati o n of t he st u d y.
T he d urati o n of t he st u d y f or eac h partici pa nt is a p pr o xi matel y  1 5 m o nt hs, c o nsisti n g of a 
scree ni n g peri o d of u p t o 6 0 da ys bef ore was h o ut, was h o ut peri o d of u p t o 4 2 da y s bef ore 
Baseli ne, a n d 1 2 m o nt hs of f oll o w- u p.
Partici pa nts w h o c o m plete all re g ularl y  sc he d ule d st u d y visits s h o ul d ha ve 9 st u d y office visits, 
2 slee p la b visits, a n d 1 p h o ne call. T he sc he d ule i ncl u des t he f oll o wi n g:

Scree ni n g ( u p t o 6 0 da y s); Was h o ut Peri o d of u p t o 4 2 da ys; a n d Baseli ne ( Office visit 
a n d Slee p La b visit)

D a y  1; Da y 2 Safety visit

D a y  8 p h o ne call

Wee ks 8
( Office a n d Slee p La b visits) a n d Wee k 1 6; a n d M o nt hs 6 , 9, a n d 1 2/ St u d y E xit 
visit s.


C O N FI D E N TI A L
Bi mat o pr ost S R
Statistical A nal y sis Pla n v 1. 0 1 6 9 8- 3 0 4- 0 0 7
Pa ge 8 of 3 1
1. 2. 2.
Sc he m a
T he st u d y  sc he ma is prese nte d i n Fi g ure 1 – 1 .
Fi g ure 1 – 1
St u d y Sc he m a
 
 
  
 
 
  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 






C O N FI D E N TI A L
Bi mat o pr ost S R
Statistical A nal y sis Pla n v 1. 0 1 6 9 8- 3 0 4- 0 0 7
Pa ge 1 1 of 3 1
T a ble 1- 3
Sc he d ule of Acti vities – Wee k 1 6 t hr o u g h M o nt h 1 2/ St u d y E xit
Visit
Wee k 
1 6
M o nt h 6  
M o nt h 9
M o nt h 1 2/ St u d y 
E xit
Visit Wi n d o ws
± 4 
d a ys
± 1 4 
d a ys
± 1 4 
d a ys
± 1 4 d a ys
A d verse E ve nts
X  
X  
X
X
C o nc o mita nt Me dicati o ns/ Pr oce d ures
X  
X  
X
X
Vital Si g ns (at rest ≥5 mi n utes)
X  
X  
X
X
Pre g na nc y Test
X
Oc ul ar E x a mi n ati o ns i n b ol d s h o ul d be perf or me d i n t he or der s h o w n
Pre -H o ur 0 E x a m s ( perf or m bef ore H o ur 0 I O P):
Macr osc o pic C o nj u ncti val H y pere mia Assess me nt
O U
O U  
O U
O U
Best -C orrecte d Vis ual Ac uit y
O U
O U  
O U
O U
I ntr a oc ul ar Press ure Me as ure me nt H o ur 0
O U
O U  
O U
O U
A nteri or Se g me nt I ma gi n g a ( ma y perf or m a n y ti me after H o ur 0 
I O P)
O U
O U
N o n -c o nt act E x a ms ( ma y perf or m i n a n y or der at a n y ti me bef ore g o ni osc o p y, i ncl u di n g pri or t o H 0 I O P)
Vis ual F iel db
O U
O U
Ma nifest Refracti o n
c
O U
S pec ular Micr osc o p y d
O U
O U  
O U
O U
Bi o micr osc o p y
O U
O U  
O U
O U
G o ni osc o p y/ A n gle Assess me nt 
O U
O U  
O U
O U
Pac h y metr y: ( ma y  be perf or me d a n y ti me after n o n -c o ntact 
e xa ms )
O U
O U  
O U
O U
P u pil Dil ati o n   ( ma y perf or m e xa ms i n a n y or der)
O U
Dilate d O p ht hal m osc o p y  
O U
O ptic Disc E xa mi nati o n
O U
C o ntact I W R S
e
X
H o ur 0 = 0 8: 0 0 ± 1 h o ur assesse d wit h a G ol d ma n n a p pla nati o n t o n o meter
a
At selecte d sites/selecte d partici pa nts o nl y, a nteri or se g me nt i ma gi n g ma y be perf or me d i n b ot h e yes of c o nse nti n g partici pa n ts usi n g
Aller ga n -a p pr o ve d i nstr u me nts.
b
F or a gi ve n part ici pa nt, t he sa me test met h o d ol o g y m ust be use d f or all vis ual fiel ds perf or me d at Scree ni n g, Baseli ne, a n d t hr o u g h o ut t he 
st u d y.
c
Ma nifest refracti o n will be use d t o pr o vi de a c orrecti o n f or best -c orrecte d vis ual ac uit y testi n g. At all st u d y visits, if t here is a 2 -li ne or m ore 
re d ucti o n i n vis ual ac uit y fr o m t he last best-c orrecte d vis ual ac uit y perf or me d, a re peat ma nifest refracti o n i n b ot h e yes a n d best -c orrecte d 
vis ual ac uit y will be perf or me d.
d
F or a gi ve n partici pa nt, t he sa me s pec ular micr osc o pe m o del a n d a nal ysis met h o d ol o g y m ust be use d at Scree ni n g, Baseli ne, a n d t hr o u g h o ut 
t he st u d y.
e
C o ntact I W R S f or st u d y c o m pleti o n or partici pa nt disc o nti n uati o n/ wit h dra wal.
1. 2. 4.
E n d of St u d y Defi niti o n
T he e n d of t he st u d y is defi ne d as t he date of t he last visit of t he last partici pa nt i n t he st u d y or 
last sc he d ule d pr oce d ure s h o w n i n t he S o A f or t he last partici pa nt i n t he st u d y.
A partici pa nt assi g ne d a n d treate d wit h Bi mat o pr ost S R is c o nsi dere d t o ha ve c o m plete d t he 
st u d y if he/s he has c o m plete d all visits of t he st u d y t o M o nt h 1 2. At t he M o nt h 1 2/ St u d y E xit 
v isit, if t he i n vesti gat or deter mi nes t hat a n y safet y c o ncer ns warra nt partici pa nt f oll o w- u p, t he 
partici pa nt ma y  be f oll o we d p ost e xit u ntil safet y c o ncer ns are res ol ve d base d o n t he 
i n vestigat or’s discreti o n. Partici pa nts assi g ne d a n d treate d wit h L U MI G A N 0. 0 1 % m a y  earl y 


C O N FI D E N TI A L
Bi mat o pr ost S R
Statistical A nal y sis Pla n v 1. 0 1 6 9 8- 3 0 4- 0 0 7
Pa ge 1 2 of 3 1
e xit t he st u d y after c o m pleti o n of t he Wee k 8 Slee p L a b visit, if t here are n o safety c o ncer ns i n 
t he o pi ni o n of t he i n vesti gat or. F or t he L U MI G A N c o h ort, a n e xit visit will be perf or me d after 
t he Wee k 8 Slee p La b visit w here all assess me nts sc he d ule d f or t he M o nt h 1 2/ St u d y  E xit visit 
will be perf or me d .
2.
St atistic al H y p ot heses
T here are n o statistical h y p ot heses f or t his st u d y .
3.
S a m ple Size Deter mi n ati o n
T he sa m ple size is base d o n practical c o nsi derati o ns. A p pr o xi matel y  3 5 partici pa nts will be 
e nr olle d: 2 5 t o 3 0 i n t he Bi mat o pr ost S R c o h ort a n d 5 i n t he L U M I G A N 0. 0 1 % c o h ort.
T we nt y -fi ve t o 3 0 partici pa nts will be e nr olle d i n t he Bi mat o pr ost S R c o h ort t o ac hie ve a
mi ni m u m t otal of 2 0 e val ua ble partici pa nts, defi ne d as partici pa nts wit h s ufficie nt data at 
baseli ne a n d Wee k 8 t o e val uate t he 2 4 -h o ur I O P -l o weri n g effect of Bi mat o pr ost S R. T his 
ass u mes a pre mat ure disc o nti n uati o n rate of u p t o 3 3 %. Partici pa nts w h o pre mat urel y 
disc o nti n ue fr o m t he st u d y will n ot be re place d . Pa rtici pa nts will be assi g ne d t o t he Bi mat o pr ost 
S R or L U M I GA N 0. 0 1 % c o h ort 
.
4.
P o p ul ati o ns f or A n al ysis
4. 1.
S afet y A n al ysis S et (S A F )
All partici pa nts w h o ha ve recei ve d st u d y i nter ve nti o n (ie, Bi mat o pr ost S R a d mi nistrati o n or 
L U M I G A N 0. 0 1 % ) will c o ntri b ute t o t he S A F. All safet y data c ollecte d fr o m t hese partici p a nts 
will be i ncl u de d i n t he S A F . 
4. 2.
F ull A n al ysis Set ( F A S )
All partici pa nts w h o ha ve recei ve d st u d y i nter ve nti o n (ie, Bi mat o pr ost S R a d mi nistrati o n or 
L U M I G A N 0. 0 1 % ) wit h at least 1 p ost baseli ne I O P assess me nt (i ncl u di n g a n u nsc he d ule d visit 
assess me nt) o n t he st u d y e ye will c o ntri b ute t o t he F A S. All efficac y  data c ollecte d fr o m t hese 
partici pa nts will be i ncl u de d i n t he F A S wit h t he f oll o wi n g e xce pti o n: 

T o a v oi d c o nf o u n di n g of efficac y  data, I O P meas ure me nts o btai ne d after i nitiati n g t he 
use of n o n -st u d y resc ue I O P-l o weri n g treat me nt (me dicati o n [s] or pr oce d ure [s] or b ot h)
i n a n e ye will be e xcl u de d fr o m F A S. 


C O N FI D E N TI A L
Bi mat o pr ost S R
Statistical A nal y sis Pla n v 1. 0 1 6 9 8- 3 0 4- 0 0 7
Pa ge 1 3 of 3 1
5.
St atistic al A n al yses
5. 1.
Ge ner al C o nsi der ati o ns
T w o data base l oc ks are pla n ne d f or t his st u d y . T he first data base l oc k (referre d t o as pri mar y 
D B L) , f or t he pri mar y a n d sec o n dar y efficac y e n d p oi nt a nal ysis, will occ ur w he n 1 0 0 % of 
partici pa nts ha ve c o m plete d t he pri mar y visit (ie, Wee k 8 Slee p La b visit) or pre mat urel y 
disc o nti n ue d pri or t o t he Wee k 8 Slee p La b visit. S i milarl y, t he sec o n d data base l oc k (referre d t o 
as fi nal D B L) f or t he f ull st u d y data base will occ ur after all partici pa nts ha ve c o m plete d t he 
st u d y at M o nt h 1 2 or pre mat urel y disc o nti n ue d fr o m t he st u d y. A nalys es will be perf or me d after 
eac h l oc k a n d t his S A P will c o ver b ot h pri mar y  a n d fi nal a nalys is.
5. 1. 1.
St atistic al N ot ati o n a n d Prese nt ati o n
C o nti n u o us varia bles will be s u m marize d b y  c oh ort (Bi mat o pr ost S R or L U MI G A N 0. 0 1 % ) f or
n u m ber of partici pa nts , mea n, sta n dar d de viati o n ( S D), me dia n, first q uartile, t hir d q uartile, 
mi ni m u m, a n d ma xi m u m val ues. Cate g orical varia bles will be s u m marize d b y  fre q ue nc y c o u nts
a n d perce nta ge of partici pa nts wit hi n eac h treat me nt c o h ort.
All statistical a nal yses will be perf or me d usi n g Statistical A nal y sis S oft ware ( S A S ®) 
versi o n 9. 4.
5. 2.
P artici p a nt Dis p ositi o n
N u m ber of partici pa nts scree ne d f or t he st u d y  will be pr o vi de d. C o u nts of t he partici pa nts i n t he 
t w o a nalys is p o p ulati o ns will be s u m marize d b y treat me nt c o h orts. T he n u m ber a n d perce nta ges 
of partici pa nts w h o c o m plete d or disc o nti n ue d fr o m t he st u d y i n t he e C R F o pe n la bel f or m, as 
well as t he disc o nti n uati o n reas o ns, will be s u m marize d b y  treat me nt co h orts. 
5. 3.
Effic ac y A n al ysis
T he efficac y a nal ys es will be base d o n t he F A S p o p ulati o n . Data ha n dli n g c o n ve nti o ns are 
descri be d i n Secti o n 6. 3 A p pe n di x 3.
Ti me -matc he d I O P will be c ollecte d at 1 2 ti me p oi nts acr oss t he 2 4-h o ur peri o d ( 0 8: 0 0, 1 0: 0 0, 
1 2: 0 0, 1 4: 0 0, 1 6: 0 0, 1 8: 0 0, 2 0: 0 0, 2 2: 0 0, 0 0: 0 0, 0 2: 0 0, 0 4: 0 0 a n d 0 6: 0 0 ). T he di ur nal I O P will 
be c ollecte d bet wee n 0 8: 0 0 t o 2 2: 0 0 a n d t he n oct ur nal I O P will be c ollecte d bet w ee n 0 0: 0 0 a n d 
0 6: 0 0. T he di ur nal I O P will be perf or me d i n s u pi ne a n d sitti n g p ositi o ns w hile t he n oct ur nal I O P 
will be perf or me d o nl y i n a s u pi ne p ositi o n. T he pri mar y  a n d sec o n dar y efficac y a nalys is will be 
perf or me d base d o n t he ha bit ual I O P (t he di ur nal I O P i n a sitti n g p ositi o n a n d t he n oct ur nal I O P 
i n a s u pi ne p ositi o n). 
H o ur 0 I O P e xa mi nati o ns will be sc he d ule d at 0 8: 0 0 ± 1 h o ur a n d all H o ur 0 I O P e xa mi nati o ns 
will be perf or me d wit h t he partici pa nts i n a sitti n g p ositi o n. 


C O N FI D E N TI A L
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Statistical A nal y sis Pla n v 1. 0 1 6 9 8- 3 0 4- 0 0 7
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5. 3. 1.
A n al ysis E n d p oi nt(s)

T he pri mar y  efficac y e n d p oi nt is t he ti me-matc he d I O P c ha n ge fr o m baseli ne at t he 
Wee k 8 Slee p La b visit fr o m t he 2 4- h o ur I O P data c ollecte d at t he Baseli ne Slee p La b 
visit i n t he st u d y e ye f or t he Bi mat o pr ost S R c o h ort.

T he sec o n dar y  efficac y e n d p oi nt is t he cha n ge fr o m baseli ne i n ra n ge of I O P i n e y es 
treate d wit h Bi mat o pr ost S R at Wee k 8 Slee p La b visit.

Ot her efficac y  e n d p oi nts i ncl u de:
o
Ti me -matc he d I O P c ha n ge fr o m baseli ne i n a s u pi ne p ositi o n.
o
H o ur 0 I O P c ha n ge fr o m baseli ne t hr o u g h M o nt h 1 2.
o
Ti me t o i nitial use of n o nst u d y IO P -l o weri n g treat me nt.
Refer t o Secti o n 6. 3 A p pe n di x 3 f or details o n IO P meas ure me nt c o n ve nti o ns a n d c orres p o n di n g 
ti me wi n d o ws.
5. 3. 2.
Pri m ar y E ffic ac y A n al yses
T he ha bit ual I O P val ues at vari o us h o urs of t he Baseli ne Slee p La b visit will be c o nsi dere d as t he 
ti me-matc he d baseli ne val ues f or t he c orres p o n di n g ti me p oi nts of Wee k 8 Slee p La b visit. F or 
e xa m ple, t he ha bit ual I O P ti me -matc he d c ha n ge f r o m baseli ne at ti me p oi nt 0 6: 0 0 of Wee k 8 
Slee p La b visit will be calc ulate d as: ha bit ual I O P at ti me p oi nt 0 6 : 0 0 of Wee k 8 Slee p La b visit –
ha bit ual I O P at ti me p oi nt 0 6 : 0 0 of Baseli ne Slee p La b visit. 
T he ha bit ual I O P ra w val ues a n d t he c orres p o n di n g ti me-matc he d c ha n ge fr o m baseli ne i n 
ha bit ual I O P will be s u m marize d descri pti vely b y visit a n d b y  ti me p oi nt f or t he st u d y e ye i n t he 
Bi mat o pr ost S R a n d Lu mi ga n 0. 0 1 % c o h orts as well as f or t he fell o w e ye i n t he p o ole d treat me nt 
c o h orts . Ni net y- fi ve perce nt CIs base d o n a paire d t-test statistic will be pr o vi de d f or t he mea n 
ti me-matc he d ha bit ual I O P c ha n ge fr o m baseli ne at 1 2 ti me p oi nts acr oss t he 2 4 -h o ur peri o d f or 
t he st u d y e ye i n t he Bi mat o pr ost S R c o h ort. 
T he mea n ha bit ual I O P a n d the mea n ti me-matc he d ha bit ual I O P c ha n ge fr o m baseli ne acr oss t he 
2 4- h o ur peri o d will be prese nte d gra p hicall y wit h t he ti me p oi nt of I O P meas ure me nts o n t he x -
a xis f or t he st u d y e ye i n t he Bi mat o pr ost S R c o h ort. T he di ur nal/ wa ke peri o d a n d n oct ur nal/slee p 
peri o d wit hi n t he 2 4 - h o ur meas ure me nt peri o d will be clearly mar ke d i n t he fi g ure.
5. 3. 3. 
Sec o n d ar y Effic ac y A n al yses
T he ha bit ual I O P fl uct uati o n will be e val uate d by t he ra n ge of ha bit ual I O P val ues f or eac h 
partici pa nt c ollecte d fr o m t he Slee p La b visit d uri n g di ur nal/ wa ke peri o d a n d n oct ur nal/slee p 
peri o d, as well as o ver a 2 4 -h o ur peri o d i n t he Bi mat o pr ost S R a n d Lu mi ga n 0. 0 1 % c o h orts .
Descri pti ve s u m mar y  statistics o n t he a nal ysis varia ble (ra n ge of I O P) at baseli ne a n d Wee k 8, as 
well as its c orres p o n di n g c ha n ges fr o m baseli ne at Wee k 8, will be prese nte d b y  treat me nt 
c o h orts f or t he st u d y e ye  a n d t he p o ole d treat me nt c o h orts f or t he fell o w e ye. T he sa me a nalys is 
will be perf or me d f or t he I O P i n a s u pi ne p ositi o n. 


C O N FI D E N TI A L
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Statistical A nal y sis Pla n v 1. 0 1 6 9 8- 3 0 4- 0 0 7
Pa ge 1 5 of 3 1
5. 3. 4.
Ot her Effic ac y A n al yses
Ot her efficac y  a nalys es will i ncl u de I O P a nal ys is b y b o d y p ositi o ns, ti me-t o-e ve nt of t he i nitial 
use of n o nst u d y  IO P -l o weri n g treat me nt a n d H o ur 0 I O P a nalys is i n a sitti n g p ositi o n. 
5. 3. 4. 1.
I O P A n al ysis b y B o d y P ositi o ns
T he sa me a nal ys is of t he ha bit ual I O P a nalys is will be perf or me d f or t he I OP i n a s u pi ne p ositi o n 
f or t he st u dy e ye i n Bi mat o pr ost S R a n d L u mi ga n 0. 0 1 % c o h orts as well as f or t he fell o w e y e i n 
t he p o ole d treat me nt c o h orts. F or t he di ur nal I O P, t he mea n differe nce of ti me-matc he d I O P 
bet wee n sitti n g a n d s u pi ne p ositi o ns will be s u m marize d. 
F or I O P i n a s u pi ne p ositi o n, t he mea n I O P a n d t he mea n ti me-matc he d I OP c ha n ge fr o m 
baseli ne acr oss t he 2 4 -h o ur peri o d will be prese nte d gra p hicall y. 
5. 3. 4. 2.
Ti me -t o-E ve nt A n al ysis
T i me t o t he e ve nt of t he i nitial use of n o nst u d y resc ue I O P l o weri n g treat me nt ( me dicati o n 
a n d/or pr oce d ure) i n t he st u d y  e ye fr o m t he date of Bi m at o pr ost S R treat me nt will be esti mate d 
usi n g Ka pla n -Meier ( K M) met h o d wit h gra p hical dis pla y .
Ti me t o i nitial use of n o nst u d y resc ue I O P l o weri n g treat me nt = ( Date of i nitial use of n o n -st u d y 
I O P-l o weri n g treat me nt – Date of t he Bi mat o pr ost treat me nt) + 1. 
I n t he calc ulati o n of ti me t o i nitial use of n o nst u d y resc ue I O P l o weri n g treat me nt, if a 
partici pa n t di d n ot use a n y n o nst u d y resc ue I O P l o weri n g treat me nt i n t he st u d y e ye, t he n t he 
e ve nt (i nitial use of n o nst u d y  resc ue I O P l o weri n g treat me nt) ti me will be ce ns ore d at t he st u dy 
e xit date or t he last visit date if t he st u d y e xit date is n ot a vaila ble.
5. 3. 4. 3.  
H o ur 0 I O P A n al yses
T he descri pti ve s u m mar y f or H o ur 0 I O P val ues i n a sitti n g p ositi o n at baseli ne wit h 
c orres p o n di n g c ha n ge fr o m baseli ne b y  visit t hr o u g h M o nt h 1 2/ St u d y E xit will be perf or me d b y  
treat me nt c o h orts f or t he st u d y e ye i n Bi mat o pr ost S R a n d Lu mi ga n 0. 0 1 % c o h orts a n d p o ole d 
treat me nt c o h orts f or t he fell o w e ye. T he mea n of t he H o ur 0 I O P a n d t he H o ur 0 I O P c ha n ge 
fr o m baseli ne f or eac h visit will be prese nte d gra p hicall y f or t he st u d y e ye i n t he Bi mat o pr ost S R 
c o h ort.
5. 4.
S afet y A n al ysis
Descri pti v e statistics will be use d t o s u m marize t he safet y data b y c o h orts base d o n t he S A F . T he 
safety para meters will i ncl u de t he f oll o wi n g n o n -oc ular safet y para meters: n o n -oc ular A Es a n d
vital si g ns; o c ular safet y para meters : vis ual fiel d e xa mi nati o n, vis ual ac uit y, macr osc o pic 
c o nj u ncti val h ypere mia assess me nt , bi o micr osc o p y, dilate d o p ht hal m osc o p y (i ncl u di n g o ptic 
disc assess me nt), pac h y metr y, g o ni osc o p y (i ncl u di n g a n gle assess me nt) , a n d s pec ular 
micr osc o p y. Res ults fr o m oc ular safet y assess me nts will be s u mmarize d b y partici pa nts a n d 
liste d, i ncl u di n g sc he d ule d a n d u nsc he d ule d assess me nts (if a ny). T he res ults will be prese nte d 
b y  treat me nt c o h orts f or t he st u d y e ye a n d p o ole d treat me nt c o h orts f or t he fell o w e y e. U nless 


C O N FI D E N TI A L
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Statistical A nal y sis Pla n v 1. 0 1 6 9 8- 3 0 4- 0 0 7
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ot her wise state d, t he la st n o n missi n g safety assess me nt bef ore t he first d ose of st u d y treat me nt 
will be use d as t he baseli ne f or all a n al y ses of t hat safety para meter.
5. 4. 1.
St u d y D ur ati o n
T he st u d y  treat me nt d urati o n will be calc ulate d as t he n u m ber of da ys bet wee n t he st u d y e xit 
date a n d Da y  1 treat me nt a d mi nistrati o n da y, i ncl usi vel y ( date of st u d y e xit or last visit a vaila ble 
– D a y  1 + 1). 
5. 4. 2.
A d verse E ve nts ( A Es)
A d verse E ve nts will be c o de d usi n g t he Me d D R A. 
A n A E is a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a cli nicall y si g nifica nt a b n or m al 
la b orat or y fi n di n g), sy m pt o m, or disease ( ne w or e xacer bate d) te m p orall y ass ociate d wit h t he use 
of st u d y  treat me nt, w het her or n ot c o nsi dere d relate d t o t he st u d y treat me nt. A n A E will be 
c o nsi dere d a treat me nt e mer ge nt a d verse e ve nt ( T E A E) if t he A E b e ga n or w orse ne d (i ncrease d 
i n se verit y or beca me seri o us) o n or after t he date (a n d ti me, if k n o w n) of t he first a d mi nistrati o n 
of st u d y  treat me nt. A n A E will be c o nsi dere d a treat me nt-e mer ge nt seri o us a d verse e ve nt 
( T E S A E) if it is a T E A E t hat a d diti o nall y meets a n y S A E criteri o n. 
A d verse e ve nts will be classifie d i nt o oc ular A Es a n d n o n - oc ular A Es. A n oc ular A E will be 
deter mi ne d b y t he l ocati o n i nf or mati o n o n t he a d verse e ve nt pa ge i n e C R F a n d t h us are n ot 
li mite d t o A Es wit h pri mar y S O Cs of e yes. A d diti o nall y , q uesti o ns a b o ut a d verse e ve nt 
relati o ns hi ps t o st u d y treat me nt a n d st u d y a d mi nistrati o n pr oce d ure will be as ke d i n e C R F, a n d 
t he a ns wers t o t hese q uesti o ns will be use d t o get her t o deri ve t he treat me nt relate d T E A E. 
Oc ular A Es will be ta b ul ate d b y treat me nt c o h orts f or t he st u dy e ye a n d p o ole d treat me nt c o h orts 
f or t he fell o w e ye, a n d n o n -oc ular A Es will be s u m marize d b y  treat me nt c o h orts f or partici pa nts.
O verall s u m maries of a d verse e ve nts will be pr o vi de d o n a per -partici pa nt basis b y  treat me nt 
c o h orts f or cate g ories i ncl u di n g t he f oll o wi n g: 

All T E A Es

Treat me nt -relate d T E A Es
o
Relate d t o st u d y  dr u g
o
Relate d t o st u d y  dr u g a d mi nistrati o n pr oce d ure

All seri o us T E A Es

Treat me nt -relate d seri o us T E A Es
o
Relate d t o st u d y  dr u g
o
Relate d t o st u d y  dr u g a d mi nistrati o n pr oce d ure

A n y  T E A E lea di n g t o Bi mat o pr ost S R i m pla nt re m o val

A n y  T E A E lea di n g t o st u d y disc o nti n uati o n

Deat hs


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A n y  n o n-oc ular T E A Es will be s u m marize d b y  t he pri mar y S O C, P T, a n d se verity i ncl u di n g 
seri o us T E A Es b y t he pri mar y S O C a n d P T, treat me nt relate d b y S O C a n d P T a n d t h ose lea di n g 
t o st u d y disc o nti n uati o n b y t he pri mar y S O C a n d P T.
F or i nci de nces of treat me nt e mer ge nt oc ular a d verse e ve nts, s u m maries will be pr o vi de d f or t he 
f oll o wi n g cate g ories:

A n y  oc ular T E A Es b y S O C, P T, a n d se verit y

A n y  treat me nt relate d oc ular T E A Es b y S O C a n d P T

A n y  seri o us oc ular T E A Es b y S O C a n d P T

A n y  oc ular T E A Es lea di n g t o st u d y disc o nti n uati o n b y S O C a n d P T

A n y  oc ular T E A Es res ulti n g i n Bi mat o pr ost S R i m pla nt re m o val b y  P T

A n y  c or neal T E A Es of i nterest b y P T ( Relate d A Es of i nterest will be i de ntifie d 
se paratel y pri or t o data base l oc k.)

A n y  a nteri or se g me nt i nfla m mati o n T E A Es of i nterest b y S O C a n d P T ( Relate d A Es of 
i nterest will be i de ntifie d se paratel y pri or t o data base loc k.)
5. 4. 3.
Vit al Si g ns
V ital si g ns (sys t olic a n d diast olic bl o o d press ure, p ulse rate, a n d te m perat ure) will be c ollecte d, 
b ut n ot a nal y ze d. 
5. 4. 4.
Cli nic al S afet y L a b or at or y Assess me nt
La b orat or y  assess me nts ( bl o o d a n d uri ne sa m ples) will be c ollecte d at t he Scree ni n g v isit, b ut 
will n ot be a nal y ze d. 
5. 4. 5.
Pre g n a nc y Test
Pre g na nc y  test will be perf or me d b ut will n ot be a nal yze d.
5. 4. 6.
A d diti o n al S afet y Assess me nts
5. 4. 6. 1.
Best C orrect Vis u al Ac uit y
Vis ual ac uit y  tests will be perf or me d at all visits e xce pt o n Da y 1 a n d at t he Slee p La b visits. 
Best c orrecte d vis ual ac uit y  ( B C V A) is rec or de d i n S nelle n e q ui vale nt u nits o n e C R F as 2 0/ 8, 
2 0/ 1 0, 2 0/ 1 2. 5, 2 0/ 1 6 ... or 2 0/ 8 0 0. A n i ncrease i n t he sec o n d n u m ber ( de n o mi nat or) i n S nelle n 
e q ui val e nt u nit i n dicates w orse ni n g of vis ual ac uit y  (V A ) a n d a decrease i n dicates a n 
i m pr o ve me nt. F or e xa m ple, c ha n ge fr o m 2 0/ 3 2 t o 2 0/ 4 0 is a w orse ni n g of V A b y o ne li ne, 2 0/ 3 2 
t o 2 0/ 2 0 ( n ote t hat 2 0/ 2 5 is i n bet wee n) is a n i m pr o ve me nt b y 2 li nes.
T he li ne c ha n ge fr o m baseli ne at eac h p ost -baseli ne e val uati o n ca n be calc ulate d usi n g t he 
f or m ula:


C O N FI D E N TI A L
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Pa ge 1 8 of 3 1
    ℎ    = 1 0 × [           ]
w here d B L = de n o mi nat or of t he S nelle n e q ui vale nt u nit at baseli ne,
d P B L = de n o mi n at or of t he S nelle n e q ui vale nt u nit at p ost -baseli ne .
T he l o garit h mic val ue i n t he f or m ula a b o ve nee ds t o be r o u n de d t o t he nearest te nt h bef ore
pr ocee di n g t o t he calc ulati o n of t he li ne c ha n ge. A p ositi ve val ue i n dicates a n i m pr o ve me nt, a 
ne gati ve val ue i n dicates a w orse ni n g, a n d a zer o i n dicates n o c ha n ge. F or e xa m ple, t he li ne 
c ha n ge f or a S nelle n e q ui vale nt u nit at baseli ne of 2 0/ 2 5 f oll o we d b y  a S nelle n e q ui vale nt u nit of 
2 0/ 8 0 at a p ost -baseli ne visit w o ul d be:
    ℎ    = 1 0 ×       2 5
8 0  = 1 0 × (−0. 5 ) =
−5
re prese nti n g a w orse ni n g of 5 li nes i n V A. N ote t hat t here are 4 S nelle n e q ui vale nt u nits ( 2 0/ 3 2, 
2 0/ 4 0, 2 0/ 5 0 a n d 2 0/ 6 3) bet wee n 2 0/ 2 5 a n d 2 0/ 8 0, t h us m o vi n g fr o m 2 0/ 2 5 t o 2 0/ 8 0 is a 
w orse ni n g b y 5 li nes i n V A beca use t he de n o mi nat or has i ncreas e d.
T he greatest li ne c ha n ge i n B C V A fr o m baseli ne will be s u m marize d wit h res pect t o n u m ber of 
li ne cha n ge cate g ories . Cate g ories will be s u m marize d as c ha n ge < -2, - 2 ≤c ha n ge ≤ 2 , a n d 
c ha n ge > 2 . T he n u m ber a n d perce nta ge of partici pa nt i n eac h cate g or y  will be prese nte d by 
treat me nt c o h orts. 
5. 4. 6. 2.
Vis u al Fiel d
Vis ual fiel d e xa mi nati o ns will be assesse d b y a ut o mate d peri metr y ( usi n g eit her H u m p hre y 2 4- 2 
f ull t hres h ol d pr o gra m or 2 4-2 SI T A Sta n dar d, or Oct o p us G 1 or 2 4 -2 a n d d y na mic or n or mal 
strate g y) at Scree ni n g, Baseli ne, M o nt h 6 , a n d M o nt h 1 2 / E xit. T he sa me test met h o d ol o g y 
s h o ul d be use d t hr o u g h o ut t he e ntire st u d y  f or a gi ve n partici pa nt . Vis ual fiel d o verall res ults will 
be rec or de d o n t he e C R F as n or mal or a b n or mal. A b n or mal fi n di n gs i ncl u de e nlar ge me nt of 
bli n d s p ot, s u peri or arc uate sc ot o ma, i nteri or arc uate sc ot o ma, parace ntral sc ot o ma, nasal ste p, 
ce ntral sc ot o ma, ge neralize d de pressi o n, a n d te m p oral sc ot o ma a n d ot her. A n e y e ma y e x hi bit 
m ult i ple a b n or malities. A n y  p ost-baseli ne a b n or mal fi n di n gs o n vis ual fiel d will be s u m marize d 
b y  e ye a n d b y visit re gar dless of t he mac hi ne ty pe usi n g n u m ber a n d perce nta ge f or mat t o 
calc ulate i nci de nces. 
I n a d diti o n, mea n de viati o n or mea n defect ( M D) a n d cha n ge fr o m baseli ne will als o be rec or de d 
i n deci bels ( d B), a n d will be a nalyz e d b y visit b y  mac hi ne ty pe ( H u m p hre y a n d Oct o p us 
res pecti vely). If t he mac hi ne t ype is differe nt bet wee n baseli ne a n d p ost baseli ne visit, n o c ha n ge 
fr o m baseli ne will be deri ved . If mac hi ne t y pe is missi n g at p ost-baseli ne, b ut a vaila ble at 
baseli ne, t he n it will be ass u me d usi n g sa me mac hi ne t y pe. F or partici pa nts w h ose vis ual fiel d 
were assesse d b y o ne mac hi ne t y pe as rec or de d, t he mea n de viati o n or mea n defect assess me nt 
wit h missi n g mac hi ne t y pe will be i m p ute d as assess me nts b y  t he c orres p o n di n g u ni q ue mac hi ne 
t ype. 


C O N FI D E N TI A L
Bi mat o pr ost S R
Statistical A nal y sis Pla n v 1. 0 1 6 9 8- 3 0 4- 0 0 7
Pa ge 1 9 of 3 1
5. 4. 6. 3.  
M acr osc o pic C o nj u ncti v al H y pere mi a
Macr osc o pic c o nj u ncti val h y pere mia assess me nt will be perf or me d at all sc he d ule d visits e xce pt 
o n t he a d mi nistrati o n da y. C o nj u ncti val h y pere mia se verity is assesse d as 0 ( N o ne), + 0. 5 ( Trace), 
+ 1 ( Mil d), + 2 ( M o derate), + 3 ( Se vere) or ‘ N ot E val ua ble .’ These data will be s u m marize d 
o verall b y  treat me nt c o h ort a n d ass ociate d e ye usi n g t he w orst se verity of h y pere mia o bser ve d.
I n a d diti o n, w orst se verit y gra de i ncreases greater t ha n 1 ( w orse ni n g ie, a c ha n ge fr o m 0 t o 2 a n d 
a b o ve, fr o m 0. 5 t o 2 a n d a b o ve, or fr o m 1 t o 3 a n d a b o ve) i n h ypere mia fr o m baseli ne will als o 
be s u m marize d o verall a n d b y  treat me nt c o h ort. If t he w orst se verit y gra de d uri n g a peri o d is less 
se vere c o m pare d t o baseli ne, it will be c o nsi dere d as ‘ n o i ncrease.’
5. 4. 6. 4.
S pec ul ar Micr osc o p y
Ce ntral e n d ot helial cell de nsit y (C E C D) mea n (cells/ m m2) will be assesse d usi n g s pec ular
micr osc o p y perf or me d o n t he ce ntral c or nea at Scree ni n g, Baseli ne , Wee k 1 6, M o nt h 6, M o nt h 9 
a n d M o nt h 1 2 / E xit. At eac h e xa mi nati o n, 3 meas ure me nts of C E C D will be re p orte d, a n d t he 
a vera ge of t he 3 meas ure me nts will be calc ulate d a n d use d f or a nal ys is. C E C D at baseli ne a n d
ra w val ues a n d t heir c ha n ges fr o m baseli ne will be s u m marize d descri pti vel y b y  visit a n d f or last 
visit b y  treat me nt c o h orts.
N ote t hat t he sa me m o del of t he s pec ular micr osc o p y  mac hi ne m ust be use d f or all patie nt visits. 
If a differe nt m o del is use d at p ost-baseli ne visit, t he data will be e xcl u de d fr o m t he a nal ys is.
T he n u m ber a n d perce nta ge of partici pa nts will be ta b ulate d b y  l oss cate g ories f or eac h visit, 
i ncl u di n g t he last visit (ie, last assess me nt), a n d d uri n g t he e ntire st u dy, e g, 1 5 % l oss ( perce nt 
c ha n ge fr o m baseli ne ≤- 1 5 %). T he last visit of a partici pa nt f or fi nal a nal ysis is defi ne d as t he 
assess me nt at e xit visit (ie, t he last assess me nt d uri n g t he st u d y). 
B y  visit ta b ulati o n will be base d o n t he a nalys is val ue. A partici pa nt will be c o u nte d i n a l oss 
cate g or y f or t he e ntire st u d y if a ny assess me nt d uri n g t he st u d y meeti n g t he criteria. T he l oss 
cate g ories are liste d b ut n ot li mite d t o t he bel o w:

Perce nt c ha n ge fr o m baseli ne > - 1 0 % 

Perce nt c ha n ge fr o m baseli ne ≤- 1 0 % 

Perce nt c ha n ge fr o m baseli ne ≤- 1 5 % 

Perce nt c ha n ge fr o m baseli ne ≤ -2 0 % 

Perce nt c ha n ge fr o m baseli ne ≤- 3 0 % 

Perce nt c ha n ge fr o m baseli ne ≤- 4 0 % 

Perce nt c ha n ge fr o m baseli ne ≤- 5 0 % 
A listi n g of pa tie nts wit h ≥2 0 % C E C D l oss will be pr o vi de d.


C O N FI D E N TI A L
Bi mat o pr ost S R
Statistical A nal y sis Pla n v 1. 0 1 6 9 8- 3 0 4- 0 0 7
Pa ge 2 0 of 3 1
5. 4. 6. 5.
P a c h y metr y
C or neal t hic k ness usi n g c o ntact pac h y m etr y will be perf or me d o n t he ce ntral c or nea at 
Scree ni n g, Baseli ne , Wee k 1 6, M o nt h 6, M o nt h 9 a n d M o nt h 1 2/ E xit visits. At eac h 
e xa mi nati o n, 3 meas ure me nts of ce ntral c or neal t hic k ness ( C C T) a n d ass ociate d sta n dar d 
de viati o n will be re p orte d, a n d t he a vera ge of t he 3 meas ure me nts will be calc ulate d a n d use d f or 
a nal ys is. C C T ra w val ues a n d t heir c ha nges fr o m baseli ne at eac h p ost - baseli ne visit will be 
s u m marized descri pti vel y b y visit a n d b y treat me nt c o h orts .
5. 4. 6. 6.
Bi o micr osc o p y a n d Dil ate d O p ht h al m osc o p y
Bi o micr osc o pic e xa mi nati o ns will be perf or me d f or eac h e ye at baseli ne a n d p ost -baseli ne visits. 
All fi n di n gs will be c o de d usi n g Me d D R A dicti o nar y . 
N u m ber a n d per ce nta ge of partici pa nts wit h fi n di n gs s h o wi n g m ore t ha n o ne gra de i ncrease i n 
se verity fr o m baseli ne or a p ositi ve stat us c ha n ge, at 1 or m ore p ost -baseli ne visits, will be 
prese nte d b y c o de d P T i n desce n di n g or der of i nci de nce rate. F or fi n di n gs t hat are ass ociate d 
wit h a se verit y gra de, m ore t ha n 1 se verit y  gra de i ncrease i n se verit y fr o m baseli ne is defi ne d as  
a c ha n ge fr o m n o fi n di n g t o 2 a n d a b o ve, fr o m 0. 5 t o 2 a n d a b o ve, or fr o m 1 t o 3 a n d a b o ve fr o m 
baseli ne at a n y of t he f oll o w - u p visits. N u m ber an d perce nta ge of partici pa nts wit h fi n di n gs t hat 
n ot ass ociate d wit h a se verit y  gra de, a p ositi ve stat us c ha n ge is defi ne d as a fi n di n g prese nt at 
p ost - baseli ne w hic h di d n ot prese nt at baseli ne will be s u m marize d.  
C ha n ge fr o m baseli ne i n se verit y gra de f or gra da ble fi n di n gs a n d stat us c ha n ge fr o m baseli ne f or 
n o n- gra da ble fi n di n gs will be deri ve d at eac h p ost -baseli ne visits. T he met h o d t o c o m pare wit h 
baseli ne will be b y e ye, e ye area, fi n di n g a n d Me d D R A P T. W he n c o n d ucti n g c o m paris o n fr o m 
baseli ne, “ Ot her” is c o nsi der as a s pecific fi n di n g itself t hat is differe nt fr o m fi n di n gs u n der a n y  
pre -defi ne d ter ms. If t he sa me P T a p pears u n der a pre -defi ne d fi n di n g a n d “ Ot her” wit hi n t he 
sa me e ye a n d e ye area, t he y will be c o m pare d wit h baseli ne se parately. 
Dil ate d o p ht hal m osc o p y i ncl u di n g vitre o us, mac ula, reti na peri p her y, le ns stat us a n d 
o pacificati o n a n d o ptic ner ve will be perf or me d at Scree ni n g, Baseli ne a n d M o nt h 1 2/ E xit visits. 
N o se verit y gra de will be assi g ne d f or vitre o us, reti na peri p her y a n d mac ula fi n di n gs, a n d 
s u m marize d t o get her wit h bi o micr osc o p y fi n di n gs as n o n- gra da ble fi n di n gs.
5. 4. 6. 6. 1.
O ptic Disc E x a mi n ati o n 
O ptic Ner ve c u p/ disc rati o will be e val uate d usi n g a 0. 0 t o 1. 0 scale, wit h lar ger val ues i n dicati n g 
gla uc o ma or ot her pat h ol o gies, t h us a re d ucti o n fr o m baseli ne is c o nsi dere d a n i m pr o ve me nt. 
Cate g orical c ha n ges i n c u p/ disc rati o fr o m baseli ne will be s u m marize d f or p ost -Baseli ne visit. 
C ha n ge fr o m baseli ne at t he f oll o w-u p visit ( visit val ue – baseli ne val ues) will be cate g orize d as 
a n i m pr o ve me nt of 0. 2 or m ore ( ≤ -0. 2), n o c ha n ge -bet wee n 0. 2 a n d -0. 2 ( > -0. 2 t o < 0. 2), or a 
w orse ni n g if t he rati o i ncreases b y 0. 2 or m ore (ie, c ha n ge ≥ 0 . 2). T he n u m ber a n d perce nta ge of 
partici pa nts i n eac h cate g or y will be pr o vi de d f or treat me nt c o h orts.
5. 4. 6. 6. 2.
Le ns St at us a n d O p acific ati o n 
At f oll o w - u p visits, t he le ns o pacity will be assesse d o nl y f or e yes e val uate d as p ha kic at 
baseli ne. T he prese nce a n d se verit y of n uclear, c ortical, a n d p osteri or s u bca ps ular cataract le ns 


C O N FI D E N TI A L
Bi mat o pr ost S R
Statistical A nal y sis Pla n v 1. 0 1 6 9 8- 3 0 4- 0 0 7
Pa ge 2 1 of 3 1
o pacities usi n g a 3 - p oi nt scale ( < sta n dar d p h ot o # 2, a n d ≥ sta n dar d p h ot o # 2) will be 
s u m marize d b y treat me nt c o h orts a n d b y visit.
5. 4. 6. 7.
G o ni osc o p y a n d Bi m at o pr ost S R I m pl a nt Assess me nt
G o ni o sc o p y will be perf or me d t o assess t he i nferi or iri d oc or neal (a nteri or c ha m ber) a n gle. 
Partici pa nts prese nti n g wit h peri p heral a nteri or s y nec hiae o n g o ni osc o p y at a n y ti me d uri n g t he 
st u d y will be prese nte d i n a listi n g wit h t he ti me i n w hic h it occ urre d.
N u m ber a n d perce nta ge of partici pa nts wit h a n i m pla nt visi ble d uri n g t he st u d y will be 
s u m marize d i n a ta b ular f or mat f urt her brea ki n g d o w n b y t he cate g orical perce nta ge visi ble of 
t he i m pla nt. Als o, t he n u m ber a n d perce nta ge of partici pa nts w h o ha ve a n i m pla nt i n c o ntact 
wit h c or neal e n d ot heli u m at a n y visit will be s u m marize d . Im pla nt assess me nt will be prese nte d 
as data listi n gs dis pla yi n g t he l ocati o n of i m pla nt ( 1 2 z o nes) a n d stat us of c o ntact wit h c or neal 
e n d ot heli u m f or eac h partici pa nt .
5. 5.
I nteri m An al yses 
T here are n o pla n ne d i nteri m a nal y ses.  S afet y a nal yses m a y  be peri o dicall y perf or me d base d o n 
rele va nt data s na ps h ots.
T here will be t w o data base l oc ks as descri be d i n Secti o n 5. 1 . A nal ys es will be perf or me d after 
eac h l oc k . T he pri mar y a n d sec o n dar y efficac y a nal ysis base d o n t he first data base l oc k will be 
c o nsi dere d as t he fi nal a nal ysis. T he a nal ys es base d o n t he sec o n d data base l oc k pr o vi de f urt her 
efficac y a n d safety i nf or mati o n.
5. 5. 1.  
D at a M o nit ori n g C o m mittee
A d ata m o nit ori n g c o m mittee is n ot re q uire d f or t his st u d y.


C O N FI D E N TI A L
Bi mat o pr ost S R
Statistical A nal y sis Pla n v 1. 0 1 6 9 8- 3 0 4- 0 0 7
Pa ge 2 2 of 3 1
6.
S u p p orti n g D oc u me nt ati o n
A d diti o nal baseli ne c haracteristics, a n d pre- def i ne d safety criteria ca n be f o u n d i n Secti o n 6. 2
A p pe n di x 2 .
6. 1.
A p pe n di x 1: List of A b bre vi ati o ns
A b bre vi ati o n
Defi niti o n
A E
A d verse e ve nt
A L T 
Ala ni ne a mi n otra nsferase
A S T 
As partate a mi n otra nsferase
A T C
A nat o mical T hera pe utic C he mical 
B C V A
Best c orrecte d vis ual ac uit y
B MI
B o d y  mass i n de x
B U N 
bl o o d urea nitr o ge n
C C T
ce ntral c or neal t hic k ness
C E C D
Ce ntral e n d ot helial cell de nsit y
CI
C o nfi de nce i nter val
C V
C oeffic ie nt of variati o n
e C R F
Electr o nic case re p ort f or m
F A S
F ull a nal ysis set
H E X
Ple o m or p his m
I O P
I ntra oc ular press ure
I W R S
I nteracti ve we b res p o nse s yste m
K M
Ka pla n -Meier
M C H C 
M ea n c or p usc ular he m o gl o bi n c o nce ntrati o n
M C H
M ea n c or p usc ular he m o gl o bi n
M C V 
M ea n c or p usc ular v ol u me
M D
Mea n defect
Me d D R A
Me dical Dicti o nar y f or Re g ulat or y Acti vities
N A
N ot a p plica ble
O A G
O pe n -a n gle gla uc o ma
O H T
Oc ular h y perte nsi o n
O U
B ot h e yes
P T
Preferre d ter m
R B C
R e d bl o o d cell
S A E
Seri o us a d verse e ve nt
S A P
Statistical a nal ysis pla n
S A F
Safet y a nal ysis set
S A S
Statistical A nal ysis S oft ware


C O N FI D E N TI A L
Bi mat o pr ost S R
Statistical A nal y sis Pla n v 1. 0 1 6 9 8- 3 0 4- 0 0 7
Pa ge 2 3 of 3 1
A b bre vi ati o n
Defi niti o n
S D
Sta n dar d de viati o n
S E
St u d y e ye
S o A
Sc he d ule of acti vities
S O C
S y st e m or ga n class
S R
S ustai ne d release
S U N
Sta n dar dizati o n of t he U veitis N o m e nclat ure
T E A E
Treat me nt- e mer ge nt a d verse e ve nt
T E S A E
Treat me nt- e mer ge nt seri o us a d verse e ve nt
U S A
U nite d States
V A
Vis ual Ac uit y
W B C
W hite bl o o d cell
W H O
W orl d Healt h Or ga nizati o n
W O C B P
W o m a n of c hil d beari n g p ote ntial


C O N FI D E N TI A L
Bi mat o pr ost S R
Statistical A nal y sis Pla n v 1. 0 1 6 9 8- 3 0 4- 0 0 7
Pa ge 2 4 of 3 1
6. 2.
A p pe n di x 2 : S u p p orti n g St u d y I nf or m ati o n
6. 2. 1.
De m o gr a p hics
De m o gra p hic para meters (a ge , se x, race, et h nicit y) will be s u m marize d descri pti vel y b y 
treat me nt c o h ort f or t he F A S p o p ulati o n. 
6. 2. 2.
B aseli ne a n d Dise ase C h ar acteristics
Baseli ne c haracteristics will be s u m marize d descri pti vel y ( hei g ht, wei g ht, B MI) b y  treat me nt 
c o h ort f or t he F A S p o p ulati o n i ncl u di n g ge neral a n d oc ular i ncl usi o n criteria. T he f oll o wi n g 
o c ular baseli ne a n d disease c haracteristics will be prese nte d f or t he st u d y e ye i n b ot h treat me nt 
c o h orts: dia g n osis ( of O A G or O H T), Baseli ne H o ur 0 I O P, iri d oc or neal a n gle S haffer gra de, 
Baseli ne ce ntral e n d ot helial cell de nsit y , a nd Baseli ne le ns stat us.
6. 2. 3. 
Pr ot oc ol De vi ati o ns
U ni q ue partici pa nts re p orti n g si g nifica nt pr ot oc ol de viati o ns will be s u m marize d i n t otal a n d b y  
treat me nt c o h ort f or t he F A S p o p ulati o n. A listi n g of a n y  si g nifica nt pr ot oc ol de viati o ns will be 
pr o vi de d.
6. 2. 4.
Me dic al Hist or y
A b n or malities i n partici pa nts’ m e dical a n d s ur gical hist or y data will be c o de d usi n g t he 
Me d D R A dicti o nar y . O p ht hal mic a n d n o n -o p ht h al mic m e dical a n d s ur gical hist or y will be 
s u m marize d b y treat me nt c o h ort f or t he S A F p o p ulati o n .
6. 2. 5.
Pri or/ C o nc o mit a nt Me dic ati o ns
T he me dicati o n data will be c o de d usi n g t he m ost rece nt versi o n of W orl d Healt h Or ga nizati o n 
( W H O) Dr u g Dicti o nar y En ha nce d . 
Pr i or me dicati o n is defi ne d as a ny me dicati o n ta ke n pri or t o t he start of st u d y  i nter ve nti o n 
re gar dless of st o p date of t he me dicati o n. C o nc o mita nt me dicati o n is defi ne d as a ny me dicati o n 
ta ke n after t he start of st u d y i nter ve nti o n re gar dless of t he start date of t he me dicati o n. 
Pri or a n d c o nc o mita nt me dicati o ns will be c o de d usi n g t he A nat o mical T hera pe utic C he mical 
c o de ( 4t h le vel, or m ost s pecific le vel a vaila ble if 4t h le vel is u na vaila ble). 
T he n u m ber a n d perce nta ge of partici pa nts re p orti n g pri or or c o nc o mita nt me dicati o ns will be 
s u m marize d b y treat me nt c o h ort, A T C class a n d c o de, a n d preferre d dr u g na me. If m ore t ha n o ne 
me dicati o n is c o de d t o t he sa me preferre d dr u g na me f or t he sa me partici pa nt, t he partici pa nt will 
be c o u nte d o nl y o nce f or t hat pr eferre d dr u g na me. Pri or a n d c o nc o mita nt me dicati o ns will be 
s u m marize d se parately .


C O N FI D E N TI A L
Bi mat o pr ost S R
Statistical A nal y sis Pla n v 1. 0 1 6 9 8- 3 0 4- 0 0 7
Pa ge 2 5 of 3 1
6. 3.
A p pe n di x 3 : D at a H a n dli n g C o n ve nti o n
6. 3. 1.
Visit Ti me p oi nts
Ta ble 6- 1 a n d Ta ble 6 - 2 prese nt t he a nal ys is visits assi g ne d f or efficac y a n d safety assess me nts 
f or partici pa nts f or b ot h t he Bi mat o pr ost S R a n d L U MI G A N 0. 0 1 % c o h orts. De pe n di n g o n 
safety assess me nts sc he d ule, eit her Ta ble 6- 1 or Ta ble 6- 2 will be use d f or b y visit a nalys is. If 
t he assess me nt date is o n or after t he date of t he a d mi nistrati o n of Bi m at o pr ost S R ( or date of t he 
first self-a d mi nistrati o n of L U MI G A N 0. 0 1 %) , t he st u dy da y is calc ulate d b y assess me nt date –
date of t he first a d mi nistrati o n or d ose of st u d y treat me nt + 1. If t he assess me nt date is bef ore t he 
date of t he first a d mi nistrati o n or d ose of st u d y treat me nt, t he st u d y da y is calc ulate d b y 
assess me nt date – dat e of t he first a d mi nistrati o n or d ose of st u d y treat me nt. T heref ore, a 
ne gati ve da y  i n dicates a da y bef ore t he start of t he st u d y treat me nt.
T a ble 6 - 1
Effic ac y a n d S afet y Visit W i n d o w
Visit N a me
T ar get D a y of t he visit a
A n al ysis Visit Wi n d o w
Baseli ne Office
-7 t o -1 fr o m Baseli ne
Slee p La b visit
≤Baseli ne Slee p La b - 1
Baseli ne Slee p La b
0 b
≤A d mi nistrati o n Da y 1 - 1
A d mi nistrati o n Da y 1
1
1
D a y  2 Safet y
2
2
Wee k 8 Office
-7 t o -1 fr o m Wee k 8
Slee p La b visit
≤Wee k 8 Slee p La b visit - 1
Wee k 8 Slee p La b
5 6 c
[ 4 2, 7 0 ]
Wee k 1 6
1 1 2
[7 1 , 1 4 2 ]
M o nt h 6
1 8 0
[ 14 3 , 2 2 5]
M o nt h 9
2 7 0
[2 2 6 , 3 1 5]
M o nt h 1 2/ St u d y E xit
3 6 0
≥3 1 6
a
Relati ve t o t he date of treat me nt a d mi nistrati o n.
b
M ust be differe nt t ha n Baseli ne Office visit.
c
Differe nt t ha n Wee k 8 Office visit.


C O N FI D E N TI A L
Bi mat o pr ost S R
Statistical A nal y sis Pla n v 1. 0 1 6 9 8- 3 0 4- 0 0 7
Pa ge 2 6 of 3 1
T a ble 6- 2
S afet y Visit W i n d o ws
Visit N a me
T ar get D a y of t he visit a
A n al ysis Visit Wi n d o w
Baseli ne Office
-7 t o -1 fr o m Baseli ne
Slee p La b visit
≤Baseli ne Slee p La b - 1
A d mi nistrati o n Da y 1
1
1
Wee k 1 6
1 1 2
[ 2, 1 4 2]
M o nt h 6
1 8 0
[ 1 4 3, 2 2 5]
M o nt h 9
2 7 0
[ 2 2 6, 3 1 5]
M o nt h 1 2/ St u d y E xit
3 6 0
≥3 1 6
a
Relati ve t o t he date of treat me nt a d mi nistrati o n.
If m ulti ple assess me nts (sc he d ule d or u nsc he d ule d visits) were ta ke n wit hi n a n a nal ys is wi n d o w, 
t he assess me nt o btai ne d o n t he da y cl osest t o t he tar get da y will be use d; i n t he case of a tie, t he 
assess me nt o btai ne d o n t he later da y  will be use d i n t he a nalys is. F or partici pa nt s treate d wit h 
L u mi ga n , t he e xit visit assess me nts will be s u m marize d i n M o nt h 1 2/st u d y  e xit re gar dless of t he 
last visit falls i nt o. Be n ote d, I O P val ues will be als o meas ure d f or safet y, a n d t hese safet y I O P 
val ues rec or de d o n u nsc he d ule d I O P e C R F pa ge. U nsc he d ule d I O P val ues i n a n a nal ys is 
wi n d o ws will n ot be use d f or efficac y  a nalys is, u nless t he I O P val ue is t he o nl y o ne i n t he 
a nal ys is visit wi n d o w. F or 2 4 h o ur ti me -matc h I O P a nal y sis, I O P assess me nts at Wee k 8 slee p 
la b visit will be use d a n d u nsc he d ule d visit assess me nts will n ot be use d . 
Ta ble 6 - 3 prese nts t he ti me wi n d o w f or I O P meas ure me nts d uri n g t he Office a n d Slee p La b 
visits at Baseli ne a n d Wee k 8 f or b ot h t he Bi mat o pr ost S R a n d L U MI G A N 0. 0 1 % c o h orts.
D uri n g eac h assess me nt, tw o c o nsec uti ve I O P meas ure me nts will be ta ke n of st u d y e ye. If t he 
first 2 meas ure me nts differ by > 1 m m H g, a t hir d meas ure me nt will be ta ke n. If t he first 
2 meas ure me nts differ b y ≤ 1 m m H g, t he I O P f or t he gi ve n e y e will be t he a vera ge of t he 
2 rea di n gs. If t he differe nce bet wee n t he first 2 meas ure me nts is > 1 m m H g, t he I O P f or t he 
gi ve n e y e will be t he me dia n of t he 3 rea di n gs.


C O N FI D E N TI A L
Bi mat o pr ost S R
Statistical A nal y sis Pla n v 1. 0 1 6 9 8- 3 0 4- 0 0 7
Pa ge 2 7 of 3 1
T a ble 6- 3
I O P M e as ure me nt T i me W i n d o ws 
Visit 
N a m e
Assess me nt N a me
Assess me nt 
T y pe
T ar get Ti me of t he 
Assess me nt
A n al ysis Ti me Wi n d o w
Slee p La b a
2 4 -h o ur I O P Meas ure me nts
Di ur nal
0 8: 0 0
0 7: 1 5 t o 0 8: 4 5
1 0: 0 0
0 9: 1 5 t o 1 0: 4 5
1 2: 0 0
1 1: 1 5 t o 1 2: 4 5
1 4: 0 0
1 3: 1 5 t o 1 4: 4 5
1 6: 0 0
1 5: 1 5 t o 1 6: 4 5
1 8: 0 0
1 7: 1 5 t o 1 8: 4 5
2 0: 0 0
1 9: 1 5 t o 2 0: 4 5
2 2: 0 0
2 1: 1 5 t o 2 2: 4 5
N oct ur nal
0 0: 0 0
2 3: 1 5 t o 0 0: 4 5
0 2: 0 0
0 1: 1 5 t o 0 2: 4 5
0 4: 0 0
0 3: 1 5 t o 0 4: 4 5
0 6: 0 0
0 5: 1 5 t o 0 6: 4 5
Office b
H o ur 0 I O P Meas ure me nt
N/ A
0 8: 0 0
0 6: 3 0 t o 0 9: 3 0
a
F or b ot h Baseli ne a n d Wee k 8
b
F or Baseli ne office visit, Da y 2 safet y visit, Wee k 8 office visit, Wee k 1 6, M o nt h 6, 9, a n d 1 2/ E xit
6. 3. 2.
Re pe ate d or U nsc he d ule d Assess me nts of S afet y P ar a meters
If a partici pa nt has re peate d assess me nts bef ore t he a d mi nistrati o n of treat me nt, u nless ot her wise 
state d, t he res ults fr o m t he latest n o n-missi n g a ssess me nt ma de pri or t o t he start of t he st u d y 
treat me nt will be use d as baseli ne. If e n d- of-st u d y assess me nts are re peate d or if u nsc he d ule d 
visits occ ur, t he last n o n -missi n g p ost baseli ne assess me nt will be use d as t he e n d - of-st u d y 
assess me nt f or ge nerati n g s u m mar y statistics. H o we ver, all p ost baseli ne assess me nts will be 
use d f or safet y e val uati o n, a n d all assess me nts will be prese nte d i n t he data listi n gs.
6. 3. 3.
Missi n g D ate of t he L ast D ose of St u d y I nter ve nti o n
F or partici pa nts w h o di d n ot recei ve d t he L U MI G A N 0. 0 1 % at t he Wee k 8 Slee p La b visit or
misse d at t he Wee k 8 Slee p La b visit , t he date will be i m p ute d wit h t he last n o n- missi n g date of 
treat me nt self-a d mi nistrati o n pri or t o Wee k 8 Slee p L a b visit. 
6. 3. 4.  
Missi n g Se verit y Assess me nt f or A d verse E ve nts
If se verit y is missi n g f or a n A E t hat starte d bef ore t he date of st u d y treat me nt, se verit y of mil d 
will be assi g ne d. If se verit y is missi n g f or a n A E t hat starte d o n or after t he date of st u d y 
treat me nt, se verit y of se vere will be assi g ne d. T he i m p ute d val ues f or se verit y  assess me nt will be 
use d f or t he i nci de nce s u m maries; t he val ues will be s h o w n as missi n g i n t he data listi n gs.


C O N FI D E N TI A L
Bi mat o pr ost S R
Statistical A nal y sis Pla n v 1. 0 1 6 9 8- 3 0 4- 0 0 7
Pa ge 2 8 of 3 1
6. 3. 5.  
Missi n g C a us al Rel ati o ns hi p t o St u d y I nter ve nti o n f or A d verse E ve nts
If t he ca usal relati o ns hi p t o a st u d y treat me nt is missi n g f or a n A E t hat starte d o n or after t he date 
of t he st u d y treat me nt, a ca usalit y  of ‘ yes’ will be assi g ne d. T he i m p ute d val ues f or ca usal 
relati o ns hi p will be use d f or t he i nci de nce s u m maries; t he val ues will be s h o w n as missi n g i n t he 
data listi n gs.
6. 3. 6.  
Missi n g D ate I nf or m ati o n f or A d verse E ve nts
I n cases of i nc o m plete dates f or A E, t he missi n g c om p o ne nt(s) will be ass u me d as t he m ost 
c o nser vati ve val ue(s) p ossi ble. T he i m p utati o n r ule is ai me d at c o nser vati vel y  ca pt uri n g A Es 
wit h missi n g start dates as treat me nt -e mer ge nt A Es ( T E A Es).
T a ble 6 - 4
I mp uti n g R ule f or P arti all y M issi n g A E St art D ates
P a r a m eter
Missi n g
A d diti o n al C o n diti o ns
I m p ut ati o n
Start date f or A Es
D o nl y
M a n d Y sa me as M a n d Y of first 
d ose of st u d y treat me nt
Date of first d ose of st u d y 
treat me nt
Y is bef ore t he Y of first d ose of 
st u d y treat me nt or if Y sa me b ut M 
is bef ore t he M of first d ose of st u d y 
treat me nt
Last da y of n o n -mi ssi n g m o nt h
Y is after t he Y of first d ose of st u d y 
treat me nt or if Y sa me b ut M is after 
t he M of first d ose of st ud y  
treat me nt
First da y of n o n -missi n g m o nt h
D a n d M
Y sa me as Y of first d ose of st u d y 
treat me nt
Date of first d ose of st u d y 
treat me nt
Y bef ore t he Y of first d ose of st u d y 
treat me nt
Use Dec 3 1 
Y after t he Y of first d ose of st u d y 
treat me nt
Use Ja n 1 
M o nl y
Treat D as missi n g as well
Use sa me pr oce d ure as D a n d M 
missi n g
N otes: D = Da y, M = M o nt h, Y = Year.
If t he st o p date is c o m plete a n d t he i m p ute d start date c o m p ute d usi n g t he r ules i n Ta ble 6- 4 is 
after t he st o p date, t he start date will be i m p ute d b y t he st o p date. If t he start date is c o m pletel y 
missi n g a n d t he st o p date is c o m plete, t he f oll o wi n g r ule will be use d t o i m p ute t he st art date:

If t he st o p date is after t he date of t he first d ose of st u d y treat me nt, t he date of t he first 
d ose of st u d y  treat me nt will be assi g ne d t o t he missi n g start date.

If t he st o p date is bef ore t he date of t he first d ose of st u dy treat me nt, t he st o p date will be 
assi g ne d t o t he missi n g start date. 


C O N FI D E N TI A L
Bi mat o pr ost S R
Statistical A nal y sis Pla n v 1. 0 1 6 9 8- 3 0 4- 0 0 7
Pa ge 2 9 of 3 1
6. 3. 7.  
Missi n g D ate I nf or m ati o n f or Pri or or C o nc o mit a nt Me dic ati o ns
F or pri or or c o nc o mita nt me dicati o ns, i ncl u di n g was h o ut a n d I O P -l o weri n g me dicati o ns, 
i nc o m plete (ie, partl y missi n g) start dates a n d/ or st o p dates will be i m p ute d. W he n t he start date 
a n d t he st o p date are b ot h i nc o m plete f or a partici pa nt , t he start date will be i m p ute d first.
6. 3. 7. 1.
I nc o m plete St art D ate
T he f oll o wi n g r ules will be a p plie d t o i m p ute t he miss i n g n u meric fiel ds f or a n i nc o m plete pri or 
or c o nc o mita nt me dicati o n start date. If t he st o p date is c o m plete ( or i m p ute d) a n d t he i m p ute d 
start date is after t he st o p date, t he start date will be i m p ute d usi n g t he st o p date. 
T a ble 6- 5
I mp uti n g R ule f or M issi n g P ri or or C o nc o mit a nt M e dic ati o ns S t art D ate
P a r a m eter
Missi n g
A d diti o n al C o n diti o ns
I m p ut ati o n
Start date f or n o n -
pri or or c o nc o mita nt 
me dicati o ns
D o nl y
M a n d Y sa me as M a n d Y of first 
d ose of st u d y treat me nt
Date of first d ose of st u d y 
treat me nt
Y is bef ore t he Y of first d ose of 
st u d y treat me nt or if Y sa me b ut M 
is bef ore t he M of first d ose of st u d y 
treat me nt
Last da y of n o n -mi ssi n g m o nt h
Y is after t he Y of first d ose of st u d y 
treat me nt or if Y sa me b ut M is after 
t he M of first d ose of st u d y 
treat me nt
First da y of n o n -missi n g m o nt h
D a n d M
Y sa me as Y of first d ose of st u d y 
treat me nt
Date of first d ose of st u d y 
treat me nt
Y bef ore t he Y of first d ose of st u d y 
treat me nt
Use Dec 3 1 
Y after t he Y of first d ose of st u d y 
treat me nt
Use Ja n 1 
M o nl y
Treat D as missi n g as well
Use sa me pr oce d ure as D a n d M 
missi n g
N otes: D = Da y, M = M o nt h, Y = Year.
6. 3. 7. 2.
I nc o m plete St o p D ate
T he f oll o wi n g r ules will be a p plie d t o i m p ute t he missi n g n u meric fiel ds f or a n i nc o m plete pri or 
or c o nc o mita nt me dicati o n st o p date u nless t he st o p date is mar ke d as o n g oi n g. If t he i m p ute d 
st o p date is bef ore t he start date (i m p ute d or n o ni m p ute d start date), t he i m p ute d st o p date will be 
e q ual t o t he start date. If t he st o p date is mar ke d as o n g oi n g, t he st u dy e xit date will be assi g ne d 
t o t he missi n g fiel ds. If t he st u d y e xit date is n ot a vaila ble, t he last visit date will be use d f or 
i m p utati o n.


C O N FI D E N TI A L
Bi mat o pr ost S R
Statistical A nal y sis Pla n v 1. 0 1 6 9 8- 3 0 4- 0 0 7
Pa ge 3 0 of 3 1
T a ble 6- 6
I mp uti n g R ule f or M issi n g P ri or or C o nc o mit a nt M e dic ati o ns S t o p D ate
P a r a m eter
Missi n g
A d diti o n al C o n diti o ns
I m p ut ati o n
St o p date f or n o n -
pri or or c o nc o mita nt 
me dicati o ns
D o nl y
M a n d Y sa me as M a n d Y of st u d y 
e xit date
Da y  of t he st u d y e xit date
Y is bef ore t he Y of st u d y e xit date
or if Y sa me b ut M is bef ore t he M 
of st u d y e xit date
Last da y of n o n -mi ssi n g m o nt h
Y is after t he Y of st u d y e xit date or 
if Y sa me b ut M is after t he M of 
st u d y e xit date
First da y of n o n -missi n g m o nt h
D a n d M
Y sa me as Y of st u d y e xit date
M o nt h a n d da y of t he st u d y e xit 
date
Y bef ore t he Y of st u d y e xit date
Use Dec 3 1 
Y after t he Y of st u d y e xit date
Use Ja n 1 
M o nl y
Treat D as missi n g as well
Use sa me pr oce d ure as D a n d M 
missi n g
N otes: D = Da y, M = M o nt h, Y = Year.
6. 3. 8.  
C h ar acter V al ues of Cli nic al L a b or at or y P ar a meters
If t he re p orte d val ue of a cli nical la b orat or y varia ble ca n n ot be use d i n a statistical a nal ysis d ue 
t o, f or e xa m ple, t hat a c haracter stri n g is re p orte d f or a n u merical varia ble, t he a p pr o priatel y 
deter mi ne d c o de d val ue will be use d i n t he statistical a na l ysis. 


C O N FI D E N TI A L
Bi mat o pr ost S R
Statistical A nal y sis Pla n v 1. 0 1 6 9 8- 3 0 4- 0 0 7
Pa ge 3 1 of 3 1
6. 4.
A p pe n di x 4: C h a n ges t o Pr ot oc ol -pl a n ne d A n al yses
T here are n o c ha n ges fr o m t he pr ot oc ol -pla n ne d a nal y ses.