Safety and Efficacy of Brimonidine Posterior Segment Drug Delivery System in Patients With Geographic Atrophy Secondary to Age-related Macular Degeneration
Phase: PHASE2
Conditions: Geographic Atrophy, Macular Degeneration
Sponsor: Allergan

NCT02087085 
 
Study ID: 190342-038 
 
Title: Safety and Efficacy of Brimonidine Posterior Segment Drug Delivery System in Patients with 
Geographic Atrophy Secondary to Age‐related Macular Degeneration 
 
Protocol Amendment 7 Date: 23‐May‐2017 
 
 
 

 
 
Approval Date: 
 
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Title Page 
ALLERGAN – CONFIDENTIAL 
The following contains confidential, proprietary information  
which is the property of Allergan 
 
Safety and Efficacy of Brimonidine Posterior Segment Drug Delivery System in 
Patients with Geographic Atrophy Secondary to Age-related Macular Degeneration 
(BEACON Study) 
 
 
 
Protocol Number:   
190342-038 Amendment 7 
EudraCT Number: 
Phase: 
2013-003320-36 
2b 
Name of Investigational Product: 
AGN-190342, Brimonidine Posterior Segment Drug Delivery 
System (Brimo DDS®) 
Sponsor: 
Allergan (North America) 
2525 Dupont Drive 
Irvine, California USA 
92612 
+1-714-246-4500 
+1-800-347-4500 
 
Allergan Ltd. 
1st Floor, Marlow 
International, 
The Parkway, Marlow 
Buckinghamshire 
SL7 1YL United Kingdom 
Tel: +44 (0) 1628 494444 
Fax: +44 (0) 1628 494449 
Emergency Telephone Numbers: 
Refer to the study contacts page in your investigator site file 
Serious Adverse Event Reporting 
Fax Numbers: 
 
   
Serious Adverse Event Reporting 
Email Address: 
Allergan Medical Safety Physician 
Contact Information: 
 
 
 
 

 
 
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Allergan Signatory: 
 
  
  
Refer to the final page of this protocol for electronic signature 
and date of approval 
 
The following information can be found on FDA Form 1572 and/or study contacts page:  
Name and contact information of Allergan study personnel; name, address, and statement of 
qualifications of each investigator; name of each subinvestigator working under the 
supervision of the investigator; name and address of the research facilities to be used; name 
and address of each reviewing IRB; 21 CFR 312.23 section 6(iii)b. 
 

 
 
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INVESTIGATOR SIGNATURE PAGE 
INVESTIGATOR: 
 
STUDY LOCATION: 
 
 
I agree to: 
• Implement and conduct this study diligently and in strict compliance with the protocol, 
good clinical practices and all applicable laws and regulations. 
• Maintain all information supplied by Allergan in confidence and, when this information 
is submitted to an Institutional Review Board (IRB), Independent Ethics Committee 
(IEC) or another group, it will be submitted with a designation that the material is 
confidential. 
• Ensure that all persons assisting with the trial are adequately informed about the protocol, 
the investigational product(s), and their trial-related duties and functions. 
I have read this protocol in its entirety and I agree to all aspects. 
 
 
 
 
 
Investigator Printed Name 
 
Signature 
 
Date 
 

 
 
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Table of Contents 
Table of Contents ...................................................................................................................... 4 
List of Tables ............................................................................................................................. 8 
List of Figures ........................................................................................................................... 8 
Protocol Summary .................................................................................................................... 9 
1 
Background and Clinical Rationale ................................................................................. 15 
2 
Study Objectives and Clinical Hypotheses ...................................................................... 20 
2.1 
Study Objectives .................................................................................................... 20 
2.2 
Clinical Hypotheses ............................................................................................... 20 
3 
Study Design .................................................................................................................... 20 
3.1 
Data Review Committee ........................................................................................ 21 
4 
Study Population and Entry Criteria ................................................................................ 21 
4.1 
Number of Patients ................................................................................................. 21 
4.2 
Study Population Characteristics ........................................................................... 21 
4.3 
Inclusion Criteria .................................................................................................... 22 
4.4 
Exclusion Criteria................................................................................................... 23 
4.5 
Permissible and Prohibited Medications/Treatments ............................................. 25 
4.5.1  Permissible Medications/Treatments ......................................................... 25 
4.5.2  Definition of Females of (Non-) Childbearing Potential and Acceptable 
Contraceptive Methods .............................................................................. 26 
4.5.3  Prohibited Medications/Treatments ........................................................... 26 
4.5.4  Escape Medications .................................................................................... 27 
4.5.5  Special Diet or Activities ........................................................................... 27 
5 
Study Treatments ............................................................................................................. 27 
5.1 
Study Treatments and Formulations ....................................................................... 27 
5.2 
Control Treatment .................................................................................................. 27 
5.3 
Methods for Masking ............................................................................................. 27 
5.4 
Treatment Allocation Ratio and Stratification........................................................ 28 
5.5 
Method for Assignment to Treatment Groups/Randomization .............................. 28 
5.6 
Treatment Regimen and Dosing ............................................................................. 29 
5.7 
Storage of Study Medications/Treatments ............................................................. 29 
5.8 
Preparation of Study Medications/Treatments ....................................................... 29 

 
 
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5.9 
Treatment Administration ...................................................................................... 29 
6 
Response Measures and Summary of Data Collection Methods ..................................... 30 
6.1 
Efficacy Measures .................................................................................................. 30 
6.1.1  Primary Efficacy Measure .......................................................................... 30 
6.1.2  Secondary Efficacy Measures .................................................................... 30 
6.1.3  Other Outcome Measures ........................................................................... 30 
 
 
 
 
 
 
6.4 
Examination Procedures, Tests, Equipment, and Techniques ................................ 31 
6.4.1  Certification of Technicians and Examiners .............................................. 31 
6.4.2  Standard and Low Luminance Best Corrected Visual Acuity .................... 32 
6.4.3  Spectral-domain Optical Coherence Tomography ..................................... 32 
6.4.4  Microperimetry .......................................................................................... 32 
6.4.5  Confocal Scanning Laser Ophthalmoscopy:  Near-infrared Reflectance 
(3-field) ...................................................................................................... 33 
6.4.6  Confocal Scanning Laser Ophthalmoscopy:  Quantitative (Central Field) 
and Standard (3-field) Fundus Autofluorescence ....................................... 33 
6.4.7  Fluorescein Angiography ........................................................................... 33 
6.4.8  Indocyanine Green Angiography (Optional) .............................................. 33 
6.4.9  Dilated Fundus Photography ...................................................................... 34 
 
 
6.5 
Other Study Supplies .............................................................................................. 39 
6.6 
Summary of Methods of Data Collection .............................................................. 39 
7 
Statistical Procedures ....................................................................................................... 39 
7.1 
Analysis Populations .............................................................................................. 39 
7.2 
Collection and Derivation of Primary and Secondary Efficacy Assessments ........ 40 
7.2.1  Primary Efficacy Variable .......................................................................... 40 
7.2.2  Secondary Efficacy Variables ..................................................................... 40 
7.3 
Hypothesis and Methods of Analysis ..................................................................... 40 
7.3.1  Primary Efficacy Analyses ......................................................................... 40 
7.3.2  Secondary Efficacy Analyses ..................................................................... 40 
 
 
7.3.4  Safety Analyses .......................................................................................... 41 
7.4 
Subgroup Analyses ................................................................................................. 41 

 
 
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7.5 
Sample Size Calculation ........................................................................................ 42 
7.6 
Interim Analyses..................................................................................................... 42 
 
 
8.1 
Patient Entry Procedures ........................................................................................ 43 
8.1.1  Overview of Entry Procedures ................................................................... 43 
8.1.2  Informed Consent and Patient Privacy ....................................................... 43 
8.2 
Procedures for Final Study Entry ........................................................................... 43 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4 
Instructions for the Patients .................................................................................... 53 
8.5 
Unscheduled Visits ................................................................................................. 53 
8.6 
Compliance With Protocol ..................................................................................... 53 
8.7 
Early Discontinuation of Patients .......................................................................... 53 
8.7.1  Treatment Failures ...................................................................................... 54 
8.8 
Study Termination .................................................................................................. 55 
9 
Adverse Events ................................................................................................................ 55 
9.1 
Definitions .............................................................................................................. 55 
9.1.1  Adverse Event ............................................................................................ 55 
9.1.2  Serious Adverse Event ............................................................................... 56 
9.1.3  Severity ...................................................................................................... 56 
9.1.4  Relationship to Study Drug or Study Procedure ........................................ 56 
9.2 
Procedures for Reporting Adverse Events ............................................................. 57 

 
 
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9.3 
Procedures for Reporting a Serious Adverse Event ............................................... 57 
9.4 
Procedures for Unmasking of Study Medication ................................................... 58 
10  Administrative Items ....................................................................................................... 58 
10.1  Protection of Human Patients ................................................................................ 58 
10.1.1  Compliance With Informed Consent Regulations (US 21 CFR Part 50) and 
Relevant Country Regulations ................................................................... 58 
10.1.2  Compliance With IRB or IEC Regulations ................................................ 59 
10.1.3  Compliance With Good Clinical Practice .................................................. 59 
10.1.4  Compliance With Electronic Records; Electronic Signatures Regulations 
(US 21 CFR Part 11) .................................................................................. 59 
10.2  Changes to the Protocol ......................................................................................... 59 
10.3  Patient Confidentiality ........................................................................................... 59 
10.3.1  Patient Privacy ........................................................................................... 60 
10.4  Documentation ....................................................................................................... 60 
10.4.1  Source Documents ..................................................................................... 60 
10.4.2  Case Report Form Completion................................................................... 61 
10.4.3  Study Summary .......................................................................................... 62 
10.4.4  Retention of Documentation ...................................................................... 62 
10.5  Labeling, Packaging, and Return or Disposal of Study Medications/Treatments .. 62 
10.5.1  Labeling/Packaging .................................................................................... 62 
10.5.2  Clinical Supply Inventory .......................................................................... 63 
10.5.3  Return or Disposal of Study Medications/Treatments ............................... 63 
10.6  Monitoring by the Sponsor .................................................................................... 63 
10.7  Handling of Biological Specimens......................................................................... 63 
10.8  Publications ............................................................................................................ 64 
10.9  Coordinating Investigator ...................................................................................... 64 
11  References ........................................................................................................................ 65 
12  Attachments ..................................................................................................................... 70 
12.1  Glossary of Terms and Abbreviations .................................................................... 70 
12.2  Protocol Amendment Summary Amendment 1 ..................................................... 72 
12.3  Protocol Amendment Summary Amendment 2 ..................................................... 74 
12.4  Protocol Amendment Summary Amendment 3 ..................................................... 78 
12.5  Protocol Amendment Summary Amendment 4 ..................................................... 80 
12.6  Protocol Amendment Summary Amendment 5 ..................................................... 82 
12.7  Protocol Amendment Summary Amendment 6 ..................................................... 84 

 
 
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12.8  Protocol Amendment Summary Amendment 7 ..................................................... 86 
 
List of Tables 
 
 
 
 
 
List of Figures 
 
 
 
 

 
 
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Protocol Summary 
Study Compound:  AGN-190342, Brimonidine Posterior Segment Drug Delivery System (Brimo DDS®) 
Phase:  2b 
Study Objectives:  to assess:  (1) the safety of the treatment; (2) the effects of treatment on the mean change in 
atrophic lesion area quantified from fundus autofluorescence (FAF) images; (3) the effects of treatment on the 
mean change in low luminance best corrected visual acuity (BCVA); (4) the effects of treatment on the mean 
change in standard BCVA; (5) the effects of treatment on the mean change in retinal sensitivity quantified using 
scotopic/mesopic microperimetry; and (6) to characterize the systemic pharmacokinetic profile of Brimo DDS  
Clinical Hypotheses: 
• 
Brimo DDS is safe and well tolerated with repeated intravitreal administration in patients with 
geographic atrophy (GA) secondary to age-related macular degeneration (AMD) as assessed by the 
incidence of adverse events 
• 
Brimo DDS is more effective than Sham treatment in slowing the growth of atrophic lesion area and 
the loss of standard and low luminance BCVA 
 
Study Design 
Structure:  Multicenter, randomized, double-masked, Sham treatment-controlled study  
Duration:  30 months 
Study Treatment Group:  400 µg Brimo DDS administered by intravitreal injection 
Control:  Sham treatment with needleless DDS applicator 
Dosage/Dose Regimen:  One treatment to the study eye every 3 months from Baseline (Day 1) through 
Month 21 
Randomization/Stratification:  Randomization to treatment groups will use a 1:1 allocation ratio and will be 
stratified by region (North America, Europe, and Australia) and by atrophic lesion area (≤ 8 mm2 versus 
> 8 mm2) in the study eye as assessed by FAF examination at Screening Visit 1 and quantified by the central 
reading center (CRC). 
  
 
 
 
 
 
 
Study Population Characteristics 
Number of Patients:  Approximately 300 (150 per treatment group) 
Condition/Disease:  GA secondary to age-related macular degeneration 
Key Inclusion Criteria:   
• 
Male or female patients 55 years of age or older  

 
 
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• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
o 
BCVA better than or equal to 45 letters (20/125 Snellen equivalent) at the Screening Visit 1 
and the Baseline visit as assessed using the standard ETDRS (Early Treatment of Diabetic 
Retinopathy Study) visual acuity protocol 
 
 
 
 
 
 
 
• 
The fellow eye must have standard BCVA of 34 letters (Snellen equivalent 20/200) or better at 
Screening Visit 1 
Key Exclusion Criteria:  
 
 
 
 
 
 
 
 
 
Response Measures 
Efficacy:  Atrophic lesion area as assessed with FAF and quantified by the CRC; retinal sensitivity threshold as 
assessed with scotopic/mesopic microperimetry (selected sites/patients); standard BCVA as assessed with the 
ETDRS visual acuity protocol, and low luminance BCVA as assessed using 2.0 log unit neutral density filter 
and the ETDRS visual acuity protocol; 
;
 
 
 
 

 
 
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General Statistical Methods and Types of Analyses:   
Analysis of safety data will be based on the safety population, ie, all patients who received at least one study 
treatment.  Analysis of efficacy data will be based on the modified intent-to-treat population (mITT), ie, all 
randomized and treated patients with baseline and at least one post-baseline data point for atrophic lesion area.  
All analyses will be based on the actual treatment that the patient received. 
The primary analysis for efficacy will be performed when all enrolled patients have completed the Month-24 
visit or have exited early, prior to Month 24.  An interim analysis may be performed after 50% of patients 
complete the Month-18 visit.  Three database locks are planned for the study:  an interim lock at Month 18 
(50% of patients), the primary lock at Month 24, and the final lock at the end of the study (Month 30). 
The primary efficacy variable is the change from Baseline in atrophic lesion area in the study eye as assessed 
with FAF and quantified by the CRC.  Statistical analysis will be based on a mixed model for repeated measures 
(MMRM). The model includes treatment, study region (North America, Europe, and Australia), analysis visit, 
and treatment-by-visit interaction as factors as well as the baseline value and baseline value-by-analysis visit 
interaction as covariates.  
The Medical Dictionary for Regulatory Activities (MedDRA) nomenclature will be used to code adverse 
events.  The number and percent of patients reporting adverse events will be tabulated by primary system organ 
class, preferred term, and severity using the safety population. 
Sample Size Calculation: 
A standard method for measuring disease progression in patients with GA secondary to AMD is to quantify the 
expansion rate of the areas of atrophy.  Over a 12-month period this expansion rate typically ranges between 1 
and 2 mm2 (Sunness et al, 2007; Holz et al, 2007; Holz et al, 2010).  The atrophic lesion expansion rate used in 
the sample size calculation for the current study was from the GAP study (Holz et al, 2010).  The selection of 
the GAP data was based on the large patient population in this natural history study and because of the 
similarities between the GAP study and the current study in both study design and patient populations.   
The 12-month lesion expansion rate from the GAP study was 1.73 mm2.  A projected 24-month expansion rate, 
2.8 mm2, was calculated by applying a 20% discount to a linear extrapolation of the GAP lesion expansion data. 
Based on this lesion expansion rate and assuming a common standard deviation of 1.65 mm2, a 2-sided t-test 
with 90% power and an alpha of 0.05 will require a sample size of 120 patients per group to detect a 25% 
reduction from the Sham treatment.  A 25% reduction from the Sham treatment corresponds to a treatment 

 
 
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difference of 0.70 mm2.  With an anticipated dropout rate of 20%, approximately 300 patients will be enrolled 
such that 240 (120 per group) will complete the Month 24 visit. 
 
 
 
 
 

 
 
 
 
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1 
Background and Clinical Rationale 
Age-related macular degeneration (AMD) is the leading cause of legal blindness in persons 
over the age of 65 years (Friedman et al, 2004; Klein et al, 2006; Chakravarthy et al, 2007).  
Vision loss with this disease is attributed in large part to the advanced stages of this disease, 
exudative AMD and geographic atrophy (GA).  While antibody fragments and antibody 
mimetics directed against vascular endothelial growth factor (VEGF) are effective treatments 
for exudative AMD (Rosenfeld et al, 2006; Brown et al, 2006; Heier et al, 2012), GA remains 
a large unmet medical need because of its high incidence and the absence of effective 
treatments.  Klein and colleagues (2006) have reported that the 15 year cumulative incidence 
of GA in individuals 43 to 86 years old with early signs of AMD was 14%.  In individuals 
over 85 years of age the incidence of GA is approximately 4 times that of exudative AMD 
(Klein et al, 2007). 
GA is characterized by the degeneration of the retinal pigment epithelium (RPE), 
photoreceptor cells and choriocapillaris (Nowak, 2006).  These morphological changes 
initially appear in the extrafoveal region and advance into the fovea as the disease progresses.  
In earlier stages when the disease is limited to the extrafoveal region, the atrophic lesions 
impair visual performance by limiting the size of the functioning fovea and patients may be 
able to see only a portion of words when reading.  As the disease progresses to include the 
parafoveal region, central vision becomes affected.  Severe vision loss occurs when these 
areas of atrophy enlarge or coalesce and expand into the foveola.  In addition to the 
formation of scotomas that progress into the foveola, patients with geographic atrophy can 
experience a variety of visual symptoms such as distorted vision, trouble discerning colors, a 
slow recovery of visual function after exposure to bright light, a loss of contrast sensitivity 
and marked visual impairment in dimly lit environments (Sunness et al, 1997; 
Sunness et al, 2007; Sunness et al, 2008). 
Previous studies have reported atrophic lesion expansion rates that range between 1.3 and 
2.8 mm2 per year (Klein et al, 2007; Age-Related Eye Disease Study [AREDS] Research 
Group, 2009; Holz et al, 2007; Fritsche et al, 2008; Sunness et al, 1999; 
Schatz and McDonald, 1989).  While the majority of these studies have shown an association 
between the development of GA and systemic and environmental factors including blood 
pressure, smoking, heavy drinking status, body mass index, sedentary lifestyle, age, and 
gender, none of these studies have found an association between differences in intra-
individual lesion expansion rates and systemic or environmental risks.  In contrast to these 
findings, several natural history studies have identified a number of atrophic lesion 
characteristics that are associated with differences in lesion growth rates.  In a 5-year 

 
 
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follow-up of 32 patients with GA, Klein and collaborators (2008b) reported that lesion 
growth is more rapid in lesions with multiple areas of atrophy, ie, multifocal lesions.  Holz 
and colleagues have demonstrated that patterns of increased fundus autofluorescence (FAF) 
outside patches of GA also predict subsequent progression (Holz et al, 2007).  In the Age 
Related Eye Disease study, baseline lesion area was an important predictor of subsequent 
lesion growth (AREDS Research Group, 2009).  The GAP natural history study with baseline 
measurements from over 500 patients not only confirmed these associations between lesion 
phenotypic characteristics and lesion growth rates, but also reported that lesion growth is 
more rapid for extrafoveal lesions compared to foveal lesions (Holz et al, 2010).  In the 
current study (BEACON Study) patients with unifocal atrophic lesions, lesions in which the 
total lesion area is greater than 18 mm2 and lesions without perilesional hyperfluorescence 
will be excluded.  The expectation is that this reduction in lesion phenotypic variability will 
decrease the variability of lesion growth rates, decreasing the sample size required to 
demonstrate a treatment effect in a study that is using atrophic lesion growth as the primary 
efficacy variable. 
A number of genetic variants have been associated with both the neovascular and GA forms 
of advanced AMD.  These include variants in complement factor H (CFH), complement 
factor B (CFB), complement factor 2 (C2), complement factor 3 (C3), apolipoprotein E and 
the age related maculopathy susceptibility 2 (ARMS2) locus (Gold et al, 2006; 
Yates et al, 2007; Seddon et al, 2007; Seddon et al, 2009).  Of these CFH, C2, C3, CFB, and 
ARMS2 have been reported to predict the progression from intermediate to advanced AMD 
(Seddon et al, 2007; Francis et al, 2008).  Together these findings prompted 
Scholl et al (2009) and Klein et al (2010) to assess whether specific alleles at these gene loci 
were associated with the rate of atrophic lesion growth.  While these 2 studies confirmed the 
association of the high risk variants for CFH, C2, C3, and ARMS2 with the presence of GA, 
with the exception of ARMS2 in the study by Klein and colleagues (2010), there was no 
association between the high risk variants and atrophic lesion growth. 
The association between genetic variants and treatment response has also been evaluated in 
several studies of advanced AMD.  In a cohort of 397 patients the mean change in best 
corrected visual acuity (BCVA) following 3 intravitreal injections with ranibizumab was a 
10-letter gain in patients homozygous for the non-risk genotype for CFH and ARMS2; in 
comparison, there was no improvement in BCVA in the group of patients homozygous for 
the CFH and ARMS2 high risk alleles (Smailhodzic et al, 2012).  Similar findings have been 
reported in the ARED Study.  In an analysis of a subgroup of category 3 and 4 patients, ie, 
those with the greatest risk for the development of advanced AMD, there was an association 
between treatment response and genetic risk factors.  Within those patients homozygous for 

 
 
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the non-risk CFH allele, 34% treated with placebo versus 11% treated with anti-oxidants plus 
zinc progressed to advanced AMD.  Within those patients homozygous for the high-risk CFH 
allele, 44% of the placebo-treated patients and 39% of the antioxidant-plus-zinc-treated 
patients progressed to advanced AMD (Klein et al, 2008a).  In contrast to these findings, in 
the CATT (Comparison of AMD Treatments Trials) trial, which compared the treatment 
effects of ranibizumab and bevacizumab in 1185 patients with exudative AMD, there was no 
association between the genetic variants for CFH, C3 nor ARMS2 and the response to 
treatment (Hagstrom et al, 2013).  More specifically, there were no high risk alleles that 
predicted final BCVA or change in BCVA, the degree of anatomical response nor the 
number of intravitreal injections.  
In the BEACON study patients will be genotyped using a genome-wide array in an effort to 
uncover novel disease-associated genes.  The variance of lesion growth explained by 
genotyped markers will be analyzed according to standard methods (Fritsche et al, 2016).  A 
generally accepted genome-wide significance threshold will be adopted to determine if a 
variant (and thus a genetic locus) is significantly associated with GA lesion growth.   
In nearly all of the epidemiological and natural history studies of GA, disease progression 
has been based on lesion growth assessments that were derived from color fundus 
photographs (Davis et al, 2005; Klein et al, 2008b; Schatz and McDonald, 1989; 
Sunness et al, 1997; Sunness et al, 1999; Sunness et al, 2007).  With color fundus 
photography, lesion identification is based on an abrupt transition of fundus pigmentation 
which results from the atrophy of RPE cells.  Due to inter-patient variability of fundus 
pigmentation, media opacities, the presence of drusen and small satellites of atrophy, graders 
at reading centers have commonly reported difficulty with reproducibly measuring atrophic 
areas from color fundus photographs (Pirbhai et al, 2005; Scholl et al, 2003; 
Sunness et al, 1999).  An alternative approach for lesion area quantification, FAF imaging, 
has been used to quantify the progression of GA in a large multicenter study (Fundus 
Autofluorescence in Age-related Macular Degeneration [FAM] study) conducted in Germany 
(Bindewald et al, 2005; Holz et al, 2001; Holz et al, 2007; Schmitz-Valckenberg et al, 2006).  
With this technique imaging of atrophic lesions is based on the normal autofluorescence 
properties of RPE cells; the loss of RPE autofluorescence indicates disruption of the 
functional interaction between RPE and photoreceptor cells due to damage or death of 
photoreceptor cells and/or RPE cells (Schmitz-Valckenberg, 2009).  While the loss of these 
cells is also visualized with color fundus photography, lesion boundary discrimination 
appears to be improved with FAF imaging (Sunness et al, 1999; Schmitz-Valckenberg, 2009; 
Schmitz-Valckenberg et al, 2011).  Due to its increased boundary discrimination, FAF 
imaging will be used to evaluate the effect of brimonidine in the BEACON study.  

 
 
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Brimonidine (AGN-190342) is a selective alpha-2 adrenergic agonist with a long history of 
clinical use in the treatment of patients with ocular hypertension and open-angle glaucoma.  
Beyond its intraocular pressure (IOP)-lowering effect, brimonidine has also been reported to 
have cyto/neuroprotective effects (Evans et al, 2003; Tsai and Chang, 2005).  It is postulated 
that the neuroprotective effect of brimonidine is mediated by activation of the alpha-2 
adrenoceptor which is expressed throughout the neurosensory retina and is involved in 
pathways that inhibit apoptosis.  In preliminary data from a rat model of retinal degeneration, 
systemic administration of brimonidine protected photoreceptors from photo-oxidative 
damage, as assessed with optical coherence tomography (OCT) and preserved photoreceptor 
function, as assessed with full-field electroretinography.  The neuroprotective effects of 
brimonidine have also been observed in animal models of retinal vein occlusion, retinal 
ischemia and retinal detachment.  Cytoprotective effects of brimonidine have been 
demonstrated in vitro, in human RPE (ARPE-19 cell line) and Müller cells (MIO-M1 cell 
line) (Ramírez et al, 2016).  The use of brimonidine to preserve structural and functional 
capacity as demonstrated in animals may provide a novel mechanism for reducing the risk of 
retinal degeneration in human diseases such geographic atrophy. 
Brimonidine solution administered by intravitreal injection has a vitreal half-life of 
approximately 1.45 hours.  Sustained retinal drug concentrations of brimonidine can be 
achieved when the drug is formulated into a solid implant composed of a biodegradable 
poly-D,L-lactide (PLA) and poly-D,L-lactide-co-glycolide polymer (PLGA) matrix and 
injected into the vitreous using the Novadur drug delivery system (DDS®).  A formulation of 
this product using brimonidine tartrate salt (Brimonidine Tartrate Posterior Segment DDS or 
Brimonidine DDS [Generation 1]) has been used in animal studies and in clinical Phase 1 
and Phase 2 studies. 
In these human clinical studies Brimonidine DDS (Generation 1) (132 µg or 264 µg) was 
well tolerated (Studies 190342-028D, 190342-030D, 190342-031D, 190342-036, and 
190342-032D).  The majority of the treatment-related adverse effects were ocular and were 
attributed in large part to the injection procedure; the most frequently reported treatment-
related adverse effects were conjunctival hemorrhage and conjunctival hyperemia. 
Study 190342-032D investigated the use of Brimonidine DDS (Generation 1) (132 µg or 
264 µg) compared with a Sham treatment in 117 patients with GA secondary to AMD; 
treatments with the sustained release formulation or Sham treatment were administered at the 
baseline visit and at the month 6 visit.  In this study the safety profile was not different from 
that in clinical studies with a single injection.  Three months after the first injection, the 
increase in atrophic lesion size was significantly smaller, p ≤ 0.032, in both brimonidine-

 
 
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treated groups compared with the Sham group; however, at the 12-month timepoint there 
were no between-group differences in lesion growth rates.  The lack of statistical significance 
at the later timepoint may have been a consequence of the small sample size, the phenotypic 
heterogeneity of the patient population and/or the advanced stage of disease within the 
patient population.  It is also conceivable that the dose and dosing frequency may have been 
insufficient to sustain an effective drug concentration in the retina. 
To address this latter issue vitreous brimonidine levels were quantified over an 8-week time 
period in patients receiving 132 µg or 264 µg Brimonidine DDS (Generation 1) and then 
undergoing a pars plana vitrectomy (Study 190342-036).  A pharmacokinetic model was then 
constructed based on these clinical data along with vitreous and retinal concentrations in 
monkeys treated with the Brimonidine DDS (Generation 1).  Based on the pharmacokinetic 
model, retinal levels in man achieved with the Brimonidine DDS (Generation 1) were 
equivalent to those that preserved photoreceptor function in the acute model of photo-
oxidative damage but only for 30 to 40 days after administration of the implant.  
To support further studies in patients with GA, a new brimonidine sustained-release 
formulation has been developed (Brimonidine Posterior Segment Drug Delivery System 
[Brimonidine DDS (Generation 2)], hereafter called Brimo DDS).  By changing the active 
ingredient from the tartrate salt to the free base, a 50% higher implant drug load can be 
achieved.  Changing the PLGA/PLA polymer blend created a more rapid degradation of the 
polymer matrix, which achieves not only a more rapid release of brimonidine, but also higher 
retinal levels.  With this new formulation, 4 months after administration of the 400-µg 
implant, macular concentrations of brimonidine in monkeys were 2-fold above the effective 
retina concentration in the acute photo-oxidative model.  Pharmacokinetic/pharmacodynamic 
modeling suggests that dosing every 3 months will maintain brimonidine concentrations in 
the retina that are equivalent to the concentrations that protected photoreceptors in an acute 
photo-oxidative model of retinal degeneration. 
In addition to the modified drug formulation, the size of the implants was modified to permit 
their delivery with a smaller needle, ie, a 25-gauge compared with a 22-gauge needle in the 
previous formulation.  Using a smaller needle for implant delivery is expected to result in 
fewer injection-related adverse events, greater patient comfort, and a better product safety 
profile. 
The cyto/neuroprotective effects of Brimonidine DDS (Generation 1) observed in animal 
studies, as well as the safety and effectiveness reported in human studies, suggest that 
brimonidine has the potential for slowing disease progression in patients with geographic 

 
 
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atrophy secondary to AMD.  The improvements in the formulation and the reduction of inter-
patient phenotypic variability, as well as the use of newer ocular imaging modalities, may 
allow better detection of an efficacy signal in this population.  Atrophic lesion area will be 
measured using FAF and correlated with spectral-domain optical coherence tomography (SD-
OCT).  The combination of these imaging modalities will provide both quantitative and 
qualitative assessments of lesion progression.  Structural measurements will be supplemented 
with assessment of photoreceptor function using microperimetry, facilitating correlations 
between functional and structural degeneration at precise areas of the retina.  Genotypic 
analysis will be performed to provide a greater understanding of the relationship between 
specific genes variants and their association with GA progression and/or treatment benefit.   
2 
Study Objectives and Clinical Hypotheses 
2.1 
Study Objectives 
The study objectives are to assess:  (1) the safety of the treatment; (2) the effects of treatment 
on the mean change in atrophic lesion area quantified from FAF images; (3) the effects of 
treatment on the mean change in low luminance BCVA; (4) the effects of treatment on the 
mean change in standard BCVA; (5) the effects of treatment on the mean change in retinal 
sensitivity quantified using scotopic/mesopic microperimetry; and (6) to characterize the 
systemic pharmacokinetic profile of Brimo DDS.  
2.2 
Clinical Hypotheses 
The clinical hypotheses are that: 
• Brimo DDS is safe and well tolerated with repeated intravitreal administration in patients 
with GA secondary to AMD as assessed by the incidence of adverse events 
• Brimo DDS is more effective than Sham treatment in slowing the growth of atrophic 
lesion area and the loss of standard and low luminance BCVA 
3 
Study Design 
This is a multicenter, double-masked, randomized, Sham treatment-controlled, 30-month 
phase 2b study designed to evaluate the safety and efficacy of Brimo DDS in patients with 
GA secondary to AMD.  Patients will be randomized in a 1:1 ratio to receive 400 µg Brimo 
DDS, administered by intravitreal injection, or Sham treatment (control).  The study 
medication will be administered every 3 months from Baseline (Day 1) through Month 21.  
The primary efficacy measure, the mean change in atrophic lesion area as assessed with FAF 
will be assessed at Month 24.  In addition to quantifying structural changes of the retina, 

 
 
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functional assessments will be performed using scotopic/mesopic microperimetry, as well as 
standard and low luminance BCVA.  Total duration of the study for each patient is 30 months 
following randomization/treatment.  
 
  
For patients who do not participate in the microperimetry procedure or patients from sites not 
participating in the microperimetry procedure, there will be only 1 Screening visit, and 
therefore 13 visits over the study duration. 
 
3.1 
Data Review Committee 
A Data Review Committee (DRC) consisting of physicians and trained study personnel, in 
addition to ad hoc internal/external experts, will assess study treatment effects throughout the 
study; these assessments will include a review of unmasked safety data and biodegradation of 
the implant to determine the appropriateness of continuing dosing and enrollment.  The 
composition and activities of the committee are described in the DRC charter, a separate 
document. 
4 
Study Population and Entry Criteria 
4.1 
Number of Patients  
Approximately 300 patients (150 per treatment group) will be enrolled in the study at 
approximately 40 sites.  Two hundred forty patients are expected to reach Month 24 for the 
primary endpoint assessment.  The anticipated dropout rate is 20%. 
4.2 
Study Population Characteristics 
To avoid selection bias, the investigator should ensure that all persons who meet the 
following inclusion and exclusion criteria are offered enrollment in the study.  To ensure that 
the study population will be representative of all eligible patients, no additional exclusions 
can be applied by the investigator.  Selection of patients will exclude all considerations of 
race, occupation, socioeconomic status, and gender.  If both eyes meet all of the 
inclusion/exclusion criteria, the eye with the worst standard BCVA will be selected as the 
study eye.  If both eyes meet all of the inclusion/exclusion criteria and BCVA values are 
identical for both eyes, the right eye will be selected as the study eye. 

 
 
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4.3 
Inclusion Criteria 
The following are requirements for entry into the study: 
General Criteria: 
1. Male or female patients 55 years of age or older as assessed at Screening Visit 1 
 
 
 
 
 
 
The Study Eye must have: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ith 
fundus photography and/or SD-OCT at Screening Visit 1 and confirmed by the CRC 
7. BCVA better than or equal to 45 letters (20/125 Snellen equivalent) at Screening Visit 1 
and the Baseline visit as assessed using the standard ETDRS (Early Treatment of 
Diabetic Retinopathy Study) visual acuity protocol 
 
 

 
 
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For patients participating in microperimetry assessments:   
 
 
 
 
The Fellow Eye must have: 
10. Standard BCVA of 34 letters (Snellen equivalent 20/200) or better at Screening Visit 1 
4.4 
Exclusion Criteria 
The following are criteria for exclusion from participating in the study: 
General Criteria: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Ocular Exclusion Criteria: 
 
 
 
 
 
 
 
10. History or evidence of the following surgeries/procedures in the study eye as assessed at 
Screening Visit 1, including: 
a. Submacular surgery or other intervention for AMD 
b. Vitrectomy 
c. Intraocular retinal laser treatments within the last 3 months prior to Screening Visit 1 
d. Incisional glaucoma surgery 
e. Cataract surgery or laser-assisted in situ keratomileusis (LASIK) within the last 3 
months prior to Screening Visit 1 
11. Periocular or ocular/intraocular infection or inflammation in either eye (such as: 
infectious conjunctivitis, keratitis, scleritis, endophthalmitis) within the 3 months prior to 
Screening Visit 1 
 
 
 
 
 
 
 
 

 
 
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4.5 
Permissible and Prohibited Medications/Treatments 
4.5.1 
Permissible Medications/Treatments 
Therapy considered necessary for the patient’s welfare may be given at the discretion of the 
investigator.  All medications and procedures should be recorded in the electronic case report 
form (eCRF).  If the permissibility of a specific medication/treatment is in question, please 
contact Allergan.  
Use of the following medications is permissible during the study: 
• Alpha-1 antagonists (eg, prazosin, terazosin, doxazosin, labetolol) and other selective 
alpha-antagonists that do not inhibit alpha-2 adrenoceptors 
• Non-ocular use of alpha-2 agonists and alpha-2 antagonists are permissible if used for at 
least 30 days prior to Baseline, and the use of the medication is expected to remain stable 
(dose and dosing regimen) for the duration of the study.  Any changes to such 
medications should be documented on the appropriate eCRFs. 
YAG capsulotomy is recommended to be scheduled no sooner than 2 to 3 weeks before a 
scheduled Brimo DDS injection, or at least 2 to 3 weeks after a Brimo DDS injection. The 
YAG opening should be kept slightly smaller than the periphery of the IOL optic to reduce 
the chance that the Brimo DDS implants will migrate from the vitreous cavity to the anterior 
chamber. 
In case of retinal tear, withhold the study treatment until the tear is successfully treated and 
resolved. Treatment may be re-initiated later at the investigator’s discretion and if the patient 
does not meet any of the discontinuation criteria in Section
 
   
If a patient develops choroidal neovascularization in the fellow eye, study treatment can 
continue in the study eye. The fellow eye should be treated according to best medical 
practice. 
If cataract surgery is necessary, attempt to schedule cataract surgery ≥ 7 days after the most 
recent study treatment. Study treatment may be resumed ≥ 14 days after cataract surgery, 
assuming no surgery-related complications. 

 
 
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4.5.2 
Definition of Females of (Non-) Childbearing Potential and 
Acceptable Contraceptive Methods 
For purposes of this study, females will be considered of childbearing potential unless they 
are naturally postmenopausal or permanently sterilized (ie, hysterectomy).  Natural 
menopause is defined as the permanent cessation of menstrual periods, determined 
retrospectively after a woman has experienced 12 months of amenorrhea without any other 
obvious pathological or physiological cause.  For women of childbearing potential who may 
participate in the study, the following methods of contraception, if properly used, are 
generally considered reliable: hormonal contraceptives (ie, oral, patch, injection, implant), 
male condom with intravaginal spermicide, diaphragm or cervical cap with spermicide, 
vaginal contraceptive ring, intrauterine device, surgical sterilization (bilateral tubal ligation, 
bilateral salpingectomy), vasectomized partner, or sexual abstinence. 
The investigator and each patient will determine the appropriate method of contraception for 
the patient during the participation in the study. 
If a female becomes pregnant during the study, the investigator will notify Allergan 
immediately after the pregnancy is confirmed and the patient will be exited from the study 
after appropriate safety follow-up.  The investigator will (1) notify the patient’s physician 
that the patient was being treated with an investigational drug (Brimo DDS or Sham) and 
(2) follow the progress of the pregnancy.  The investigator should document the outcome of 
the pregnancy and provide a copy of the documentation to Allergan. 
4.5.3 
Prohibited Medications/Treatments 
The decision to administer a prohibited medication/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.  Use of the following 
medications is prohibited during the study: 
• Any periocular injection or intravitreally injected therapy  
• Ocular use (other than the study medication) of brimonidine, apraclonidine, 
oxymetazoline, naphazoline, tetrahydrozoline, or any other medications with known 
alpha-2 agonist activity  
• Inconsistent or intermittent use of systemic medications with known alpha-2 antagonism 
(eg, phentolamine, phenoxybenzamine, yohimbine, risperidone) or medications with 
known alpha-2 agonism (eg, methyldopa, clonidine, guanfacine, tizanidine) 
• Use of roflumilast (Daliresp®) or other oral phosphodiesterase-4 inhibitors 

 
 
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4.5.4 
Escape Medications 
There are no escape medications for this study.  
4.5.5 
Special Diet or Activities 
Patients are not required to fast prior to blood and urine collections for laboratory tests.   
5 
Study Treatments 
5.1 
Study Treatments and Formulations 
Brimonidine DDS Applicator System contains implant dosage of 400 µg 
 
 in a PLA/PLGA biodegradable polymer matrix. 
 
 
 
5.2 
Control Treatment 
The Sham treatment will consist of a needleless DDS Applicator without study medication 
and is provided as a sterile finished product. 
5.3 
Methods for Masking 
The following individuals at the site will be masked to the study treatment for the duration of 
the study:   
• Patients 
• Assessing investigator(s) who performs ocular assessments (excluding post-injection 
assessment and DDS assessment) 
• Study technicians, ie, individuals administering the following study assessments:  
microperimetry, standard BCVA, low luminance BCVA, FAF (standard and quantitative), 
IR, and SD-OCT  
These masked technicians must not perform unmasking procedures such as fundus 
photography.  They must not be present during the study treatment procedure, implant 
assessments, implant photography, or post-injection assessments and they must not 
complete case report forms (CRFs) or have access to other study data.   

 
 
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Masked study site staff members who become aware of the study treatment of an individual 
patient shall not continue to collect efficacy variables (excluding patient-reported outcomes 
[PROs]) for that patient.  
 
 
 
  
CRC staff will be masked to the study treatment for the duration of the study. 
Sponsor personnel masking, including handling of the interim analysis, is detailed in the 
Sponsor Masking Plan.  
5.4 
Treatment Allocation Ratio and Stratification 
Patients will be randomized to treatment groups (Brimo DDS or Sham) in a 1:1 allocation 
ratio.  Randomization will be stratified by region (North America, Europe, and Australia) and 
by atrophic lesion area (≤ 8 mm2 versus > 8 mm2) in the study eye as assessed by FAF 
examination at Screening Visit 1 and quantified by the CRC. 
5.5 
Method for Assignment to Treatment Groups/Randomization 
Prior to initiation of study treatment, each patient who provides informed consent will be 
assigned a patient study number that will serve as the identification number on all study 
documents. 
An automated interactive voice response system/interactive web response system 
(IVRS/IWRS) will be used to manage the randomization and treatment assignment based on 
a randomization scheme prepared by Allergan Biostatistics. 
Study medication will be labeled with medication kit numbers.  The IVRS/IWRS will 
provide the site with the specific medication kit number(s) for each randomized patient at the 
time of randomization.  Sites will dispense study medication according to the IVRS/IWRS 
instructions.  Sites will also call the IVRS or log onto the IWRS at subsequent visits to obtain 
a study medication kit number for dispensing study medication.  Sites will receive the 
IVRS/IWRS confirmation notifications for each transaction.  All notifications are to be 
maintained with the study source documents. 

 
 
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At the time of randomization at Baseline, eligible patients will be randomly assigned to either 
400 µg Brimo DDS or Sham treatment. 
5.6 
Treatment Regimen and Dosing 
Patients who are eligible for the study and have been randomized to receive active treatment, 
400 µg Brimo DDS, will receive treatment during the Baseline visit of the study.  
 
 
 
Patients who are eligible for the study and have been randomized to the Sham treatment will 
receive the Sham treatment during the Baseline visit of the study.  
 
 
5.7 
Storage of Study Medications/Treatments 
The study medication must be stored in a secure area and administered at no cost to the 
patient and only to patients entered into the clinical study.  Administration must be in 
accordance with the conditions specified in this protocol.  
The Brimo DDS Applicator System must be stored at controlled room temperature in the 
original sealed foil pouch; temperature will be monitored by the sites.  Exposure to excessive 
light and heat should be avoided.  Please see the Procedure Manual for further instructions. 
5.8 
Preparation of Study Medications/Treatments 
Prior to study treatment, the study eye of each patient will be anesthetized with topical 
anesthetic and prepared according to the standard protocol detailed in the Procedure Manual.  
The preparation of the patient for treatment (injection) and Sham procedures will be 
identical.  Refer to the Procedure Manual for the detailed instructions. 
5.9 
Treatment Administration 
Brimo DDS 400 µg will be administered by intravitreal injection in the study eye.  The 
implant will be injected into the vitreous of the study eye through the pars plana.  Refer to the 
Procedure Manual for the detailed instructions. 
The Sham treatment is administered using a needleless DDS Applicator.  Refer to the 
Procedure Manual for the detailed instructions. 

 
 
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6 
Response Measures and Summary of Data Collection Methods 
6.1 
Efficacy Measures 
6.1.1 
Primary Efficacy Measure 
• Atrophic lesion area in the study eye as assessed with FAF and quantified by the CRC 
6.1.2 
Secondary Efficacy Measures 
• Low luminance BCVA of the study eye as assessed using a 2.0 log unit neutral density 
filter and the ETDRS visual acuity protocol  
• Standard BCVA of the study eye assessed using the ETDRS visual acuity protocol 
6.1.3 
Other Outcome Measures 
In addition to the primary and secondary efficacy measurements, the following outcomes will 
be measured in the study eye: 
• Retinal sensitivity threshold as assessed with scotopic/mesopic microperimetry 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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6.4 
Examination Procedures, Tests, Equipment, and Techniques 
Additional details about the procedures may be found in the Procedure Manual. 
6.4.1 
Certification of Technicians and Examiners 
To enhance standardization and quality, technicians performing dilated fundus photography, 
fluorescein angiography, FAF (standard and quantitative), near-IR, SD-OCT, and 

 
 
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scotopic/mesopic microperimetry will be certified.  Certification by the CRC of the 
equipment and examiners at each investigative site will occur prior to patient screening.  
6.4.2 
Standard and Low Luminance Best Corrected Visual Acuity 
Standard BCVA will be quantified using the ETDRS visual acuity protocol.  BCVA testing 
should precede any examination requiring contact with the eye.  BCVA should be performed 
following manifest refraction.  Low luminance BCVA will be measured using 2.0 log unit 
neutral density filter and the ETDRS visual acuity protocol.  Certification and procedures for 
performing the standard and low luminance BCVA measurements are included in the 
Procedure Manual.   
6.4.3 
Spectral-domain Optical Coherence Tomography 
SD-OCT images collected in the study may be collected only with the 
 
  A standardized procedure for obtaining  SD-OCT images using 
 
 is included in the 
Procedure Manual.  SD-OCT images from each of the specified study visit will be sent to the 
CRC; images from the Screening Visit 1 will be used to define foveal involvement and 
patient eligibility as confirmed by the CRC. 
6.4.4 
Microperimetry 
Scotopic/mesopic microperimetry will be performed at selected sites.  Patients at these sites 
can enroll into the study if they decline to participate in the scotopic/mesopic microperimetry 
assessments, or if they do not meet inclusion criterion #9 (Section 4.3).  Scotopic/mesopic 
microperimetry assessments may only be performed with the Nidek MP-1 Scotopic (MP-1S) 
microperimeter.  A customized procedure for microperimetry using the Nidek MP-1S is 
included in the Procedure Manual.  Nidek MP-1S images will be sent to the CRC. 
The reproducibility of the mean retinal sensitivity threshold measurements from the repeat 
assessment performed during the Screening Visit 2 will be used to evaluate patient eligibility 
for the microperimetry procedure, as confirmed by the CRC.  The Nidek MP-1S image-
assessment report from each visit, beginning with the Baseline visit, will be submitted to the 
CRC; these reports will include the fundus images submitted in an uncompressed format.   

 
 
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6.4.5 
Confocal Scanning Laser Ophthalmoscopy:  Near-infrared 
Reflectance (3-field) 
A standardized procedure for obtaining near-IR images using the 
 
 is included in the Procedure Manual.  
Three-field images collected at the specified visits will be sent to the CRC.  
6.4.6 
Confocal Scanning Laser Ophthalmoscopy:  Quantitative 
(Central Field) and Standard (3-field) Fundus 
Autofluorescence 
A standardized procedure for obtaining FAF images using the confocal scanning laser 
ophthalmoscopy (cSLO) capability of the 
 
 is included in the Procedure Manual.   
In addition to the standard FAF imaging, quantitative FAF images will be obtained in the 
study eye at the specified study visits (as per Table 1) for assessing changes in 
autofluorescence intensity mapping/retinal sensitivity in patients who participate in the 
microperimetry procedure.  Both the standard FAF and quantitative FAF images will be sent 
to the CRC.  The standard FAF images from Screening Visit 1 will be used by the CRC to 
assess patient eligibility.   
6.4.7 
Fluorescein Angiography 
Fluorescein angiographic imaging should be performed with the 
 
; if this system is not available investigators may collect these images with a 
standard fundus camera based system (the minimum requirements for settings are described 
in the Procedure Manual).  Images collected at the Screening Visit 1 will be used by the CRC 
to confirm patient eligibility.  Images from the Screening Visit 1 and the Exit visit will be 
sent to the CRC.  Fluorescein angiography may be performed at any visit if needed to 
confirm development of choroidal neovascularization. 
6.4.8 
Indocyanine Green Angiography (Optional) 
Indocyanine green (ICG) angiography may be performed during Screening Visit 1 if it is 
considered necessary to exclude patients with late-onset Stargardt disease.  A standardized 
procedure for the collection of ICG angiograms from both eyes is included in the Procedure 
Manual.  
 should be used to collect the images; if 
this system is not available, investigator may collect these images with a standard fundus 

 
 
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camera based system (the minimum requirements for settings are described in the Procedure 
Manual).  Images may be collected at the Screening Visit 1 if the investigator suspects late-
onset Stargardt disease.  If ICG is performed, the images will be sent to the CRC to confirm 
patient eligibility.   
6.4.9 
Dilated Fundus Photography 
Dilated fundus photographic images (fundus reflex, 3-field color imaging, and central field 
red-free photographs) will be collected from both eyes at the Screening Visit 1 and the Exit 
visit.  These fundus images will be kept at the site and copies will be sent to the CRC.  The 
images collected at the Screening Visit 1 will be used by the CRC to confirm patient 
eligibility.   
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 

 
 
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6.5 
Other Study Supplies 
Allergan will make provisions (directly or indirectly) to supply the study sites with 
pregnancy test kits; ETDRS instrumentation (if needed); medications or supplies (eg, anti-
infective ophthalmic solution, local anesthetic eye drop, dilating eye drop, povidone iodine, 
syringe, needles, cotton tip swabs, cellulose sponges), and blood sampling kits for 
pharmacokinetic analysis (at selected sites), genotyping, and gene expression.  Tubes for 
collection of samples for clinical laboratory analysis will be provided by a central laboratory. 
6.6 
Summary of Methods of Data Collection 
Clinical data for this study will be collected in eCRFs using the Phase Forward Inform 
System.  Data entered into the eCRF will correspond to and be supported by source 
documentation maintained at the site.  Data will be transferred to Allergan from the CRC and 
genotyping laboratory. 
7 
Statistical Procedures 
The primary analysis for efficacy will be based on data collected through Month 24.  An 
interim analysis may be performed after 50% of patients complete the Month 18 visit.  Up to 
3 database locks are planned for the study:  an interim lock at Month 18 (50% of patients), 
the primary lock at Month 24, and the final lock at the end of the study (Month 30). 
Statistical methods for data analyses will be detailed in the analysis plan as a separate 
document which will be finalized prior to the first interim lock. 
7.1 
Analysis Populations 
The following 2 populations will be used for statistical analyses:  modified intent-to-treat 
(mITT) and safety. 
The mITT population will include all randomized and treated patients with Baseline and at 
least one post-baseline measurement for the atrophic lesion area.  The mITT population will 
be used for analyses of efficacy variables.  The safety population will include all treated 
patients and will be used for safety analyses.  All analyses will be performed based on the 
randomized treatment. 

 
 
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7.2 
Collection and Derivation of Primary and Secondary Efficacy 
Assessments 
The primary efficacy measure in this study is the atrophic lesion area measured by FAF 
examination.  The primary timepoint for the efficacy analysis is Month 24.   
7.2.1 
Primary Efficacy Variable 
The primary efficacy variable is the change from Baseline in the atrophic lesion area in the 
study eye, assessed with FAF and quantified by the CRC.  
7.2.2 
Secondary Efficacy Variables 
The secondary efficacy variables are (1) change from Baseline in low luminance BCVA in 
the study eye as assessed using a 2.0 log unit neutral density filter and the ETDRS visual 
acuity protocol (2) change from Baseline in standard BCVA in the study eye as assessed with 
the ETDRS visual acuity protocol.  
7.3 
Hypothesis and Methods of Analysis 
7.3.1 
Primary Efficacy Analyses 
The primary efficacy variable is the change from Baseline in atrophic lesion area in the study 
eye.  The primary analysis will use the mITT population and will be based on a mixed model 
for repeated measures (MMRM) that includes treatment, study region (North America, 
Europe, and Australia), analysis visit, and treatment-by-visit interaction as factors as well as 
the baseline value and baseline value-by-analysis visit interaction as covariates.  The least-
squares means (LS means) for change from baseline will be calculated for each group.  
Statistical test for the between-group difference (Brimo DDS versus Sham) in LS means and 
the construction of the corresponding 2-sided 95% confidence intervals will be done using 
the same MMRM model.  If warranted, data transformation will be applied to the effective 
diameter (ED) (such as the square root transformation), and the final statistical analysis for 
the change from baseline will be based on the transformed data. 
7.3.2 
Secondary Efficacy Analyses 
Analysis of data collected for both standard and low luminance BCVA will include change 
from baseline in BCVA scores as the number of letters read correctly and categorical change 
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Analyses will be performed using the mITT population.  MMRM that includes treatment, 
study region (North America, Europe, and Australia), analysis visit, and treatment-by-visit 
interaction as factors as well as the baseline value and baseline value-by-analysis visit 
interaction as covariates will be applied. The LS means for change from baseline will be 
calculated for each group.  Statistical test for the between-group difference (Brimo DDS 
versus Sham) in LS means and the construction of the corresponding 2-sided 95% confidence 
intervals will be done using the same MMRM model. 
 
 
.   
7.3.4 
Safety Analyses 
Statistical analysis for safety will be based on the safety population.  The Medical Dictionary 
for Regulatory Activities (MedDRA) nomenclature will be used to code adverse events and 
biomicroscopy and ophthalmoscopy data.  The number and percent of patients reporting 
adverse events will be tabulated by primary system organ class, preferred term, and severity.  
The summary tables will be generated separately for adverse events reported during the 
screening to baseline period (pre-treatment adverse events) and treatment period (treatment-
emergent adverse events [TEAEs]).  Summaries for TEAEs will be organized into the 
following:  all adverse events regardless of causality; treatment-related adverse events; ocular 
adverse events in the study eye; treatment-related ocular adverse events in the study eye; and 
primary safety measures as outlined in Section 6.3.  Group comparisons will be done using a 
chi-square test or Fisher’s exact test as appropriate. 
 
 
 
 
 
7.4 
Subgroup Analyses 
Analyses of subgroups defined by important baseline disease characteristics (such as lesion 
size), will be performed, if applicable. 

 
 
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7.5 
Sample Size Calculation 
A standard method for measuring disease progression in patients with GA secondary to AMD 
is to quantify the expansion rate of the areas of atrophy.  Over a 12-month period this 
expansion rate typically ranges between 1 and 2 mm2 (Sunness et al, 2007; Holz et al, 2007; 
Holz et al, 2010).  The atrophic lesion expansion rate used in the sample size calculation for 
the current study was from the GAP study (Holz et al, 2010).  The selection of the GAP data 
was based on the large patient population in this natural history study and because of the 
similarities between the GAP study and the current study in both study design and patient 
populations.   
The 12-month lesion expansion rate from the GAP study was 1.73 mm2.  A projected 
24-month expansion rate, 2.8 mm2, was calculated by applying a 20% discount to a linear 
extrapolation of the GAP lesion expansion data.  Based on this lesion expansion rate and 
assuming a common standard deviation of 1.65 mm2, a 2-sided t-test with 90% power and an 
alpha of 0.05 will require a sample size of 120 patients per group to detect a 25% reduction 
from the Sham treatment.  A 25% reduction from the Sham treatment corresponds to a 
treatment difference of 0.70 mm2.  With an anticipated dropout rate of 20%, approximately 
300 patients will be enrolled such that 240 (120 per group) will complete the Month 24 visit. 
The sample size calculations are based on the procedure MTTO-1 in nQuery (v6.01). 
7.6 
Interim Analyses 
An interim analysis may be performed after 50% of patients have completed the Month 18 
visit or have exited early from the study.  To maintain an overall Type I error rate at 0.05 
level, the significance level will be 0.001 for the interim analysis at Month 18 and 0.05 
(Haybittle–Peto method) for the Month 24 analysis.  The purpose of the interim analysis is to 
support the decision making process and the planning of further development. 
To maintain the integrity of the study, individuals who are directly involved in study conduct 
and data management will remain masked to treatment assignment of individual patients until 
study completion.  
 
 
 
 
 
 

 
 
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8.1 
Patient Entry Procedures  
8.1.1 
Overview of Entry Procedures 
Prospective patients as defined by the criteria in Sections 4.3 and 4.4 (inclusion/exclusion 
criteria) will be considered for entry into this study. 
8.1.2 
Informed Consent and Patient Privacy 
The study will be discussed with the patient and a patient wishing to participate must give 
informed consent prior to any study-related procedures or change in treatment.  The patient 
must also give authorization (US only), data protection consent (Europe only), and other 
written documentation in accordance with the relevant country and local privacy 
requirements (where applicable) prior to any study-related procedures or change in treatment.   
Each patient who provides informed consent will be assigned a patient number that will be 
used on patient documentation throughout the study.   
8.2 
Procedures for Final Study Entry 
Patient eligibility based on lesion characteristics, as well as the reproducibility of the retinal 
sensitivity measurements, must be confirmed by the CRC prior to patient randomization.  
Patients at sites participating in scotopic/mesopic microperimetry can enroll into the study if 
they decline to participate in the microperimetry procedure , or if they do not meet inclusion 
criterion #9 (Section 4.3).  In addition, all screening laboratory tests must be performed, and 
the results must be evaluated and determined to be acceptable to the investigator prior to 
patient randomization into the study.  Screening laboratory tests may be repeated once at the 
discretion of the investigator or Allergan. 
Female patients of childbearing potential must have a negative pregnancy test result prior to 
entry into the study. 
A patient is considered to have entered the study at the time of randomization to treatment on 
Day 1.  See Section 5.5 for the method for assignment to treatment groups/randomization. 

 
 
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8.4 
Instructions for the Patients 
If a site dispenses pre- and/or post-injection anti-infectives, at the time the anti-infectives are 
dispensed, the patient should be instructed when and how to use them. 
8.5 
Unscheduled Visits 
Additional examinations may be performed as necessary to ensure the safety and wellbeing 
of patients during the study.  The eCRF should be completed for each unscheduled visit. 
8.6 
Compliance With Protocol 
Allergan must be informed of any patients who are inadvertently enrolled despite significant 
deviation from protocol-specified criteria.  A decision regarding the patient’s continued 
participation will be made on a case-by-case basis. 
8.7 
Early Discontinuation of Patients 
Patients may voluntarily withdraw from the study at any time.  The investigator may stop the 
patient’s participation at any time.  Notification of patient discontinuation from the study and 
the reason for discontinuation will be made to Allergan and will be clearly documented on 
the appropriate CRF.   

 
 
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Patients who develop neovascular AMD must be discontinued.  Any patient who develops a 
concomitant retinal disorder in the study eye that prevents retinal visualization and 
quantification of the area of atrophic lesions, or causes a sustained ≥ 30 letter loss of BCVA 
(a sustained loss is defined as a loss evident on 2 consecutive study visits) must be 
discontinued. 
For patients who discontinue from the study early, every effort should be made to have these 
patients return to the clinical center for completion of the exit visit.  Additionally, patients 
who discontinue from the study early should be encouraged to return to the clinical center for 
an ophthalmological evaluation 12 weeks after their most recent study treatment.  Adverse 
events leading to patient early discontinuation must be followed-up as appropriate. 
8.7.1 
Treatment Failures 
Allergan considers the benefit-risk of study participation to be positive, and does not 
recommend study discontinuation due to treatment failure.  Currently, there are no approved 
treatments for GA, and consequently there are no standard-of-care treatment options 
available for patients who fail study treatments.  Further, inclusion of treatment failure 
criteria in a masked study may introduce bias.  As an example, treatment failure criteria 
based on lesion progression may apply unequally by treatment assignment (Sham versus 
active), where potentially more Sham-treated patients would be identified as treatment 
failures.  Likewise, removal of patients who fail active treatment would also create a bias 
towards the appearance of more significant study drug effects. 
Results from clinical studies to date suggest a positive benefit-risk profile of the study 
treatment.  The Phase 2a clinical study 190342-032D results in patients with GA suggest a 
modest effect of Brimo DDS.  In the 190342-032D study, patients treated with Brimo DDS 
(Generation 1) 264 µg experienced a 27.4% reduction in GA progression rate at the 12-month 
primary timepoint compared with sham-treated patients.  Exploratory analysis of these data 
(Kuppermann et al, 2017) indicates that the effects of Brimo DDS may be even larger in a 
subpopulation of fast-progressing patients (defined as patients with baseline GA ≥ 9 mm2).  
Reductions in progression rate in this subpopulation were nearly 38% and this effect was 
statistically significant.  As a progressive disease, continuation of treatment may be necessary 
to realize a clinically meaningful outcome on disease progression.  Clinical study safety 
results to date, including a long-term safety study, suggest that Brimo DDS is well tolerated, 
and risks associated with the study treatment are mainly related to the intravitreal injection.  
Likewise, patients randomized to Sham have no increased risk with additional Sham 
treatments, as these are needleless.  Given these considerations, Allergan considers the 

 
 
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preponderance of evidence to favor study participation, as compared with absence of 
treatment.  Therefore, criteria for treatment failure are not included in this protocol. 
8.8 
Study Termination 
The study may be stopped at his/her study site at any time by the site investigator.  Allergan 
may stop the study (and/or the study site) for any reason with appropriate notification.  
9 
Adverse Events  
Adverse events occurring during the study will be recorded on an adverse event eCRF.  If 
adverse events occur, the first concern will be the safety of the study participants.  
9.1 
Definitions 
9.1.1 
Adverse Event 
An adverse event is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product.  In addition, during the screening period, adverse events 
will be assessed regardless of the administration of a pharmaceutical product.   
Progression of the treatment indication, including new or worsening of anticipated clinical 
signs or symptoms, which are collected as clinical efficacy variables and assessed as 
unequivocally associated with the disease progression and/or lack of efficacy, should not be 
reported as adverse events unless the disease progression is greater than anticipated in the 
natural course of the disease. 
Note:  Adverse events must be collected once informed consent has been obtained, regardless 
of whether or not the patient has been administered study drug. 
Adverse events will be assessed, documented, and recorded in the eCRF throughout the study 
(ie, after informed consent has been obtained).  At each visit, the investigator will begin by 
querying for adverse events by asking each patient a general, non-directed question such as 
“How have you been feeling since the last visit?”  Directed questioning and examination will 
then be done as appropriate.  All reported adverse events will be documented on the 
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9.1.2 
Serious Adverse Event 
A serious adverse event is any adverse event occurring at any dose that results in any of the 
following outcomes:  death, a life-threatening adverse event, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a 
congenital anomaly/birth defect.  Important medical events that may not result in death, be 
life threatening, or require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, they may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  (See Section 9.3 for procedures for reporting a serious adverse event.) 
Allergan considers all cancer adverse events as serious adverse events.  In addition, Allergan 
considers any abortion (spontaneous or nonspontaneous) as a serious adverse event. 
Pre-planned surgeries or procedures for pre-existing, known medical conditions for which a 
patient requires hospitalization are not reportable as serious adverse events. 
Any pre-planned surgery or procedure should be clearly documented in the site source 
documents by the medically qualified investigator at the time of the patient’s entry into the 
study.  If it has not been documented at the time of the patient’s entry into the study, then it 
should be documented as a serious adverse event and reported to Allergan. 
9.1.3 
Severity 
A clinical determination will be made of the intensity of an adverse event.  The severity 
assessment for a clinical adverse event must be completed using the following definitions as 
guidelines: 
Mild 
Awareness of sign or symptom, but easily tolerated. 
Moderate 
Discomfort enough to cause interference with usual activity. 
Severe 
Incapacitating with inability to work or do usual activity. 
Not applicable 
In some cases, an adverse event may be an “all or nothing” finding 
which cannot be graded. 
 
9.1.4 
Relationship to Study Drug or Study Procedure 
A determination will be made of the relationship (if any) between an adverse event and the 
study drug or study procedure, as applicable.  A causal relationship is present if a 

 
 
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determination is made that there is a reasonable possibility that the adverse event may have 
been caused by the drug or study procedure.   
Note:  a study procedure occurring during the screening/baseline period can include a 
washout of medication or introduction of a run-in medication or study required diagnostic 
procedure.   
For treatment-related adverse events, the investigator will note on the eCRF whether the 
event is related to the study drug (DDS) and/or the applicator, and/or the insertion procedure. 
9.2 
Procedures for Reporting Adverse Events 
Any adverse event must be recorded on the appropriate CRF. 
All adverse events that are drug-related and unexpected (not listed as treatment-related in the 
current Investigator’s Brochure) must be reported to the governing Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) as required by the IRB/IEC, local 
regulations, and the governing health authorities.  Any adverse event that is marked 
“ongoing” at the exit visit must be followed-up as appropriate. 
9.3 
Procedures for Reporting a Serious Adverse Event 
Any serious adverse event occurring during the study period (beginning with informed 
consent) and any serious ocular adverse event occurring within 4 months after the last dose 
of study treatment must be immediately reported but no later than 24 hours after learning of a 
serious adverse event.   
Serious adverse events must be reported to Allergan as listed on the Allergan Study Contacts 
Page and recorded on the serious adverse event form.  All patients with a serious adverse 
event must be followed up and the outcomes reported.  The investigator must supply Allergan 
and the IRB/IEC with any additional requested information (eg, autopsy reports and 
discharge summaries).  
In the event of a serious adverse event, the investigator must: 
1. Notify Allergan immediately by fax or email using the serious adverse event form 
(contact details can be found on page 1 of the serious adverse event form; phone numbers 
and relevant Allergan personnel contacts are also on the front page of protocol). 
2. Obtain and maintain in his/her files all pertinent medical records, information, and 
medical judgments from colleagues who assisted in the treatment and follow-up of the 
patient. 

 
 
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3. Provide Allergan with a complete, written description of the adverse event(s) on the 
serious adverse event form describing the event chronologically, including any treatment 
given (eg, medications administered, procedures performed) for the adverse event(s).  
Summarize relevant clinical information about the event:  signs, symptoms, diagnosis, 
clinical course and relevant clinical laboratory tests, etc.  Include any additional or 
alternative explanations for the causality which includes a statement as to whether the 
event was or was not related to the use of the investigational drug. 
4. Promptly inform the governing IRB/IEC of the serious adverse event as required by the 
IRB/IEC, local regulations, and the governing health authorities. 
9.4 
Procedures for Unmasking of Study Medication 
When necessary for the safety and proper treatment of the patient, the investigator can 
unmask the patient’s treatment assignment to determine which treatment has been assigned 
and institute appropriate follow-up care.  When possible, the Allergan Medical Safety 
Physician should be notified prior to unmasking study medication.  The investigator should 
inform the Allergan Medical Safety Physician of the unmasking if there is no notification 
prior to the unmasking.   
The treatment assignment for the patient can be determined by designated site personnel 
calling into the IVRS or IWRS system via password protected access.  The reason for 
breaking the code must be recorded in the patient’s source documents. 
10 
Administrative Items 
This protocol is to be conducted in accordance with the applicable Good Clinical Practice 
(GCP) regulations and guidelines, eg, the International Conference on Harmonisation (ICH) 
Guideline on GCP. 
10.1 
Protection of Human Patients 
10.1.1 
Compliance With Informed Consent Regulations (US 21 CFR 
Part 50) and Relevant Country Regulations 
Written informed consent is to be obtained from each patient prior to any study-related 
activities or procedures in the study, and/or from the patient’s legally authorized 
representative.  If the patient is under the legal age of consent, the consent form must be 
signed by the legally authorized representative in accordance with the relevant country and 
local regulatory requirements. 

 
 
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10.1.2 
Compliance With IRB or IEC Regulations 
This study is to be conducted in accordance with IRB regulations (US 21 CFR Part 56.103) 
or applicable IEC regulations.  The investigator must obtain approval from a properly 
constituted IRB/IEC prior to initiating the study and re-approval or review at least annually.  
Allergan is to be notified immediately if the responsible IRB/IEC has been disqualified or if 
proceedings leading to disqualification have begun.  Copies of all IRB/IEC correspondence 
with the investigator should be provided to Allergan. 
10.1.3 
Compliance With Good Clinical Practice 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines.  
10.1.4 
Compliance With Electronic Records; Electronic Signatures 
Regulations (US 21 CFR Part 11) 
This study is to be conducted in compliance with the regulations on electronic records and 
electronic signature. 
10.2 
Changes to the Protocol 
The investigator must not implement any deviation from or changes to the protocol without 
approval by Allergan and prior review and documented approval/favorable opinion from the 
IRB/IEC of a protocol amendment, except where necessary to eliminate immediate hazards 
to study patients, or when the changes involve only logistical or administrative aspects of the 
study (eg, change in monitors, change of telephone numbers). 
10.3 
Patient Confidentiality 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study drug may ultimately be marketed, but the 
patient’s name will not be disclosed in these documents.  The patient’s name may be 
disclosed to the sponsor of the study, Allergan, or the governing health authorities or the 
Food and Drug Administration if they inspect the study records.  Appropriate precautions will 
be taken to maintain confidentiality of medical records and personal information. 

 
 
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10.3.1 
Patient Privacy 
Written authorization (US sites only), data protection consent (European sites only), and 
other documentation in accordance with the relevant country and local privacy requirements 
(where applicable) are to be obtained from each patient prior to enrollment into the study.  
These authorizations are to be obtained from each patient and/or from the patient’s legally 
authorized representative in accordance with the applicable privacy requirements (eg, the 
Health Insurance Portability and Accountability Act (“HIPAA”) Standards for Privacy of 
Individually Identifiable Health Information, EU Data Protection Directive 95/46/EC [“EU 
Directive”]). 
In accordance with HIPAA requirements, additional purposes of this study include the 
following:  to publish anonymous patient data from the study; and to create and maintain a 
data repository. 
10.4 
Documentation 
10.4.1 
Source Documents 
Source documents may include a patient’s medical records, hospital charts, clinic charts, the 
investigator’s patient study files, as well as the results of diagnostic tests such as X-rays, 
laboratory tests, and electrocardiograms.  The investigator’s copy of the CRFs serves as part 
of the investigator’s record of a patient’s study-related data.   
The following information should be entered into the patient’s medical record and/or 
maintained as source documents: 
• Patient’s name 
• Patient’s contact information 
• The date that the patient entered the study, patient number, and patient randomization (or 
medication kit) number 
• The study title and/or the protocol number of the study and the name of Allergan 
• A statement that informed consent was obtained (including the date); a statement that 
written authorization (US sites only), data protection consent (EU sites only), or other 
country and local patient privacy required documentation for this study has been obtained 
(including the date) 
• Dates of all patient visits 
• Medical history and ophthalmic history 

 
 
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• All concurrent medications (list all prescription and non-prescription medications being 
taken at the time of enrollment.  At each subsequent visit, changes to the list of 
medications should be recorded.) 
• Visual acuity worksheets (standard BCVA and low luminance BCVA) 
• Results of abnormal findings from complete ophthalmic examination (including external 
examination of the eye and adnexa, screening for eyelid/pupil responsiveness, slit-lamp 
biomicroscopy, indirect ophthalmoscopy, dilated fundus examination, and IOP) 
• Occurrence and status of any adverse events 
• The date the patient exited the study, and a notation as to whether the patient completed 
the study or reason for discontinuation 
• Copies of the laboratory reports generated by the central laboratory for the analysis of 
blood and urine samples 
• SD-OCT electronic files (including back-up files) 
• Nidek MP-1S microperimetry electronic files (including back-up files) 
• cSLO 3-field near-IR electronic files (including back-up files) 
• cSLO 3-field FAF electronic files (including back-up files) 
• cSLO central field qFAF electronic files (including back-up files) 
• Fluorescein angiography electronic files (including back-up files) 
• Dilated fundus photography (fundus reflex, 3-field color imaging, central field red-free 
photograph) electronic files (including back-up files)  
• ICG angiography (if ICG is performed) files (including back-up files) 
• Procedure notes of the study treatment procedure should include the following: 
o date and time of the procedure  
o evaluation of the injection site 
o location of the injection to the nearest clock hour 
o complications, if any 
 
 
10.4.2 
Case Report Form Completion 
The investigator is responsible for ensuring that data are properly recorded on each patient’s 
CRFs and related documents.  An investigator who has signed the protocol signature page 
should personally sign for the CRFs (as indicated in the CRFs) to ensure that the 
observations and findings are recorded on the CRFs correctly and completely.  The CRFs are 
to be submitted to Allergan in a timely manner at the completion of the study, or as otherwise 
specified by Allergan. 

 
 
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10.4.3 
Study Summary 
An investigator’s summary will be provided to Allergan within a short time after the 
completion of the study, or as designated by Allergan.  A summary is also to be provided to 
the responsible IRB/IEC. 
10.4.4 
Retention of Documentation 
All study related correspondence, patient records, consent forms, patient privacy 
documentation, records of the distribution and use of all investigational products, and copies 
of CRFs should be maintained on file. 
For countries falling within the scope of the ICH guidelines, the Allergan-specific essential 
documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirement(s) or if needed by Allergan. 
In addition, for countries not falling within the scope of the ICH guidelines, local regulatory 
requirements should be followed regarding the retention of clinical study documentation. 
Allergan requires that it be notified in writing if the investigator wishes to relinquish 
ownership of the data so that mutually agreed-upon arrangements can be made for transfer of 
ownership to a suitably qualified, responsible person. 
10.5 
Labeling, Packaging, and Return or Disposal of Study 
Medications/Treatments 
10.5.1 
Labeling/Packaging 
Study medication will be packaged, labeled, and supplied by Allergan.  The assembled 
Brimo DDS Applicator System is individually packaged in foil pouches with desiccant and 
sealed. The entire foil pouch package is sterilized.  Each foil pouch is packaged in a carton 
with a single-panel label and a unique identifier.  The medication will be identified as 
containing an investigational compound or Sham. 

 
 
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10.5.2 
Clinical Supply Inventory 
The investigator must keep an accurate accounting of the number of investigational units 
received from Allergan, dispensed to the patients, and the number of units returned to 
Allergan during and at the completion of the study.  A detailed inventory must be completed 
for the study medication.  The study medication must be dispensed only by an appropriately 
qualified person to patients in the study.  The medication is to be used in accordance with the 
protocol by patients who are under the direct supervision of an investigator.   
10.5.3 
Return or Disposal of Study Medications/Treatments 
All used applicators shall be disposed of on-site by unmasked site personnel, using a standard 
syringe sharps container, and destroyed according to the site’s sharps disposal procedures. 
All unused investigational product kits, attributed or not attributed to patients, and 
malfunctioning applicators shall be returned to a third party contractor as designated by 
Allergan.  See the Procedure Manual for details. 
10.6 
Monitoring by the Sponsor 
A representative of Allergan will monitor the study on a periodic basis.  The determination of 
the extent and nature of monitoring will be based on considerations such as the objective, 
purpose, design, complexity, blinding, size, and endpoints of the study.   
Authorized representatives of Allergan or regulatory authority representatives will conduct 
on-site visits to review, audit and copy study-related documents.  These representatives will 
meet with the investigator(s) and appropriate staff at mutually convenient times to discuss 
study-related data and questions. 
10.7 
Handling of Biological Specimens 
Samples of blood and urine for evaluation of hematology, chemistries, and urinalysis will be 
analyzed at a centralized clinical laboratory with certification from a recognized accreditation 
agency (eg, College of American Pathology [CAP] or Clinical Laboratory Improvement 
Amendments [CLIA] certification).  
Blood samples obtained at selected sites will be analyzed for AGN-190342 by an Allergan-
designated laboratory using a validated method.  This laboratory will meet Good Laboratory 
Practice requirements. 

 
 
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Blood samples obtained for genotyping and gene expression analysis will be sent to the 
central laboratory for storage until the samples can be sent to the Institute of Human Genetics 
at the University of Regensburg for analysis using a validated method.  This laboratory meets 
Good Laboratory Practice requirements. 
Details about the handling, processing, and shipment of all biological specimens are provided 
in the Procedure Manual.   
All samples will be destroyed by Allergan or Allergan designee.  Allergan shall have full 
ownership rights to any biological specimens/samples derived from the study. 
10.8 
Publications 
Allergan as the sponsor, has proprietary interest in this study. Authorship and manuscript 
composition will reflect joint cooperation between multiple investigators and sites and 
Allergan personnel.  Authorship will be established prior to the writing of the manuscript.  As 
this study involves multiple centers, no individual publications will be allowed prior to 
completion of the final report of the multicenter study except as agreed with Allergan.   
10.9 
Coordinating Investigator 
A signatory Coordinating Investigator will be designated prior to the writing of the Clinical 
Study Report. 

 
 
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11 
References 
AREDS Research Group.  Change in area of geographic atrophy in the Age-Related Eye 
Disease Study.  Arch Ophthalmol. 2009;127:1168-1174. 
Bindewald A, Bird AC, Dandekar SS, Dolar-Szczasny J, Dreyhaupt J, Fitzke FW, et al.  
Classification of fundus autofluorescence patterns in early age-related macular disease.  
Invest Ophthalmol Vis Sci. 2005;46(9):3309-3314. 
Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY, et al (ANCHOR Study 
Group). Ranibizumab versus verteporfin for neovascular age-related macular degeneration.  
N Engl J Med. 2006;355:1432-1444.   
Chakravarthy U, Augood C, Bentham GC, de Jong PTVM, Rahu M, Seland J, Subrane G, 
et al. Cigarette smoking and age-related macular degeneration in the EUREYE Study. 
Ophthalmol. 2007;114:1157-1163. 
Davis MD, Gangnon RE, Lee LY, Hubbard LD, Klein BE, Klein R, et al. The Age-Related 
Eye Disease Study severity scale for age-related macular degeneration: AREDS Report 
No. 17. Arch Ophthalmol. 2005;123:1484-1498. 
Evans DW, Hosking SL, Gherghel D, Bartlett JD. Contrast sensitivity improves after 
brimonidine therapy in primary open angle glaucoma: a case for neuroprotection. 
Br J Ophthalmol. 2003;87:1463-1465. 
Francis PJ, Zhang H, DeWan A, Hoh J, Klein ML.  Joint effects of polymorphisms in 
HTRA1, LOC387715/ARMS2, and CFH genes on AMD in a Caucasian population.  
Mol Vis. 2008;14:1395-1400. 
Friedman DS, O'Colmain BJ, Muñoz B, Tomany SC, McCarty C, de Jong PT, et al. 
Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol. 
2004;122(4):564-572. 
Fritsche LG, Loenhardt T, Janssen A, Fisher SA, Rivera A, Keilhauer CN, et al. Age-related 
macular degeneration is associated with an unstable ARMS2 (LOC 387715) mRNA.  
Nat Genet. 2008;40:892-896. 
Fritsche LG, Igl W, Bailey JN, Grassmann F, Sengupta S, Bragg-Gresham JL, et al. A large 
genome-wide association study of age-related macular degeneration highlights contributions 
of rare and common variants. Nat Genet. 2016 Feb;48(2):134-43 

 
 
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Gold B, Merriam JE, Zernant J, Hancox LS, Taiber AJ, Gehrs K, et al.  Variation in factor B 
(BF) and complement component 2 (C2) genes is associated with age-related macular 
degeneration.  Nat Genet. 2006;38:458-462. 
Hagstrom SA, Ying G-s, Pauer GTJ, Sturgill-Short GM, Huang J, Callanan DG, et al.  
Pharmacogenetics for genes associated with age-related macular degeneration in the 
comparison of AMD treatments Trials (CATT). Ophthalmol. 2013;120:593-599. 
Heier JS, Brown DM, Chong V, Korobelnik J-F, Kaiser PK, Nguyen QD, et al. Intravitreal 
Aflibercept (VEGF Trap-Eye) in wet age-related macular degeneration. Ophthalmol. 
2012;119:2537-2548. 
Holz FG, Bellman C, Staudt S, Schütt F, Völcker HE. Fundus autofluorescence and 
development of geographic atrophy in age-related macular degeneration. Invest Ophthalmol 
Vis Sci. 2001;42(5):1051-1060. 
Holz FG, Bindewald-Wittich A, Fleckenstein M, Dreyhaupt J, Scholl HP, Schmitz-
Valckenberg S; FAM-Study Group. Progression of geographic atrophy and impact of fundus 
autofluorescence patterns in age-related macular degeneration. Am J Ophthalmol. 
2007;143(3):463-472. 
Holz, FG, Schmidt-Valckenberg S, Fleckenstein M, Jaffe GJ, Hohman T. Lesion 
characteristics and progression in the natural history of Geographic Atrophy (GAP) Study. 
Invest Ophthalmol Vis Sci. 2010; 94:a141.  
Klein ML, Ferris FL, Francis PJ, Lindblad AS, Chew Ey, Hamon SC, et al.  Progression of 
geographic atrophy and genotype in age-related macular degeneration.  Ophthalmol. 
2010;117:1554-1559. 
Klein ML, Francis PJ, Rosner B, Reynolds R, Hamon SC, Schultz DW, et al. CFH and 
LOC387715/ARMS2 genotypes and treatment with antioxidants and zinc for age-related 
macular degeneration.  Ophthalmol. 2008a;115:1019-1025. 
Klein R, Klein BE, Knudtson MD, Meuer SM, Swift M, Gangnon RE. Fifteen-year 
cumulative incidence of age-related macular degeneration: the Beaver Dam Eye Study. 
Ophthalmol. 2007;114:253-262. 
Klein R, Klein BE, Lee KE, Cruickshanks KJ, Gangnon RE. Changes in visual acuity in a 
population over a 15-year period: the Beaver Dam Eye Study. Am J Ophthalmol. 
2006;142:539-549.e2. 

 
 
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Klein R, Meuer SM, Knudtson MD, Klein BE.  The epidemiology of progression of pure 
geographic atrophy: the Beaver Dam Eye Study.  Am J Ophthalmol. 2008b;146:692-699. 
Kuppermann BD, Patel SS, Boyer DS, Augustin AJ, Freeman WR, Kim T, et al. Brimonidine 
Drug Delivery System (DDS) Generation 1 in Patients with Geographic Atrophy:  Post-hoc 
analysis of a Phase 2 Study. Poster presentation at The Association for Research and Vision 
in Ophthalmology Annual Conference; 2017 May 7-11; Baltimore, MD 
Nowak JZ. Age-related macular degeneration (AMD): pathogenesis and therapy. Pharmacol 
Rep. 2006;58:353-363. 
Pirbhai A, Sheidow T, Hooper P. Prospective evaluation of digital non-stereo color fundus 
photography as a screening tool in age-related macular degeneration. Am J Ophthalmol. 
2005;139(3):455-461. 
Rainen L, Oelmueller U, Jurgensen S, Wyrich R, Ballas C, Schram J, et al.  Stabilization of 
mRNA expression in whole blood samples. Clin Chem. 2002; 48(11):1883-1890. 
Ramírez C, Cáceres-del-Carpio J, Chu J, Chu J, Moustafa MT, Chwa M, et al. Brimonidine 
can prevent in vitro hydroquinone damage on retinal pigment epithelium cells and retinal 
Müller cells. J Ocul Pharmacol Ther. 2016; 32(2):102-108. 
Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, et al (MARINA Study 
Group). Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 
2006; 355:1419-1431. 
Schatz H, McDonald HR. Atrophic macular degeneration. Rate of spread of geographic 
atrophy and visual loss. Ophthalmol. 1989;96(10):1541-1551. 
Schmitz-Valckenberg S, Bindewald-Wittich A, Dolar-Szczasny J, Dreyhaupt J, Wolf S, 
Scholl HP, et al.; Fundus Autofluorescence in Age-Related Macular Degeneration Study 
Group. Correlation between the area of increased autofluorescence surrounding geographic 
atrophy and disease progression in patients with AMD. Invest Ophthalmol Vis Sci. 
2006;47(6):2648-2654. 
Schmitz-Valckenberg S, Fleckenstein M, Scholl HP, Holz FG. Fundus autofluorescence and 
progression of age-related macular degeneration. Surv Ophthalmol. 2009;54(1):96-117. 

 
 
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Schmitz-Valckenberg S, Brinkmann CK, Alten F, Hermann P, Stratmann NK, Gobel AP, et al.  
Semiautomated image processing method for identification and quantification of geographic 
atrophy in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2011;52:7640-7646. 
Scholl HP, Fleckenstein M, Fritsche LG, Schmitz-Valckenberg S, Göbel A, Adrion C, et al. 
CFH, C3 and ARMS2 are significant risk loci for susceptibility but not for disease 
progression of geographic atrophy due to AMD. PLoS One. 2009;4(10):e7418. 
Scholl HP, Peto T, Dandekar S, Bunce C, Xing W, Jenkins S, et al. Inter- and intra-observer 
variability in grading lesions of age-related maculopathy and macular degeneration. Graefes 
Arch Clin Exp Ophthalmol. 2003;241(1):39-47. 
Seddon JM, Francis PJ, George S, Schultz DW, Rosner B, Klein ML. Association of CFH 
Y402H and LOC387715 A69S with progression of age-related macular degeneration. JAMA. 
2007;297:1793-1800. 
Seddon JM, Reynolds R, Maller J, Fagerness JA, Daly MJ, Rosner B.  Prediction model for 
prevalence and incidence of advanced age-related macular degeneration based on genetic, 
demographic and environmental variables. Invest Ophthalmol Vis Sci. 2009;50:2044-2053. 
Silveira AC, Morrison MA, Ji F, Xu H, Reinecke JB, Adams SM, et al.  Convergence of 
linkage, gene expression and association data demonstrates the influence of the RAR-related 
orphan receptor alph (RORA) gene on neovascular AMD:  A systems biology based 
approach.  Vision Res. 2010;50:698-715. 
Smailhodzic D, Muether PS, Chen J, Kwestro A, Zhang AY, Omar A, et al.  Cumulative 
effect of risk alleles in CFH, AMS2 and VEGFA on the response to ranibizumab treatment in 
age-related macular degeneration.  Ophthalmol. 2012;119:2304-2311. 
Sunness JS, Applegate CA, Bressler NM, Hawkins BS. Designing clinical trials for age-
related geographic atrophy of the macula. Retina. 2007;27:204-210. 
Sunness JS, Gonzales-Baron J, Applegate CA, Bressler NM, Tian Y, Hawkins B, et al.  
Enlargement of atrophy and visual acuity loss in the geographic atrophy form of age related 
macular degeneration.  Ophthalmol. 1999;106:1768-1779. 
Sunness JS, Rubin GS, Applegate CA, Bressler NM, Marsh MJ, Hawkins BS, et al.  Visual 
function abnormalities and prognosis in eyes with age-related geographic atrophy of the 
macula and good visual acuity. Ophthalmol. 1997;104:1677-1691. 

 
 
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Sunness JS, Rubin GS, Broman A, Applegate CA, Bressler NM, Hawkins BS. Low 
luminance visual dysfunction as a predictor of subsequent visual acuity loss from geographic 
atrophy in age related macular degeneration.  Ophthalmol. 2008;115(9):1480-1488, 
1488.el-2. 
Tsai JC, Chang HW. Comparison of the effects of brimonidine 0.2% and timolol 0.5% on 
retinal nerve fiber layer thickness in ocular hypertensive patients: a prospective, unmasked 
study. J Ocul Pharmacol Ther. 2005;21:475-482. 
Whitmore SS, Braun TA, Skeie JM, Haas CM, Sohn EH, Stone EM, et al.  Altered gene 
expression in dry age-related macular degeneration suggests early loss of choroidal 
endothelial cells. Molecular Vision. 2013;19:2274-2297. 
Yates JRW, Sepp T, Matharu BK, Khan JC, Thurlby DA, Shahid H, et al. Complement C3 
variant and the risk of age-related macular degeneration.  N Engl J Med. 2007;357:553-561. 

 
 
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12 
Attachments 
12.1 
Glossary of Terms and Abbreviations 
Term/Abbreviation 
Definition 
AMD 
age-related macular degeneration 
AREDS 
Age-Related Eye Disease Study 
ARMS2 
age related maculopathy susceptibility 2 [locus] 
BCVA 
best corrected visual acuity 
Brimo DDS® 
Brimonidine Posterior Segment Drug Delivery System 
BUN 
blood urea nitrogen 
C2 
complement factor 2  
C3 
complement factor 3  
CFB 
complement factor B 
CFH 
complement factor H 
CRC 
central reading center 
CRF 
case report form 
cSLO 
confocal scanning laser ophthalmoscopy 
DRC 
Data Review Committee 
DDS® 
Drug Delivery System 
eCRF 
electronic case report form 
ED 
effective diameter 
 
 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
EU 
European Union 
FAF 
fundus autofluorescence 
GA 
geographic atrophy 
 
  
GCP 
Good Clinical Practices 
HIPAA 
Health Insurance Portability and Accountability Act 
ICG 
indocyanine green 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IOP 
intraocular pressure 
IR 
infrared reflectance 
IRB 
Institutional Review Board 

 
 
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IVRS 
interactive voice response system 
IWRS 
interactive web response system 
LASIK 
Laser-Assisted in situ Keratomileusis 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
MMRM 
mixed model for repeated measures 
MP-1S 
MP-1 Scotopic    
 
 
OCT 
optical coherence tomography 
PLA 
poly-(D,L-lactide)  
PLGA 
poly-(D,L-lactide-co-glycolide) 
PRO 
patient-reported outcome 
qFAF 
quantitative fundus autofluorescence 
RBC 
red blood cell 
RPE 
retinal pigment epithelium 
SD-OCT 
spectral-domain optical coherence tomography 
 
 
US 
United States 
VEGF 
vascular endothelial growth factor 
WBC 
white blood cell 
YAG 
yttrium aluminum garnet 

 
 
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12.2 
Protocol Amendment Summary Amendment 1 
Title:  Safety and Efficacy of Brimonidine Posterior Segment Drug Delivery System in 
Patients with Geographic Atrophy Secondary to Age-related Macular Degeneration 
Protocol 190342-038 Amendment 1 
Date of Amendment:  March 2014 
Amendment Summary 
This summary includes changes made to Protocol 190342-038 (approved August 2013).   
Following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes.  Minor editorial and document formatting 
revisions have not been summarized. 
Section 
Revision 
Rationale 
Investigator 
Signature Page 
Updated text and removed all but 1 
investigator signature space 
To make consistent with current version 
of protocol template 
Summary 
Revised wording for BCVA entry 
criteria 
Deleted (mm2) following lesion 
area for primary efficacy variable 
For clarification 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 4.5.3 
Added roflumilast as prohibited 
medication 
Roflumilast would have confounding 
effect on the study 
 
 
 

 
 
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Section 
Revision 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
.   
Section 7.3.1 
Added data transformation for 
primary efficacy analysis 
For clarification 
 
 
   
 
 
 
 
 
 
 
Section 10.7 
Added name of new laboratory  
A different laboratory will analyze 
pharmacokinetic samples 
Section 11 
Added references for gene 
expression analysis 
To support Section 6.4.10.3 
 

 
 
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12.3 
Protocol Amendment Summary Amendment 2 
Title:  Safety and Efficacy of Brimonidine Posterior Segment Drug Delivery System in 
Patients with Geographic Atrophy Secondary to Age-related Macular Degeneration 
Protocol 190342-038 Amendment 2 
Date of Amendment:  August 2014 
Amendment Summary 
This summary includes changes made to Protocol 190342-038 Amendment 1 (March 2014).   
Following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes.  Minor editorial and document formatting 
revisions have not been summarized. 
Section 
Revision 
Rationale 
Summary; 
Sections 2.1, 3, 
4.3, 6.1.2, 6.4.1, 
6.4, and 7.2.2 
Updated scotopic microperimetry to 
be scotopic/mesopic 
microperimetry 
Patients will use one of 3 neutral density 
filters (0, 1.0, 2.0) with the Nidek MP-1S 
microperimetry instrument; this filter is 
selected based on the filter section test. 
Use of the 0 density filter is considered 
mesopic whereas the use of the 1.0 or 2.0 
neutral density filters are considered 
scotopic. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Section 
Revision 
Rationale 
Summary; 
Sections 6.4.10.4, 
7.3.4, 8.3.1, 8.3.3 
to 8.3.14, and 
10.4.1 
Updated complete ophthalmic 
examinations to include:  external 
examination of the eye and adnexa, 
screening for eyelid/pupil 
responsiveness, slit-lamp 
biomicroscopy, indirect 
ophthalmoscopy, dilated fundus 
examination, and IOP  
For clarification and consistency, to 
include all components of the ophthalmic 
exam in each section 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 1; 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Section 
Revision 
Rationale 
 
 
 
 
 
 
 
Included information about study 
technicians not performing fundus 
photography and not being present 
during implant assessments, implant 
photography, or post-injection 
assessments  
For clarification  
 
 
 
 
 
 
 
 
Section 6.4.2 
Added:  “Individuals performing 
the BCVA measurements will be 
certified by an Allergan 
representative or third-party vendor 
if they have not been certified 
within the previous 12 months or 
have not performed at least 2 
standard ETDRS manifest protocol 
refractions and 2 standard ETDRS 
visual acuity assessments within the 
previous 12 months.” 
Clarification of BCVA certification 
requirements 
Section 6.4.4 
Added italicized text:  “The 
reproducibility of the mean retinal 
sensitivity threshold measurements 
from the repeat assessment 
performed during the 
Screening Visit 2 will be used to 
confirm patient eligibility by the 
CRC.”   
The results from mean retinal sensitivity 
threshold eligibility assessments are to be 
assessed by the CRC to confirm the 
patients’ eligibility. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Section 
Revision 
Rationale 
Section 8.8 
Added text:  “Study treatment will 
be discontinued in patients who 
develop neovascular AMD or any 
retinal disorder that prevents retinal 
visualization and quantification of 
the area of atrophic lesions or 
causes a sustained ≥ 30 letter loss of 
BCVA; a sustained loss is defined 
as a loss evident on 2 consecutive 
study visits.”  
Also added rationale for these 
criteria. 
Clarification of criteria to define 
discontinuation of study treatment 
 
Section 10.5.3 
Revision of text describing return 
and disposal of study medications 
For clarification  
Section 11 
Added new references 
Added new references that were cited  in 
Section 1 
 

 
 
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12.4 
Protocol Amendment Summary Amendment 3 
Title:  Safety and Efficacy of Brimonidine Posterior Segment Drug Delivery System in 
Patients with Geographic Atrophy Secondary to Age-related Macular Degeneration 
Protocol 190342-038 Amendment 3 
Date of Amendment:  September 2014 
Amendment Summary 
This summary includes changes made to Protocol 190342-038 Amendment 2 (August 2014).   
Following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes.  Minor editorial and document formatting 
revisions have not been summarized. 
Section 
Revision 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  

 
 
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Section 
Revision 
Rationale 
Table 1, 6.4.6 
Added row in Table 1 to clarify 
visit schedule for Fundus 
Autofluorescence (3-field) and 
Quantitative Fundus 
Autofluorescence (central field) 
Revised verbiage in section  6.4.6 
 
For clarity 
 
 
 
 
 
 
  
4.1 
Revised number of sites from 
approximately 15 to 20 to 
approximately 15 to 30 
To facilitate patient recruitment  
Figure 2 
Deleted figure 
Deleted as this figure is no longer relevant 
with adjusted entry criteria 
 

 
 
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12.5 
Protocol Amendment Summary Amendment 4 
Title:  Safety and Efficacy of Brimonidine Posterior Segment Drug Delivery System in 
Patients with Geographic Atrophy Secondary to Age-related Macular Degeneration 
Protocol 190342-038 Amendment 4 
Date of Amendment:  October 2014 
Amendment Summary 
This summary includes changes made to Protocol 190342-038 Amendment 3 
(September 2014).   
Following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes.  Minor editorial and document formatting 
revisions have not been summarized. 
Section 
Revision 
Rationale 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 

 
 
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Section 
Revision 
Rationale 
Section 1 
Changed lesions in which the total 
lesion area is greater than 
“12.5 mm2” to “18 mm2” 
 
Correction 
Section 5.9 
Added text “The Sham treatment is 
administered using a needleless 
DDS Applicator.  Refer to the 
Procedure Manual for the detailed 
instructions.” 
 
Added for completeness  
Section 6.4.2 
Removed specific instructions on 
Standard and Low Luminance 
BCVA certification process  
 
Simplification 
 
 
 
 
 
 
 
 
 

 
 
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12.6 
Protocol Amendment Summary Amendment 5 
Title:  Safety and Efficacy of Brimonidine Posterior Segment Drug Delivery System in 
Patients with Geographic Atrophy Secondary to Age-related Macular Degeneration 
Protocol 190342-038 Amendment 5 
Date of Amendment:  January 2015 
Amendment Summary 
This summary includes changes made to Protocol 190342-038 Amendment 4 (October 2014).   
Following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes.  Minor editorial and document formatting 
revisions have not been summarized. 
Section 
Revision 
Rationale 
Summary 
Removed “loss of retinal 
sensitivity” from clinical 
hypotheses  
Change in retinal sensitivity is an 
exploratory assessment. 
Summary, 
Table 1, Sections 
4.3, 6.4.4, 8.2, 
8.3.3, 8.3.7, 8.3.9, 
8.3.11, 8.3.13, 
and 8.3.14 
Microperimetry will be conducted 
only at selected sites in patients 
who qualify and consent to the 
procedure 
To ease patient recruitment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Summary, 
Sections 2.1, 
6.1.2, 6.1.3, 7.2.2, 
and 7.3.2 
Changes in retinal sensitivity 
moved to an “Other” endpoint 
rather than a “Secondary” endpoint 
Change in retinal sensitivity is an 
exploratory assessment 

 
 
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Section 
Revision 
Rationale 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
Summary, 
Sections 7 and 
7.6 
Addition of possible interim 
analysis with first 50% of patients 
completing Month 18 
To facilitate earlier project planning 
 
 
 
   
 
 
 
   
 
 
 
 
 
 
Section 5.3 
Added “Corneal curvature, 
indocyanine green angiography 
(ICG), fluorescein Angiography 
(FA), and drug accountability may 
be performed by either masked or 
unmasked personnel.”   
Clarification of masking procedures 

 
 
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12.7 
Protocol Amendment Summary Amendment 6 
Title:  Safety and Efficacy of Brimonidine Posterior Segment Drug Delivery System in 
Patients with Geographic Atrophy Secondary to Age-related Macular Degeneration 
Protocol 190342-038 Amendment 6 
Date of Amendment:  May 2015 
Amendment Summary 
This summary includes changes made to Protocol 190342-038 Amendment 5 (January 2015).   
Following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes.  Minor editorial and document formatting 
revisions have not been summarized. 
Section 
Revision 
Rationale 
Summary, 
Section 4.3 
Inclusion criterion changed:  the study eye must 
have BCVA better than or equal to 45 letters 
(20/125 Snellen equivalent) rather than 55 letters 
(20/80 Snellen equivalent). 
To facilitate patient recruitment 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 4.1 
Increased the number of sites from 
approximately 30 to approximately 40. 
To facilitate patient recruitment 
Table 2 
Clarified footnote “b” to indicate that additional 
assessments beyond those listed in the table may 
be performed at the investigator’s discretion. 
Clarification 
 
 
 
 
 
 

 
 
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Section 
Revision 
Rationale 
 
 
 
 
 
 
 
 
 
  
Section 10.7 
Removed the name of the specific laboratory 
used for blood sample analyses. 
To prevent deviation if a 
different laboratory is chosen 
 

 
 
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12.8 
Protocol Amendment Summary Amendment 7 
Title:  Safety and Efficacy of Brimonidine Posterior Segment Drug Delivery System in 
Patients with Geographic Atrophy Secondary to Age-related Macular Degeneration 
Protocol 190342-038 Amendment 7 
Date of Amendment:  May 2017 
Amendment Summary 
This summary includes changes made to Protocol 190342-038 Amendment 6 (May 2015).   
Following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes.  Minor editorial and document formatting 
revisions have not been summarized. 
Section 
Revision 
Rationale 
Title page 
Updated contact information 
Provided updated information 
 
 
 
 
 
. 
Summary, 
Sections 7.3.1 
and 7.3.2 
Revised primary efficacy analysis method from 
ANCOVA to MMRM 
Changed to a method with 
greater statistical power 
Summary, 
Sections 7, 7.6 
Removed interim analysis when 100% of 
patients completed Month 18 and thus reduced 
number of database locks from 4 to 3 
Management decision to 
perform the Month 18 analysis 
with 50% of patients made the 
later analysis unnecessary. 
Table 1, 
Sections 6.4.5 
and 8.3 
Changed near-IR measurement from 7-field to 
3-field 
Sufficient data can be collected 
with 3-field method 
 
 
 
 
 
Section 1 
Added reference for cytoprotective effects of 
brimonidine 
Additional data available 
Section 1 
Changed terminology from Brimonidine tartrate 
DDS to Brimonidine DDS Generation 1 and 
from Brimonidine free-base DDS to Brimonidine 
DDS Generation 2 
For clarity and consistency with 
the investigator’s brochure 
Section 1 
Changed concentration for Generation 1 from 
200 and 400 µg to 132 and 264 µg 
To better reflect the amount of 
active ingredient 
Section 1 
Changed percentage increase in brimonidine 
drug load from 30% to 50%, changing from 
tartrate to free base 
Corrected error 

 
 
Approval Date: 
 
23-May-2017
Allergan Confidential 
Protocol 190342-038 Amendment 7 
 
 
87 
GDD-TA-T-004 v2013.8 
 
Section 
Revision 
Rationale 
Section 4.5.1 
Added information on timing of YAG 
capsulotomy and cataract surgery and 
instructions regarding retinal tear and choroidal 
neovascularization in the fellow eye 
Provided additional information 
to address frequent questions on 
these topics 
Section 5.3 
Added description of masking and unmasking at 
the sponsor after the interim analysis and 
clarified that the assessing investigator is masked 
To show data integrity after the 
interim analysis 
Table 2 
Clarified that further monitoring should be for 
new intraocular pathology 
Clarification 
Sections 6.1.1, 
6.1.2, 6.1.3, 
7.2.1, 7.2.2 
Added that efficacy measures and analyses refer 
to the study eye 
Clarification 
Section 6.4.1 
Added standard and quantitative to FAF 
measurements 
Clarification 
 
 
 
 
 
 
 
 
 
 
Section 7.1 
For the mITT population, specified that analyses 
will be performed based on the randomized 
treatment 
Changed to match standard 
sponsor definition 
 
 
 
 
Section 7.2 
Removed LOCF analyses 
No longer needed because of 
change to primary analysis 
method 
Section 7.3.4 
Changed terminology from AEs of special 
interest to the primary safety measures outlined 
in Section 6.3 
Clarification 
Section 8.7 
Moved text requiring that patients who develop 
neovascular AMD or concomitant retinal 
disorder in the study eye be discontinued from 
Section 8.8, required discontinuation from the 
study rather than just from treatment, and 
stipulated that discontinuation for a concomitant 
retinal disorder only applies to the study eye 
Patients who develop 
concomitant retinal disease (as 
defined) are to be exited from 
the study in order to limit 
analysis to mITT population 
patients with GA secondary to 
AMD 

 
 
Approval Date: 
 
23-May-2017
Allergan Confidential 
Protocol 190342-038 Amendment 7 
 
 
88 
GDD-TA-T-004 v2013.8 
 
Section 
Revision 
Rationale 
Section 8.8 
Removed language about treatment failures and 
deleted section; added new section 8.7.1 to 
provide rationale for not discontinuing patients 
due to treatment failure 
 
Potential for bias as more sham 
patients may be removed for 
treatment failure; hurts potential 
to realize a treatment difference 
between sham and Brimo DDS; 
there are no available 
treatments to which patients can 
escape 
Section 10.4.1 
Removed references to printouts for source 
documents 
Only electronic versions are 
needed 
Section 11 
Updated reference list 
To align with changes in 
Section 1 
 

 
 
Approval Date: 
 
23-May-2017
ALLERGAN 
 
 
 
 
 
 
 
 
 
Date (DD/MMM/YYYY)/Time (PT) 
Signed by: 
Justification 
  
 
 
            
 
           
 
            
 
           
 
            
 
           
 
     
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
 
Protocol 190342-038 Amd 7