Clinical trial NCT02462928
Conditions: Macular Degeneration
Sponsor: Allergan
Start date: 2015-06-25; Completion date: 2019-06-19
Enrollment: 939 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a safety and efficacy study of abicipar pegol in participants with neovascular age-related macular degeneration.

Detailed description:

Arms: arm 1: Abicipar pegol 2 mg was administered to the study eye by intravitreal injection on Day 1, Week 4, Week 8 and every 8 weeks (2Q8) thereafter through Week 96. Scheduled visits occurred every 4 weeks. To maintain masking, sham was administered to the study eye at scheduled visits where abicipar was not administered. arm 2: Abicipar pegol 2 mg was administered to the study eye by intravitreal injection on Day 1, Week 4, Week 12, and every 12 weeks (2Q12) thereafter through week 96. Scheduled visits occurred every 4 weeks. To maintain masking, sham was administered to the study eye at scheduled visits where abicipar was not administered. arm 3: Ranibizumab (Lucentis®) 0.5 mg was administered to the study eye by intravitreal injection every 4 weeks (rQ4) from Day 1 through Week 96.
Interventions: intervention 1: Abicipar Pegol intervention 2: Ranibizumab intervention 3: Sham Procedure
Intervention descriptions: intervention 1: Abicipar pegol intravitreal injection. intervention 2: Ranibizumab intravitreal injection. intervention 3: Sham injection.

Protocol documents:
Prot_001.pdf: 
NCT02462486 
 
Study ID: 150998‐006 
 
 
 
Title: Safety and Efficacy of Abicipar Pegol (AGN‐150998) in Patients With Neovascular Age‐related 
Macular Degeneration 
 
Protocol Amendment 4 Date: 10 April 2018 
 
 


 
 
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Title Page 
ALLERGAN – CONFIDENTIAL 
The following contains confidential, proprietary information  
which is the property of Allergan 
Safety and Efficacy of Abicipar Pegol (AGN-150998) in Patients 
With Neovascular Age-related Macular Degeneration  
SEQUOIA STUDY 
Protocol Number:   
150998-006 Amendment 4 
EudraCT Number: 
Phase: 
2014‐004580‐20 
3 
Name of Investigational Product: 
Abicipar Pegol (AGN-150998) 
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 
 
  
 
 
 
   
 
 
 
 
 
  
 
 
 
 
  
Refer to the final page of this protocol for electronic signature 
and date of approval. 


 
 
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The following information can be found on FDA Form 1572 and/or study contacts page 
and/or Trial Master File:  Name and contact information of Allergan study personnel and 
Emergency Telephone Numbers; name, address, and statement of qualifications of each 
investigator; name of each subinvestigator working under the supervision of the investigator; 
name and address of the research facilities to be used; name and address of each reviewing 
IRB; US 21 CFR 312.23 section 6(iii)b. 
 


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


 
 
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Table of Contents 
Table of Contents ...................................................................................................................... 4 
List of Tables ............................................................................................................................. 8 
List of Figures ........................................................................................................................... 8 
Protocol Summary .................................................................................................................... 9 
1. 
Background and Clinical Rationale ................................................................................. 16 
2. 
Study Objectives and Clinical Hypotheses ...................................................................... 19 
2.1 
Study Objectives .................................................................................................... 19 
2.2 
Clinical Hypotheses ............................................................................................... 19 
 
 
3.1 
Data and Safety Monitoring Committee ................................................................ 20 
4. 
Study Population and Entry Criteria ................................................................................ 20 
4.1 
Number of Patients ................................................................................................. 20 
4.2 
Study Population Characteristics ........................................................................... 20 
4.3 
Inclusion Criteria .................................................................................................... 21 
4.4 
Exclusion Criteria................................................................................................... 22 
4.5 
Permissible and Prohibited Medications/Treatments ............................................. 25 
4.5.1  Permissible Medications/Treatments ......................................................... 25 
4.5.1.1 
Definition of Females of (Non-)Childbearing Potential and 
Acceptable Contraceptive Methods ........................................... 25 
4.5.2  Prohibited Medications/Treatments ........................................................... 26 
4.5.3  Escape Medications .................................................................................... 26 
4.5.4  Special Diet or Activities ........................................................................... 26 
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 ............................................................................. 28 
5.6.1  Treatment Regimen Adjustments ............................................................... 29 
5.6.2  Escape to Standard of Care ........................................................................ 30 
5.7 
Storage of Study Medications/Treatments ............................................................. 30 


 
 
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5.8 
Preparation of Study Medications/Treatments ....................................................... 30 
5.9 
Treatment Administration ...................................................................................... 30 
6. 
Response Measures and Summary of Data Collection Methods ..................................... 31 
6.1 
Efficacy Measures .................................................................................................. 31 
6.1.1  Primary Efficacy Measure .......................................................................... 31 
6.1.2  Secondary Efficacy Measures .................................................................... 31 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.4.2  Efficacy ...................................................................................................... 33 
6.4.2.1 
Best-corrected Visual Acuity ..................................................... 33 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.5 
Other Study Supplies .............................................................................................. 37 
6.6 
Summary of Methods of Data Collection .............................................................. 38 
7. 
Statistical Procedures ....................................................................................................... 38 
7.1 
Analysis Populations .............................................................................................. 38 
7.2 
Collection and Derivation of Primary and Secondary Efficacy Assessments ........ 38 
7.2.1  Primary Efficacy Variables ......................................................................... 38 
7.2.2  Secondary Efficacy Variables ..................................................................... 39 
7.3 
Methods of Analysis ............................................................................................... 39 
7.3.1  Primary Efficacy Analyses ......................................................................... 39 


 
 
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7.3.2  Secondary Efficacy Analyses ..................................................................... 40 
7.3.3  Secondary Efficacy Analyses for US FDA ................................................ 40 
 
 
 
 
 
 
7.4 
Sample Size Calculation ........................................................................................ 42 
7.5 
Interim Analyses..................................................................................................... 42 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4 
Instructions for the Patients .................................................................................... 55 
8.5 
Unscheduled Visits ................................................................................................. 55 
8.6 
Compliance With Protocol ..................................................................................... 55 


 
 
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8.7 
Early Discontinuation of Patients .......................................................................... 55 
8.8 
Withdrawal Criteria ................................................................................................ 56 
8.9 
Study Termination .................................................................................................. 56 
9. 
Adverse Events ................................................................................................................ 56 
9.1 
Definitions .............................................................................................................. 56 
9.1.1  Adverse Event ............................................................................................ 56 
9.1.2  Serious Adverse Event ............................................................................... 57 
9.1.3  Severity ...................................................................................................... 58 
9.1.4  Relationship to Study Drug or Study Procedure ........................................ 58 
9.2 
Procedures for Reporting Adverse Events ............................................................. 58 
9.3 
Procedures for Reporting a Serious Adverse Event ............................................... 58 
9.4 
Procedures for Unmasking of Study Medication ................................................... 59 
10.  Administrative Items ....................................................................................................... 60 
10.1  Protection of Study Patients ................................................................................... 60 
10.1.1  Compliance With Informed Consent Regulations (US 21 Code of Federal 
Regulations [CFR] Part 50) and Relevant Country Regulations ............... 60 
10.1.2  Compliance With IRB or IEC Regulations ................................................ 60 
10.1.3  Compliance With Good Clinical Practice .................................................. 60 
10.1.4  Compliance With Electronic Records; Electronic Signatures Regulations 
(US 21 CFR Part 11) .................................................................................. 61 
10.2  Changes to the Protocol ......................................................................................... 61 
10.3  Patient Confidentiality ........................................................................................... 61 
10.3.1  Patient Privacy ........................................................................................... 61 
10.4  Documentation ....................................................................................................... 62 
10.4.1  Source Documents ..................................................................................... 62 
10.4.2  Case Report Form Completion................................................................... 63 
10.4.3  Study Summary .......................................................................................... 64 
10.4.4  Retention of Documentation ...................................................................... 64 
10.5  Labeling, Packaging, and Return or Disposal of Study Medications/Treatments .. 64 
10.5.1  Labeling/Packaging .................................................................................... 64 
10.5.2  Clinical Supply Inventory .......................................................................... 65 
10.5.3  Return or Disposal of Study Medications/Treatments and/or Supplies ..... 65 
10.6  Monitoring by the Sponsor .................................................................................... 65 
10.7  Handling of Biological Specimens......................................................................... 65 
10.8  Publications ............................................................................................................ 66 


 
 
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10.9  Coordinating Investigator ...................................................................................... 66 
11.  References ........................................................................................................................ 66 
12.  Attachments ..................................................................................................................... 68 
12.1  Glossary of Abbreviations ...................................................................................... 68 
12.2  Protocol Amendment Summary Amendment 1 ..................................................... 70 
12.3  Protocol Amendment Summary Amendment 2 ..................................................... 74 
12.4  Protocol Amendment Summary Amendment 3 ..................................................... 80 
12.5  Protocol Amendment Summary Amendment 4 ..................................................... 81 
 
List of Tables 
 
 
 
 
 
  
List of Figures 
 
 
  


 
 
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Protocol Summary 
 
Study Compound:  Abicipar pegol (hereafter referred to as abicipar) 
Phase:  3 
Study Objective:   
To assess the safety and efficacy of abicipar compared with ranibizumab in treatment-naïve patients with 
neovascular age-related macular degeneration (AMD) 
Study Design 
  
Duration:  104 weeks participation for each patient following randomization  
Study Treatment Groups and Dosage/Dose Regimen:   
• 
Treatment group 2Q8:  2 mg abicipar administered at baseline (day 1) and weeks 4 and 8, followed by 
doses at 8-week intervals through week 96  
• 
Treatment group 2Q12:  2 mg abicipar administered at baseline (day 1), and weeks 4 and 12, followed 
by doses at 12-week intervals through week 96  
Controls:   
• 
Treatment group rQ4:  0.5 mg ranibizumab administered every 4 weeks through week 96  
The treating investigator will administer the masked2 study medication by intravitreal injection into the study 
eye at the assigned visits. 
                                                 
1 Defined as a loss of fewer than 15 letters in best-corrected visual acuity [BCVA] compared to baseline using 
the Early Treatment Diabetic Retinopathy Study [ETDRS] method [hereafter referred to as letters] 
2 To maintain masking, patients randomized to abicipar will receive a sham injection during the study visits 
when they are not scheduled to receive their assigned study medication.  For the sham injections, the study eye 
of each patient will be prepared using a standard protocol as if they were to receive an intravitreal injection as 
defined in the procedure manual.  For the sham injection, the treating investigator will press the blunt end of the 
syringe against the eye, mimicking an intravitreal injection. 


 
 
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Visit Schedule:  Patients will have visits at screening, baseline (day 1), and every 4 weeks until week 104/early 
exit.  For patients at selected sites who will have pharmacokinetic (PK) blood sampling, there will be additional 
visits 2 days after the baseline (day 1) and week 24, 48, and 96 visits.  
 
Study Population Characteristics 
Number of Patients:  Approximately 900 patients will be enrolled at an estimated 200 sites in order to have 
720 patients (240 per treatment group) complete the 52 week follow-up visit allowing for an early-
discontinuation rate of approximately 20%. 
Condition/Disease:  Treatment-naïve patients with neovascular AMD 
Key Inclusion Criteria:  One eye will be selected and treated as the study eye. 
 
 
General Inclusion Criterion: 
• 
Male or female patients, 50 years of age or older at the time of informed consent   
Key Ocular Inclusion Criteria (study eye): 
• 
BCVA ≤ 73 and ≥ 24 letters (20/40 to 20/320 Snellen equivalents, respectively) at screening and 
baseline (day 1, prior to treatment) visits  
Ocular Inclusion Criterion (Non-study Eye): 
• 
BCVA of 34 letters (Snellen equivalent 20/200) or better at baseline (day 1), prior to treatment 
Key Ocular Exclusion Criteria (Either Eye) 
Key Ocular Exclusion Criteria (Study Eye): 


 
 
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o 
Cataract or refractive surgery 
 
 within the last 3 months prior to baseline (day 1) 
Response Measures 
Efficacy:  
BCVA assessed by the ETDRS letters  
 
CRT assessed with spectral-domain optical coherence tomography (SD-OCT) and 
quantified by the central reading center  
 
 
 
 
 
 
  
 
 
 
Masked safety data will be reviewed throughout the study by Allergan.  An external independent Data and 
Safety Monitoring Committee (DSMC) will review selected unmasked data for safety assessment.  The review 
frequency, criteria, and the process for making recommendations will be defined in the charter. 
 


 
 
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General Statistical Methods and Types of Analyses:  The primary analysis will occur when all patients have 
completed the week 52 visit or exited early and the final analysis will occur when all patients have completed 
the week 104 visit or exited earlier from the study.  Three populations will be used for the analyses; intent-to-
treat (ITT), per-protocol (PP), and safety. 
The primary efficacy endpoint will be the proportion of patients with stable vision (ie, patients who lose fewer 
than 15 letters in BCVA from baseline) at week 52.  This statistical analysis will use the PP population.  The 
difference in the proportions between each abicipar arm and ranibizumab (abicipar group minus ranibizumab 
group) and the corresponding 2-sided 95.1% confidence interval for non-inferiority testing will be constructed 
based on Cochran-Mantel-Haenszel (CMH) method with the baseline BCVA stratification factor (≤ 55 ETDRS 
letters versus > 55 ETDRS letters).  The non-inferiority test will be performed at week 52 with a non-inferiority 
margin of 10%.  A gatekeeping procedure will be used to control the overall type I error rate at the 0.05 level, 
first testing abicipar 2Q8 against ranibizumab followed by the comparison between abicipar 2Q12 and 
ranibizumab. 
Missing values will be imputed using the last observation carried forward (LOCF) method.  Sensitivity analyses 
of handling missing data will be performed using multiple imputation. 
The non-inferiority comparisons will also be performed in the ITT population as a sensitivity analysis to 
confirm the primary analysis. 
The Medical Dictionary for Regulatory Activities (MedDRA) nomenclature will be used to code adverse 
events.  The proportion of patients reporting each treatment emergent adverse event will be summarized by 
primary system organ class and preferred term for each treatment group. 
Sample Size Calculation:  A sample size of 240 patients in each treatment group will provide approximately 
95% power with a 2-sided alpha level of 0.05 to demonstrate non-inferiority of an abicipar group versus the 
ranibizumab group for stable vision (ie, patients who lose fewer than 15 letters in BCVA from baseline) at 
week 52, with a non-inferiority margin of 10%.  This calculation is based on the assumption of a 90% response 
rate for both groups. 
With an anticipated dropout rate of approximately 20% during a 52 week period, a total of 900 patients will be 
enrolled so that approximately 720 patients (240 per group) will complete the 52 week follow-up as required for 
the primary endpoint evaluation. 
 
 


 
 
 
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1. 
Background and Clinical Rationale 
Age-related macular degeneration (AMD) is the leading cause of severe vision loss in people 
over the age of 65 in the United States (US) and other Western countries (Rein et al, 2009).  
AMD is a macular disorder characterized by drusen deposits, retinal pigment epithelium 
abnormalities, geographic atrophy, and neovascular maculopathy (Pieramici et al, 2006).  
The advanced stages of AMD, which are associated with severe loss of vision, consist of 
either choroidal neovascularization (neovascular or exudative AMD) or central geographic 
atrophy (non-exudative AMD).  The majority of severe vision loss due to advanced AMD is 
attributable to the development of choroidal neovascularization (CNV) (Ferris, 1983; 
Sommer et al, 1991).  Neovascular AMD is characterized by the growth of choroidal vessels 
into the subretinal space.  These newly formed vessels have a tendency to leak blood and 
fluid, causing retinal edema which is accompanied by symptoms of metamorphopsia.  The 
new vessels are accompanied by proliferation of fibrous tissue, and the continued growth of 
this lesion into the macula results in progressive, severe, and irreversible central vision loss 
(Shah and Del Priore, 2007; Shah and Del Priore, 2009).  Without treatment, neovascular 
AMD results in severe visual impairment with an average loss of around 4 lines of visual 
acuity within 2 years of disease onset (Blinder et al, 2003; Wong et al, 2008). 
Vascular endothelial growth factor-A (VEGF-A) is implicated in the development and 
maintenance of the neovascularization that is characteristic of the neovascular form of AMD 
(Ding et al, 2009).  Studies have shown elevated VEGF-A levels in areas of laser-induced 
CNV in primates, and clinically in patients with AMD.  VEGF-A is a potent mitogen for 
endothelial cells, which causes increased vascular permeability and promotes leukocyte-
induced damage to retinal endothelial cells (Grisanti and Tatar, 2008).  Degenerated tissues 
produce and release VEGF-A which binds to specific receptors located on the endothelial 
cells of nearby pre-existing blood vessels.  These endothelial cells then proliferate and 
migrate out through the diseased tissue.  Pericytes, smooth muscle-like cells, provide 
structural support to these newly-formed blood vessel loops and blood flow begins in these 
vessels.  Thus, VEGF-A serves as a rate-limiting step in angiogenesis 
(Ciulla and Rosenfeld, 2009).  It also increases vascular permeability by leukocyte-mediated 
endothelial cell injury, formation of fenestrae, and the dissolution of tight junctions.  This 
leads to intraretinal fluid accumulation and subsequent distortion of the macula, resulting in 
decreased visual acuity.  As a result, VEGF-A has been the target of most anti-VEGF 
treatments (Cheung et al, 2013). 
The discovery of VEGF-A’s role in the pathogenesis of neovascular ocular disease provided a 
strong rationale for the development of highly-specific and targeted anti-VEGF-based 


 
 
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therapies (Ciulla and Rosenfeld, 2009).  Three anti-VEGF agents, pegaptanib sodium, 
ranibizumab, and aflibercept are currently approved in many countries for the treatment of 
neovascular AMD.  In addition, off-label use of a fourth anti-VEGF agent, bevacizumab, as a 
treatment option for neovascular AMD has become common worldwide.  These agents are 
delivered to the vitreal cavity by intravitreal injection.   
One drawback of these treatments is the need to frequently administer intravitreal injections.  
It would be highly desirable to develop an agent that requires less frequent injections.  Not 
only would this remove a significant treatment burden on patients and their healthcare 
providers, it would decrease the risk of complications associated with frequent intravitreal 
injections. 
Abicipar pegol (hereafter referred to as abicipar) was in-licensed from Molecular Partners 
(MP).  The drug substance (abicipar-1) was evaluated in 2 phase 1 studies; one in patients 
with neovascular AMD, and one in patients with diabetic macular edema. 


 
 
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These data support the proposed dosing regimens of both abicipar treatment arms in the 
phase 3 study. These abicipar treatment regimens afford the possibility to reduce the 
treatment burden of the number of intravitreal injections (8 or 6 abicipar intravitreal 
injections in Year 1 for the 2Q8 and 2Q12 abicipar arms, respectively, versus 13 for the 
ranibizumab arm), while maintaining the efficacy of an anti-VEGF therapy, including 
3 initial doses followed by 8- or 12-week dosing intervals to assess the efficacy and safety of 
abicipar in a phase 3 study. 


 
 
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For further information, please refer to the Investigator’s Brochure for abicipar. 
The purpose of this study is to evaluate the safety and efficacy of abicipar (2 mg), compared 
to 0.5 mg ranibizumab in treatment-naïve patients with neovascular AMD. 
2. 
Study Objectives and Clinical Hypotheses 
2.1 
Study Objectives 
To assess the safety and efficacy of abicipar compared with ranibizumab in treatment-naïve 
patients with neovascular AMD 
2.2 
Clinical Hypotheses 
                                                 
3 Defined as a loss of fewer than 15 letters in best-corrected visual acuity [BCVA] compared to baseline using 
the Early Treatment Diabetic Retinopathy Study [ETDRS] method [hereafter referred to as letters] 


 
 
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3.1 
Data and Safety Monitoring Committee 
Masked safety data will be continually monitored throughout the study by Allergan to 
identify new safety signals for risk mitigation.  In addition, an external independent Data and 
Safety Monitoring Committee (DSMC) will review selected unmasked data for safety 
assessment.  The review frequency, criteria, and the process for making recommendations 
will be defined in the charter. 
4. 
Study Population and Entry Criteria 
4.1 
Number of Patients 
Approximately 900 patients will be enrolled at an estimated 200 sites in order to have 
720 patients (240 per treatment group) complete the 52 week follow-up visit allowing for an 
early-discontinuation rate of approximately 20%. 
4.2 
Study Population Characteristics 
Treatment-naïve patients with neovascular AMD will be enrolled in the study. 
Only one eye will be selected as the study eye for the duration of the study.  
 
 
 
 
 
 


 
 
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4.3 
Inclusion Criteria 
The following are requirements for entry into the study:  
General Inclusion Criteria 
1. Male or female patients, 50 years of age or older at the time of informed consent  
2. Patient has completed/signed an informed consent prior to conduct of any study-related 
procedures or examinations, is able to follow study instructions, and is likely to complete 
all required visits 
3. Patient has provided, at screening, written documentation in accordance with the relevant 
country and local privacy requirements (eg, Written Authorization for Use and Release of 
Health and Research Study Information and written Data Protection consent, as required 
by regional health authorities) 
Ocular Inclusion Criteria (Study Eye) 
 
 
 
 
 
 
 
 
6. BCVA ≤ 73 and ≥ 24 letters (20/40 to 20/320 Snellen equivalents, respectively) at 
screening and at baseline (day 1, prior to treatment) visits  
 
 
Ocular Inclusion Criteria (Non-study Eye) 
8. BCVA of 34 letters (Snellen equivalent 20/200) or better at baseline (day 1), prior to 
treatment 


 
 
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4.4 
Exclusion Criteria 
Patients must have NONE of the following criteria in order to be considered eligible to 
participate in the study:  
General Exclusion Criteria 
1. Females who are pregnant, nursing, planning a pregnancy during the study, or who are of 
childbearing potential and not using a reliable method of contraception (Section 4.5.1.1) 
and/or not willing to use a reliable method of contraception during their participation in 
the study.  A pregnancy test administered to women of childbearing potential at the 
baseline visit (day 1, prior to treatment) must be negative for the patient to receive study 
medication 


 
 
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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 any time at the 
discretion of the investigator.  All medications should be recorded in the electronic case 
report form (eCRF).  If the permissibility of a specific medication/treatment is in question, 
please contact Allergan.  
4.5.1.1 
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 (eg, have undergone 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 or 
vaginal contraceptive ring), intrauterine device, surgical sterilization (bilateral tubal ligation, 
bilateral salpingectomy), vasectomized partner, or sexual abstinence.  For male patients who 
participate in the study, condoms should be used as method of contraception. 
The investigator and each patient will determine the appropriate method of contraception for 
the patient during the participation in the study. 


 
 
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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 (abicipar) or approved control 
(ranibizumab), and (2) follow the progress of the pregnancy.  The investigator must 
document the outcome of the pregnancy and provide a copy of the documentation to 
Allergan. 
If a female partner of a male study patient becomes pregnant during the study, the 
investigator will notify Allergan immediately after the pregnancy is confirmed.  The 
investigator will (1) obtain a consent from the female partner for pregnancy follow-up, and 
(2) follow the progress of the pregnancy to term.  The investigator should document the 
outcome of the pregnancy and provide a copy of the documentation to Allergan. 
4.5.2 
Prohibited Medications/Treatments 
The decision to administer a prohibited medication/treatment is done with the safety of the 
study participant as the primary consideration.  Whenever possible, Allergan should be 
notified before the prohibited medication/treatment is administered.  Use of the following 
medications is prohibited during the study: 
4.5.3 
Escape Medications 
Patients who meet the escape criteria (see Section 5.6.2) may escape to standard of care.  
Standard of care is defined as the preferred anti-VEGF intravitreal treatment per the site’s 
practice. 
4.5.4 
Special Diet or Activities 
None 


 
 
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5. 
Study Treatments 
5.1 
Study Treatments and Formulations 
5.2 
Control Treatment 
The control treatment, 0.5 mg ranibizumab (Lucentis), will be provided (for the study eye 
only).  
5.3 
Methods for Masking 
The following individuals or roles will be masked to study medication for the duration of the 
study:  
• Patients 
• All site personnel responsible for performing BCVA and CRT 
• Assessing investigator responsible for all assessments except the post-injection 
assessment 
• Central reading center personnel involved in the assessment of images  
Ranibizumab (Lucentis®) will be provided and masked by packaging the commercial 
supplies inside of an outer carton which looks identical to the packaging of abicipar.  The 
injecting ophthalmologist and any assistants who prepare the material for injection (or sham 
treatment) will be unmasked to treatment.  To maintain masking, patients randomized to 
abicipar will receive a sham injection during the study visits when they are not scheduled to 
receive their assigned study medication; see Section 5.6. 
In an effort to avoid bias, staff members who are made aware of the study treatment of an 
individual patient shall not continue to collect efficacy variables (BCVA and CRT) for that 
patient. 
For more details, refer to the procedure manual. 


 
 
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5.4 
Treatment Allocation Ratio and Stratification 
Patients will be randomized 
 to 3 treatment groups (2Q8, 2Q12, and rQ4).  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
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 number that will serve as the patient 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 central randomization scheme prepared by Allergan Biostatistics.  The randomization 
scheme will be based on region. 
Study medication will be labeled with medication kit numbers.  At the time of randomization, 
the IVRS/IWRS will provide the site with the specific medication kit number for each 
randomized patient.  Sites will receive the IVRS/IWRS confirmation notifications for each 
transaction.  All notifications are to be maintained with the study source documents.  A list of 
patients assigned to abicipar groups will be provided to the bioanalytical laboratories to 
facilitate analysis of serum samples. 
5.6 
Treatment Regimen and Dosing 
• Treatment group 2Q8: 
 
 
 


 
 
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• Treatment group 2Q12: 
 
 
• Treatment group rQ4:  0.5 mg ranibizumab administered every 4 weeks from baseline 
(day 1) through week 96  
Masked study treatment will be administered into the study eye by intravitreal injection 
(or sham treatment).  One eye will be assigned as the study eye for the duration of the 
study.  To maintain masking, patients randomized to abicipar will receive a sham 
injection during the study visits when they are not scheduled to receive their assigned 
study medication.  For the sham injections, the study eye of each patient will be prepared 
using a standard protocol as if they were to receive an intravitreal injection as defined in 
the procedure manual.  For the sham injection, the treating investigator will press the 
blunt end of the needleless syringe against the eye, mimicking an intravitreal injection.   
5.6.1 
Treatment Regimen Adjustments 
If the study eye develops a treatment-related adverse event at any time during the study, 
treatment dose may be temporarily held and the reason for dose holding will be recorded on 
the eCRF.   
The treatment regimen will be adjusted based on the following criteria:  
The investigator may hold or discontinue study treatment for other safety reasons at his/her 
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5.6.2 
Escape to Standard of Care  
During the first 52 weeks of the study, if a patient has met the following criteria, he/she will 
be qualified to escape to standard of care: 
Patients who escape to standard of care will be required to complete the study exit 
procedures indicated at the week 104/early exit visit and will be reevaluated at the 
subsequent follow-up visits:  
 
 
 
 
 
5.7 
Storage of Study Medications/Treatments 
The study medication must be stored in a secure area and administered only to patients 
enrolled into the clinical study, at no cost to the patient, in accordance with the conditions 
specified on the study medication kit label and in the procedure manual.  Only assigned 
individuals authorized by the investigator may have access to study medication. 
5.8 
Preparation of Study Medications/Treatments 
Abicipar should be prepared in a hospital pharmacy or by an investigator or trained assistant 
in the clinic using aseptic technique.  The instructions for preparation of the individual doses 
are provided in the procedure manual. 
Ranibizumab should be prepared per the Lucentis prescribing information. 
5.9 
Treatment Administration 
Abicipar and ranibizumab will be administered by intravitreal injection as specified in the 
procedure manual.  The injection volume is 0.05 mL (50 µL). 
Prior to study treatment administration, the study eye of each patient will be prepared using 
the standard protocol as described in the procedure manual.  


 
 
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6. 
Response Measures and Summary of Data Collection Methods 
Details of measures and data collection methods are outlined in the procedure manual. 
6.1 
Efficacy Measures 
6.1.1 
Primary Efficacy Measure 
• BCVA assessed using the ETDRS letters (Age-Related Eye Disease Study [AREDS] 
Research Group, 2001) 
6.1.2 
Secondary Efficacy Measures 
• BCVA assessed using the ETDRS letters 
• CRT assessed with spectral-domain optical coherence tomography (SD-OCT) and 
quantified by the central reading center 
• National Eye Institute Visual Functioning Questionnaire-25 Item (NEI-VFQ-25) 
composite score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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6.4.2 
Efficacy 
6.4.2.1 
Best-corrected Visual Acuity 
BCVA will be quantified using the ETDRS method (AREDS Research Group, 2001).  
BCVA testing should precede any examination requiring contact with the study eye.  BCVA 
should be performed following manifest refraction and completed according to the 
procedures outlined in the procedure manual.  
 
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6.4.3.6 
Best-corrected Visual Acuity 
All BCVA measures will be used as safety measures to evaluate vision loss over time.  BCVA 
is also used as a measure of efficacy as described in Section 6.4.2.1. 
6.4.3.7 
Pregnancy Test 
Females of childbearing potential will have a pregnancy test (urine or serum) performed as 
indicated in Table 1.   
6.4.3.8 
Adverse Events 
All adverse events will be monitored and reported on an adverse event eCRF, including 
onset, seriousness, severity, action taken, and relationship to study drug.  If adverse events 
occur, the first concern will be the safety of the study patient. 
6.5 
Other Study Supplies 
Allergan will make provisions (directly or indirectly) to supply the study sites with 
pregnancy test kits, ETDRS supplies (if needed), study medications, intravitreal injection 
supplies, PK blood sampling kits, and immunogenicity (anti-drug antibody) blood sampling 
kits.  Details are provided in the procedure manual. 
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6.6 
Summary of Methods of Data Collection 
Clinical data will be entered into an eCRF.  Data entered into the eCRF will correspond to 
and be supported by source documentation maintained at the site. 
7. 
Statistical Procedures 
There will be two database locks.  The primary analysis will occur when all patients have 
completed the week 52 visit, or exited earlier.  The final analysis will occur when all patients 
have completed week 104 visit or exited early from the study.  The details of all analyses will 
be provided in the analysis plan which will be finalized before database lock for the primary 
analysis at week 52. 
7.1 
Analysis Populations 
The following 3 populations will be used for statistical analysis:  intent-to-treat (ITT), per-
protocol (PP), and safety. 
The ITT population will include all randomized patients.  The ITT population will be used 
for all efficacy analyses.  The PP population will include all randomized and treated patients 
who do not have protocol deviations that impact the primary efficacy variable.  The PP 
population will be used for analyses of primary and key secondary efficacy variables.  The 
safety population will include all treated patients. 
7.2 
Collection and Derivation of Primary and Secondary Efficacy 
Assessments 
Efficacy measures will be based on BCVA and CRT measured in the study eye.  
 
Missing 
data will be imputed with values using last observation carried forward (LOCF) methods for 
the primary and secondary analyses.  
7.2.1 
Primary Efficacy Variables 
• Proportion of patients with stable vision (ie, patients who lose fewer than 15 letters in 
BCVA) from baseline at week 52  


 
 
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7.2.2 
Secondary Efficacy Variables 
• 
Mean change from baseline in BCVA at week 52 
• Mean change from baseline in CRT as assessed with SD-OCT and quantified by the 
central reading center at week 52 
• Proportion of patients with a gain of 15 or more ETDRS letters in BCVA from 
baseline at week 52 
• Mean change from baseline in NEI-VFQ-25 composite score at week 52 
7.3 
Methods of Analysis 
7.3.1 
Primary Efficacy Analyses 
The primary efficacy endpoint will be the proportion of patients with stable vision (ie, 
patients who lose fewer than 15 letters in BCVA from baseline) at week 52.  The difference in 
the proportion between each abicipar arm and ranibizumab (abicipar group minus 
ranibizumab group) and the corresponding 2-sided 95.1% confidence interval (CI) for non-
inferiority testing will be constructed based on Cochran-Mantel-Haenszel (CMH) method 
with the baseline BCVA stratification factor (≤ 55 ETDRS letters versus > 55 ETDRS 
letters).  The non-inferiority test will be performed at week 52 using the PP population and 
with a non-inferiority margin of 10%.  If the lower limit of 95.1% CI of difference in 
proportion of response (abicipar minus ranibizumab) is ≥ -10%, non-inferiority of abicipar to 
ranibizumab will be established.  
 
 
. 
 
 
. 
The non-inferiority comparisons will also be performed in the ITT population as a sensitivity 
analysis to confirm the primary analysis. 
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7.3.2 
Secondary Efficacy Analyses 
The secondary efficacy analyses will be performed at week 52 for variables listed in 
Section 7.2.2 using the ITT and PP populations.   
For the key secondary efficacy endpoint (mean change from baseline in BCVA at week 52), 
the statistical analysis for the non-inferiority test will be based on the PP population 
 
 
 
 
 
  The difference in mean change from baseline in BCVA between each abicipar 
arm and ranibizumab (abicipar group minus ranibizumab group) and the corresponding 
2-sided 95.1% CI will be calculated based on the MMRM model.  The non-inferiority test 
will be performed using a non-inferiority margin of 5 letters.  Non-inferiority of abicipar is 
established if the lower limit of the CI is > - 5.0 letters.  The same 
 model will be 
applied to the ITT population and the lower limit of the CI will be compared to the 5-letter 
margin for non-inferiority testing and to zero for superiority testing. 
As a sensitivity analysis, mean change in BCVA will be analyzed using an analysis of 
covariance (ANCOVA) model, which includes the treatment group, baseline CRT (≤ 400 or 
> 400 microns), and lesion type of choroidal neovascularization (predominantly classic 
versus minimally classic or occult) as fixed effects and baseline BCVA as a covariate. 
For the analysis of secondary efficacy variables, change from baseline in CRT and change 
from baseline in NEI-VFQ-25 composite scores, similar analysis procedure will be used as 
outlined for BCVA above for superiority testing using the ITT population. 
For the secondary efficacy endpoint, proportion of patients with a gain of 15 or more letters, 
a similar analysis procedure will be used as outlined for the primary efficacy variable of 
stable vision for superiority testing using the ITT population. 
7.3.3 
Secondary Efficacy Analyses for US FDA 
 
 
 
.  If non-inferiority of both abicipar 
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change from baseline in BCVA at week 52 will be performed following the same sequence as 
defined above.  
 
 
 
 
 
  


 
 
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7.4 
Sample Size Calculation 
For the primary efficacy endpoint of stable vision (ie, patients who lose fewer than 15 letters 
in BCVA from baseline) at week 52, a sample size of 240 patients in each treatment group 
will provide approximately 95% power with a 2-sided alpha level of 0.05 to demonstrate 
non-inferiority of an abicipar group versus ranibizumab with a non-inferiority margin of 
10%.  This calculation is based on the assumption of a 90% response rate for both groups. 
With an anticipated dropout rate of approximately 20% during a 52 week period, a total of 
900 patients will be enrolled so that approximately 720 patients (240 per group) will 
complete the 52 week follow-up as required for the primary endpoint evaluation. 
7.5 
Interim Analyses 
No interim analyses are planned for this study.  However, an external independent DSMC 
will assess the safety during the study.  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
   


 
 
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8.4 
Instructions for the Patients 
Patients are instructed that they do not need to fast before visits. 
Patients are instructed to strictly follow the study visit schedule and to report all changes in 
condition to the investigative site.   
8.5 
Unscheduled Visits 
Additional examinations may be performed as necessary to ensure the safety and well-being 
of patients during the study.  The eCRFs 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.  A patient’s participation in the 
study may be terminated if it is deemed by the investigator or Allergan that it is unsafe for the 
patient to continue in the study.   


 
 
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Notification of early patient discontinuation from the study and the reason for discontinuation 
will be made to Allergan and will be clearly documented on the appropriate eCRF.  Patients 
who discontinue early from the study will not be replaced. 
Patients who discontinue early due to escape to standard of care must complete the 
week 104/early exit visit procedures and follow-up visits as described in Section 5.6.2.   
 
 
 
 
 
. 
8.8 
Withdrawal Criteria 
See Section 5.6.2.  
8.9 
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.   


 
 
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Note:  Adverse events must be collected once informed consent has been obtained, regardless 
of whether or not the patient has been administered study drug. 
Progression of neovascular AMD, including new or worsening of anticipated clinical signs or 
symptoms, which are collected as clinical efficacy variables and assessed as unequivocally 
associated with the disease progression and /or lack of efficacy, should NOT be reported as 
adverse events unless the disease progression is greater than anticipated in the natural course 
of the disease. 
Adverse events will be assessed, documented, and recorded in the 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 
appropriate eCRF.   
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.) 
 
 
Pre-planned surgeries or procedures for pre-existing, known medical conditions for which a 
patient requires hospitalization is not reportable as a serious adverse event. 
Any pre-planned surgery or procedure should be clearly documented in the site source 
documents by the medically qualified investigator at the time of the patient’s entry into the 
study.  If it has not been documented at the time of the patient’s entry into the study, then it 
should be documented as a serious adverse event and reported to Allergan. 


 
 
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9.1.3 
Severity 
A clinical determination will be made of the intensity of an adverse event.  The severity 
assessment for a clinical adverse event must be completed using the following definitions as 
guidelines: 
Mild 
Awareness of sign or symptom, but easily tolerated. 
Moderate 
Discomfort enough to cause interference with usual activity. 
Severe 
Incapacitating with inability to work or do usual activity. 
Not applicable 
In some cases, an adverse event may be an ‘all or nothing’ finding 
which cannot be graded. 
 
9.1.4 
Relationship to Study Drug or Study Procedure 
A determination will be made of the relationship (if any) between an adverse event and the 
study drug or study procedure, as applicable.  A causal relationship is present if a 
determination is made that there is a reasonable possibility that the adverse event may have 
been caused by the drug or study procedure.  A study procedure occurring during the 
screening/baseline period can include a study required diagnostic procedure. 
For treatment-related adverse events, the investigator will note on the eCRF whether the 
event is related to the study medication, and/or the injection procedure. 
9.2 
Procedures for Reporting Adverse Events 
Any adverse event must be recorded on the appropriate eCRF. 
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 for at least 16 weeks after the last administration of study drug must be 
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Serious adverse events must be reported to Allergan (or Agent of Allergan) as listed on the 
Allergan Study Contacts Sheet and recorded on the serious adverse event Form.  All patients 
with a  serious adverse event must be followed up and the outcomes reported.  The 
investigator must supply the sponsor and the IRB/IEC with any additional requested 
information (eg, autopsy reports and discharge summaries).  
In the event of a serious adverse event, the investigator must: 
1. Notify Allergan immediately by fax or email using the serious adverse event form 
(contact details can be found on page 1 of the serious adverse event form); phone 
numbers and relevant Allergan personnel contacts are also on the front page of 
protocol. 
2. Obtain and maintain in his/her files all pertinent medical records, information, and 
medical judgments from colleagues who assisted in the treatment and follow-up of 
the patient. 
3. Provide Allergan with a complete, written description of the adverse event(s) on the 
serious adverse event form describing the event chronologically, including any 
treatment given (eg, medications administered, procedures performed) for the adverse 
event(s).  Summarize relevant clinical information about the event:  signs, symptoms, 
diagnosis, clinical course and relevant clinical laboratory tests, etc.  Include any 
additional or alternative explanation(s) for the causality which includes a statement as 
to whether the event was or was not related to the use of the investigational drug. 
4. Promptly inform the governing IRB/IEC of the serious adverse event as required by 
the IRB/IEC, local regulations, and the governing health authorities. 
9.4 
Procedures for Unmasking of Study Medication 
When necessary for the safety and proper treatment of the patient, the investigator can 
unmask the patient’s treatment assignment to determine which treatment has been assigned 
and institute appropriate follow-up care.  When possible, the sponsor (Allergan Medical 
Safety Physician) should be notified prior to unmasking study medication.  The investigator 
should inform the sponsor (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 via password protected access.  The reason for breaking the 
code must be recorded in the patient’s source documents. 


 
 
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10. 
Administrative Items 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines 
• Applicable ICH GCP guidelines 
• Applicable laws and regulations 
 
10.1 
Protection of Study Patients 
10.1.1 
Compliance With Informed Consent Regulations (US 21 Code 
of Federal Regulations [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.   
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 
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10.1.4 
Compliance With Electronic Records; Electronic Signatures 
Regulations (US 21 CFR Part 11) 
This study is to be conducted in compliance with the regulations on electronic records and 
electronic signature. 
10.2 
Changes to the Protocol 
The investigator must not implement any deviation from or changes of the protocol without 
approval by Allergan and prior review and documented approval/favorable opinion from the 
IRB/IEC of a protocol amendment, except where necessary to eliminate immediate hazards 
to study patients, or when the changes involve only logistical or administrative aspects of the 
study (eg, change in monitors, change of telephone numbers). 
10.3 
Patient Confidentiality 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study drug may ultimately be marketed, but the 
patient’s name will not be disclosed in these documents.  The patient's name may be 
disclosed to the Sponsor of the study, Allergan, or the governing health authorities or the 
FDA if they inspect the study records.  Appropriate precautions will be taken to maintain 
confidentiality of medical records and personal information. 
10.3.1 
Patient Privacy 
Written authorization (US sites only), data protection consent (European Union [EU] sites 
only), and other documentation in accordance with the relevant country and local privacy 
requirements (where applicable) is to be obtained from each patient prior to enrollment into 
the study, and/or from the patient's legally authorized representative in accordance with the 
applicable privacy requirements (eg, the Health Insurance Portability and Accountability Act 
Standards for Privacy of Individually Identifiable Health Information (“HIPAA”), European 
Union Data Protection Directive 95/46/EC [“EU Directive”]). 
In accordance with HIPAA requirements, additional purposes of this study may include 
publishing of anonymous patient data from the study.  


 
 
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10.4 
Documentation 
10.4.1 
Source Documents 
Source documents may include a patient’s medical records, hospital charts, clinic charts, the 
investigator’s patient study files, as well as the results of diagnostic tests such as X-rays, 
laboratory tests, and electrocardiograms.  The investigator’s copy of the 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: 
• 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 
• all concurrent medications (list all prescription and non-prescription medications 
being taken at the time of enrollment.  At each subsequent visit, changes to the list of 
medications should be recorded.) 
• occurrence and status of any adverse events 
• the results of pregnancy tests performed by the site 
• vital signs and general physical examination findings 
• copies of the laboratory reports generated by the central laboratory for the analysis of 
blood and urine samples 
• visual acuity worksheets 


 
 
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• procedure notes of the study medication procedure should include the following: 
o date and time the vial is removed from the refrigerator 
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  
• the date the patient exited the study, and a notation as to whether the patient 
completed the study or reason for discontinuation 
. 
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 and will be maintained in a central data repository. 


 
 
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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 sponsor-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 the sponsor. 
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 or an Allergan 
approved labeling, packaging and distribution vendor.  All study medications will be supplied 
in identical appearing packaging, identified as an investigational compound and will be 
labeled with the protocol study number and medication kit number.  The label will contain 
information per country specific regulatory requirements and may include but is not limited 
to storage conditions and a caution statement regarding investigational use. 


 
 
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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, the number of units returned to the 
investigator by the patient, and the number of units returned to Allergan during and at the 
completion of the study.  A detailed inventory must be completed for the study medication.  
The study medication must be dispensed only by an appropriately qualified person to patients 
in the study.  The medication is to be used in accordance with the protocol by patients who 
are under the direct supervision of an investigator.  A unit is defined as a single-dose vial. 
10.5.3 
Return or Disposal of Study Medications/Treatments and/or 
Supplies 
 
  If local policy does not allow storage of used study 
medication vials, the site may destroy the used vials per their local policy, but must keep the 
kit box for the detailed inventory of the study medication. 
10.6 
Monitoring by the Sponsor 
A representative of the sponsor will monitor the study on a periodic basis.  The determination 
of the extent and nature of monitoring will be based on considerations such as the objective, 
purpose, design, complexity, blinding, size, and endpoints of the study.   
Authorized representatives of Allergan or regulatory authority representatives will conduct 
on-site visits to review, audit and copy study-related documents.  These representatives will 
meet with the investigator(s) and appropriate staff at mutually convenient times to discuss 
study-related data and questions. 
10.7 
Handling of Biological Specimens  


 
 
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Details about the handling, processing, and shipment of all biological specimens are provided 
in the procedure manual. 
 
 
10.8 
Publications 
 
 
 
 
   
10.9 
Coordinating Investigator 
A signatory Coordinating Investigator will be designated prior to the writing of the Clinical 
Study Report. 
11. 
References 
Age-Related Eye Disease Study Research Group.  A randomized, placebo-controlled, clinical 
trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-
related macular degeneration and vision loss:  AREDS Report No. 8.  Arch Ophthalmol.  
2001;119:1417-1436. 
Blinder KJ, Bradley S, Bressler NM, Bressler SB, Donati G, Hao Y, et al.  Effect of lesion 
size, visual acuity, and lesion composition on visual acuity change with and without 
verteporfin therapy for choroidal neovascularization secondary to age-related macular 
degeneration:  TAP and VIP Report No.1.  Am J Ophthalmol.  2003;136:407-418. 
Cheung LK and Eaton A. Age-related Macular Degeneration. Pharmacotherapy 
2013;33(8):838-855. 
Ciulla TA, Rosenfeld PJ.  Antivascular endothelial growth factor therapy for neovascular 
age-related macular degeneration.  Curr Opin Ophthalmol.  2009;20:158-165. 
Ding X, Patel M, Chan CC.  Molecular pathology of age-related macular degeneration.  Prog 
Retin Eye Res.  2009;28(1):1-18. 


 
 
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Ferris FL 3rd.  Senile macular degeneration:  review of epidemiologic features.  Am J 
Epidemiol.  1983 Aug;118(2):132-151. 
Grisanti S, Tatar O.  The role of vascular endothelial growth factor and other endogenous 
interplayers in age-related macular degeneration.  Prog Retin Eye Res.  
2008 Jul;27(4):372-390. 
Pieramici DJ, Bressler SB, Koester JM, Bressler NM.  Occult with no classic subfoveal 
choroidal neovascular lesions in age-related macular degeneration:  clinically relevant natural 
history information in larger lesions with good vision from the Verteporfin in Photodynamic 
Therapy (VIP) Trial:  VIP Report No. 4.  Arch Ophthalmol.  2006;124:660-664. 
Rein DB, Wittenborn JS, Zhang X, Honeycutt AA, Lesesne SB, Saaddine J, et al.  
Forecasting age-related macular degeneration through the year 2050:  the potential impact of 
new treatments.  Arch Ophthalmol.  2009;127:533-540. 
Shah AR, Del Priore LV.  Natural history of predominantly classic, minimally classic, and 
occult subgroups in exudative age-related macular degeneration.  Ophthalmology.  
2009 Oct;116(10):1901-1907. 
Shah AR, Del Priore LV.  Progressive visual loss in subfoveal exudation in age-related 
macular degeneration:  a meta-analysis using Lineweaver-Burke plots.  Am J Ophthalmol. 
2007 Jan;143(1):83-89. 
Sommer A, Tielsch JM, Katz J, Quigley HA, Gottsch JD, Javitt JC, et al.  Racial differences 
in the cause-specific prevalence of blindness in East Baltimore.  N Engl J Med. 
1991;14(20):1412-1417. 
Wong TY, Chakravarthy U, Klein R, Mitchell P, Zlateva G, Buggage R, et al. The natural 
history and prognosis of neovascular age-related macular degeneration: A systematic review 
of the literature and meta-analysis. Ophthalmology 2008;115:116-126. 


 
 
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12. 
Attachments 
12.1 
Glossary of Abbreviations 
Term/Abbreviation 
Definition 
2Q8  
treatment group that has 2 mg abicipar administered at baseline 
(day 1) and weeks 4 and 8, followed by doses at 8-week intervals 
through week 96  
2Q12 
treatment group that has 2 mg abicipar administered at baseline 
(day 1), and weeks 4 and 12, followed by doses at 12-week 
intervals through week 96 
AMD 
age-related macular degeneration 
ANCOVA 
analysis of covariance 
AREDS 
Age-Related Eye Disease Study  
BCVA 
best-corrected visual acuity 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CMH 
Cochran-Mantel-Haenszel 
CNV 
choroidal neovascularization 
CRF 
case report form 
CRT 
central retinal thickness 
eCRF 
electronic case report form 
DA 
disc area 
DSMC 
Data and Safety Monitoring Committee 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
 
 
EU 
European Union 
GCP 
Good Clinical Practices 
FDA 
Food and Drug Administration 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IOP 
intraocular pressure 
IRB 
Institutional Review Board 
IVRS 
interactive voice response system 


 
 
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Term/Abbreviation 
Definition 
IWRS 
interactive web response system 
ITT 
intent-to-treat (population) 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed-effect model for repeated measures 
MP 
Molecular Partners 
 
 
 
OCT 
optical coherence tomography 
OU 
both eyes 
PDT 
photodynamic therapy 
PEG 
polyethylene glycol 
PK 
pharmacokinetic(s) 
PP 
per-protocol (population) 
PPV 
pars plana vitrectomy 
RBC 
red blood cell 
REACH 
Study 150998-001 
RPE 
retinal pigment epithelium 
rQ4 
control treatment group that has 0.5 mg ranibizumab administered 
every 4 weeks through week 96 
SD-OCT 
spectral-domain optical coherence tomography 
SE 
study eye 
SEQUOIA 
Study 150998-006 (current study) 
TEAE 
treatment-emergent adverse event 
US 
United States 
VEGF 
vascular endothelial growth factor 
WBC 
white blood cell 
 
 
 


 
 
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12.2 
Protocol Amendment Summary Amendment 1 
Title:  Safety and Efficacy of Abicipar Pegol (AGN-150998) in Patients With Neovascular 
Age-related Macular Degeneration  
Protocol 150998-006 Amendment 1 
Date of Amendment:  March 2015 
Amendment Summary 
This summary includes changes made to Protocol 150998-006 (approved November 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 
Title page  
(page 2) 
Added the underlined text: 
“The following information can 
be found on FDA Form 1572 
and/or study contacts page 
and/or Trial Master File:  Name 
and contact information of 
Allergan study personnel and 
Emergency Telephone Numbers; 
name, address, and statement of 
qualifications of each 
investigator; name of each 
subinvestigator working under 
the supervision of the 
investigator; name and address 
of the research facilities to be 
used; name and address of each 
reviewing IRB; US 
21 CFR 312.23 section 6(iii)b.” 
FDA Form 1572 is a US-specific 
document and will only be collected 
for US study sites. 
Investigator information may also be 
found in the trial master file. 
 
 
 
 
 
 
 


 
 
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Section 
Revision 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


 
 
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Section 
Revision 
Rationale 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Section 
Revision 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Stricken text was removed and underlined text was added 
 


 
 
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12.3 
Protocol Amendment Summary Amendment 2 
Title:  Safety and Efficacy of Abicipar Pegol (AGN-150998) in Patients With Neovascular 
Age-related Macular Degeneration  
Protocol 150998-006 Amendment 2 
Date of Amendment:  April 2016 
Amendment Summary 
This summary includes changes made to Protocol 150998-006 Amendment 1 (approved 
March 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 
(page 2) 
Updated title of Allergan Signatory 
Administrative change 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Section 
Revision 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 


 
 
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Section 
Revision 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 1 
Updated to include additional 
support for dosing regimens used in 
the study 
Revised language for purposes of 
clarification only 
 
 
 
 
 
 
Section 3.1 
Updated to include purpose of 
monitoring. 
Revised language for purposes of 
clarification only 
 
 
 
 
 
 
Section 4.5.1.1 
Updated to include use of condoms 
as preferred method of 
contraception for male patients 
participating in the study 
To specify male contraceptive 
measures 


 
 
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Section 
Revision 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 7.3.1 
Added that if non-inferiority for 
both abicipar arms is established, 
that superiority testing of abicipar 
over ranibizumab will be performed
Updated to reflect changes to the 
statistical analysis plan 


 
 
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Section 
Revision 
Rationale 
 
 
 
 
 
 
Section 7.3.3 
Updated to describe additional 
analyses if non-inferiority for both 
abicipar arms is established 
Updated to align with FDA’s 
comments at the end-of-phase 2 
meeting 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Section 
Revision 
Rationale 
Section 10.5.3 
Added the following: If local policy 
does not allow storage of used 
study medication vials, the site may 
destroy the used vials per their local 
policy, but must keep the kit box 
for the detailed inventory of the 
study medication. 
Revised language for 
accommodating the local policy of 
handling the used study medication
Section 12.1 
Added abbreviations for the 
following: ANCOVA, PDT, and 
PEG  
Included abbreviations that were 
either added or not previously 
defined.  
Note:  Stricken text was removed and underlined text was added 
 


 
 
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12.4 
Protocol Amendment Summary Amendment 3 
Title:  Safety and Efficacy of Abicipar Pegol (AGN-150998) in Patients With Neovascular 
Age-related Macular Degeneration  
Protocol 150998-006 Amendment 3 
Date of Amendment:  February 2017 
Amendment Summary 
This summary includes changes made to Protocol 150998-006 Amendment 2 (approved 
April 2016).   
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 10 
Updated to reflect the current 
template language with regards to 
conducting the study in accordance 
with applicable laws and 
regulations. 
Administrative change. 
 


 
 
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12.5 
Protocol Amendment Summary Amendment 4 
Title:  Safety and Efficacy of Abicipar Pegol (AGN-150998) in Patients With Neovascular 
Age-related Macular Degeneration  
Protocol 150998-006 Amendment 4 
Date of Amendment:  April 2018 
Amendment Summary 
This summary includes changes made to Protocol 150998-006 Amendment 3 (approved 
February 2017).   
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 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


 
 
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ALLERGAN 
 
 
 
 
 
 
 
 
 
 
 
            
 
           
 
            
 
           
 
     
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
 
150998-006 Protocol Amendment 4

SAP_000.pdf: 
NCT02462928 
 
Study ID: 150998‐005 
 
 
 
Title: Safety and Efficacy of Abicipar Pegol (AGN‐150998) in Patients with Neovascular Age‐Related 
Macular Degeneration 
 
Statistical Analysis Plan Amendment 2 Date: 16 May 2018 
 
 


Allergan Confidential 
150998-005 Analysis Plan 
 
Statistical Analysis Plan for 150998-005 CSR (Amendment 2) 
1 
16.1.9 Statistical Methods 
 
Allergan 
Biostatistics 
Analysis Plan – Clinical Study Report 
 
Study ID: 
150998-005 
 
Study Title: 
Safety and Efficacy of Abicipar Pegol (AGN-150998) in Patients with 
Neovascular Age-Related Macular Degeneration 
 
 
 
 
 
 


Allergan Confidential 
150998-005 Analysis Plan 
 
Statistical Analysis Plan for 150998-005 CSR (Amendment 2) 
2 
Table of Contents 
Table of Contents ...................................................................................................................... 2 
List of Tables ............................................................................................................................. 4 
List of Figures ........................................................................................................................... 4 
1. 
Introduction ........................................................................................................................ 5 
1.1 
Primary Study Objectives and Design ..................................................................... 5 
1.2 
Sample Size .............................................................................................................. 6 
1.3 
Database Lock and Procedures of Maintaining Masking ........................................ 7 
2. 
Analysis Populations and Data Conventions ..................................................................... 7 
2.1 
Analysis Populations ................................................................................................ 7 
2.2 
Handling Mis-randomization and Mis-stratification ................................................ 8 
2.3 
Analysis Visit Windows ........................................................................................... 8 
2.4 
Data Conventions ..................................................................................................... 9 
3. 
Disposition and Exit Status .............................................................................................. 10 
3.1 
Disposition and Exit Status .................................................................................... 10 
3.2 
Significant Protocol Deviations ............................................................................. 11 
4. 
Demographics and Other Baseline Characteristics .......................................................... 11 
4.1 
Demographics ........................................................................................................ 11 
4.2 
Baseline Characteristics ......................................................................................... 11 
4.3 
Prior Medications/Procedures ................................................................................ 11 
4.4 
Concomitant Medications/Procedures ................................................................... 12 
4.5 
Medical History ...................................................................................................... 13 
5. 
Efficacy Analyses ............................................................................................................ 13 
5.1 
Collection of Primary Efficacy Measurement and Derivation of Primary Efficacy 
Variable .................................................................................................................. 14 
5.2 
Primary Efficacy Analyses ..................................................................................... 14 
5.2.1  Statistical Hypothesis ................................................................................. 14 
5.2.2  Primary Analyses of Primary Efficacy Variable ........................................ 15 
5.3 
Secondary Efficacy Analyses ................................................................................. 18 
5.3.1  BCVA Mean Change from Baseline .......................................................... 18 


Allergan Confidential 
150998-005 Analysis Plan 
 
Statistical Analysis Plan for 150998-005 CSR (Amendment 2) 
3 
5.3.2  SD-OCT CRT Mean Change from Baseline .............................................. 19 
5.3.3  BCVA Improvement of ≥ 15 Letters from Baseline ................................... 20 
5.3.4  NEI-VFQ-25 Mean Change from Baseline in Composite Score ............... 20 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1 
Study Treatment – Exposure and Administration .................................................. 23 
6.1.1  Exposure to Study Treatments ................................................................... 23 
6.2 
Adverse Events ...................................................................................................... 24 
6.2.1  TEAEs of Special Interest .......................................................................... 25 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8. 
Subgroup Analyses .......................................................................................................... 35 
9. 
Interim Analyses .............................................................................................................. 35 
11.  Deviations from Protocol ................................................................................................. 38 
12.  References ........................................................................................................................ 38 
13.  Amendment(s) ................................................................................................................. 38 


Allergan Confidential 
150998-005 Analysis Plan 
 
Statistical Analysis Plan for 150998-005 CSR (Amendment 2) 
4 
13.1  Amendment 1 ......................................................................................................... 38 
13.2  Amendment 2 ......................................................................................................... 39 
14.  Appendix A ...................................................................................................................... 39 
 
List of Tables 
 
Table 1 
Definitions for Analysis Visit Windows............................................................ 9 
 
 
 
 
 
 
 
 
 
 
 
List of Figures 
 
 
 
 
 


Allergan Confidential 
150998-005 Analysis Plan 
 
Statistical Analysis Plan for 150998-005 CSR (Amendment 2) 
5 
1. 
Introduction 
This document describes the planned analysis that will be used for Study 150998-005 clinical 
study report. This randomized, parallel-group study is designed to assess the safety and 
efficacy of abicipar pegol (hereafter referred to as abicipar) compared with ranibizumab in 
treatment-naïve patients with neovascular age-related macular degeneration (nAMD). 
There will be two database locks. The first database lock (referred to as primary DBL) will 
occur when all patients have completed the Week 52 visit, or exited earlier. The study will be 
unmasked to a restricted group for primary analyses. 
The second database lock (referred to as final DBL) will occur when all patients have 
completed the study entirely (Week 104 visit) or exited early from the study. 
The analysis plan will support both primary and final DBL, but some analyses will be 
reduced for the final DBL. For example, demographic, baseline disease characteristics, and 
medical history will not be re-produced at the final DBL.  
1.1 
Primary Study Objectives and Design 
The study objectives are to assess the safety and efficacy of abicipar compared with 
ranibizumab in treatment-naïve patients with nAMD. 
The clinical hypotheses are: 
• Multiple intravitreal injections of 2 mg abicipar have an acceptable safety profile in 
treatment-naïve patients with nAMD  
• The efficacy of at least 1 of the 2 abicipar regimens is noninferior to that of monthly 
ranibizumab intravitreal injections as assessed by the proportion of patients with stable 
vision at Week 52 
This is a multicenter, double-masked, randomized, 104-week, parallel-group, active-
controlled study to evaluate the safety and efficacy of abicipar in treatment-naïve patients 
with nAMD. Approximately 900 patients will be randomized by region with a 1:1:1 
allocation ratio to receive one of the following three treatments: 
• Treatment group 2Q8: 2 mg abicipar administered at baseline (Day 1) and Weeks 4 and 8, 
followed by doses at 8-week intervals through Week 96  


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With an anticipated dropout rate of approximately 20% during a 52-week period, a total of 
900 patients will be enrolled so that approximately 720 patients (240 per group) will 
complete 52 weeks as required for the primary endpoint evaluation. 
1.3 
Database Lock and Procedures of Maintaining Masking 
The study will be unmasked to a restricted group for the primary analysis following the 
Week 52 database lock. Access to randomization codes and unmasked information will be 
strictly limited to team members who will be working on data analysis, study report 
completion, and submission-related documents. To maintain the integrity of the ongoing 
study, Allergan personnel who become unmasked after the Week 52 database lock will not 
participate in any masked activities during the remaining part of the study until after the final 
database lock at study completion. In particular, the unmasked study statistician(s) and 
programmer(s) will no longer be involved in any ongoing study conduct or data review 
activities. Other statisticians and programmers, who are still masked to study treatment, will 
assume these responsibilities until study completion.  
2. 
Analysis Populations and Data Conventions 
2.1 
Analysis Populations 
The following 3 populations will be used for statistical analysis: intent-to-treat (ITT), per-
protocol (PP), and safety. 
The ITT population includes all randomized patients. The ITT population will be used for all 
efficacy analyses. 
The PP population includes all randomized and treated patients who do not have protocol 
deviations that impact the primary efficacy variable. The PP population will be used for 
analyses of the primary and secondary efficacy variables. Primary considerations for PP 
definition include treatment compliance that would represent the intended regimen 
adequately.  
Specifically, the PP population will include patients who 
1. Received at least 9 study treatments (including sham) and attended at least 9 scheduled 
monthly visits during the first year (before the Week 52 visit), and; 
2. Had not missed 3 or more consecutive study treatments (including sham) before the 9th 
study treatment, and; 


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3. Did not have any major protocol deviations that impacted efficacy outcomes prior to the 
Week 52 visit   
The PP population will also include patients who discontinued from the study as a result of 
treatment failure without a major deviation prior to Week 52 that impacted efficacy outcomes 
(even if they met criteria #1 or #2 above).  Patients who escaped to standard of care by 
meeting the protocol criteria before Week 52 and study exit are considered as treatment 
failures. Final determination of the PP population will be made based on masked review of 
the data. Detailed specification will be documented separately prior to the primary database 
lock.   
The safety population includes all treated patients and will be used for all safety analyses. 
Analyses for ITT and PP populations will be based on randomized treatment group, whereas 
analyses for safety populations will be as treated, ie, based on the actual treatment that the 
patient received. 
2.2 
Handling Mis-randomization and Mis-stratification 
In the event of mis-stratification that resulted in randomization under the wrong stratum, all 
PP analyses will be based on the actual stratum to which the patient belongs. ITT analysis 
that uses the randomization stratification factor(s) will be based on the stratum as randomized 
for the primary efficacy analysis and the actual stratum to which the patient belongs for other 
analyses such as model-based approaches. 
2.3 
Analysis Visit Windows 
Analysis visit windows are defined according to study days, which are defined in Table 1. 
Visit windows defined in Table 1 will be applied to all by-visit analyses of efficacy and safety 
variables. Out-of-window visits (including the exit visit) and unscheduled visits will be 
reassigned to the visit that the actual study days fall within. 
In cases where multiple visits occurred within a single visit window, which resulted in 
multiple data points for the same window, the last visit with non-missing data will be used 
for analysis.   


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Table 1 
Definitions for Analysis Visit Windows 
Visit 
Target Day of Visit 
Analysis Visit Window 
(Study Days) 
Baseline (Day 1) 
1 
≤ 1 
Week 4 
28 
2-42 
Week 8 
56 
43-70 
Week 12 
84 
71-98 
Week 16 
112 
99-126 
Week 20 
140 
127-154 
Week 24 
168 
155-182 
Week 28 
196 
183-210 
Week 32 
224 
211-238 
Week 36 
252 
239-266 
Week 40 
280 
267-294 
Week 44 
308 
295-322 
Week 48 
336 
323-350 
Week 52 
364 
351-378 
Week 56 
392 
379-406 
Week 60 
420 
407-434 
Week 64 
448 
435-462 
Week 68 
476 
463-490 
Week 72 
504 
491-518 
Week 76 
532 
519-546 
Week 80 
560 
547-574 
Week 84 
588 
575-602 
Week 88 
616 
603-630 
Week 92 
644 
631-658 
Week 96 
672 
659-686 
Week 100 
700 
687-714 
Week 104 
728 
715-742 
 
2.4 
Data Conventions 
Unless stated otherwise in specific subsequent sections, data conventions and definitions 
listed below will be applied to all analyses. 
• Day 1 is defined as the day when the patient receives the 1st study treatment. 
Study day = visit date – date of the 1st study treatment + 1 
• For patients who were randomized but did not receive any study treatments after 
randomization, the date of randomization will be used as Day 1. 


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• Study duration will be calculated for each patient as: 
Study duration for the primary DBL = date of the Week 52 visit (or early exit if 
discontinued before the primary DBL ) – date of the 1st study treatment + 1 
Study duration for the final DBL = date of the Week 104 visit (or early exit) – date of the 
1st study treatment + 1  
• Unless otherwise specified, baseline data refer to assessments performed at the Baseline 
(Day 1) visit prior to the 1st study treatment. Screening or unscheduled visits prior to 
Day 1 visit will be used for baseline in the absence of pertinent data at the baseline visit. 
• If ungradable images result in missing baseline CRT, the manual read data for retinal 
thickness at the center point, if available, will be used for analysis. If the manual read 
data at baseline is not available, CRT on confirmation reading at screening will serve as 
baseline CRT. 
• Descriptive statistics include the sample size (N), mean, standard deviation (SD), median, 
minimum (Min), and maximum (Max) for continuous/ordinal data and the frequency 
distribution includes sample size (N), frequency count, and percentage for categorical 
data. 
• The difference between groups will be calculated as abicipar minus ranibizumab. 
• Medical Dictionary of Regulatory Activities (MedDRA) nomenclature will be used to 
code adverse events, medical procedures, biomicroscopy, and ophthalmoscopy findings. 
• The Anatomical-Therapeutic-Chemical classification text from World Health 
Organization (WHO) Drug Dictionary will be used to code all medications for drug class 
and for drug name. 
• Whenever applicable, the metric system will be used (eg, kilograms [kg] and centimeters 
[cm]) and all clinical laboratory data will be presented with the Standard International 
(SI) units. 
3. 
Disposition and Exit Status 
3.1 
Disposition and Exit Status 
Patient disposition will be summarized as a frequency distribution by treatment group using 
the ITT and PP populations. For the Week 52 analysis, patients who are still in the study will 


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be classified into the ongoing category. Reasons for early exit will be summarized into the 
following categories as captured on the study exit eCRF. 
3.2 
Significant Protocol Deviations 
Significant protocol deviations will be classified based on the type of deviation for each 
treatment group. Summary of significant protocol deviations will be done for the ITT 
population.  
4. 
Demographics and Other Baseline Characteristics 
4.1 
Demographics 
Demographic data are collected at the screening visit. Patient’s age (years), sex, and race will 
be summarized for each treatment group using the ITT and PP populations. Patient age will 
be classified into categories of less than or equal to 65 years and greater than 65 years.   
4.2 
Baseline Characteristics 
Baseline characteristics include height (cm), weight (kg), iris color, lesion type 
(predominantly classic, minimally classic, or occult), lesion size, subretinal or intraretinal 
fluid, intraretinal cysts, pigment epithelial detachments, polypoidal choroidal vasculopathy, 
and smoking status. Ocular characteristics of the study eye at baseline include lens status, 
study eye as the better-seeing eye (defined as baseline BCVAstudy-eye > BCVAnon-study eye), 
BCVA, CRT, and intraocular pressure. Summaries of baseline characteristics will be done for 
the ITT and PP populations.   
4.3 
Prior Medications/Procedures 
Prior medications are defined as those received prior to the first study treatment. For analysis 
purposes, a medication will be considered as a prior medication if it satisfies at least one of 
the following: 
• The start date is prior to Day 1, regardless of the stop date; 
• The start date is unknown but marked as > 1 year; or 
• The stop date is prior to or on Day 1, regardless of the start date 


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For medications with a partial start or stop date where > 1 year is not marked for the start 
date or ongoing is not marked for the stop date and the day and/or the month is unknown, 
comparison to the 1st study treatment date (Day 1) will start with the year followed by the 
month, if applicable, for determination of prior medications. In cases where a full 
determination cannot be made based on the partial information, the start date will be assigned 
to the 1st day of the month if the day of the month is missing or to January if the month of the 
year is missing; conversely, the stop date will be assigned to the last day of the month if the 
day of the month is missing or to December if the month is missing. This missing data 
imputation will only be used to determine whether a certain medication is considered a prior 
medication. Prior medications will be summarized by treatment group under each drug class 
and drug name. A separate analysis for prior ophthalmic medications used in the study eye 
will be performed based on WHODDE base preferred names. 
Summary of prior medications will be based on the ITT population. 
4.4 
Concomitant Medications/Procedures 
Concomitant medications are defined as those non-study medications received after the first 
study treatment. For analysis purposes, a medication will be considered as concomitant if it 
satisfies at least one of the following: 
• The start date is on or after the Day 1 treatment date regardless of the stop date;   
• The stop date is after the Day 1 treatment date, regardless of the start date; or 
• The stop date is unknown but marked as ongoing  
For medications with a partial start or stop date, the same conventions and algorithms as 
described for prior medications will be used for determination of concomitant medications. 
Concomitant medications will be summarized in the same way as prior medications.   
Concurrent procedures including those ocular and nonocular procedures performed after 
study treatment will be coded using MedDRA. The number and percentage of patients with 
any concurrent procedures will be tabulated and presented by treatment group as a frequency 
distribution for each primary system organ class (SOC) and preferred term. A separate 
summary for ocular concurrent procedures in the study eye will be performed. 
The number and percentage of patients who escaped to standard-of-care will be tabulated by 
medication names for each treatment group. 


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Summary of concomitant medications/procedures will be based on the ITT population. 
4.5 
Medical History 
Medical history will be coded using MedDRA. 
Data will be summarized by frequency distribution for each unique primary SOC and 
preferred terms using the ITT population based on the following two categories: 
• Previous medical conditions, and 
• Medical conditions at study initiation 
Further, ocular history for the study eye will be summarized similarly. 
5. 
Efficacy Analyses 
The primary and secondary efficacy endpoints are listed below. 
Primary efficacy endpoint:  
• The proportion of patients with stable vision (ie, patients who lose fewer than 15 letters in 
BCVA) from baseline at Week 52 
Secondary efficacy endpoints: 
• Mean change from baseline in BCVA at Week 52 (key secondary endpoint) 
• Mean change from baseline in CRT as assessed with SD-OCT and quantified by the 
central reading center at Week 52 
• Proportion of patients with a gain of 15 or more ETDRS letters in BCVA from baseline at 
Week 52 
• Mean change from baseline in The National Eye Institute Visual Function Questionnaire-
25 (NEI-VFQ-25) composite score at Week 52 
Analyses of the primary efficacy endpoint and the key secondary endpoint for testing non-
inferiority will be performed using the PP population. Analyses of the primary and secondary 
efficacy endpoints for testing superiority will be performed using the ITT population.  


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5.1 
Collection of Primary Efficacy Measurement and Derivation of 
Primary Efficacy Variable 
BCVA will be recorded on the CRF as the number of letters correctly read. For a given eye, 
the 4-meter distance (standard) of BCVA is tested first. If the patient correctly reads at least 
20 letters at 4 meters, BCVA score will be set as the sum of 30 and the number of letters read 
correctly. If the patient correctly reads less than 20 letters at 4 meters, the BCVA is measured 
again at 1 meter. The BCVA score will be set to the number of letters read correctly at 
1 meter plus the number of letters read correctly at 4 meters. For each patient, BCVA data 
will be collected for both eyes at the screening, baseline visit (Day 1 but prior to the study 
treatment), and at Weeks 12, 24, 36, 52, 76, and 104/early exit visits; and for the study eye 
only at all other scheduled visits. 
For patients who received any non-study anti-vascular endothelial growth factor (VEGF) 
treatments in the study eye, data after the 1st such treatment will be excluded from all efficacy 
analyses. 
5.2 
Primary Efficacy Analyses 
The primary efficacy endpoint is the proportion of patients with stable vision at Week 52, 
defined as vision loss of fewer than 15 letters in BCVA from baseline. Patients who escaped 
to standard of care by meeting the protocol criteria will be set to failures for the primary 
endpoint of stable vision at Week 52. Confirmation for meeting the protocol criteria is based 
on the marked reasons captured on the Standard of Care eCRF, which states: “Loss of 
≥ 30 letters in BCVA from baseline (in any post-baseline visit), and persistent fluid 
(subretinal and intraretinal) by OCT, judged to be the cause of the BCVA loss (not explained 
by reasons other than the progression of neovascular AMD).” 
5.2.1 
Statistical Hypothesis 
The statistical hypothesis for testing non-inferiority of abicipar to ranibizumab with regard to 
stable vision at Week 52 can be stated as follows: 
Null hypothesis: 
Abicipar (2Q12 or 2Q8) is inferior to ranibizumab by the specified non-inferiority margin of 
10% or more in the proportion of patients with stable vision at Week 52. 


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Alternative hypothesis: 
Abicipar (2Q12 or 2Q8) is inferior to ranibizumab by less than the specified non-inferiority 
margin of 10% or is superior to ranibizumab in the proportion of patients with stable vision 
at Week 52. 
The null and alternative hypotheses can be mathematically stated as follows: 
Ho1:  P2Q8 -  PrQ4 ≤  - 10%  
Ha1:  P2Q8 -  PrQ4 >  - 10%  
And 
Ho2:  P2Q12 -  PrQ4 ≤  - 10% 
Ha2: P2Q12 -  PrQ4 >  - 10% 
where P2Q8, P2Q12 , and PrQ4 are the probabilities of stable vision at Week 52 for the abicipar 
2Q8, abicipar 2Q12, and ranibizumab treatment groups, respectively. 
5.2.2 
Primary Analyses of Primary Efficacy Variable 
The primary analysis of the primary efficacy variable will be performed using the PP 
population based on a stratified method with Cochran-Mantel-Haenszel (CMH) weights. 
Within the framework of this method, the difference in the proportions between each abicipar 
arm and ranibizumab (abicipar group minus ranibizumab group) and the corresponding 
2-sided 95.1% confidence interval for non-inferiority testing will be calculated. Specifically, 
the confidence intervals for treatment group differences will be calculated using the CMH 
weighted method with the baseline BCVA (≤ 55 versus > 55 ETDRS letters) as a 
stratification factor as described in Yan and Su (2010). Missing data for BCVA will be 
imputed using the last observation carried forward (LOCF). The formal non-inferiority test 
will be performed at Week 52 with a non-inferiority margin of 10% at an alpha level of 0.049. 
This alpha reflects an adjustment of 0.001 for the unmasked data review by the data safety 
monitoring committee (DSMC) for safety assessments. The total alpha spent of 0.001 for the 
DSMC is based on the assumption of no more than 10 unmasked reviews during the study, 
with 0.0001 allocated to each review. Thus, the overall alpha for the study is preserved at 
0.05 level. 


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150998-005 Analysis Plan 
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5.3 
Secondary Efficacy Analyses 
The key secondary efficacy variable is the mean change in BCVA from baseline. Other 
secondary efficacy variables include the mean change from baseline in CRT as assessed by 
SD-OCT, proportion of patients with BCVA improvement of 15 letters or more from baseline, 
and mean change from baseline in Health Outcomes NEI-VFQ-25 composite score.   
5.3.1 
BCVA Mean Change from Baseline   
For the key secondary efficacy endpoint mean change from baseline in BCVA at Week 52, 
statistical analysis for non-inferiority will be based on the PP population using a mixed-effect 
model for repeated measures (MMRM), which includes BCVA data from baseline (Day 1) to 
Week 52. The model will include treatment group, region, baseline BCVA in the study eye, 
baseline CRT (≤ 400 µm or > 400 µm) in the study eye, lesion type of choroidal 
neovascularization (predominantly classic versus minimally classic or occult) from the 
confirmation at screening, visit, visit-by-baseline BCVA interaction, and treatment-by-visit 
interaction as fixed covariates using an unstructured covariance matrix. The difference in 


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BCVA mean change from baseline between each abicipar arm and ranibizumab (abicipar 
group minus ranibizumab group) and the corresponding 2-sided 95.1% confidence interval 
(CI) will be calculated based on the MMRM model. The formal non-inferiority test will be 
performed at Week 52 using a margin of 5 letters. Non-inferiority of abicipar will be 
established if the lower limit of the CI is > - 5.0 letters. Testing for non-inferiority in mean 
change will also be performed using the ITT population and the same MMRM model as a 
sensitivity analysis. 
Testing for superiority of abicipar over ranibizumab in BCVA mean change will be 
performed using the ITT population with the same MMRM model.   
As a sensitivity analysis, BCVA mean change will be analyzed using an analysis of 
covariance (ANCOVA) model, which includes the treatment group, region, baseline CRT 
(≤ 400 or > 400 microns), and lesion type of choroidal neovascularization (predominantly 
classic versus minimally classic or occult) from the confirmation at screening as fixed effects 
and baseline BCVA as a covariate. In this model, missing data will be replaced by LOCF and 
the analysis will be performed for the PP population. Treatment differences between each 
abicipar group and ranibizumab and the corresponding 2-sided 95.1% confidence intervals 
for the difference will be calculated based on the least–square means and appropriate 
contrasts from the same ANCOVA model. 
Tipping point analysis as described in Section 5.2.4.2 will be performed for BCVA change 
using the PP population. The tipping region will be constructed based on the combinations of 
values for δ2Q8, δ2Q12, or δrQ4 that resulted in a lower bound of the 95.1% CI for the difference 
of abicipar (2Q8 or 2Q12) minus ranibizumab less than -5 letters. 
5.3.2 
SD-OCT CRT Mean Change from Baseline   
The electronic SD-OCT images will be evaluated and graded by the Fundus Photograph 
Reading Center (FPRC). The graded results will be captured on the evaluation form and used 
for statistical analysis. In the event of excess fluid at baseline and ungradable images that 
result in missing baseline CRT, the manual read data for retinal thickness at the center point, 
if available, will be used for analysis. 
CRT is measured as the thickness of the subfields, which is the central 1000 µm from the 
center of the fovea. 
Analysis of CRT mean change from baseline in the study eye will be performed using the 
same MMRM model for superiority testing based on the ITT population as described in 


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Section 5.3.1 for the key efficacy variable of BCVA change. The only difference is that 
baseline CRT will be included in the model as a continuous variable instead of a dichotomy 
(eg, ≤ 400 µm or > 400 µm) as used for randomization.   
5.3.3 
BCVA Improvement of ≥ 15 Letters from Baseline 
The proportion of patients with a BCVA improvement of ≥ 15 letters from baseline in the 
study eye at each postbaseline visit will be calculated for each treatment group. Between-
group comparisons and the 95.1% confidence intervals for the between-group difference will 
be performed using the same method as described for the primary efficacy variable in 
Section 5.2.2 for superiority testing using the ITT population.  
5.3.4 
NEI-VFQ-25 Mean Change from Baseline in Composite Score  
The NEI-VFQ-25 will be administered at the Baseline/Day 1, and at Weeks 12, 24, 36, 52, 76, 
and 104/early exit visits. Detailed analyses and analysis visit windows are described in 
Section 7 for health outcome data analysis. 
As a secondary efficacy variable, change from baseline at Week 52 in the overall composite 
score will be analyzed for superiority testing using the ITT population and MMRM as 
described in Section 5.3.1 for the key secondary efficacy variable of BCVA change. The 
model will include the treatment group, region, baseline BCVA in the study eye, baseline 
VFQ score, visit, and treatment-by-visit interaction as fixed covariates using an unstructured 
covariance matrix. Treatment differences and the corresponding 95.1% confidence intervals 
will be constructed using the MMRM model. 
 
 
 
 
 
  


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6.2 
Adverse Events 
A TEAE is an adverse event that occurs after the initiation of the study treatment (ie, the 
onset date is the same as or after the study treatment date), or an adverse event with onset 
prior to the study treatment that worsened in severity or became serious after the initiation of 
the study treatment. The incidence of TEAEs will be calculated by treatment group and 
presented as the number and percentage of patients experiencing the TEAE during the 
reporting period.   
The following summaries of TEAE data will be performed: 1) overall summary, 2) all 
TEAEs regardless of causality, 3) treatment-related TEAEs, 4) ocular TEAEs (study eye 
versus non-study eye), 5) nonocular TEAEs, 6) treatment-related ocular TEAEs, and 7) 
TEAEs of special interest. An additional summary will be provided for 8) treatment-emergent 
serious adverse events (TE SAEs) and 9) AEs leading to study discontinuation. 
The 1) overall summary will present the number and percentage of patients with TEAEs, 
ocular/nonocular TEAEs in the study eye, treatment-related ocular/nonocular TEAEs, AEs 
leading to study discontinuation, TE SAEs, and death in each treatment group. Treatment-
related ocular TEAEs will also be summarized for injection-related and drug-related TEAEs. 
Injection-related TEAEs are those TEAEs marked as related to the study treatment 
administration. 
Further, tabulations of TEAEs or TE SAEs based on MedDRA coded terms, primary system 
organ class (SOC) and/or preferred terms (PTs) will be sorted by the frequency of occurrence 
as detailed below. 
• Summary for 3) treatment-related TEAEs, 5) nonocular TEAEs, 8) TE SAEs, and 9) AEs 
leading to study discontinuation will be sorted by primary SOC in alphabetical order. 
Within each SOC name, TEAEs (TE SAEs or AEs) will be tabulated by PT in descending 
order. A patient with multiple occurrences of the same PT within the reporting period will 
be counted only once for that PT.   
• Summary for 2) TEAEs by severity will be sorted by primary SOC in alphabetical order 
and by the worst severity (maximum severity) experienced for a given patient. Within 
each SOC, TEAEs will be tabulated by PT in descending order and by severity. The 
severity of a TEAE is defined as the greater of the onset severity and maximum severity 
recorded on the CRF for each unique PT reported by the patient. 


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• Summary for 4) ocular TEAEs, 6) treatment-related ocular TEAEs, and 7) TEAEs of 
special interest of intraocular inflammation will be sorted by preferred term in descending 
order. A patient with multiple occurrences of the same preferred term within the reporting 
period will be counted only once for that PT. 
All tabulations will be sorted in descending order of frequency following this sequence from 
left to right: starting from abicipar groups 2Q8, 2Q12, and ranibizumab every 4 weeks (rQ4).  
For the Week 52 analysis, AEs reported from baseline to Week 52 will be determined by AE 
onset date using the following criteria: 
• For patients who completed the Week 52 visit, include AEs with an onset date ≤ Week 52 
visit date 
• For patients who did not complete the Week 52 visit due to early dropout or missed visit, 
include AEs with an onset date ≤ 365 days from the date of the 1st injection prior to early 
exit 
For cases where the AE onset date is partially or completely missing and does not allow for a 
full determination of whether the AE occurred within the Week 52 period, those AEs will be 
included in the Week 52 analysis.  
6.2.1 
TEAEs of Special Interest 
TEAEs of special interest include intraocular inflammation and those potentially related to 
systemic VEGF inhibition. TEAEs related to systemic VEGF inhibition will be categorized 
as arterial-thromboembolic events (ATEs, defined as nonfatal stroke, nonfatal myocardial 
infarction, or vascular death [including deaths of unknown cause]), hypertension, nonocular 
hemorrhage, proteinuria, and others. Data for these two types of TEAEs will be summarized 
by MedDRA preferred terms. 
TEAEs included in the intraocular inflammation table will follow a two-step selection 
process: first to identify the MedDRA preferred terms that may represent an intraocular 
inflammation followed by a thorough medical review of any relevant details reported for the 
adverse event including ocular examination findings. The incidence of TEAEs for intraocular 
inflammation of special interest will be summarized by treatment group and presented as the 
number and percentage of patients. TEAEs identified based on MedDRA preferred terms but 
not considered as intraocular inflammation of special interest will be displayed in a separate 
data listing. 


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TEAEs included in the events potentially related to systemic VEGF inhibition table will be 
identified following the same process. A summary for arterial thromboembolic events or 
other adverse events that are potentially related to systemic VEGF inhibition will be done by 
the following categories of ATE, hypertension, nonocular hemorrhage, proteinuria, and others 
by preferred terms. 
In addition, TEAEs potentially related to systemic VEGF inhibition will be summarized 
separately for patients who received the following anti-VEGF injections in the non-study 
eye: ranibizumab, bevacizumab, pegaptanib, and aflibercept. 
The selection and review of all TEAEs of special interest will be performed in a masked 
fashion and finalized prior to database lock and study unmasking. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8. 
Subgroup Analyses  
Subgroup analyses will be performed on the pooled data from the 2 pivotal Phase 3 studies. 
Analysis will be carried out for the integrated summaries of safety and efficacy. Subgroup 
analyses will not be performed for the individual clinical studies. 
9. 
Interim Analyses 
No interim analyses are planned for this study. However, an independent DSMC will assess 
the unmasked safety data during the study. To preserve an overall alpha of 0.05 for the study, 
an adjustment of 0.001 will be made and an alpha level of 0.049 will be used for testing 
purposes. Therefore, 95.1% confidence intervals will be constructed for the primary efficacy 
analysis. 
 
 
 
 
 
 
 
 
   


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11. 
Deviations from Protocol  
There are no deviations from the current study protocol. 
12. 
References 
 
Yan X. and Su X.G Stratified Wilson and Newcombe confidence intervals for multiple 
binomial proportions. Statistics in Biopharmaceutical Research. 2010;2(3):329-335. 
13. 
Amendment(s) 
13.1 
Amendment 1 
The following changes were made in Amendment 1: 


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13.2 
Amendment 2 
The following changes are made in Amendment 2: 
 
 
• For Japan Pharmaceuticals and Medical Devices Agency (PMDA) review, clarified the 
gatekeeping procedure for multiplicity adjustment to be applied to statistical tests of 
secondary efficacy variables (Section 10) 
14. 
Appendix A 
 
 


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Appendix A: Modified Wald Confidence Interval with Stratifications  
Single Imputation (LOCF) 
Let i=1, 2,…, k index strata and let ݌ଵ௜ and ݌ଶ௜ denote stratum-specific response rates for 
treatment 1 and 2 in stratum i, respectively.  Let ݀௜ൌ݌ଵ௜ െ݌ଶ௜,  where ݌ଵ௜ ൌ ݔଵ௜݊ଵ௜
ൗ
 , with 
ݔଵ௜ being the number of responders and ݊ଵ௜ being the sample size for treatment 1 in stratum i. 
Similar definition for ݌ଶ௜ ൌ ݔଶ௜݊ଶ௜
ൗ
. 
Let ݌ଵ௜
כ ൌ
௫భ೔ାଶ
௡భ೔ାସ   and ݌ଶ௜
כ ൌ
௫మ೔ାଶ
௡మ೔ାସ 
With corresponding variance,  
߭ଵ௜ൌ
௣భ೔
כ ሺଵି௣భ೔
כ ሻ
௡భ೔
 and ߭ଶ௜ൌ
௣మ೔
כ ሺଵି௣మ೔
כ ሻ
௡మ೔
 
And the variance for the difference in response rates between treatment groups in stratum i, 
߭௜ൌ߭ଵ௜൅߭ଶ௜ 
Define weight ݓ௜ൌ
௡భ೔כ௡మ೔
௡భ೔ା௡మ೔ 
The weighted difference, 
݀ൌ∑
ݓ௜݀௜
௞
௜ୀଵ
∑
ݓ௜
௞
௜ୀଵ
 
And the variance for the weighted difference is, 
߭ሺ݀ሻൌ∑
ݓ௜
ଶߥ௜
௞
௜ୀଵ
൫∑
ݓ௜
௞
௜ୀଵ
൯
ଶ 
The Wald confidence interval for the weighted difference is, 
݀ േ ܼଵି஑/ଶכ ඥ߭ሺ݀ሻ 
where ܼଵି஑/ଶ is the critical value corresponding to the 1- α/2 quantile of the standard normal 
distribution.  
 


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Multiple Imputation 
Let ܸሺ௝ሻ denote the variance ܸሺ݀ሻ for the point estimate from the jth imputed dataset. 
Hence, the within-imputation variance over all imputed data can be calculated as following: 
ܸതൌ1
݉෍ܸሺ௝ሻ
௠
௝ୀଵ
 
And the between-imputation variance is  ܤൌ 
ଵ
௠∑
ሺ݀ሺ௝ሻെ݀ҧሻଶ
௠
௝ୀଵ
 
Where ݀ሺ௝ሻ is the weighted difference for the j th imputation invocation and ݀ҧ is the average 
of weighted differences over all imputation invocations. 
The total variance is the combination of within- and between-imputation variance: 
ܶൌ ܸത൅ ൬1 ൅ 1
݉൰ܤ 
For SAS application, plugging in d as the MODELEFFECTS and ඥܸሺ݀ሻ as the STDERR for 
PROC MIANALYZE.  
The lower bound of the confidence interval is,  
ܮܤൌ݀ҧ െ ܼଵି஑/ଶכ √ܶ 
and the upper bound of the confidence interval is,  
 
ܷܤൌ݀ҧ ൅ ܼଵି஑/ଶכ √ܶ 
where T is the total variance from imputed data. 
 
IOP is not assessed at 5-min postinjection; only 20 min postinjection 
 


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Statistical Analysis Plan for AMD P3  CEDAR Amendment 2