Clinical trial NCT02247531
Conditions: Geographic Atrophy
Sponsor: Hoffmann-La Roche
Start date: 2014-10-06; Completion date: 2018-01-23
Enrollment: 975 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a Phase III, double-masked, multicenter, randomized, sham injection-controlled study evaluating the efficacy and safety of lampalizumab administered by intravitreal injections in participants with geographic atrophy (GA) secondary to age-related macular degeneration (AMD).

Detailed description:

Arms: arm 1: Participants will receive 10 mg (milligrams) dose of lampalizumab by intravitreal injection, Q4W, starting at the Day 1 visit for approximately 92 weeks. arm 2: Participants will receive 10 mg dose of lampalizumab by intravitreal injection, Q6W, starting at the Day 1 visit for approximately 90 weeks. arm 3: Participants will receive sham comparator, Q4W, starting at the Day 1 visit for approximately 92 weeks or Q6W, starting at the Day 1 visit for approximately 90 weeks.
Interventions: intervention 1: Lampalizumab intervention 2: Sham Comparator
Intervention descriptions: intervention 1: 10 mg dose of lampalizumab administered intravitreally. intervention 2: A sham injection is a procedure that mimics an intravitreal injection of lampalizumab.

Protocol documents:
Prot_000.pdf: 
 
Official Title: 
 
A Phase III, Multicenter, Randomized, Double-Masked, 
Sham-Controlled Study to Assess the Efficacy and Safety of 
Lampalizumab Administered Intravitreally to Patients With 
Geographic Atrophy Secondary to Age-Related Macular 
Degeneration  
NCT Number: 
NCT02247531 
Document Date: 
Protocol, Version 6, 24-Sep-2015 
 
 
 




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PROTOCOL AMENDMENT, VERSION 6: 
RATIONALE 
Changes to the protocol, along with a rationale for each change, are summarized below: 
• 
Section 1.3 was updated to reflect the number of patients who have received at 
least one 10-mg dose of lampalizumab as part of two completed clinical studies 
(Phase 1a Study CFD4711g and Phase 1b/II Study CFD4870g) and an ongoing 
study (Study GX28198), which is an extension of Study CFD4870g. 
• 
Section 3.1 was updated to guide sites in handling specific patient screening and 
scheduling issues.Section 3.1.1 has been updated to provide a more accurate 
number of global sites that will be participating in Study GX29185. 
• 
Section 3.1.2 was revised to remove repetitive information regarding Data 
Monitoring Committee review of efficacy data for Study GX29185.   
• 
Section 3.5 had been added to indicate that exploratory substudies might be added 
to Study GX29185.   
• 
Section 4.1 includes guidance regarding the procedure for handling patients who 
need an extended screening period to prevent unnecessary re-screening as a result 
of missing the screening visit window due to unforeseen circumstances.   
• 
In Section 4.1.1, the inclusion criteria regarding contraceptive methods for women of 
childbearing potential and men have been harmonized with current international 
recommendations. The definition of women of childbearing potential has been 
harmonized with current international recommendations. 
• 
In Section 4.1.2, the exclusion criteria for concurrent systemic conditions have been 
updated to include treatment for localized in addition to systemic infection and that 
ongoing prophylactic use of antimicrobial therapy should be discussed with Medical 
Monitor.   
• 
Section 4.2.2 contains additional details regarding the masked and unmasked roles, 
how they are documented, and under what conditions they may be switched to 
maintain the study masking and proper conduct of study procedures. 
• 
In Section 4.4.1 updated instructions are given in the event that Lucentis treatment 
is given at the same visit as a study eye treatment with lampalizumab/sham to help 
ensure patient safety. 
• 
Section 4.5.1 was updated to include re-screening tests as events requiring written 
informed consent to remind the site personnel of this requirement. 
• 
Section 5.1 was updated to include transient vision loss as a potential ocular safety 
issue currently thought to be associated with the route of administration to help 
ensure patient safety.  Table 6 has been revised to provide more detailed guidance 
for the assessment of causality.  
• 
Section 5.3.5.10 was updated to clarify criteria when hospitalization does not require 
immediate reporting as a serious adverse event (SAE). 
• 
Sections 5.4 − 5.5 were revised to update the procedures for submitting various 
types of safety reports  


 
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• 
Appendix 4 has been revised to further clarify the pre-treatment procedures for 
patients undergoing treatment or sham injections to help ensure patient safety. 
• 
Appendix 5 has been revised to include equivalent study treatment supplies 
(needles) available outside of the United States and to further clarify the steps 
required to prepare and administer a lampalizumab injection to help ensure patient 
safety. 
• 
Appendix 20 has been updated to emphasize that the treating physician collects the 
optional aqueous humor samples. 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 


 
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PROTOCOL AMENDMENT, VERSION 6: 
SUMMARY OF CHANGES 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 1.3:  STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
…A total of 133147 patients have received at least one 10-mg dose of lampalizumab as 
part of two completed clinical studies (Studies CFD4711g and CFD4870g) and an 
ongoing study (Study GX28198), which is an extension of Study CFD4870g. 
SECTION 3.1:  DESCRIPTION OF STUDY 
…Screen-failed patients may be eligible for re-screening up to two additional times 
during the enrollment period of the study.  At re-screening, all screening visit 
assessments will be performed except for CFI biomarker sample and FA imaging 
collection, provided that a valid CFI result is available and reading center-eligible FA 
images were taken within 8 weeks before the new Day 1 visit (randomization).  
…The first study treatment will be administered on the same day as randomization 
(Day 1 visit).  If a site has an unexpected issue (e.g., the IxRS is not able to assign the 
study kit), with the Medical Monitor’s permission, the patient’s first study treatment 
may be administered within 3 working days of the Day 1 visit.  The following 
assessments will be repeated on the day of the study treatment: slit lamp examination, 
indirect ophthalmoscopy, and pre- and post-treatment IOP measurement (recorded on 
Day 1 eCRF and dated accordingly).   
…After the Day 1 visit, if a patient misses a study visit when ocular images are 
scheduled to be taken (see Appendix 1), the images must be obtained at the next 
scheduled visit. 
Patients are not expected to attend their scheduled visits if there are extenuating 
circumstances justifying their inability to come to the clinic.    
SECTION 3.1.1:  Planned Total Sample Size  
Approximately 936 patients (188 biomarker-positive patients per treatment group 
[lampalizumab Q4W, lampalizumab Q6W, and pooled sham] and 
124 biomarker-negative patients per treatment group [lampalizumab Q4W, 
lampalizumab Q6W, and pooled sham) will be enrolled in the study at approximately 
125140 sites located globally. 
SECTION 3.1.2:  Data Monitoring Committee 
…The iDMC will meet approximately every 6 months (frequency adjustable as required) 
to evaluate the benefit-risk profile of lampalizumab treatment through reviewing both 
safety and efficacy data. No formal efficacy/futility analysis is planned to be done by 


 
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iDMC. If the iDMC deems a benefit risk assessment necessary, the iDMC may also 
review unmasked efficacy data.   
SECTION 3.5:  EXPLORATORY SUBSTUDIES 
At selected sites, the Sponsor may propose exploratory substudies associated with the 
Study GX29185 protocol.  Each substudy will be documented in a separate substudy 
protocol and associated ICF(s).  
SECTION 4.1:  PATIENTS 
Patient Selection and Sex Distribution 
Written informed consent will be obtained prior to initiation of any study procedures.  The 
screening evaluation will be performed within 28 days preceding the Day 1 visit (the day 
of the first study treatment). 
Note: Some patients may require an extended screening period as a result of 
repeated evaluation of images or other issues.  Upon agreement with the Medical 
Monitor, the screening period may be extended for up to 5 days for such cases. 
 
SECTION 4.1.1:  Inclusion Criteria 
General Inclusion Criteria 
• 
For women who are not postmenopausal (≥12 months of non-therapy-induced 
amenorrhea) or surgically sterile (absence of ovaries and/or uterus):of childbearing 
potential:  agreement to remain abstinent or (refrain from heterosexual intercourse) 
or use single or combined contraceptive methods that result in a failure rate of <1% 
per year during the treatment period and for at least 30 days after the last dose of 
study treatment drug 
Abstinence A woman is only acceptable considered to be of childbearing 
potential if itshe is in line postmenarcheal, has not reached a postmenopausal 
state ( ≥ 12 months of amenorrhea with no identified cause other than 
menopause), and has not undergone surgical sterilization (removal of ovaries 
and/or uterus). 
Examples of contraceptive methods with a failure rate of < 1% per year include 
bilateral tubal ligation, male sterilization, established, proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices 
and copper intrauterine devices.   
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
Examples of contraceptive methods with a failure rate of < 1% per year include 
tubal ligation, male sterilization, hormonal implants, established, proper use of 
combined oral or injected hormonal contraceptives, and certain intrauterine 
devices.  Alternatively, two methods (e.g., two barrier methods such as a 
condom and a cervical cap) may be combined to achieve a failure rate 


 
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of < 1% per year.  Barrier methods must always be supplemented with the use 
of a spermicide. 
Sexually active men will be required to use a barrier contraceptive method (condom), 
even if they have been surgically sterilized, for the duration of the For men: 
Agreement to remain abstinent or use contraceptive measures and agreement to 
refrain from donating sperm, as defined below: 
With female partners of childbearing potential, men must remain abstinent or 
use a condom plus an additional contraceptive method that together result in a 
failure rate of < 1% per year during the treatment period and for at least 30 
days plus 90 days (a spermatogenesis cycle) after the last dose of study 
treatment drug.  Men must refrain from donating sperm during this same time 
period. 
SECTION 4.1.2:  Exclusion Criteria 
Ocular Exclusion Criteria:  Concurrent Ocular Conditions 
• 
History of recurrent infectious or inflammatory ocular disease in either eye 
Concurrent Systemic Conditions Exclusion Criteria 
• 
Treatment for active systemic or localized infection  
The ongoing prophylactic use of antimicrobial therapy should be discussed 
with the Medical Monitor.  
• 
Women who are pregnant or lactating or intending to become pregnant during the 
study 
Women who are not postmenopausal (≥12 months of non therapy induced 
amenorrhea) or surgically sterile Women of childbearing potential must have a 
negative serum pregnancy test result within 28 days prior to initiation of study 
treatment. 
SECTION 4.2.2:  Masking 
…At least one other investigator (and designated, unmasked assistant, as needed) will 
be designated as the treating (injecting) physician who will be unmasked to patients’ 
treatment assignment and will administer injections (lampalizumab or sham).  The 
Principal Investigator must be masked to patients’ treatment assignment.  All roles for 
each study staff member should be clearly documented on the Site Delegation Log.  The 
Delegation Log should be signed by the Principal Investigator. 
Once the designated masked vs. unmasked roles are determined, delineated and the site 
study staff have started to perform them, the roles will not cannot be switched or 
reversed at any time during the conduct of the study.  In the event an alternate 
investigator needs to be substituted for an investigator, that alternate physician may 
assume only one role (i.e., treating physician or evaluating physician) for the duration of 
the study.  In case a site is dealing with an experiencing unexpected extreme situation, 
sponsor situations, the Medical Monitor’s permission might be granted to switch an 
investigator the study staff member from the masked role (evaluating physician) to the 
unmasked role (treating physician), but not the other way around.  In the event an 


 
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alternate study staff member needs to be added or substituted, that alternate study staff 
member may assume only one role for the duration of the study. 
Starting at a the patient’s Day 1 visit, the treating physician(s) (performing the 
lampalizumab or sham injections), post-treatment finger counting, and optional 
aqueous humor sample collection) must not continue their role as treating physician 
only, cannot be involved in any other aspect of the study, in any way and must not 
divulge treatment assignment to anyone. 
SECTION 4.4.1:  Permitted Therapy 
…NOTE: If (as per masked investigator judgment) treatment with Lucentis is to be given 
(to study and/or non-study eye) at the same visit as a study eye treatment with 
lampalizumab/sham, the treatment with Lucentis must be administered first.  Following 
this, a safety assessment (including an IOP check) to proceed to must be completed by 
the physician in the masked role prior to the study eye treatment with 
lampalizumab/sham must be assessed prior to.  If there are no concerns, the site may 
proceed with calling IxRS for the study treatment kit assignment.    
SECTION 4.5.1:  Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening or re-screening tests or evaluations.  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site.  
SECTION 5.1:  SAFETY PLAN 
Potential ocular safety issues currently thought to be associated with the route of 
administration or pharmacology of lampalizumab include decreased BCVA, conjunctival 
hemorrhage, ocular inflammation (see Section 5.3.5 and Appendix 3 for anterior 
chamber and vitreous inflammation grading scales), intraocular infection 
(endophthalmitis), transient and/or sustained elevation of IOP, transient vision loss, 
cataract development or progression, retinal or vitreous hemorrhage, and retinal break 
or detachment.  The occurrence of all AEs (serious and non-serious) and pregnancies 
will be recorded on eCRFs for the duration of this study. 
TABLE 6:  Causal Attribution Guidance 
Table 6 has been revised to update the guidance for causal attribution. 
SECTION 5.3.5.10:  Hospitalization or Prolonged Hospitalization or Surgery 
There are some hospitalization scenarios that do not require reporting as an SAE when 
there is no occurrence of an AE.  These scenarios include a planned hospitalization or 
prolonged hospitalization to undergo a diagnostic or elective surgical procedure for a 
preexisting medical condition other than ocular that has not changed. 
• 
Hospitalization for a preexisting condition, provided that the following criteria are 
met: 


 
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– 
The hospitalization was planned prior to the study or was scheduled 
during the study when elective surgery became necessary because of the 
expected normal progression of the disease. 
– 
The patient has not experienced an adverse event. 
 
SECTION 5.4.2.1:  Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only SAEs 
caused by a protocol-mandated intervention should be reported.  A paper Serious 
Adverse Event/Adverse Event of Special Interest Reporting Form and fax cover sheet 
provided to investigators should be completed and faxed to Roche Safety Risk 
Management submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the event), either by faxing or scanning and emailing the form 
using the fax numbers number or email address provided to investigators (“Protocol 
Administrative and Contact Information and List of Investigators”). 
SECTION 5.4.2.2:  Events That Occur after Study Drug Initiation 
…In the event that the EDC system is unavailable, a paper the Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form and fax cover sheet provided 
to investigators should be completed and faxed submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the event), either by 
faxing or by scanning and emailing the form using the fax numbers number or email 
address provided to investigators (“Protocol Administrative and Contact Information and 
List of Investigators”).  Once the EDC system is available, all information will need to be 
entered and submitted via the EDC system. 
SECTION 5.4.3.1:  Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or until the last study visit.  A 
Clinical Trial Pregnancy Report eCRF Reporting Form should be completed by the 
investigator and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy) and submitted via), either by faxing or by 
scanning and emailing the EDC system.  A pregnancy report will automatically be 
generated and sent to the Sponsor. form using the fax number or email address 
provided to investigators.  Pregnancy should not be recorded on the Adverse Event 
eCRF.  The investigator should discontinue study drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy.  Any SAEs associated 
with the pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial 
Pregnancy Reporting Form when updated information on the course and outcome of the 
pregnancy becomes available. 


 
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In the event that the EDC system is unavailable, a paper Clinical Study Pregnancy 
Reporting Form and fax cover sheet should be completed and faxed to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
using the fax numbers provided to investigators (“Protocol Administrative and Contact 
Information and List of Investigators”).  Once the EDC system is available, all information 
will need to be entered and submitted via the EDC system. 
SECTION 5.4.3.2:  Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or until the last 
study visit.  A Clinical Trial Pregnancy Report eCRF Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy) either by the investigator immediately (i.e., no 
more than 24 hours after learning of the pregnancy) and submitted via the EDC system. 
faxing or by scanning and emailing the form using the fax number or email address 
provided to investigators.  Attempts should be made to collect and report details of the 
course and outcome of any pregnancy in the partner of a male patient exposed to study 
drug.  The pregnant partner will need to sign an Authorization for Use and Disclosure of 
Pregnancy Health Information to allow for follow-up on her pregnancy.  Once After the 
authorization has been signed, the investigator will update the submit a Clinical Trial 
Pregnancy Report eCRF with additional Reporting Form when updated information on 
the course and outcome of the pregnancy becomes available.  An investigator who is 
contacted by the male patient or his pregnant partner may provide information on the 
risks of the pregnancy and the possible effects on the fetus, to support an informed 
decision in cooperation with the treating physician and/or obstetrician. 
In the event that the EDC system is unavailable, follow reporting instructions provided in 
Section 5.4.3.1. 
SECTION 5.5.1:  Investigator Follow-Up 
All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3.1. 
APPENDIX 4:  Pre-Injection Procedures for All Patients 
Appendix 4 has been revised to further clarify the pre-treatment procedures for patients 
undergoing treatment or sham injections. 
APPENDIX 5:  Preparation and Administration of Lampalizumab Injection 
Appendix 5 has been revised to include equivalent study treatment supplies (needles) 
available outside of the United States and to further clarify the steps required to properly 
prepare and administer a lampalizumab injection. 


 
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APPENDIX 20:  Biological Sample Collection and Shipping Instructions 
Appendix 20 has been revised to stress that the treating physician collects the optional 
aqueous humor samples. 
MASTER INFORMED CONSENT FORM 
The master Informed Consent Form has been revised to reflect the changes to the 
protocol. 


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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 18 
PROTOCOL SYNOPSIS .................................................................................... 19 
1. 
BACKGROUND .......................................................................................... 29 
1.1 
Background on Geographic Atrophy Secondary 
to Age-Related Macular Degeneration .................................. 29 
1.2 
Background on Lampalizumab .............................................. 29 
1.3 
Study Rationale and Benefit-Risk Assessment...................... 31 
1.3.1 
Study CFD4711g:  Phase Ia.................................................. 32 
1.3.2 
Study CFD4870g:  Phase Ib/II............................................... 32 
1.3.3 
Study GX28198 Open-Label Extension................................. 35 
1.3.4 
Summary ............................................................................... 35 
2. 
OBJECTIVES.............................................................................................. 36 
2.1 
Efficacy Objectives ................................................................ 36 
2.2 
Safety Objectives................................................................... 36 
2.3 
Pharmacokinetic Objective .................................................... 36 
2.4 
Diagnostic Objective.............................................................. 37 
2.5 
Exploratory Objectives........................................................... 37 
3. 
STUDY DESIGN ......................................................................................... 37 
3.1 
Description of Study .............................................................. 37 
3.1.1 
Planned Total Sample Size ................................................... 43 
3.1.2 
Data Monitoring Committee................................................... 43 
3.2 
End of Study.......................................................................... 43 
3.3 
Rationale for Study Design.................................................... 43 
3.3.1 
Rationale for Lampalizumab Dose and Schedule.................. 43 
3.3.2 
Rationale for Patient Population and Analysis 
Groups................................................................................... 44 
3.3.2.1 
Rationale for Evaluating Lampalizumab 
Treatment Effect in Patients with Geographic 
Atrophy Secondary to Age-Related Macular 
Degeneration......................................................................... 44 
3.3.2.2 
Enrichment of Complement Factor I Profile 
Biomarker-Positive Patients................................................... 45 


 
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3.3.3 
Rationale for Control Group................................................... 46 
3.3.4 
Rationale for Biomarker Assessments................................... 46 
3.4 
Outcome Measures ............................................................... 47 
3.4.1 
Efficacy Outcome Measures.................................................. 47 
3.4.2 
Safety Outcome Measures .................................................... 47 
3.4.3 
Pharmacokinetic Outcome Measure...................................... 47 
3.4.4 
Diagnostic Outcome Measure ............................................... 47 
3.4.5 
Exploratory Outcome Measures ............................................ 48 
3.5 
Exploratory Substudies ......................................................... 48 
4. 
MATERIALS AND METHODS .................................................................... 48 
4.1 
Patients.................................................................................. 48 
4.1.1 
Inclusion Criteria.................................................................... 49 
4.1.2 
Exclusion Criteria................................................................... 50 
4.1.3 
Microperimetry Criteria at Selected Sites Only ...................... 52 
4.2 
Method of Treatment Assignment and Masking .................... 53 
4.2.1 
Treatment Assignment........................................................... 53 
4.2.2 
Masking ................................................................................. 54 
4.2.3 
Unmasking............................................................................. 55 
4.3 
Study Treatment.................................................................... 56 
4.3.1 
Formulation, Packaging, and Handling.................................. 56 
4.3.1.1 
Lampalizumab Formulation ................................................... 56 
4.3.1.2 
Sham ..................................................................................... 56 
4.3.2 
Dosage, Administration, and Compliance.............................. 56 
4.3.2.1 
Lampalizumab and Sham...................................................... 56 
4.3.3 
Investigational Medicinal Product Accountability ................... 57 
4.3.4 
Post-Study Access to Lampalizumab .................................... 57 
4.4 
Concomitant Therapy ............................................................ 58 
4.4.1 
Permitted Therapy ................................................................. 58 
4.4.2 
Prohibited Therapy ................................................................ 60 
4.4.3 
Dose-Interruption and/or Treatment 
Discontinuation Criteria.......................................................... 60 
4.5 
Study Assessments ............................................................... 62 
4.5.1 
Informed Consent Forms and Screening Log........................ 62 


 
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4.5.2 
Medical History and Demographic Data ................................ 62 
4.5.3 
Physical Examinations........................................................... 63 
4.5.4 
Vital Signs.............................................................................. 63 
4.5.5 
Other Disease-Specific Assessments.................................... 63 
4.5.6 
Laboratory Biological Samples Collection.............................. 65 
4.5.7 
Serial Electrocardiogram Evaluation (Selected 
Sites) ..................................................................................... 66 
4.5.8 
Patient-Reported Outcomes .................................................. 67 
4.5.9 
Samples for Roche Clinical Repository.................................. 67 
4.5.9.1 
Overview of the Roche Clinical Repository............................ 67 
4.5.9.2 
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 68 
4.5.9.3 
Sample Collection.................................................................. 68 
4.5.9.4 
Confidentiality for RCR Genetic Specimens .......................... 69 
4.5.9.5 
Consent to Participate in the Roche Clinical 
Repository ............................................................................. 69 
4.5.9.6 
Withdrawal from the Roche Clinical Repository..................... 70 
4.5.9.7 
Monitoring and Oversight....................................................... 70 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 70 
4.6.1 
Patient Discontinuation.......................................................... 70 
4.6.2 
Study Treatment Discontinuation........................................... 71 
4.6.3 
Study and Site Discontinuation.............................................. 71 
5. 
ASSESSMENT OF SAFETY....................................................................... 72 
5.1 
Safety Plan ............................................................................ 72 
5.2 
Safety Parameters and Definitions ........................................ 73 
5.2.1 
Adverse Events ..................................................................... 74 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 74 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 75 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 76 
5.3.1 
Adverse Event Reporting Period ........................................... 76 
5.3.2 
Eliciting Adverse Event Information ....................................... 76 


 
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5.3.3 
Assessment of Severity of Adverse Events ........................... 76 
5.3.4 
Assessment of Causality of Adverse Events ......................... 77 
5.3.5 
Procedures for Recording Adverse Events............................ 78 
5.3.5.1 
Diagnosis versus Signs and Symptoms................................. 78 
5.3.5.2 
Adverse Events That Are Secondary to Other 
Events.................................................................................... 78 
5.3.5.3 
Persistent or Recurrent Adverse Events................................ 79 
5.3.5.4 
Abnormal Laboratory Values ................................................. 79 
5.3.5.5 
Abnormal Vital Sign Values ................................................... 80 
5.3.5.6 
Abnormal Liver Function Tests.............................................. 81 
5.3.5.7 
Deaths ................................................................................... 81 
5.3.5.8 
Preexisting Medical Conditions.............................................. 81 
5.3.5.9 
Worsening of Geographic Atrophy in Study Eye.................... 82 
5.3.5.10 
Hospitalization or Prolonged Hospitalization or 
Surgery.................................................................................. 82 
5.3.5.11 
Adverse Events Associated with an Overdose ...................... 82 
5.3.5.12 
Patient-Reported Outcome Data ........................................... 82 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 83 
5.4.1 
Emergency Medical Contacts................................................ 83 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest...................................................................... 84 
5.4.2.1 
Events That Occur prior to Study Drug Initiation.................... 84 
5.4.2.2 
Events That Occur after Study Drug Initiation........................ 84 
5.4.3 
Reporting Requirements for Pregnancies.............................. 84 
5.4.3.1 
Pregnancies in Female Patients............................................ 84 
5.4.3.2 
Pregnancies in Female Partners of Male Patients................. 85 
5.4.3.3 
Abortions ............................................................................... 85 
5.4.3.4 
Congenital Anomalies/Birth Defects ...................................... 85 
5.5 
Follow-Up of Patients after Adverse Events .......................... 85 
5.5.1 
Investigator Follow-Up........................................................... 85 
5.5.2 
Sponsor Follow-Up ................................................................ 86 
5.6 
Post-Study Adverse Events................................................... 86 


 
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5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 86 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 87 
6.1 
Determination of Sample Size ............................................... 87 
6.2 
Summaries of Study Conduct................................................ 89 
6.3 
Summaries of Treatment Group Comparability ..................... 89 
6.4 
Efficacy Analyses .................................................................. 89 
6.4.1 
Primary Efficacy Endpoint...................................................... 90 
6.4.2 
Secondary Efficacy Endpoints............................................... 91 
6.5 
Safety Analyses..................................................................... 93 
6.5.1 
Adverse Events ..................................................................... 93 
6.5.2 
Alternative Complement Pathway Activity 
Assessment........................................................................... 93 
6.5.3 
Anti-Therapeutic Antibodies................................................... 93 
6.5.4 
Death..................................................................................... 93 
6.5.5 
Electrocardiogram Evaluation at Selected Sites.................... 93 
6.5.6 
Ocular Assessments.............................................................. 93 
6.6 
Pharmacokinetic Analyses..................................................... 93 
6.7 
Optional Interim Analyses...................................................... 94 
7. 
DATA COLLECTION AND MANAGEMENT ............................................... 95 
7.1 
Data Quality Assurance......................................................... 95 
7.2 
Electronic Case Report Forms............................................... 95 
7.3 
Source Data Documentation.................................................. 95 
7.4 
Use of Computerized Systems .............................................. 96 
7.5 
Retention of Records............................................................. 96 
8. 
ETHICAL CONSIDERATIONS.................................................................... 97 
8.1 
Compliance with Laws and Regulations ................................ 97 
8.2 
Informed Consent .................................................................. 97 
8.3 
Institutional Review Board or Ethics Committee.................... 98 
8.4 
Confidentiality........................................................................ 98 
8.5 
Financial Disclosure .............................................................. 99 


 
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9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 99 
9.1 
Study Documentation ............................................................ 99 
9.2 
Protocol Deviations................................................................ 99 
9.3 
Site Inspections ..................................................................... 99 
9.4 
Administrative Structure......................................................... 99 
9.5 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 100 
9.6 
Protocol Amendments ......................................................... 100 
10.  REFERENCES ......................................................................................... 101 
 
 
LIST OF TABLES 
Table 1 
Definition of Biomarker Status Using the CFI Profile Test........... 35 
Table 2 
Every 4 Weeks Dosing Treatment Arms ..................................... 40 
Table 3 
Every 6 Weeks Dosing Treatment Arms ..................................... 41 
Table 4 
Dose-Interruption and Treatment Discontinuation Criteria .......... 61 
Table 5 
Adverse Event Severity Grading Scale ....................................... 77 
Table 6 
Causal Attribution Guidance ....................................................... 77 
Table 7 
Power and Minimum Detectable Difference for Primary 
Endpoint in This Study ................................................................ 88 
 
 
LIST OF FIGURES 
Figure 1 
Pathways of Complement Activation and Site of Inhibition by 
Lampalizumab............................................................................. 31 
Figure 2 
Study Schema............................................................................. 38 
Figure 3 
Order of Hypothesis Tests for the Primary Endpoint................... 91 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments......................................................... 103 
Appendix 2 
Study Flowchart: Unscheduled Safety Assessment Visit .......... 120 
Appendix 3 
Grading Scale for Assessment of Anterior Chamber Flare or 
Cells and Vitreous Cells............................................................ 121 
Appendix 4 
Pre-Injection Procedures for All Patients .................................. 123 
Appendix 5 
Preparation and Administration of Lampalizumab Injection ...... 125 
Appendix 6 
Preparation and Administration of Sham Injection .................... 128 
Appendix 7 
Post-Injection Procedures for All Patients................................. 129 


 
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Appendix 8 
Best Corrected Visual Acuity Testing........................................ 130 
Appendix 9 
Low Luminance Best Corrected Visual Acuity Testing.............. 131 
Appendix 10 
Color Fundus Photography ....................................................... 132 
Appendix 11 
Fluorescein Angiography .......................................................... 133 
Appendix 12 
Fundus Autofluorescence ......................................................... 134 
Appendix 13 
Spectral Domain-Optical Coherence Tomography.................... 135 
Appendix 14 
Near-Infrared Imaging............................................................... 136 
Appendix 15 
 Mesopic Microperimetry at Selected Sites ............................... 137 
Appendix 16 
National Eye Institute Visual Functioning Questionnaire 
25-Item Version......................................................................... 138 
Appendix 17 
Functional Reading Independence Index.................................. 151 
Appendix 18 
Minnesota Low-Vision Reading Test (MNRead) ....................... 159 
Appendix 19 
Radner Reading Cards ............................................................. 162 
Appendix 20 
Biological Sample Collection and Shipping Instructions............ 165 
Appendix 21 
Electrocardiogram Data Collection at Selected Sites................ 167 
Appendix 22 
The cobas® CFI Profile Clinical Trial Assay (CTA).................... 168 


 
Lampalizumab—F. Hoffmann-La Roche Ltd 
18/Protocol GX29185, Version 6 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE III, MULTICENTER, RANDOMIZED, 
DOUBLE-MASKED, SHAM-CONTROLLED STUDY 
TO ASSESS THE EFFICACY AND SAFETY OF 
LAMPALIZUMAB ADMINISTERED 
INTRAVITREALLY TO PATIENTS WITH 
GEOGRAPHIC ATROPHY SECONDARY TO 
AGE-RELATED MACULAR DEGENERATION 
PROTOCOL NUMBER: GX29185 
VERSION NUMBER: 
6 
EUDRACT NUMBER: 
2014-000106-35 
IND NUMBER: 
104996 
TEST PRODUCT: 
Lampalizumab (RO5490249) 
MEDICAL MONITOR: 
, M.D., Ph.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please return the signed copy of this form to the local study monitor.  Please retain the 
original for your study files.


 
Lampalizumab—F. Hoffmann-La Roche Ltd 
19/Protocol GX29185, Version 6 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE-MASKED, 
SHAM-CONTROLLED STUDY TO ASSESS THE EFFICACY AND 
SAFETY OF LAMPALIZUMAB ADMINISTERED INTRAVITREALLY 
TO PATIENTS WITH GEOGRAPHIC ATROPHY SECONDARY TO 
AGE-RELATED MACULAR DEGENERATION 
PROTOCOL NUMBER: 
GX29185 
VERSION NUMBER: 
6 
EUDRACT Number: 
2014-000106-35  
IND NUMBER: 
104996 
TEST PRODUCT: 
Lampalizumab (RO5490249) 
PHASE: 
III 
INDICATION: 
Geographic Atrophy 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
Objectives 
Efficacy Objectives 
The primary efficacy objective of this study is to evaluate the efficacy of intravitreal injections of 
10-mg lampalizumab administered every 4 weeks (Q4W) or every 6 weeks (Q6W) in 
complement factor I (CFI) profile biomarker-positive and CFI profile biomarker-negative patients 
compared with sham control assessed by change in the geographic atrophy (GA) area from 
baseline as measured by fundus autofluorescence (FAF). 
The secondary efficacy objective of this study is to evaluate the effect of lampalizumab 
compared with sham control, with respect to: 
• 
Macular functional response as assessed by mesopic microperimetry 
• 
Best corrected visual acuity (BCVA) as measured by the Early Treatment Diabetic 
Retinopathy Study (ETDRS) chart (at a starting distance of 4 m) 
• 
BCVA as measured by ETDRS chart (at a starting distance of 4 m) under low luminance 
conditions 
• 
Binocular reading speed as assessed by the Minnesota Low-Vision Reading (MNRead) 
Test or by Radner Reading Charts 
• 
Binocular critical print size as assessed by the MNRead or by Radner Reading Charts 
• 
Patient-reported visual function as assessed by the National Eye Institute Visual 
Functioning Questionnaire 25-item Version (NEI VFQ-25) 
• 
Patient-reported independent reading as assessed by the Functional Reading 
Independence Index (FRI Index) 
Safety Objectives 
The safety objectives for this study are as follows: 
• 
To evaluate the local and systemic safety and tolerability of intravitreal injections of 10-mg 
lampalizumab administered Q4W or Q6W relative to sham control 
• 
To evaluate the clinical significance of anti-therapeutic antibodies directed against 
lampalizumab 


 
 
Lampalizumab—F. Hoffmann-La Roche Ltd 
20/Protocol GX29185, Version 6 
Pharmacokinetic Objective 
The pharmacokinetic (PK) objective for this study is to characterize the systemic PK of 
lampalizumab administered by 10-mg intravitreal injections Q4W or Q6W. 
Diagnostic Objective 
A diagnostic objective for this study is to evaluate the prognostic value of the CFI profile 
biomarker on the mean change in the GA area from baseline as measured by FAF. 
Exploratory Objectives 
The exploratory objectives for this study are as follows: 
• 
To evaluate the effect of lampalizumab compared with sham control, with respect to: 
• 
Monocular reading speed as assessed by MNRead charts or by Radner Reading Charts 
• 
Monocular critical print size as assessed by MNRead charts or by Radner Reading 
Charts 
• 
Monocular reading acuity as assessed by MNRead charts or by Radner Reading Charts  
• 
Binocular reading acuity as assessed by MNRead charts or by Radner Reading Charts 
• 
To evaluate the aqueous levels of total lampalizumab and factor D following study treatment 
• 
To evaluate the potential association of genetic variants in CFI and complement-pathway 
genes with disease characteristics and response to administration of lampalizumab 
• 
To evaluate the relationship of genetic variants in CFI and complement-pathway genes to 
levels in the blood of messenger RNA (mRNA) and proteins of CFI and complement-
pathway genes 
Study Design 
Description of Study 
This study is a Phase III, double-masked, multicenter, randomized, sham injection-controlled 
study evaluating the efficacy and safety of a 10-mg dose of lampalizumab administered Q4W or 
Q6W by intravitreal injections for approximately 2 years (96 weeks) treatment period in patients 
with GA secondary to age-related macular degeneration (AMD).   
Number of Patients 
The study will randomize approximately 936 patients at approximately 140 investigational sites 
globally. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
General Inclusion Criteria 
• 
Willingness and the ability to provide signed informed consent.  Additionally, at U.S. sites, 
patients must provide Health Insurance Portability and Accountability Act (HIPAA) 
authorization, and in other countries, as applicable according to national laws. 
• 
Age ≥50 years 
• 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate of <1% 
per year during the treatment period and for at least 30 days after the last dose of study 
drug 
A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state ( ≥ 12 months of amenorrhea with no identified cause 
other than menopause), and has not undergone surgical sterilization (removal of 
ovaries and/or uterus). 
Examples of contraceptive methods with a failure rate of < 1% per year include 
bilateral tubal ligation, male sterilization, established, proper use of hormonal 


 
 
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21/Protocol GX29185, Version 6 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices and 
copper intrauterine devices.   
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and 
withdrawal are not acceptable methods of contraception. 
For men: Agreement to remain abstinent or use contraceptive measures and agreement to 
refrain from donating sperm, as defined below: 
With female partners of childbearing potential, men must remain abstinent or use a 
condom plus an additional contraceptive method that together result in a failure rate 
of < 1% per year during the treatment period and for at least 30 days plus 90 days (a 
spermatogenesis cycle) after the last dose of study drug.  Men must refrain from 
donating sperm during this same time period. 
• 
Ability and willingness to undertake all scheduled visits and assessments 
• 
Valid CFI profile biomarker result (i.e., CFI profile biomarker-positive or CFI profile 
biomarker-negative) 
Ocular Inclusion Criteria:  Study Eye 
• 
BCVA letter score of ≥ 49 letters (Snellen equivalent of 20/100 or better) using ETDRS 
charts at starting distance of 4 m 
If BCVA letter score is   ≥ 79 letters (Snellen equivalent of 20/25 or better), at least one 
GA lesion must be within 250 μm of the foveal center 
• 
Well demarcated area(s) of GA secondary to AMD with no evidence of prior or active CNV 
The total GA lesion size ≥2.54 mm2 (approximately ≥1 disc area [DA]) and ≤17.78 mm2 
(approximately ≤7 DA) and must reside completely within the FAF imaging field (Field 2−30 
degree image centered on the fovea) 
If GA is multifocal, at least 1 focal lesion must be ≥1.27 mm2 (approximately ≥0.5 DA) 
• 
Presence of hyperautofluorescence of either banded or diffuse patterns adjacent to the area 
of GA 
• 
Sufficiently clear ocular media, adequate pupillary dilation, and fixation to permit quality 
fundus imaging 
Ocular Inclusion Criteria:  Non-study Eye 
• 
GA secondary to AMD with no evidence of prior or active CNV 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
GA Characteristics Exclusion Criteria 
• 
GA in either eye due to causes other than AMD (monogenetic macular dystrophies [e.g., 
Stargardt disease, cone rod dystrophy] or toxic maculopathies [e.g., 
chloroquine/hydroxychloroquine maculopathy]) 
Ocular Exclusion Criteria:  Study Eye 
• 
History of vitrectomy surgery, submacular surgery, or any surgical intervention for AMD 
• 
Previous laser photocoagulation for CNV, diabetic macular edema, retinal vein occlusion, 
and proliferative diabetic retinopathy 
• 
Prior treatment with Visudyne®, external-beam radiation therapy, or transpupillary 
thermotherapy 
• 
History of prophylactic subthreshold laser treatment for AMD 


 
 
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• 
Previous intravitreal drug delivery (e.g., intravitreal corticosteroid injection, anti-angiogenic 
drugs, anti-complement agents, or device implantation).  A single intraoperative 
administration of a corticosteroid during cataract surgery for cystoid macular edema 
prophylaxis at least 3 months prior to screening is permitted. 
Ocular Exclusion Criteria: Non-study eye 
• 
Non-functioning non-study eye defined as either: 
BCVA of hand motion or worse 
OR  
No physical presence of non-study eye (i.e., monocular) 
 
Ocular Exclusion Criteria:  Both Eyes 
• 
Previous participation in interventional clinical trials for geographic atrophy or dry AMD 
(except of vitamins and minerals) irrespective of the route of administration (ocular or 
systemic)  
• 
Previous treatment with eculizumab, lampalizumab, fenretidine or any other drugs for 
geographic atrophy or dry AMD treatment 
Ocular Exclusion Criteria:  Concurrent Ocular Conditions 
• 
Retinal pigment epithelium (RPE) tear that involves the macula in either eye 
• 
Any concurrent ocular or intraocular condition in the study eye (e.g., cataract or diabetic 
retinopathy) that, in the opinion of the investigator, could do either of the following: 
Require medical or surgical intervention during the study period to prevent or treat 
vision loss that might result from that condition 
If allowed to progress untreated, could likely contribute to loss of at least two Snellen 
equivalent lines of BCVA during the study period 
• 
Active uveitis and/or vitritis (grade trace or above) in either eye 
• 
History of idiopathic or autoimmune-associated uveitis in either eye 
• 
Active, infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye 
• 
Current vitreous hemorrhage in the study eye 
• 
History of retinal detachment or macular hole (Stage 3 or 4) in the study eye 
• 
Aphakia or absence of the posterior capsule in the study eye 
• 
Previous violation of the posterior capsule in the study eye unless it occurred as a result of 
yttrium aluminum garnet (YAG) laser posterior capsulotomy in association with prior 
posterior chamber intraocular lens implantation 
• 
Spherical equivalent of the refractive error in the study eye demonstrating >8 diopters of 
myopia 
• 
For patients who have undergone prior refractive or cataract surgery in the study eye, the 
preoperative refractive error in the study eye should not have exceeded 8 diopters of 
myopia. 
• 
Intraocular surgery (including cataract surgery) in the study eye within 3 months preceding 
Day 1 
• 
Uncontrolled glaucoma in the study eye (defined as intraocular pressure [IOP] ≥30 mm Hg 
despite treatment with anti-glaucoma medication) 
• 
History of glaucoma-filtering surgery in the study eye 
• 
History of corneal transplant in the study eye 
• 
Proliferative diabetic retinopathy in either eye 
• 
Prior or active CNV in either eye 
• 
Central serous retinopathy in either eye 


 
 
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• 
History of recurrent infectious or inflammatory ocular disease in either eye 
Concurrent Systemic Conditions Exclusion Criteria 
• 
Uncontrolled blood pressure (defined as systolic >180 mm Hg and/or diastolic >110 mm Hg 
while patient is sitting) 
If a patient’s initial measurement exceeds these values, a second reading may be 
taken 30 or more minutes later.  If the patient’s blood pressure must be controlled by 
anti-hypertensive medication, the patient can become eligible if medication is taken 
continuously for at least 30 days prior to Day 1. 
• 
History of other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that gives reasonable suspicion of a disease or condition that 
contraindicates the use of lampalizumab or that might affect interpretation of the results of 
the study or that renders the patient at high risk of treatment complications 
• 
Treatment for active systemic or localized infection 
The ongoing prophylactic use of antimicrobial therapy should be discussed with the 
Medical Monitor.  
• 
Predisposition or history of increased risk of infection (i.e., history of splenectomy or chronic 
immunosuppression) 
• 
Active malignancy within past 12 months except for appropriately treated carcinoma in situ 
of the cervix, non-melanoma skin carcinoma and prostate cancer with a Gleason score 
of  ≤ 6 and a stable prostate-specific antigen (PSA) for  ≥ 12 months. 
• 
History of allergy to fluorescein that is not amenable to treatment 
• 
History of a severe allergic reaction or anaphylactic reaction to a biologic agent or known 
hypersensitivity to any component of the lampalizumab injection 
• 
Inability to comply with study or follow-up procedures 
• 
Inability to obtain color fundus photograph (CFP), FAF, and fluorescein angiogram (FA) of 
sufficient quality to be analyzed and graded by the central reading center 
• 
Previous participation in any studies of investigational drugs within 3 months (except as 
listed in the section 4.1.2d) preceding Day 1 (excluding vitamins and minerals) 
• 
Requirement for continuous use of any medications/treatments indicated in the “Prohibited 
Therapy” section of the protocol 
• 
Women who are pregnant or lactating or intending to become pregnant during the study 
• 
Women of childbearing potential must have a negative serum pregnancy test result within 
28 days prior to initiation of study treatment. 
 
Microperimetry criteria at selected sites only  
Inclusion Criteria 
• 
Patients must meet all other eligibility criteria for study entry. 
• 
Microperimetry screening test criteria for eligibility: 
Must be able to detect fixation target. 
Total elapsed time to complete the 10-2 68 point exam is ≤30 minutes in duration. 
Reliability Test ratio ≤ 20% (false positive rate). 
Ability and willingness to undertake MP assessment as determined by investigator. 
 


 
 
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Exclusion Criteria 
• 
Any exclusion criteria listed for the study entry 
• 
Investigator determines that patient is unable to perform the test reliably (e.g. Difficulty 
sitting still against the supporting chinrest for >10 minutes; Unable to physically operate the 
clicker or joystick; Unable to follow the instructions for the test [i.e. cognitive impairment]) 
Note: disqualification from the microperimetry assessment doesn’t exclude a patient from the 
trial participation if she/he qualifies as per the rest of the study entry criteria. 
Length of Study 
The duration of the study is approximately 2 years (96 weeks) after the last patient is 
randomized to the study. 
End of Study 
The end of the study is defined as the date when the last patient, last visit (LPLV) occurs.  LPLV 
is expected to occur approximately 96 weeks after the last patient is randomized to the study. 
Outcome Measures 
Efficacy Outcome Measures 
The primary efficacy outcome measure for this study is GA area at 1 year as assessed by FAF. 
The secondary efficacy outcome measures for this study over time are as follows: 
• 
Number of scotomatous points assessed by mesopic microperimetry for the evaluation of 
the macular functional response 
• 
Change in macular sensitivity as assessed by mesopic microperimetry for the evaluation of 
the macular functional response 
• 
GA area as assessed by FAF 
• 
BCVA score as assessed by ETDRS chart at a starting distance of 4 m 
• 
BCVA score as assessed by ETDRS chart under low luminance conditions at a starting 
distance of 4 m 
• 
Binocular reading speed as assessed by MNRead charts or Radner Reading Charts 
• 
Binocular critical print size as assessed by MNRead charts or Radner Reading Charts 
• 
NEI VFQ-25 composite score  
• 
NEI VFQ-25 near activity subscale score  
• 
NEI VFQ-25 distance activity subscale score 
• 
FRI Index score 
 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
The incidence and severity of ocular adverse events 
• 
The incidence and severity of systemic (non-ocular) adverse events 
• 
Changes and abnormalities in ECG parameters 
• 
The incidence of anti-lampalizumab antibodies 
 
Pharmacokinetic Outcome Measure 
The PK outcome measure for this study is serum lampalizumab concentration over time. 
Diagnostic Outcome Measure 
The evaluation of the prognostic value of the CFI profile biomarker will be based on the 
biomarker status at baseline and the primary clinical outcome of change in the GA area from 
baseline as measured by FAF. 


 
 
Lampalizumab—F. Hoffmann-La Roche Ltd 
25/Protocol GX29185, Version 6 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
Monocular reading speed as assessed by MNRead charts or Radner Reading Charts over 
time 
• 
Monocular critical print size as assessed by MNRead charts or Radner Reading Charts over 
time 
• 
Monocular reading acuity as assessed by MNRead charts or Radner Reading Charts over 
time 
• 
Binocular reading acuity as assessed by MNRead charts or Radner Reading Charts over 
time 
• 
Total lampalizumab and factor D levels in aqueous humor as assessed by ELISA 
• 
To evaluate the potential association of genetic variants in CFI and complement-pathway 
genes with disease characteristics and response to administration of lampalizumab 
• 
To evaluate the relationship of genetic variants in CFI and complement-pathway genes to 
levels in the blood of mRNA and proteins of CFI and complement-pathway genes 
 
Exploratory Substudies 
At selected sites, the Sponsor may propose exploratory substudies associated with the Study 
GX29185 protocol.  Each substudy will be documented in a separate substudy protocol and 
associated ICF(s). 
Investigational Medicinal Products 
Lampalizumab 
Lampalizumab Drug Product is provided as a sterile, white to off-white, lyophilized powder in a 
6-cc USP/European Pharmacopoeia Type 1 glass vial and is intended for intravitreal 
administration.  For the Phase III clinical studies, each glass vial contains a nominal 40 mg of 
lampalizumab.  After reconstitution with Sterile Water for Injection, the Drug Product is 
formulated as 100 mg/mL lampalizumab in 40 mM L-histidine hydrochloride, 28 mM sodium 
chloride, 160 mM sucrose, 0.04% (w/v) polysorbate 20, pH 5.3. 
Lampalizumab intravitreal injections 
A 10-mg dose of lampalizumab will be used in this study and will be administered to patients 
randomized to lampalizumab treatment arms intravitreally Q4W or Q6W during the 2-year 
treatment period. 
Comparator 
Sham vials will be identical to vials of lampalizumab, but the sham vials will be empty. 
A sham injection is a procedure that mimics an intravitreal injection of lampalizumab, except that 
the blunt end of an empty syringe is pressed against an anesthetized eye instead of a needle 
attached to a lampalizumab-filled syringe. 
Patients randomized to the control arms will receive sham injections Q4W or Q6W during the 
2-year treatment period and will undergo the same assessments as the lampalizumab treatment 
arm. 
Non-Investigational Medicinal Products 
None 
Statistical Methods 
Primary Analysis 
The primary and secondary efficacy analyses will be based on the intent-to-treat (ITT) approach.  
All randomized patients (i.e., ITT population) will be included in the analysis, with patients 
grouped according to the treatment assigned at randomization. 
Detailed specifications of the statistical methods will be described in the statistical analysis plan 
(SAP). 


 
 
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Determination of Sample Size 
Patients will be randomized in a 2:1:2:1 ratio to receive treatment with lampalizumab Q4W, 
sham Q4W, lampalizumab Q6W, or sham Q6W.  Data from the two sham groups will be pooled 
in the analysis.  
The study is sized to achieve adequate power for detecting a meaningful reduction rate in the 
GA area growth for a given lampalizumab dosing frequency compared with pooled sham within 
CFI profile biomarker-positive and CFI profile biomarker-negative groups and to meet health 
authority requirements for the safety database.  
The primary endpoint is the mean change in GA area from baseline to 1 year as assessed by 
FAF.  Assuming a standard deviation of 2.51 mm2 for the change from baseline in GA area at 
1 year in biomarker-positive patients, 188 CFI profile biomarker-positive patients per 
lampalizumab treatment group and 94 CFI profile biomarker-positive patients per sham group 
will provide > 95% power to declare a difference between each lampalizumab treatment group 
and the pooled sham for a targeted difference of 1.45 mm2 (approximately 40% reduction 
relative to sham control) in the change from baseline in GA area at 1 year.  Assuming a 
standard deviation of 1.68 mm2 for the change from baseline in GA area at 1 year in CFI profile 
biomarker-negative patients, 124 CFI profile biomarker-negative patients per lampalizumab 
treatment group and 62 CFI profile biomarker-negative patients per sham group will provide 
80% power to detect a targeted difference of 0.66 mm2 (approximately 40% reduction) between 
each lampalizumab treatment group and the pooled sham group in the change from baseline in 
GA area at 1 year.  Calculations were based on two-sided t-test at the α = 0.0495 level (after 
adjustment for planned interim data reviews conducted by the iDMC prior to analysis of the 
primary efficacy endpoint; see Section 3.1.4), with the assumption of a 15% dropout rate by 
1 year.  Due to lack of reliable information to estimate the impact of partially missing data on the 
power, the power calculation is based on the analysis of data from the patients who complete 
the first year of the study.  However, the primary analysis of the study will include all available 
data from patients in all treatment arms, which will have more power than an analysis of just 
those patients completing the first year of the study period. 
The Sponsor may conduct a masked evaluation of the variance of the primary efficacy endpoint 
and study dropout rate before the end of enrollment and compare the information to the 
assumptions used in planning the study.  If this comparison suggests the initial assumptions for 
the dropout rate and/or the variance of the primary efficacy endpoint were substantially lower 
and the study is consequently underpowered, the study sample size will be increased to 
maintain the desired study power and safety database.  Details will be provided in the SAP.   
For patients who are eligible to undergo a microperimetry assessment, at least 46 CFI profile 
biomarker-positive patients per lampalizumab treatment group and 23 CFI profile 
biomarker-positive patients per sham group will provide 80% power to detect a targeted 
difference of 6.91 points with a standard deviation of 9.88 points between each lampalizumab 
treatment group and the pooled sham group in the change from baseline in the number of 
scotomatous points at 2 years.  Calculation was based on a two-sided t-test at α = 0.05 level 
with the assumption of a 25% dropout rate by 2 years. 
Optional Interim Analyses 
In order to adapt to information that may emerge during the course of this study (e.g., additional 
information of the biomarker characteristics, additional results of natural history studies), the 
Sponsor may choose to conduct one interim efficacy analysis.  Section 6.7 contains the 
specifications in place to ensure the study continues to meet the highest standards of integrity 
when such an optional interim analysis is executed. 


 
 
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27/Protocol GX29185, Version 6 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ACP 
alternative complement pathway 
AE 
adverse event 
AESI 
adverse event of special interest 
AH50 
Alternative Complement Pathway activity assay 
AMD 
age-related macular degeneration 
anti-VEGF 
anti-vascular endothelial growth factor 
ATA 
anti-therapeutic antibody 
BCVA 
best corrected visual acuity 
C 
complement component 
CFB 
complement factor B 
CFD 
complement factor D 
CFH 
complement factor H 
CFI 
complement factor I 
CFP 
color fundus photograph 
CNV 
choroidal neovascularization 
CTA 
clinical trial assay 
DA 
disc area 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FA 
fluorescein angiogram 
FAF 
fundus autofluorescence 
FDA 
U.S. Food and Drug Administration 
FRI Index 
Functional Reading Independence Index 
GA 
geographic atrophy 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonisation 
iDCC 
independent data coordinating center 
iDMC 
independent Data Monitoring Committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug Application 
IOP 
intraocular pressure 


 
 
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IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IxRS 
Interactive Voice and Web Response Systems 
LPLV 
last patient, last visit 
MNRead 
Minnesota Low-Vision Reading Test 
mRNA 
messenger RNA 
MTD 
maximum tolerated dose 
NEI VFQ-25 
National Eye Institute Visual Functioning Questionnaire 
25-item Version 
NI 
near infrared 
OCT 
optical coherence tomography 
OCT-A 
optical coherence tomography angiography 
PCR  
polymerase chain reaction 
PD 
pharmacodynamics 
PK 
pharmacokinetic(s) 
PRO 
patient-reported outcome 
Q4W 
every 4 weeks 
Q6W 
every 6 weeks 
qAF 
quantitative fundus autofluorescence 
RCR 
Roche Clinical Repository 
RPE 
retinal pigment epithelium 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD-OCT 
spectral domain optical coherence tomography 
SNP 
single nucleotide polymorphism 
ULN 
upper limit of normal 
VA 
visual acuity 
YAG 
yttrium aluminum garnet 


 
 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON GEOGRAPHIC ATROPHY SECONDARY TO 
AGE-RELATED MACULAR DEGENERATION 
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in 
people aged 50 years or older in the developed world (Friedman et al. 2004).  The 
majority of the visual loss occurs in the advanced stage of AMD, which has two clinical 
forms:  a non-exudative form, geographic atrophy (GA), which is characterized by loss of 
choriocapillaris, retinal pigment epithelium (RPE), and photoreceptors; and an exudative 
or wet form, which is characterized by choroidal neovascularization (CNV) 
(Lindblad et al. 2009; Sunness et al. 1999b).  The prevalence of GA increases 
exponentially with age and approximately quadruples per decade beyond 50 years of 
age.  The estimated prevalence of GA in populations of European ancestry at 70 years 
of age is 0.70%, rising to 2.91% at 80 years of age and 11.29% at 90 years of age 
(Rudnicka et al. 2012). 
In the early stages of GA, patients typically show minimal changes in central visual 
acuity (VA).  However, while central VA may not yet be affected, patients often still 
experience significant symptoms from visual dysfunction, such as dense parafoveal 
scotomas (e.g., leading to difficulties with face recognition), delayed dark adaptation, 
reduced contrast sensitivity, and a decrease in reading rate (Sunness et al. 1995, 
1996, 1999a).  In the later stages, as the GA lesion expands into the fovea, a profound 
decrease in central VA occurs with a decline in activities of daily living 
(Lindblad and Clemons 2005).  Moreover, GA is bilateral in most patients with advanced 
AMD (Lindblad et al. 2009; Sunness et al. 1999b).  As such, GA is a significant cause of 
both moderate and severe central visual loss. 
Currently, there are no approved treatments to prevent the worsening of GA or the 
associated declines in visual function.  Consequently, a significant unmet need exists for 
the treatment of this serious condition.  The Phase III clinical development plan for 
lampalizumab is designed to test the efficacy and safety of lampalizumab in patients with 
GA secondary to AMD. 
1.2 
BACKGROUND ON LAMPALIZUMAB 
The pathogenesis of AMD is complex and not well understood; however, genetics and 
environmental factors (such as smoking), as well as the alternative complement pathway 
(ACP), have all been implicated in AMD pathophysiology (de Jong 2006).  Increased 
activation of the ACP has been found in drusen, which are lipoproteinous depositions in 
the space between the RPE and Bruch’s membrane, and a hallmark clinical observation 
associated with AMD.  Moreover, a role for ACP in AMD has been supported by human 
genetics (Yates et al. 2007; Scholl et al. 2008).  The largest study evaluating AMD 
genetics to date is a meta-analysis with  17,000 AMD cases and  > 60,000 control that 
identified multiple genetic risk loci, including four genes (complement factor H [CFH], 


 
 
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complement factor B [CFB], complement factor I [CFI], and complement component 
[C3]) in the ACP as confirmed genetic risk factors (Fritsche et al. 2013). 
Complement factor D (CFD) is a highly specific chymotrypsin-like serine protease that 
plays a pivotal and rate-limiting role in the activation and amplification of the ACP (see 
Figure 1).  The substrate for CFD is another alternative pathway, serine protease, 
factor B.  Following cleavage by CFD, CFB converts into the proteolytically active factor 
Bb and initiates the ACP. 
Lampalizumab is an antigen-binding fragment of a humanized monoclonal antibody 
directed against CFD.  Lampalizumab inhibits CFD-mediated cleavage of CFB, 
preventing activation of the ACP.  Lampalizumab is specific for the ACP and shows no 
inhibitory effect on classical complement pathway activation.   
By inhibiting ACP activity, lampalizumab may offer the potential to impede or arrest the 
progression of GA and vision loss.  Evidence for CFD in the pathogenesis of AMD 
included protection against oxidative stress-mediated photoreceptor degeneration in a 
murine model with genetic deficiency of factor D (Rohrer et al. 2007) and detection of 
increased systemic activation of complement components, including CFD, in the serum 
of patients with AMD versus controls, suggesting that AMD may be a systemic disease 
with local manifestations in the aging macula (Scholl et al. 2008). 
See the Lampalizumab Investigator’s Brochure for additional details on nonclinical and 
clinical studies. 


 
 
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Figure 1 Pathways of Complement Activation and Site of Inhibition by 
Lampalizumab 
 
 
MAC = membrane attack complex; MBL = Mannose binding lectin. 
 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
The Phase Ia (Study CFD4711g) and Phase Ib/II (Study CFD4870g) studies provided 
preliminary evidence of a positive benefit-risk profile for the use of lampalizumab in 
patients with GA secondary to AMD and support the evaluation of lampalizumab in a 
Phase III study. 
A total of 147 patients have received at least one 10-mg dose of lampalizumab as part of 
two completed clinical studies (Studies CFD4711g and CFD4870g) and an ongoing 
study (Study GX28198), which is an extension of Study CFD4870g. 


 
 
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1.3.1 
Study CFD4711g:  Phase Ia 
Study CFD4711g was a Phase Ia, first-in-human study of lampalizumab; it was an 
open-label, multicenter, single-dose, dose-escalation study designed to investigate the 
safety, tolerability, pharmacokinetics (PK), and immunogenicity of six dose levels 
(0.1, 0.5, 1, 2, 5, and 10 mg) of lampalizumab administered as a single intravitreal 
injection to patients with GA.  Determination of the maximum tolerated dose (MTD) of 
lampalizumab was also an objective of this study.  Study CFD4711g enrolled 18 patients 
in the United States.  Lampalizumab was found to have an acceptable safety and 
tolerability profile at all six doses tested following a single intravitreal administration.  The 
MTD for the study was considered to be 10 mg, the highest dose tested.  All enrolled 
patients completed the study. 
1.3.2 
Study CFD4870g:  Phase Ib/II 
Phase Ib 
The Phase Ib portion of Study CFD4870g served as the initial assessment of the safety 
and tolerability of multiple, monthly, intravitreal administrations with the 10-mg dose of 
lampalizumab.  This safety run-in portion of Study CFD4870 was designed to obtain 
10 evaluable patients with GA exposed to a minimum of three monthly doses of 
lampalizumab at 10 mg to evaluate the safety and tolerability of lampalizumab 
administered by intravitreal injection prior to initiating the Phase II randomized 
component of this study.  At the safety hiatus assessment for the run-in portion of the 
Phase Ib component of Study CFD4870g, the 10-mg dose was found to be well tolerated 
following multiple, monthly, intravitreal injections, and these results enabled enrollment 
into of the Phase II component of Study CFD4870g. 
Phase II 
The Phase II component of Study CFD4870g was a multicenter, randomized, 
single-masked, sham injection-controlled study of the safety, tolerability, and efficacy of 
lampalizumab (10-mg dose) intravitreal injections administered monthly or every other 
month to patients with GA.  This study enrolled 129 patients at 26 sites in the United 
States and 6 sites in Germany. 
Preliminary clinical evidence of lampalizumab’s efficacy was demonstrated in the 
Phase Ib/II Study CFD4870g.  The Phase II component of Study CFD4870g met its 
primary endpoint of mean change from baseline in GA area at 18 months as measured 
by fundus autofluorescence (FAF) and met its secondary endpoint of mean change from 
baseline in GA area at 18 months as assessed by color fundus photographs (CFPs) in 
the lampalizumab monthly group.  A positive treatment effect in slowing the progression 
of GA area growth was observed in the monthly group beginning at 6 months and 
extending through 18 months.  The mean difference in GA growth between the monthly 
group compared to the sham group at Month 18 was 0.595 mm2 (80% CI: 0.109, 1.081; 
p = 0.1170, less than the pre-specified type I error rate of 0.2), corresponding to a 
reduction rate in GA of 20.4% (80% CI: 4%, 37%); the reduction rate is calculated as 


 
 
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100% × [(mean change in sham pooled−mean change in lampalizumab group)/mean 
change in sham pooled]. 
The Phase II results demonstrated a clinically meaningful and statistically significant 
effect of lampalizumab administered monthly on reducing the GA area growth over the 
18-month study treatment period.  No apparent treatment benefit was observed in the 
lampalizumab every-other-month treatment group. 
The reported safety data from Study CFD4870g demonstrated an acceptable safety and 
tolerability profile with no clinically important safety concerns observed with 
lampalizumab administered as 10-mg intravitreal injections monthly or every other month 
over 18 months. 
Exploratory Genetic Analysis Using Four Single Nucleotide Polymorphisms 
(SNPs) in the ACP 
Although AMD risk involves many factors, it is well accepted that there is a strong 
genetic contribution.  The largest study evaluating AMD genetics to date, a 
meta-analysis with > 17,000 AMD cases and > 60,000 controls, identified 
AMD-associated single nucleotide polymorphisms (SNPs) at multiple genetic loci, 
including five genes (CFH, CFB, CFI, C2, and C3) in the complement pathway 
(Fritsche et al. 2013).  Except for C2, all of these proteins are implicated in the ACP.  
The strong correlation of these genetic variants in the ACP with the risk of AMD led to 
the hypothesis that patients with GA and with risk-associated variants at the ACP loci 
may have higher basal complement activation through the ACP and may derive greater 
potential benefit from inhibition of the ACP by lampalizumab. 
Four SNPs representing CFH, C2/CFB, C3, and CFI were selected and individually 
tested for an association with the observed efficacy of lampalizumab and for an 
association with the rate of GA progression in patients in the sham treatment group.  The 
SNPs were chosen based on the most statistically significant AMD risk SNPs in these 
ACP genes that had previously been reported in a genome-wide meta-analysis 
(Fritsche et al. 2013).  C2 and CFB are tightly linked genetically and, thus, are 
represented by a single risk SNP.  Patients who were heterozygous or homozygous for 
the risk alleles were grouped together for this analysis and were referred to as risk allele 
carriers.  In patients who had genetic testing performed in the Phase II component of 
Study CFD4870g, approximately 96%, 98%, 47%, and 57% were carriers of CFH, 
C2/CFB, C3, and CFI risk alleles, respectively. 
Results of Exploratory Analyses of the Phase II Component of CFH, C2/CFB, 
C3, and CFI SNPs 
Because very few patients in Study CFD4870g were non-carriers of the risk alleles for 
CFH and C2/CFB, these two SNPs could not be evaluated for an association with 
treatment response or for the rate of GA progression in patients receiving sham 
treatment. 


 
 
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Exploratory analysis of the C3 SNP did not find a significant association with treatment 
response or with the rate of GA progression in patients receiving sham treatment. 
Exploratory analysis of the CFI SNPs indicated that there was greater efficacy in the 
subgroup of patients who were carriers of the CFI risk allele compared to patients who 
were non-carriers of the CFI risk allele.  In CFI risk allele carriers, the mean difference in 
GA growth between the monthly group and the sham group at Month 18 was 1.839 mm2, 
corresponding to a reduction rate of 44% (approximately 80% CI: 25%, 63%; p = 0.0037).  
In CFI risk allele carriers, the mean difference in GA growth between the every-other-
month group and the sham group at Month 18 was 0.734 mm2, corresponding to a 
reduction rate of 18% (approximately 80% CI:  − 1%, 36%; p = 0.2266).  In non-carriers of 
the CFI risk allele, there was no apparent lampalizumab treatment response in either the 
monthly or every-other-month group. 
The prognostic effects of the CFI risk allele were also examined.  In patients in the sham 
group, the change in GA area at Month 18 was 4.169 mm2 (80% CI: 3.582, 4.756) in CFI 
risk allele carriers and 2.792 mm2 (80% CI: 2.293, 3.292) in non-carriers of the CFI risk 
allele; the difference in the GA progression between CFI risk allele carriers and 
non-carriers was approximately 49%. 
The results from the exploratory analysis suggest that the CFI risk allele may be both 
prognostic for a more rapid progression of GA and predictive for the treatment response 
to lampalizumab. 
Definition of CFI Profile Biomarker 
The CFI profile biomarker-positive is defined as risk allele carriers of CFI that are also 
risk allele carriers at CFH and/or C2/CFB, and the CFI profile biomarker-negative is 
defined as non-carriers of the CFI risk allele or carriers of the CFI risk allele that are 
non-carriers of the risk alleles at both CFH and C2/CFB (see Table 1).  The CFI profile 
biomarker was defined using these three risk alleles on the basis of the association of 
the CFI risk allele with lampalizumab response and on the basis of the high frequency of 
risk alleles at CFH and C2/CFB in Study CFD4870g and the fact that the CFH and 
C2/CFB SNPs are highly significant in genome-wide studies of AMD genetic risk 
(p = 1 × 10 − 434 and p = 4 × 10 − 89, respectively; Fritsche et al. 2013).  The inclusion of CFH 
and C2/CFB genotypes in the definition of the CFI profile biomarker-positive is intended 
to increase the likelihood of identifying patients with complement-driven GA disease.  Of 
note, all CFI risk allele carriers in Study CFD4870g were also risk allele carriers at CFH 
and/or C2/CFB.   


 
 
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Table 1 
Definition of Biomarker Status Using the CFI Profile Test 
 
CFI 
CFH 
C2/CFB 
CFI profile 
biomarker-positive 
+ 
+ 
+ 
 
+ 
+ 
− 
 
+ 
− 
+ 
CFI profile 
biomarker-negative 
+ 
− 
− 
 
− 
+ 
+ 
 
− 
+ 
− 
 
− 
− 
+ 
 
− 
− 
− 
Note:   “+” indicates that the patient is a risk allele carrier (i.e., heterozygous or homozygous for 
the risk allele) and “−” indicates that the patient is a non-carrier of the risk allele. 
 
See Section 3.3.2.2 for details on the assay used to determine valid CFI biomarker 
status and Appendix 22 for the full specifications of the cobas® CFI Profile Test. 
1.3.3 
Study GX28198 Open-Label Extension 
Study GX28198 is a multicenter, open-label, extension study of the safety and tolerability 
of lampalizumab administered by intravitreal injection to patients with GA who have 
completed the 18-month treatment in Study CFD4870g.  This study is currently ongoing. 
1.3.4 
Summary 
In summary, the Phase II results from Study CFD4870g provided evidence that inhibition 
of the ACP with lampalizumab may slow the progression of GA and that lampalizumab 
administered as 10-mg intravitreal injections monthly over 18 months demonstrated an 
acceptable safety and tolerability profile in patients with GA secondary to AMD.  In 
addition, the exploratory genetic analyses suggest that there may be a 
biomarker-defined population (CFI profile biomarker-positive) that may have more rapid 
progression of disease and potentially derive greater efficacy benefit from lampalizumab 
than a group that is negative for the biomarker (CFI profile biomarker-negative). 
On the basis of the findings from the Phase I and II studies, the Phase III study aims to 
further evaluate the efficacy and safety of lampalizumab as well as the potential for the 
CFI profile biomarker to identify patients who may have more rapid progression of 
disease and may derive greater benefit from lampalizumab treatment. 
For additional details regarding nonclinical and clinical studies, see the Lampalizumab 
Investigator’s Brochure. 


 
 
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2. 
OBJECTIVES 
The study will assess the efficacy and safety of 10-mg lampalizumab administered by 
intravitreal injections every 4 weeks (Q4W) or every 6 weeks (Q6W) relative to sham 
control for the treatment of GA secondary to AMD.  Efficacy, safety, and PK will be 
evaluated in CFI profile biomarker-positive and CFI profile biomarker-negative patients. 
2.1 
EFFICACY OBJECTIVES 
The primary efficacy objective of this study is to evaluate the efficacy of intravitreal 
injections of 10-mg lampalizumab administered Q4W or Q6W in CFI profile 
biomarker-positive and CFI profile biomarker-negative patients compared with sham 
control assessed by change in the GA area from baseline as measured by FAF. 
The secondary efficacy objective of this study is to evaluate the effect of lampalizumab 
compared with sham control, with respect to: 
• 
Macular functional response as assessed by mesopic microperimetry 
• 
Best corrected visual acuity (BCVA) as measured by the Early Treatment Diabetic 
Retinopathy Study (ETDRS) chart (at a starting distance of 4 m) 
• 
BCVA as measured by ETDRS chart (at a starting distance of 4 m) under low 
luminance conditions 
• 
Binocular reading speed as assessed by the Minnesota Low-Vision Reading Test 
(MNRead) or by Radner Reading Charts 
• 
Binocular critical print size as assessed by the MNRead or by Radner Reading 
Charts 
• 
Patient-reported visual function as assessed by the National Eye Institute Visual 
Functioning Questionnaire 25-item Version (NEI VFQ-25) 
• 
Patient-reported independent reading as assessed by the Functional Reading 
Independence Index (FRI Index) 
 
2.2 
SAFETY OBJECTIVES 
The safety objectives for this study are as follows: 
• 
To evaluate the local and systemic safety and tolerability of intravitreal injections of 
10-mg lampalizumab administered Q4W or Q6W relative to sham control 
• 
To evaluate the clinical significance of anti-therapeutic antibodies directed against 
lampalizumab 
2.3 
PHARMACOKINETIC OBJECTIVE 
The PK objective for this study is to characterize the systemic PK of lampalizumab 
administered by 10-mg intravitreal injections Q4W or Q6W. 


 
 
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2.4 
DIAGNOSTIC OBJECTIVE 
A diagnostic objective for this study is to evaluate the prognostic value of the CFI profile 
biomarker on the mean change in the GA area from baseline as measured by FAF. 
2.5 
EXPLORATORY OBJECTIVES 
The exploratory objectives for this study are as follows: 
• 
To evaluate the effect of lampalizumab compared with sham control, with respect to: 
– 
Monocular reading speed as assessed by MNRead charts or by Radner 
Reading Charts 
– 
Monocular critical print size as assessed by MNRead charts or by Radner 
Reading Charts 
– 
Monocular reading acuity as assessed by MNRead charts or by Radner 
Reading Charts 
– 
Binocular reading acuity as assessed by MNRead charts or by Radner Reading 
Charts 
• 
To evaluate the aqueous levels of total lampalizumab and factor D following study 
treatment 
• 
To evaluate the potential association of genetic variants in CFI and 
complement-pathway genes with disease characteristics and response to 
administration of lampalizumab 
• 
To evaluate the relationship of genetic variants in CFI and complement-pathway 
genes to levels in the blood of messenger RNA (mRNA) and proteins of CFI and 
complement-pathway genes 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
This study is a Phase III, double-masked, multicenter, randomized, sham 
injection-controlled study evaluating the efficacy and safety of a 10-mg dose of 
lampalizumab administered Q4W or Q6W by intravitreal injections for approximately 
96 weeks, excluding screening period, in patients with GA secondary to AMD.  The 
study will randomize approximately 936 patients at approximately 140 investigational 
sites globally.  The site investigators will be qualified ophthalmologists. 
The study will consist of a screening period of up to 28 days (−28 to −1) and an 
approximately 2-year treatment period (Day 1 to Week 92 for the Q4W treatment arms 
and Day 1 to Week 90 for the Q6W treatment arms; see Table 2 and Table 3, 
respectively), followed by the final study visit at Week 96.  The duration of the study is 
approximately 2 years (96 weeks) after the last patient is randomized to the study 
(see Figure 2). 


 
 
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Figure 2 Study Schema 
 
1 year = Week 48; 1° EP = primary endpoint; 2 year = Week 96; 2° EP = secondary endpoint; CFI 
Profile BM + = CFI profile biomarker-positive; CFI Profile BM − = CFI profile biomarker-negative; 
Day  − 28 = end of screening period; Day 1 = randomization and first study treatment visit; 
ITV = intravitreal; Q4W = every 4 weeks; Q6W = every 6 weeks. 
 
Each consented patient must satisfy all eligibility criteria at both the screening period and 
the Day 1 visit.  As part of the screening process, the central reading center will evaluate 
FAF images, CFPs, and fluorescein angiograms (FA) to provide an objective, masked 
assessment of patient eligibility.  The investigational cobas® CFI profile assay results of 
blood sample analysis will be used to determine a patient’s biomarker-positive 
or -negative status and must be obtained during the screening period prior to Day 1 visit.  
Patients must also meet BCVA and other eligibility criteria (see Section 4.1 for details).  
Screen-failed patients may be eligible for re-screening up to two additional times during 
the enrollment period of the study.  At re-screening, all screening visit assessments will 
be performed except for CFI biomarker sample and FA imaging collection, provided that 
a valid CFI result is available and reading center-eligible FA images were taken within 
8 weeks before the new Day 1 visit (randomization).  
Only one eye will be chosen as the study eye.  If both eyes are eligible to become the 
study eye, the eye with the worse visual function as determined by the investigator and 
the patient will be the study eye.  If both eyes have the same visual function, the eye 
with the larger area of GA will be selected as the study eye. 
 


 
 
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After screening has been completed, eligible patients will be randomized in a 
2:1:2:1 ratio so that approximately 312 patients will receive study drug treatment Q4W 
and 156 patients will receive sham treatment Q4W for a total of 24 treatments; 
312 patients will receive study drug treatment Q6W and 156 patients will receive sham 
treatment Q6W for a total of 16 treatments.  The study population will be enriched (ratio 
of 1.5:1) for the biomarker-positive population relative to the biomarker-negative 
population (see Section 3.3.2.2). 
Randomization will be stratified by biomarker status (positive vs. negative) (as 
determined by the investigational cobas® CFI Profile assay), baseline BCVA ETDRS 
chart Snellen equivalent (20/50 or better vs. worse than 20/50), sex (women vs. men), 
and microperimetry eligibility (yes vs. no). 
Patients will be treated according to the dosing schedule for the assigned treatment 
arms as outlined in Table 2 and Table 3. 


 
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Table 2 
Every 4 Weeks Dosing Treatment Arms 
Day 
Visit 
Week Visit 
Treatment 
Arm 
1 
8a 
4 
8 
12 
16
20
24
28
32
36
40
44
48
52 
56 
60
64
68
72 
76 
80
84
88
92
96a 
BM+ 
Lampalizumab 
(N = 188) 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
BM+ Sham 
(N = 94) 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
BM- 
Lampalizumab 
(N = 124) 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
BM- Sham 
(N = 62) 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
a Study treatment is not administered at the Day 8 visit and Week 96 (final visit). 
BM+ = CFI profile biomarker-positive; BM − = CFI profile biomarker-negative. 
 


 
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Table 3 
Every 6 Weeks Dosing Treatment Arms 
Day Visit 
Week Visit 
Treatment Arm 
1 
8a 
6 
12 
18 
24 
30 
36 
42 
48 
54 
60 
66 
72 
78 
84 
90 
96a 
BM+ Lampalizumab 
(N = 188) 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
BM+ Sham 
(N = 94) 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
BM- Lampalizumab 
(N = 124) 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
BM- Sham 
(N = 62) 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
a Study treatment is not administered at the Day 8 visit and Week 96 (final visit).  
BM+  = CFI profile biomarker-positive; BM − = CFI profile biomarker-negative 
 


 
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The first study treatment will be administered on the same day as randomization 
(Day 1 visit).  If a site has an unexpected issue (e.g., the IxRS is not able to assign the 
study kit), with the Medical Monitor’s permission, the patient’s first study treatment 
may be administered within 3 working days of the Day 1 visit.  The following 
assessments will be repeated on the day of the study treatment: slit lamp examination, 
indirect ophthalmoscopy, and pre- and post-treatment IOP measurement (recorded on 
Day 1 eCRF and dated accordingly).    
Study treatment visits will be scheduled Q4W (±5 days) or Q6W (±5 days) relative to the 
Day 1 visit date.  Randomized patients will have the first intravitreal injection of 
lampalizumab or sham injection administered by the investigator on Day 1 and will have 
safety and ocular assessments performed on Day 8 (± 2 days) visit.  At the subsequent 
scheduled visits (Q4W or Q6W), patients will have safety evaluations performed by the 
investigator prior to receiving study drug or sham injection  They will be contacted by site 
personnel 4 (± 2) days after each injection to elicit reports of decrease in vision, eye pain, 
unusual redness, or any other new ocular symptoms in the study eye.  If warranted, 
patients will be asked to return to the clinic as soon as possible for an unscheduled 
safety assessment visit (see Appendix 2).  Patient self-administered antimicrobials pre- 
and post-injection may be used at the investigator’s discretion.  Patients will be 
instructed to contact the investigator at any time if they have any health-related 
concerns. 
All assessments for a scheduled visit are to be performed on the same day, except 
those performed during the screening period. 
Study treatment should not occur earlier than 22 days after the previous treatment.  
Missed study treatments will not be made up. 
After the Day 1 visit, if a patient misses a study visit when ocular images are scheduled 
to be taken (see Appendix 1), the images must be obtained at the next scheduled visit. 
Patients are not expected to attend their scheduled visits if there are extenuating 
circumstances justifying their inability to come to the clinic.    
For masking requirements, see Section 4.2.2.   
Patients who are prematurely discontinued from study treatment will be encouraged to 
undergo as many scheduled visits as possible with emphasis on completing Week 48 
and Week 96 visits. 
Patients discontinued from the study prior to completion will be asked to return for an 
early termination visit after a minimum of 30 days have elapsed following their last study 
treatment for monitoring of adverse events and the early termination visit assessments.  


 
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3.1.1 
Planned Total Sample Size 
Approximately 936 patients (188 biomarker-positive patients per treatment group 
[lampalizumab Q4W, lampalizumab Q6W, and pooled sham] and 
124 biomarker-negative patients per treatment group [lampalizumab Q4W, 
lampalizumab Q6W, and pooled sham) will be enrolled in the study at approximately 
140 sites located globally. 
At selected sites, microperimetry assessment will be performed on a subgroup of 
approximately 138 CFI profile biomarker-positive patients and approximately 90 CFI 
profile biomarker-negative patients.   
At selected sites, serial ECG evaluations will be performed on approximately 100 study 
patients, independent of CFI profile biomarker status (see Section 4.5.7). 
3.1.2 
Data Monitoring Committee 
An independent Data Monitoring Committee (iDMC) will monitor safety and study 
conduct on an ongoing basis.  Members of the iDMC will be external to the Sponsor and 
will follow a charter that outlines the iDMC roles and responsibilities.  The iDMC will 
meet approximately every 6 months (frequency adjustable as required) to evaluate the 
benefit-risk profile of lampalizumab treatment through reviewing both safety and efficacy 
data. No formal efficacy/futility analysis is planned to be done by iDMC.  The iDMC may 
recommend stopping the study early for safety reasons.   
A nominal type I error penalty of 0.0001 will be taken for each time the iDMC reviews 
unmasked data prior to the formal analysis of the primary efficacy endpoint.  At the time 
of the primary efficacy endpoint analysis, it is estimated that five interim data reviews will 
have been conducted by the iDMC; therefore, efficacy analyses will be performed with a 
family-wise significance level of 0.0495. 
3.2 
END OF STUDY 
The end of the study is defined as the date when the last patient, last visit (LPLV) occurs.  
LPLV is expected to occur approximately 96 weeks after the last patient is randomized 
to the study. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Lampalizumab Dose and Schedule 
To provide assessment of the dose response to lampalizumab and to allow for additional 
masking for the study, two lampalizumab treatment arms are included in this Phase III 
study.  The 10-mg dose of lampalizumab will be administered intravitreally at Q4W or 
Q6W intervals. 
The 10-mg monthly dosage was the dosing regimen that was found to be the most 
efficacious and was also well tolerated in the Phase II component of Study CFD4870g. 


 
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In Study CFD4870g, the 10-mg every-other-month dosing regimen did not result in 
efficacy for the overall study population but did result in efficacy in the biomarker-positive 
group.  On the basis of PK/pharmacodynamic (PD) and efficacy modeling of the 
biomarker-positive group, 10 mg administered Q6W is expected to achieve lower but 
efficacious drug exposures relative to 10-mg Q4W.  Additionally, the Q6W dosing 
regimen represents less of a treatment burden to patients, caregivers, and physicians 
relative to a Q4W dosing regimen. 
Taken together, the two dosing regimens included in this Phase III study are expected to 
demonstrate a dose response, with 10-mg Q4W expected to provide maximally feasible 
efficacious dosage, whereas the 10-mg Q6W is expected to be an effective dose while 
reducing treatment burden to patients, caregivers, and physicians. 
3.3.2 
Rationale for Patient Population and Analysis Groups 
3.3.2.1 
Rationale for Evaluating Lampalizumab Treatment Effect in 
Patients with Geographic Atrophy Secondary to Age-Related 
Macular Degeneration 
Currently, there are no approved treatments to prevent the progression of GA secondary 
to AMD and the associated decrease in visual function.  Consequently, a significant 
unmet need exists for treatment of this serious condition.  This study will enroll a target 
population of patients with the diagnosis of GA secondary to AMD.  Key eligibility criteria 
were chosen to enrich the study population for GA patients who may have more rapid 
growth of GA lesions to maximize the chances of detecting progression of disease and 
treatment effects over the planned study duration as well as to identify the patients most 
likely to potentially benefit from the treatment.  The key eligibility criteria and rationale for 
the criteria are presented below: 
Evidence of Geographic Atrophy in Both Study Eye and Non-study (Fellow) 
Eye 
Bilateral GA represents the majority of the population (approximately 60%−67%) 
diagnosed with GA as reported in two natural history studies (Holz et al. 2007; 
Sunness et al. 2007) and has been associated with an increased rate of GA lesion 
growth compared to unilateral GA (Sunness et al. 2007). 
Presence of Hyperautofluorescence Adjacent to the Geographic Atrophy 
Area in the Study Eye (i.e., Banded or Diffuse Junctional Fundus 
Autofluorescence Patterns) 
Holz et al. (2007) described four major perilesional FAF patterns (none, focal, banded, 
and diffuse) that were correlated with the rate of GA lesion growth in the longitudinal 
natural history arm of patients with GA secondary to AMD in the multi-center FAM-study.  
Holz reported that GA lesions with banded or diffuse junctional patterns expanded at a 
significantly higher rate than lesions with focal or no hyperautofluorescence.  Of note, 
approximately 70% of the patients in the FAM study exhibited the banded or diffuse 
junctional perilesional FAF patterns. 


 
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Best Corrected Visual Acuity 20/100 or Better (Snellen Equivalent) in the 
Study Eye Using Early Treatment Diabetic Retinopathy Study Chart 
Sunness et al. (1999b) have reported on populations of patients with GA who may have 
worsening of VA loss in a manner and timeframe that would be suitable for study in a 
clinical study.  In a study of the natural history of GA, approximately 41% of patients with 
GA with baseline VA of 20/50 or better lost at least three lines of vision at 2 years and 
70% by 4 years.  Among these, patients with VA 20/100 or better but worse than 20/50, 
15% lost at least three lines of vision at 2 years. 
Association between Female Sex and Rate of GA Progression 
Caire et al. reported on a prospective study of 73 patients with GA in which they 
evaluated whether certain genetic and demographic risk factors were associated with 
the progression of established GA secondary to AMD.  In the logistic regression 
analysis, Caire et al. reported a statistically significant risk association between female 
sex and the rate of progression of GA (p=0.02 with an adjusted odds ratio of 7.31 [95% 
CI of 1.30-41.80]; Caire et al. 2014). 
A similar trend of females having a faster rate of GA progression relative to males was 
also observed in the Phase II Study CFD4870g.  At month 18, the subgroups of female 
vs. male patients had a mean change from baseline in GA area of 3.831 mm2 with 80% 
CI of (3.340, 4.321) and 2.310 mm2 with 80% CI of (1.813, 2.808).  Similar trends were 
also noted when evaluating the subgroups of sex by CFI profile biomarker status.  Note 
that the subgroups analyses in the Phase II study contained small numbers and should 
be interpreted with caution. 
3.3.2.2 
Enrichment of Complement Factor I Profile Biomarker-Positive 
Patients 
Exploratory analyses of the Phase II component of Study CFD4870g suggest that the 
CFI profile biomarker-positive population may have a greater benefit from lampalizumab 
treatment than the CFI profile biomarker-negative population.  As the data from this 
Phase II study were exploratory and hypothesis-generating (based on a small sample 
size), the Phase III study population will be enriched (ratio of 1.5:1) for the CFI profile 
biomarker-positive population relative to the CFI profile biomarker-negative population.  
Enriching for CFI profile biomarker-positive patients ensures a comprehensive 
evaluation of the CFI profile biomarker-positive population while, importantly, also 
studying a sufficient number of the CFI profile biomarker-negative patients to allow 
adequate benefit-risk assessment in this group.  Biomarker status will be determined 
using the investigational cobas® CFI profile assay that will be run at a designated study 
laboratory testing site. 
The cobas® CFI Profile Clinical Trial Assay 
A valid CFI biomarker result will be determined at a designated study laboratory testing 
site using the cobas® CFI Profile Clinical Trial Assay (CTA), which is a real-time 
polymerase chain reaction (PCR) test developed by Roche Molecular Systems to 


 
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identify genotypes of three SNPs associated with CFH, CFI, and C2/CFB in DNA 
extracted from whole blood samples from patients with GA secondary to AMD.  The 
cobas® CFI Profile CTA is intended to be used as an Investigational Use Only assay to 
characterize the complement factor profile of study participants.  The cobas® CFI Profile 
CTA biomarker status results will then be used to stratify patients at randomization. 
The cobas® CFI Profile CTA consists of two kits and will use the cobas® 4800 platform.  
The cobas® DNA Sample Preparation Kit (DNA isolation kit) provides the necessary 
components to manually extract genomic DNA from whole blood samples.  The cobas® 
CFI Profile CTA contains the necessary PCR master mix, oligonucleotides, cofactor, and 
controls to detect three SNPs associated with CFI, CFH, and C2/CFB. 
3.3.3 
Rationale for Control Group 
A sham control group will be used in this study to assess the differences in GA 
progression, change in clinical function measures, and safety in patients who receive 
lampalizumab compared with patients who receive sham.  Patients randomized to the 
sham control group will undergo the same assessments as patients randomized to the 
study drug intravitreal injection group. 
Sham injections were chosen instead of placebo intravitreal injections to minimize the 
known risk of intravitreal injection-related adverse events (e.g., endophthalmitis) and 
because no potential patient value would be derived from an intravitreal injection of 
placebo. 
3.3.4 
Rationale for Biomarker Assessments 
The response to lampalizumab treatment will be evaluated in pre-specified subgroups 
defined by the genetic biomarker test (cobas® CFI Profile Trial Assay) based on the 
common genetic variants of CFI, CFH, and C2/CFB.  The whole blood sample CFI 
profile results will be determined by utilizing an investigational cobas® CFI Profile CTA 
(see Appendix 22) at the designated central laboratory.  Although the CFI profile test is 
based on the common genetic variants of CFI, CFH, and C2/CFB test, recent studies 
have identified rare variants in CFI that have been associated with increased AMD risk 
(van de Ven et al. 2013).  Given the potential for rare variants in CFI and other 
complement pathway genes to affect disease characteristics including progression and 
the response to lampalizumab treatment, additional exploratory genetic analysis will be 
conducted using the biomarker clinical genotyping sample including sequencing of CFI 
and other complement-pathway genes. 
In addition to the genetic analysis, pre-injection plasma levels and whole blood mRNA 
levels of CFI and complement-pathway genes will be measured.  Exploratory analyses 
will evaluate the relationship of blood levels of CFI and complement-pathway mRNA and 
proteins to genetic variants in the complement pathway and to disease characteristics, 
including progression and the response to lampalizumab treatment. 


 
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3.4 
OUTCOME MEASURES 
3.4.1 
Efficacy Outcome Measures 
The primary efficacy outcome measure for this study is GA area at 1 year as assessed 
by FAF. 
The secondary efficacy outcome measures for this study over time are as follows: 
• 
Number of scotomatous points assessed by mesopic microperimetry for the 
evaluation of the macular functional response 
• 
Change in macular sensitivity as assessed by mesopic microperimetry for the 
evaluation of the macular functional response 
• 
GA area as assessed by FAF 
• 
BCVA score as assessed by ETDRS chart at a starting distance of 4 m 
• 
BCVA score as assessed by ETDRS chart under low luminance conditions at a 
starting distance of 4 m 
• 
Binocular reading speed as assessed by MNRead charts or Radner Reading Charts  
• 
Binocular critical print size as assessed by MNRead charts or Radner Reading 
Charts 
• 
NEI VFQ-25 composite score 
• 
NEI VFQ-25 near activity subscale score 
• 
NEI VFQ-25 distance activity subscale score 
• 
FRI Index score 
 
3.4.2 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
The incidence and severity of ocular adverse events 
• 
The incidence and severity of systemic (non-ocular) adverse events 
• 
Changes and abnormalities in ECG parameters 
• 
The incidence of anti-lampalizumab antibodies 
 
3.4.3 
Pharmacokinetic Outcome Measure 
The PK outcome measure for this study is serum lampalizumab concentration over time. 
3.4.4 
Diagnostic Outcome Measure 
The evaluation of the prognostic value of the CFI profile biomarker will be based on the 
biomarker status at baseline and the primary clinical outcome of change in the GA area 
from baseline as measured by FAF. 


 
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3.4.5 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
Monocular reading speed as assessed by MNRead charts or Radner Reading 
Charts over time 
• 
Monocular critical print size as assessed by MNRead charts or Radner Reading 
Charts over time 
• 
Monocular reading acuity as assessed by MNRead charts or Radner Reading 
Charts over time 
• 
Binocular reading acuity as assessed by MNRead charts or Radner Reading Charts 
over time 
• 
Total lampalizumab and factor D levels in aqueous humor as assessed by ELISA 
• 
The association of genetic variants in CFI and complement-pathway genes with 
disease characteristics and response to administration of lampalizumab 
• 
The relationship of genetic variants in CFI and complement-pathway genes to levels 
in the blood of mRNA and proteins of CFI and complement-pathway genes 
 
3.5 
EXPLORATORY SUBSTUDIES 
At selected sites, the Sponsor may propose exploratory substudies associated with the 
Study GX29185 protocol. Each substudy will be documented in a separate substudy 
protocol and associated ICF(s).  
4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
Patient Selection and Sex Distribution 
Written informed consent will be obtained prior to initiation of any study procedures.  The 
screening evaluation will be performed within 28 days preceding the Day 1 visit (the day 
of the first study treatment). 
Note: Some patients may require an extended screening period as a result of 
repeated evaluation of images or other issues.  Upon agreement with the Medical 
Monitor, the screening period may be extended for up to 5 days for such cases. 
  
Only one eye will be chosen as the study eye.  If both eyes are eligible, the eye with the 
worse visual function (as determined by the investigator and patient) will be the study 
eye.  If both eyes have the same visual function, the eye with the larger area of GA will 
be selected as the study eye. 
The protocol allows enrollment of both men and women, provided the entry criteria are 
met.  However, women who are pregnant or breastfeeding will be excluded from the 
study.  The remaining inclusion/exclusion criteria apply to both male and female patients 
and pertain to issues of patient health performance and safety. 


 
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4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
General Inclusion Criteria 
• 
Willingness and the ability to provide signed informed consent.  Additionally, at U.S. 
sites, patients must provide Health Insurance Portability and Accountability Act 
(HIPAA) authorization, and in other countries, as applicable according to national 
laws. 
• 
Age ≥50 years 
• 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate 
of <1% per year during the treatment period and for at least 30 days after the last 
dose of study drug 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state ( ≥ 12 months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical 
sterilization (removal of ovaries and/or uterus). 
Examples of contraceptive methods with a failure rate of < 1% per year include 
bilateral tubal ligation, male sterilization, established, proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices 
and copper intrauterine devices.   
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
For men: Agreement to remain abstinent or use contraceptive measures and 
agreement to refrain from donating sperm, as defined below: 
With female partners of childbearing potential, men must remain abstinent or 
use a condom plus an additional contraceptive method that together result in a 
failure rate of < 1% per year during the treatment period and for at least 30 
days plus 90 days (a spermatogenesis cycle) after the last dose of study drug.  
Men must refrain from donating sperm during this same time period. 
• 
Ability and willingness to undertake all scheduled visits and assessments 
• 
Valid CFI profile biomarker result (i.e., CFI profile biomarker-positive or CFI profile 
biomarker-negative) 
Ocular Inclusion Criteria:  Study Eye 
• 
BCVA letter score of  ≥  49 letters (Snellen equivalent of 20/100 or better) using 
ETDRS charts at starting distance of 4 m 
If BCVA letter score is  ≥  79 letters (Snellen equivalent of 20/25 or better), at 
least one GA lesion must be within 250 μm of the foveal center 
• 
Well demarcated area(s) of GA secondary to AMD with no evidence of prior or 
active CNV 


 
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The total GA lesion size ≥2.54 mm2 (approximately ≥1 disc area [DA]) and 
≤17.78 mm2 (approximately ≤7 DA) and must reside completely within the FAF 
imaging field (Field 2−30 degree image centered on the fovea) 
If GA is multifocal, at least 1 focal lesion must be ≥1.27 mm2 
(approximately ≥0.5 DA) 
• 
Presence of hyperautofluorescence of either banded or diffuse patterns adjacent to 
the area of GA 
• 
Sufficiently clear ocular media, adequate pupillary dilation, and fixation to permit 
quality fundus imaging 
Ocular Inclusion Criteria:  Non-study Eye 
GA secondary to AMD with no evidence of prior or active CNV 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
GA Characteristics Exclusion Criteria 
• 
GA in either eye due to causes other than AMD (monogenetic macular dystrophies 
[e.g., Stargardt disease, cone rod dystrophy] or toxic maculopathies 
[e.g., chloroquine/hydroxychloroquine maculopathy]) 
Ocular Exclusion Criteria:  Study Eye 
• 
History of vitrectomy surgery, submacular surgery, or any surgical intervention for 
AMD 
• 
Previous laser photocoagulation for CNV, diabetic macular edema, retinal vein 
occlusion, and proliferative diabetic retinopathy 
• 
Prior treatment with Visudyne®, external-beam radiation therapy (for intraocular 
conditions), or transpupillary thermotherapy 
• 
History of prophylactic subthreshold laser treatment for AMD 
• 
Previous intravitreal drug delivery (e.g., intravitreal corticosteroid injection, 
anti−angiogenic drugs, anti-complement agents, or device implantation).  A single 
intraoperative administration of a corticosteroid during cataract surgery for cystoid 
macular edema prophylaxis at least 3 months prior to screening is permitted. 
Ocular Exclusion Criteria:  Non-Study Eye 
• 
Non-functioning non-study eye defined as either: 
BCVA of hand motion or worse 
OR  
No physical presence of non-study eye (i.e., monocular) 
Ocular Exclusion Criteria:  Both Eyes 
• 
Previous participation in interventional clinical trials for geographic atrophy or dry 
AMD (except of vitamins and minerals) irrespective of the route of administration 
(ocular or systemic)  


 
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• 
Previous treatment with eculizumab, lampalizumab, fenretidine or any other drugs 
for geographic atrophy or dry AMD treatment 
Ocular Exclusion Criteria:  Concurrent Ocular Conditions 
• 
RPE tear that involves the macula in either eye 
• 
Any concurrent ocular or intraocular condition in the study eye (e.g., cataract or 
diabetic retinopathy) that, in the opinion of the investigator, could do either of the 
following: 
Require medical or surgical intervention during the study period to prevent or 
treat vision loss that might result from that condition 
If allowed to progress untreated, could likely contribute to loss of at least 
two Snellen equivalent lines of BCVA during the study period 
• 
Active uveitis and/or vitritis (grade trace or above) in either eye 
• 
History of idiopathic or autoimmune-associated uveitis in either eye 
• 
Active, infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye 
• 
Current vitreous hemorrhage in the study eye 
• 
History of retinal detachment or macular hole (Stage 3 or 4) in the study eye 
• 
Aphakia or absence of the posterior capsule in the study eye 
• 
Previous violation of the posterior capsule in the study eye unless it occurred as a 
result of yttrium aluminum garnet (YAG) laser posterior capsulotomy in association 
with prior posterior chamber intraocular lens implantation 
• 
Spherical equivalent of the refractive error in the study eye demonstrating 
>8 diopters of myopia 
• 
For patients who have undergone prior refractive or cataract surgery in the study 
eye, the preoperative refractive error in the study eye should not have exceeded 
8 diopters of myopia. 
• 
Intraocular surgery (including cataract surgery) in the study eye within 3 months 
preceding Day 1 
• 
Uncontrolled glaucoma in the study eye (defined as intraocular pressure 
[IOP] ≥30 mm Hg despite treatment with anti-glaucoma medication) 
• 
History of glaucoma-filtering surgery in the study eye 
• 
History of corneal transplant in the study eye 
• 
Proliferative diabetic retinopathy in either eye 
• 
Prior or active CNV in either eye 
• 
Central serous retinopathy in either eye 
• 
History of recurrent infectious or inflammatory ocular disease in either eye 
Concurrent Systemic Conditions Exclusion Criteria 
• 
Uncontrolled blood pressure (defined as systolic >180 mm Hg and/or 
diastolic >110 mm Hg while patient is sitting) 


 
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If a patient’s initial measurement exceeds these values, a second reading may 
be taken 30 or more minutes later.  If the patient’s blood pressure must be 
controlled by anti-hypertensive medication, the patient can become eligible if 
medication is taken continuously for at least 30 days prior to Day 1. 
• 
History of other diseases, metabolic dysfunction, physical examination finding, or 
clinical laboratory finding that gives reasonable suspicion of a disease or condition 
that contraindicates the use of lampalizumab or that might affect interpretation of the 
results of the study or that renders the patient at high risk of treatment complications 
• 
Treatment for active systemic or localized infection  
The ongoing prophylactic use of antimicrobial therapy should be discussed 
with the Medical Monitor.  
• 
Predisposition or history of increased risk of infection (i.e., history of splenectomy or 
chronic immunosuppression) 
• 
Active cancer within past 12 months except for appropriately treated carcinoma in 
situ of the cervix, non-melanoma skin carcinoma and prostate cancer with a 
Gleason score of  < 6 and a stable prostate-specific antigen (PSA) for  > 12 months. 
• 
History of allergy to fluorescein that is not amenable to treatment 
• 
History of a severe allergic reaction or anaphylactic reaction to a biologic agent or 
known hypersensitivity to any component of the lampalizumab injection 
• 
Inability to comply with study or follow-up procedures 
• 
Inability to obtain CFP, FAF, and FA of sufficient quality to be analyzed and graded 
by the central reading center 
• 
Previous participation in any studies of investigational drugs within 3 months (except 
as listed in the above Section ‘Ocular Exclusion Criteria: Both Eyes’) preceding Day 
1 (excluding vitamins and minerals) 
• 
Requirement for continuous use of any medications/treatments indicated in the 
“Prohibited Therapy” section of the protocol (see Section 4.4.2) 
• 
Women who are pregnant or lactating or intending to become pregnant during the 
study 
Women of childbearing potential must have a negative serum pregnancy test 
result within 28 days prior to initiation of study treatment. 
4.1.3 
Microperimetry Criteria at Selected Sites Only  
Inclusion Criteria 
• 
Patients must meet all other eligibility criteria for study entry. 
• 
Microperimetry screening test criteria for eligibility: 
Must be able to detect fixation target. 
Total elapsed time to complete the 10-2 68 point exam is  ≤ 30 minutes in 
duration. 
Reliability Test ratio  ≤ 20% (false positive rate). 


 
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Ability and willingness to undertake MP assessment as determined by 
investigator. 
 
Exclusion Criteria 
• 
Any exclusion criteria listed for the study entry 
• 
Investigator determines that patient is unable to perform the test reliably (e.g. 
Difficulty sitting still against the supporting chinrest for > 10 minutes; Unable to 
physically operate the clicker or joystick; Unable to follow the instructions for the test 
[i.e. cognitive impairment]) 
Note: disqualification from the microperimetry assessment doesn’t exclude a 
patient from the trial participation if she/he qualifies as per the rest of the study 
entry criteria. 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND MASKING 
4.2.1 
Treatment Assignment 
After written informed consent has been obtained, all patients will receive a screening 
number assigned through the Interactive Voice and Web Response Systems (IxRS).  
A patient must satisfy all eligibility criteria (see Sections 4.1.1 and 4.1.2) at both the 
screening and the Day 1 visit (first study treatment) prior to randomization.  As part of 
the screening process, the central reading center (masked to patient treatment 
assignment) will evaluate FAF images, CFP, and FA to provide an objective, masked 
assessment of patient eligibility.  After all patient eligibility requirements are confirmed, 
site personnel will contact the IxRS on Day 1 visit for assignment of a patient 
identification number (a separate number from the screening number).  Patients will be 
randomized in a 2:1:2:1 ratio to one of the study treatment arms (lampalizumab Q4W, 
sham Q4W, lampalizumab Q6W, or sham Q6W).  The study treatment kit number will be 
also assigned by IxRS at that time.  Patients will be randomized on the same day the 
study treatment is to be initiated (Day 1 visit). 
Randomization will be stratified by biomarker status (positive vs. negative, as 
determined by the investigational cobas® CFI Profile assay), baseline BCVA ETDRS 
chart Snellen equivalent (20/50 or better vs. worse than 20/50), sex (woman vs. man), 
and microperimetry eligibility (yes vs. no).  A permuted-block randomization method will 
be used to obtain an approximately 2:1 ratio between lampalizumab and sham arms for 
each dosing frequency within each stratum. 
Once the study randomizes the allotted number of CFI profile biomarker-negative or CFI 
profile biomarker-positive patients (see Figure 2), the additional screened patients who 
would have been randomized in the already-filled biomarker arms will be screen-failed. 
Patients and all study site personnel will be masked for CFI profile biomarker status until 
study completion.  Sponsor study team members who have direct contact with study 
sites will be masked to CFI profile biomarker status, but team members who do not 
interact with study sites may review individual patient CFI profile biomarker status. 


 
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Details of the randomization procedure will be described in the Statistical Analysis Plan 
(SAP). 
4.2.2 
Masking 
This is a double-masked study.  There must be a minimum of two investigators per site 
to fulfill the masking requirements of this study.  Study visits must be scheduled when 
both investigators are present.  At least one investigator will be designated as the 
evaluating physician who will be masked to patients’ treatment assignment and will 
evaluate all ocular assessments.  At least one other investigator (and designated, 
unmasked assistant, as needed) will be designated as the treating (injecting) physician 
who will be unmasked to patients’ treatment assignment and will administer injections 
(lampalizumab or sham).  The Principal Investigator must be masked to patients’ 
treatment assignment.  All roles for each study staff member should be clearly 
documented on the Site Delegation Log.  The Delegation Log should be signed by the 
Principal Investigator.  
Once the designated masked vs. unmasked roles are delineated and the site study staff 
have started to perform them, the roles cannot be switched or reversed at any time 
during the conduct of the study.  In case a site is experiencing unexpected extreme 
situations, the Medical Monitor’s permission might be granted to switch the study staff 
member from the masked role to the unmasked role, but not the other way around.  In 
the event an alternate study staff member needs to be added or substituted, that 
alternate study staff member may assume only one role for the duration of the study. 
Starting at the patient’s Day 1 visit, the treating physician(s) (performing the 
lampalizumab or sham injections), post-treatment finger counting, and optional 
aqueous humor sample collection) must continue their role as treating physician only, 
cannot be involved in any other aspect of the study, and must not divulge treatment 
assignment to anyone. 
Patients, study site personnel (with the exception of the treating physician[s], assistant[s], 
and pharmacist if any), the designated evaluating physician(s), central reading center 
personnel, and the Sponsor and its agents (with the exception of drug accountability 
monitors) will be masked to treatment assignment. 
The VA examiner (performing the refraction, BCVA examinations, and reading speed 
assessment) will be masked to patient treatment assignment and the treated study eye 
and will only perform refraction, BCVA, BCVA under low luminance conditions, and 
reading speed assessments.  The BCVA examiner will have no access to the VA scores 
of a patient’s previous visits and may have access only to patient’s refraction data from 
previous visits.  The VA examiner is not allowed to perform any other tasks involving 
direct patient care. 


 
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Every effort must be made to limit the number of unmasked study personnel to ensure 
the integrity of this masked study.  There must be no more than five unmasked 
personnel at an investigative site at one time.  In special circumstances more than five 
unmasked personnel may be permitted after consultation with the medical monitor. 
Documented procedures will be put in place to avoid inadvertently unmasking study 
team members.  Only the IxRS provider and the external iDCC responsible for verifying 
a patient’s randomization and study treatment kit assignment, who are not otherwise 
involved in the study, will have access to the unmasking code. 
For the duration of the study, the patient treatment assignment will not be unmasked 
unless required for patient safety. 
All study visit assessments, except those at screening, should be performed by masked 
site personnel only.  Starting at a patient Day 1 visit, the unmasked treating physician 
will only perform the study treatment and the 15 minutes post-treatment vision testing 
(finger counting and, if applicable, hand movement and/or light perception).  The 
injecting physician will also perform a Lucentis injection if it was prescribed for either eye. 
Study assessments include PK sample collection in all patients (Section 4.5.9.3).  While 
PK samples must be collected from patients assigned to the sham arm to maintain the 
masking of treatment assignment, PK assay results for these patients are generally not 
needed for the safe conduct or proper interpretation of this study.  Sponsor personnel 
responsible for performing PK assays will be unmasked to patients’ treatment 
assignments to identify appropriate PK samples to be analyzed.  Samples from patients 
assigned to the sham arm will not be analyzed except by request (i.e., to evaluate a 
possible error in dosing). 
4.2.3 
Unmasking 
If unmasking is necessary for patient management (e.g., in the case of a serious 
adverse event for which patient management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  Treatment codes should not be broken except in emergency 
situations.  If the investigator wishes to know the identity of the study treatment for any 
other reason, he or she should contact the Medical Monitor directly.  The investigator 
should document and provide an explanation for any premature unmasking 
(e.g., accidental unmasking or unmasking due to serious adverse events). 
For regulatory reporting purposes and if required by local health authorities, the Sponsor 
will break the treatment code for all serious, unexpected suspected adverse reactions 
that are considered by the investigator or Sponsor to be related to study drug. 


 
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4.3 
STUDY TREATMENT 
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
Lampalizumab Formulation 
Lampalizumab Drug Product is provided as a sterile, white to off-white, lyophilized 
powder in a 6-cc USP/European Pharmacopoeia Type 1 glass vial and is intended for 
intravitreal administration.  For the Phase III clinical studies, each glass vial contains a 
nominal 40 mg of lampalizumab.  After reconstitution with Sterile Water for Injection, the 
drug product is formulated as 100 mg/mL lampalizumab in 40 mM L-histidine 
hydrochloride, 28 mM sodium chloride, 160 mM sucrose, 0.04% (w/v) polysorbate 20, 
pH 5.3. 
Storage 
Upon receipt of lampalizumab, vials should be refrigerated at 2°C−8°C (36°F−46°F) until 
use.  Lampalizumab vials should not be used beyond the expiration date provided by the 
manufacturer.  No preservative is used in lampalizumab drug product; therefore, the vial 
is intended for single use only.  Vial contents should not be frozen or shaken and should 
be protected from direct sunlight.  Within 2 hours following dose preparation 
(reconstitution), lampalizumab should be administered; the prepared dose may be 
maintained at room temperature prior to administration. 
For further details, see the Lampalizumab Investigator’s Brochure and/or Pharmacy 
Binder. 
4.3.1.2 
Sham 
Sham vial is empty and will remain empty throughout the sham treatment. It does not 
contain any lyophilized powder.  There is no reconstitution process for the sham vial.  
4.3.2 
Dosage, Administration, and Compliance 
4.3.2.1 
Lampalizumab and Sham 
Dosage 
Study treatment should not occur earlier than 22 days after the previous treatment. 
Guidelines for treatment interruption or discontinuation are provided in Section 4.6.2 and 
Section 4.4.3. 
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF. 
Lampalizumab Intravitreal Injections 
A 10-mg dose of lampalizumab will be used in this study and will be administered 
intravitreally to patients randomized to the lampalizumab Q4W or Q6W treatment arms 
during the 2-year treatment period (see Appendix 1 for the study flowcharts). 


 
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Sham Injections 
Patients randomized to the control arms will receive sham injections Q4W or Q6W 
during the 2-year treatment period and will undergo the same assessments as the 
lampalizumab treatment arm (see Appendix 1 for the study flowcharts). 
Sham injection is a procedure that mimics an intravitreal injection of lampalizumab, 
except that the blunt end of an empty syringe is pressed against an anesthetized eye 
instead of a needle attached to a lampalizumab-filled syringe. 
Administration 
See Appendix 4 for the pre-injection procedures of both treatments (lampalizumab and 
sham) for all patients, Appendix 5 for the injection procedures of the study drug, 
Appendix 6 for the injection procedures of the sham treatment procedure, and 
Appendix 7 for the post-injection procedures for all treated patients. 
Compliance 
This study will be conducted in accordance with the U.S. Food and Drug Administration 
(FDA) regulations; the International Conference on Harmonisation (ICH) E6 Guideline for 
Good Clinical Practice (GCP); and applicable local, state, and federal laws, as well as 
other applicable country laws. 
4.3.3 
Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for completion of this study 
(lampalizumab and sham) will be provided by the Sponsor.  The study site will 
acknowledge receipt of IMPs and confirm the shipment condition and content.  Any 
damaged shipments will be replaced. 
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site’s method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed.  
IMP destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log. 
4.3.4 
Post-Study Access to Lampalizumab 
The Sponsor will offer post-study access to the study drug lampalizumab free of charge 
to eligible patients in accordance with the Roche Global Policy on Continued Access to 
IMPs as outlined below. 


 
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A patient will be eligible to receive study drug after the end of the study if all of the 
following conditions are met: 
• 
The patient has a sight-threatening or severe medical condition and requires study 
drug treatment for his or her well-being 
• 
There are no appropriate alternative treatments available to the patient 
• 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
A patient will not be eligible to receive study drug after the end of the study if any of the 
following conditions are met: 
• 
The study drug is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or would not 
otherwise create a financial hardship for the patient) 
• 
The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for GA 
• 
The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for GA 
• 
Provision of study drug is not permitted under the laws and regulations of the 
patient's country 
The Roche Global Policy on Continued Access to IMPs is available at 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf. 
4.4 
CONCOMITANT THERAPY 
4.4.1 
Permitted Therapy 
Concomitant medications are any prescription drugs or over-the-counter preparations 
other than protocol-specified procedural medications (e.g., dilating drops or fluorescein 
dyes) and pre- and post-injection medications (e.g., proparacaine or antimicrobials 
[if applicable]) used by a patient within 7 days preceding Day 1 visit and through the 
conclusion of the patient’s study participation or early termination visit.  All concomitant 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF log except of Lucentis® for either eye treatment (if applicable), which 
will have a separate eCRF. 
Patients required to use medications that are prohibited (see Section 4.4.2) will not be 
eligible for the study.  Patients who use other maintenance therapies should continue 
their use.  Of note, the following are some common therapies that are permitted: 
• 
Onset of ocular hypertension or glaucoma in the study eye during a patient’s study 
participation should be treated as clinically indicated 
• 
Onset of cataract or posterior capsular opacification in either eye during the patient’s 
study participation may be treated as clinically indicated.  Dose-interruption criteria 
(see Section 4.4.3, Table 4) may apply with cataract surgery. 


 
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• 
Short-term use of topical corticosteroids after cataract surgery, YAG capsulotomy, 
or peripheral iridotomy 
• 
At the discretion of the evaluating physician, randomized patients who are receiving 
study treatment may be treated with Lucentis® if they are diagnosed in either eye 
with an ocular condition for which Lucentis is approved in the country.  Consult with 
the region specific Lucentis Prescribing Information for the recommended dose and 
frequency of treatment.   
NOTE: If (as per masked investigator judgment) treatment with Lucentis is to be 
given (to study and/or non-study eye) at the same visit as a study eye treatment with 
lampalizumab/sham, the treatment with Lucentis must be administered first.  
Following this, a safety assessment (including an IOP check) must be completed by 
the physician in the masked role prior to the study eye treatment with 
lampalizumab/sham.  If there are no concerns, the site may proceed with calling 
IxRS for the study treatment kit assignment.  Individual trays and sterile prep must 
be separately prepared for each treatment.  The injecting physician will perform the 
treatment with Lucentis to preserve the masking. 
• 
Oral corticosteroids at doses ≤10 mg/day prednisone or equivalent 
 


 
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4.4.2 
Prohibited Therapy 
At the discretion of the investigator, patients may continue to receive medications and 
standard treatments administered for other conditions.  However, the following 
medications/treatments are prohibited from use during the patient’s participation in the 
study treatment, and patients will be discontinued from study treatment and/or study to 
receive these therapies: 
• 
Systemic anti-vascular endothelial growth factor (anti-VEGF) agents 
• 
Intravitreal anti-VEGF agents (other than Lucentis) in either eye 
• 
Intravitreal, subtenon, or chronic topical (ocular) corticosteroids in study eye  
• 
Systemic or intravenous immunomodulatory therapy (e.g., azathioprine, 
methotrexate, mycophenolate mofetil, cyclosporine, cyclophosphamide, anti-tumor 
necrosis factors, eculizumab) 
• 
Treatment with Visudyne in study eye 
• 
Other experimental therapies (except those with vitamins and minerals) 
 
4.4.3 
Dose-Interruption and/or Treatment Discontinuation Criteria 
Study treatment interruption and patient discontinuation from the study treatment for 
adverse events will be determined using the criteria listed in Table 4.  If any of these 
criteria are met, treatment will be interrupted (or discontinued if applicable) and will not 
be resumed earlier than the next scheduled study visit.  The reason for study treatment 
interruption/discontinuation should be recorded on the appropriate eCRF and, if 
applicable, on the Adverse Event eCRF. 


 
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Table 4 
Dose-Interruption and Treatment Discontinuation Criteria 
Event 
Dose-Interruption Criteria 
Intraocular inflammation 
Interrupt study treatment if intraocular 
inflammation (iritis, iridocyclitis or vitritis) is ≥1+ 
in the study eye (see the grading scales of 
intraocular inflammation in Section 5.3.5 and 
Appendix 3).  Patients with ≥3+ intraocular 
inflammation will be discontinued from the study 
treatment. 
VA loss 
Interrupt study treatment if there is a 
treatment-related decrease in BCVA of 
≥30 letters in the study eye compared with the 
last assessment of BCVA prior to the most 
recent treatment.  Study treatment may be 
permitted subsequently as determined by the 
Sponsor and investigator. 
Elevated IOP 
Interrupt study treatment if IOP in the study eye 
is ≥30 mm Hg.  Treatment may be permitted 
when IOP has been lowered to <30 mm Hg, 
either spontaneously or by treatment, as 
determined by the investigator. 
Vitreous hemorrhage 
Interrupt study treatment in the event of a 
vitreous hemorrhage in the study eye.  Study 
treatment may be permitted subsequently as 
determined by the Sponsor and investigator. 
Rhegmatogenous retinal break 
Interrupt study treatment if a retinal break is 
present in the study eye.  Study treatment may 
be resumed no earlier than 30 days after 
successful laser retinopexy as determined by 
the investigator.  
Rhegmatogenous retinal detachment or 
macular hole 
Discontinue patients from study treatment for 
the duration of the study if rhegmatogenous 
retinal detachment or Stage 3 or 4 macular 
holes is observed. 
Active local or systemic infection  
Interrupt study treatment if any of the following 
are present:  infectious conjunctivitis, infectious 
keratitis, infectious scleritis, or endophthalmitis 
in either eye or if the patient is currently 
receiving treatment for an active local or 
systemic infection.  Patients with 
endophthalmitis in the study eye will be 
discontinued from the study treatment.  
BCVA = best corrected visual acuity; IOP = intraocular pressure; IV = intravenous; VA = visual 
acuity; YAG = yttrium aluminum garnet. 
 
 
 
 
 


 
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Table 4 
Dose-Interruption and Treatment Discontinuation Criteria (cont.) 
Event 
Dose-Interruption Criteria 
Cataract surgery in study eye 
Interrupt study treatment after cataract surgery 
in study eye.  Study treatment may be resumed 
no earlier than 30 days after an uncomplicated 
cataract surgery and no evidence of 
post-operational inflammation.  For cataract 
surgery with complications, study treatment 
may be permitted as determined by Sponsor 
and investigator.   
Oral corticosteroids (prednisone >10 mg/day or 
equivalent) 
Interrupt study treatment.  Study treatment may 
be resumed when oral corticosteroids dosing is 
prednisone ≤10 mg/day or equivalent. 
IV corticosteroids 
Interrupt study treatment.  Study treatment may 
be resumed when the patient has finished IV 
corticosteroid course and oral corticosteroid 
dosing is prednisone ≤10 mg/day or equivalent. 
BCVA = best corrected visual acuity; IOP = intraocular pressure; IV = intravenous; VA = visual 
acuity; YAG = yttrium aluminum garnet. 
 
If a patient misses more than 2 doses of study treatment within any 24-week treatment 
period, the investigator and the Sponsor may consider discontinuing the patient from the 
study treatment. 
4.5 
STUDY ASSESSMENTS 
See Appendix 1 for the schedule of assessments performed during the study. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening or re-screening tests or evaluations.  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site. 
All screening evaluations and evaluations at Day 1 must be completed and reviewed to 
confirm that patients meet all eligibility criteria before randomization.  The investigator 
will maintain a screening log to record details of all patients screened and to confirm 
eligibility or record reasons for screening failure, as applicable. 
4.5.2 
Medical History and Demographic Data 
Medical history includes clinically significant diseases, including chronic and ongoing 
conditions (e.g., trauma, cancer, cardiovascular, and ophthalmic history); tobacco use; 
surgeries; cancer history; reproductive status; previous ECGs (if available within the 
previous 12 months from patients who are not part of selected sites serial ECG 
collection); and all medications (e.g., prescription drugs, over-the-counter drugs, herbal 


 
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or homeopathic remedies, nutritional supplements) used by the patient within 7 days 
prior to Day 1 visit. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.3 
Physical Examinations 
A targeted physical examination should include an evaluation of the head, eyes, ears, 
nose, throat, and cranial nerves.  A patient’s height and weight will be collected as well.  
If any abnormalities are noted during the study, the patient may be referred to another 
doctor. 
Changes from baseline abnormalities should be recorded in patient notes.  New or 
worsened clinically significant abnormalities should be recorded as adverse events on 
the Adverse Event eCRF. 
4.5.4 
Vital Signs 
Vital signs will include measurements of temperature, respiratory rate, heart rate, and 
systolic and diastolic blood pressures; taken with the patient in a seated position after 
resting for 5 minutes. 
4.5.5 
Other Disease-Specific Assessments 
Patient-Reported Outcomes 
The PRO measures (NEI VFQ-25 and FRI Index; see Appendix 16 and Appendix 17, 
respectively) will be administered by the masked site staff (except for the VA examiner) 
prior to any other visit assessments being performed.   
Ocular Assessments 
• 
BCVA assessed on ETDRS chart at a starting distance of 4 m (perform prior to 
dilating eyes; see Appendix 8) 
• 
BCVA assessed by ETDRS chart at a starting distance of 4 m (perform prior to 
dilating eyes; see Appendix 9) under low luminance conditions 
• 
MNRead charts (see Appendix 18 for details on specific countries where test will be 
administered) or Radner Reading Charts (see Appendix 19 for details on specific 
countries where test will be administered; perform prior to dilating eyes).  The test 
will be administered first monocularly (right/left eye) and then binocularly (both eyes). 
• 
IOP measurement of both eyes (perform prior to dilating eyes; the method of IOP 
measurement used for a patient must remain consistent throughout the study) 
• 
Slit-lamp examination (for grading scales for anterior and vitreous cells, see 
Appendix 3) 
• 
Dilated binocular indirect high-magnification ophthalmoscopy 
• 
Finger-counting test followed by hand motion and light perception tests (when 
necessary) performed within 15 minutes post-injection for the study eye only by the 
treating physician who has unmasked role 


 
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• 
At study treatment visits, post-injection IOP measurement in the study eye only 
between 30 and 50 minutes after study treatment (drug or sham) by qualified 
masked site staff (except for the VA examiner).  If the IOP is increased by ≥10 mm 
from pre-injection, the IOP will be measured again at 60−80 minutes post-injection.  
If there are no safety concerns, the patient will be permitted to leave the clinic.  If the 
IOP value is of concern to the investigator, the patient will remain in the clinic and 
will be managed in accordance with the investigator’s clinical judgment.  Both, the 
last post-injection IOP measured prior to any intervention for increased IOP (if 
applicable) and the last post intervention IOP (if applicable) will be recorded on the 
post-treatment IOP eCRF. 
Note: if the study eye is treated with a Lucentis injection during the same visit 
as the study treatment (lampalizumab/sham), the treatment with Lucentis has to 
be performed first. Please measure and record the post-Lucentis treatment IOP 
value on the appropriate eCRF. 
The method of IOP measurement used for a patient must remain consistent 
throughout the study. 
 
Ocular Imaging and Microperimetry 
The central reading center will provide sites with the Central Reading Center manual and 
training materials for specified study ocular images and microperimetry (at selected 
sites).  Before any study images and microperimetry are obtained, site personnel, test 
images, and systems and software (where applicable) will be certified/validated by the 
reading center as specified in the Central Reading Center manual.  All ocular images 
and microperimetry results will be obtained by trained site personnel at the study sites 
and forwarded to the central reading center for independent analysis and/or storage (see 
Appendix 10, Appendix 11, Appendix 12, Appendix 13, Appendix 14, and Appendix 15). 
Note: after randomization, if a patient misses a study visit during which ocular 
images were scheduled to be taken (see Appendix 1), the images should be 
obtained at the next scheduled visit.  
 
Ocular images, keratometry, and microperimetry obtained include the following: 
• 
Stereoscopic, CFP of both eyes 
• 
FAs of both eyes (performed after laboratory samples are obtained) 
• 
FAF (with keratometry measurements), near infrared (NI), and spectral domain 
optical coherence tomography (SD-OCT) images of both eyes 
• 
Mesopic Microperimetry (at selected sites) of selected study eye only; to account for 
testing learning curve, patient is allowed up to 3 attempts to meet screening criteria 
Note: if the Investigator determines that both eyes of a patient meet the 
eligibility criteria for study eye, mesopic microperimetry will be performed on 
both eyes at screening. 
 
Additional details on obtaining these images, keratometry, and microperimetry are 
included in the Central Reading Center Manual. 


 
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4.5.6 
Laboratory Biological Samples Collection 
At the scheduled visit, specimens should be collected prior to study eye treatment and 
FA assessments (if applicable).  Fasting is not required prior to specimen collection.  
The specimens will be forwarded to the central laboratory.  The central laboratory will 
either perform the analysis or forward samples to Sponsor or its designee for analysis 
and/or storage.  The CFI profile biomarker whole blood samples (will be tested on the 
investigational cobas® CFI Profile Assay) and buccal swab will be forwarded from the 
sites directly to the Sponsor designated central laboratory testing site for testing and/or 
storage.  Instructions for obtaining, processing, storing, and shipping of all specimens 
are provided in the Laboratory Manual.  Laboratory supply kits will be provided to the 
sites by the central laboratory.  See Appendix 1 for sample collection timepoints and 
Appendix 20 for biological sample collection and shipping instructions.  Except as noted 
(see Appendix 1), all samples collected during screening from patients who are not 
randomized will be discarded. 
The following assessments will be performed: 
• 
Hematology:  hemoglobin, hematocrit, quantitative platelet count, red blood cell 
counts, white blood cell counts, and differentials, including neutrophils, bands, 
lymphocytes, basophils, eosinophils, and monocytes (absolute) 
• 
Serum chemistry:  sodium, potassium, chloride, bicarbonate, glucose, blood urea 
nitrogen, creatinine, calcium, phosphorus, total and direct bilirubin, total protein, 
albumin, aspartate aminotransferase, alanine aminotransferase, lactate 
dehydrogenase, alkaline phosphatase, and uric acid 
• 
Urinalysis:  specific gravity, pH, blood, protein, ketones, glucose, bilirubin, 
urobilinogen, and microscopic examination (if any of the preceding urinalysis tests, 
other that glucose and ketones, are abnormal) 
• 
Coagulation:  activated partial thromboplastin time and prothrombin time 
• 
Initial serum pregnancy test (β-human chorionic gonadotropin) for women of 
childbearing potential, including those who have had tubal ligation.  If positive, study 
treatment will not be administered. 
• 
Urine pregnancy test prior to each study treatment for women of childbearing 
potential, including those who have had tubal ligation.  If positive, perform the serum 
pregnancy test.  If the serum pregnancy test is positive, do not administer the study 
treatment.  
• 
Alternative Complement pathway assessment assay (AH50) 
• 
Serum samples for measurement of anti-lampalizumab antibodies 
• 
Serum samples to measure lampalizumab concentration 
• 
Optional anterior chamber (aqueous humor) paracentesis samples to measure 
lampalizumab and CFD levels for assessment of PK and PD relationships 
CFI profile biomarker whole blood sample for determination of CFI profile to stratify 
patients at randomization and to support further development of the investigational 


 
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cobas® CFI Profile assay (see Section 3.3.2.2).  The sample will be retained for 
screen-failed patients as well. 
• 
CFI biomarker buccal swab to support further development of the CFI profile assay.  
The sample will be retained for the screen-failed patients as well. 
• 
Biomarker plasma sample for determination of levels of CFI and 
complement-pathway proteins 
• 
Biomarker paxgene tube sample for determination of complement pathway mRNA 
expression levels 
• 
Biomarker whole blood sample for clinical genotyping of CFI and other complement 
pathway genes 
 
These samples (except for hematology, serum chemistry, urinalysis, coagulation, and 
serum and urine pregnancy tests that will be destroyed after their analysis during the 
study) will be stored for up to 5 years after the date of final closure of the associated 
clinical database. 
In addition, remainders of serum PK, serum anti-therapeutic antibodies (ATAs), 
biomarker plasma, biomarker paxgene sample, biomarker whole blood clinical 
genotyping sample, and aqueous humor samples will be stored for up to 15 years after 
the date of the final closure of the associated clinical database if the patient gave 
specific Roche Clinical Repository (RCR) consent for the remainders of the samples to 
be stored for the optional research. 
Data arising from clinical genotyping will be subject to the confidentiality standards 
described in Section 8.4. 
Drug concentration will be determined in serum using an ELISA method.  ATAs will be 
detected in serum using a bridging ELISA. 
4.5.7 
Serial Electrocardiogram Evaluation (Selected Sites) 
Serial electrocardiogram evaluations will be conducted at selected U.S. sites 
participating in this study.  The evaluations will be performed to characterize and 
compare common clinical ECG parameters in patients treated with lampalizumab and 
those receiving sham interventions for GA secondary to AMD.  These evaluations will 
utilize study-supplied ECG devices to collect digital patient ECGs at Day 1 (prior to first 
study treatment), Day 8, Week 4 (for Q4W arms) or Week 6 (for QW6 arms), Week 24, 
and Early Termination visits (collect only if early termination occurs prior to Week 24 
visit) in approximately 100 patients.  All ECGs will undergo central interpretation by 
qualified cardiologists.  The details of the evaluations are in the ECG manual and also 
detailed in Appendix 21. 


 
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Optional Historical ECG 
Study patients who are not part of the serial ECG evaluation will provide (if available) 
historical results from a clinical 12-lead ECG performed within the 12 months preceding 
Day 1 study treatment.  The results should be stored in a patient source document.  If 
no baseline ECG is available, sites are not required to obtain a Screening/Day 1 ECG.  
4.5.8 
Patient-Reported Outcomes 
PRO (i.e., NEI VFQ-25 and FRI Index) data will be collected via interviewer-administered 
questionnaires to help characterize the clinical profile of lampalizumab from the patient 
perspective. 
The questionnaires will be translated as required to different languages.  The 
questionnaires will be administered by the masked site staff (except for the VA examiner) 
prior to any other study visit assessments being performed on that day.  
The National Eye Institute Visual Functioning Questionnaire 25-Item 
Version 
The NEI VFQ-25 is a 25-item, interviewer-administered assessment of visual functioning 
(see Appendix 16).  The appendix items for the near and distance domains will also be 
included (three additional items for each domain).  It is scored on a scale of 0−100, with 
higher scores indicating better visual function.  It has a composite score and 12 domains 
(general health, general vision, ocular pain, near activities, distance activities, social 
functioning, mental health, role difficulties, dependency, driving, color vision, and 
peripheral vision).  It does not have a specified recall period. 
The Functional Reading Independence Index 
The FRI Index is a 7-item, interviewer-administered assessment of functional reading 
independence (see Appendix 17).  It has one total index score.  The index score is an 
ordinal scale with higher levels representing higher functional reading independence.  
The FRI Index has a specified recall period of 7 days. 
4.5.9 
Samples for Roche Clinical Repository 
4.5.9.1 
Overview of the Roche Clinical Repository 
The RCR is a centrally administered group of facilities used for the long-term storage of 
human biologic specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides).  The collection and analysis of RCR specimens will 
facilitate the rational design of new pharmaceutical agents and the development of 
diagnostic tests, which may allow for individualized drug therapy for patients in the future. 
Specimens for the RCR will be collected from patients who give specific consent to 
participate in this optional research.  RCR specimens will be used to achieve the 
following objectives: 
• 
To study the association of biomarkers with efficacy, adverse events, or disease 
progression 


 
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• 
To discover genetic changes and study variants within the genome that underlie 
disease through use of whole genome sequencing 
• 
To increase knowledge and understanding of disease biology 
• 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
• 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.9.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection and submission of biological samples to the RCR is contingent upon the 
review and approval of the exploratory research and the RCR portion of the Informed 
Consent Form by each site’s IRB or EC and, if applicable, an appropriate regulatory 
body.  If a site has not been granted approval for RCR sampling, this section of the 
protocol (Section 4.5.9) will not be applicable at that site. 
4.5.9.3 
Sample Collection 
The following samples will be collected for research purposes, including but not limited 
to research on dynamic (non-inherited) biomarkers related AMD and related diseases, 
lampalizumab, and signaling pathways related to AMD and the complement pathway: 
• 
Residual aqueous humor sample 
• 
Residual biomarker plasma sample 
• 
Residual serum PK sample 
• 
Residual serum ATA sample 
• 
Residual biomarker paxgene sample 
• 
Residual biomarker whole blood clinical genotyping sample 
 
For all samples, dates of consent and specimen collection should be recorded on the 
associated RCR page of the eCRF.  For sampling procedures, storage conditions, and 
shipment instructions, see the Laboratory Manual. 
RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
The non-genetic RCR biomarker specimens will be subject to the confidentiality 
standards described in Section 8.4.  The genetic biomarker specimens (residual whole 
blood clinical genotyping sample) will undergo additional processes to ensure 
confidentiality as described below. 


 
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4.5.9.4 
Confidentiality for RCR Genetic Specimens 
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR genetic specimens and associated data.  Upon 
receipt by the RCR, each genetic specimen is “double-coded” by replacing the patient 
identification number with a new independent number.  Data generated from the use of 
these specimens and all clinical data transferred from the clinical database and 
considered relevant are also labeled with this same independent number.  A “linking key” 
between the patient identification number and this new independent number is stored in 
a secure database system.  Access to the linking key is restricted to authorized 
individuals and is monitored by an audit trail.  Legitimate operational reasons for 
accessing the linking key are documented in a standard operating procedure.  Access to 
the linking key for any other reason requires written approval from the Pharma 
Repository Governance Committee and Roche’s Legal Department, as applicable. 
Data generated from RCR genetic specimens must be available for inspection upon 
request by representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate. 
Patient medical information associated with RCR specimens is confidential and may only 
be disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to the patients or to study investigators unless a request for research use is 
granted or required by law.  The aggregate results of any research conducted using 
RCR specimens will be available in accordance with the effective Roche policy on study 
data publication. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise. 
4.5.9.5 
Consent to Participate in the Roche Clinical Repository 
The Informed Consent Form will contain a separate section or separate Informed 
Consent Form that addresses participation in the RCR.  The investigator or authorized 
designee will explain to each patient the objectives, methods, and potential hazards of 
participation in the RCR.  Patients will be told that they are free to refuse to participate 
and may withdraw their specimens at any time and for any reason during the storage 
period.  A separate, specific signature will be required to document a patient’s 
agreement to provide optional RCR specimens.  Patients who decline to participate will 
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The investigator should document whether the patient has given consent to participate 
by completing the RCR Research Sample Informed Consent eCRF. 
In the event of an RCR participant’s death or loss of competence, the participant’s 
specimens and data will continue to be used as part of the RCR research. 
4.5.9.6 
Withdrawal from the Roche Clinical Repository 
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient’s wishes using the RCR Patient Withdrawal Form and, if 
the study is ongoing, must enter the date of withdrawal on the RCR Research Sample 
Withdrawal of Informed Consent eCRF.  The patient will be provided with instructions on 
how to withdraw consent after the study is closed.  A patient’s withdrawal from 
Study GX29185 does not, by itself, constitute withdrawal of specimens from the RCR.  
Likewise, a patient’s withdrawal from the RCR does not constitute withdrawal from 
Study GX29185. 
4.5.9.7 
Monitoring and Oversight 
RCR specimens will be tracked in a manner consistent with GCP by a quality-controlled, 
auditable, and appropriately validated laboratory information management system to 
ensure compliance with data confidentiality as well as adherence to authorized use of 
specimens as specified in this protocol and in the Informed Consent Form.  Roche 
monitors and auditors will have direct access to appropriate parts of records relating to 
patient participation in the RCR for the purposes of verifying the data provided to Roche.  
The site will permit monitoring, audits, IRB/EC review, and health authority inspections 
by providing direct access to source data and documents related to the RCR samples. 
4.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
Patients withdrawn from the study prior to completion will be asked to return for an early 
termination evaluation after a minimum of 30 days lapsed following their last study 
treatment for monitoring of adverse events and assessments listed for the early 
termination visit (see Appendix 1).  The reason for the study discontinuation should be 
recorded on the appropriate eCRF.  Discontinued patients will not be replaced or 
allowed to re-enter the study. 
4.6.1 
Patient Discontinuation 
Patients have the right to voluntarily discontinue from the study at any time for any 
reason.  In addition, the investigator has the right to discontinue a patient from the study 
at any time.  Reasons for discontinuation from the study may include but are not limited 
to the following: 
• 
Patient withdrawal of consent at any time 


 
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• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
 
Every effort should be made to obtain information on patients who are discontinued from 
the study.  The primary reason for discontinuation from the study should be documented 
on the appropriate eCRF.   
If a patient discontinued the study but has not withdrawn the informed consent, the site 
should make every effort to continue to follow up on serious adverse events, deaths, and 
adverse events of special interest (AESIs) in these patients.  In order to avoid loss-to-
follow-up, the Investigator should ask the patient at the study start for the contact details 
of a relative or friend who can be contacted in case the patient cannot be reached.  
However, patients will not be followed for any reason after consent has been withdrawn.  
Patients who discontinue from the study will not be replaced. 
4.6.2 
Study Treatment Discontinuation 
The investigator has the right to discontinue a patient from the study treatment for any 
medical condition that the investigator determines may jeopardize the patient’s safety if 
he or she continues in the study treatment, for reasons of non-compliance (e.g., missed 
doses, visits), if the patient becomes pregnant, or if the investigator determines it is in 
the best interest of the patient.  The reason for the treatment discontinuation should be 
recorded on the appropriate eCRF. 
Treatment discontinued patients will not be replaced or allowed to re-start the study 
treatment.  However, they should be strongly encouraged to stay in the study and 
undergo as many scheduled visits as possible with emphasis on the Weeks 48 and 96 
visits. 
4.6.3 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include but are not limited to the following: 
• 
Incidence or severity of adverse events in this or other studies indicates a potential 
health hazard to patients. 
• 
Patient enrollment is unsatisfactory. 
• 
Data recording is inaccurate or incomplete. 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study. 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include but are not limited to the following: 
• 
Excessively slow recruitment 
• 
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• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the ICH guideline for GCP 
• 
No study activity (i.e., all patients have completed and all obligations have been 
fulfilled) 
 
5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PLAN 
Lampalizumab is not an approved drug and is currently in clinical development.  Thus, 
the full safety profile is not completely known at this time.  The safety plan for this study 
is designed to help minimize patient risk and will include specific eligibility criteria and 
monitoring assessments as detailed below. 
Potential ocular safety issues currently thought to be associated with the route of 
administration or pharmacology of lampalizumab include decreased BCVA, conjunctival 
hemorrhage, ocular inflammation (see Section 5.3.5 and Appendix 3 for anterior 
chamber and vitreous inflammation grading scales), intraocular infection 
(endophthalmitis), transient and/or sustained elevation of IOP, transient vision loss, 
cataract development or progression, retinal or vitreous hemorrhage, and retinal break 
or detachment.  The occurrence of all AEs (serious and non-serious) and pregnancies 
will be recorded for the duration of this study. 
Systemic levels of lampalizumab following multiple intravitreal administrations are 
anticipated to be low.  Systemic side effects of lampalizumab are not anticipated based 
on nonclinical data and clinical studies conducted to date, but are possible.  As part of 
the safety plan, masked aggregate AE reports will be reviewed periodically to assess for 
potential systemic safety effects such as cardiovascular events, neoplasms, or alteration 
in immune function (e.g., reports of infections to encapsulated bacteria such as 
Neisseria meningitidis, Streptococcus pneumonia, and Haemophilus influenza). 
The incidence and characteristics of AEs, SAEs, and laboratory abnormalities will be 
assessed as described within this protocol.  An iDMC will be established to monitor 
patient safety and study conduct on an ongoing basis (see Section 3.1.2).  The iDMC will 
conduct periodic reviews (approximately every 6 months but the frequency is adjustable 
as required) of unmasked ocular and systemic (non-ocular) safety events with an 
emphasis on the evaluation of the rates of ocular inflammation, increased IOP, 
endophthalmitis, and clinically significant decreases in BCVA, which will be prepared for 
them by an iDCC. 
After the first study treatment on Day 1, all patients will return for a safety assessment 
visit on Day 8 (± 2 days).  For subsequent injections, patients will be contacted by study 
site personnel 4 (± 2) days after each injection to elicit reports of any decrease in vision, 
eye pain, unusual redness, or any other new ocular symptoms in the study eye.  At the 
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antimicrobials, the patients will also be asked whether they have taken the prescribed, 
self-administered, pre- and post-injection antimicrobials.  Patients will be instructed to 
contact the investigator at any time if they have any health-related concerns.  
If warranted, patients will be asked to return to the clinic as soon as possible for an 
unscheduled safety assessment visit (see Appendix 2). 
A finger-counting test will be conducted for each patient within 15 minutes following 
study treatment by the treating physician; hand motion and light perception tests will be 
performed when necessary.  Following the study treatment, IOP will be measured 
between 30 and 50 minutes after study treatment for the study eye only by masked 
(except for the VA examiner) site staff; if the IOP is increased by ≥10 mm Hg from 
pre-injection IOP will be measured again at 60−80 minutes post-injection.  If there are no 
safety concerns, the patient will be permitted to leave the clinic.  If the IOP value is of 
concern to the investigator, the patient will remain in the clinic and will be managed in 
accordance with the investigator’s clinical judgment.  Both the last post-injection IOP 
measured prior to any intervention for increased IOP (if applicable) and the last post 
intervention IOP value (if applicable) will be recorded on the appropriate eCRF.  
If applicable, an Adverse Event eCRF page will also be completed. 
Note: if the study eye treatment with Lucentis injection is performed at the same visit 
as the study treatment (lampalizumab/sham), the treatment with Lucentis has to be 
performed first. Please measure and record the post-Lucentis treatment IOP value 
on the eCRF irrespective of the study treatment administration later.  
 
Detailed ocular examinations, including indirect ophthalmoscopy and slit-lamp 
examination, will be performed throughout the study. Blood samples for serum study 
drug concentrations, AH50 assays, and antibodies to lampalizumab and other biomarker 
samples (see Appendix 1) will be obtained from all patients at selected timepoints.  The 
optional aqueous humor samples will be obtained from the patients who consent to this 
procedure and sample collection. 
Patients discontinued from the study prior to completion (Week 96) will be asked to 
return for early termination visit assessments if a minimum of 30 days have elapsed 
following the last study treatment visit (see Appendix 1).  The visit will include 
assessment of all AEs (serious and non-serious; ocular and non-ocular).  SAEs will be 
reported in compliance with GCP guidelines. 
Treatment interruption and/or treatment discontinuation for AEs will be determined using 
the criteria in Table 4. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording AEs, including SAEs and 
non-serious AEs of special interest (AESIs); and other protocol-specified tests that are 
deemed critical to the safety evaluation of the study. 


 
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Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for GCP, an AE is any untoward medical occurrence in a 
clinical investigation subject administered a pharmaceutical product, regardless of 
causal attribution.  An AE can therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.9 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• 
AEs that are related to a protocol-mandated intervention, including those that occur 
prior to assignment of study treatment (e.g., screening invasive procedures such as 
biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
An SAE is any AE that meets any of the following criteria: 
• 
Fatal (i.e., the AE actually causes or leads to death) 
• 
Life threatening (i.e., the AE, in the view of the investigator, places the patient at 
immediate risk of death) 
This does not include any AE that, had it occurred in a more severe form or was 
allowed to continue, might have caused death. 
• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.10) 
• 
Results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions) 
• 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
Significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of 
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be of relatively minor medical significance (such as severe headache without any further 
findings). 
Severity and seriousness need to be independently assessed for each AE recorded on 
the eCRF. 
SAEs are required to be reported by the investigator to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2 for reporting 
instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Non-serious or serious AESIs are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  AESIs for this study include the following: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law (see Section 5.3.5.6) 
• 
Suspected transmission of an infectious agent by the study drug, as defined below 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings indicating an infection 
in a patient exposed to a medicinal product.  This term only applies when a 
contamination of the study drug is suspected. 
• 
AEs resulting from medication error 
Examples of medication errors include but are not limited to overdose, incorrect 
dose, incorrect route, incorrect drug, incorrect administration, or incorrect kit. 
If the medication error did result in an AE, the primary event term should reflect 
the AE that occurred as a result of the medication error and identify it in 
“other suspected causes of SAE/AE” data field as a medication error. 
• 
Sight-threatening AEs 
An AE is considered to be sight threatening and should be reported expeditiously if 
it meets one or more of the following criteria: 
o It causes a decrease of ≥ 30 letters in VA score (compared with the last 
assessment of VA prior to the most recent assessment) lasting more than 
1 hour 
o It requires surgical intervention (i.e., conventional surgery, vitreous tap, or 
biopsy with intravitreal injection of anti-infectives, or laser or retinal 
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o It is associated with severe intraocular inflammation (i.e., endophthalmitis, 
4 + anterior chamber cell/flare or 4 + vitritis; see Section 5.3.5 
and Appendix 3 for intraocular inflammation grading scales) 
o In the opinion of the investigator, it may require medical intervention to 
prevent permanent loss of sight 
All above listed sight-threatening AEs should be reported as serious events, listing the 
underlying cause (if known) of the event as primary event term. 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all AEs (see Section 5.2.1 for definition) 
are recorded on the Adverse Event eCRF and reported to the Sponsor in accordance 
with instructions provided in this section and in Sections 5.4−5.6. 
For each AE recorded on the Adverse Event eCRF, the investigator will make an 
assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4). 
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on AEs at each patient contact.  All AEs, whether 
reported by the patient or noted by study personnel, will be recorded in the patient’s 
medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
SAEs caused by a protocol-mandated intervention (e.g., invasive procedures such as 
biopsies, discontinuation of medications) should be reported (see Section 5.4.2 for 
instructions for reporting SAEs). 
After initiation of study drug, all AEs will be reported until the last study visit.  After this 
period, the investigator should report any serious adverse events that are believed to be 
related to study treatment. (see Section 5.6). 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting AE 
information at all patient evaluation timepoints.  Examples of non-directive questions 
include the following: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last here?” 
 
5.3.3 
Assessment of Severity of Adverse Events 
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Table 5 
Adverse Event Severity Grading Scale 
Severity 
Description 
Mild 
Discomfort noticed, but no disruption of normal daily activity 
Moderate 
Discomfort sufficient to reduce or affect normal daily activity 
Severe 
Incapacitating with inability to work or to perform normal daily activity 
Note:  Regardless of severity, some events may also meet seriousness criteria.  Refer to 
definition of a serious adverse event (see Section 5.2.2). 
 
5.3.4 
Assessment of Causality of Adverse Events 
The masked, evaluating investigators should use their knowledge of the patient, the 
circumstances surrounding the event, and an evaluation of any potential alternative 
causes to determine whether an AE is considered to be related to the study drug, 
indicating “yes” or “no” accordingly.  The following guidance should be taken into 
consideration (see Table 6): 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 
Table 6 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the adverse 
event abates or resolves upon discontinuation of the study drug and, if applicable, 
reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified 
below.   
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
AE = adverse event; SAE = serious adverse event. 
 


 
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5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording AEs on 
the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one AE term should be recorded in the event field on the Adverse Event eCRF. 
For the purposes of reporting events of infection and inflammation, the following terms 
and definitions should be used: 
• 
Iritis:  the presence of inflammatory cells in the anterior chamber 
The presence of aqueous flare alone will not constitute iritis but should be 
documented as an anterior chamber flare for AE reporting purposes. 
• 
Iridocyclitis:  the presence of inflammatory cells in both the aqueous and vitreous 
• 
Vitritis:  the presence of active inflammation in the vitreous, demonstrated by the 
presence of inflammatory cells (trace or greater) 
• 
Active inflammation in the vitreous should be clinically differentiated from cellular 
debris from prior episodes of inflammation, hemorrhage, or other causes. 
• 
Endophthalmitis:  diffuse intraocular inflammation predominantly involving the 
vitreous cavity but also involving the anterior chamber, implying a suspected 
underlying infectious cause.  A culture is required prior to initiating antibiotic 
treatment for presumed endophthalmitis.  Results of bacterial or fungal cultures, 
treatment given, and final ophthalmologic outcome should also be provided in the 
details section of the event eCRF. 
 
Note:  Trace benign, aqueous pigmented cells visible on slit-lamp examination that are 
caused by dilation and are not RBCs or WBCs or the result of any ocular disorder should 
not be recorded as an AE. 
5.3.5.1 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported AEs based on 
signs and symptoms should be nullified and replaced by one AE report based on the 
single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis. 
5.3.5.2 
Adverse Events That Are Secondary to Other Events 
In general, AEs occurring secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause, with the exception of severe or 
serious secondary events.  However, medically significant AEs occurring secondary to 


 
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an initiating event that are separated in time should be recorded as independent events 
on the Adverse Event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
• 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All AEs should be recorded separately on the Adverse Event eCRF if it is unclear as to 
whether the events are associated. 
5.3.5.3 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient 
evaluation timepoints.  The initial severity (intensity) of the event will be recorded at the 
time the event is first reported.  If a persistent AE becomes more severe, the most 
extreme intensity should also be recorded on the Adverse Event eCRF.  If the event 
becomes serious, it should be reported to the Sponsor immediately (i.e., no more than 
24 hours after learning that the event became serious; see Section 5.4.2 for reporting 
instructions).  The Adverse Event eCRF should be updated by changing the event from 
“non-serious” to “serious,” providing the date that the event became serious, and 
completing all data fields related to SAEs. 
A recurrent AE is one that resolves between patient evaluation timepoints and 
subsequently recurs.  Each recurrence of an AE should be recorded as a separate event 
on the Adverse Event eCRF. 
5.3.5.4 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an AE.  A laboratory test result must be 
reported as an AE if it meets any of the following criteria: 
• 
Accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Clinically significant in the investigator’s judgment 
 


 
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It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an AE. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 × upper limit of normal [ULN] associated with 
cholestasis), only the diagnosis (i.e., cholestasis) should be recorded on the Adverse 
Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., “elevated 
potassium,” as opposed to “abnormal potassium”).  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the AE.  For example, an elevated serum potassium level of 7.0 mEq/L 
should be recorded as “hyperkalemia.” 
Observations of the same clinically significant laboratory abnormality from visit to visit, if 
applicable, should not be repeatedly recorded on the Adverse Event eCRF, unless the 
etiology changes.  The initial severity of the event should be recorded, and the severity 
or seriousness should be updated any time the event worsens. 
5.3.5.5 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an AE.  A vital sign result must be reported 
as an AE if it meets any of the following criteria: 
• 
Accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Clinically significant in the investigator’s judgment 
 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an AE. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit, if 
applicable, should not be repeatedly recorded on the Adverse Event eCRF, unless the 
etiology changes.  The initial severity of the event should be recorded, and the severity 
or seriousness should be updated any time the event worsens. 


 
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5.3.5.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × ULN) in combination with either an elevated 
total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy’s Law).  Therefore, investigators must report as an AE the occurrence of 
either of the following: 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with total bilirubin 
> 2 × ULN 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as an SAE or as a non-serious AESI (see Section 5.4.2). 
5.3.5.7 
Deaths 
All deaths that occur during the protocol-specified AE reporting period 
(see Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2). 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  The term “sudden death” should only be used for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a patient with or 
without preexisting heart disease, within 1 hour of the onset of acute symptoms or, in the 
case of an unwitnessed death, within 24 hours after the patient was last seen alive and 
stable.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, “unexplained death” should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), “unexplained death” should 
be replaced by the established cause of death. 
5.3.5.8 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an AE only if the frequency, 
severity, or character of the condition worsens during the study.  When recording such 
events on the Adverse Event eCRF, it is important to convey the concept that the 
preexisting condition has changed by including applicable descriptors (e.g., worsening, 
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5.3.5.9 
Worsening of Geographic Atrophy in Study Eye 
Medical occurrences or symptoms of deterioration that are anticipated as part of the 
normal progression of GA of the study eye should be recorded as an AE only if judged 
by the investigator to have unexpectedly worsened in severity or frequency or changed 
in nature at any time during the study.  When recording an unanticipated worsening of 
study eye GA on the Adverse Event eCRF, it is important to convey the concept that the 
condition has changed by including applicable descriptors (e.g., “accelerated GA”).  The 
expedited reporting requirements for sight threatening events (listed in the Section 5.2.3) 
apply to these unexpected changes in the study eye GA.   
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as AEs. 
5.3.5.10 
Hospitalization or Prolonged Hospitalization or Surgery 
Any AE that results in hospitalization (i.e., in-patient admission to a hospital) or 
prolonged hospitalization should be documented and reported as a SAE (per the 
definition of SAE in Section 5.2.2), except as outlined below. 
• 
Hospitalization for a preexisting condition, provided that the following criteria are 
met: 
– 
The hospitalization was planned prior to the study or was scheduled 
during the study when elective surgery became necessary because of the 
expected normal progression of the disease. 
– 
The patient has not experienced an adverse event. 
 
5.3.5.11 
Adverse Events Associated with an Overdose 
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an AE, but it may result in an AE.  All AEs associated with an overdose or incorrect 
administration of study drug should be recorded on the Adverse Event eCRF as an AESI 
(see Section 5.2.3) and should be reported to the Sponsor immediately (i.e., no more 
than 24 hours after learning of the event; see Section 5.4.2). 
No safety data related to overdosing of lampalizumab are available. 
5.3.5.12 
Patient-Reported Outcome Data 
AE reports will not be derived from PRO data by the Sponsor, and safety analyses will 
not be performed using PRO data.  However, if any PRO responses suggestive of a 
possible AE are identified during site review of the PRO data, the investigator will 
determine whether the criteria for an AE have been met and, if so, will report the event 
on the Adverse Event eCRF. 


 
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5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical study.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
• 
SAEs 
• 
Non-serious AESIs 
• 
Pregnancies 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting SAEs to the local 
health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
Medical Monitor Contact Information for Western Hemisphere 
Medical Monitor: 
, M.D., Ph.D. (
) 
Mobile Telephone No.: 
 
  
or  
Medical Monitor: 
, M.D. 
Mobile Telephone No.: 
  
 
Medical Monitor Contact Information for Eastern Hemisphere 
Medical Monitor: 
, M.D. 
Telephone No.: 
 
Mobile Telephone No.: 
 
or 
Medical Monitor: 
, MBChB, MFPM, MRCOphth 
Mobile Telephone No.: 
 
 
 


 
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To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Monitor, and track all calls.  The Emergency Medical Call Center Help Desk will be 
available 24 hours per day, 7 days per week.  Toll-free numbers for the Help Desk and 
Medical Monitor contact information will be distributed to all investigators (see “Protocol 
Administrative and Contact Information and List of Investigators”). 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only SAEs 
caused by a protocol-mandated intervention should be reported.  A Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the event), either by faxing or scanning and 
emailing the form using the fax number or email address provided to investigators 
(“Protocol Administrative and Contact Information and List of Investigators”). 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, SAEs and non-serious AESIs will be reported until the last 
study visit.  Investigators should record all case details that can be gathered immediately 
(i.e., within 24 hours after learning of the event) on the Adverse Event eCRF and submit 
the report via the electronic data capture (EDC) system.  A report will be generated and 
sent to Roche Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators (“Protocol Administrative and 
Contact Information and List of Investigators”).  Once the EDC system is available, all 
information will need to be entered and submitted via the EDC system. 
Instructions for reporting post-study AEs are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or until the last study visit.  A 
Clinical Trial Pregnancy Reporting Form should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy, either by faxing or by scanning and emailing the form using the fax number 
or email address provided to investigators.  Pregnancy should not be recorded on the 


 
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Adverse Event eCRF.  The investigator should discontinue study drug and counsel the 
patient, discussing the risks of the pregnancy and the possible effects on the fetus.  
Monitoring of the patient should continue until conclusion of the pregnancy.  Any SAEs 
associated with the pregnancy (e.g., an event in the fetus, an event in the mother during 
or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the Adverse Event eCRF.  In addition, the investigator will submit a 
Clinical Trial Pregnancy Reporting Form when updated information on the course and 
outcome of the pregnancy becomes available. 
5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or until the last 
study visit.  A Clinical Trial Pregnancy Form should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy) either by faxing or by scanning and emailing the form using the fax number 
or email address provided to investigators.  Attempts should be made to collect and 
report details of the course and outcome of any pregnancy in the partner of a male 
patient exposed to study drug.  The pregnant partner will need to sign an Authorization 
for Use and Disclosure of Pregnancy Health Information to allow for follow-up on her 
pregnancy.  After the authorization has been signed, the investigator will submit a 
Clinical Trial Pregnancy Reporting Form when updated information on the course and 
outcome of the pregnancy becomes available.  An investigator who is contacted by the 
male patient or his pregnant partner may provide information on the risks of the 
pregnancy and the possible effects on the fetus, to support an informed decision in 
cooperation with the treating physician and/or obstetrician. 
5.4.3.3 
Abortions 
Any abortion should be classified as an SAE (as the Sponsor considers abortions to be 
medically significant), recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2). 
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as an SAE, recorded on the Adverse Event eCRF, and reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each AE until the event has resolved to baseline grade or 
better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or 
the patient withdraws consent.  Every effort should be made to follow all SAEs considered 


 
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to be related to study drug or study-related procedures until a final outcome can be 
reported. 
During the study period, resolution of AEs (with dates) should be documented on the 
Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.  If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF. 
All pregnancies reported during the study should be followed until pregnancy outcome.   
5.5.2 
Sponsor Follow-Up 
For SAEs, non-serious AESIs, and pregnancies, the Sponsor or a designee may 
follow up by telephone, fax, electronic mail, and/or a monitoring visit to obtain additional 
case details and outcome information (e.g., from hospital discharge summaries, 
consultant reports, autopsy reports) in order to perform an independent medical 
assessment of the reported case. 
5.6 
POST-STUDY ADVERSE EVENTS 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
the last study visit), if the event is believed to be related to study drug treatment.   
The investigator should report these events directly to the Sponsor or its designee, either 
by faxing or by scanning and emailing the Serious Adverse Event/Adverse Event of 
Special Interest Reporting Form using the fax number or email address provided to 
investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious and non-serious AESIs against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators, IRBs, ECs, and applicable health authorities based on 
applicable legislation. 
To determine reporting requirements for single AE cases, the Sponsor will assess the 
expectedness of these events using the following reference document{s}: 
• 
Lampalizumab Investigator’s Brochure 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 


 
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Reporting requirements will also be based on the investigator’s assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
Analysis of data for the first year of the study period will be performed when all patients 
have either completed the first year of study period or have discontinued from the study 
prior to Year 1 (i.e., Week 48), and all data from this period are in the database and have 
been cleaned and verified.  The analysis of complete data for the study will be performed 
when all patients have either completed the 2-year study period (i.e., Week 96) or 
discontinued early from the study, all data from the study are in the database, and the 
database is locked. 
Results of the first year analysis, summarized by treatment group and biomarker group, 
may be reported to the public before completion of the study.  However, patients, 
masked study site personnel, central reading center personnel, and Sponsor study team 
members who have direct contact with study sites will remain masked to individual 
treatment assignment until the study is completed, the database is locked, and the study 
analyses are final. 
Detailed specifications of the statistical methods will be described in the SAP. 
6.1 
DETERMINATION OF SAMPLE SIZE 
Patients will be randomized in a 2:1:2:1 ratio to receive treatment with lampalizumab 
Q4W, sham Q4W, lampalizumab Q6W, or sham Q6W.  Data from the two sham groups 
will be pooled in the analysis.  
The study is sized to achieve adequate power for detecting a meaningful reduction rate 
in the GA area growth for a given lampalizumab dosing frequency compared with pooled 
sham within CFI profile biomarker-positive and CFI profile biomarker-negative groups 
and to meet health authority requirements for the safety database.  
The primary endpoint is the mean change in GA area from baseline to 1 year as 
assessed by FAF.  Table 7 summarizes the power calculation and minimum detectable 
difference for this primary endpoint.  Assuming a standard deviation of 2.51 mm2 for the 
change from baseline in GA area at 1 year in biomarker-positive patients, 188 CFI profile 
biomarker-positive patients per lampalizumab treatment group and 94 CFI profile 
biomarker-positive patients per sham group will provide > 95% power to declare a 
difference between each lampalizumab treatment group and the pooled sham for a 
targeted difference of 1.45 mm2 (approximately 40% reduction relative to sham control) 
in the change from baseline in GA area at 1 year.  Assuming a standard deviation of 
1.68 mm2 for the change from baseline in GA area at 1 year in CFI profile biomarker-
negative patients, 124 CFI profile biomarker-negative patients per lampalizumab 
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provide 80% power to detect a targeted difference of 0.66 mm2 (approximately 40% 
reduction) between each lampalizumab treatment group and the pooled sham group in 
the change from baseline in GA area at 1 year.  Calculations were based on two-sided 
t-test at the α = 0.0495 level (after adjustment for planned interim data reviews conducted 
by the iDMC prior to analysis of the primary efficacy endpoint; see Section 3.1.2), with 
the assumption of a 15% dropout rate by 1 year.  Due to lack of reliable information to 
estimate the impact of partially missing data on the power, the power calculation is 
based on the analysis of data from the patients who complete the first year of the study.  
However, the primary analysis of the study will include all available data from patients in 
all treatment arms, which will have more power than an analysis of just those patients 
completing the first year of the study period. 
Table 7 
Power and Minimum Detectable Difference for Primary Endpoint 
in This Study 
Two-Sided α = 0.0495 
Endpoint 
Target Treatment Effect 
Power 
MDD 
Mean change from baseline in 
GA area at 1 year in 
biomarker-positive patients 
(n = 188 per arm) 
Δ = 1.45 mm2 (approximately 
40%a reduction) SD = 2.51  
>95% 
0.56 mm2 
(approximately 
15% a 
reduction) 
Mean change from baseline in 
GA area at 1 year in 
biomarker-negative patients 
(n = 124 per arm) 
Δ = 0.66 mm2 (approximately 
40%a reduction) SD = 1.68 
80% 
0.46 mm2 
(approximately 
28% a 
reduction) 
GA = geographic atrophy; MDD = minimum detectable difference. 
The sample size takes into account the dropout rate of 15% by 1 year.  The power and MDD 
are for each comparison between one lampalizumab treatment group and the pooled sham 
group. 
a Relative to the sham group and assuming the mean change from baseline in GA area at 
1 year (48 weeks) is 1.645 mm2 for biomarker-negative group and 3.631 mm2 for 
biomarker-positive group. 
 
The Sponsor may conduct a masked evaluation of the variance of the primary efficacy 
endpoint and study dropout rate before the end of enrollment and compare the 
information to the assumptions used in planning the study.  If this comparison suggests 
the initial assumptions for the dropout rate and/or the variance of the primary efficacy 
endpoint were substantially lower, and the study is consequently underpowered, the 
study sample size will be increased to maintain the desired study power and safety 
database.  Details will be provided in the SAP.   
For patients who are eligible to undergo a microperimetry assessment, at least 46 CFI 
profile biomarker-positive patients per lampalizumab treatment group and 23 CFI profile 
biomarker-positive patients per sham group will provide 80% power to detect a targeted 
difference of 6.91 points with a standard deviation of 9.88 points between each 


 
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lampalizumab treatment group and the pooled sham group in the change from baseline 
in the number of scotomatous points at 2 years.  Calculation was based on a two-sided 
t-test at α = 0.05 level with the assumption of a 25% dropout rate by 2 years. 
6.2 
SUMMARIES OF STUDY CONDUCT 
The clinical database will be used to assess study conduct.  The number of patients 
randomized will be tabulated by treatment arm and biomarker status.  Patient disposition 
(the number of patients randomized, treated, and completing each study period) will be 
tabulated by treatment arm and biomarker status.  Reasons for premature study 
treatment discontinuation and study discontinuation, any eligibility criteria deviation, and 
other major protocol deviations will also be tabulated. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Demographic and baseline characteristics such as age, sex, race, region, and baseline 
safety (such as baseline vital signs and laboratory test results), baseline disease 
characteristics (such as baseline GA area, baseline BCVA, and baseline VA under low 
luminance conditions) will be summarized for all randomized patients by treatment group 
and biomarker status using descriptive statistics.  Exposure to study treatment (number 
of study treatments and duration of treatment) will be summarized by treatment arm and 
biomarker status. 
6.4 
EFFICACY ANALYSES 
The primary and secondary efficacy analyses will be based on the intent-to-treat (ITT) 
approach.  All randomized patients (i.e., ITT population) will be included in the analysis, 
with patients grouped according to the treatment assigned at randomization. 
Unless otherwise noted, analyses of efficacy outcome measures will be stratified by 
biomarker status (positive vs. negative), baseline BCVA (20/50 [inclusive] or better vs. 
worse than 20/50), sex (woman vs. man), and eligibility for microperimetry assessment 
(yes vs. no).  A data-as-observed approach with the mixed-effect model will be used to 
handle missing data in the primary analysis, which assumes that the missing data are 
missing at random.  Sensitivity/supportive analyses based on imputed data will be 
provided in the SAP. 
In addition to the analyses described in Sections 6.4.1 and 6.4.2, the following analyses 
will be performed for the primary efficacy endpoint and key secondary efficacy endpoints.  
Details of these analyses, including additional missing data handling rules, will be 
described in the SAP. 
• 
Sensitivity analyses to evaluate the robustness of the results to the primary analysis 
method (e.g., missing data handling, derivation of primary outcome measure based 
on the rate of change) 


 
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• 
Subgroup analyses to evaluate the consistency of the results across prespecified 
subgroup (e.g., based on age, sex, baseline BCVA) 
 
6.4.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the mean change in GA area from baseline at 1 year 
(Week 48) as assessed by FAF. 
For each biomarker group, the mean change in GA area from baseline will be compared 
between each active treatment arm and the pooled sham arm by use of a linear 
mixed-effect model.  The primary analysis will be based on all available data up to 1 year, 
with no imputation for missing data. 
The dependent variable in the mixed-effect model is the change from baseline in GA 
area at post-baseline visits, up to 1 year, and the independent variables are the 
randomized treatment group, time, treatment-by-time interaction, baseline GA area, and 
the randomization stratification factors of (biomarker status, baseline BCVA ETDRS 
chart Snellen equivalent category, sex, and microperimetry eligibility).  The mixed-effect 
model will assume an unstructured covariance structure.  If there are convergence 
problems with the model, then a compound symmetry covariance structure will be fitted.  
A similar model with two additional independent variables, the biomarker status and the 
interaction of treatment and biomarker status, will be used to evaluate the predictive 
value of the genetic-defined biomarker.  Also, for patients treated with sham, a 
comparison of change from baseline in GA area between biomarker-positive patients 
and biomarker-negative patients will be performed to evaluate the prognostic value of 
the CFI profile biomarker.  
To manage the type I error of 0.0495 (two-sided), testing of the primary endpoint will be 
conducted in the following sequential order: 
• 
Step 1:  lampalizumab Q4W CFI profile biomarker-positive group versus pooled 
sham CFI profile biomarker-positive group 
If there is no statistically significant difference found in this treatment 
comparison at the significance level of 0.0495, then the test for the next stage 
will not be considered statistically significant regardless of the p-value. 


 
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• 
Step 2:  lampalizumab Q4W CFI profile biomarker-negative group versus pooled 
sham CFI profile biomarker-negative group, and lampalizumab Q6W CFI profile 
biomarker-positive group versus pooled sham CFI profile biomarker-positive group 
If statistically significant difference is not found in both treatment comparisons 
at the significance level of 0.0495, then the test for the next stage will not be 
considered statistically significant regardless of the p-value.  If a statistically 
significant difference is found in only one treatment comparison at the 
significance level of 0.0495, then the statistical significance will be concluded 
only for that testing of the primary endpoint. 
• 
Step 3:  lampalizumab Q6W CFI profile biomarker-negative group versus pooled 
sham CFI profile biomarker-negative group 
The statistical test will be conducted at a significance level of 0.0495. 
Figure 3 illustrates the order in which hypothesis tests for the primary endpoint will be 
performed.   
Figure 3 Order of Hypothesis Tests for the Primary Endpoint 
 
BM + = CFI profile biomarker-positive; BM − = CFI profile biomarker-negative; Q4W = every 
4 weeks; Q6W = every 6 weeks. 
Note:  The arrows indicate the order of subsequent comparisons for the primary endpoint.  
Testing proceeds to a subsequent comparison only if all prior test(s) leading to that comparison 
are significant at α = 0.0495.  p refers to the p-value of a statistical testing. 
 
6.4.2 
Secondary Efficacy Endpoints 
The secondary endpoints for this study are as follows: 
• 
Mean change in number of scotomatous points from baseline to 2 years as 
assessed by mesopic microperimetry 
• 
Mean change in macular sensitivity from baseline to 2 years as assessed by  
mesopic microperimetry 
• 
Mean change from baseline in GA area at 2 years as assessed by FAF 
• 
Mean change from baseline in GA area over time (all timepoints) as assessed by 
FAF 
• 
Mean change from baseline in BCVA at 2 years as assessed by ETDRS chart at a 
starting distance of 4 m 
• 
Mean change from baseline in BCVA over time as assessed by ETDRS chart at a 
starting distance of 4 m 


 
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• 
Mean change from baseline in BCVA at 2 years as assessed by ETDRS chart under 
low luminance conditions at a starting distance of 4 m 
• 
Mean change from baseline in BCVA over time as assessed by ETDRS chart under 
low luminance conditions at a starting distance of 4 m 
• 
Proportion of patients with < 15 letters loss in BCVA score compared to baseline at 
2 years as assessed by ETDRS chart at a starting distance of 4 m 
• 
Proportion of patients with < 15 letters loss in BCVA score compared to baseline at 
2 years as assessed by ETDRS chart under low luminance conditions at a starting 
distance of 4 m 
• 
Mean change from baseline in mean binocular reading speed at 2 years as 
assessed by MNRead charts or Radner Reading Charts 
• 
Mean change from baseline in binocular critical print size at 2 years as assessed by 
MNRead charts or Radner Reading Charts 
• 
Mean change from baseline in NEI VFQ-25 composite score at 2 years 
• 
Mean change from baseline in NEI VFQ-25 near activity subscale score at 2 years 
• 
Mean change from baseline in NEI VFQ-25 distance activity subscale score at 
2 years 
• 
Mean change from baseline in FRI Index score at 2 years 
 
The continuous secondary endpoints will be analyzed in the same fashion as the primary 
endpoint:  using a linear mixed-effect model.  Baseline is defined here as the last 
available value prior to randomization.  The binary secondary endpoints will be analyzed 
using a Cochran-Mantel-Haenszel test stratified by adequate randomization stratification 
factors, biomarker status (positive or negative), baseline BCVA (20/50 [inclusive] or 
better vs. worse than 20/50), sex (woman vs. man), and eligibility for microperimetry 
assessment (yes vs. no). 
For three key secondary endpoints (mean change in the number of scotomatous points 
from baseline to 2 years as assessed by microperimetry, mean change from baseline in 
BCVA at 2 years as assessed ETDRS chart under low luminance conditions at a starting 
distance of 4 m, and mean change from baseline in mean binocular reading speed at 
2 years), within each dosing frequency and CFI profile biomarker group, the hypothesis 
testing will be gated on the success of the primary endpoint test for that specific dosing 
frequency and CFI profile biomarker group and be performed sequentially at a 
significance level of 0.0495.  For a specific dosing frequency, if both lampalizumab CFI 
profile biomarker groups are considered significantly different from the corresponding 
sham group in the primary endpoint, the hypothesis testing for the key secondary 
endpoints may be conducted on the basis of combined CFI profile biomarker groups for 
that specific dosing frequency.   
Additional details regarding the analysis of secondary and exploratory endpoints will be 
provided in the SAP. 


 
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6.5 
SAFETY ANALYSES 
The safety analyses will include all randomized patients who receive at least one 
lampalizumab injection or sham injection, with patients grouped according to the 
treatment actually received.  Safety summaries will be presented for all treated patients. 
Safety will be assessed through descriptive summaries of AEs, death, alternative 
complement assessment, serial ECG, anti-therapeutic antibodies to lampalizumab, and 
ocular assessments. 
6.5.1 
Adverse Events 
Verbatim descriptions of treatment-emergent AEs will be coded and their incidence will 
be summarized, as appropriate.  A treatment-emergent AE is defined as any new AE 
reported or any worsening of an existing condition on or after the first dose of study 
treatment.  In addition, separate summaries will be generated for SAEs, deaths, AEs 
leading to discontinuation of study treatment, and AEs judged to be related to treatment 
(lampalizumab or sham).  Separate summaries will be prepared for systemic (non-ocular) 
and ocular AEs, with events in the study eye and non-study eye (fellow eye) summarized 
separately. 
6.5.2 
Alternative Complement Pathway Activity Assessment 
Descriptive summaries of alternative complement pathway activity assessments will be 
generated. 
6.5.3 
Anti-Therapeutic Antibodies 
Data on ATAs directed against lampalizumab will be summarized by the number and 
percentage of patients with confirmed positive ATAs. 
6.5.4 
Death 
Patient deaths and primary cause of death will be summarized. 
6.5.5 
Electrocardiogram Evaluation at Selected Sites 
Descriptive summaries of common clinical ECG parameters at baseline and throughout 
the study will be generated.  The number and percentage of patients with abnormal ECG 
findings will be summarized.  See Section 4.5.7 for details of serial ECG subgroup 
assessment. 
6.5.6 
Ocular Assessments 
Descriptive summaries will be generated for ocular assessments, such as VA and IOP. 
6.6 
PHARMACOKINETIC ANALYSES 
The PK analyses will include all randomized patients who have at least one serum 
sample, with patients grouped according to treatment actually received.  Serum 
concentrations of lampalizumab will be summarized descriptively. 


 
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Additional PK/PD and exposure-response analyses may be conducted as appropriate.  
Population PK modeling may be performed to characterize inter-individual variability, 
which may be reported separately from the Clinical Study Report. 
6.7 
OPTIONAL INTERIM ANALYSES 
In order to adapt to information that may emerge during the course of this study 
(e.g., additional information of the biomarker characteristics, additional results of natural 
history studies), the Sponsor may choose to conduct one interim efficacy analysis.  
Below are the specifications in place to ensure the study continues to meet the highest 
standards of integrity when such an optional interim analysis is executed. 
The Sponsor will remain masked to individual treatment assignment.  The interim 
analysis will be conducted by an external statistical group and reviewed by the iDMC.  
Interactions between the iDMC and Sponsor will be carried out as specified in the iDMC 
charter to ensure integrity.  
The decision to conduct the optional interim analysis, along with the rationale, timing, 
and statistical details for the analysis will be documented in the SAP, and the SAP will 
be submitted to relevant Health Authorities at least 2 months prior to the conduct of the 
interim analysis.  The iDMC charter will document potential recommendations the iDMC 
can make as a result of the analysis (e.g., stop the study for positive efficacy, stop the 
study for futility), and the iDMC charter will also be made available to relevant health 
authorities. 
If there is a potential for the study to be stopped for positive efficacy as a result of the 
interim analysis, the type I error rate will be controlled to ensure statistical validity is 
maintained.  Specifically, the Lan-DeMets α-spending function that approximates the 
O’Brien-Fleming boundary will be applied to determine the critical value for stopping for 
positive efficacy at the interim analysis (DeMets et al. 1994).  Additional criteria for 
recommending that the study be stopped for positive efficacy may be added to the iDMC 
charter.  If the study continues beyond the interim analysis, the critical value at the final 
analysis would be adjusted accordingly to maintain the protocol-specified overall type I 
error rate, as described in the standard Lan-DeMets theory. 
If there is a potential for the study to be stopped for futility as a result of the interim 
analysis, the threshold for declaring futility will include an assessment of the predictive 
probability that the specified endpoint will achieve statistical significance.  If the 
predictive probability is below 20%, the iDMC should consider recommending that the 
study be stopped for futility.  Additional criteria for recommending that the study be 
stopped for futility may be added to the iDMC charter.  An interim analysis that might 
lead to stopping the study for futility will not occur before at least 40% information has 
been accumulated. 


 
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7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC using eCRFs.  
Sites will be responsible for data entry into the EDC system.  In the event of discrepant 
data, the Sponsor will request data clarification from the sites, which the sites will resolve 
electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data and Reading 
Center Images data will be sent directly to the Sponsor, using the Sponsor’s standard 
procedures to handle and process the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 
The Sponsor will supply eCRF specifications for this study. 
Data from PRO questionnaires will be recorded on worksheets and the data will be 
entered into EDC by sites.   
7.2 
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed using a Sponsor-designated EDC system.  Sites will receive 
training and have access to help text for appropriate eCRF completion.  eCRFs will be 
submitted electronically to the Sponsor and should be handled in accordance with 
instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include but are not limited to hospital records, 
clinical and office charts, laboratory notes, memoranda, PRO measures, evaluation 


 
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checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies of transcriptions that are certified after verification as being accurate and 
complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical study. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for study-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic PRO data (if applicable), Informed Consent Forms, 
laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for at least 15 years after completion or discontinuation of the 
study, or for the length of time required by relevant national or local health authorities, 
whichever is longer.  After that period of time, the documents may be destroyed, subject 
to local regulations. 
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 


 
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8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for GCP and 
the principles of the Declaration of Helsinki, or the laws and regulations of the country in 
which the research is conducted, whichever affords the greater protection to the 
individual.  The study will comply with the requirements of the ICH E2A guideline 
(Clinical Safety Data Management:  Definitions and Standards for Expedited Reporting).  
Studies conducted in the United States or under a U.S. Investigational New Drug 
Application (IND) will comply with FDA regulations and applicable local, state, and 
federal laws.  Studies conducted in the European Union or European Economic Area will 
comply with the E.U. Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver’s Informed Consent Form, if applicable) will 
be provided to each site.  If applicable, it will be provided in a certified translation of in 
the local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor’s sample Informed Consent Forms or any alternative 
consent forms proposed by the site (collectively, the “Consent Forms”) before IRB/EC 
submission.  The final IRB/EC−approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
The Informed Consent Form will contain a separate section or separate Informed 
Consent Form that addresses the use of remaining mandatory samples for optional 
exploratory research.  The investigator or authorized designee will explain to each 
patient the objectives of the exploratory research.  Patients will be told that they are free 
to refuse to participate and may withdraw their specimens at any time and for any 
reason during the storage period.  A separate, specific signature will be required to 
document a patient’s agreement to allow any remaining specimens to be used for 
exploratory research.  Patients who decline to participate will not provide a separate 
signature. 
The Consent Forms must be signed and dated by the patient before his or her 
participation in the study.  The case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 


 
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Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient.  All signed and 
dated Consent Forms must remain in each patient’s study file or in the site file and must 
be available for verification by study monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
HIPAA of 1996.  If the site utilizes a separate Authorization Form for patient 
authorization for use and disclosure of personal health information under the HIPAA 
regulations, the review, approval, and other processes outlined above apply except that 
IRB review and approval may not be required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may only be 
disclosed to third parties as permitted by the Informed Consent Form (or separate 


 
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authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of the FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., LPLV). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, which includes an audit trail containing a complete record of all changes 
to data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol violations.  The investigator 
should promptly report any violations that might affect patient safety and data integrity to 
the Sponsor and to the IRB/EC in accordance with established IRB/EC policies and 
procedures. 
9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
This research study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland and may be implemented in individual countries by Roche’s local affiliates.  


 
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The Sponsor will perform project management, study management, monitoring, vendor 
management, and statistical programming.  An IxRS will be used for patient screening 
and randomization and for management of study drug requests and shipments.  A 
central laboratory will be used for most laboratory assessments and for storage of other 
laboratory samples (i.e., anti-lampalizumab antibody serum samples) prior to being 
shipped to Sponsor or its designee for analysis.  Data will be recorded by an EDC 
system using eCRFs (see Section 7.1) or forwarded to Sponsor electronically 
(e.g., serial ECG data).  A central reading center will be used for ocular imaging 
analyses (FAF, NI, CFP, FA, and SD-OCT) and microperimetry data, which will be 
forwarded to Sponsor electronically. 
9.5 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsor 
prior to submission.  This allows the Sponsor to protect proprietary information and to 
provide comments based on information from other studies that may not yet be available 
to the investigator. 
The Sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
center data.  In this case, a coordinating investigator will be designated by mutual 
agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 


 
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10. 
REFERENCES 
de Jong PT. Age-related macular degeneration. N Engl J Med 2006;355:1474−85. 
Caire J, Recalde S, Velazquez-Villoria A, et al. Growth of Geographic Atrophy on 
Fundus Autofluorescence and Polymorphisms of CFH, CFB, C3, FHR1-3, and ARMS2 
in Age-Related Macular Degeneration. JAMA Ophthalmol. 2014;132(5):528-534. 
doi:10.1001/jamaophthalmol.2013.8175. 
DeMets DL, Lan KK. Interim analysis: the alpha spending function approach. Stat Med 
1994;13(13−14):1341−52; discussion 1353−6. 
Friedman DS, O’Colmain BJ, Muñoz B, et al., for the Eye Diseases Prevalence 
Research Group. Prevalence of age-related macular degeneration in the United States. 
Arch Ophthalmol 2004;122:564−72. 
Fritsche L, Chen W, Schu M, et al., for the AMD Gene Consortium. Seven new loci 
associated with age-related macular degeneration. Nat Genet 2013;45:433−9. 
Holz FG, Bindewald-Wittich A, Fleckenstein M, et al. Progression of geographic atrophy 
and impact of fundus autofluorescence patterns in age-related macular degeneration. 
Am J Ophthalmol 2007;143(3): 463−72. 
Lindblad AS, Clemons TE, for the Age-Related Eye Disease Study Research Group. 
Responsiveness of the National Eye Institute Visual Function Questionnaire to 
progression to advanced age-related macular degeneration, vision loss, and lens 
opacity. AREDS report number 14. Arch Ophthalmol 2005;123(9):1207−14. 
Lindblad AS, Lloyd PC, Clemons TE, et al., for the Age-Related Eye Diseases Research 
Group. Change in area of geographic atrophy in the Age-Related Eye Disease Study. 
AREDS report number 26. Arch Ophthalmol 2009;127(9):1168−74. 
Rohrer B, Guo Y, Kunchithapautham K, et al. Eliminating complement factor D reduces 
photoreceptor susceptibility to light-induced damage. Invest Ophthalmol Vis Sci 
2007;48(11):5282−9. 
Rudnicka AR, Jarrar Z, Wormald R, et al. Age and gender variations in age-related 
macular degeneration prevalence in populations of European ancestry: a meta-analysis. 
Ophthalmology 2012;119(3):571-580. 
Scholl HPN, Charbel Issa P, Walier M, et al. Systemic complement activation in 
age-related macular degeneration. PLoS One 2008;3(7):e2593. 
Sunness JS, Schuchard R, Shen N, et al. Landmark-driven fundus perimetry using the 
scanning laser ophthalmoscope. Invest Ophthalmol Vis Sci 1995;36(9):1863−74. 
Sunness JS, Applegate CA, Haselwood D, et al. Fixation patterns and reading rates in 
eye with central scotomas from advanced atrophic age-related macular degeneration 
and Stargardt disease. Ophthalmology 1996;103(9):1458−66. 
Sunness JS, Bressler NM, Tian Y, et al. Measuring geographic atrophy in advanced 
age-related macular degeneration. Invest Ophthalmol Vis Sci 1999a;40(8):1761−9. 


 
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Sunness JS, Gonzalez-Baron J, Applegate CA, et al. Enlargement of atrophy and visual 
acuity loss in the geographic atrophy form of age-related macular degeneration. 
Ophthalmology 1999b;106(9):1768−79. 
Sunness JS, Margalit E, Srikumaran D, et al. The long-term natural history of geographic 
atrophy from age-related macular degeneration: enlargement of atrophy and implications 
for interventional clinical trials. Ophthalmology 2007;114(2):271-7 
van de Ven JPH, Nilsson SC, Tan PL, et al. A functional variant in the CFI gene confers 
a high risk of age-related macular degeneration. Nat Genet 2013;45(7):813−7. 
Vingerling JR, Dielemans I, Hofman A, et al. The prevalence of age-related maculopathy 
in the Rotterdam Study. Ophthalmology 1995;102(2):205−10. 
Yates JRW, Sepp T, Matharu BK, et al. Complement C3 variant and the risk of 
age-related macular degeneration. N Engl J Med 2007;357:553−61. 
 


 
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Appendix 1 Schedule of Assessments 
Table 1 
Study Flowchart for Q4W Arms: Day 1, Day 8, Week 4 through Week 52, and Early Termination 
Day 
Week Visit 
 
Screening 
1 
8 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
Early 
Term a 
Assessment Windows (Days) 
−28 to −1 
NA 
±2 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
See 
footnote 
a 
Written informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of inclusion and exclusion 
criteria 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and surgical history 
including tobacco history b 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic information 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NEI VFQ-25 c 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
FRI Index c 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
Physical examination 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Height and weight 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Historical ECG d 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG at selected sites e, f 
 
x 
x 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
Vital signs f, g 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Central laboratory samples 
(hematology, coagulation, serum 
chemistry, and urinalysis) f 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 


 
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Appendix 1 Schedule of Assessments (cont.) 
 
Table 1 
Study Flowchart for Q4W Arms: Day 1, Day 8, Week 4 through Week 52, and Early Termination (cont.) 
 
Day 
Week Visit 
 
Screening 
1 
8 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
Early 
Term a 
Assessment Windows (Days) 
−28 to −1 
NA 
±2 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
See 
footnote 
a 
CFI whole blood sample (SF 
patients included)  f, h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CFI buccal swab sample (SF 
patients included)  f, h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker plasma sample f 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker paxgene sample f 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker whole blood clinical 
genotyping sample f 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy sample f, i, j 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Urine pregnancy test f, j 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Serum ATA sample f 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
x 
Serum PK sample for 
lampalizumab concentration f 
 
x 
x 
x 
 
 
 
 
x 
 
 
 
 
 
x 
 
x 
Optional aqueous sample f 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
x 
 
 
 
AH50 sample f 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
BCVA testing (starting at 4 m) k 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
LL BCVA testing (starting at 4 m) k 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
x 
MNRead or Radner Reading 
Charts k, l 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 


 
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Appendix 1 Schedule of Assessments (cont.) 
 
Table 1 
Study Flowchart for Q4W Arms: Day 1, Day 8, Week 4 through Week 52, and Early Termination (cont.) 
 
Day 
Week Visit 
 
Screening 
1 
8 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
Early 
Term a 
Assessment Windows (Days) 
−28 to −1 
NA 
±2 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
See 
footnote 
a 
Pre-treatment IOP measurement k 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mesopic microperimetry at 
selected sites (study eye only) m 
x 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
x 
Slit-lamp examination 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Dilated binocular indirect 
ophthalmoscopy 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
FAF n 
x 
 
 
 
 
 
 
 
x 
 
 
x 
 
 
x 
 
x 
Keratometry n 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SD-OCT n 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
x 
Near infrared imaging n 
x 
 
 
 
 
 
 
 
x 
 
 
x 
 
 
x 
 
x 
Fundus photography n 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
Fluorescein angiography n 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
Administration of lampalizumab 
injection/sham to study eye  
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Post-treatment finger counting 
and IOP measurement o 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Concomitant medications p 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events q 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concurrent ocular procedures r 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Follow-up call s 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 


 
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Appendix 1 Schedule of Assessments (cont.) 
 
Table 1 
Study Flowchart for Q4W Arms: Day 1, Day 8, Week 4 through Week 52, and Early Termination (cont.) 
 
AH50 = Alternative Complement Pathway activity assay; ATA = anti-therapeutic antibody; BCVA = best corrected visual acuity; CFI = complement 
factor I; eCRF = electronic Case Report Form; FAF = fundus autofluorescence; FRI Index = Functional Reading Independence Index; 
IOP = intraocular pressure; LL BCVA = Low Luminance BCVA; MNRead = Minnesota Low-Vision Reading Test; NA = not applicable; NEI VFQ-
25 = National Eye Institute Visual Functioning Questionnaire 25-item Version; PK = pharmacokinetic; Q4W = every 4 weeks; SD-OCT = spectral 
domain optical coherence tomography; SF = screen fail. 
Note:  All ocular assessments are to be performed for both eyes unless noted otherwise.  All assessments are to be performed on the same day, 
except those at screening.  All study visits will be scheduled relative to date of Day 1 visit (first study treatment). 
a For patients who discontinue early from the study, early termination assessments will be performed after minimum of 30 days have lapsed 
following the last study treatment. 
b Significant medical and surgical history, including chronic and ongoing conditions (e.g., trauma, cancer, and ophthalmic history), and tobacco 
use. 
c To be administered by the masked site staff (except for the VA examiner) prior to any other visit assessments being performed on that day.   
d If available, the study patients who are not part of the serial ECG evaluation (Section 4.5.7) will provide historical results of a clinical 12-lead 
ECG performed within the 12 months preceding Day 1 study treatment.  The results will be stored in a patient source document. If there was no 
ECG performed within the 12 months preceding Day 1, it is not required to obtain at Screening/Day 1 ECG.  
e At selected sites, ECG will be performed at the timepoints listed.  Perform ECG at early termination visit only if a patient is discontinuing study 
prior to the Week 24 visit.  Patients should be in a resting position for 10 min. prior to each ECG evaluation.  Body position should be consistently 
maintained for each ECG evaluation to prevent changes in heart rate.  Environmental distractions (e.g., television, radio, conversation) should be 
minimized before and during ECG recording.  The ECG result will be read by the central reader. See ECG manual for details. 
f Obtain prior to fluorescein angiograph (if applicable) and prior to study treatment. 
g Vital signs consist of blood pressure, respiratory rate, heart rate, and temperature; on Day 1 visit; this should be collected before study treatment. 
h CFI whole blood sample and CFI buccal swab sample will be collected at screening and will also be retained for the screen-failed patients. 
i At screening, collect serum pregnancy sample for women of childbearing potential, including those who have had tubal ligation.  If positive, 
record the patient as a screen fail. 
j Starting at Day 1, collect and perform the urine pregnancy test for women of childbearing potential, including those who have had tubal ligation, 
at each study treatment visit.  If positive, collect the serum pregnancy sample and forward to central lab for testing; if the serum pregnancy test is 
positive, do not administer the study treatment. At ET visit, collect the serum pregnancy sample and forward to the central lab for testing. 
k Perform the assessments prior to dilating the eyes. 
l MNRead charts or Radner Reading Charts can be done during study visit, prior to dilating the eyes (see the tables in Appendix 18 and 
Appendix 19 for which chart to use according to country of the site).  The test will be administered first monocularly (right/left eye) and then 
binocularly (both eyes). 


 
Lampalizumab—F. Hoffmann-La Roche Ltd 
107/Protocol GX29185, Version 6 
Appendix 1 Schedule of Assessments (cont.) 
 
Table 1 
Study Flowchart for Q4W Arms: Day 1, Day 8, Week 4 through Week 52, and Early Termination (cont.) 
 
m Microperimetry assessments will be performed post-dilation on the study eye only, and the data will be forwarded to the central reading center. 
Note: If the Investigator determines that both eyes of a patient meet the eligibility criteria for the study eye, mesopic microperimetry will be 
performed on both eyes at screening. 
n SD-OCT and FAF images (including keratometry), near infrared images, fluorescein angiograms, and fundus photographs (as applicable) will be 
performed for both eyes and will be forwarded to the central reading center. See reading center manual.  Note: after randomization, if a patient 
misses a study visit when ocular images were scheduled to be taken (Appendix 1), the images should be obtained at the next scheduled visit.   
o Finger-counting test followed by hand-motion and light-perception tests (when necessary) will be performed by the unmasked physician within 
15 minutes after study treatment.  At study treatment visits, post-treatment IOP measurement in the study eye only between 30−50 minutes after 
study treatment (drug or sham) will be performed by the masked site staff (except for the VA examiner).  If the IOP is increased by ≥10 mm Hg 
from pre-treatment, the IOP will be measured again at 60−80 minutes post-treatment.  If there are no safety concerns, the patient will be 
permitted to leave the clinic.  If the IOP value is of concern to the investigator, the patient will remain in the clinic and will be managed in 
accordance with the investigator’s clinical judgment. Both the last post-treatment IOP measured prior to any intervention for increased IOP (if 
applicable) and the last post-intervention IOP (if applicable) will be recorded on the post-treatment IOP eCRF. Note: if the study eye is treated 
with a Lucentis injection during the same visit as the study treatment (lampalizumab/sham), the treatment with Lucentis must be performed first. 
Measure and record the post-Lucentis treatment IOP value on the eCRF.   
p Record any concomitant medications (i.e., any prescription medications or over-the-counter preparations other than protocol-specified 
procedural medications such as proparacaine, etc.) used by the patient within 7 days preceding Day 1 and through the conclusion of the 
patient’s study participation or early termination visit. 
q After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by a protocol-mandated 
intervention (e.g., procedures such as fluorescein angiography) should be reported.  Adverse events will be recorded starting on Day 1 after the 
study treatment through the last study visit.  Adverse events assessed by the physician as related to lampalizumab should be followed until the 
event resolves or the event is assessed as irreversible, chronic, or stable, even if patient’s participation in the study has ended. 
r Record all concurrent ocular procedures performed on the study or non-study eye. 
s Starting at Week 4, study patients will be contacted by study site personnel 4 (± 2) days after each study treatment to elicit reports of any 
decrease in vision, eye pain, unusual redness, or any other new ocular symptoms in the study eye.  At sites where the investigator’s decision is 
for the patients to take pre- and post-treatment antimicrobials, patients will also be asked whether they have taken the prescribed, self-
administered, post-treatment antimicrobials.  Patients will be instructed to contact the investigator at any time if they have any health-related 
concerns.  If warranted, patients will be asked to return to the clinic as soon as possible for a safety assessment visit. 
 


 
Lampalizumab—F. Hoffmann-La Roche Ltd 
108/Protocol GX29185, Version 6 
Appendix 1 Schedule of Assessments (cont.) 
 
Table 2 
Study Flowchart for Q4W Arms:  Week 56 through Week 96 and Early Termination 
Week Visit 
 
56 
60 
64 
68 
72 
76 
80 
84 
88
92 
96 
Early 
Term a 
Assessment Windows (Days) 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5
±5 
±5 
See footnote a 
Written informed consent 
 
 
 
 
 
 
 
 
 
 
 
 
Review of inclusion and exclusion criteria 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and surgical history including tobacco history b 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic information 
 
 
 
 
 
 
 
 
 
 
 
 
NEI VFQ-25 c 
 
 
 
 
x 
 
 
 
 
 
x 
x 
FRI Index c 
 
 
 
 
x 
 
 
 
 
 
x 
x 
Physical examination 
 
 
 
 
 
 
 
 
 
 
 
x 
Height and weight 
 
 
 
 
 
 
 
 
 
 
 
 
Historical ECG d 
 
 
 
 
 
 
 
 
 
 
 
 
ECG at selected sites e, f 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs f, g  
 
 
 
 
 
 
 
 
 
 
 
x 
Central laboratory samples (hematology, coagulation, serum 
chemistry, and urinalysis) f  
 
 
 
 
 
 
 
 
 
 
 
x 
CFI whole blood sample (SF patients included) f, h 
 
 
 
 
 
 
 
 
 
 
 
 
CFI buccal swab sample (SF patients included) f, h 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker plasma sample f 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker paxgene sample f 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker whole blood clinical genotyping sample f 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Lampalizumab—F. Hoffmann-La Roche Ltd 
109/Protocol GX29185, Version 6 
Appendix 1 Schedule of Assessments (cont.) 
 
Table 2 
Study Flowchart for Q4W Arms:  Week 56 through Week 96 and Early Termination (cont.)  
Week Visit 
 
56 
60 
64 
68 
72 
76 
80 
84 
88
92 
96 
Early 
Term a 
Serum pregnancy sample f, i  
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test f, j  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Serum ATA sample f 
 
 
 
 
x 
 
 
 
 
 
x 
x 
Serum PK sample for lampalizumab concentration f 
 
 
 
 
x 
 
 
 
 
 
x 
x 
Optional aqueous sample f 
 
 
 
 
x 
 
 
 
 
x 
 
 
AH50 sample f 
 
 
 
 
 
 
 
 
 
 
x 
x 
BCVA testing (starting at 4 m) k 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
LL BCVA (staring at 4 m) k 
 
 
 
 
x 
 
 
 
 
 
x 
x 
MNRead or Radner Reading Charts k,l 
 
 
 
 
x 
 
 
 
 
 
x 
x 
Pre-treatment IOP measurement k 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mesopic microperimetry at selected sites(study eye only) m 
 
 
 
 
x 
 
 
 
 
 
x 
x 
Slit-lamp examination 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Dilated binocular indirect ophthalmoscopy 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
FAF n 
 
 
 
 
x 
 
 
 
 
 
x 
x 
Keratometry n 
 
 
 
 
 
 
 
 
 
 
 
 
SD-OCT n 
 
 
 
 
x 
 
 
 
 
 
x 
x 
Near infrared imaging n 
 
 
 
 
x 
 
 
 
 
 
x 
x 
Fundus photography n 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
 


 
Lampalizumab—F. Hoffmann-La Roche Ltd 
110/Protocol GX29185, Version 6 
Appendix 1 Schedule of Assessments (cont.) 
 
Table 2 
Study Flowchart for Q4W Arms:  Week 56 through Week 96 and Early Termination (cont.)  
Week Visit 
 
56 
60 
64 
68 
72 
76 
80 
84 
88
92 
96 
Early 
Term a 
Fluorescein angiography n 
 
 
 
 
 
 
 
 
 
 
x 
x 
Administration of lampalizumab injection/sham to study eye  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Post-treatment finger counting and IOP measurement o 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Concomitant medications p 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events q 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concurrent ocular procedures r 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Follow-up call s 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
AH50 = Alternative Complement Pathway activity assay; ATA = anti-therapeutic antibody; BCVA = best corrected visual acuity; CFI = complement 
factor I; eCRF = electronic Case Report Form; FAF = fundus autofluorescence; FRI Index = Functional Reading Independence Index; 
IOP = intraocular pressure; LL BCVA = Low Luminance BCVA; MNRead = Minnesota Low-Vision Reading Test; NA = not applicable; NEI VFQ-
25 = National Eye Institute Visual Functioning Questionnaire 25-item Version; PK = pharmacokinetic; Q4W = every 4 weeks; SD-OCT = spectral 
domain optical coherence tomography; SF = screen fail. 
Note:  All ocular assessments are to be performed for both eyes unless noted otherwise.  All assessments are to be performed on the same day, 
except those at screening.  All study visits will be scheduled relative to date of Day 1 visit (first study treatment). 
a For patients who discontinue early from the study, early termination assessments will be performed after minimum of 30 days have lapsed 
following the last study treatment. 
b Significant medical and surgical history, including chronic and ongoing conditions (e.g., trauma, cancer, and ophthalmic history), and tobacco 
use. 
c To be administered by the masked site staff (except for the VA examiner) prior to any other visit assessments being performed on that day.   
d If available, the study patients who are not part of the serial ECG evaluation (Section 4.5.7) will provide historical results of a clinical 12-lead 
ECG performed within the 12 months preceding Day 1 study treatment.  The results will be stored in a patient source document. If there was no 
ECG performed within the 12 months preceding Day 1, it is not required to obtain a Screening/Day 1 ECG.  
 
 


 
Lampalizumab—F. Hoffmann-La Roche Ltd 
111/Protocol GX29185, Version 6 
Appendix 1 Schedule of Assessments (cont.) 
 
Table 2 
Study Flowchart for Q4W Arms:  Week 56 through Week 96 and Early Termination (cont.)  
e At selected sites, ECG will be performed at the timepoints listed.  Perform ECG at early termination visit only if a patient is discontinuing study 
prior to the Week 24 visit.  Patients should be in a resting position for 10 min. prior to each ECG evaluation.  Body position should be consistently 
maintained for each ECG evaluation to prevent changes in heart rate.  Environmental distractions (e.g., television, radio, conversation) should be 
minimized before and during ECG recording.  The ECG result will be read by the central reader. See ECG manual for details. 
f Obtain prior to fluorescein angiograph (if applicable) and prior to study treatment. 
g Vital signs consist of blood pressure, respiratory rate, heart rate, and temperature; on Day 1 visit; this should be collected before study treatment. 
h CFI whole blood sample and CFI buccal swab sample will be collected at screening and will also be retained for the screen-failed patients. 
i At screening, collect serum pregnancy sample for women of childbearing potential, including those who have had tubal ligation.  If positive, 
record the patient as a screen fail. 
j Starting at Day 1, collect and perform the urine pregnancy test for women of childbearing potential, including those who have had tubal ligation, 
at each study treatment visit.  If positive, collect the serum pregnancy sample and forward to central lab for testing; if the serum pregnancy test is 
positive, do not administer the study treatment. At ET visit, collect the serum pregnancy sample and forward to the central lab for testing. 
k Perform the assessments prior to dilating the eyes. 
l MNRead charts or Radner Reading Charts can be done during study visit, prior to dilating the eyes (see the tables in Appendix 18 and 
Appendix 19 for which chart to use according to country of the site).  The test will be administered first monocularly (right/left eye) and then 
binocularly (both eyes). 
m Microperimetry assessments will be performed post-dilation on the study eye only, and the data will be forwarded to the central reading center. 
Note: If the Investigator determines that both eyes of a patient meet the eligibility criteria for the study eye, mesopic microperimetry will be 
performed on both eyes at screening. 
n SD-OCT and FAF images (including keratometry), near infrared images, fluorescein angiograms, and fundus photographs (as applicable) will be 
performed for both eyes and will be forwarded to the central reading center. See reading center manual.  Note: after randomization, if a patient 
misses a study visit when ocular images were scheduled to be taken (Appendix 1), the images should be obtained at the next scheduled visit.   
o Finger-counting test followed by hand-motion and light-perception tests (when necessary) will be performed by the unmasked physician within 
15 minutes after study treatment.  At study treatment visits, post-treatment IOP measurement in the study eye only between 30−50 minutes after 
study treatment (drug or sham) will be performed by the masked site staff (except for the VA examiner).  If the IOP is increased by ≥10 mm Hg 
from pre-treatment, the IOP will be measured again at 60−80 minutes post-treatment.  If there are no safety concerns, the patient will be 
permitted to leave the clinic.  If the IOP value is of concern to the investigator, the patient will remain in the clinic and will be managed in 
accordance with the investigator’s clinical judgment. Both the last post-treatment IOP measured prior to any intervention for increased IOP (if 
applicable) and the last post-intervention IOP (if applicable) will be recorded on the post-treatment IOP eCRF. Note: if the study eye is treated 
with a Lucentis injection during the same visit as the study treatment (lampalizumab/sham), the treatment with Lucentis must be performed first. 
Measure and record the post-Lucentis treatment IOP value on the eCRF.   


 
Lampalizumab—F. Hoffmann-La Roche Ltd 
112/Protocol GX29185, Version 6 
Appendix 1 Schedule of Assessments (cont.) 
 
Table 2 
Study Flowchart for Q4W Arms:  Week 56 through Week 96 and Early Termination (cont.)  
p Record any concomitant medications (i.e., any prescription medications or over-the-counter preparations other than protocol-specified 
procedural medications such as proparacaine, etc.) used by the patient within 7 days preceding Day 1 and through the conclusion of the 
patient’s study participation or early termination visit. 
q After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by a protocol-mandated 
intervention (e.g., procedures such as fluorescein angiography) should be reported.  Adverse events will be recorded starting on Day 1 after the 
study treatment through the last study visit.  Adverse events assessed by the physician as related to lampalizumab should be followed until the 
event resolves or the event is assessed as irreversible, chronic, or stable, even if patient’s participation in the study has ended. 
r Record all concurrent ocular procedures performed on the study or non-study eye. 
s Starting at Week 4, study patients will be contacted by study site personnel 4 (± 2) days after each study treatment to elicit reports of any 
decrease in vision, eye pain, unusual redness, or any other new ocular symptoms in the study eye.  At sites where the investigator’s decision is 
for the patients to take pre- and post-treatment antimicrobials, patients will also be asked whether they have taken the prescribed, self-
administered, post-treatment antimicrobials.  Patients will be instructed to contact the investigator at any time if they have any health-related 
concerns.  If warranted, patients will be asked to return to the clinic as soon as possible for a safety assessment visit. 
 
 
 


 
Lampalizumab—F. Hoffmann-La Roche Ltd 
113/Protocol GX29185, Version 6 
Appendix 1 Schedule of Assessments (cont.) 
 
Table 3 
Study Flowchart for Q6W Arms: Day 1, Day 8, Week 6 through Week 96, and Early Termination 
Day 
Week Visit 
 
Screening 
1 
8 
6 
12 
18 
24 
30 
36 
42 
48 
54 
60 
66 
72 
78 
84 
90 
96 
Early 
Term a 
Assessment Windows 
(Days) 
−28 to −1 
NA 
±2 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
See 
footnote 
a 
Written informed 
consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of inclusion 
and exclusion criteria 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and surgical 
history including 
tobacco history b 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic 
information 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NEI VFQ-25 c 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
x 
FRI Index c 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
x 
Physical examination 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Height and weight 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Historical ECG d 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG at selected sites 
e, f 
 
x 
x 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Vital signs f, g 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 


 
Lampalizumab—F. Hoffmann-La Roche Ltd 
114/Protocol GX29185, Version 6 
Appendix 1 Schedule of Assessments (cont.) 
 
Table 3 
Study Flowchart for Q6W Arms: Day 1, Day 8, Week 6 through Week 96, and Early Termination (cont.)  
Day 
Week Visit 
 
Screening 
1 
8 
6 
12 
18 
24 
30 
36 
42 
48 
54 
60 
66 
72 
78 
84 
90 
96 
Early 
Term a 
Assessment Windows 
(Days) 
−28 to −1 
NA 
±2 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
See 
footnote 
a 
Central laboratory 
samples (hematology, 
coagulation, serum 
chemistry, and 
urinalysis) f 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
CFI whole blood  
sample (SF patients 
included) f, h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CFI buccal swab  
sample (SF patients 
included) f, h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker plasma 
sample f 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker paxgene 
sample f 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker whole blood 
clinical genotyping  
sample f 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy 
sample f, i, j 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Urine pregnancy test f,j 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Serum ATA sample f 
 
x 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
x 
 


 
Lampalizumab—F. Hoffmann-La Roche Ltd 
115/Protocol GX29185, Version 6 
Appendix 1 Schedule of Assessments (cont.) 
 
Table 3 
Study Flowchart for Q6W Arms: Day 1, Day 8, Week 6 through Week 96, and Early Termination (cont.)  
Day 
Week Visit 
 
Screening 
1 
8 
6 
12 
18 
24 
30 
36 
42 
48 
54 
60 
66 
72 
78 
84 
90 
96 
Early 
Term a 
Assessment Windows 
(Days) 
−28 to −1 
NA 
±2 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
See 
footnote 
a 
Serum PK sample for 
lampalizumab 
concentration f 
 
x 
x 
x 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
x 
Optional aqueous 
sample f 
 
x 
 
 
 
 
x 
 
 
x 
 
 
 
 
x 
 
 
x 
 
 
AH50 sample f 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
x 
BCVA testing (starting 
at 4 m) k 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
LL BCVA testing 
(starting at 4 m) k 
 
x 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
x 
MNRead or Radner 
Reading Charts k, l 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
x 
Pre-treatment IOP 
measurement k 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mesopic 
microperimetry at 
selected sites (study 
eye only) m 
x 
x 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
x 
Slit-lamp examination 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


 
Lampalizumab—F. Hoffmann-La Roche Ltd 
116/Protocol GX29185, Version 6 
Appendix 1 Schedule of Assessments (cont.) 
 
Table 3 
Study Flowchart for Q6W Arms: Day 1, Day 8, Week 6 through Week 96, and Early Termination (cont.)  
Day 
Week Visit 
 
Screening 
1 
8 
6 
12 
18 
24 
30 
36 
42 
48 
54 
60 
66 
72 
78 
84 
90 
96 
Early 
Term a 
Assessment Windows 
(Days) 
−28 to −1 
NA 
±2 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
See 
footnote 
a 
Dilated binocular 
indirect 
ophthalmoscopy 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
FAF n 
x 
 
 
 
 
 
x 
 
x 
 
x 
 
 
 
x 
 
 
 
x 
x 
Keratometry n 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SD-OCT n 
x 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
x 
Near infrared 
imaging n 
x 
 
 
 
 
 
x 
 
x 
 
x 
 
 
 
x 
 
 
 
x 
x 
Fundus photography n 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
x 
Fluorescein 
angiography n 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
x 
Administration of 
lampalizumab 
injection/sham to 
study eye 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Post-treatment finger 
counting and IOP 
measurement o 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 


 
Lampalizumab—F. Hoffmann-La Roche Ltd 
117/Protocol GX29185, Version 6 
Appendix 1 Schedule of Assessments (cont.) 
 
Table 3 
Study Flowchart for Q6W Arms: Day 1, Day 8, Week 6 through Week 96, and Early Termination (cont.)  
Day 
Week Visit 
 
Screening 
1 
8 
6 
12 
18
24 
30
36 
42
48 
54 
60 
66
72 
78
84 
90
96 
Early 
Term a 
Assessment 
Windows (Days) 
−28 to −1 
NA
±2 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
See 
footnote 
a 
Concomitant 
medications p 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events q 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concurrent ocular 
procedures r 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Follow-up call s 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
AH50 = Alternative Complement Pathway activity assay; ATA = anti-therapeutic antibody; BCVA = best corrected visual acuity; 
CFI = complement factor I; eCRF = electronic Case Report Form; FAF = fundus autofluorescence; FRI Index = Functional Reading 
Independence Index; IOP = intraocular pressure; LL BCVA = Low Luminance BCVA; MNRead = Minnesota Low-Vision Reading Test; NA = not 
applicable; NEI VFQ-25 = National Eye Institute Visual Functioning Questionnaire 25-item Version; PK = pharmacokinetic; Q4W = every 4 
weeks; SD-OCT = spectral domain optical coherence tomography; SF = screen fail. 
Note:  All ocular assessments are to be performed for both eyes unless noted otherwise.  All assessments are to be performed on the same 
day, except those at screening.  All study visits will be scheduled relative to date of Day 1 visit (first study treatment). 
a For patients who discontinue early from the study, early termination assessments will be performed after minimum of 30 days have lapsed 
following the last study treatment. 
b Significant medical and surgical history, including chronic and ongoing conditions (e.g., trauma, cancer, and ophthalmic history), and 
tobacco use. 
c To be administered by the masked site staff (except for the VA examiner) prior to any other visit assessments being performed on that 
day.   
d If available, the study patients who are not part of the serial ECG evaluation (Section 4.5.7) will provide historical results of a clinical 
12-lead ECG performed within the 12 months preceding Day 1 study treatment.  The results will be stored in a patient source document. If 
there was no ECG performed within the 12 months preceding Day 1, it is not required to obtain a Screening/Day 1 ECG.  


 
Lampalizumab—F. Hoffmann-La Roche Ltd 
118/Protocol GX29185, Version 6 
Appendix 1 Schedule of Assessments (cont.) 
 
Table 3 
Study Flowchart for Q6W Arms: Day 1, Day 8, Week 6 through Week 96, and Early Termination (cont.)  
e At selected sites, ECG will be performed at the timepoints listed.  Perform ECG at early termination visit only if a patient is discontinuing 
study prior to the Week 24 visit.  Patients should be in a resting position for 10 min. prior to each ECG evaluation.  Body position should be 
consistently maintained for each ECG evaluation to prevent changes in heart rate.  Environmental distractions (e.g., television, radio, 
conversation) should be minimized before and during ECG recording.  The ECG result will be read by the central reader. See ECG 
manual for details. 
f Obtain prior to fluorescein angiograph (if applicable) and prior to study treatment. 
g Vital signs consist of blood pressure, respiratory rate, heart rate, and temperature; on Day 1 visit; this should be collected before study 
treatment. 
h CFI whole blood sample and CFI buccal swab sample will be collected at screening and will also be retained for the screen-failed patients. 
i At screening, collect serum pregnancy sample for women of childbearing potential, including those who have had tubal ligation.  If positive, 
record the patient as a screen fail. 
j Starting at Day 1, collect and perform the urine pregnancy test for women of childbearing potential, including those who have had tubal 
ligation, at each study treatment visit.  If positive, collect the serum pregnancy sample and forward to central lab for testing; if the serum 
pregnancy test is positive, do not administer the study treatment. At ET visit, collect the serum pregnancy sample and forward to the 
central lab for testing. 
k Perform the assessments prior to dilating the eyes. 
l MNRead charts or Radner Reading Charts can be done during study visit, prior to dilating the eyes (see the tables in Appendix 18 and 
Appendix 19 for which chart to use according to country of the site).  The test will be administered first monocularly (right/left eye) and then 
binocularly (both eyes). 
m Microperimetry assessments will be performed post-dilation on the study eye only, and the data will be forwarded to the central reading 
center. Note: If the Investigator determines that both eyes of a patient meet the eligibility criteria for the study eye, mesopic microperimetry 
will be performed on both eyes at screening. 
n SD-OCT and FAF images (including keratometry), near infrared images, fluorescein angiograms, and fundus photographs (as applicable) 
will be performed for both eyes and will be forwarded to the central reading center. See reading center manual.  Note: after randomization, 
if a patient misses a study visit when ocular images were scheduled to be taken (Appendix 1), the images should be obtained at the next 
scheduled visit.   


 
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Appendix 1 Schedule of Assessments (cont.) 
 
Table 3 
Study Flowchart for Q6W Arms: Day 1, Day 8, Week 6 through Week 96, and Early Termination (cont.)  
o  Finger-counting test followed by hand-motion and light-perception tests (when necessary) will be performed by the unmasked physician 
within 15 minutes after study treatment.  At study treatment visits, post-treatment IOP measurement in the study eye only between 30−50 
minutes after study treatment (drug or sham) will be performed by the masked site staff (except for the VA examiner).  If the IOP is 
increased by ≥10 mm Hg from pre-treatment, the IOP will be measured again at 60−80 minutes post-treatment.  If there are no safety 
concerns, the patient will be permitted to leave the clinic.  If the IOP value is of concern to the investigator, the patient will remain in the 
clinic and will be managed in accordance with the investigator’s clinical judgment. Both the last post-treatment IOP measured prior to any 
intervention for increased IOP (if applicable) and the last post-intervention IOP (if applicable) will be recorded on the post-treatment IOP 
eCRF. Note: if the study eye is treated with a Lucentis injection during the same visit as the study treatment (lampalizumab/sham), the 
treatment with Lucentis must be performed first. Measure and record the post-Lucentis treatment IOP value on the eCRF.   
p Record any concomitant medications (i.e., any prescription medications or over-the-counter preparations other than protocol-specified 
procedural medications such as proparacaine, etc.) used by the patient within 7 days preceding Day 1 and through the conclusion of the 
patient’s study participation or early termination visit. 
q After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by a protocol-
mandated intervention (e.g., procedures such as fluorescein angiography) should be reported.  Adverse events will be recorded starting 
on Day 1 after the study treatment through the last study visit.  Adverse events assessed by the physician as related to lampalizumab 
should be followed until the event resolves or the event is assessed as irreversible, chronic, or stable, even if patient’s participation in the 
study has ended. 
r Record all concurrent ocular procedures performed on the study or non-study eye. 
s Starting at Week 6, study patients will be contacted by study site personnel 4 (± 2) days after each study treatment to elicit reports of any 
decrease in vision, eye pain, unusual redness, or any other new ocular symptoms in the study eye.  At sites where the investigator’s 
decision is for the patients to take pre- and post-treatment antimicrobials, patients will also be asked whether they have taken the 
prescribed, self-administered, post-treatment antimicrobials.  Patients will be instructed to contact the investigator at any time if they have 
any health-related concerns.  If warranted, patients will be asked to return to the clinic as soon as possible for a safety assessment visit. 
 


 
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Appendix 2 Study Flowchart: 
Unscheduled Safety Assessment Visit 
Assessments a 
Vital signs (blood pressure, respiration rate, pulse, and temperature) 
Best corrected visual acuity (4-m starting distance) b 
Slit-lamp examination 
Dilated binocular indirect high-magnification ophthalmoscopy 
Intraocular pressure c 
Adverse events d 
Concurrent ocular procedures 
Concomitant medications 
IOP = intraocular pressure. 
a If determined to be necessary by the physician, perform the listed assessments.  All ocular 
assessments should be performed on both eyes. 
b Perform finger-counting test followed by hand motion and light perception tests when 
necessary. 
c The method used for the IOP measurement for a patient must remain consistent throughout 
the study. 
d Adverse event causality to be evaluated by the masked qualified ophthalmologist. 
 


 
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Appendix 3 Grading Scale for Assessment of Anterior Chamber 
Flare or Cells and Vitreous Cells 
Table 1 
Grading Scale for Anterior Chamber Flare or Cells 
Grade 
Description 
Flare 
0 
No protein is visible in the anterior chamber when viewed by an experienced observer 
using slit-lamp biomicroscopy; a small, bright, focal slit-beam of white light; and high 
magnification. 
Trace 
Trace amount of protein is detectable in the anterior chamber.  This protein is visible 
only with careful scrutiny by an experienced observer using slit-lamp biomicroscopy; a 
small, bright, focal slit-beam of white light; and high magnification. 
1+ 
Slight amount of protein is detectable in the anterior chamber:  the presence of protein in 
the anterior chamber is immediately apparent to an experienced observer using slit-lamp 
biomicroscopy and high magnification, but such protein is detected only with careful 
observation with the naked eye and a small, bright, focal slit-beam of white light. 
2−3+ 
Moderate amount of protein is detectable in the anterior chamber.  These grades are 
similar to 1+ but the opacity would be readily visible to the naked eye of an observer 
using any source of a focused beam of white light.  This is a continuum of moderate 
opacification, with 2+ being less apparent than 3+. 
4+ 
A large amount of protein is detectable in the anterior chamber.  This grade is similar to 
3+, but the density of the protein approaches that of the lens.  Additionally, frank fibrin 
deposition is frequently seen in acute circumstances.  It should be noted that because 
fibrin may persist for a period of time after partial or complete restoration of the 
blood−aqueous barrier, it is possible to have resorbing fibrin present with lower numeric 
assignations for flare (e.g., 1+ flare with fibrin). 
Cells 
0 
No cells are seen in any optical section when a large slit-lamp beam is swept across the 
anterior chamber. 
Trace 
Few (1−3) cells are observed when the slit-lamp beam is swept across the anterior 
chamber.  When the instrument is held stationary, not every optical section contains 
circulating cells. 
1+ 
3−10 cells per optical section are seen when the slit-lamp beam is swept across the 
anterior chamber.  When the instrument is held stationary, every optical section contains 
circulating cells. 
2+ 
10−25 cells are seen when the slit-lamp beam is swept across the anterior chamber.  
When the instrument is held stationary, every optical section contains circulating cells. 
 


 
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Appendix 3 Grading Scale for Assessment of Anterior Chamber 
Flare or Cells and Vitreous Cells (cont.) 
 
Table 1 
Grading Scale for Anterior Chamber Flare or Cells (cont.)  
Grade 
Description 
3+ 
25−50 cells are seen when the slit-lamp beam is swept across the anterior chamber.  
When the instrument is held stationary, every optical section contains circulating cells.  
Keratic precipitates or cellular deposits on the anterior lens capsule may be present. 
4+ 
More than 50 cells are seen when the slit-lamp beam is swept across the anterior 
chamber.  When the instrument is held stationary, every optical section contains cells, or 
hypopyon is noted.  As for fibrin deposition, hypopyon may persist for some period of 
time after the active exudation of cells into the anterior chamber has diminished or 
ceased entirely, making it possible to have 1+ circulating cells in the anterior chamber 
with a resolving hypopyon. 
Modified from:  Hogan et al. (1959). 
 
Table 2 
Grading Scale for Vitreous Cells 
Cells in Retro-Illuminated Field 
Description 
Grade 
0 
Clear 
0 
1−20 
Few opacities 
Trace 
21−50 
Scattered opacities 
1 
51−100 
Moderate opacities 
2 
101−250 
Many opacities 
3 
≥251 
Dense opacities 
4 
Modified from:  Nussenblatt et al. (1996). 
 
REFERENCES 
Hogan MH, Kimura SJ, Thygeson P. Signs and symptoms of uveitis. I. Anterior uveitis. 
Am J Ophthalmol 1959;47(5, Part 2):155−70. 
Nussenblatt RB, Whitcup SM, Palestine AG. Uveitis: fundamentals and clinical practice. 
In: Nussenblatt RB, Whitcup SM, Palestine AG, eds. Examination of the patient with 
uveitis. 2nd ed. St Louis: Mosby, 1996; 64. 
 


 
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Appendix 4 Pre-Injection Procedures for All Patients 
Note: If (as per masked investigator judgment) treatment with Lucentis is to be given (to 
study and/or non-study eye) at the same visit as a study eye treatment with 
lampalizumab/sham, the treatment with Lucentis must be administered first. Following 
this, a safety assessment (including an IOP check) must be completed prior to proceeding 
to the study eye treatment with lampalizumab/sham.  If there are no concerns, proceed 
with calling IxRS for the study treatment kit assignment.  Individual trays and sterile prep 
must be separately prepared for each treatment. The injecting physician will perform the 
treatment with Lucentis to preserve the masking.    
PRE-INJECTION PROCEDURES 
The pre-injection procedure, lampalizumab reconstitution and intravitreal injection or 
sham (fake) injection procedures and post-injection procedures are also described in 
details in the Pharmacy Binder. 
While reconstituting lampalizumab, a sterile field must be used and any personnel must 
wear a surgical face mask.  Lampalizumab should be administered within 2 hours 
following reconstitution; the prepared dose may be maintained at room temperature prior 
to administration.  There is no reconstitution process for the sham injection.   
The following procedures will be used to minimize the risk of potential adverse events 
(AEs) associated with intravitreal injections (e.g., endophthalmitis).  Aseptic technique 
must be observed by clinic staff involved in the injection tray assembly, anesthetic 
preparation, and study drug (lampalizumab) and/or sham treatment preparation and 
administration.  In addition to the procedures outlined below, any additional safety 
measures in adherence to specific institutional policies associated with intravitreal 
injections will be observed. 
As per individual site investigator decision, patients may self-administer antimicrobial 
drops prior to treatment and after treatment following each injection (study drug or 
sham). 
PROCEDURE FOR LIDOCAINE-BASED ANESTHESIA 
The injecting physician or technician (if applicable) assembles the supplies and prepares 
a sterile field.  Supplies include 10% povidone iodine swabs, sterile surgical gloves, 
4 × 4 sterile pads, a pack of sterile cotton-tipped applicators, eyelid speculum, sterile 
ophthalmic drape, 0.5% proparacaine hydrochloride (or equivalent), 5% povidone iodine 
ophthalmic solution, 1% or 2% lidocaine for injection, ophthalmic antimicrobial solution (if 
applicable) and injection supplies.  The procedure is as follows: 
• 
Instill two drops of 0.5% proparacaine hydrochloride (or equivalent) into the study 
eye, followed by two drops of antimicrobial solution (if applicable)   


 
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Appendix 4 Pre-Injection Procedures for All Patients (cont.)  
• 
Disinfect the periocular skin and eyelid of the study eye in preparation for 
injection.  Scrub the eyelid, lashes, and periorbital skin with 10% povidone iodine 
swabs, starting with the eyelid and lashes and continuing with the surrounding 
periocular skin.  Ensure that the eyelid margins and lashes are swabbed, 
and proceed in a systematic fashion, from medial to temporal aspects. 
• 
The physician will glove, place sterile ophthalmic drape to isolate the field, and place 
the speculum underneath the eyelid of the study eye. 
• 
Instill two drops of 5% povidone iodine ophthalmic solution in the study eye, 
ensuring that the drops cover the planned study treatment (lampalizumab/sham) site 
on the conjunctiva. 
• 
Wait 90 seconds. 
• 
Saturate a sterile, cotton-tipped applicator with 0.5% proparacaine hydrochloride (or 
equivalent) drops and hold the swab against the planned injection site for 
10 seconds in preparation for the subconjunctival injection of 1% or 2% lidocaine 
hydrochloride ophthalmic solution for injection (without epinephrine). 
• 
Inject lidocaine (without epinephrine) subconjunctivally. 
• 
Use a sterile 4 × 4 pad in a single wipe to absorb excess liquid and to dry 
the periocular skin. 
Note: For patients that develop adverse reaction to povidone-iodine, the 
following approaches are permitted:   
• 
irrigate the eye with sterile saline after the study treatment (lampalizumab/sham) 
aiming to rinse away any remaining povidone-iodine  
or  
• 
use a limited amount of povidone-iodine by placing a swab directly on the treatment 
site after the lid speculum has been placed   
 


 
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Appendix 5 Preparation and Administration of Lampalizumab 
Injection 
The drug must be reconstituted using a sterile field while personnel (the unmasked 
technician or treating physician) are wearing a surgical face mask.  Within 2 hours 
following dose preparation (reconstitution), lampalizumab should be administered; the 
prepared dose may be maintained at room temperature prior to administration.   
Reconstitute for the 10-mg lampalizumab dose as follows: 
1. 
Remove the plastic flip-off seal from one vial of lampalizumab lyophilized powder 
(6-cc vial), and swab the top of the vial with an alcohol swab. 
2. 
Remove the plastic flip-off seal from one vial of Sterile Water for Injection (SWFI) 
(10-cc vial), and swab the top of the vial with an alcohol swab. 
3. 
Using a 1 cc tuberculin (or equivalent) syringe with an 18 or 19-gauge needle, 
withdraw enough volume of SWFI (10-cc vial), to deliver 0.50 mL of SWFI, expel 
any air bubbles, insert the needle into the lampalizumab vial, and add. 
4. 
Swirl the lampalizumab vial gently until the lyophilized powder dissolves; do not 
shake or vortex the vial vigorously.  Let stand for approximately 5 minutes until 
bubbles dissolve. 
  
Filter the lampalizumab as follows: 
1. 
Withdraw 0.2 mL of lampalizumab dose solution through an 18 or 19-gauge, 5-μm 
filter needle attached to a new 1-cc tuberculin (or equivalent) syringe. 
2. 
After withdrawing lampalizumab in through the filter; remove filter needle; replace 
it with a 30-gauge, 0.5-inch needle (without safety needle device attached); and 
expel excess lampalizumab and air bubbles so that the syringe contains 0.1 mL of 
lampalizumab solution for dosing. 
 


 
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Appendix 5 Preparation and Administration of Lampalizumab 
Injection (cont.)  
Table 1 
Lampalizumab Reconstitution 
Step 
Procedure 
Materials 
Methods 
1 
Reconstitute the lyophilized 
lampalizumab 
Note:  Vials of lampalizumab 
should remain refrigerated 
(2°C-8°C or 36°F−46°F) until 
just prior to reconstitution with 
SWFI. 
• One vial of lyophilized 
lampalizumab 
•  18 or 19-gauge 
needle  
• 1-cc tuberculin(or 
equivalent) syringes 
• 10-cc vial of SWFI 
• Alcohol swabs 
Swab the top of lampalizumab 
vial with an alcohol swab after 
removing the flip-top seal. 
Swab the top of SWFI vial with 
an alcohol swab after removing 
the flip-top seal.  
Using a 1 cc tuberculin (or 
equivalent) syringe with an 18 
or 19-gauge needle, withdraw 
enough volume of SWFI 
(10-cc vial) to deliver 0.50 mL 
of SWFI, expel any air 
bubbles, insert the needle into 
the lampalizumab vial, and 
add. 
Swirl the lampalizumab vial 
containing the SWFI gently 
until the lyophilized powder 
dissolves.  Do not shake 
vigorously or vortex the 
vials.  Let stand for 
approximately 5 minutes until 
bubbles dissolve.   
2 
Filter the lampalizumab 
• 5-μm filter needle 
(needle is 18 or 
19-gauge) 
• New 1-cc tuberculin 
(or equivalent) 
syringe 
• 30 gauge, 0.5-inch 
needle (without 
safety needle device 
attached) 
 
Withdraw 0.2 mL of 
lampalizumab dose solution 
through a new 5-μm filter 
needle attached to a new 1-cc 
tuberculin (or equivalent) 
syringe. 
• After withdrawing 
lampalizumab in through the 
filter, remove filter needle, 
replace it with a 30-gauge, 
0.5-inch, needle (without 
safety needle device 
attached), expel excess 
lampalizumab and air so 
that the syringe contains 0.1 
mL of lampalizumab 
solution. 
SWFI = Sterile Water for Injection. 
  


 
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Appendix 5 Preparation and Administration of Lampalizumab 
Injection (cont.)  
ADMINISTRATION OF LAMPALIZUMAB 
To administer intravitreal lampalizumab, the treating physician will conduct the following 
procedures: 
• 
Put on gloves, place sterile ophthalmic drape to isolate the field, and place the 
speculum underneath the eyelid of the study eye. 
• 
Instill two drops of 5% povidone iodine ophthalmic solution in the study eye, 
ensuring that the drops cover the planned injection site on the conjunctiva. 
• 
Wait approximately 90 seconds. 
• 
Saturate a sterile, cotton-tipped applicator with 0.5% proparacaine hydrochloride 
drops (or equivalent) and hold the swab against the planned intravitreal injection 
site for 10 seconds in preparation for the subconjunctival injection of 1% or 2% 
lidocaine hydrochloride solution for injection (without epinephrine). 
• 
Inject 1% or 2% lidocaine (without epinephrine) subconjunctivally. 
For patients who become intolerant to lidocaine as evidenced by an associated 
adverse event, alternative anesthetic drug for sub-conjunctival anesthesia may 
be permitted after consultation with the Medical Monitor. 
• 
Use a sterile 4 × 4 pad in a single wipe to absorb excess liquid and to dry the 
periocular skin. 
• 
Instruct the patient to direct gaze away from syringe prior to lampalizumab injection. 
• 
Physician will wear surgical face mask and refrain from talking, coughing, or 
sneezing during the injection. 
Administer lampalizumab as follows:  
• 
Insert the needle through an area 3.5−4.0 mm posterior to the limbus, avoiding the 
horizontal meridian and aiming toward the center of the globe.  Rotate the injection 
site at every treatment visit. 
• 
At the physician's discretion, maneuvers such as mild ocular digital massage may 
be applied to the globe prior to the injection to reduce the risk of complications 
secondary to increased IOP.  Inject the dose solution slowly. 
• 
Remove the needle slowly to ensure that all drug solution is in the eye. 
• 
Refer to Appendix 7 for detailed post-injection procedures 
 


 
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Appendix 6 Preparation and Administration of Sham Injection 
Refer to Appendix 4 for detailed instructions for pre-injection procedures. 
The designated unmasked technician (if applicable) or treating physician will prepare the 
sham (fake) injection as outlined below. 
PREPARATION 
Assembly of the tray for the sham (fake) injection will appear identical to that of the study 
drug injection (see Appendix 5).   
Sham vial is empty and will remain empty throughout the sham treatment. It does not 
contain any lyophilized powder.  There is no drug reconstitution step performed for the 
sham treatment.   
ADMINISTRATION 
Patients receiving sham (fake) injections do not receive an actual intravitreal 
injection.  The treating physician will use a needle only for the lidocaine injection given 
subconjunctivally.  The procedures for cleansing and anesthetizing the study eye will be 
performed as outlined in Appendix 4.  The patient should be instructed to direct his or 
her gaze away from the syringe prior to administration of the sham injection.  The 
treating physician will withdraw the tuberculin (or equivalent) syringe plunger to the 
0.1-mL mark on the syringe, and then place the hub of the syringe-without the 
needle−against the pre-anesthetized conjunctival surface.  The treating physician will 
then press the syringe hub firmly against the globe and then slowly depress the plunger, 
mimicking the action of an injection. 
It is essential that the sham injection, including preparation and the sham injection itself, 
mimic as much as possible those used for the administration of study drug.  For 
subsequent sham injection the criteria governing the selection of the study eye when 
both eyes meet eligibility criteria, follow the same procedure of rotating the location of 
the injection site, as is done with the study drug injections (see Appendix 5). 
The treating physician or unmasked technician (if applicable) will discard all injection 
materials (i.e., syringes and needles) in a sharps container immediately following each 
sham injection, and the empty vial will be placed in the kit box.  Refer to Appendix 7 for 
detailed post-injection procedures. 


 
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Appendix 7 Post-Injection Procedures for All Patients 
The patient will be monitored with a finger-counting test within 15 minutes of the study 
treatment by the treating physician. 
The unmasked technician or treating physician will discard the supplies in order to 
preserve patient’s masking.  Discard all syringes and needles in the sharps container. 
Unless country regulatory prohibits, the used study drug or sham kit, including the used 
vial should be stored until the Sponsor representative conducts the study drug or sham 
accountability and the site is instructed to discard or ship to the Sponsor. 
Any materials that could disclose the identity of study treatment kit or patient treatment 
assignment should be removed from the tray. 
As per individual site investigator decision, patients may self-administer antimicrobial 
drops pre- and post-injection (study drug or sham).   
A measurement of intraocular pressure in the study eye only will be obtained between 
30 and 50 minutes after study treatment (drug or sham) by the qualified masked (except 
for the VA examiner) site staff.  If the IOP is increased by ≥10 mm  from pre-injection, 
the IOP will be measured again at 60−80 minutes post-injection.  If there are no safety 
concerns, the patient will be permitted to leave the clinic.  If the IOP value is of concern 
to the investigator, the patient will remain in the clinic and will be managed in 
accordance with the investigator’s clinical judgment.  Both, the last post-injection IOP 
measured prior to any intervention for increased IOP (if applicable) and the last post 
intervention IOP value (if applicable) will be recorded on the appropriate eCRF.  If 
applicable, an Adverse Event eCRF page will be completed.  
 


 
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Appendix 8 Best Corrected Visual Acuity Testing 
SCOPE 
Best corrected visual acuity will be measured by trained and certified personnel at the 
study sites.  The visual acuity (VA) examiner must be masked to each patient’s study 
(treated) eye and treatment arm (study drug vs. sham) assignment.  VA will be 
measured at the intervals specified in the protocol (see Section 4.5 of the protocol and 
Appendix 1). 
EQUIPMENT 
The following are needed to conduct the examination: 
• 
Examination lane of adequate dimensions to allow testing at required distances 
• 
Standard chair with a firm back 
• 
Set of three Precision Vision™ or Lighthouse distance acuity charts (modified Early 
Treatment Diabetic Retinopathy Study Charts R, 1, and 2 in the United States and 
Charts 1, 2, 3 in the European Union) 
• 
Retro-Illuminated box 
• 
Study frame 
• 
Study lens set 
TRAINING AND CERTIFICATION 
A VA specifications document, procedure manual, and training materials will be provided 
to the investigational sites, and examiner certification will be obtained.  The VA 
examination room also must be certified before any VA examinations are performed. 
 


 
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Appendix 9 Low Luminance Best Corrected Visual Acuity 
Testing 
There are the same requirements as the best corrected visual acuity described in 
Appendix 8; however, the low luminance visual acuity will be measured by placing a 
2.0-log-unit neutral density filter (Kodak Wratten 2.0 Neutral Density Filter) over the best 
correction for that eye and having the participant read the normally illuminated Early 
Treatment Diabetic Retinopathy Study chart.  
 


 
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Appendix 10   Color Fundus Photography 
SCOPE 
Stereo color fundus photographs will be taken by trained personnel at the study sites.  
Fundus photography will be performed at the intervals specified in the protocol 
(see Appendix 1).  Analysis (if applicable) of fundus photographs will be performed by 
the central reading center. 
EQUIPMENT 
See the Central Reading Center Manual. 
PROCEDURE 
The central reading center will provide a study manual and training materials.  The 
fundus photographer and photography equipment will be certified by the reading center 
before any study images are taken.  See the Central Reading Center Manual for further 
details. 
 


 
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Appendix 11   Fluorescein Angiography 
SCOPE 
Fluorescein angiography will be performed at the study sites by trained personnel who 
are certified by the central reading center.  The fluorescein angiograms (FAs) will be 
obtained at the intervals specified in the protocol (see Appendix 1).  Analysis (if 
applicable) of FAs will be performed by the central reading center. 
EQUIPMENT 
Digital angiograms must be used while conducting an angiographic evaluation for the 
study. 
Film-based angiography is not acceptable. 
DIGITAL IMAGING SYSTEMS AND CERTIFICATION 
Digital imaging systems are required.  The system and software at the site will be 
certified by the central reading center prior to obtaining any study angiograms.  This 
certification and validation process will ensure that the central reading center will be able 
to correctly calculate the required measurements. 
PROCEDURES 
The central reading center will provide a study manual and training materials.  
Photographers, systems, and software will be certified prior to obtaining angiograms of 
patients. 
 


 
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Appendix 12   Fundus Autofluorescence 
SCOPE 
Fundus autofluorescence (FAF) will be performed at the study sites by trained personnel 
who are certified by the central reading center.  FAF imaging will be performed for each 
patient at the intervals specified in the protocol (see Appendix 1) and will be forwarded to 
the central reading center.  Analysis (if applicable) of FAF images will be performed by 
the central reading center. 
EQUIPMENT 
Equipment utilized during this study is described in the Central Reading Center Manual.  
The ability to transfer images to electronically exportable digital files is required (i.e., no 
printed FAF images will be sent to the central reading center). 
PROCEDURES AND CERTIFICATION 
The central reading center will provide the study manual and training materials.  
FAF operators, systems, and software will be certified prior to any evaluation of patients. 
 


 
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Appendix 13   Spectral Domain-Optical Coherence Tomography 
SCOPE 
Spectral domain optical coherence tomography (SD-OCT) will be performed at the study 
sites by trained personnel who are certified by the central reading center.  SD-OCT 
imaging will be performed for each patient at the intervals specified in the protocol 
(see Appendix 1). 
The SD-OCT images of both eyes will be obtained at protocol-specified visits and will be 
forwarded to the central reading center. 
EQUIPMENT 
Equipment utilized during this study is described in the Central Reading Center Manual.  
The ability to transfer images to electronically exportable digital files is required 
(i.e., no printed SD-OCT images will be sent to the central reading center). 
PROCEDURES AND CERTIFICATION 
The central reading center will provide the study manual and training materials.  
SD-OCT operators, systems, and software will be certified prior to any evaluation of 
patients. 
 


 
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Appendix 14   Near-Infrared Imaging 
Note:  Near infrared (NI) images are taken to complement the central reading center 
evaluation of fundus autofluorescence images. 
SCOPE 
NI imaging will be performed at the study sites by trained personnel who are certified by 
the central reading center.  NI imaging will be performed for each patient at the intervals 
specified in the protocol (see Appendix 1). 
The NI images of both eyes will be obtained at protocol-specified visits and will be 
forwarded to the central reading center. 
EQUIPMENT 
Equipment utilized during this study is described in the Central Reading Center Manual.  
The ability to transfer images to electronically exportable digital files is required 
(i.e., no printed NI images will be sent to the central reading center). 
PROCEDURES AND CERTIFICATION 
The central reading center will provide the study manual and training materials.  
NI operators, systems, and software will be certified prior to any evaluation of patients. 
 


 
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Appendix 15  
Mesopic Microperimetry at Selected Sites 
SCOPE 
Mesopic microperimetry of the study eye only will be performed at selected study sites 
by trained personnel who are certified by the central reading center.  The microperimetry 
will be performed on patients who meet eligibility criteria as defined in the Central 
Reading Center Manual. 
The microperimetry results of the study eye will be obtained at protocol-specified visits 
(see Appendix 1) and will be forwarded to the central reading center. 
Note: If the Investigator determines that both eyes of a patient meet the eligibility 
criteria for study eye, mesopic microperimetry will be performed on both eyes at 
screening.    
EQUIPMENT 
Equipment utilized during this study is described in the Central Reading Center Manual.  
The ability to transfer images to electronically exportable digital files is required (i.e., no 
printed microperimetry results will be sent to the central reading center). 
PROCEDURES AND CERTIFICATION 
The central reading center will provide the study manual and training materials.  
Microperimetry operators, systems, and software will be certified prior to any evaluation 
of patients. 
 


 
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Appendix 16  National Eye Institute Visual Functioning 
Questionnaire 25-Item Version 
The study center and investigator will include the following credit or attribution statement 
for the National Eye Institute Visual Functioning Questionnaire 25-Item Version (NEI 
VFQ-25) questionnaire in any public presentation, publication, or other dissemination of 
or reference to the NEI VFQ-25 as used in this study. 
The following form, based upon NEI VFQ-25, was developed at RAND under the 
sponsorship of the NEI and was adapted by the Sponsor for use in this study.  Six 
questions from the appendix of optional additional questions for the NEI VFQ, pertaining 
to the near activities and distance activities, were added to the form.  Minor changes (not 
affecting the items of the questionnaire) were made to the form, and a header was 
added with the study number, Sponsor’s name, visit, and patient identifiers. 
INSTRUCTIONS TO PARTICIPANTS 
I am going to read you some statements about problems, which involve your vision or 
feelings that you have about the condition of your vision.  After each question, I will read 
you a list of possible answers.  Please choose the response that best describes your 
situation. 
Please answer all the questions as if you were wearing your glasses or contact lenses 
(if any). 
Please take as much time as you need to answer each question.  All your answers are 
confidential.  In order for this study survey to improve our knowledge about vision 
problems and how they affect your quality of life, your answers must be as accurate as 
possible.  Remember, if you wear glasses or contact lenses for a particular activity, 
please answer all of the following questions as though you were wearing them. 
 
 
 
 
 
 
 
 


 
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Appendix 16  National Eye Institute Visual Functioning 
Questionnaire 25-Item Version (cont.)  
 
 


 
Lampalizumab—F. Hoffmann-La Roche Ltd 
140/Protocol GX29185, Version 6 
Appendix 16  National Eye Institute Visual Functioning 
Questionnaire 25-Item Version (cont.)  
 
 
 


 
Lampalizumab—F. Hoffmann-La Roche Ltd 
141/Protocol GX29185, Version 6 
Appendix 16  National Eye Institute Visual Functioning 
Questionnaire 25-Item Version (cont.)  
 
 
 


 
Lampalizumab—F. Hoffmann-La Roche Ltd 
142/Protocol GX29185, Version 6 
Appendix 16  National Eye Institute Visual Functioning 
Questionnaire 25-Item Version (cont.)  
 
 
 
 


 
Lampalizumab—F. Hoffmann-La Roche Ltd 
143/Protocol GX29185, Version 6 
Appendix 16  National Eye Institute Visual Functioning 
Questionnaire 25-Item Version (cont.)  
 
 
 


 
Lampalizumab—F. Hoffmann-La Roche Ltd 
144/Protocol GX29185, Version 6 
Appendix 16  National Eye Institute Visual Functioning 
Questionnaire 25-Item Version (cont.)  
 
 
 
 


 
Lampalizumab—F. Hoffmann-La Roche Ltd 
145/Protocol GX29185, Version 6 
Appendix 16  National Eye Institute Visual Functioning 
Questionnaire 25-Item Version (cont.)  
 
 
 
 
 
 
 
 
 
 
 
 


 
Lampalizumab—F. Hoffmann-La Roche Ltd 
146/Protocol GX29185, Version 6 
Appendix 16  National Eye Institute Visual Functioning 
Questionnaire 25-Item Version (cont.)  
 
 
 
 
 
 
 
 
 


 
Lampalizumab—F. Hoffmann-La Roche Ltd 
147/Protocol GX29185, Version 6 
Appendix 16  National Eye Institute Visual Functioning 
Questionnaire 25-Item Version (cont.)  
 
 
 
 
 


 
Lampalizumab—F. Hoffmann-La Roche Ltd 
148/Protocol GX29185, Version 6 
Appendix 16  National Eye Institute Visual Functioning 
Questionnaire 25-Item Version (cont.)  
 
 
 


 
Lampalizumab—F. Hoffmann-La Roche Ltd 
149/Protocol GX29185, Version 6 
Appendix 16  National Eye Institute Visual Functioning 
Questionnaire 25-Item Version (cont.)  
 
 
 


 
Lampalizumab—F. Hoffmann-La Roche Ltd 
150/Protocol GX29185, Version 6 
Appendix 16  National Eye Institute Visual Functioning 
Questionnaire 25-Item Version (cont.)  
 
 


 
Lampalizumab—F. Hoffmann-La Roche Ltd 
151/Protocol GX29185, Version 6 
Appendix 17   Functional Reading Independence Index 
THE FUNCTIONAL READING INDEPENDENCE INDEX (FRI INDEX) 
Please read the following instructions to the patient. 
Instructions to Patient: 
We are interested in learning more about how your vision affects your everyday reading.  
I’m going to ask you about seven (7) activities that involve reading.  If you wear 
eyeglasses or contact lenses, please answer all the questions as if you were wearing 
them during the activity. 
Please take as much time as you need to answer each question.  Remember, there are 
no right or wrong answers.  All of your answers are confidential.  Do you have any 
questions before we begin? 
















 
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Appendix 18   Minnesota Low-Vision Reading Test (MNRead) 
READING SPEED ASSESSMENT 
THE MNREAD READING SPEED ASSESSMENT 
The Minnesota Low-Vision Reading Test (MNRead) acuity cards are continuous-text 
reading-acuity cards suitable for measuring the reading acuity and reading speed of 
normal and low-vision patients.  These cards were developed at the Minnesota 
Laboratory for Low-Vision Research, University of Minnesota, Minneapolis, Minnesota, 
in research funded by the National Institutes of Health. 
MEASURING READING SPEED 
The MNRead acuity cards consist of single, simple sentences with equal numbers of 
characters.  The print is a proportionally spaced font, similar to that found in many 
newspapers and books.  The cards contain sentences with 19 different print sizes.  The 
text is printed with high contrast (approximately 85%).  Each sentence contains 60 
characters (including space between each word and at the end of each line) printed as 
three lines with even left and right margins.  The vocabulary used in the sentences is 
selected from words appearing with high frequency in second- to third-grade reading 
materials. 
EQUIPMENT 
MNRead acuity card is used to measure reading speed at different print sizes to 
determine the print that supports the patient’s maximum reading speed.  A stopwatch is 
required to record time to a tenth of a second.  An easel or adjustable stand may be 
needed for some patients. 
TESTING 
Card Illumination 
The cards should be evenly lit so that no shadows or glare will interfere with reading.  
The luminance of the white background on the cards should be should be between 
80−120 cd/m2. 
Viewing Distance 
The print sizes and markings on the cards are designed for a testing distance of 40 cm, 
but may be tested at a distance of 32 cm.  We recommend using a headrest set to the 
appropriate viewing distance in front of the cards, to prevent the patient from creeping 
forward throughout the test.  For patients with central field loss, we find it easier to allow 
the patient to position the MNRead card so that the sentence to be read will fall into their 
preferred location for reading. 
Testing Procedure 
The MNRead assessment is to be conducted first in each eye separately and then with 
both eyes open.  A different card must be used for each test to prevent memorization of  


 
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Appendix 18   Minnesota Low-Vision Reading Test (MNRead) 
(cont.) 
the printed material.  Rotate cards from one examination to another to vary the text for 
each eye.  Conduct the reading tests in the following order.  Start by testing the right eye 
with the left eye occluded.  Next, conduct the reading speed test in the left eye with the 
right eye occluded and lastly with both eyes open. 
The card should be read from a distance of exactly 32 cm.  To keep the testing distance 
constant, use a piece of transparent fishing line, pre-measured at 32 cm from the card.  
Measure the 32 cm to the patient’s eye by holding the fishing line parallel to the floor.  A 
ruler or 32-cm measuring device may also be used to set and monitor the distance.  
Instruct the patient that the card may be moved up and down or side to side, but not 
closer to or farther from the eyes.  The card must remain upright and must not tilt away 
from or toward the patient.  Either the patient or the examiner may hold the card, 
depending on the physical ability of the patient.  Alternatively, the card may be placed on 
an easel or adjustable stand. 
Check to ensure that the reading card number on the scoring sheet corresponds to the 
reading card number that you are using.  The MNRead scoring sheet contains the test 
sentences corresponding to the card beginning on the left-hand column in descending 
order of acuity.  Indicate which eye is being tested.  Start with the largest sentence and 
move onto the subsequent sentences.  Keep on going until the patient cannot read any 
words in a sentence.  Use a blank card to cover each sentence as you work your way 
down the card:  uncover the sentence to be read when you say “start”.  Present the test 
sentence; simultaneously, tell the patient to start reading and activate the stopwatch to 
start the timer.  As the patient reads the text, strike out words not read, not attempted, or 
read incorrectly.  Use a stopwatch to record the time taken to read each sentence (to the 
nearest 0.1 second). 
INSTRUCTIONS TO THE PARTICIPANT 
“When I say ‘start’, read the sentence aloud as quickly as you can without making errors.  
But if you do make an error, or realize that you have missed a word, read to the end of 
the sentence and then go back and correct yourself.” 
SCORING 
Two pieces of information are required to be recorded on the score sheet for each test 
sentence:  the time and the number of errors.  Use a stopwatch to record the time taken 
to read each sentence (to the nearest 0.1 second).  For each sentence on the score 
sheet, mark the total number of words missed, read incorrectly or not able to be read, 
and the time taken to read the sentence (i.e., the time between when you say “start” and 
when the patient finishes uttering the last word in the sentence).  Sentences that could 
not be read or were not attempted due to vision should be recorded as 0 for time and 10 
for errors. 


 
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161/Protocol GX29185, Version 6 
Appendix 18   Minnesota Low-Vision Reading Test (MNRead) 
(cont.) 
MEASURING READING FUNCTION 
Patients’ average reading speed, critical print size, and reading acuity will be calculated 
using the data transcribed from the scoring sheet to the electronic Case Report Form 
(eCRF) and will not be calculated by the interviewers.   
Detailed Table for Administration of MNRead 
Selected Countries 
Primary language 
MNRead 
Argentina 
Spanish 
x 
Australia 
English 
x 
Mexico 
Spanish 
x 
Peru 
Spanish 
x 
US 
English/Spanish 
x 
UK 
English 
x 
 
 
 


 
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Appendix 19  Radner Reading Cards 
The Radner Reading Cards consist of “sentence optotypes,” which are optimized 
reading test items, standardized by construction and statistical selection.  The Radner 
Reading Cards are suitable for measuring reading speed, reading visual acuity, and 
critical print size. 
MEASURING READING SPEED 
The test consists of 24 short sentences that are highly comparable in terms of number of 
words, word length, position of words, lexical difficulty, and syntactical complexity.  
These cards were developed by ophthalmologist Wolfgang Radner, MD, in Vienna in 
interdisciplinary cooperation with psychologists, linguists, physicists, and statisticians. 
EQUIPMENT 
The Radner Reading Cards are in the form of a letter-sized booklet with the reading 
cards and includes clear instructions and evaluation sheets.  Eight sentences are printed 
per page.  Each sentence of 14 words is printed on three lines and print sizes vary from 
6.3 M to 0.25 M (20/400 to 20/16 at 32 cm). 
A stopwatch is required to record time to a tenth of a second.  An easel or adjustable 
stand may be needed for some patients. 
TESTING 
The Radner Reading Cards assessment is to be conducted in each eye separately and 
then with both eyes open.  A different card must be used for each test to prevent 
memorization of the printed material.  Rotate cards from one examination to another to 
vary the text for each eye.  Conduct the reading tests in the following order.  Start by 
testing the right eye with the left eye occluded.  Next, conduct the reading speed test in 
the left eye with the right eye occluded and lastly with both eyes open. 
CARD ILLUMINATION 
The cards should be evenly lit so that no shadows or glare will interfere with reading.  
The luminance of the white background on the cards should be between 80 and 
120 cd/m2. 
VIEWING DISTANCE 
The test should be conducted at a viewing distance of 32 cm.  To keep the testing 
distance constant, use a piece of transparent fishing line, pre-measured at 32 cm from 
the card.  Measure the 32 cm to the patient’s eye by holding the fishing line parallel to 
the floor.  A ruler or 32-cm measuring device may also be used to set and monitor the 
distance.  Instruct the patient that the card may be moved up and down or side to side, 
but not closer to or farther from the eyes.  The card must remain upright and must not tilt  


 
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163/Protocol GX29185, Version 6 
Appendix 19  Radner Reading Cards (cont.)  
away from or toward the patient.  Either the patient or the examiner may hold the card, 
depending on the physical ability of the patient.  Alternatively, the card may be placed on 
an easel or adjustable stand. 
TESTING PROCEDURE 
Check to ensure that the reading card number on the scoring sheet corresponds to the 
reading card number that you are using. Sentences should be covered with a piece of 
paper, and the patient should be asked to uncover sentence by sentence and to read 
only one sentence per measurement.  Start the measurement with the stopwatch when 
the patient starts reading and measure the reading time until the end of the sentence.  
Write the reading time on the scoring sheet (to the nearest 0.1 second) and record any 
reading errors on the sheet.  The reading test should be stopped when the reading time 
is longer than 20 seconds or when the patient is making severe errors. 
INSTRUCTIONS TO THE PARTICIPANT 
“Please read the sentences aloud as quickly and accurately as possible. Read each 
sentence to the end, and do not correct reading errors.” 
“Please uncover the first sentence and start reading.”   
 
MEASURING READING FUNCTION 
Patient’s average reading speed, critical print size, and visual acuity will be calculated 
using the data transcribed from the scoring sheet to the electronic Case Report Form 
(eCRF) and will not be calculated by the interviewers. 
 


 
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164/Protocol GX29185, Version 6 
Appendix 19  Radner Reading Cards (cont.)  
Detailed Table for Administration of Radner Reading Card 
Selected Countries 
Primary Language 
Radner 
Austria 
German 
x 
Brazil 
Portuguese 
x 
Canada 
English, French 
x 
Denmark 
Danish 
x 
France 
French 
x 
Germany 
German 
x 
Italy 
Italian 
x 
Netherlands 
Dutch 
x 
Spain 
Spanish 
x 
Switzerland 
German, Italian, French 
x 
Belgium 
French, German, Dutch 
x 
Hungary 
Hungarian 
x 
Portugal 
Portuguese 
x 
Sweden 
Swedish 
x 
Turkey 
Turkish 
x 
 
 
 


 
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Appendix 20   Biological Sample Collection and Shipping 
Instructions 
BIOLOGICAL SAMPLES 
Biological samples for the assessment of lampalizumab concentrations 
(pharmacokinetics), anti-lampalizumab antibodies, Alternative Complement Pathway 
activity assay, complement factor I (CFI) whole blood sample, biomarker plasma, 
biomarker paxgene and biomarker whole blood clinical genotyping samples, and 
laboratory assessment (hematology, serum chemistry, coagulation, and urinalysis) 
samples will be collected at the timepoints specified in Appendix 1. 
Refer to the Central Laboratory Manual for detailed sample collection, storage, and 
shipping instructions.  All necessary transfer tubes, Vacutainers™, labels, shipping 
boxes, and forms will be provided by the central laboratory. 
OPTIONAL ANTERIOR CHAMBER (AQUEOUS HUMOR) SAMPLE 
COLLECTION 
The optional aqueous humor paracentesis samples will be collected by the treating 
physician from patients who consent to the procedure and sample acquisition.  An 
aqueous humor sample will be collected before the patient’s study eye treatment at the 
visits as indicated in Appendix 1.  The aqueous humor sample collection consists of an 
anterior chamber paracentesis (removing approximately 0.1 mL of fluid from the anterior 
chamber of the eye). 
The anterior chamber paracentesis will be performed by a qualified physician by placing 
a drop of topical anesthetic on the cornea, passing a 30-gauge needle through the 
limbus into the anterior chamber and removing 0.1 mL of aqueous fluid.   
Samples will be collected with the kit provided by central laboratory and shipped on dry 
ice to the central laboratory as soon as possible after the draw. 
For administration of study treatment following the collection of the aqueous humor 
sample, the subconjunctival lidocaine anesthetic must be injected into the eye prior to 
study drug/sham injection. 
BUCCAL SWAB COLLECTION 
Note:  See Central Laboratory Manual for the details of buccal swab collection. 
Buccal swabs kits are special collection devices to collect mucosal cells from the cheek.  
They are designed for the collection, storage, stabilization, and transportation of total 
samples for CFI profile testing from the clinical swab material.  They include the swab 
and swab collection tube, which includes stabilizer/polymerase chain reaction lysis buffer. 


 
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166/Protocol GX29185, Version 6 
Appendix 20   Biological Sample Collection and Shipping 
Instructions (cont.)  
Buccal swab collection will take place at the screening visit.  The buccal swabs will be 
the alternative sample source collection devices for the genetic testing of patients for the 
CFI profile biomarker status.  The reason for collecting this additional sample is to 
investigate the equivalence of the recovery, quality, and genotype information from 
whole blood versus that from cheek swabs.  Because this collection process is less 
invasive than the whole blood collection process, the CFI profile sample may be 
collected by this more preferable method in the future, if both systems are proven to give 
comparable genotyping results. 
The clinical site personnel/coordinator will be trained in this process in order to ensure 
the appropriate collection and storage of buccal swabs from patients.  The buccal swabs 
will be banked for future concordance analysis with the whole blood CFI profile test prior 
to regulatory filings and not for exploratory purposes. 
 


 
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167/Protocol GX29185, Version 6 
Appendix 21   Electrocardiogram Data Collection  
at Selected Sites 
PURPOSE 
Cardiovascular effects of lampalizumab are not anticipated based on nonclinical data 
and clinical studies conducted to date.  However, in order to fulfill a regulatory 
requirement, an evaluation of clinical cardiovascular parameters using ECGs will be 
conducted in approximately 100 patients at selected sites within the United States.  The 
purpose is to summarize common clinical cardiovascular parameters across a sample of 
active-treatment and sham-treatment patients over time.   
DESCRIPTION 
Each patient enrolled at participating sites will automatically participate in the ECG data 
collection activities.  Using study-provided equipment, each patient will undergo four 
digital 12-lead ECGs (see Appendix 1 for the timepoints).  To minimize variability, it is 
important that patients be in a resting position for approximately 10 minutes prior to each 
ECG evaluation.  Body position should be consistently maintained for each ECG 
evaluation to prevent changes in heart rate.  Environmental distractions (e.g., television, 
radio, conversation) should be minimized before and during ECG recording.  
INTERPRETATION AND DATA ENTRY 
All ECGs will be transferred electronically to the study-designated central vendor for data 
extraction, central cardiology interpretation, and final direct data exportation.  Central 
ECG interpretation will be performed for each patient recording, and the results will be 
forwarded to the relevant site’s Principal Investigator (or designee) for clinical correlation 
and inclusion in the appropriate site records.  In the case of a new-onset or changed 
clinically meaningful abnormal finding(s), the central vendor will contact the site’s 
Principal Investigator (or designee) directly with an expedited report (within 24 hours) of 
the abnormal findings for the purpose of adverse event reporting or any other necessary 
clinical intervention(s).  Any clinically meaningful ECG changes (in the opinion of the 
investigator) relative to Day 1 assessment, which are associated with symptoms, lead to 
a change in study treatment or concomitant treatment, or lead to discontinuation from 
study treatment, must be reported as an adverse event on the Adverse Event electronic 
Case Report Form.


 
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168/Protocol GX29185, Version 6 
Appendix 22   The cobas® CFI Profile Clinical Trial Assay (CTA) 
The cobas® complement factor I (CFI) Profile Clinical Trial Assay (CTA) is a real-time 
polymerase chain reaction (PCR) test developed by Roche Molecular Systems (RMS) to 
identify genotypes of three single nucleotide polymorphisms (SNPs) associated with CFI, 
complement factor H (CFH), and C2/complement factor B (CFB) in DNA extracted from 
whole blood samples from patients with geographic atrophy (GA) secondary to age-
related macular degeneration (AMD). The cobas® CFI Profile CTA is intended to be used 
as an Investigational-Use-Only assay to characterize the complement factor profile of 
study participants.  It may also be used to stratify research participants for randomization 
or to enrich the study population with CFI biomarker-positive participants in specific type 
clinical studies. 
The cobas® CFI Profile CTA consists of two kits and will use the cobas® 4800 platform.  
The cobas® DNA Sample Preparation Kit (DNA isolation kit) provides the necessary 
components to manually extract genomic DNA from whole blood samples.  The cobas® 
CFI Profile CTA contains the necessary PCR master mix, oligonucleotides, cofactor, and 
controls to detect three SNPs associated with CFI, CFH, and C2/CFB. 
Valid cobas® Test Results 
 
AMD 
Gene 
chr. 
No. 
Tagging 
SNP 
Tagging 
SNP 
Location
Risk 
Allele
Major 
Allele Risk Hmzy
Het 
Non-Risk 
Hmzy 
MMx1 
CFI 
4 
rs4698775
CCDC 
G 
T 
rs4698775 
GG 
rs4698775 
TG 
rs4698775 
TT 
MMx2 
C2/ 
CFB 
6 
rs429608 SKIV2L
G 
G 
rs429608 
GG 
rs429608 
GA 
rs429608 
AA 
MMx3 CFH 
1 
rs1329428
CFH 
C 
C 
rs1329428 
CC 
rs1329428 
CT 
rs1329428 
TT 
AMD = age-related macular degeneration; C = complement component; CF = complement factor; 
chr = chromosome; het = heterozygous; hmzy = homozygous; SNP = single nucleotide 
polymorphism. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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169/Protocol GX29185, Version 6 
Appendix 22   The cobas® CFI Profile Clinical Trial Assay (CTA) 
(cont.) 
MMx1 
MMx2  
MMx3 
  
CFI 
C2/CFB 
CFH 
Biomarker Status 
rs4698775 GG 
rs429608 GG 
rs1329428 CC 
+ 
rs4698775 GG 
rs429608 GG 
rs1329428 CT 
+ 
rs4698775 GG 
rs429608 GG 
rs1329428 TT 
+ 
rs4698775 GG 
rs429608 GA 
rs1329428 CC 
+ 
rs4698775 GG 
rs429608 GA 
rs1329428 CT 
+ 
rs4698775 GG 
rs429608 GA 
rs1329428 TT 
+ 
rs4698775 GG 
rs429608 AA 
rs1329428 CC 
+ 
rs4698775 GG 
rs429608 AA 
rs1329428 CT 
+ 
rs4698775 GG 
rs429608 AA 
rs1329428 TT 
− 
rs4698775 TG 
rs429608 GG 
rs1329428 CC 
+ 
rs4698775 TG 
rs429608 GG 
rs1329428 CT 
+ 
rs4698775 TG 
rs429608 GG 
rs1329428 TT 
+ 
rs4698775 TG 
rs429608 GA 
rs1329428 CC 
+ 
rs4698775 TG 
rs429608 GA 
rs1329428 CT 
+ 
rs4698775 TG 
rs429608 GA 
rs1329428 TT 
+ 
rs4698775 TG 
rs429608 AA 
rs1329428 CC 
+ 
rs4698775 TG 
rs429608 AA 
rs1329428 CT 
+ 
rs4698775 TG 
rs429608 AA 
rs1329428 TT 
− 
rs4698775 TT 
rs429608 GG 
rs1329428 CC 
− 
rs4698775 TT 
rs429608 GG 
rs1329428 CT 
− 
rs4698775 TT 
rs429608 GG 
rs1329428 TT 
− 
rs4698775 TT 
rs429608 GA 
rs1329428 CC 
− 
rs4698775 TT 
rs429608 GA 
rs1329428 CT 
− 
rs4698775 TT 
rs429608 GA 
rs1329428 TT 
− 
rs4698775 TT 
rs429608 AA 
rs1329428 CC 
− 
rs4698775 TT 
rs429608 AA 
rs1329428 CT 
− 
rs4698775 TT 
rs429608 AA 
rs1329428 TT 
− 
 
 
 
 

SAP_001.pdf: 
 
Official Title: 
 
A Phase III, Multicenter, Randomized, Double-Masked, 
Sham-Controlled Study to Assess the Efficacy and Safety of 
Lampalizumab Administered Intravitreally to Patients With 
Geographic Atrophy Secondary to Age-Related Macular 
Degeneration  
NCT Number: 
NCT02247531 
Document Date: 
Statistical Analysis Plan, Version 3, 17-Aug-2017 
 
 
 


STATISTICAL ANALYSIS PLAN AMENDMENT APPROVAL 
CONFIDENTIAL 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
Lampalizumab—F. Hoffmann-La Roche Ltd 
1/Statistical Analysis Plan GX29185 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE-
MASKED, SHAM-CONTROLLED STUDY TO ASSESS THE 
EFFICACY AND SAFETY OF LAMPALIZUMAB 
ADMINISTERED INTRAVITREALLY TO PATIENTS WITH 
GEOGRAPHIC ATROPHY SECONDARY TO AGE-RELATED 
MACULAR DEGENERATION 
PROTOCOL NUMBER: 
STUDY DRUG: 
VERSION NUMBER: 
IND NUMBER: 
EUDRACT NUMBER: 
SPONSOR: 
PLAN PREPARED BY: 
DATE FINAL: 
DATE AMENDED 
GX29185 / NCT02247531
Lampalizumab (RO5490249) 
3 
104996  
2014-000106-35 
F. Hoffmann-La Roche Ltd.
, Ph.D.
Version 1:  11 March 2015
Version 2:  15 April 2015 
Version 3:  See electronic stamp below. 
Name
Reason for Signing
Date and Time
(UTC)
17-Aug-2017 23:15:28
Company Signatory


Lampalizumab—F. Hoffmann-La Roche Ltd 
2/Statistical Analysis Plan GX29185 
TABLE OF CONTENTS 
1. 
BACKGROUND ............................................................................................ 4 
2. 
STUDY DESIGN ........................................................................................... 5 
2.1 
Endpoints/Outcome Measures ................................................ 5 
2.1.1 
Primary Efficacy Endpoint ........................................................ 5 
2.1.2 
Secondary Efficacy Endpoints ................................................. 5 
2.1.3 
Exploratory Efficacy Endpoints ................................................ 6 
2.1.4 
Supplemental Efficacy Endpoints Related to 
Primary Endpoint ..................................................................... 7 
2.1.5 
Pharmacokinetic and Pharmacodynamic 
Outcome Measures ................................................................. 8 
2.1.6 
Safety Endpoints ..................................................................... 8 
2.1.7 
Diagnostic Outcome Measures ................................................ 8 
2.2 
Biomarker Considerations ....................................................... 8 
2.3 
Sample Size .......................................................................... 10 
2.3.1 
Determination of Sample Size ............................................... 10 
2.3.2 
Estimated Power Based on Information from 
Study GX29633 ..................................................................... 10 
2.4 
Analysis Timing and Unmasking ............................................ 11 
2.5 
Definition of 48-Week Data .................................................... 12 
3. 
STUDY CONDUCT ..................................................................................... 13 
3.1 
Randomization ....................................................................... 13 
3.2 
Independent Data Review ..................................................... 14 
3.2.1 
Central Reading Center ......................................................... 14 
3.2.2 
Independent Data Monitoring Committee .............................. 14 
4. 
STATISTICAL METHODS .......................................................................... 14 
4.1 
Analysis Populations ............................................................. 14 
4.1.1 
Intent-to-Treat Population ...................................................... 14 
4.1.2 
Safety-Evaluable Population .................................................. 15 
4.1.3 
Microperimetry-Analysis Population ...................................... 15 
4.1.4 
ECG-Analysis Population ...................................................... 15 
4.2 
Definition of Baseline ............................................................. 15 


Lampalizumab—F. Hoffmann-La Roche Ltd 
3/Statistical Analysis Plan GX29185 
4.3 
Analysis of Study Conduct ..................................................... 15 
4.4 
Analysis of Treatment Group Comparability .......................... 16 
4.5 
Efficacy Analysis .................................................................... 16 
4.5.1 
Primary Efficacy Endpoint ...................................................... 17 
4.5.1.1 
Overall Patient Population Analysis ....................................... 18 
4.5.1.2 
Biomarker Subgroup Analyses .............................................. 19 
4.5.1.3 
Other Subgroup Analyses ...................................................... 19 
4.5.1.4 
Sensitivity Analyses ............................................................... 20 
4.5.1.5 
Supplemental Analyses ......................................................... 23 
4.5.2 
Secondary Efficacy Endpoints ............................................... 23 
4.5.2.1 
Type I Error Management ...................................................... 25 
4.5.2.2 
Subgroup Analyses ............................................................... 26 
4.5.3 
Exploratory Efficacy Endpoints .............................................. 27 
4.5.4 
Additional Biomarker Analyses .............................................. 28 
4.6 
Pharmacokinetic and Pharmacodynamic 
Analyses ................................................................................ 29 
4.7 
Safety Analyses ..................................................................... 29 
4.7.1 
Exposure of Study Medication ............................................... 29 
4.7.2 
Adverse Events ..................................................................... 30 
4.7.3 
Laboratory Data ..................................................................... 31 
4.7.4 
Immunogenicity ..................................................................... 31 
4.7.5 
Ocular Assessments .............................................................. 31 
4.7.6 
ECG Results .......................................................................... 31 
4.8 
Interim Analyses .................................................................... 32 
5. 
REFERENCES ........................................................................................... 32 
 
 
LIST OF TABLES 
Table 1 
Definition of Biomarker Status Using the CFI Profile Test ............. 9 
Table 2 
Power and Minimum Detectable Difference for Analysis of 
Primary Endpoint Using Assumptions Based on the 
Epidemiological Study GX29633 ................................................. 11 
Table 3 
Timing of Planned Analyses ........................................................ 12 


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1. 
BACKGROUND 
The purpose of this document is to provide details of the planned analyses for 
Study GX29185 (Spectri).  Analyses for both the primary study analysis and the final 
study analysis are described. 
The primary study analysis will be based on complete data from the first 48-weeks of the 
study, and performed after all patients have completed 48-weeks in the study or 
discontinued early, and all corresponding data have been entered into the database, 
reviewed, and verified.  Analysis will include hypothesis testing of the primary efficacy 
endpoint (anatomic outcome) at Week 48.  Secondary and exploratory endpoints (visual 
function outcomes) will be evaluated based on 48-week data in an exploratory manner, 
although formal statistical testing for these endpoints will be at Week 96.  An analysis of 
the 48-week safety data will be performed. 
At the time of the primary 48-week analysis, the second year of the study will be ongoing.  
An analysis of the available second year safety data (after Week 48 and up to a 
specified clinical cutoff date) will also be performed.  Such results will be reported with, 
but separate from, the 48-week study results to provide additional safety information for 
lampalizumab. 
The final study analysis will be based on data from the complete study, and performed 
after all patients have either completed 96-weeks in the study or discontinued early, and 
all data from the study are in the database and the database is locked.  Secondary and 
exploratory endpoints (visual function outcomes) will be analyzed based on Week 96 
data.  At the time of the final analysis, safety summaries will be produced based on 
cumulative Week 96 data. 
See Section 2.4 for further details on analysis timing. 
The analyses specified in this document supersede the analysis plan described in the 
study protocol (Version 6).  Of particular note, the hypotheses of interest and order of 
hypothesis tests for the primary efficacy endpoint (see Section 4.5.1) have been 
modified since the protocol was written based on information obtained from an interim 
analysis of Study GX29633, a prospective epidemiological study of the progression of 
geographic atrophy (GA) secondary to age-related macular degeneration (AMD).  Study 
GX29633 is being conducted to gain a better understanding of the rate of GA lesion 
progression, the prognostic effect of the complement factor I (CFI)-profile biomarker, and 
the correlation of GA lesion area with visual function outcomes. 
A separate analysis plan will be prepared for purposes of a health technology 
assessment.  In addition, a separate analysis plan will be prepared for additional 
exploratory genetic analyses (see Section 4.5.4). 


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2. 
STUDY DESIGN 
Study GX29185 is a Phase III, double-masked, multicenter, randomized, 
sham-injection-controlled study evaluating the efficacy and safety of a 10 mg dose of 
lampalizumab administered every 4-weeks (Q4W) or every 6-weeks (Q6W) by 
intravitreal injection during a 96-week (approximately 2 year) treatment period in patients 
with GA secondary to AMD.  The study consists of a screening period (of up to 28 days 
duration), followed by a 96-week treatment period. 
Approximately 936 patients will be randomized into the study at approximately 
140 investigational sites located globally.  The study will enroll both CFI-profile 
biomarker-positive and CFI-profile biomarker-negative patients (see Section 2.2); 
enrollment will be in a ratio of 1.5:1 for biomarker-positive patients relative to 
biomarker-negative patients.  Eligible patients are randomized in a 2:1:2:1 ratio to 
receive 10 mg lampalizumab Q4W, sham Q4W, 10 mg lampalizumab Q6W, or sham 
Q6W during the 96-week treatment period.  Study treatment is given Day 1 to Week 92 
for the Q4W treatment arms and Day 1 to Week 90 for the Q6W treatment arms, with a 
final study visit at Week 96 for all patients. 
Efficacy, safety, and pharmacokinetic (PK) measures are assessed throughout the 
treatment period, as detailed in the Schedule of Assessments (see study protocol). 
Further study design details are provided in the study protocol. 
 
2.1 
ENDPOINTS/OUTCOME MEASURES 
Unless otherwise specified, ocular efficacy outcome measures refer to the study eye. 
2.1.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is change from baseline in GA area at 1 year (48-weeks) 
as assessed by fundus autofluorescence (FAF). 
2.1.2 
Secondary Efficacy Endpoints 
The following secondary efficacy endpoints will be assessed over time up to Week 96, 
with formal statistical testing at Week 96.  Hypothesis testing for three key secondary 
endpoints will be performed in the order specified in Section 4.5.2.1 based on the 
Week 96 timepoint. 
• 
Change from baseline in number of absolute scotomatous points as assessed 
by mesopic microperimetry 
– Assessed for subset of patients at selected study sites only.  Endpoint will 
be evaluated based on pooled data from GX29176 and GX29185. 


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• 
Change from baseline in mean macular sensitivity as assessed by mesopic 
microperimetry 
– Assessed for subset of patients at selected study sites only.  Endpoint will 
be evaluated based on pooled data from GX29176 and GX29185. 
• 
Change from baseline in best corrected visual acuity (BCVA) as assessed by 
the Early Treatment Diabetic Retinopathy Study (ETDRS) chart at a starting 
distance of 4 m 
• 
Patients with < 15 letters loss from baseline in BCVA score as assessed by the 
ETDRS chart at a starting distance of 4 m 
• 
Change from baseline in low luminance visual acuity (LLVA) as assessed by 
the ETDRS chart at a starting distance of 4 m  
– Note:  In the protocol, LLVA was referred to as BCVA score as assessed 
by ETDRS chart under low luminance conditions. 
• 
Patients with < 15 letters loss from baseline in LLVA score as assessed by the 
ETDRS chart at a starting distance of 4 m 
• 
Change from baseline in binocular maximum reading speed as assessed by 
Minnesota low-vision reading test (MNRead) or Radner Charts 
• 
Change from baseline in monocular maximum reading speed as assessed by 
MNRead or Radner Charts 
• 
Change from baseline in National Eye Institute Visual Functioning 
Questionnaire 25-item Version (NEI VFQ-25) composite score 
• 
Change from baseline in NEI VFQ-25 near activity subscale score 
• 
Change from baseline in NEI VFQ-25 distance activity subscale score 
• 
Change from baseline in Mean Functional Reading Independence (FRI) Index 
score 
 
2.1.3 
Exploratory Efficacy Endpoints 
The following exploratory efficacy endpoints will be assessed over time up to Week 96, 
with formal statistical testing at Week 96. 
• 
Patients with < 20% increase from baseline in GA area as assessed by FAF 
• 
Change from baseline in GA area over time (all additional timepoints 
[Weeks 24, 36, 72, and 96]) as assessed by FAF 
• 
Change from baseline in number of absolute or relative scotomatous points as 
assessed by mesopic microperimetry 
– Assessed for subset of patients at selected study sites only.  Endpoint will 
be evaluated based on pooled data from GX29176 and GX29185. 
• 
Percent change from baseline in binocular maximum reading speed as 
assessed by MNRead or Radner Charts 


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• 
Patients with at least a 2-level decline from baseline in binocular maximum 
reading speed (based on the following levels:   < 40, ≥  40 to < 60, ≥  60 to < 80, 
≥  80 to < 120, ≥  120 to < 160, ≥  160 wpm) as assessed by MNRead or Radner 
Charts 
• 
Percent change from baseline in monocular maximum reading speed as 
assessed by MNRead or Radner Charts 
• 
Patients with at least a 2-level decline from baseline in monocular maximum 
reading speed (based on the following levels:   < 40, ≥  40 to < 60, ≥  60 to < 80, 
≥  80 to < 120, ≥  120 to < 160, ≥  160 wpm) as assessed by MNRead or Radner 
Charts 
• 
Change from baseline in binocular critical print size as assessed by MNRead or 
Radner Charts 
• 
Change from baseline in monocular critical print size as assessed by MNRead 
or Radner Charts 
• 
Change from baseline in binocular reading acuity as assessed by MNRead or 
Radner Reading Charts 
• 
Change from baseline in monocular reading acuity as assessed by MNRead or 
Radner Reading Charts 
• 
Patients with no decline from baseline in FRI Level score 
• 
Patients with visual function worsening, as defined by (i) a ≥ 5 letter decrease in 
BCVA (as assessed by the ETDRS chart), AND (ii) a ≥ 20% decrease in 
monocular maximum reading speed (as assessed by MNRead or Radner 
Reading Charts) 
• 
Patients with overall disease worsening, as defined by (i) a ≥ 5 letter decrease 
in BCVA (as assessed by the ETDRS chart), AND (ii) a ≥ 20% decrease in 
monocular maximum reading speed (as assessed by MNRead or Radner 
Reading Charts), AND (iii) a ≥ 20% increase in GA area (as assessed by FAF) 
 
2.1.4 
Supplemental Efficacy Endpoints Related to Primary Endpoint 
The following efficacy endpoints, closely related to the primary efficacy endpoint, will be 
assessed over time up to Week 48 to provide supplemental information to the primary 
endpoint analysis.  The endpoints will also be assessed over time up to Week 96 at the 
time of the final study analysis. 
• 
Rate of change in GA area (growth slope) as assessed by FAF 
• 
Change from baseline in square root of GA area as assessed by FAF 
• 
Percent change from baseline in GA area as assessed by FAF 
 


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2.1.5 
Pharmacokinetic and Pharmacodynamic Outcome Measures 
As specified in the protocol, the PK outcome measure for this study is serum 
lampalizumab concentrations over time.  Total lampalizumab and complement factor D 
(CFD) levels in aqueous humor are specified as an exploratory outcome measure.  
(Note, aqueous humor samples are only available for the subset of patients who 
consented to optional aqueous humor sampling.) 
2.1.6 
Safety Endpoints 
The safety outcome measures are as follows: 
• 
The incidence and severity of ocular adverse events 
• 
The incidence and severity of non-ocular adverse events 
• 
Changes and abnormalities in electrocardiogram (ECG) parameters  
– Assessed through Week 24 for patients at selected sites who have 
undergone ECG evaluation (approximately 100 patients in total) 
• 
The incidence of anti-drug antibodies 
 
2.1.7 
Diagnostic Outcome Measures 
The evaluation of the predictive value of the CFI-profile biomarker will be assessed 
through the evaluation of the primary efficacy endpoint.  The evaluation of the prognostic 
value of the CFI-profile biomarker will be based on the primary clinical outcome of 
change from baseline in the GA area as measured by FAF in the sham arm. 
In addition, the following exploratory diagnostic outcome measures are specified: 
• 
The association of genetic variants in CFI and complement-pathway genes with 
disease characteristics and response to lampalizumab 
• 
The relationship of genetic variants in CFI and complement-pathway genes to 
levels in the blood of mRNA and proteins of CFI and complement-pathway 
genes 
 
2.2 
BIOMARKER CONSIDERATIONS 
Exploratory genetic analyses of data from the Phase II Study CFD4870g suggested that 
a biomarker-defined population (CFI-profile biomarker-positive) may have more rapid 
disease progression and potentially derive greater efficacy benefit from lampalizumab 
than the population that is negative for the biomarker (CFI-profile biomarker-negative).  
In order to further evaluate this hypothesis, this Phase III study (GX29185) will enroll 
both CFI-profile biomarker-positive and biomarker-negative patients; enrollment will be in 
a ratio of 1.5:1 for CFI-profile biomarker-positive patients relative to CFI-profile 
biomarker-negative patients. 


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Complement factor I profile is based on the common genetic variants of CFI, 
complement factor H (CFH), and complement component 2/complement factor B 
(C2/CFB).  The following two patient groups are defined (see Table 1): 
• 
CFI profile biomarker-positive patients:  Patients who are carriers of CFI risk 
allele, who are also risk allele carriers at CFH and/or C2/CFB. 
• 
CFI profile biomarker-negative patients:  Patients who are (i) non-carriers of 
the CFI risk allele or (ii) carriers of the CFI risk allele, who are non-carriers of 
the risk alleles at both CFH and C2/CFB. 
 
Table 1 
Definition of Biomarker Status Using the CFI Profile Test 
 
CFI 
CFH 
C2/CFB 
CFI profile 
biomarker-positive 
+ 
+ 
+ 
 
+ 
+ 
− 
 
+ 
− 
+ 
CFI profile 
biomarker-negative 
+ 
− 
− 
 
− 
+ 
+ 
 
− 
+ 
− 
 
− 
− 
+ 
 
− 
− 
− 
C2 = complement component 2; CFB = complement factor B; CFH = complement factor H; 
CFI = complement factor I. 
Note:   “+” indicates that the patient is a risk-allele carrier (i.e., heterozygous or homozygous for 
the risk allele) and “−” indicates that the patient is a non-carrier of the risk allele. 
 
For this study, CFI-profile biomarker status is determined using the investigational 
cobas® CFI Profile Clinical Trial Assay (CTA).  The cobas® CFI Profile CTA biomarker 
status results are used for patient enrollment (to achieve a 1.5:1 ratio for 
biomarker-positive relative to biomarker-negative patients) and for stratification of 
patients at randomization.  In addition, all biomarker-related analyses specified in this 
SAP will be performed on the basis of CFI profile results from the cobas® CFI Profile 
CTA. 
Enrollment of both biomarker-positive and biomarker-negative patients allows for 
evaluation of the treatment benefit in both patient groups, as well as the overall enrolled 
population.  The hypotheses of interest and order of hypothesis tests for the primary 
efficacy endpoint are specified in Section 4.5.1, and take precedence over that specified 
in the study protocol.  In addition to data from exploratory analyses of Study CFD4870g, 
interim data from the epidemiological Study GX29633 were considered for the order of 
hypothesis testing. 


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2.3 
SAMPLE SIZE 
2.3.1 
Determination of Sample Size 
Approximately 936 patients will be enrolled in the study.  Patients are randomized in a 
2:1:2:1 ratio to receive treatment with lampalizumab Q4W, sham Q4W, 
lampalizumab Q6W, or sham Q6W.  Data from the two sham treatment arms will be 
pooled in the analysis. 
The study was originally sized to achieve adequate power for detecting a meaningful 
reduction rate in the GA area growth for a given lampalizumab dosing frequency 
compared with pooled sham within each of the biomarker-positive and 
biomarker-negative groups and to meet health authority requirements for the size of the 
safety database.  At the time of the study design, sample size and power calculations 
used assumptions based on results from the Phase II Study CFD4870g.  For details of 
the determination of sample size, see study protocol Section 6.1. 
As outlined in Section 6.1, the protocol also specified that the Sponsor may conduct a 
masked evaluation of the variance of the primary efficacy endpoint and study dropout 
rate before the end of enrollment, with the intent to potentially increase the study sample 
size if deemed necessary in order to maintain the desired study power.  However, such 
an evaluation was not conducted and the sample size of the study remained unchanged 
from that originally planned. 
2.3.2 
Estimated Power Based on Information from Study GX29633 
The primary efficacy endpoint is the change from baseline in GA area at 1 year 
(48 weeks) as assessed by FAF.  As specified in Section 4.5.1, the primary efficacy 
objectives will be assessed by analysis of the primary efficacy endpoint in the overall 
patient population and in the biomarker-positive group for each dosing frequency 
separately. 
Table 2 summarizes the power and minimum detectable difference for the primary 
endpoint analysis when evaluated for the overall patient population and the 
biomarker-positive group using progression rates and variability assumptions based on 
data from Study GX29633, a prospective epidemiological study of the progression of GA 
secondary to AMD (May 2017 interim analysis).  Namely, calculations assumed a 
progression rate (mean change from baseline in GA area at 48-weeks) of 2.08 mm2 for 
both the biomarker-positive and biomarker-negative patient groups and a SD of 
1.53 mm2 for the change from baseline in GA area at 48-weeks.  With these 
assumptions, 312 patients per lampalizumab treatment arm and 156 patients per sham 
arm will provide 88% power to declare a difference between each lampalizumab 
treatment arm and the pooled sham arm in the overall patient population for a targeted 
difference of 0.42 mm2 (approximately 20% reduction relative to sham control) in the 
change from baseline in GA area at 48 weeks (Table 2).  Estimated power to detect 
specified differences in the primary efficacy endpoint within the biomarker-positive 


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patient population is as shown in Table 2.  Calculations were based on two-sided t-tests 
at the α = 0.0496 level (after adjustment for the four data reviews conducted by the iDMC 
prior to analysis of the primary efficacy endpoint), with the assumption of a 15% dropout 
rate by 48 weeks. 
Table 2 
Power and Minimum Detectable Difference for Analysis of 
Primary Endpoint Using Assumptions Based on the 
Epidemiological Study GX29633 
Endpoint Summary  
and Population 
Target Treatment Effect 
Two-Sided α = 0.0496 
Power 
MDD 
Mean change from baseline in 
GA area at 1 year (48 weeks) 
in all patients (n = 312 per arm) 
∆ = 0.42 mm2 (approximately 
20%a reduction) SD = 1.53  
88% 
0.26 mm2 
(approximately 
13% a 
reduction) 
Mean change from baseline in 
GA area at 1 year (48 weeks) 
in biomarker-positive patients 
(n = 188 per arm) 
∆ = 0.83 mm2 (approximately 
40%a reduction) SD = 1.53  
> 95% 
0.34 mm2 
(approximately 
16% a 
reduction) 
GA = geographic atrophy; MDD = minimum detectable difference. 
The sample size takes into account the dropout rate of 15% by 48 weeks.  The power and MDD 
are for each comparison between one lampalizumab treatment arm and the pooled sham arm. 
a Relative to the sham arm and assuming the mean change from baseline in GA area at 
48 weeks is 2.08 mm2 for both the biomarker-positive and biomarker-negative patient groups. 
 
2.4 
ANALYSIS TIMING AND UNMASKING 
The analysis of data from the first 48-weeks of the study will be performed when (i) all 
patients have completed study visits through Week 48 or have discontinued from the 
study prior to Week 48 and (ii) all data from the first 48-weeks of the study are in the 
database and have been reviewed per the Data Quality Plan and verified per the Trial 
Monitoring Plan. 
At that time, Sponsor personnel who are analyzing data from the first 48-weeks of the 
study will be unmasked to treatment assignment.  To maintain data integrity for the 
remainder of the study, internal guidelines are to be followed to avoid unnecessary 
unmasking of investigator site staff or patients. 
Analyses will include formal hypothesis testing of the primary efficacy endpoint 
(anatomic outcome) at Week 48.  Secondary and exploratory endpoints (visual function 
outcomes) will be evaluated based on 48-week data in an exploratory manner, although 
formal statistical testing for these endpoints will be at Week 96.  An analysis of the 48-
week safety data will also be performed. 


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The second year of the study will be ongoing at the time of the 48-week primary analysis.  
An analysis of the second year safety data that is available at the time of the 48-week 
primary analysis will be performed; it will include all safety data after Week 48 and up to 
a single specified calendar cutoff date.  Such results will be reported with, but separate 
from, the 48-week study results to provide additional safety information for lampalizumab. 
The final study analysis based on data from the complete study will be performed when 
all patients have either completed the 2-year study period (i.e., study visits through 
Week 96) or have discontinued early from the study, all data from the study are in the 
database, and the database is locked.  Secondary and exploratory endpoints (visual 
function outcomes) will be analyzed based on Week 96 data.  At the time of the final 
analysis, safety summaries will be produced based on cumulative Week 96 data. 
Aggregate results of the 48-week analysis may be reported to the public before 
completion of the study.  However, patients, masked study site personnel, and central 
reading center personnel will remain masked to individual treatment assignment until 
after the study is completed (after all patients have either completed Week 96 or 
discontinued early from the study), the database is locked, and the study analyses 
are final.  Sponsor study team members who are aware of individual patient-level 
treatment assignments and have direct contact with the study site will sign a 
non-disclosure form and will not reveal treatment assignment information to site staff. 
Table 3 provides an overview of the timing for the planned analyses. 
Table 3 
Timing of Planned Analyses 
Analysis 
Timing of Analysis 
Adjusted Two-Sided  
Alpha Level 
Primary  
All patients complete 1 year (48 week) 
assessment or discontinue study early 
0.0496 for primary endpoint 
tested at Week 48 
Final  
All patients complete 2 year (96 week) 
assessment or discontinue study early 
0.0496 for secondary and 
exploratory endpoints tested at 
Week 96 
Note:  Secondary and exploratory efficacy endpoints (visual function outcomes) will be evaluated 
based on Week 48 data in an exploratory manner, although formal statistical testing for these 
endpoints will be at Week 96. 
 
2.5 
DEFINITION OF 48-WEEK DATA 
All screening and post-baseline data with a clinical date (i.e., 
administration/assessment/onset/start date) on or before the defined Week 48 data 
cutoff date will be included in the primary 48-week analysis.  The 48-week data cutoff will 
include all data regardless of the type of study visit at which it was collected.  This may 


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include data collected at unscheduled visits or early termination visits, if the visit date 
was on or before the 48-week data cutoff date.  The data cutoffs for Week 48 data are 
defined as follows: 
• 
For all assessments except imaging and microperimetry:  The Week 48 
data cutoff will be Study Day 350 (i.e., Study Day 337 [Week 48 day] + 13 day 
window) for the Q4W treatment arms and Study Day 357 (i.e., Study Day 337 
[Week 48 day] + 20 day window) for the Q6W treatment arms. 
• 
For all imaging (including FAF) and microperimetry assessments:  The 
Week 48 data cutoff will be Study Day 384 (i.e., Study Day 337 [Week 48 
day] + 47 day window) for all treatment arms.  The wider analysis window for 
imaging and microperimetry assessments is to allow for capture of missed 
images that were taken at the next scheduled visit, as permitted by the protocol. 
 
3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION 
Patients are randomized to the treatment arms through an IxRS.  After all patient 
eligibility requirements are confirmed at both the screening and Day 1 visit, patients are 
randomized in a 2:1:2:1 ratio to one of four arms (10 mg lampalizumab Q4W, sham 
Q4W, 10 mg lampalizumab Q6W, or sham Q6W).  Study treatment is to be initiated on 
the same day that the patient is randomized (Day 1 visit). 
Randomization is stratified by biomarker status (positive vs. negative, as determined by 
the cobas® CFI Profile CTA), baseline BCVA ETDRS chart Snellen equivalent (20/50 or 
better vs. worse than 20/50), sex (male vs. female), and microperimetry eligibility (yes 
vs. no).  A permuted-block randomization method is used to obtain an approximately 
2:1 ratio between lampalizumab and sham arms for each dosing frequency within each 
stratum. 
Once the study randomizes the allotted number of CFI profile biomarker-positive or 
CFI profile biomarker-negative patients necessary to achieve the targeted 1.5:1 ratio for 
biomarker groups (see Section 2.2), the additional screened patients who would have 
been randomized in the already filled biomarker group will be screen-failed. 
Following randomization and during the treatment period, the IxRS makes study 
treatment kit assignments. 
Patient randomization and study treatment kit assignments are verified on an ongoing 
basis by an external and independent data coordinating center (iDCC).  The iDCC 
independently reviews the logs to ensure that randomization and kit assignments are 
conducted correctly by the IxRS. 


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3.2 
INDEPENDENT DATA REVIEW 
3.2.1 
Central Reading Center 
All ocular images and microperimetry results are obtained by trained site personnel at 
the study sites and forwarded to an external central reading center for independent 
analysis and storage.  As part of the screening process, the central reading center 
evaluates ocular images and microperimetry results to provide an objective assessment 
of patient eligibility.  Throughout the study, the central reading center evaluates ocular 
images and microperimetry data in an objective and masked manner (masked to patient 
treatment assignment), with resulting data forwarded to the Sponsor electronically. 
3.2.2 
Independent Data Monitoring Committee 
An independent Data Monitoring Committee (iDMC) monitors safety and study conduct 
on an ongoing basis.  Members of the iDMC are external to the Sponsor and follow a 
charter that outlines the iDMC roles and responsibilities.  The iDMC meets 
approximately every 6 months (frequency adjustable as required) to review unmasked 
safety and study conduct data prepared by an external iDCC.  Further, the iDMC may 
review efficacy data if deemed necessary to assess the benefit-risk profile of 
lampalizumab. 
The iDMC may recommend stopping the study early for safety reasons.  No formal 
efficacy or futility analysis is planned for the study.  While there are no formal efficacy or 
futility analyses, per FDA request, a nominal Type I error penalty of 0.0001 will be taken 
for each time the iDMC reviews unmasked data reports prior to the formal analysis of the 
primary efficacy endpoint.  At the time of the primary efficacy endpoint analysis, four 
scheduled data reviews will have been conducted by the iDMC (July 2015, 
February 2016, August 2016, and March 2017); therefore, analyses of the primary 
efficacy endpoint will be performed at α = 0.0496. 
4. 
STATISTICAL METHODS 
4.1 
ANALYSIS POPULATIONS 
Two main analysis populations are defined for this study:  the intent-to-treat (ITT) 
population and the safety-evaluable population.  In addition, as microperimetry 
assessments and serial ECG evaluations were each performed on a subset of patients 
at selected study sites, a microperimetry-analysis population and an ECG-analysis 
population are defined. 
4.1.1 
Intent-to-Treat Population 
The ITT population will be comprised of all patients who were randomized in the study.  
For analyses based on this patient population, patients will be grouped according to the 
treatment assigned at randomization. 


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4.1.2 
Safety-Evaluable Population 
The safety-evaluable population will be comprised of all patients who received at least 
one injection of study treatment (lampalizumab or sham injection).  For analyses based 
on this patient population, patients will be grouped according to the actual treatment 
received as follows.  Patients who receive only sham injections will be classified in the 
sham treatment arm with the frequency (Q4W or Q6W) as assigned at randomization.  
Any patient who receives one or more injection of lampalizumab will be classified in the 
lampalizumab treatment arm with the frequency (Q4W or Q6W) as assigned at 
randomization.  This includes patients randomized to sham who accidentally received 
one or more injections of lampalizumab. 
It is expected that most patients will receive their assigned treatment at all dosing 
timepoints and that only a small number of dosing errors will occur.  Nonetheless, dosing 
errors will be reviewed in conjunction with the corresponding patient safety data to 
assess for any impact on the defined safety populations or the overall safety conclusions. 
 
4.1.3 
Microperimetry-Analysis Population 
Microperimetry assessments were performed on a subset of patients at selected study 
sites only.  The microperimetry analysis population will be comprised of all ITT patients 
with microperimetry assessments who met the microperimetry eligibility criteria as 
evaluated by the central reading center, and validation checks will be applied to identify 
microperimetry assessments of sufficient quality for inclusion in the analysis.  For 
analyses based on this patient population, patients will be grouped according to the 
treatment assigned at randomization.  Due to the smaller sample size enrolled than 
anticipated, statistical inferences for efficacy endpoints based on microperimetry 
assessments will be based on pooled data from Studies GX29176 and GX29185. 
4.1.4 
ECG-Analysis Population 
Electrocardiogram assessments were performed on a subset of patients at selected U.S. 
study sites only.  The ECG-analysis population will be comprised of all safety-evaluable 
patients who did not have atrial fibrillation at baseline per ECG assessment, and who 
had numerical results reported from at least one ECG assessment.  For analyses based 
on this patient population, patients will be grouped according to the actual treatment 
received, consistent with patient groupings for the safety-evaluable population. 
4.2 
DEFINITION OF BASELINE 
Baseline will be defined as the last available pre-treatment value taken on or before the 
day of randomization, and will be used for summary of demographic characteristics, as 
well as for all change-from-baseline analyses of efficacy and safety endpoints. 
4.3 
ANALYSIS OF STUDY CONDUCT 
The number of patients randomized will be tabulated by region, country, study site, and 
treatment arm.  Patient disposition (the number of patients randomized, receiving at 


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least one dose of study treatment [lampalizumab or sham], completing study treatment 
[through Week 48 or Week 96, as appropriate], and completing study visit assessments 
[through Week 48 or Week 96, as appropriate]) and time on study will be tabulated by 
treatment arm in the overall and biomarker patient groups.  Reasons for premature 
discontinuation from study treatment and reasons for premature discontinuation from 
study assessment visits will be summarized.  Eligibility criteria deviations, dosing errors, 
and other major protocol deviations will be summarized.  All summaries for analysis of 
study conduct will be produced based on the primary 48-week analysis data, and also 
based on the final study data as appropriate. 
4.4 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
Demographic and baseline characteristics such as age, sex, race, ethnicity, and 
baseline ocular characteristics (such as baseline GA area, location of GA lesion, GA 
lesion multifocality, baseline BCVA, baseline LLVA, and history of glaucoma, glaucoma 
suspect, and ocular hypertension) will be summarized for the ITT population by 
treatment arm in the overall and biomarker patient groups using descriptive statistics. 
4.5 
EFFICACY ANALYSIS 
Efficacy analyses will be based on the ITT patient population or microperimetry-analysis 
population, as appropriate (Section 4.1.1), with patients grouped according to the 
treatment assigned at randomization.  Available data from all randomized and treated 
patients regardless of adherence to the protocol will be included in the efficacy analyses; 
this includes data from patients who discontinued study drug early but continued with 
study assessments. 
Unless otherwise noted, hypothesis testing and estimation of treatment effects will be 
performed with a regression model that includes data from all three treatment arms 
(sham pooled, lampalizumab Q4W, and lampalizumab Q6W).  When analyzing data by 
biomarker group, separate regression models will be fit for the biomarker-positive and 
biomarker-negative patient groups (as defined in Section 2.2).  All hypothesis tests for 
efficacy endpoints will be two-sided. 
Unless otherwise noted, analyses of efficacy endpoints (primary, secondary, and 
exploratory) in the overall patient population will be adjusted for the following 
randomization stratification factors and baseline covariates: 
• 
Biomarker status (positive vs. negative, as determined by the cobas® CFI 
Profile CTA)  
• 
Baseline BCVA ETDRS chart Snellen equivalent (20/50 or better vs. worse 
than 20/50) 
• 
Sex (male vs. female) 
• 
Baseline GA lesion contiguity (multifocal vs. non-multifocal)  


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– For efficacy endpoints based on GA area and microperimetry assessments 
(e.g. number of absolute scotomatous points) only. 
• 
Baseline GA lesion location (subfoveal, non-subfoveal)  
– For efficacy endpoints based on GA area, microperimetry assessments 
(e.g. number of absolute scotomatous points), and visual acuity (BCVA or 
LLVA) only. 
 
Analyses of efficacy endpoints performed by biomarker group will include the above 
listed randomization stratification factors and baseline covariates with the exception of 
biomarker status. 
All patients are expected to have the randomization stratification factors and baseline 
covariates that are specified above.  One exception is that a small number of patients do 
not have a valid baseline BCVA score recorded per the corresponding electronic case 
report form.  In order to include these patients in the efficacy analyses based on 
regression modeling with covariate adjustment, the BCVA category (20/50 or better vs. 
worse than 20/50) captured in the IxRS will be used. 
For endpoints that are defined in terms of change from baseline, patients who do not 
have a baseline value reported for a particular assessment will be excluded from the 
change-from-baseline analyses for that assessment.  Similarly, in general, patients who 
do not have at least one post-baseline value reported for a particular assessment will be 
excluded from the change from baseline analyses for that assessment.  For selected 
endpoints, sensitivity analyses that include patients without observed post-baseline 
values will be performed. 
For continuous outcomes, a data-as-observed approach with a mixed-effect model 
repeated measures (MMRM) will be used to handle missing data, which assumes that 
the missing data are missing at random (MAR).  For binary outcomes, analysis of the 
outcome at a specific time point will be based on observed data, unless otherwise noted.  
Study discontinuations and the reasons for study discontinuations will be summarized by 
treatment arm (see Section 4.3) to evaluate the potential impact of missing data on the 
results.  In addition, a number of sensitivity analyses to assess the robustness of the 
primary analysis results to missing data assumptions will be performed. 
For patient-reported outcome measures (e.g., NEI VFQ-25), there are two types of 
missing data:  missing at the form level and missing at the item level.  Missing form level 
data will be handled as described above.  Missing item values will follow the rules for 
scoring and handling of missing item-level data as described in the user’s manual. 
4.5.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from baseline in GA area at 1 year 
(48-weeks) as assessed by FAF.  The primary efficacy endpoint will be analyzed for the 
overall patient population (Section 4.5.1.1), in addition to being analyzed for the 


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biomarker-positive and biomarker-negative groups separately (Section 4.5.1.2).  The 
hypotheses of interest and Type I error management for analyses of the primary 
endpoint are specified below, and take precedence over that specified in the study 
protocol. 
The null hypotheses for the primary efficacy endpoint are the following: 
• 
H01: There is no difference between lampalizumab Q4W and sham with regard 
to mean change from baseline in GA area at Week 48 measured by FAF for 
the overall patient population. 
• 
H02: There is no difference between lampalizumab Q4W and sham with regard 
to mean change from baseline in GA area at Week 48 measured by FAF for 
the CFI-profile biomarker-positive patient population. 
• 
H03: There is no difference between lampalizumab Q6W and sham with regard 
to mean change from baseline in GA area at Week 48 measured by FAF for 
the overall patient population. 
• 
H04: There is no difference between lampalizumab Q6W and sham with regard 
to mean change from baseline in GA area at Week 48 measured by FAF for 
the CFI profile biomarker-positive patient population. 
 
For hypothesis testing of the primary efficacy endpoint, Type I error will be controlled 
using a fixed sequencing approach by testing the four hypotheses (H01, H02, H03, and H04) 
sequentially, beginning with H01.  All hypothesis tests for the primary endpoint will be 
based on a two-sided alpha level of 0.0496.  Testing for statistical significance proceeds 
to a subsequent hypothesis only if the tests for all prior hypotheses are significant at the 
0.0496 level.  Note, the study will be considered positive if the first hypothesis (H01) is 
rejected (i.e., if a statistically significant difference is observed when comparing the 
lampalizumab Q4W arm with the sham pooled arm for the primary efficacy endpoint in 
the overall patient population). 
For the primary efficacy endpoint, a number of additional subgroup analyses 
(Section 4.5.1.3), sensitivity analyses (Section 4.5.1.4), and supplemental analyses 
(Section 4.5.1.5) will be performed.  Included in the sensitivity analyses are analyses to 
assess the robustness of the primary analysis results to missing data assumptions. 
4.5.1.1 
Overall Patient Population Analysis 
For the overall patient population, the mean change in GA area from baseline at 
Week 48 will be compared between each lampalizumab treatment arm (Q4W or Q6W) 
and the pooled sham arm by use of a MMRM analysis.  The primary analysis will be 
based on all available data up to Week 48, with no imputation for missing data.  The 
model will use absolute change from baseline in GA area at post-baseline visits, up to 
and including 48-weeks, as the response variable, and will include independent 
variables for treatment arm, study visit, treatment arm by study visit interaction, baseline 
GA area, and the randomization stratification factors and baseline covariates as 


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described in Section 4.5.  Study visit will be included as a categorical variable.  An 
unstructured covariance matrix will be used to model the within-subject errors.  If there 
are convergence problems with the model, then a heterogeneous compound symmetry 
covariance structure will be used. 
Point estimates, 95% CIs, and p-values for the treatment effect (difference in mean 
change in GA area from baseline for lampalizumab vs. sham pooled) will be calculated 
for each lampalizumab treatment arm on the basis of the model for each assessed 
timepoint, including Week 48. 
4.5.1.2 
Biomarker Subgroup Analyses 
For each biomarker group (CFI-profile biomarker-positive and CFI-profile 
biomarker-negative, defined per Section 2.2), the mean change in GA area from 
baseline at Week 48 will be compared between each lampalizumab treatment arm (Q4W 
or Q6W) and the pooled sham arm by use of a MMRM analysis.  The regression model 
will be the same as that specified for the primary analysis in the overall patient 
population (Section 4.5.1.1), with the exception that the model will be fit separately for 
each biomarker group.  In addition, given a separate model fit for each biomarker group, 
biomarker status will not be included as an independent variable in the model.  Point 
estimates for the treatment effect (lampalizumab vs. sham) within each biomarker group 
will be presented for each lampalizumab treatment arm, along with corresponding 
95% CIs and p-values. 
Patient profile of GA lesion size change over time will be plotted by treatment arm and 
biomarker group. 
To compare the treatment effect in the biomarker-positive patients vs. the 
biomarker-negative patients, the difference in the treatment effect between 
biomarker-positive and biomarker-negative patient groups (as estimated from the 
individual models above) will be calculated.  A corresponding 95% CI for the difference 
in the treatment effect and the associated p-value will be provided based on the property 
that the treatment effect estimates from the individual models are independent and 
asymptotically normally distributed. 
 
4.5.1.3 
Other Subgroup Analyses 
Exploratory subgroup analyses will be performed to evaluate the consistency of the 
primary analysis results across subgroups defined by demographic and baseline 
characteristics.  Analyses will be performed for the primary efficacy endpoint (change 
from baseline in GA area at Week 48) for each of the following subgroups (as 
appropriate per actual subgroup sample size): 
• 
Age (< 75 years, 75 to < 85 years, ≥ 85 years) 
• 
Sex (male, female) 


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 
Race (White, Black or African American, Asian, American Indian or Alaskan 
Native, Native Hawaiian or other Pacific Islander, multiple, unknown) 
– 
Note:  If the vast majority of patients (e.g.  95%) are of a single race, this 
analysis will not be conducted. 
 
Geographic region 
– 
US and Canada 
– 
Western Europe (Austria, Belgium, Denmark, France, Germany, Italy, 
Netherlands, Portugal, Spain, Sweden, Switzerland, UK) 
– 
Rest of World (Argentina, Australia, Hungary, Mexico, Peru, Poland, Russia, 
Slovakia, Turkey) 
 
Baseline BCVA ( 64 letters [worse than 20/50],  64 letters [20/50 or better]) 
 
Baseline low luminance deficit (LLD) ( 30 letters,  30 letters), where  
LLD = BCVA - LLVA 
– 
Note:  The median LLD at baseline is expected to be approximately 
30 letters based on data from Study GX29633. 
 
Baseline GA area (  4DA,  4DA), where 1 disc area (DA) = 2.54 mm2 
 
Baseline GA contiguity (multifocal, non-multifocal) 
 
Baseline GA lesion location (subfoveal, non-subfoveal) 
 
Tobacco use history (ever, never) 
 
Subgroup analyses based on CFI-profile biomarker status are specified in 
Section 4.5.1.2. 
For the primary efficacy endpoint, a MMRM similar to that specified for the primary 
analysis (Section 4.5.1.1) will be used for each subgroup analysis based on the data 
subset for the patient subgroup of interest.  Baseline covariates included in the primary 
analysis but no longer relevant given the subgroup of interest will be excluded from the 
model.  The estimated treatment effects (lampalizumab vs. sham) and corresponding 
95% CIs from the models will be displayed graphically for each lampalizumab treatment 
arm and each level of the subgroups specified (e.g. via forest plots). 
 
4.5.1.4 
Sensitivity Analyses 
Sensitivity analyses will be performed to evaluate the robustness of the primary analysis 
results.  Analyses will be performed for the overall patient population and/or the 
biomarker subgroup populations, as deemed appropriate based on the outcome of the 
primary analyses including all patients in the ITT population. 


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Multiple Imputation 
The following sensitivity analysis based on multiple imputation will be performed, as 
appropriate, using the same statistical approach as the one used in the primary analysis: 
 
Change from baseline in GA area as measured using FAF, with missing data 
imputed by multiple imputation using the Markov Chain Monte Carlo (MCMC) 
method assuming MAR 
 
Change from baseline in GA area as measured using FAF, with missing data 
imputed by multiple imputation using regression method assuming MAR 
 
Change from baseline in GA area as measured using FAF, with missing data 
imputed by multiple imputation using pattern mixture model method assuming 
missing not at random (MNAR) 
 
Change from baseline in GA area as measured using FAF, with missing data 
imputed by multiple imputation using tipping point analysis method assuming 
MNAR 
Considering the details of the four multiple imputation methods (MCMC, regression 
method, pattern mixture model, and tipping point analysis) further, MCMC and 
regression methods assume MAR, where the imputed data will follow the same 
distribution as the observed data within the same treatment group.  Pattern mixture 
model and tipping point analysis methods assume MNAR, where the imputed data for 
the active treatment group will follow either the distribution of the control group or 
adjusted by a shift parameter. 
Geographic atrophy is progressive and irreversible, so changes in GA area over time 
should be  0 mm2. In order to incorporate this data pattern, imputation for missing data 
will be performed on the difference in GA area at a visit from the previous visit.  
Imputation for the non-monotone missing pattern (i.e., arbitrary missing pattern) will be 
performed prior to the multiple imputation for the monotone missing pattern (i.e., where a 
missing GA area measurement at a visit for a patient implies that GA area 
measurements at all subsequent visits for that patient are missing).  For the non-
monotone missing pattern, missing value(s) between two visits with measured GA area 
will be imputed according to a linear growth line passing through the two measured sizes.  
Multiple imputation will only be carried out for monotone missing pattern. 
All four imputation methods will be implemented in SAS using the three standard steps 
to generate inference from imputed data: imputation step, analysis step, and pooling 
step. 
1. 
The missing data are filled in 100 times to generate 100 complete data sets. 
2. 
The 100 complete data sets are analyzed by using the same approach as for the 
analysis for the primary objective. 
3. 
The results from the 100 complete data sets are combined for the inference. 
Methods used in the imputation step are described below.  The actual parameters used 
in all imputations will be documented in the programming specifications.  Analysis and 


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pooling steps will be carried out following the imputation step will also be documented in 
the programming specifications. 
 
MCMC Method.  The MCMC method will be implemented for each treatment 
arm (the two sham arms will be pooled) and by biomarker status. 
 
Regression Method.  The regression method will be implemented for each 
treatment arm and by biomarker status.  This method assumes MAR, and 
serves as the reference for the pattern mixture model and tipping point analysis 
methods which assume MNAR. 
 
Pattern Mixture Model Method.  The pattern mixture model method will be 
implemented for each active treatment arm and by biomarker status.  For the 
active treatment arms, the missing data will be imputed based on the observed 
values in the pooled sham arm.  
 
Tipping Point Analysis Method.  The tipping point analysis method will be 
implemented for each active treatment arm and by biomarker status under the 
MNAR assumption by searching for a tipping point that reverses the conclusion 
regarding positive treatment effect.  For the active treatment arms, monotone 
missing data will be imputed based on the available values (observed values 
plus values imputed for non-monotone missing data) in the same treatment 
arm with a shift parameter added to the imputed values.  Multiple imputation 
will be implemented on the differences between two consecutive visits, with the 
shift parameter allocated to the missing data point(s) proportionally across the 
48 weeks.  (e.g. For a shift parameter of 1 mm2, incremental shifts of 0.5 mm2, 
0.25 mm2, and 0.25 mm2 would apply to Week 24, Week 36, and Week 48, 
respectively.)  The range of the shift parameters will depend on the observed 
treatment effect, i.e., the difference in the change of GA area from baseline at 
Week 48 between lampalizumab and the pooled sham arms.  The precision of 
the tipping point will be at one decimal point.  A tipping point may not exist 
within reasonable clinical assumptions. 
 
Additional Sensitivity Analyses: 
Moreover, the following sensitivity analysis will be conducted based on observed data for 
the primary endpoint: 
 
ANCOVA:  Comparison of the mean change in GA area from baseline at Week 
48 between each lampalizumab arm (Q4W or Q6W) and the pooled sham arm 
using an analysis of covariance (ANCOVA) regression model with change from 
baseline at Week 48 as the response variable and independent variables for 
treatment arm, baseline GA area, and the randomization stratification factors 
and baseline covariates as described in Section 4.5. 
 
Van Elteren Test:  Comparison of the distribution of change in GA area from 
baseline at Week 48 between each lampalizumab arm (Q4W or Q6W) and the 
pooled sham arm respectively, using the non-parametric Van Elteren test 
stratified by baseline GA area ( 4DA,  4DA, where 1 disc 
area [DA] = 2.54 mm2) and the randomization stratification factors and baseline 
covariates as described in Section 4.5. 
 


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4.5.1.5 
Supplemental Analyses 
Analyses of the following endpoints, closely related to the primary efficacy endpoint, will 
be performed to provide supplemental information.  Analyses will be performed for the 
overall patient population and/or the biomarker subgroup populations, as deemed 
appropriate based on the outcome of the primary analyses. 
Rate of Change in GA Area (Growth Slope) over 48 Weeks 
The mean rate of change in GA area (mm2/year [365.25 days]) will be compared 
between each lampalizumab treatment arm (Q4W or Q6W) and the pooled sham arm by 
use of a random intercept and random slope regression model.  GA area (at baseline 
and post-baseline visits up to Week 48) will be used as the response variable, and the 
model will include terms for treatment arm, time (continuous variable assuming linearity), 
treatment arm by time interaction, and the randomization stratification factors and 
baseline covariates as described in Section 4.5.  Random effects will include the 
intercept and slope (time) with an unstructured covariance matrix, with all other variables 
as fixed effects.  The within patient error will be assumed to be independent and 
normally distributed with variance component as the covariance structure. 
Change in Square Root of GA Area at Week 48 
For each patient and timepoint, the square root of GA area will be calculated.  The 
change from baseline in square root of GA area will be analyzed using the same 
methodology as described for the primary endpoint analysis, except that change from 
baseline in the square root of GA area will be the response variable. 
Percent Change in GA Area at Week 48 
For each patient and timepoint, the percent change in GA area will be defined as the 
change from baseline in GA area (mm2) divided by the GA area (mm2) at baseline.  The 
percent change in GA area from baseline will be analyzed using the same methodology 
as described for the primary endpoint analysis, except that percent change from 
baseline will be the response variable.  In addition, baseline GA area will not be included 
as a covariate in the model. 
 
4.5.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are listed in Section 2.1.2.  At the time of primary 
analysis, all secondary endpoints will be evaluated based on data from baseline to 
Week 48 (see Section 2.4).  At the time of the final study analysis, all secondary 
endpoints will be evaluated based on data from baseline to Week 96. 
Analysis of secondary efficacy endpoints assessed by mesopic microperimetry will be 
based on the microperimetry-analysis population.  Statistical inferences for efficacy 
endpoints based on microperimetry assessments will be based on pooled data from 
Studies GX29176 and GX29185.  Analysis of all other secondary efficacy endpoints will 
be based on the ITT patient population. 


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Hypothesis testing for three key secondary endpoints will be performed in the order 
specified in Section 4.5.2.1 based on the Week 96 timepoint.  Subgroup analyses 
(Section 4.5.2.2) for the key secondary efficacy endpoints will be performed. 
Treatment-effect related analyses to compare each lampalizumab treatment arm (Q4W 
or Q6W) and the pooled sham arm for secondary efficacy endpoints will be undertaken 
as follows.  In general, continuous secondary endpoints will be analyzed using a MMRM 
analysis, with change from baseline as the response variable.  For the Week 48 
analyses, post-baseline visits, up to and including Week 48, will be included.  For the 
Week 96 analyses, post-baseline visits, up to and including Week 96, will be included.  
Independent variables for treatment arm, study visit (categorical variable), treatment arm 
by study visit interaction, baseline value of the endpoint, and the randomization 
stratification factors and baseline covariates as described in Section 4.5 will be included 
in the model.  An unstructured covariance matrix will be used to model the within-subject 
errors.  If there are convergence problems with the model, then a heterogeneous 
compound symmetry covariance structure will be used. 
In general, binary secondary endpoints will be analyzed using a logistic regression 
model.  The model will include independent variables for treatment arm, baseline value 
of the endpoint (continuous scale), and the randomization stratification factors and 
baseline covariates as described in Section 4.5, as appropriate.  If the response rate is 
low, an unadjusted analysis may be performed.  Analyses will be based on the observed 
data for the timepoint, with no imputation for missing data. 
For analyses of BCVA, the model will include the major assessment timepoints of 
Weeks 12, 24, 36, 48, 60, 72, 84, and 96 that are in common between the Q4W and 
Q6W dosing arms.  In addition, the stratification factor of baseline BCVA category will 
not be included in the model, given baseline BCVA is included as a continuous covariate. 
Reading speed will be calculated per the MNRead or Radner user’s manuals, with no 
adjustment for reading inaccuracy.   An addition step to cap resulting reading speed 
values at a maximum of 300 words per minute will be implemented.  Values above 300 
words per minute exceed values reported in the literature for adults with no vision 
impairment for MNRead (Calabrese et al. 2016) or Radner (Radner et al. 2002; Radner 
and Diendorfer 2014) assessments.  Maximum reading speed will be calculated as the 
mean of the three highest reading speeds obtained per the user’s manuals.  Data 
collected via the two reading charts will be pooled for analysis and the model will include 
an additional covariate for reading chart type (MNRead or Radner).  Additional subgroup 
analyses will be performed to assess the consistency of finding across the two reading 
charts (see Section 4.5.2.2). 
NEI VFQ-25 scores (composite, near activity subscale, and distance activity subscale) 
and mean FRI Index scores will be calculated per the scoring algorithms in the 
corresponding user’s manuals. 


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For analyses of binocular maximum reading speed, NEI VFQ-25 composite score, 
NEI VFQ-25 near activity subscale score, NEI VFQ-25 distance activity subscale score, 
and mean FRI Index score, an additional adjustment for baseline BCVA of the better 
seeing eye will be included (instead of study eye baseline BCVA [20/50 or better vs. 
worse than 20/50]).  In the event that baseline BCVA is missing for the study or fellow 
eye (but not both), then the non-missing baseline BCVA will be used for this covariate. 
4.5.2.1 
Type I Error Management 
Significance testing for secondary efficacy endpoints will be gated on the success of the 
primary efficacy endpoint evaluated at Week 48.  Secondary efficacy endpoints will be 
tested at Week 96 for the lampalizumab dose frequency or frequencies (Q4W or Q6W) 
and patient populations (overall or biomarker-positive) found to demonstrate statistically 
significant treatment effect for the primary efficacy endpoint. 
The following secondary efficacy endpoints will be tested in the order listed below: 
• 
Change from baseline in number of absolute scotomatous points at Week 96 
as assessed by mesopic microperimetry 
– 
Note:  Due to small sample size, statistical inferences for this endpoint to be 
based on pooled data from Studies GX29176 and GX29185. 
• 
Change from baseline in LLVA at Week 96 as assessed by ETDRS chart at a 
starting distance of 4 m 
• 
Change from baseline in binocular maximum reading speed at Week 96 as 
assessed by MNRead or Radner Charts 
A list of the hypothesis testing of the key secondary clinical endpoints is given below: 
• 
H05: There is no difference between lampalizumab and sham with regard to 
mean change from baseline in the number of absolute scotomatous points at 
Week 96. 
• 
H06: There is no difference between lampalizumab and sham with regard to 
mean change from baseline in LLVA at Week 96. 
• 
H07: There is no difference between lampalizumab and sham with regard to 
mean change from baseline in binocular maximum reading speed at Week 96. 
 
For each lampalizumab dosing frequency and patient population found to be statistically 
different from sham for the test of the primary endpoint, testing of the three key 
secondary endpoints will be performed (e.g. if H01 is positive per the Type I error control 
plan, then the key secondary endpoints would be tested for the Q4W dose frequency in 
the overall patient population).  The aim is to manage the Type I error rate with respect 
to conclusions about secondary endpoints within a given dose frequency and patient 
population.  Thus, within each dose frequency and patient population, Type I error for 
key secondary endpoints will be controlled using a fixed sequencing approach by testing 
the secondary endpoint hypotheses sequentially in the order specified above, beginning 
with H05. 


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All hypotheses for the key secondary endpoints will be tested for significance at the 
study level, except for H05.  The secondary endpoint of number of absolute scotomatous 
points will be based on the microperimetry-analysis population, which is estimated to be 
10-15% of the total ITT population.  Microperimetry was assessed in a subset of patients 
at selected study sites only.  For this secondary endpoint, data from both 
Studies GX29176 and GX29185 will be combined to achieve a sample size sufficient to 
evaluate and test for treatment differences with a reliable level of precision. 
As a consequence of this, for analyses of secondary efficacy endpoints at the individual 
study level: 
• 
For H05, the study-level p-value will be presented.  However, interpretation of 
significance in a confirmatory manner will be based on the analysis of pooled 
data from Studies GX29176 and GX29185. 
• 
H06 will be tested in a confirmatory manner at the study-level if and only if, 
based on an analysis of pooled data from Studies GX29176 and GX29185, H05 
is rejected (i.e., pooled analysis p ≤ 0.0496). 
• 
H07 will be tested in a confirmatory manner at the study-level if and only if H06 is 
rejected at the study-level 
As noted above, significance testing for H05 will not be done at the study level, but rather 
interpretation of significance in a confirmatory manner will be based on the analysis of 
pooled data from Studies GX29176 and GX29185 for the microperimetry-based endpoint. 
All hypothesis tests for the secondary endpoints will be on the basis of a two-sided alpha 
level of 0.0496. 
4.5.2.2 
Subgroup Analyses 
Exploratory subgroup analyses will be performed to evaluate the consistency of the 
analysis results for two of the key secondary efficacy endpoints (change from baseline in 
LLVA at Week 96 and change from baseline in binocular maximum reading speed at 
Week 96).  Subgroup analyses will not be performed at the study level for the key 
secondary endpoint of change from baseline in number of absolute scotomatous points 
at Week 96 due to the smaller sample size in the microperimetry-analysis population. 
The subgroups evaluated for secondary endpoints will be based on demographic and 
baseline characteristics, as done for the primary efficacy endpoint (see Section 4.5.1.3).  
For binocular maximum reading speed, an additional subgroup analysis based on eye 
with greater BCVA at baseline (study vs. fellow) will be performed.  Patients with 
equivalent baseline BCVA in the study and fellow eye (if any) will be grouped with 
patients with greater BCVA in the study eye for this subgroup analysis.  
For analysis maximum reading speed assessed by MNRead or Radner charts, additional 
subgroup analyses by reading chart type (MNRead or Radner) will also be performed to 
assess the consistency of findings across the two reading charts. 


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For each endpoint, a MMRM similar to that specified for the main analysis (Section 4.5.2) 
will be used for each subgroup analysis based on the data subset for the patient 
subgroup of interest.  Baseline covariates included in the main analysis but no longer 
relevant given the subgroup of interest will be excluded from the model.  The estimated 
treatment effects (lampalizumab vs. sham) and corresponding 95% CIs from the models 
will be displayed graphically for each lampalizumab treatment arm and each level of the 
subgroups specified (e.g. via forest plots). 
4.5.3 
Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints are listed in Section 2.1.3.  Similar to the secondary 
endpoints, exploratory endpoints will be summarized based on data from baseline to 
Week 48 at the time of the primary analysis.  At the time of the final study analysis, 
exploratory endpoints will be evaluated based on data from baseline to Week 96. 
Exploratory efficacy endpoints based on mesopic microperimetry assessments will be 
based on the microperimetry-analysis population; statistical inferences for efficacy 
endpoints based on microperimetry assessments will be based on pooled data from 
Studies GX29176 and GX29185.  All other secondary efficacy endpoints will be based 
on the ITT patient population. 
Analysis of exploratory endpoints is planned for the overall patient population and for 
each biomarker subgroup.  However, similar to the secondary efficacy endpoints, 
analysis of the exploratory efficacy endpoints may focus on the evaluation for either the 
overall patient group or the biomarker subgroups depending on the primary endpoint 
results. 
Treatment-effect related analyses to compare each lampalizumab treatment arm (Q4W 
or Q6W) and the pooled sham arm for exploratory efficacy endpoints will be similar to 
that for secondary endpoints.  In general, continuous secondary endpoints will be 
analyzed using a MMRM analysis, with change from baseline as the response variable.  
Independent variables for treatment arm, study visit (categorical variable), treatment arm 
by study visit interaction, baseline value of the endpoint, and the randomization 
stratification factors and baseline covariates as described in Section 4.5 will be included 
in the model.  An unstructured covariance matrix will be used to model the within-subject 
errors, and a heterogeneous compound symmetry covariance structure used if there are 
convergence problems. 
In general, binary secondary endpoints will be analyzed using a logistic regression 
model.  The model will include independent variables for treatment arm, baseline value 
of the endpoint (continuous scale), and the randomization stratification factors and 
baseline covariates as described in Section 4.5, as appropriate.  If the response rate is 
low, an unadjusted analysis may be performed.  Unless noted otherwise, analyses will 
be based on the observed data for the timepoint, with no imputation for missing data. 


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For the analysis of the proportion of patients with < 20% increase in GA area, patients 
with missing GA assessment at the analysis timepoint (e.g. Week 48) will be included in 
the analysis and counted as having a ≥ 20% increase if such an outcome was observed 
at any earlier timepoint. 
Reading function scores will be calculated per MNRead or Radner user’s manuals, with 
no adjustment for reading inaccuracy.  For reading function endpoints (maximum 
reading speed, critical print size, and reading acuity), data collected via the two reading 
charts will be pooled for analysis and the model will include an additional covariate for 
reading chart type (MNRead or Radner).  Additional subgroup analyses by reading chart 
type (MNRead or Radner) will be performed to assess the consistency of findings across 
the two reading charts.  In addition, for analyses based on percent change in reading 
speed, the baseline reading speed will not be included in the model.  
FRI Level will be calculated per the scoring algorithm in the FRI Index user’s manual. 
For analyses of binocular maximum reading speed, binocular critical print size, and 
binocular reading acuity, an additional adjustment for better seeing eye BCVA at 
baseline will be included (instead of study eye baseline BCVA [20/50 or better vs. worse 
than 20/50]). 
In addition, the relationship between GA area and visual function outcomes (e.g. LLVA 
etc.) will be explored.  Observed data will be used.  Spearman correlation coefficient will 
be estimated and a 95% CI for the correlation coefficient provided. 
 
4.5.4 
Additional Biomarker Analyses 
Additional biomarker-related analyses will be performed as specified below: 
• 
Analysis of biomarker prognostic effects: 
– 
For patients in the sham treatment group, a comparison of change from 
baseline in GA area between biomarker-positive patients and biomarker-
negative patients will be performed to evaluate the prognostic value of the 
CFI-profile biomarker using a similar model as the primary analysis. 
• 
Analysis of potential association of genetic variants in CFI and complement 
pathway genes with disease characteristics and response to administration of 
lampalizumab 
– 
Patients with rare coding variants in CFI will be identified by sequencing 
and a modified exploratory analysis will be conducted in which all rare 
coding variant carriers are combined with CFI-profile biomarker-positive to 
define an exploratory “CFI-profile plus rare variant” biomarker-positive 
subgroup.  For this exploratory analysis, the primary efficacy analysis as 
described in Section 4.5.1 (including predictive and prognostic aspects) will 
be performed, but using this modified exploratory biomarker definition. 


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– 
A pre-specified set of SNPs associated with complement-related genes will 
be evaluated using multivariate statistical methods for an exploratory 
evaluation of genetics associated with disease characteristics and/or 
lampalizumab treatment response.  Detailed methods will be described 
separately in an Exploratory Genetic Analysis Plan that will be finalized 
prior to Sponsor unmasking for the analysis of the primary efficacy endpoint.  
Given the exploratory nature of these analyses, the results may not be 
included in the CSR. 
 
4.6 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
The PK analyses will include all randomized patients who have at least one serum 
and/or aqueous humor PK sample, with patients grouped according to treatment actually 
received.  Lampalizumab concentrations in serum and aqueous humor, as well as 
complement factor D levels (PD) in aqueous humor will be summarized by timepoint 
using descriptive statistics.  Noncompartmental analysis may be performed with serum 
PK as appropriate. 
Additional PK and exposure-response analyses may be conducted as appropriate.  
Population PK and PK/PD modeling may be performed to characterize the lampalizumab 
pharmacokinetics, GA area dynamic over time with and without lampalizumab treatment, 
and their associated variability, with results reported separately from the CSR.  A 
separate modeling and simulation analysis plan will be prepared prior to any analysis. 
4.7 
SAFETY ANALYSES 
The safety profile of lampalizumab will be assessed through the summary of adverse 
events, deaths, laboratory results for alternative complement pathway activity, serial 
ECG results, incidence of anti-drug antibodies, and ocular assessments (e.g., intraocular 
pressure [IOP]). 
At the time of the Week 48 primary efficacy analysis, safety summaries will be produced 
based on the complete Week 48 data.  In addition, summaries for ongoing second year 
safety data (after Week 48 and up to a single specified clinical cutoff date) will also be 
produced.  At the time of the final analysis, safety summaries will be produced based on 
cumulative Week 96 data. 
Safety outcomes will be summarized based on the safety-evaluable population or 
ECG-analysis population as appropriate, with patients grouped according to the 
treatment actually received (see Sections 4.1.2 and 4.1.4). 
4.7.1 
Exposure of Study Medication 
Exposure to study treatment (total number of injections [lampalizumab or sham] and 
duration of treatment [through Week 48 or Week 96, as appropriate]) will be summarized 
by treatment arm.  Duration of treatment will be defined based on the difference (in days) 


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between the dates of the first and last injection (lampalizumab or sham) plus 1 day for 
the time period summarized. 
4.7.2 
Adverse Events 
Verbatim descriptions of treatment-emergent adverse events will be coded using the 
latest version of MedDRA.  A treatment-emergent adverse event is defined as any new 
adverse events reported or any worsening of an existing condition on or after the first 
dose of study treatment.  Adverse events with missing onset date will be considered to 
be treatment emergent.  Adverse events with partially missing onset date will also be 
included as treatment emergent when the month (if it was recorded) and the year occur 
on or later than the month and year of the initial study treatment date. 
Adverse events will be tabulated by body system and preferred term.  Separate 
summaries will be prepared for all non-ocular and all ocular adverse events, with ocular 
events in the study eye and fellow eye summarized separately as appropriate.  
Summaries will be provided for each of the following categories: 
• 
All adverse events 
• 
All adverse events by severity 
• 
Serious adverse events 
• 
Adverse events suspected to be caused by study treatment as assessed by the 
investigator 
• 
Adverse events leading to discontinuation of study treatment 
• 
Adverse events leading to interruption of study treatment 
• 
Adverse events of special interest as defined in the protocol, specifically: 
– 
Sight-threatening adverse events (causes a decrease of ≥ 30 letters in 
visual acuity score lasting more than 1 hour, requires surgical intervention 
to prevent permanent loss of sight, associated with severe intraocular 
inflammation, in the opinion of the investigator, it may require medical 
intervention to prevent permanent loss of sight) 
– 
Suspected transmission of an infectious agent by the study drug 
– 
Adverse events resulting from medication error 
– 
Cases of potential drug-induced liver injury 
Ocular adverse events will also be presented on a per-injection basis (i.e., number of 
events/total number of injections given).  Selected adverse events will be reviewed 
separately (e.g. adverse events that occurred in patients who received treatment with 
both Lucentis [ranibizumab injection] and lampalizumab in the study eye or adverse 
events that are IOP-related). 
Patient deaths and primary cause of death will be summarized. 


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4.7.3 
Laboratory Data 
A descriptive summary of laboratory values for alternative complement pathway activity 
(AH50), including changes from baseline and values outside the normal limits, will be 
generated. 
General chemistry, hematology, and urinalysis laboratory results were collected as part 
of screening eligibility and subsequently only for patients who discontinued study 
treatment early.  Therefore, laboratory results are reviewed by the Sponsor on an 
individual patient basis.  Aggregate summaries will not be provided.  Clinically significant 
laboratory abnormalities will be reported as adverse events and evaluated as part of the 
adverse event assessments. 
4.7.4 
Immunogenicity 
The number and percentage of patients with positive serum anti-drug antibodies at 
baseline and post-baseline during the study period will be tabulated.  Adverse events 
occurring in patients with positive serum anti-drug antibodies will be reviewed. 
4.7.5 
Ocular Assessments 
Results of the following ocular assessments will be summarized by timepoint and by eye 
(study vs. fellow) using descriptive summaries:  IOP, slit-lamp examination, and indirect 
ophthalmoscopy.  Changes from baseline in pre-dose IOP and changes between pre-
dose and post-dose IOP will be summarized.  In addition, the incidence of IOP above 
specified thresholds (e.g.  ≥ 30 mmHg) will be summarized.  The presence of intraocular 
inflammation and vitreous hemorrhage, as determined on slitlamp examination, will be 
tabulated by grade.  Ophthalmoscopy results, including retinal breaks and retinal 
detachments, will be summarized. 
4.7.6 
ECG Results 
For the ECG-analysis population, ECG results for patients with normal ECG findings at 
baseline and abnormal ECG findings at any post-baseline timepoint based on the overall 
interpretation will be listed and discussed. 
ECG interval data will also be summarized.  For corrected QT interval using Fridericia’s 
method (QTcF), PR, and QRS intervals as well as heart rate (HR), the values at 
baseline, Day 8, Week 4 (Q4W arms), Week 6 (Q6W arms), and Week 24, as well as 
changes from baseline, will be summarized descriptively by treatment arm.  The 
proportion of patients with a QTcF value ≤ 450, > 450 to ≤ 480, > 480 to ≤ 500, and > 500 
msec at a given visit, or an increase from baseline in QTcF of > 30 and > 60 ms will be 
summarized.  As ECG data was collected on a subset of patients, interpretation of these 
ECG results will also be conducted  on pooled data from Studies GX29176 and 
GX29185. 


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4.8 
INTERIM ANALYSES 
No formal efficacy or futility interim analyses are currently planned or have been 
conducted. 
Safety and study conduct is monitored on a regular basis by an iDMC (see 
Section 3.2.2).  
5. 
REFERENCES 
Calabrese A, Cheong AMY, Cheung S-H, et al. Baseline MNREAD measures for 
normally sighted subjects from childhood to old age. Invest Ophthalmol Vis 
Sci 2016;57(8):3836-3843. 
Radner W and Diendorfer G. English sentence optotypes for measuring reading acuity 
and speed - The English version of the Radner Reading Charts. Graefes Arch Clin Exp 
Ophthalmol. 2014;252:1297-1303. 
Radner W, Obermayer W, Richter-Meuksch S, et al. The validity and reliability of short 
German sentences for measuring reading speed. Graefes Arch Clin Exp Ophthalmol. 
2002;240:461-367.