Clinical trial NCT05571267
Conditions: Neovascular Age-Related Macular Degeneration
Keywords: Neovascular age-related macular degeneration (NVAMD)
Sponsor: IVERIC bio, Inc.
Start date: 2016-10-20; Completion date: 2018-04-24
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective is to assess the safety of intravitreal (IVT) Zimura® administered in combination with anti-VEGF Therapy (AVASTIN®, EYLEA®, OR LUCENTIS®) in anti-VEGF treatment experienced subjects with neovascular age-related macular degeneration (AMD)

Detailed description:

Arms: arm 1: Participants receive three monthly Avastin treatments (Day 1, Month 1, and Month 2) followed by Avacincaptad Pegol administered on the same day. All participants will receive treatment every 3 months for a total of 18 months. If there is a loss of visual acuity during the intervening visits, participants may be retreated with Avastin and Avacincaptad Pegol. arm 2: Participants receive three monthly Lucentis treatments (Day 1, Month 1, and Month 2) followed by Avacincaptad Pegol administered on the same day. All participants will receive treatment every 3 months for a total of 18 months. If there is a loss of visual acuity during the intervening visits, participants may be retreated with Lucentis and Avacincaptad Pegol. arm 3: Participants receive three monthly Eylea treatments (Day 1, Month 1, and Month 2) followed by Avacincaptad Pegol administered on the same day. All participants will receive treatment every 3 months for a total of 18 months. If there is a loss of visual acuity during the intervening visits, participants may be retreated with Eylea and Avacincaptad Pegol.
Interventions: intervention 1: Avacincaptad Pegol intervention 2: Avastin intervention 3: Lucentis intervention 4: Eylea
Intervention descriptions: intervention 1: Zimura 2 mg, administered by intravitreal injection intervention 2: Avastin 1.25 mg, administered by intravitreal injection intervention 3: Lucentis 0.5 mg, administered by intravitreal injection intervention 4: Eylea 2 mg, administered by intravitreal injection

Protocol documents:
Prot_SAP_000.pdf: 
Official Study Title: A Phase 2A Randomized Open-Label Trial to Assess 
the Safety of Zimura® (Anti-C5 Aptamer) Administered in Combination with 
Anti-VEGF Therapy in Treatment Experienced Subjects with Neovascular 
Age Related Macular Degeneration 
NCT#: NCT05571267 
Document: Protocol 
Document Date: 22 March 2016 


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A PHASE 2A RANDOMIZED OPEN-LABEL TRIAL TO ASSESS 
THE SAFETY OF ZIMURA® (ANTI-C5 APTAMER) ADMINISTERED 
IN COMBINATION WITH ANTI-VEGF THERAPY IN TREATMENT 
EXPERIENCED SUBJECTS WITH NEOVASCULAR AGE RELATED 
MACULAR DEGENERATION  
 
 
PROTOCOL NO:  OPH2004 
Amendment A 
 
 
Version Date:  
22 March 2016 
 
 
 
SPONSOR: 
OPHTHOTECH CORP. 
One Penn Plaza – 19th Floor 
New York, NY 10119 
 
FOR MEDICAL EMERGENCIES REFER TO THE 
“SAFETY CONTACT LIST” PROVIDED SEPARATELY 
                                               Confidentiality Statement 
The information in this document is confidential and will not be disclosed to others without written authorization 
from Ophthotech Corp., except to the extent necessary to obtain informed consent from persons receiving the 
investigational drug or their legal guardians, or for discussions with local regulatory authorities, institutional 
review boards (IRB), or persons participating in the conduct of the trial. 


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TABLE OF CONTENTS 
1 
GLOSSARY OF ABBREVIATIONS ...................................................................... 4 
2 
SUMMARY OF PROTOCOL OPH2004 ............................................................... 5 
3 
STUDY ASSESSMENTS ..................................................................................... 8 
4 
INTRODUCTION ................................................................................................ 10 
4.1 
Age-Related Macular Degeneration (AMD) ............................................ 10 
4.2 
The Complement Pathway and AMD ...................................................... 11 
4.3 
Zimura® ................................................................................................... 12 
4.4 
Clinical Data ............................................................................................ 13 
4.5 
Trial Rationale ......................................................................................... 15 
5 
TRIAL OBJECTIVES .......................................................................................... 17 
5.1 
Objectives ............................................................................................... 17 
5.2 
Endpoints ................................................................................................ 17 
6 
TRIAL DESIGN .................................................................................................. 18 
6.1 
Retreatment Criteria................................................................................ 19 
7 
PROCEDURES .................................................................................................. 20 
7.1 
Procedures for Refraction and Vision Testing ......................................... 20 
7.2 
Tonometry ............................................................................................... 20 
7.3 
Ophthalmologic Examination .................................................................. 21 
7.4 
Fundus Photography and Fluorescein Angiography ............................... 21 
7.5 
Optical Coherence Tomography (SD-OCT) ............................................ 21 
7.6 
Laboratory Tests ..................................................................................... 21 
8 
SUBJECT POPULATION ................................................................................... 23 
8.1 
Sample Size ............................................................................................ 23 
8.2 
Inclusion Criteria ..................................................................................... 23 
8.3 
Exclusion Criteria .................................................................................... 24 
9 
TRIAL MEDICATION .......................................................................................... 27 
9.1 
Drug Supply ............................................................................................ 27 
9.2 
Dose and Administration ......................................................................... 29 
9.3 
Previous or Concomitant Therapy .......................................................... 31 
10 TRIAL CONDUCT .............................................................................................. 32 
10.1 
Subject Enrollment .................................................................................. 32 
10.2 
Trial Assessments................................................................................... 32 
10.3 
Withdrawal from Trial .............................................................................. 43 
10.4 
Trial Discontinuation ............................................................................... 43 




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1 GLOSSARY OF ABBREVIATIONS 
 
AE 
Adverse Event 
AMD 
Age-Related Macular Degeneration 
CATT 
Comparison of AMD Treatments Trials 
CNV 
Choroidal Neovascularization 
CRF 
Case Report Form 
DA 
Disc Area 
DNA 
Deoxyribonucleic Acid 
EC 
Ethics Committee 
EC 
Endothelial Cell 
ECG 
Electrocardiography 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
EW 
Early Withdrawal 
FA 
Fluorescein Angiography 
FDA 
Food and Drug Administration 
FP 
Color Fundus Photograph 
GCP 
Good Clinical Practice 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
NLP 
No Light Perception 
NV 
Neovascular 
NVAMD 
Neovascular Age-Related Macular Degeneration 
NYHA 
New York Heart Association 
OCT 
Optical Coherence Tomography 
OGTT 
Oral Glucose Tolerance Test 
OU 
Both eyes 
PDGF 
Platelet Derived Growth Factor 
PDT 
Photodynamic Therapy 
PED 
Pigment Epithelial Detachment  
RPE 
Retinal Pigment Epithelium 
SAE 
Serious Adverse Event 
SE 
Study Eye 
SHRM 
Subretinal Hyper-Reflective Material 
VA 
Visual Acuity 
VEGF 
Vascular Endothelial Growth Factor 
 
 


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2 SUMMARY OF PROTOCOL OPH2004 
SYNOPSIS 
TITLE: 
A Phase 2A Randomized Open-Label Trial to Assess the Safety of 
Zimura® (Anti-C5 Aptamer) Administered in Combination With Anti-
VEGF Therapy in Treatment Experienced Subjects with Neovascular 
Age Related Macular Degeneration  
OBJECTIVES: 
To assess the safety of intravitreal (IVT) Zimura® administered in 
combination with anti-VEGF Therapy (AVASTIN®, EYLEA®, OR 
LUCENTIS®) in anti-VEGF treatment experienced subjects with 
neovascular age related macular degeneration (AMD)  
STUDY DESIGN: 
 
 
 
 
All enrolled subjects will be anti-VEGF “treatment experienced” (with 
1 prior intravitreal anti-VEGF treatment with AVASTIN®, EYLEA®, OR 
LUCENTIS® within the past 8 weeks for NVAMD in the study eye). 
For all subjects, there must be < 0 letters of visual improvement in 
Snellen (not ETDRS Snellen equivalent) visual acuity since the start 
of anti-VEGF treatment. 
 
Stratified sampling will be employed to enroll equal subgroups 
previously treated with Lucentis® (n=15), Eylea® (n=15), or Avastin® 
(n=15). 
 
Treatment experienced subjects will receive the same anti-VEGF 
agent as administered prior to enrollment. 
 
INDUCTION PHASE 
 
Subjects Previously Treated with Avastin® 
Subjects will receive three monthly intravitreal Avastin® treatments 
(Day 1, Months 1, and 2) followed by Zimura® 2.0 mg/eye 
(administered on the same day). 
 
Subjects Previously Treated with Lucentis® 
Subjects will receive three monthly intravitreal Lucentis® treatments 
(Day 1, Months 1, and 2) followed by Zimura® 2.0 mg/eye 
(administered on the same day). 
 
Subjects Previously Treated with Eylea® 
Subjects will receive three monthly intravitreal Eylea® treatments (Day 
1, Months 1, and 2) followed by Zimura® 2.0 mg/eye (administered on 
the same day).   
 
 
 
 


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SYNOPSIS 
MAINTENANCE PHASE 
 
Subjects will continue to be treated with the same anti-VEGF therapy 
as administered during the Induction Phase. 
 
After the Induction Phase, all subjects will receive treatment every 3 
months (Month 5, 8, 11, 14, and 17), for a total of 18 months.  
 
Injection of anti-VEGF therapy will be administered first followed by 
Zimura® on the same day during the Maintenance Phase. 
 
All subjects will have a final follow-up visit at Month 18. 
 
Retreatment Criteria  
During the intervening visits (Month 3, 4, 6, 7, 9,10, 12, 13, 15, 16) 
subjects will be retreated with anti-VEGF therapy followed by Zimura® 
2.0 mg/eye administered on the same day if  
• 
The visual acuity decreases ≥ 5 ETDRS letters, compared 
to the previous visit 
 OR  
• 
If there is a cumulative decrease of ≥ 5 ETDRS letters at 
consecutive visits since the previous injection.  
Subjects should not be retreated if the visual acuity loss is solely 
attributed to new foveal atrophy and/or new opacified media 
(per investigator discretion).  
 
  
Safety Endpoints: 
• 
Visual Acuity Loss (Proportion of subjects with >0 letter loss at 
Month 12, 18) 
• 
Visual Acuity Loss (Proportion of subjects with >5 letter loss at 
Month 12, 18) 
• 
Visual Acuity Loss (Proportion of subjects with >10 letter loss at 
Month 12, 18) 
• 
Ophthalmic Adverse Events (AEs) 
• 
Systemic Adverse Events (AEs) 
• 
Laboratory variables 
PLANNED SAMPLE SIZE: Approximately 45 treatment experienced subjects will be enrolled: 
15 will receive Avastin® and Zimura® 
15 will receive Lucentis® and Zimura® 
15 will receive Eylea® and Zimura® 








 
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4 INTRODUCTION 
4.1 Age-Related Macular Degeneration (AMD) 
Age-related macular degeneration is a disease characterized by progressive 
degenerative abnormalities in the macula of the eye, a small area in the central portion 
of the retina. It is characteristically a disease of individuals >50 years of age and is the 
leading cause of visual loss in developed countries.  In the United States, it is estimated 
that approximately 6% of individuals 65-74 years of age and 20% of those older than 75 
years of age are affected with AMD (Busbee et al., 2013; Leibowitz et al., 1980).   
Because of the increasing life expectancy in developed and developing countries, the 
elderly sector of the general population is expected to rise at a greater rate in the 
coming decades.  While 1 of 8 Americans was considered to be elderly in 1994, it is 
expected that 1 of 5 will fall into this category in 2030.  Using U.S. Census Bureau 
projections, the number of Americans over 65 years of age will more than double to 80 
million by the middle of this century (Cheeseman-Day, 1993).  In the absence of 
adequate prevention or treatment measures, the number of cases of AMD with visual 
loss is expected to grow accordingly. 
Age-related macular degeneration is classified into one of two general subgroups: the 
non-neovascular (non-exudative or dry) form of the disease and the neovascular 
(exudative or wet) form of the disease.  The non-neovascular form of AMD is more 
prevalent, accounting for approximately 90% of all AMD cases, and is often 
characterized by a slow degeneration of the macula resulting in atrophy of the central 
retina with gradual vision loss over a period of years.  By contrast, neovascular AMD, 
although less prevalent, commonly causes sudden, often substantial, loss of central 
vision and is responsible for most cases of severe loss of visual acuity in this disease 
(Vingerling, 1995). This type of AMD results when abnormal blood vessels 
(neovascularization) proliferate under and/or within the retina.  These blood vessels leak 
blood and fluid into and under the retina, which results in rapid vision loss.  The end 
stage of the disease features scarring with irreversible destruction of the central retina.   
The current FDA approved pharmacologic therapies for wet AMD target and inhibit 
Vascular Endothelial Growth Factor (VEGF). VEGF is an endothelial cell survival factor 
and a mitogen. Endothelial cells are a key component of neovascular tissue. All 
approved anti-VEGF agents for wet AMD are administered by the intravitreal route of 
administration. These include Lucentis® (ranibizumab), Eylea® (aflibercept), and 
Macugen® (pegaptanib sodium) (Brown et al., 2006; Gragoudas et al., 2004; Heier et al., 


 
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2012; Rosenfeld et al., 2006). 
In addition, although not labeled by the FDA for the treatment of neovascular AMD, the 
anti-VEGF agent Avastin® (bevacizumab) is currently used to treat ~50% of the eyes 
with neovascular AMD in the United States. A multicenter, prospective, randomized trial, 
funded by the US National Eye Institute, “The Comparison of Age-Related Macular 
Degeneration Treatments Trials” (CATT) demonstrated that monthly dosing with 
Avastin® 1.25 mg (0.05 mL) was non-inferior to monthly dosing of Lucentis® for eyes 
with neovascular AMD (Martin et al., 2012).  
Avastin®, Lucentis®, and Eylea®, on average, all improve the visual outcome in eyes 
with neovascular AMD. The primary functional impact of these anti-VEGF agents is to 
decrease intraretinal and subretinal fluid associated with abnormal blood vessels. 
Despite maximal therapy with intravitreal monotherapy anti-VEGF agents, majority of 
patients do not achieve significant visual gain (≥ 15 letters of vision), and approximately 
20% to 30% lose additional vision from baseline.  
4.2 The Complement Pathway and AMD 
The etiology of AMD is not completely understood.  In addition to advanced age, there 
are environmental and genetic risk factors for AMD including ocular pigmentation, 
dietary factors, a positive family history for AMD, high blood pressure, and smoking 
(Vingerling, 1995). Recent work suggests inflammation as a major contributor to the 
pathogenesis of the disease (Bok, 2005; Donoso et al., 2006). 
There is mounting evidence that both the wet and dry forms of AMD are associated with 
an inflammatory process. Patients with AMD are known to have elevated systemic 
inflammatory biomarkers such as c-reactive protein (CRP), interleukin-6 (IL-6), and 
homocysteine (Bok, 2005; Seddon et al., 2005). Furthermore, surgically excised 
choroidal neovascular tissue in patients with AMD has been shown to contain 
inflammatory cells (Submacular Surgery Trials Report No. 7, 2005).   
The complement pathway is part of the innate immune system and is a complex system 
of serum proteins that interact in a cascade. This complement cascade is activated via 
the classical (antibody-dependent), the alternative (antibody-independent) and the lectin 
pathways.  Local inflammation and activation of the complement cascade has been 
implicated in drusen formation (Klein, 2004, Bora, 2005).  Recent studies have 
implicated local inflammation and activation of the complement cascade in drusen 
formation (Donoso et al., 2006; Hageman et al., 2001; Nozaki et al., 2006).  Additionally, 


 
Protocol OPH2004 Amendment A– Confidential                                   Page 12                                                   22 March 2016 
the complement components may induce VEGF up-regulation, a well known mediated 
of choroidal neovascularization (CNV). (Nozaki et al., 2006). Preclinical laser-induced 
CNV models have also implicated complement activation. In experimental models of 
CNV, membrane attack complex (MAC: C5b-9) formation has been shown to be 
important (Johnson et al., 2000). The MAC is responsible for causing pores in the 
affected cells that eventually leads to cell death. Inhibition of the alternate pathway of 
complement activation led to decreased pro-angiogenic factors and decreased CNV 
formation in experimental CNV (Bora et al., 2006; Haines et al. 2005). Evidence for 
complement-mediated inflammation in AMD is further reinforced by genetic linkage and 
association studies, which suggest that approximately 50 to 75% of AMD cases have 
polymorphism in complement regulatory proteins compared to age-matched controls. 
Furthermore, polymorphism in genes coding for complement or complement regulatory 
proteins have demonstrated increased risk in age-related macular degeneration 
(Edwards et al., 2005; Hageman et al., 2005, Haines et al., 2005; Klein et al., 2005, 
Naranyan et al., 2007). 
4.3 Zimura® 
Zimura®, a pegylated RNA aptamer, is a potent and specific inhibitor of complement 
activation. It inhibits C5, a central component of the complement cascade, which plays 
multiple roles in innate immunity and inflammatory diseases. Inhibition of this key step in 
the complement cascade at the level of C5 prevents the formation of key terminal 
fragments (C5a and C5b-9) regardless of which pathway (alternate, classical or lectin) 
induced their generation. The C5a fragment is an important inflammatory activator 
inducing vascular permeability, recruitment and activation of phagocytes. C5b is 
involved in the formation of membrane attack complex (MAC: C5b-9), which initiates cell 
lysis. By inhibiting these C5-mediated inflammatory and MAC activities, therapeutic 
benefit may be achieved in neovascular AMD. 
4.3.1 NonClinical Efficacy  
The preclinical data demonstrating the anti-C5 properties of Zimura® are described in 
detail in the Investigator Brochure (IB). 
4.3.2 NonClinical Pharmacokinetics of Zimura® 
Nonclinical pharmacology studies have been conducted with Zimura®, and, in some 
cases, with aptamers (Hoehlig et al., 2013).  
 
  
 


 
Protocol OPH2004 Amendment A– Confidential                                   Page 13                                                   22 March 2016 
 
 
 
The safety pharmacology studies did not reveal any effects on cardiovascular, 
respiratory or neurologic function that would raise concerns for the intended ocular 
administration. 
Further information regarding the pharmacology of Zimura® is presented in detail in the 
IB.   
4.3.3 Toxicology 
 
 
 
 
   
Additional details of the results of these studies, as well as the results of the various 
intravenous toxicity studies that were previously conducted, can be found in the IB.  
4.4 
Clinical Data 
In a phase 1 ascending dose and parallel group clinical trial the safety, tolerability, and 
pharmacokinetic profile of multiple intravitreous injections of Zimura® in combination 
with Lucentis® 0.5mg was evaluated in subjects with wet AMD (OPH 2000).  
Zimura® was well-tolerated and no particular safety concerns were identified. No 
significant evidence of intraocular inflammation, retinal vasculitis, or choroidal 
vasculopathy was evident. One patient was noted to develop a mild cataract, which was 
related to the drug by the investigator and visual acuity improved in this patient.  No AEs 
were assessed to be related to Lucentis® administration. VA assessments were 
primarily safety assessments to detect any decrease in vision associated with the 
intravitreous injections. There were no safety issues identified through measurement of 
VA. Assessment of VA was focused on the treatment-naive (TN) patient subgroup of 43 
patients who had received 6 injections at doses of 0.3 mg, 1 mg or 2 mg. There was a 
trend towards a mean increase in VA (number of ETDRS letters) from baseline at all 
time points for patients in the 0.3, 1 and 2 mg dose groups in the TN subgroup who 
received 6 injections. At Week 24, there was an improvement in mean VA from baseline 
of 13.6 ETDRS letters for the 0.3 mg dose group, 11.7 ETDRS letters for the 1 mg dose 
group and 15.3 ETDRS letters for the 2 mg dose group. 


 
Protocol OPH2004 Amendment A– Confidential                                   Page 14                                                   22 March 2016 
51% of patients in the TN subgroup (n=43 patients) gained >15 ETDRS letters at Week 
24. This included 6 patients (46%) in the 0.3 mg dose group, 7 patients (47%) in the 1 
mg dose group, and 9 patients (60%) in the 2 mg dose group gaining >15 ETDRS 
letters of VA. 
A separate phase 1 study was also performed in subjects diagnosed with geographic 
atrophy (GA). In this study, a total of 47 subjects were enrolled, in the 0.3 mg dose arm 
(n=24) and 1 mg dose arm (n=23). Subjects received treatment with 3 initial intravitreal 
injections of Zimura® 0.3 mg/eye or 1 mg/eye, administered at Day 0, Week 4 and Week 
8 with a follow up visit at Week 16. Subjects received 2 subsequent injections at Week 
24 and Week 36 followed by a final follow up visit at Week 48. Standard safety 
assessments were performed for ophthalmic variables that included VA, IOP, 
ophthalmic examination, Fundus Autofluorescence (FAF), Fluorescein Angiography 
(FA), and Optical Coherence Tomography (SD-OCT) together with Adverse Events 
(AEs), vital signs and laboratory variables.  
Zimura® was well tolerated and there were no AEs considered to be related to Zimura®. 
Fifteen subjects (32%) had AEs, predominantly Eye Disorder AEs in the study eye, 
assessed to be related to the injection procedure. The most frequently reported AEs 
were conjunctival hemorrhage (4 subjects, 9%), corneal edema (4 subjects, 9%), and 
dry eye (3 subjects (6%).  No other study eye AEs were reported by more than 2 
subjects. The majority of AEs were mild or moderate in severity. There were 2 subjects 
with AEs of severe intensity: gastrointestinal inflammation and nasopharyngitis. 
Five subjects experienced Serious Adverse Events (SAEs), namely device failure, 
pelvic fracture, angina pectoris, chest pain and gastrointestinal inflammation, but none 
were related to the study drug or injection procedure. There were no discontinuations 
due to AEs. 
Vital signs and laboratory assessments did not show any particular clinically significant 
patterns or changes. Study eye ophthalmic examinations did not indicate any 
unexpected clinical findings. There were some transient findings post-injection 
(conjunctiva/sclera and cornea) that resolved prior to the next injection. Vitreous haze 
was also reported for a few subjects. IOP showed a small mean increase following 
injections but no indication of any cumulative increases.  
Visual acuity (VA) assessments did not show any safety signals. Visual acuity 
measurements are not particularly meaningful in GA given the marked irreversible 
atrophy of neural and supportive tissue and the variable involvement of the macular 


 
Protocol OPH2004 Amendment A– Confidential                                   Page 15                                                   22 March 2016 
region. There was suggestion of a drug exposure and dose related slowing of the rate of 
GA growth during the period of increased frequency of drug exposure (i.e. monthly 
dosing for 3 months) from baseline to Week 24, as well as a suggestion of stabilized 
VA, including VA under low light conditions. The data supported further investigation of 
Zimura® in larger clinical trials. 
4.5 Trial Rationale 
There is widespread acceptance that the therapeutic benefit of anti-VEGF monotherapy 
is primarily a result of its potent anti-permeability effects. Studies have shown that 
VEGF is the most potent inducer of permeability in biologic systems (Dvorak, Brown, 
Detmar, & Dvorak, 1995).  Multiple investigations of currently available anti-VEGF 
agents (Lucentis®, Avastin® and Eylea®) suggest that they are essentially similar with 
respect to their safety and efficacy profiles (Brown et al., 2006; Martin et al., 2012; 
Rosenfeld et al., 2006; Schmidt-Erfurth et al., 2014).  Furthermore, the “ceiling” of anti-
VEGF mediated therapeutic benefit in NVAMD appears to have been reached as 
attempts at improving visual outcomes by altering the dose and regimen of anti-VEGF 
therapy have been unsuccessful (Busbee et al., 2013; Schmidt-Erfurth et al., 2014). 
Despite maximal therapy with intravitreal monotherapy anti-VEGF agents, the majority 
of patients do not achieve significant visual gain (≥ 15-ETDRS Letters) or achieve visual 
acuity of 20/40 or better. In addition, approximately 25% of the patients lose additional 
vision (Martin et al., 2012). Further, less than monthly regimen results in worse visual 
outcomes in the real world setting since over the years patients lose vision with anti-
VEGF monotherapy. (Rakic et al., Rasmussen et al., 2013; Rofagha et al, 2013).  Taken 
together, anti-VEGF resistance in connection to current anti-VEGF strategies results in 
a significant unmet need, related to treatment burden and sub-optimal visual outcome. 
Anti-VEGF resistance may result from multiple mechanisms including involvement of 
cytokines other than VEGF, cell based endothelial protection (i.e. pericyte mediated), 
and inflammation (Bergers & Hanahan, 2008; Jain, 2001; Wang et al., 2011).  As 
indicated earlier, there is mounting evidence that both the wet and dry forms of AMD 
may involve an inflammatory process. In preclinical models of CNV, inhibition of 
inflammatory adhesion molecules results in anti-angiogenesis (Sakurai et al., 2003). 
Furthermore, surgically excised choroidal neovascular tissue in patients with AMD has 
been shown to contain inflammatory cells (Submacular Surgery Trials Report No. 7, 
2005).   
The specific type of inflammation involved in AMD is yet to be definitively defined. 


 
Protocol OPH2004 Amendment A– Confidential                                   Page 16                                                   22 March 2016 
However, Complement mediated inflammation may play a significant role. Drusen 
complement components contain multiple complent pathway proteins. Preclinical laser-
induced choroidal neovascularization (CNV) models have implicated complement 
activation as well. Complement activation has also induced the up-regulation of key 
mediators of angiogenesis such as VEGF (Nozaki et al., 2006) and PDGF (Benzaquen, 
1994). Evidence for complement-mediated inflammation in AMD is further reinforced by 
genetic linkage and association studies that suggest that approximately 50 to 75% of 
AMD cases have polymorphism in complement regulatory proteins compared to age-
matched controls. Furthermore, polymorphism in genes coding for complement or 
complement regulatory proteins have demonstrated increased risk in AMD (Bora et al, 
2006; Donoso et al, 2006; Hageman et al., 2001; Johnson et al. 2000; Nozaki et al., 
2006). 
The totality of pre-clinical and genetic related evidence significantly implicates 
inflammation secondary to the activation of the complement cascade in AMD. Hence, 
inhibition of complement activation may improve outcomes in AMD patients.  In addition, 
the potential upstream position of complement activation leading to release of VEGF 
and PDGF could reduce the required frequency for anti-VEGF therapy. Thus, targeting 
the complement pathway may result in a new therapeutic class for improvement of 
visual outcome and reduction of treatment burden in neovascular AMD. 
Zimura® is currently being developed by Ophthotech Corporation for the treatment of 
dry and wet AMD.  Zimura® is a pegylated RNA aptamer.  It is a potent and specific 
inhibitor of complement activation.  Zimura® inhibits C5, a central component of the 
complement cascade, which plays multiple roles in innate immunity and inflammatory 
diseases. Inhibition of this key step in the complement cascade at the level of C5 
prevents the formation of key terminal fragments (C5a and C5b-9) regardless of which 
pathway (alternate, classical or lectin) induced their generation. The C5a fragment is an 
important inflammatory activator inducing vascular permeability, recruitment and 
activation of phagocytes. C5b is involved in the formation of membrane attack complex 
(MAC: C5b-9) that initiates cell lysis. By inhibiting these C5-mediated inflammatory and 
MAC activities, additional therapeutic benefit may be achieved in NVAMD patients 
receiving anti-VEGF monotherapy. 
 
 


 
Protocol OPH2004 Amendment A– Confidential                                   Page 17                                                   22 March 2016 
5 TRIAL OBJECTIVES 
5.1 Objectives 
To assess the safety of intravitreal (IVT) Zimura® administered in combination with anti-
VEGF Therapy (AVASTIN®, EYLEA®, OR LUCENTIS®) in anti-VEGF treatment 
experienced subjects with neovascular age related macular degeneration (AMD). 
 
5.2 Endpoints 
Safety Endpoints: 
• Visual Acuity Loss (Proportion of subjects with >0 letter loss at Month 12, 18) 
• Visual Acuity Loss (Proportion of subjects with >5 letter loss at Month 12, 18) 
• Visual Acuity Loss (Proportion of subjects with >10 letter loss at Month 12, 18) 
• Ophthalmic Adverse Events (AEs) 
• Systemic Adverse Events (AEs) 
• Laboratory variables 
 
 


 
Protocol OPH2004 Amendment A– Confidential                                   Page 18                                                   22 March 2016 
6 TRIAL DESIGN 
 
All enrolled subjects will be anti-VEGF “treatment experienced” (with 1 prior intravitreal 
anti-VEGF treatment with AVASTIN®, EYLEA®, OR LUCENTIS® within the past 8 
weeks for NVAMD in the study eye). For all subjects, there must be ≤ 0 letters of visual 
improvement in Snellen (not ETDRS Snellen equivalent) visual acuity since the start of 
anti-VEGF treatment.  
Stratified sampling will be employed to enroll equal subgroups previously treated with 
Lucentis® (n=15), Eylea® (n=15), or Avastin® (n=15). 
Treatment experienced subjects will receive the same anti-VEGF agent as administered 
prior to enrollment. 
INDUCTION PHASE 
Subjects Previously Treated with Avastin® 
Subjects will receive three monthly intravitreal Avastin® treatments (Day 1, Months 1, 
and 2) followed by Zimura® 2.0 mg/eye (administered on the same day) . 
Subjects Previously Treated with Lucentis® 
Subjects will receive three monthly intravitreal Lucentis® treatments (Day 1, Months 1, 
and 2) followed by Zimura® 2.0 mg/eye (administered on the same day). 
Subjects Previously Treated with Eylea® 
Subjects will receive three monthly intravitreal Eylea® treatments (Day 1, Months 1, and 
2) with followed by Zimura® 2.0 mg/eye (administered on the same day).   
MAINTENANCE PHASE 
Subjects will continue to be treated with the same anti-VEGF therapy as administered 
during the Induction Phase. 
After the Induction Phase, all subjects will receive treatment every 3 months (Month 5, 
8, 11, 14, and 17), for a total of 18 months.  
Injection of anti-VEGF therapy will be administered first followed by Zimura® on the 
same day during the Maintenance Phase. 
All subjects will have a final follow-up visit at Month 18. 
 


 
Protocol OPH2004 Amendment A– Confidential                                   Page 19                                                   22 March 2016 
6.1 Retreatment Criteria 
 
During the intervening visits (Month 3, 4, 6, 7, 9,10, 12, 13, 15, 16) subjects will 
be retreated with anti-VEGF therapy followed by Zimura® 2.0 mg/eye 
administered on the same day if  
 
• The visual acuity decreases ≥ 5 ETDRS letters, compared to the 
previous visit 
OR 
• If there is a cumulative decrease of ≥ 5 ETDRS letters at consecutive 
visits since the previous injection.  
 
Subjects should not be retreated if the visual acuity loss is solely attributed to 
new foveal atrophy and/or new opacified media (per investigator discretion).  
 
 


 
Protocol OPH2004 Amendment A– Confidential                                   Page 20                                                   22 March 2016 
7 PROCEDURES 
7.1 Procedures for Refraction and Vision Testing 
Refraction and Vision Testing will be performed at all time-points specified in 
Section 10.2“Trial Assessments”.   
For Snellen testing at SCREENING ONLY, standard Snellen clinic charts will be utilized 
to assess, for “treatment experienced” subjects, that there must be ≤ 0 letters of 
improvement in Snellen (not ETDRS Snellen equivalent) visual acuity since the start of 
anti-VEGF treatment. 
For ETDRS testing, retroilluminated modified Ferris-Bailey ETDRS (Early Treatment 
Diabetic Retinopathy Study) charts are used starting at 4 meters (see Appendix 17.3). 
When protocol refraction and best-corrected visual acuity measurement is required by 
the trial protocol, this will be performed only by certified visual acuity examiners. The 
examiner will be supplied with the previous protocol refraction only.   
 
7.2 Tonometry  
Tonometry will be performed at all time-points specified Section 10.2 “Trial 
Assessments”.  When Zimura® is given on the same day as anti-VEGF, tonometry 
should be performed before the first injection to confirm that IOP is ≤21 mm Hg.  
Tonometry should be repeated after the first injection, to confirm perfusion of the optic 
nerve and return of IOP to ≤21 mm Hg or within 5 mm of pre-injection.  After the second 
injection IOP must return to <30 mm Hg before the subject leaves the clinic.  For the 
post-injection tonometry, proper care should be taken to minimize the risk of 
contamination. 
Goldmann applanation tonometry must be performed at Screening and at Month 
18/Early Withdrawal.  Tonopens may be used at all other time-points, but Goldmann 
applanation tonometry must be used to verify IOP for a post-injection reading of ≥ 30 
mm Hg occurring more than 30 minutes post-injection, or for a reading of ≥ 30 mm Hg 
at any other time. 
 
 


 
Protocol OPH2004 Amendment A– Confidential                                   Page 21                                                   22 March 2016 
7.3 Ophthalmologic Examination 
The following examinations will be performed at all time-points specified in Section 10.2 
“Trial Assessments”. 
• Inspection of the eyelids 
• Examination of the extra-ocular muscle movement  
• Inspection of the cornea 
• Examination of the anterior chamber for inflammation (Appendix 17.1) 
• Examination of the pupils 
• Examination of the iris 
• Inspection of the lens 
• Inspection of the vitreous body (Appendix 17.2) 
• Inspection of the retina and optic disc 
 
7.4 Fundus Photography and Fluorescein Angiography 
Color fundus photographs (FP) and fluorescein angiography (FA) will be performed at 
all time-points specified in Section 10.2 “Trial Assessments”.  Investigators will 
determine eligibility based on findings from diagnostic imaging.   
 
7.5 Optical Coherence Tomography (SD-OCT) 
Spectral Domain Optical Coherence Tomography (SD-OCT) will be performed at all 
time-points specified in Section 10.2 “Trial Assessments”.   
Investigators will determine eligibility based on findings from diagnostic imaging.   
 
7.6 Laboratory Tests 
The following laboratory tests will be performed as specified in Section 10.2 “Trial 
Assessments”: 
• Hematology: hemoglobin, platelet count, WBC and differential 
• Renal Function: serum creatinine and BUN 
• Hepatic function: serum bilirubin, alkaline phosphatase, GGT, SGOT/AST 
and SGPT/ALT 


 
Protocol OPH2004 Amendment A– Confidential                                   Page 22                                                   22 March 2016 
• Electrolytes: sodium, potassium, chloride, bicarbonate, calcium and 
phosphate 
• Serum pregnancy test (for women of child-bearing potential) 
If the Investigator judges a laboratory value outside of the normal range as clinically 
significant, the Investigator will repeat the laboratory determination as judged 
appropriate to ensure the validity of the abnormal result. If any clinically significant 
abnormal results are noted, the tests are to be repeated until the results are normal, are 
no longer considered clinically significant by the investigator, or an explanation for the 
change is obtained. 
 
 




 
Protocol OPH2004 Amendment A– Confidential                                   Page 24                                                   22 March 2016 
days prior to the first injection of trial medication with a negative result.  The two 
forms of effective contraception must be implemented during the trial and for at 
least 60 days following the last dose of test medication. 
8.2.10 Provide written informed consent. 
8.2.11 Ability to comply with study and follow-up procedures and return for all trial 
visits. 
8.3 Exclusion Criteria 
Subjects will not be eligible for the trial if any of the following criteria are present in the 
study eye or systemically: 
 
Ophthalmic Exclusion Criteria 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Protocol OPH2004 Amendment A– Confidential                                   Page 25                                                   22 March 2016 
 
 
 
   
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
General Exclusion Criteria 
8.3.18 Any of the following underlying conditions or diseases including: 
• History of other disease, metabolic dysfunction, physical examination finding or 
clinical laboratory finding giving reasonable suspicion of a disease or condition 
that contraindicates the use of an investigational drug or that might affect 
interpretation of the results of the study or render the subject at high risk for 
treatment complications. 
• History or evidence of severe cardiac disease (e.g., NYHA Functional Class III or 
IV - see Appendix 17.5), history or clinical evidence of unstable angina, acute 
coronary syndrome, myocardial infarction or coronary artery revascularization 
within 6 months, or ventricular tachyarrythmias requiring ongoing treatment. 
• Stroke (within 12 months of trial entry). 


 
Protocol OPH2004 Amendment A– Confidential                                   Page 26                                                   22 March 2016 
• Any major surgical procedure within one month of trial entry. 
8.3.19 Any treatment with an investigational agent in the 60 days prior to enrollment 
for any condition. 
8.3.20 Known serious allergies to the fluorescein dye used in angiography (mild 
allergy amenable to treatment is allowable), or iodine, or to the components or 
formulation of either Zimura®, Avastin®, Lucentis®, Eylea®. 
 
 


 
Protocol OPH2004 Amendment A– Confidential                                   Page 27                                                   22 March 2016 
9 TRIAL MEDICATION 
9.1 Drug Supply  
9.1.1 Zimura®  
Zimura® is a pegylated RNA aptamer 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
   
 
 
 
 
 
 
   
 
 
 
 




 
Protocol OPH2004 Amendment A– Confidential                                   Page 29                                                   22 March 2016 
molecular weight of 115 kDa.  Eylea® is produced in recombinant Chinese Hamster 
Ovary (CHO) cells. 
 
9.2 Dose and Administration 
9.2.1 Preparation 
Zimura®, Lucentis®, Avastin®, and Eylea® will be injected without dilution.   
Zimura® is supplied in a single-use glass vial as noted in Section 9.1.1 above.  
 
 
 
 
 
 
 
 
Lucentis® injection is a preservative-free colorless to pale yellow sterile solution, 
supplied in a single-use glass vial designed to deliver 0.05 mL of 10 mg/mL ranibizumab 
injection aqueous solution with 10 mM histidine HCl, 10% α, α-trehalose dihydrate, 
0.01% polysorbate 20, pH 5.5.  Using aseptic technique, all (0.2 mL) of the Lucentis® 
injection vial contents are withdrawn through a 5-micron 19-gauge filter needle attached 
to a 1-cc tuberculin syringe. The filter needle should be discarded after withdrawal of the 
vial contents and should not be used for intravitreal injection. The filter needle should be 
replaced with a sterile 30-gauge × 1/2-inch needle for the intravitreal injection. The 
contents should be expelled until the plunger tip is aligned with the line that marks 0.05 
mL on the syringe.  
Avastin® injection is a preservative-free, clear to slightly opalescent, colorless to pale 
brown, sterile, pH 6.2 solution supplied in a single-use glass vial containing 100 mg in 4 
mL, of which 0.05 mL will be administered for intravitreal injection. The 100 mg product 
is formulated in 240 mg α,α-trehalose dihydrate, 23.2 mg sodium phosphate 
(monobasic, monohydrate), 4.8 mg sodium phosphate (dibasic, anhydrous), 1.6 mg 
polysorbate 20, and Water for Injection, USP.   Using aseptic technique, 0.2 mL of the 
Avastin® injection vial contents are withdrawn through a 5-micron 19-gauge filter needle 
attached to a 1-cc tuberculin syringe. The filter needle should be discarded after 
withdrawal of the vial contents and should not be used for intravitreal injection. The filter 
needle should be replaced with a sterile 30-gauge × 1/2-inch needle for the intravitreal 
injection. The contents should be expelled until the plunger tip is aligned with the line 
that marks 0.05 mL on the syringe. 


 
Protocol OPH2004 Amendment A– Confidential                                   Page 30                                                   22 March 2016 
The Avastin® vial is for single use.  Any Avastin® remaining in the vial is non-
sterile and may not be used to treat any additional study subjects or non-study 
patients. 
Eylea® is a sterile, clear, and colorless pale yellow solution.  Eylea® is supplied as a 
preservative-free, sterile, aqueous solution in a single-use, glass vial designed to deliver 
0.05 mL (50 microliters) of Eylea® (40 mg/mL in 10 mM sodium phosphate, 40 mM 
sodium chloride, 0.03% polysorbate 20, and 5% sucrose, pH 6.2).  Using aseptic 
technique, all (0.28 mL) of the Eylea®  injection vial contents are withdrawn through a 5-
micron 19-gauge filter needle attached to a 1-cc syringe. The filter needle should be 
discarded after withdrawal of the vial contents and should not be used for intravitreal 
injection. The filter needle should be replaced with a sterile 30-gauge × 1/2-inch needle 
for the intravitreal injection. The contents should be expelled until the plunger tip is 
aligned with the line that marks 0.05 mL on the syringe. 
 
9.2.2 Treatment Regimen and Duration 
Enrolled subjects will receive 8-18 injections of Zimura® 2.0 mg/eye and 8-18 injections 
of anti-VEGF therapy.   
9.2.3 Administration of Trial Drug 
The method for intravitreous administration of Zimura®, Lucentis®, Avastin® and Eylea® 
is described in detail in Appendix 17.4.  
 
9.2.4 Storage 
The investigator, or an approved representative (e.g. pharmacist), will ensure that all 
trial drugs are stored in a secured area, under recommended storage conditions and in 
accordance with applicable regulatory requirements. 
 
 
  
 
 
 


 
Protocol OPH2004 Amendment A– Confidential                                   Page 31                                                   22 March 2016 
9.3 Previous or Concomitant Therapy 
Previous treatment for AMD in the study eye prior to Day 1 is not permitted with the 
exception of two prior anti-VEGF treatments or any oral supplements or vitamins and 
minerals.  
Any treatment with any investigational agent for any condition in the 60 days prior to 
Screening, or treatment with an investigational agent for any condition during the trial, is 
not permitted.   
Treatment for AMD in the fellow eye during the study with an approved product is 
permitted at any time. If intravitreal treatment in the fellow eye is administered on 
the same day as study drug, the injection(s) in the study eye should be 
administered first (before the injection in the fellow eye). 
Although not labeled for the treatment of wet AMD, Avastin® is also allowed in the fellow 
eye at the discretion of the investigator. 
 
 


 
Protocol OPH2004 Amendment A– Confidential                                   Page 32                                                   22 March 2016 
10 TRIAL CONDUCT 
10.1 Subject Enrollment 
Before recruitment of subjects into the trial, written Institutional Review Board (IRB) or 
Ethics Committee (EC) approval of the protocol and informed consent must be 
obtained. 
Subjects who meet the eligibility criteria and have provided written informed consent will 
be enrolled in the trial.  If any inclusion or exclusion criteria are not met, treatment with 
trial drug should not commence without prior written approval from Ophthotech Corp. or 
its designee. 
Written informed consent must be obtained before any of the Screening procedures 
listed below are performed.  However, if a routine office procedure (e.g. FA, OCT) is 
performed to diagnose AMD independent of this clinical trial, and subsequently the 
subject provides informed consent for this study, these procedures performed prior to 
informed consent may be used as screening assessments for this study, provided the 
14-day period of screening evaluations is respected and provided the assessments are 
acceptable to the standards of the study.  An explanation of the trial and discussion of 
the possible risks and discomforts will be given by the investigator.  Only those subjects 
who fulfill all eligibility criteria will be entered into the trial.  
For the Screening visit only, assessments can be broken into 2 days if necessary.  For 
all other visits, all assessments indicated must be performed on the same day.  
The following assessments will be performed during the study.   
 
10.2 Trial Assessments 
The following evaluations, as outlined in the Study Assessments Chart (see Section 3), 
will be performed on the days specified below: 
Note:  
• Concomitant Medications should be assessed at every study visit. 
• Adverse events (AEs) should be assessed starting at Day 1 after the first 
dose of trial drug.   
 


 
Protocol OPH2004 Amendment A– Confidential                                   Page 33                                                   22 March 2016 
10.2.1 Screening Assessments  
The following Screening evaluations, as outlined in the Study Assessments Chart (see 
Section 3), will be performed within 14 days prior to Day 1.   
• Informed consent 
• Medical history 
• Ophthalmologic history (OU) 
• Snellen visual acuity (comparable standard Snellen chart used previously in 
clinic for “treatment experienced” subjects) 
• Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• Ophthalmologic Examination and Goldmann Applanation Tonometry (OU) 
• Color fundus photographs (OU)  
• Fluorescein Angiograms (FA) (OU, transit study eye) 
• Optical Coherence Tomography (OCT) (OU)  
• Serum pregnancy test within 14 days of first trial injection (if applicable) 
• Laboratory Tests 
• Concomitant Medication Assessment 
 
10.2.2 Day 1 Visit  
Pre-injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• Tonometry and Ophthalmologic Examination (OU) 
• Optical Coherence Tomography (OCT) (OU)  
Injection 
• 
Anti-VEGF – administered 1st  
• 
Zimura® 2.0 mg/eye – administered 2nd  
Post-injection 
• 
Ophthalmic Exam/Tonometry (SE) - After the first injection, to confirm perfusion 
of the optic nerve and return of IOP to ≤21 mm Hg or within 5 mm of pre-
injection.  After the second injection, the optic nerve perfusion must be confirmed 
with indirect ophthalmoscopy and IOP must be <30 mm Hg before the subject 
leaves the clinic. 


 
Protocol OPH2004 Amendment A– Confidential                                   Page 34                                                   22 March 2016 
3-Day Post-Injection Safety Check (±1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.3 Month 1 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• 
Tonometry and Ophthalmologic examination (OU) 
• 
Optical Coherence Tomography (OCT) (OU) 
Injection 
• 
Anti-VEGF – administered 1st  
• 
Zimura® 2.0 mg/eye – administered 2nd  
Post-injection 
• 
Ophthalmic Exam/Tonometry (SE) - After the first injection, to confirm perfusion 
of the optic nerve and return of IOP to ≤21 mm Hg or within 5 mm of pre-
injection.  After the second injection, the optic nerve perfusion must be confirmed 
with indirect ophthalmoscopy and IOP must be <30 mm Hg before the subject 
leaves the clinic. 
3-Day Post-Injection Safety Check (±1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.4 Month 2 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• 
Tonometry and Ophthalmologic examination (OU) 
• 
Optical Coherence Tomography (OCT) (OU) 
Injection 
• 
Anti-VEGF – administered 1st  
• 
Zimura® 2.0 mg/eye – administered 2nd  
Post-injection 
• 
Ophthalmic Exam/Tonometry (SE) - After the first injection, to confirm perfusion 
of the optic nerve and return of IOP to ≤21 mm Hg or within 5 mm of pre-
injection.  After the second injection, the optic nerve perfusion must be confirmed 


 
Protocol OPH2004 Amendment A– Confidential                                   Page 35                                                   22 March 2016 
with indirect ophthalmoscopy and IOP must be <30 mm Hg before the subject 
leaves the clinic. 
3-Day Post-Injection Safety Check (±1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.5 Month 3 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• 
Tonometry and Ophthalmologic examination (OU) 
• 
Assessment if Retreatment is necessary (refer to Section 6.1) 
Injection (Only if Retreatment Criteria is Met) 
• 
Anti-VEGF– administered 1st  
• 
Zimura® 2.0 mg/eye– administered 2nd  
Post-injection– if subject is retreated Ophthalmic Exam/Tonometry (SE) - After the 
first injection, to confirm perfusion of the optic nerve and return of IOP to ≤21 mm Hg 
or within 5 mm of pre-injection.  After the second injection, the optic nerve perfusion 
must be confirmed with indirect ophthalmoscopy and IOP must be <30 mm Hg 
before the subject leaves the clinic. 
3-Day Post-Injection Safety Check – (±1 day) – if subject is retreated 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.6 Month 4 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• 
Tonometry and Ophthalmologic examination (OU) 
• 
Assessment if Retreatment is necessary (refer to Section 6.1) 
Injection (Only if Retreatment Criteria is Met)  
• 
Anti-VEGF – administered 1st  
• 
Zimura® 2.0 mg/eye – administered 2nd  
Post-injection– if subject is retreated Ophthalmic Exam/Tonometry (SE) - After the 
first injection, to confirm perfusion of the optic nerve and return of IOP to ≤21 mm Hg 
or within 5 mm of pre-injection.  After the second injection, the optic nerve perfusion 


 
Protocol OPH2004 Amendment A– Confidential                                   Page 36                                                   22 March 2016 
must be confirmed with indirect ophthalmoscopy and IOP must be <30 mm Hg 
before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (±1 day)– if subject is retreated 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.7 Month 5 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• 
Tonometry and Ophthalmologic examination (OU) 
• 
Color fundus photographs (OU)  
• 
Fluorescein Angiograms (FA) (OU, transit study eye) 
• 
Optical Coherence Tomography (OCT) (OU)  
Injection  
• 
Anti-VEGF – administered 1st  
• 
Zimura® 2.0 mg/eye – administered 2nd  
Post-injection 
• 
Ophthalmic Exam/Tonometry (SE) - After the first injection, to confirm perfusion 
of the optic nerve and return of IOP to ≤21 mm Hg or within 5 mm of pre-
injection.  After the second injection, the optic nerve perfusion must be confirmed 
with indirect ophthalmoscopy and IOP must be <30 mm Hg before the subject 
leaves the clinic. 
3-Day Post-Injection Safety Check (±1 day)  
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.8 Month 6 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• 
Tonometry and Ophthalmologic examination (OU) 
• 
Laboratory Tests 
• 
Assessment if Retreatment is necessary (refer to Section 6.1) 
Injection (Only if Retreatment Criteria is Met) 
• 
Anti-VEGF – administered 1st  


 
Protocol OPH2004 Amendment A– Confidential                                   Page 37                                                   22 March 2016 
• 
Zimura® 2.0 mg/eye – administered-2nd  
Post-injection – if subject is retreated 
• 
Ophthalmic Exam/Tonometry (SE) - After the first injection, to confirm perfusion 
of the optic nerve and return of IOP to ≤21 mm Hg or within 5 mm of pre-
injection.  After the second injection, the optic nerve perfusion must be confirmed 
with indirect ophthalmoscopy and IOP must be <30 mm Hg before the subject 
leaves the clinic. 
3-Day Post-Injection Safety Check (±1 day) – if subject is retreated 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.9 Month 7 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• 
Tonometry and Ophthalmologic examination (OU) 
• 
Assessment if Retreatment is necessary (refer to Section 6.1) 
Injection (Only if Retreatment Criteria is Met) 
• 
Anti-VEGF – administered 1st  
• 
Zimura® 2.0 mg/eye – administered 2nd  
Post-injection – if subject is retreated 
• 
Ophthalmic Exam/Tonometry (SE) - After the first injection, to confirm perfusion 
of the optic nerve and return of IOP to ≤21 mm Hg or within 5 mm of pre-
injection.  After the second injection, the optic nerve perfusion must be confirmed 
with indirect ophthalmoscopy and IOP must be <30 mm Hg before the subject 
leaves the clinic. 
3-Day Post-Injection Safety Check (±1 day) – if subject is retreated 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.10 
Month 8 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• 
Tonometry and Ophthalmologic examination (OU) 
Injection 
• 
Anti-VEGF – administered 1st  


 
Protocol OPH2004 Amendment A– Confidential                                   Page 38                                                   22 March 2016 
• 
Zimura® 2.0 mg/eye – administered 2nd  
Post-injection  
• 
Ophthalmic Exam/Tonometry (SE) - After the first injection, to confirm perfusion 
of the optic nerve and return of IOP to ≤21 mm Hg or within 5 mm of pre-
injection.  After the second injection, the optic nerve perfusion must be confirmed 
with indirect ophthalmoscopy and IOP must be <30 mm Hg before the subject 
leaves the clinic. 
3-Day Post-Injection Safety Check (±1 day)  
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.11 
Month 9 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• 
Tonometry and Ophthalmologic examination (OU) 
• 
Assessment if Retreatment is necessary (refer to Section 6.1) 
Injection (Only if Retreatment Criteria is Met) 
• 
Anti-VEGF – administered 1st  
• 
Zimura® 2.0 mg/eye – administered 2nd  
Post-injection – if subject is retreated 
• 
Ophthalmic Exam/Tonometry (SE) - After the first injection, to confirm perfusion 
of the optic nerve and return of IOP to ≤21 mm Hg or within 5 mm of pre-
injection.  After the second injection, the optic nerve perfusion must be confirmed 
with indirect ophthalmoscopy and IOP must be <30 mm Hg before the subject 
leaves the clinic. 
3-Day Post-Injection Safety Check (±1 day) – if subject is retreated 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.12 
Month 10 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• 
Tonometry and Ophthalmologic examination (OU)  
• 
Assessment if Retreatment is necessary (refer to Section 6.1) 
Injection (Only if Retreatment Criteria is Met) 


 
Protocol OPH2004 Amendment A– Confidential                                   Page 39                                                   22 March 2016 
• 
Anti-VEGF – administered 1st  
• 
Zimura® 2.0 mg/eye – administered 2nd  
Post-injection– if subject is retreated 
• 
Ophthalmic Exam/Tonometry (SE) - After the first injection, to confirm perfusion 
of the optic nerve and return of IOP to ≤21 mm Hg or within 5 mm of pre-
injection.  After the second injection, the optic nerve perfusion must be confirmed 
with indirect ophthalmoscopy and IOP must be <30 mm Hg before the subject 
leaves the clinic. 
3-Day Post-Injection Safety Check (±1 day) – if subject is retreated 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.13 
Month 11 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• 
Tonometry and Ophthalmologic examination (OU) 
• 
Color fundus photographs (OU)  
• 
Fluorescein Angiograms (FA) (OU, transit study eye) 
• 
Optical Coherence Tomography (OCT) (OU) 
Injection  
• 
Anti-VEGF – administered 1st  
• 
Zimura® 2.0 mg/eye – administered 2nd  
Post-injection  
• 
Ophthalmic Exam/Tonometry (SE) - After the first injection, to confirm perfusion 
of the optic nerve and return of IOP to ≤21 mm Hg or within 5 mm of pre-
injection.  After the second injection, the optic nerve perfusion must be confirmed 
with indirect ophthalmoscopy and IOP must be <30 mm Hg before the subject 
leaves the clinic. 
3-Day Post-Injection Safety Check (±1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.14 
Month 12 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 


 
Protocol OPH2004 Amendment A– Confidential                                   Page 40                                                   22 March 2016 
• 
Tonometry and Ophthalmologic examination (OU) 
• 
Laboratory Tests 
• 
Assessment if Retreatment is necessary (refer to Section 6.1) 
Injection (Only if Retreatment Criteria is Met) 
• 
Anti-VEGF – administered 1st  
• 
Zimura® 2.0 mg/eye – administered 2nd  
Post-injection – if subject is retreated  
• 
Ophthalmic Exam/Tonometry (SE) - After the first injection, to confirm perfusion 
of the optic nerve and return of IOP to ≤21 mm Hg or within 5 mm of pre-
injection.  After the second injection, the optic nerve perfusion must be confirmed 
with indirect ophthalmoscopy and IOP must be <30 mm Hg before the subject 
leaves the clinic. 
3-Day Post-Injection Safety Check (±1 day) – if subject is retreated  
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.15 
Month 13 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• 
Tonometry and Ophthalmologic examination (OU) 
• 
Assessment if Retreatment is necessary (refer to Section 6.1) 
Injection (Only if Retreatment Criteria is Met) 
• 
Anti-VEGF – administered 1st  
• 
Zimura® 2.0 mg/eye – administered 2nd  
Post-injection – if subject is retreated 
• 
Ophthalmic Exam/Tonometry (SE) - After the first injection, to confirm perfusion 
of the optic nerve and return of IOP to ≤21 mm Hg or within 5 mm of pre-
injection.  After the second injection, the optic nerve perfusion must be confirmed 
with indirect ophthalmoscopy and IOP must be <30 mm Hg before the subject 
leaves the clinic. 
3-Day Post-Injection Safety Check (±1 day) – if subject is retreated 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 


 
Protocol OPH2004 Amendment A– Confidential                                   Page 41                                                   22 March 2016 
 
10.2.16 
Month 14 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• 
Tonometry and Ophthalmologic examination (OU) 
Injection  
• 
Anti-VEGF – administered 1st  
• 
Zimura® 2.0 mg/eye – administered-2nd  
Post-injection  
• 
Ophthalmic Exam/Tonometry (SE) - After the first injection, to confirm perfusion 
of the optic nerve and return of IOP to ≤21 mm Hg or within 5 mm of pre-
injection.  After the second injection, the optic nerve perfusion must be confirmed 
with indirect ophthalmoscopy and IOP must be <30 mm Hg before the subject 
leaves the clinic. 
3-Day Post-Injection Safety Check (±1 day)  
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.17 
Month 15 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• 
Tonometry and Ophthalmologic examination (OU) 
• 
Assessment if Retreatment is necessary (refer to Section 6.1) 
Injection (Only if Retreatment Criteria is Met) 
• 
Anti-VEGF – administered 1st  
• 
Zimura® 2.0 mg/eye – administered 2nd  
Post-injection- if subject is retreated  
• 
Ophthalmic Exam/Tonometry (SE) - After the first injection, to confirm perfusion 
of the optic nerve and return of IOP to ≤21 mm Hg or within 5 mm of pre-
injection.  After the second injection, the optic nerve perfusion must be confirmed 
with indirect ophthalmoscopy and IOP must be <30 mm Hg before the subject 
leaves the clinic. 
3-Day Post-Injection Safety Check (±1 day) - if subject is retreated 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 


 
Protocol OPH2004 Amendment A– Confidential                                   Page 42                                                   22 March 2016 
 
10.2.18 
Month 16 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• 
Tonometry and Ophthalmologic examination (OU)  
• 
Assessment if Retreatment is necessary (refer to Section 6.1) 
Injection (Only if Retreatment Criteria is Met) 
• 
Anti-VEGF – administered 1st  
• 
Zimura® 2.0 mg/eye – administered 2nd  
Post-injection - if subject is retreated 
• 
Ophthalmic Exam/Tonometry (SE) - After the first injection, to confirm perfusion 
of the optic nerve and return of IOP to ≤21 mm Hg or within 5 mm of pre-
injection.  After the second injection, the optic nerve perfusion must be confirmed 
with indirect ophthalmoscopy and IOP must be <30 mm Hg before the subject 
leaves the clinic. 
3-Day Post-Injection Safety Check (±1 day) - if subject is retreated 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.19 
Month 17 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• 
Tonometry and Ophthalmologic examination (OU) 
Injection  
• 
Anti-VEGF – administered 1st  
• 
Zimura® 2.0 mg/eye – administered-2nd  
Post-injection  
• 
Ophthalmic Exam/Tonometry (SE) - After the first injection, to confirm perfusion 
of the optic nerve and return of IOP to ≤21 mm Hg or within 5 mm of pre-
injection.  After the second injection, the optic nerve perfusion must be confirmed 
with indirect ophthalmoscopy and IOP must be <30 mm Hg before the subject 
leaves the clinic. 
3-Day Post-Injection Safety Check (±1 day)  
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 


 
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10.2.20 
Month 18/Early Withdrawal (±7 days) 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• 
Goldmann Applanation Tonometry and Ophthalmologic examination (OU) 
• 
Color fundus photographs (OU)  
• 
Fluorescein Angiograms (FA) (OU, transit study eye) 
• 
Optical Coherence Tomography (OCT) (OU) 
• 
Serum pregnancy test (if applicable) 
• 
Laboratory Tests 
 
10.3 Withdrawal from Trial 
Subjects have the right to withdraw from the trial at any time for any reason.  The 
Investigator (after consultation with the Sponsor) or Sponsor also have the right to 
withdraw subjects from the trial in the event of concurrent illness, adverse events, 
treatment-failure after a prescribed procedure, protocol violations, cure, administrative 
or other reasons. 
Final trial assessments as outlined in the Study Assessments Chart, Section 3, should 
be performed on all subjects who withdraw.  Subjects who withdraw due to an adverse 
event should be followed until resolution of the adverse event, or an adequate 
explanation for the event is obtained. 
Subjects who withdraw for any reason should have assessments performed according 
to the Early Withdrawal schedule.  If an alternative treatment for AMD is initiated, the 
subject will no longer be evaluated according to this protocol. 
 
10.4 Trial Discontinuation 
The reason for a subject discontinuing from the trial will be recorded in the case report 
form.  A discontinuation occurs when an enrolled subject ceases participation in the 
trial, regardless of the circumstances, prior to completion of the protocol.  The 
investigator must determine the primary reason for discontinuation.  A discontinuation 
must be reported immediately to the clinical monitor or his/her designated 
representative if it is due to a serious adverse event (SAE) (see Section 12).  The final 
evaluation required by the protocol will be performed at the time of trial discontinuation.  
The investigator will record the reason for trial discontinuation, provide or arrange for 


 
Protocol OPH2004 Amendment A– Confidential                                   Page 44                                                   22 March 2016 
appropriate follow-up (if required) for such subjects, and document the course of the 
subject’s condition. 
Premature termination of this clinical trial may occur because of a regulatory authority 
decision, change in opinion of the IRB/EC, drug safety problems, or at the discretion of 
Ophthotech Corp. 
 
 
11 STATISTICAL METHODS 
11.1 Experimental Design 
All enrolled subjects will be anti-VEGF “treatment experienced” (with 1 prior intravitreal 
anti-VEGF treatment with AVASTIN®, EYLEA®, OR LUCENTIS® within the past 8 
weeks for NVAMD in the study eye). For all subjects, there must be ≤ 0 letters of visual 
improvement in Snellen (not ETDRS Snellen equivalent) visual acuity since the start of 
anti-VEGF treatment. 
Stratified sampling will be employed to enroll equal subgroups previously treated with 
Lucentis® (n=15), Eylea® (n=15), or Avastin® (n=15). 
Treatment experienced subjects will receive the same anti-VEGF agent as administered 
prior to enrollment. 
INDUCTION PHASE 
Subjects Previously Treated with Avastin® 
Subjects will receive three monthly intravitreal Avastin® treatments (Day 1, Months 1, 
and 2) followed by Zimura® 2.0 mg/eye(administered on the same day) . 
Subjects Previously Treated with Lucentis® 
Subjects will receive three monthly intravitreal Lucentis® treatments (Day 1, Months 1, 
and 2) followed by Zimura® 2.0 mg/eye (administered on the same day). 
Subjects Previously Treated with Eylea® 
Subjects will receive three monthly intravitreal Eylea® treatments (Day 1, Months 1, and 
2) with followed by Zimura® 2.0 mg/eye (administered on the same day).  


 
Protocol OPH2004 Amendment A– Confidential                                   Page 45                                                   22 March 2016 
MAINTENANCE PHASE 
Subjects will continue to be treated with the same anti-VEGF therapy as administered 
during the Induction Phase. 
After the Induction Phase, all subjects will receive treatment every 3 months (Month 5, 
8, 11, 14, and 17), for a total of 18 months.  
Injection of anti-VEGF therapy will be administered first followed by Zimura® on the 
same day during the Maintenance Phase. 
All subjects will have a final follow-up visit at Month 18. 
Retreatment Criteria  
During the intervening visits (Month 3, 4, 6, 7, 9,10, 12, 13, 15, 16) subjects will be 
retreated with anti-VEGF therapy followed by Zimura® 2.0 mg/eye administered on the 
same day if  
 
• The visual acuity decreases ≥ 5 ETDRS letters, compared to the previous 
visit 
OR 
• If there is a cumulative decrease of ≥ 5 ETDRS letters at consecutive visits 
since the previous injection.  
 
Subjects should not be retreated if the visual acuity loss is solely attributed to new 
foveal atrophy and/or new opacified media (per investigator discretion).  
 
11.2 Endpoints 
Safety Endpoints: 
• Visual Acuity Loss (Proportion of subjects with >0 letter loss at Month 12, 18) 
• Visual Acuity Loss (Proportion of subjects with >5 letter loss at Month 12, 18) 
• Visual Acuity Loss (Proportion of subjects with >10 letter loss at Month 12, 18) 
• Ophthalmic Adverse Events (AEs) 
• Systemic Adverse Events (AEs)  
• Laboratory variables 
11.3 Number of Subjects 
Approximately 45 treatment-experienced subjects will be enrolled: 
15 will receive Avastin® and Zimura® 


 
Protocol OPH2004 Amendment A– Confidential                                   Page 46                                                   22 March 2016 
15 will receive Lucentis® and Zimura® 
15 will receive Eylea® and Zimura®  
11.3.1 Sample Size Required 
As this study is not designed to perform formal hypothesis testing, there is no formal 
sample size calculation.  The sample size selected is based on a reasonable number of 
subjects to understand the safety and of the proposed regimen and to improve upon the 
study design prior to performance of controlled trials that may be initiated in the future. 
 
11.3.2 Statistical Analyses 
No formal hypothesis testing will be performed. 
 
11.3.3 Descriptive Statistics 
Descriptive statistics will be provided to document baseline and on-trial comparability, 
including demographic information, treatment administration, and protocol violations.   
 
11.3.4 Safety Analysis 
The safety analysis will be conducted on all subjects who had at least one 
administration of trial drug. 
Adverse events will be summarized using MedDRA terms. The incidence and severity 
of adverse events will be listed and grouped by body system.  
Summary statistics will be given on the number of subjects for whom the trial medication 
had to be permanently stopped. 
 
 


 
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12 ADVERSE EVENTS 
12.1 Definition of Adverse Events 
An Adverse Event (AE) is defined as follows:  Any untoward medical occurrence in a 
patient or subject including unfavorable and unintended signs, symptoms or disease 
temporally associated with the use of a medicinal product and which does not 
necessarily have to have a causal relationship to this treatment. 
Adverse events include illnesses with onset during the trial, or exacerbations of pre-
existing illnesses. Exacerbation of pre-existing illness is defined as a significant 
increase in the severity of the illness as compared to the start of the trial, and should be 
considered when a subject requires new or additional treatment for that illness.  Lack of 
or insufficient clinical response or efficacy should not be recorded as an adverse event. 
In addition, clinically significant changes in objective findings (e.g., laboratory, ECG, X-
ray, physical examination) should also be considered as to whether they are adverse 
events.  The criteria for determining whether an objective finding should be reported as 
an adverse event are as follows: 
1. Associated with accompanying symptoms; and/or 
2. Requires medical/surgical intervention; and/or 
3. Leads to a change in trial dosing or discontinuation from the trial, significant 
additional concomitant drug treatment or other therapy; and/or 
4. Leads to any of the outcomes included in the definition of a serious adverse 
event; and/or 
5. Is considered to be an adverse event by the investigator or Sponsor. 
Any abnormal test result that is determined to be an error does not require reporting as 
an adverse event. 
 
12.2 Assessment and Reporting of Adverse Events 
Adverse events will be recorded starting after the first dose of trial drug and 
continuing until 30 days after the last dose or until the last follow-up visit 
required by the protocol, whichever comes later.  An adverse event that is ongoing 
at the last follow up study visit is required to be followed up until the event resolves or 
stabilizes at a level acceptable to the investigator and/or Sponsor. 


 
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All adverse events spontaneously reported, elicited or observed by the investigators will 
be recorded. The events will be recorded in the source documents and onto the adverse 
event pages of the case report form, including date of onset and resolution, severity, 
relationship to trial treatment and determination of “serious”. 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, 
should not be reported as adverse events.  However, the medical condition for which 
the procedure was performed should be reported if it meets the definition of an adverse 
event.  For example, an acute appendicitis that begins during the adverse event 
reporting period should be reported as the adverse event, and the resulting 
appendectomy should be recorded as treatment of the adverse event. 
The investigator will take all therapeutic measures necessary for resolution of the 
adverse event.  Any medication necessary for treatment of the adverse event must be 
recorded in the subject’s source documents and on the appropriate pages of the 
subject’s case report form. 
Adverse events are recorded up until 30 days after the last dose of study drug or until 
the last follow up visit of the trial, whichever comes later.  An adverse event that is 
ongoing at the last follow-up study visit is required to be followed up until the event 
resolves or stabilizes at a level acceptable to the Investigator and/or Sponsor.  If the 
subject still presents with any treatment-related toxicity, the follow-up period will be 
extended until return to baseline status or until the condition has stabilized. 
 
To assist with grading of adverse event severity, the following definitions are provided: 
Mild 
= Aware of sign or symptom, but easily tolerated;  
Moderate 
= Discomfort enough to cause interference with usual 
activity; 
Severe 
= Incapacitating with inability to work or do usual activity; 
Adverse events are assessed as either related to the intravitreous injection procedure 
(eyelid speculum, anesthetic drops, mydriatic drops, antibiotic drops, povidone-iodine 
drops or flush, subconjunctival injection of anesthetic, intravitreous injection), termed 
“injection procedure-related”, or to study drug (Zimura®, Lucentis®, Avastin® or Eylea®). 
The relationship to the intravitreous injection procedure or to study drug will be 


 
Protocol OPH2004 Amendment A– Confidential                                   Page 49                                                   22 March 2016 
assessed using the following definitions: 
Not Related 
= There is not a reasonable possibility that the adverse 
event is related to the injection procedure or to the study 
drug. 
Related  
=  There is a reasonable possibility that the adverse event 
is related to the injection procedure or to the study drug. 
 
12.3 Definition of Serious Adverse Events 
A serious adverse event is any event that: 
1. Results in death; 
2. Is life-threatening (immediate risk of death); 
3. Results in inpatient hospitalization or prolongation of existing hospitalization; 
4. Results in a persistent or significant disability/incapacity; or 
5. Results in congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse events when, based upon 
appropriate medical judgment, they may jeopardize the patient/subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.  
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse. 
A life-threatening adverse event is any event that places the patient/subject at 
immediate risk of death from the reaction as it occurred; i.e., it does not include a 
reaction that, had it occurred in a more severe form, might have caused death. 
Disability is a substantial disruption of a person’s ability to conduct normal life functions. 
Hospitalization is defined as any formal inpatient admission (even if less than 24 hours).  
For chronic or long-term inpatients, inpatient admission also includes transfer within the 
hospital to an acute/intensive care inpatient unit (e.g., from the psychiatric wing to a 
medical floor, from a medical floor to the coronary care unit).   


 
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• Inpatient admission does not include the following: 
o Emergency Room/Casualty Department visits 
o Outpatient/same-day/ambulatory procedures and observation/short-stay 
units 
o Hospice facilities and Respite care (e.g., caregiver relief) 
o Rehabilitation facilities, skilled nursing facilities, nursing homes, custodial 
care facilities 
• Inpatient admission in the absence of a precipitating, treatment-emergent, clinical 
adverse event may meet criteria for “seriousness” but is not an adverse event 
and thus is not subject to immediate reporting to the Sponsor.  For example: 
o Admission for treatment of a pre-existing condition not associated with the 
development of a new adverse event or with a worsening of the pre-
existing condition (e.g., for work-up of persistent pretreatment lab 
abnormality) 
o Social admission (e.g., subject has no place to sleep) 
o Optional admission not associated with a precipitating clinical adverse 
event (e.g., yearly physical, elective cosmetic surgery) 
 
12.4 Assessment and Reporting of Serious Adverse Events 
Serious adverse events will be recorded starting after the first dose of trial drug 
and continuing until 30 days after the last dose or until the last follow-up visit 
required by the protocol, whichever comes later.  Any serious adverse event 
occurring at any other time after completion of the trial must be promptly reported if a 
causal relationship to trial drug is suspected.  
If a serious adverse event occurs, the Sponsor is to be notified within 24 hours of 
awareness of the event by the investigator.  In particular, if the serious adverse event is 
fatal or life-threatening, notification to the Sponsor must be made regardless of the 
extent of available adverse event information.  This timeframe also applies to additional 
new information (follow-up) on previously forwarded serious adverse event reports. 
 


 
Protocol OPH2004 Amendment A– Confidential                                   Page 51                                                   22 March 2016 
All Serious Adverse Events must be reported to the  
Sponsor or Designee within 24 hours. 
Refer to the “Safety Contact List” provided separately 
 
12.5 Exposure in Utero 
Ophthotech Drug Safety or contracted CRO must be notified of any patient who 
becomes pregnant or their partner who becomes pregnant, while participating in a 
clinical trial.  The Investigator must immediately notify the Sponsor’s Medical Monitor of 
any pregnancy associated with study medication exposure (at least 6 half-lives after 
drug administration) and record the event using sponsor provided pregnancy report 
form.  Protocol-required procedures for study discontinuation must be performed on the 
patient unless contraindicated by pregnancy.  All pregnancies must be followed to 
conclusion to determine their outcome.  Infants should be followed for a minimum of 8 
weeks. 
 
 


 
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13 RESPONSIBILITIES 
13.1 Emergency Equipment 
All participating sites should have emergency resuscitation equipment available, 
including at a minimum, an Ambu bag, IV tubing, D5W IV fluid, oxygen, and epinephrine 
1:1000, and Diphenhydramine Hydrochloride (Benadryl).  It is each center’s 
responsibility to ensure that all equipment is within specifications for the duration of the 
trial.  Each center should have written policies regarding resuscitation procedures.   
 
13.2 Case Report Forms and Trial Documentation 
The Investigator or designee will complete the appropriate case report form pages 
within 3   business days following completion of each procedure or evaluation. 
All data recorded on case report forms will be supported by source documents.  For 
certain trial parameters, with prior written agreement by the trial sponsor and monitor, 
the case report form may be used to record source data. 
All source documents will be made available to Ophthotech Corp. clinical monitors 
during scheduled monitoring visits, to auditors during any audits requested by 
Ophthotech Corp., and to regulatory agencies during inspections. 
The investigator will maintain a Trial File containing all trial related documentation 
required by Good Clinical Practice (GCP). This Trial File will be reviewed periodically for 
completeness by Ophthotech Corp.’s clinical monitors and must be made available to 
auditors and regulatory agencies. 
All case report forms and original source documents including ocular images should be 
stored for a minimum of two years after a marketing application has been approved, or 
two years after formal discontinuation of development of the investigational drug, or five 
years after completion of the trial, whichever is longer.  Documents should not be 
destroyed without the permission of Ophthotech Corp.  In the event of the Principal 
Investigator leaving the clinical site, it is the Principal Investigator’s responsibility to 
notify Ophthotech Corp. in writing and to designate which trial material will be 
transferred at the clinical site. 
 


 
Protocol OPH2004 Amendment A– Confidential                                   Page 53                                                   22 March 2016 
13.3 Drug Accountability/Storage Conditions 
The investigator is responsible for the accountability of all used and unused trial 
medication and for recording and documenting the drug storage temperature at arrival 
and throughout the trial.  Drug accountability records will be reviewed during monitoring 
visits.  Adequate drug accountability records include documentation of all trial drug 
supplies received, dispensed to trial subjects, and returned to Ophthotech Corp. 
At the end of the trial, all drug supplies and documentation will be reviewed and verified 
by the trial monitors.  The sites will be instructed to destroy unused trial drug supplies 
when the trial is completed, or the site may choose to return the drug to an Ophthotech 
Corp. contracted drug management facility for destruction.  If the drug is destroyed at 
the site, the drug accountability form must be completed and sent to Ophthotech Corp. 
for archiving. 
 
13.4 Protocol Compliance 
Ophthotech Corp. will not compensate the Investigator for evaluation of cases in which 
the procedures and evaluations are conducted in a manner other than that specified by 
the protocol. 
Under certain circumstances, individual protocol criteria may be waived by Ophthotech 
Corp. and in agreement with the investigator.  Any such waiver will be documented in 
writing and provided to the investigator by Ophthotech Corp. 
13.5 Ethical Aspects 
Local Regulations/Declaration of Helsinki 
The investigator will ensure that this trial is conducted in full conformance with the 
principles of the “Declaration of Helsinki” (as amended in Tokyo, Venice, Hong Kong, 
South Africa, and Scotland) and with the laws and regulations of the country in which 
the research is conducted, whichever affords the greater protection to the individual.  
The trial must fully adhere to the principles outlined in “Guideline for Good Clinical 
Practice” ICH Tripartite Guideline (May 9th 1997) and with local law if it affords greater 
protection to the subject. For studies conducted in the USA or under US IND, the 
investigator will additionally ensure adherence to the basic principles of “Good Clinical 
Practice” as outlined in the current version of 21 CFR, subchapter D, part 312, 
“Responsibilities of Sponsors and Investigators”, part 50, “Protection of Human 
Subjects”, and part 56, “Institutional Review Boards”. 


 
Protocol OPH2004 Amendment A– Confidential                                   Page 54                                                   22 March 2016 
 
13.6 Institutional Review Board (IRB) or Ethics Committee (EC) Approval 
and Informed Consent 
The investigator is responsible for obtaining approval of the trial protocol, informed 
consent, and any advertising used for subject recruitment from the appropriate IRB/EC 
prior to initiating the trial.  The investigator will forward the following documents prior to 
commencement of subject enrollment:  
• 
IRB/EC approval documentation 
• 
Approved trial subject informed consent 
• 
A list of IRB/EC members, or statement of compliance 
Prior to enrollment, written informed consent must be obtained from each subject or 
his/her legally authorized representative.  The informed consent must contain all of the 
elements prescribed by the relevant regulatory authorities and must be appropriately 
signed, dated and witnessed. Any changes by the Investigator or local IRB/EC to 
the sample consent provided by the Sponsor must be approved by the Sponsor 
before initiating enrollment. 
 
13.7 Clinical Trial Insurance 
Ophthotech Corp. has insurance coverage for medicine-induced injury and other 
liabilities incurred during clinical trials with its compounds. 
 
13.8 Trial Report and Publications 
The trial will be documented in a final report, which will contain appropriate statistical 
analysis and medical overview. No individual site or investigator may publish or present 
any results from the trial until a joint, multi-center publication of the trial results is made 
by Sponsor in conjunction with various participating investigators and appropriate sites 
contributing data and comments. Subsequently, individual investigators may request to 
publish or present results from the trial; however, approval will be at the sole discretion 
of the Sponsor. Should the foregoing language be in conflict with the language 
addressing publication in the clinical trial agreement, the language in the clinical trial 
agreement will prevail. 
 
 


 
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14 MONITORING 
The investigator will permit representatives of Ophthotech Corp. to review all case 
report forms, trial documentation, and subject medical records at regular intervals 
throughout the trial.  These monitoring visits are for the purpose of verifying protocol 
compliance, subject safety, and the adequacy of data collected. 


 
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