Conditions: Von Hippel-Lindau Syndrome
Keywords: Intravitreal Injection Retinal Capillary Hemangioma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 3
Healthy volunteers: no

Brief summary:
Background: People with Von-Hippel-Lindau (VHL) disease may experience significant vision loss as a result of retinal capillary hemangiomas (RCH), the most common and often earliest manifestation of VHL.

Objective: To investigate the safety and possible efficacy of combination investigational treatment with serial intravitreal injections of E10030, a PDGF-B antagonist, and ranibizumab, a VEGF-A antagonist, in participants with severe ocular VHL disease.

Design: Three participants with severe ocular VHL disease will receive the combination investigational treatment in one eye and will be followed for 104 weeks.

Primary Outcome: The safety of the combination investigational treatment, assessed by tabulation of adverse events reported through Week 52.

Detailed description:
Objective: Von Hippel-Lindau (VHL) disease is an autosomal dominant heritable disorder in which multiple benign and malignant neoplasms and cysts of specific histopathologies develop in the kidney, adrenal gland, pancreas, brain, spinal cord, eye, inner ear, epididymis and broad ligament. The disease affects about 7,000 individuals in the United States. Retinal capillary hemangiomas (RCH) are the most common and often the earliest manifestation of VHL disease and may lead to significant vision loss. In some such eyes, inexorable progression of RCH leads to blindness and phthisis bulbi despite aggressive treatment. Levels of vascular endothelial growth factor (VEGF), a potent mediator of angiogenesis and vascular permeability, have been shown to be elevated in multiple cell types deficient in the VHL protein (pVHL). Platelet-derived growth factor (PDGF), which has an important role in stabilization of immature new vessels during angiogenesis, is upregulated in pVHL-defective cell lines and expressed in other pVHL-defective tumors. Anti-VEGF therapy alone had no beneficial effect on ocular VHL disease in two previous phase 1 studies. The objective of this study is to investigate the safety and possible efficacy of combination investigational treatment with serial intravitreal injections of E10030, a PDGF-B antagonist, and ranibizumab, a VEGF-A antagonist, in participants with severe ocular VHL disease.

Study Population: Three participants with severe ocular VHL disease will receive the combination investigational treatment in one eye and will be followed for 104 weeks.

Design: In this phase I/II, single-center, prospective, open label, non-randomized, uncontrolled, single group trial, one eye of eligible participants will be treated with investigational products, E10030, a PDGF-B antagonist, and ranibizumab, a VEGF-A antagonist. Participants will receive combination investigational treatment consisting of intravitreal injections of E10030 (1.5 mg in 0.05 mL) and ranibizumab (0.5 mg in 0.05 mL) every four weeks from baseline through Week 16 (totaling five treatments) and then every eight weeks through Week 48 (totaling nine treatments from baseline). All participants will be followed for 104 weeks.

Outcome Measures: The primary outcome for the study will be safety of the combination investigational treatment, assessed by tabulation of adverse events reported through Week 52. Secondary outcomes will include tabulation of adverse events at Week 104, and the following measures in the study eye at Week 52 and 104: the proportion of participants experiencing reduction in size of at least one RCH in the absence of other ablative treatment (assessed by fundus photography and fluorescein angiography (FA)); the proportion of participants experiencing moderate vision loss (defined as a loss of greater than or equal to 15 letters from baseline on Electronic Visual Acuity (EVA) testing); mean change in visual acuity; change in size of RCH (measured by fundus photography and FA); change in exudation (measured by fundus photography, optical coherence tomography (OCT) and FA); change in epiretinal proliferation, fibrosis or retinal traction (assessed by OCT and fundus photography); proportion of participants undergoing ablative treatment of RCH or ocular surgery; proportion of participants with successful ablative treatment of RCH; and the proportion of participants with appearance of one or more new RCH.

Arms:
arm 1: Intravitreal injections of E10030 and Ranibizumab

Interventions: intervention 1: Ranibizumab intervention 2: E10030
Intervention descriptions: intervention 1: Intravitreal injections of the commercially-available 10 mg/mL formulation of ranibizumab. Ranibizumab is formulated as a sterile solution (pH 5.5) with histidine, trehalose and polysorbate 20. The vial contains no preservative. Each vial contains 0.5 mL of 10 mg/mL ranibizumab aqueous solution. The intravitreal injection volume of ranibizumab is 50 microliter, which correlates to 0.5 mg of dry ranibizumab. intervention 2: E10030 is not a commercially available drug product, and will be provided by Ophthotech Corp. The drug product is provided as a sterile aqueous solution of E10030 at a concentration of 30 mg (oligo weight)/mL. The solution contains monobasic sodium phosphate monohydrate and dibasic sodium phosphate heptahydrate as buffering agents as well as sodium chloride as a tonicity adjuster. The intravitreal injection volume of E10030 is 50 microliter, which correlates to 1.5 mg of dry E10030.

Protocol document:
Prot_000.pdf: 
ER-VHL 
November 7, 2018 
 
Version 7.0 
CONFIDENTIAL 
 
Page i 
Protocol Title:  
A Phase I/II Trial for Intravitreous Treatment of Severe Ocular von  
Hippel-Lindau Disease Using a Combination of the PDGF Antagonist 
E10030 and the VEGF Antagonist Ranibizumab 
Abbreviated Title: ER-VHL 
Protocol Number: 16-EI-0159 
Date of This Submission/Version: November 7, 2018/v7.0 
 
Principal Investigator 
Henry Wiley, MD 
NEI/NIH 
Building 10, 
Rm. 10D45 
301-451-4260 
wileyhe@nei.nih.gov 
 
Lead Associate Investigator 
Emily Chew, MD 
NEI/NIH 
Building 10, 
Rm. 3-2531 
301-496-6583 
echew@nei.nih.gov 
 
Accountable Investigator 
Emily Chew, MD 
NEI/NIH 
Building 10, 
Rm. 3-2531 
301-496-6583 
echew@nei.nih.gov 
 
Associate Investigators 
Wai T. Wong, MD, 
PhD 
NEI/NIH 
Building 6, 
Rm. 217 
301-496-7566 
wongw@nei.nih.gov 
Catherine Cukras, 
MD, PhD 
NEI/NIH 
Building 10, 
Rm. 10D45 
301-435-5061 
cukrasc@nei.nih.gov 
Tiarnan Keenan, 
MD, PhD 
NEI/NIH 
Building 10, 
Rm. 10D45 
301-496-5847 
tiarnan.keenan@nih.gov 
Prashant 
Chittiboina, MD 
NINDS/ 
NIH 
Building 10, 
Rm. 3D20 
301-496-5728 
prashant.chittiboina@nih.gov 
Alexander Kaplan, 
MD 
NIH/NEI 
Building 10, 
Rm. 10D45 
301-49443-
8557 
alex.kaplan@nih.gov 
Munir Iqbal, MD, 
FRCSC 
NIH/NEI 
Building 10, 
Rm. 10D45 
301-496-6583 
munir.iqbal@nih.gov 
Christopher 
Hwang, MD 
NIH/NEI 
Building 10, 
Rm. 10D45 
301-443-8557 
christopher.hwang@nih.gov 
W. Marston 
Linehan, MD 
NCI/NIH 
Building 10,  
Rm. 1-5940 
301-496-6353 
w.linehan@nih.gov 
Karel Pacak, MD, 
PhD, DSc 
NICHD/ 
NIH 
Building 10, 
Rm. 1-3140 
301-402-4594 
karel.pacak@nih.gov 
Angela Kibiy, 
MPH, BSN, RN 
NEI/NIH 
Building 10, 
Rm. 10D45 
301-435-1833 
angela.kibiy@nih.gov 
 
Referral Contact  
Angela Kibiy, 
MPH, BSN, RN 
NEI/NIH 
Building 10, 
Rm. 10D45 
301-435-1833 
angela.kibiy@nih.gov 


ER-VHL 
November 7, 2018 
 
Version 7.0 
CONFIDENTIAL 
 
Page ii 
Coordinating Center: 
The Emmes Corporation (Emmes) 
401 North Washington St. 
Suite 700 
Rockville, MD 20850 USA 
Phone: (301) 251-1161 
Fax: (202) 478-0243 
 
Human Research Protections Program Investigator and Staff Training: 
“Just in time” human subjects protection training courses are required for investigators and staff 
participating on this protocol: None. 
 
Total Requested Accrual: 
 3  
Participants  
 0  
Healthy Volunteers 
 
Project Uses Ionizing Radiation: 
 No   Yes 
 
 
IND/IDE: 
 No  Yes 
Drug/Device #: 
11,833 
Sponsor:  
Emily Chew, MD, NEI 
 
 
Durable Power of Attorney: 
 No  Yes 
 
Multi-institutional Project: 
 No  Yes 
 
Data and Safety Monitoring Board:  
 No Yes 
 
NEI SAE Review Committee: 
 
 
 
 
 No   Yes 
 
Technology Transfer Agreement:  
 No  Yes 
Agreement Type: 
CRADA with Ophthotech Corp. 
Number: 
03024 
Expiration Date: 
June 9, 2020 
 
Samples Being Stored for Future Research:  
 No  Yes 
 
Flesch-Kincaid Reading Level of Consent Form:  
9.8 
 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page iii 
TABLE OF CONTENTS 
 
PROTOCOL ABBREVIATION LIST ................................................................................................... V 
PRÉCIS ............................................................................................................................................ 1 
1.0 
INTRODUCTION/SCIENTIFIC RATIONALE ............................................................................ 3 
1.1 
VHL Disease...................................................................................................................... 3 
1.2 
Ocular VHL Disease .......................................................................................................... 3 
1.3 
Vascular Endothelial Growth Factor (VEGF) in VHL Disease ........................................ 5 
1.4 
PDGF in Angiogenesis and in VHL Disease ..................................................................... 6 
1.5 
Combined Inhibition of VEGF and PDGF ........................................................................ 7 
1.6 
VEGF-A Antagonist Ranibizumab and PDGF-B Antagonist E10030 for Treatment  of 
NVAMD ............................................................................................................................ 7 
1.7 
Treatment of Severe Ocular VHL Disease with Intravitreal Injections of E10030  and 
Ranibizumab .................................................................................................................... 10 
2.0 
STUDY OBJECTIVE .............................................................................................................. 11 
3.0 
PARTICIPANTS .................................................................................................................... 11 
3.1 
Participant Eligibility Criteria ......................................................................................... 11 
3.1.1 
Inclusion Criteria ...................................................................................................... 11 
3.1.2 
Exclusion Criteria ..................................................................................................... 12 
3.2 
Study Eye Eligibility Criteria .......................................................................................... 13 
3.2.1 
Inclusion Criteria ...................................................................................................... 13 
3.2.2 
Exclusion Criteria ..................................................................................................... 14 
3.2.3 
Choice of Study Eye in Cases of Bilateral Eligibility ............................................... 15 
4.0 
STUDY DESIGN AND METHODS .......................................................................................... 15 
4.1 
Recruitment ..................................................................................................................... 15 
4.2 
Screening ......................................................................................................................... 15 
4.3 
Study Design.................................................................................................................... 16 
4.4 
Study Procedures ............................................................................................................. 17 
4.5 
Ocular and Systemic Evaluations .................................................................................... 17 
4.5.1 
Reporting of Expected Events .................................................................................. 18 
4.6 
Study Therapy and Concomitant Medications Administration ....................................... 19 
4.6.1 
E10030 Description .................................................................................................. 19 
4.6.2 
E10030 Preparation and Administration ................................................................... 19 
4.6.3 
Ranibizumab Description.......................................................................................... 20 
4.6.4 
Ranibizumab Preparation and Administration .......................................................... 20 
4.6.5 
Investigational Product Storage ................................................................................ 20 
4.6.6 
Drug Accountability.................................................................................................. 20 
4.6.7 
Concomitant Medications or Treatments .................................................................. 21 
4.7 
Follow-Up/Termination Procedures ................................................................................ 22 
5.0 
MANAGEMENT OF DATA AND SAMPLES ............................................................................ 22 
5.1 
Data Sharing Plan ............................................................................................................ 23 
6.0 
RISKS/DISCOMFORTS ......................................................................................................... 23 
6.1 
Examination Risks ........................................................................................................... 23 
6.2 
Potential Risks of E10030 ............................................................................................... 25 
6.3 
Potential Risks of Ranibizumab ...................................................................................... 29 
6.4 
Potential Risks of Any Intravitreal Injection ................................................................... 29 


ER-VHL 
November 7, 2018 
 
TABLE OF CONTENTS (CONTINUED) 
 
Version 7.0 
CONFIDENTIAL 
 
Page iv 
7.0 
PARTICIPANT SAFETY MONITORING ................................................................................. 30 
7.1 
Treatment of Endophthalmitis, Retinal Tear/Detachment, Intraocular Hemorrhage,  
Cataract and Glaucoma ................................................................................................... 30 
7.2 
Individual Withdrawal Criteria ........................................................................................ 30 
7.3 
Pregnancy Monitoring ..................................................................................................... 31 
8.0 
OUTCOME MEASURES ........................................................................................................ 31 
8.1 
Primary Outcome ............................................................................................................. 31 
8.2 
Secondary Outcomes ....................................................................................................... 32 
9.0 
STATISTICAL ANALYSIS ..................................................................................................... 32 
9.1 
Primary Outcome Analysis .............................................................................................. 32 
9.2 
Secondary Outcome Analysis .......................................................................................... 32 
9.3 
Sample Size/Accrual Rate ............................................................................................... 33 
10.0 HUMAN PARTICIPANTS PROTECTION ................................................................................ 33 
10.1 Equitability ...................................................................................................................... 33 
10.1.1 Justification for Exclusion of Children ..................................................................... 33 
10.1.2 Justification for Exclusion of Pregnant or Lactating Women ................................... 33 
10.1.3 Justification for Exclusion of Individuals without Consent Capacity ...................... 33 
10.2 Qualifications of Investigators ......................................................................................... 34 
11.0 BENEFITS ............................................................................................................................ 36 
12.0 SUMMARY/CLASSIFICATION OF RISK ................................................................................ 36 
13.0 CONSENT DOCUMENTS AND PROCESS ............................................................................... 36 
13.1 Unanticipated Enrollment of Non-English Speaking Participants .................................. 37 
14.0 DATA AND SAFETY MONITORING ...................................................................................... 37 
14.1 Coordinating Center ........................................................................................................ 38 
14.2 NEI Serious Adverse Event Review Committee ............................................................. 38 
14.3 Criteria for Stopping the Study ........................................................................................ 38 
15.0 QUALITY ASSURANCE ........................................................................................................ 38 
16.0 REPORTING OF UNANTICIPATED PROBLEMS, PROTOCOL DEVIATIONS AND ADVERSE  
EVENTS ......................................................................................................................................... 39 
17.0 ALTERNATIVES TO PARTICIPATION ................................................................................... 40 
18.0 PRIVACY ............................................................................................................................. 40 
19.0 CONFIDENTIALITY .............................................................................................................. 40 
20.0 CONFLICT OF INTEREST ..................................................................................................... 41 
21.0 TECHNOLOGY TRANSFER................................................................................................... 41 
22.0 RESEARCH AND TRAVEL COMPENSATION......................................................................... 41 
23.0 REFERENCES ....................................................................................................................... 42 
APPENDIX 1: DETERMINING CHILDBEARING POTENTIAL .......................................................... 45 
APPENDIX 2: STUDY FLOWSHEET ................................................................................................ 46 
APPENDIX 2: STUDY FLOWSHEET, CONTINUED: EXTENSION PHASE ......................................... 48 
APPENDIX 3: INJECTION PROCEDURES FOR ALL PARTICIPANTS ............................................... 49 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page v 
PROTOCOL ABBREVIATION LIST 
> 
Greater Than or Equal To 
µL 
Microliter 
AE 
Adverse Event 
AMD 
Age-related macular degeneration 
ATE 
Arterial thromboembolic event 
BCVA 
Best-corrected visual acuity 
CBC 
Complete blood count 
CC 
Clinical Center 
CD 
Clinical Director 
CRADA 
Cooperative Research and Development Agreement 
DME 
Diabetic macular edema 
DoH 
Declaration of Helsinki 
ERG 
Electroretinography 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
EVA 
Electronic visual acuity 
FA 
Fluorescein angiography 
FDA 
Food and Drug Administration 
FWA 
Federal Wide Assurance 
HIF 
Hypoxia inducible factor 
HRPP 
Human Research Protection Program 
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
mL 
Milliliter 
Mm 
Millimeter 
NCI 
National Cancer Institute 
NEI 
National Eye Institute 
NIH 
National Institutes of Health 
NIMH 
National Institute of Mental Health 
NINDS 
National Institute of Neurologic Disorders and Stroke 
NVAMD 
Neovascular age-related macular degeneration 
OCT 
Optical coherence tomography 
OHSRP 
Office of Human Subject Research Protection 
PDGF 
Platelet-derived growth factor 
PDGFR-β 
PDGF Receptor-β 
PDT 
Photodynamic therapy 
PI 
Principal Investigator 
pVHL 
VHL protein 
RCH 
Retinal capillary hemangioma(s) 
SAE 
Serious Adverse Event 
SOP 
Standard operating procedure 
VEGF 
Vascular endothelial growth factor 
VHL 
Von Hippel-Lindau 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 1 
PRÉCIS 
Objective: Von Hippel-Lindau (VHL) disease is an autosomal dominant heritable disorder in 
which multiple benign and malignant neoplasms and cysts of specific histopathologies develop in 
the kidney, adrenal gland, pancreas, brain, spinal cord, eye, inner ear, epididymis and broad 
ligament. The disease affects about 7,000 individuals in the United States. Retinal capillary 
hemangiomas (RCH) are the most common and often the earliest manifestation of VHL disease 
and may lead to significant vision loss. In some such eyes, inexorable progression of RCH leads 
to blindness and phthisis bulbi despite aggressive treatment. Levels of vascular endothelial growth 
factor (VEGF), a potent mediator of angiogenesis and vascular permeability, have been shown to 
be 
elevated 
in 
multiple 
cell 
types 
deficient 
in 
the 
VHL 
protein 
(pVHL).  
Platelet-derived growth factor (PDGF), which has an important role in stabilization of immature 
new vessels during angiogenesis, is upregulated in pVHL-defective cell lines and expressed in 
other pVHL-defective tumors. Anti-VEGF therapy alone had no beneficial effect on ocular VHL 
disease in two previous phase 1 studies. The objective of this study is to investigate the safety and 
possible efficacy of combination investigational treatment with serial intravitreal injections of 
E10030, a PDGF-B antagonist, and ranibizumab, a VEGF-A antagonist, in participants with severe 
ocular VHL disease. 
Study Population: Three participants with severe ocular VHL disease will receive the 
combination investigational treatment in one eye and will be followed for 104 weeks.  
Design: In this phase I/II, single-center, prospective, open label, non-randomized, uncontrolled, 
single group trial, one eye of eligible participants will be treated with investigational products, 
E10030, a PDGF-B antagonist, and ranibizumab, a VEGF-A antagonist. Participants will receive 
combination investigational treatment consisting of intravitreal injections of E10030 (1.5 mg in 
0.05 mL) and ranibizumab (0.5 mg in 0.05 mL) every four weeks from baseline through  
Week 16 (totaling five treatments) and then every eight weeks through Week 48 (totaling nine 
treatments from baseline). All participants will be followed for 104 weeks. 
Outcome Measures: The primary outcome for the study will be safety of the combination 
investigational treatment, assessed by tabulation of adverse events (AE) reported through 
Week 52. Secondary outcomes will include tabulation of AEs at Week 104, and the following 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 2 
measures in the study eye at Week 52 and 104: the proportion of participants experiencing 
reduction in size of at least one RCH in the absence of other ablative treatment (assessed by fundus 
photography and fluorescein angiography [FA]); the proportion of participants experiencing 
moderate vision loss (defined as a loss of ≥ 15 letters from baseline on Electronic Visual Acuity 
[EVA] testing); mean change in visual acuity; change in size of RCH (measured by fundus 
photography and FA); change in exudation (measured by fundus photography, optical coherence 
tomography [OCT] and FA); change in epiretinal proliferation, fibrosis or retinal traction (assessed 
by OCT and fundus photography); proportion of participants undergoing ablative treatment of 
RCH or ocular surgery; proportion of participants with successful ablative treatment of RCH; and 
the proportion of participants with appearance of one or more new RCH. 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 3 
1.0 
INTRODUCTION/SCIENTIFIC RATIONALE 
1.1 
VHL Disease 
VHL disease is an autosomal dominant heritable disorder in which multiple benign and malignant 
neoplasms and cysts of specific histopathologies develop in the kidney, adrenal gland, pancreas, 
brain, spinal cord, eye, inner ear, epididymis and broad ligament. VHL disease arises from germ 
line 
mutations 
in 
the 
VHL 
tumor 
suppressor 
gene 
at 
chromosome 
3p25-26. 
Incidence is approximately one in 40,000 to one in 54,000 live births, with prevalence of 
approximately 7,000 affected individuals in the United States.1 
The two proteins encoded by the VHL gene, designated together as pVHL, play a key role in the 
cellular response to varying levels of oxygen. Under normoxic conditions, pVHL serves as the 
substrate-binding subunit of an ubiquitin ligase complex that targets the alpha subunit of the 
transcription factor hypoxia inducible factor (HIF) for proteasomal degradation through 
polyubiquitylation.2,3,4 HIF is a master transcription regulator for over a hundred genes, important 
for adaptation and survival of cells in the setting of hypoxia. In VHL disease, germline mutation 
in one allele of the VHL gene, followed by somatic loss of the remaining allele in a vulnerable 
cell, results in unchecked activity of HIF under normoxic conditions and consequent transcription 
of a wide variety of growth factors and cytokines stimulating anaerobic metabolism, cell 
proliferation, angiogenesis and cell survival. pVHL possesses other functions independent of the 
HIF signaling pathway; for example, it exerts effects on the primary cilium of the cell and on the 
extracellular matrix.5 Both HIF-dependent and HIF-independent effects may contribute to the 
tumor suppressor activity of pVHL in various cell types.  
1.2 
Ocular VHL Disease 
Retinal capillary hemangiomas (RCH) are the most common and often the earliest manifestation 
of VHL and may lead to significant vision loss.1 Arising within the neurosensory retina and 
composed of endothelial cells, pericytes and foamy stromal cells, RCH are benign lesions 
classified by their location in the retina (juxtapapillary or peripheral) and by their morphology 
(endophytic, exophytic or sessile).6 Though RCH can remain stable for years or even rarely 
spontaneously regress, the majority enlarge. Small RCH appear as a subtle red or grayish lesion of 
the neurosensory retina; early juxtapapillary lesions are more variable in appearance.  


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 4 
With growth, many RCH develop one or more dilated and tortuous feeding arterioles and draining 
venules, though juxtapapillary RCH often do not. RCH demonstrate a variable amount of vascular 
leakage and exudation, manifesting as intraretinal edema, lipid deposition, exudative retinal 
detachment or hemorrhage. Though early leakage is usually confined to the retina in proximity to 
the RCH, the macula can become affected with resulting decrease in vision. Epiretinal fibrous 
proliferation stimulated by the RCH can develop. Fibrovascular proliferation, similar in some 
respects to the retinal neovascularization that occurs in ischemic retinopathies, can appear in the 
presence or absence of RCH. Vision loss can result from intraretinal and subretinal exudation and 
lipid deposition, epiretinal fibrous or fibrovascular proliferation resulting in macular pucker or 
tractional retinal detachment, or intraocular hemorrhage. 
The goal of treatment for RCH is ablation of the lesion, resulting in cessation of exudation, 
hemorrhage and epiretinal proliferation.6 Choice of ablative treatment depends on the location and 
size of the lesions. Small (< 1.5 mm in diameter) peripheral RCH are readily treated with thermal 
laser photocoagulation. Larger (1.5 – 3.0 mm in diameter) peripheral RCH can be treated with 
laser photocoagulation, but often respond more readily to trans-scleral cryotherapy. Cryotherapy 
causes more inflammation and post-treatment exudation than laser photocoagulation, and this can 
lead to retinal detachment and epiretinal scarring in some cases. Still larger lesions (> 3.0 mm) are 
more difficult to treat, especially if associated with significant exudation, hemorrhage or fibrosis. 
Episcleral brachytherapy and external beam radiotherapy have been employed with limited 
success. Photodynamic therapy (PDT) has also been used for refractory tumors, both juxtapapillary 
and peripheral, with mixed results. In some reported cases, PDT may help stabilize tumor size and 
exudation.7,8,9 Vitreoretinal surgery is used as an adjunct to ablative therapy in order to address 
vision-threatening epiretinal proliferation, tractional or rhegmatogenous retinal detachment, or 
vitreous hemorrhage.1 RCH arising in proximity to the optic nerve head and/or macula represent a 
particularly problematic subset of lesions because of the risk of iatrogenic vision loss from present 
ablative modalities.10 RCH refractory to one or more sessions of laser photocoagulation and/or 
cryotherapy are also problematic, particularly when large in size or in the setting of substantial 
regions of retinal vascular incompetence with or without exudative and/or tractional retinal 
detachment. Even small and medium-sized RCH can be hazardous to treat with laser and 
cryotherapy in the setting of multiple tumors; evolving hyaloid or epiretinal condensation and 
traction; or chorioretinal scarring from previous ablative attempts. 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 5 
1.3 
Vascular Endothelial Growth Factor (VEGF) in VHL Disease 
The highly vascular nature of tumors in VHL disease suggest that VEGF, a HIF-inducible factor 
and potent mediator of angiogenesis and vascular permeability, might be important in the evolution 
of both the benign and malignant lesions found in this disease. Renal carcinoma cell lines defective 
for pVHL manifest increased production of VEGF mRNA and protein, and show a corresponding 
decrease when pVHL function is restored.11 VEGF protein levels are elevated in pathologic 
specimens from renal carcinomas exhibiting mutations of the VHL gene.12 Neutralizing antibodies 
to VEGF reduce rates of progression among patients with advanced clear cell renal carcinoma, in 
which sporadic tumors harbor frequent inactivation of pVHL.13,14 VEGF messenger RNA is 
upregulated in the hepatic cavernous hemangiomas seen in mice heterozygous for VHL mutation.15 
pVHL-defective cell lines derived from central nervous system hemangioblastomas and RCH have 
not been developed. However, analysis of pathologic specimens has revealed increased VEGF 
production.16,17,18 Vacuolated stromal cells in VHL-associated RCH exhibit high levels of VEGF 
messenger RNA and protein. Finally, VEGF upregulation has been shown to lead to tumor 
hypervascularity in C6 glioma xenografts engineered to overexpress VEGF.19 
Administration of VEGF antagonists has been evaluated in ocular VHL not amenable or refractory 
to standard ablative treatment. Dahr et al. evaluated use of intravitreal injections of pegaptanib 
sodium (3 mg) in five patients with VHL manifesting juxtapapillary or large peripheral RCH.20 
Pegaptanib sodium, a pegylated aptamer antagonizing the VEGF165 isoform, was administered 
every six weeks for at least six injections, and two of five patients completed the course of 
treatment and one year of follow-up. These two patients experienced a decrease in RCH-associated 
exudation, but no change in size of the tumors. The other three patients demonstrated progression 
of ocular disease and did not complete the course of treatment. 
Wong et al. (NCT00089765) studied use of intravitreal ranibizumab in five patients with RCH not 
amenable or responsive to standard treatments.21 Ranibizumab (0.5 mg), a humanized monoclonal 
antibody fragment binding all VEGF-A isoforms, was given every four weeks for six months, with 
additional treatment considered through 12 months. Participants received a mean of 10 injections 
over an average of 47 weeks. Visual acuity decreased by nine (± 20) letters and there was no 
consistent improvement in RCH exudation or tumor size. No SAEs were reported. The only related 
AE consisted of transient eyelid edema and erythema immediately following an injection. 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 6 
No VEGF antagonist, administered intravitreally at doses sufficient to produce measurable 
biologic effects in other ocular diseases, has produced regression of VHL-associated RCH. 
Regression of pathologic neovascularization in other retinal diseases, such as neovascular  
age-related macular degeneration (NVAMD) and proliferative diabetic retinopathy, is often 
incomplete in the setting of VEGF antagonism. Experimental models suggest that an important 
factor limiting regression of neovascularization in response to VEGF antagonists and other  
anti-vascular treatments may be the maturity of new vessels.22,23,24 Immature vessels often regress 
in the setting of VEGF blockade, while more mature vessels frequently do not. Limitations in the 
efficacy of VEGF antagonism in the treatment of cancer have led to consideration of pleiotropic 
inhibitors and combination therapies targeting multiple factors.2,25,26 The search for agents capable 
of rendering pathologic vessels and tumors more susceptible to anti-VEGF therapy has led to 
consideration of PDGF blockade. 
1.4 
PDGF in Angiogenesis and in VHL Disease 
An important pathway for stabilization of immature new vessels during angiogenesis involves 
release of PDGF-B by endothelial cells to attract PDGF receptor-β (PDGFR-β) positive mural 
cells.27,28,29 PDGF-B – PDGFR-β signaling leads to mature capillaries invested with pericytes, 
which maintain an intimate supportive role with associated endothelial cells. Tissue-specific 
knock-out of PDGF-B and PDGFR-β shows reduction in pericyte populations, particularly in the 
central nervous system.30,31 The retinal microvasculature shows a higher pericyte density than any 
other capillary bed, and an endothelium-specific PDGF-B mouse knock-out model has 
demonstrated capillary regression and retinal vascular proliferative lesions in retinas with pericyte 
counts less than 50 percent of normal. Neutralizing PDGFR-β antibodies disrupt normal capillary 
development in the mouse via effects on pericytes.30,32 
pVHL has been shown to reduce expression of PDGF-B messenger RNA via a specificity  
protein 1 (Sp1)-mediated pathway, and PDGF expression is upregulated by HIF.33,34  
Co-expression of PDGFR-α and PDGFR-β has been demonstrated in the endothelial cells of 
central nervous system hemangioblastoma.35 No analysis of RCH for expression of PDGF or its 
receptors has been reported, but the upregulation of PDGF in pVHL-defective cell lines, the 
expression of PDGF in other pVHL-defective tumors, and the hypervascular nature of RCH 
suggest that PDGF signaling may play an important role in pathogenesis of these ocular lesions. 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 7 
1.5 
Combined Inhibition of VEGF and PDGF 
Study of angiogenesis in the context of development, wound healing and tumorigenesis has 
provided insight into the roles of VEGF and PDGF in controlling the growth and maturation of 
new blood vessels.28 Pericytes recruited by PDGF have been demonstrated to promote survival of 
nearby endothelial cells by secretion of VEGF and other factors. In vitro studies have shown that 
pericytes release VEGF-A sensed by nearby endothelial cells.36 Mural cells surrounding tumor 
vessels secrete VEGF-A.37,38 Tumor vessels that lack pericytes are more dependent on VEGF-A 
for survival than vessels that have them.22,24 Such observations have led to the hypothesis that 
pericyte-endothelial cell interactions may confer resistance of new vessels to VEGF blockade, and 
that combined antagonism of PDGF and VEGF pathways jointly targeting pericytes and 
endothelial cells may offer a strategy for circumventing such resistance. Investigation of this 
hypothesis in some models of tumorigenesis suggests the possible efficacy of this approach.39,40 
The merits of combined blockade of VEGF and PDGF pathways have also been evaluated in 
pathologic ocular neovascularization. Jo et al. studied the effects of inhibiting PDGF-B,  
VEGF-A or both in murine models for corneal neovascularization and choroidal 
neovascularization.41 PDGF-B antagonism, achieved with a monoclonal antibody (APB-5) against 
murine PDGFR-β, did not show appreciable effects on neovascularization in either model when 
used alone. VEGF-A inhibition, achieved using pegaptanib, resulted in a reduced area of new 
blood vessels in both models. But, combination treatment using both antagonists showed a 
significantly greater reduction in new blood vessel area in both models compared to VEGF 
inhibition alone. 
1.6 
VEGF-A Antagonist Ranibizumab and PDGF-B Antagonist E10030 for Treatment 
 
of NVAMD 
Present treatment for NVAMD consists of intravitreal injections with the VEGF-A antagonists 
ranibizumab, bevacizumab and aflibercept. Ranibizumab was FDA-approved for treatment of 
NVAMD in 2006 on the basis of efficacy and safety demonstrated in randomized controlled 
clinical trials.42,43,44 Studies and clinical experience have shown that serial ranibizumab injections 
reduce exudation from pathologic vessels, but frequently do not cause neovascularization to 
disappear.45,46 A significant proportion of eyes receiving ranibizumab for NVAMD demonstrate 
incomplete resolution of exudation with monthly injections, or recurrence of growth and leakage 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 8 
from neovascularization when ranibizumab is withheld, prompting search for supplemental agents 
offering more definitive treatment. The efficacy of combination investigational treatment of 
NVAMD with intravitreal injections of the VEGF-A antagonist ranibizumab and the 
investigational PDGF-B antagonist E10030 is presently under study in two phase 3 clinical trials 
(designated as OPH1002 and OPH1003 in the Ophthotech Corp. Investigator Brochure, v5.0, 
February 29, 2016). 
The active moiety of E10030 is an aptamer, a novel class of oligonucleotide-based therapeutic 
agents. Specifically, E10030 is a pegylated aptamer containing 32 monomeric units (32-mer) 
arranged as a linear sequence of three oligonucleotide segments connected by non-nucleotide 
hexaethylene glycol spacers. E10030 binds to PDGF-B with high specificity and affinity and 
inhibits the functions of PDGF-B both in vitro and in vivo. Specifically, E10030 binds selectively 
to PDGF-BB and to PDGF-AB heterodimers and, with reduced affinity, to the  
PDGF-AA homodimer.  
Vitreous humor concentrations of E10030 have been shown to decline in an apparent first order 
process with elimination half-lives of approximately three days in rabbits and two days in dogs. 
Following an IV bolus dose, E10030 was eliminated from plasma in an apparent first-order process 
with an elimination half-life of approximately three hours in rats, 30 to 50 minutes in rabbits and 
16 minutes in dogs. The E10030 volume of distribution was approximately equal to the plasma 
volume of the animal.  
There were no significant ocular or systemic safety issues identified during the E10030 nonclinical 
toxicology program. Chronic intravitreal studies in dogs (nine months) and rabbits (six months) 
have been completed, and no ocular or other effects of E10030 were observed at the highest dose 
levels tested, which were 1.5 and 3.0 mg/eye, respectively. These dose levels were the maximum 
that could be administered based on limitations of E10030 solution viscosity and intravitreal 
injection volumes for each species. When adjusted for the relative differences in vitreous volume 
across species (i.e., between the animal species and humans), these no-effect levels are equivalent 
to human doses of 4.5 mg/eye (for both species). There was also no indication of any adverse 
interaction with an anti-VEGF agent (i.e., pegaptanib sodium or ranibizumab) when  
co-administered in the intravitreal studies. 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 9 
A phase 1, dose-escalating, uncontrolled, multiple-dose, multicenter clinical study (OPH1000) was 
completed in 0patients with subfoveal neovascular lesions secondary to age-related macular 
degeneration.47 Subjects were enrolled in a dose escalation scheme to three monthly intravitreal 
injections of E10030 (0.03, 0.3, 1.5 or 3.0 mg/eye) in combination with ranibizumab 0.5 mg. 
Twenty-two subjects who met the inclusion/exclusion criteria were enrolled in this study. 
One additional subject who did not meet criteria was discontinued shortly after entry into the study, 
and therefore a total of 23 patients were included in the safety database for the study.  
A progressive improvement of visual acuity and a decrease in macular thickness were noted at all 
time points. Visual acuity results showed 8 (36%), 10 (45%) and 13 (59%) subjects  
gaining ≥ 15 letters at Weeks 4, 8 and 12, respectively. Analysis of FA by independent readers 
revealed a mean decrease in choroidal neovascularization (CNV) area of 86% at Week 12 
compared to baseline. 
There was no evidence of drug-related AEs and no dose limiting toxicities were identified. 
Twenty-one patients (91%) experienced at least one AE and 18 patients (78%) experienced at least 
one ocular AE in the study eye. Almost all study eye AEs were considered to be related to the 
injection procedure. No study eye AEs were assessed to be related to E10030 or ranibizumab 
administration. The most frequently occurring study eye AEs were foreign body sensation in eyes 
(six patients, 26%), conjunctival hemorrhage (five patients, 22%), eye irritation (four patients, 
17%) and punctate keratitis (three patients, 13%). Other ocular AEs reported by more than one 
patient were anterior chamber cells (trace), conjunctival edema and myodesopsia (floaters)  
(each reported by two patients, 9%). The majority of AEs were mild in severity. There was only 
one SAE (atrial fibrillation) reported by a patient in the 0.3 mg dose group; the event was unrelated 
to study drugs or injection procedure.  
Recently, a phase 2b, randomized, prospective, double-masked, sham-controlled trial using 
combination investigational treatment with E10030 and ranibizumab (OPH1001) has been 
completed in patients with subfoveal neovascular lesions secondary to AMD. Patients received six 
monthly intravitreous injections of E10030 given in combination with ranibizumab. In this 
multicenter study, 449 patients were randomly assigned in a 1:1:1 ratio to the following dose 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 10 
groups: E10030 0.3 mg/eye + ranibizumab 0.5 mg/eye, E10030 1.5 mg/eye + ranibizumab  
0.5 mg/eye or E10030 sham + ranibizumab 0.5 mg/eye. 
E10030 (1.5 mg) combination investigational treatment resulted in superior visual outcome 
compared to ranibizumab alone at the Week 24 time point. The combination of E10030 (1.5 mg) 
and ranibizumab (0.5 mg) met the pre-specified, alpha protected primary endpoint of superiority 
in mean visual acuity gain compared to ranibizumab alone (10.6 ETDRS letters at Week 24, 
compared to 6.5 letters, p=0.019). Fluorescein angiography and OCT studies confirmed marked 
disease modification (neovascular regression). 
Combination investigational treatment was well tolerated. The most common ocular AEs were, as 
expected in intravitreal studies, related to the intravitreal preparation and injection procedure and 
not drug-related, e.g., conjunctival hemorrhage, punctate keratitis and eye pain. There were no 
events of endophthalmitis, retinal detachment, retinal tear or iatrogenic traumatic cataract after a 
total of 4431 intravitreal injections (1776 administrations of E10030 and 2655 administrations of 
ranibizumab). As expected, the mean Intraocular pressure (IOP) increased after each intravitreal 
injection consistent with the volume effect. However, mean IOP in all arms returned to pre-
injection level at the next visit, including at the end of the study. The systemic safety profile of 
E10030/ranibizumab was similar to that of ranibizumab alone.  
1.7 
Treatment of Severe Ocular VHL Disease with Intravitreal Injections of E10030 
 
and Ranibizumab 
This is a phase I/II study designed to evaluate the safety and possible efficacy of combination 
intravitreal investigational treatment using E10030 and ranibizumab for severe ocular VHL 
disease. The prognosis for eyes with ocular VHL disease not amenable or refractory to standard 
therapies is poor, and the morbidities of any intervention, such as ablation of RCH in proximity to 
the optic nerve or macula, vitreoretinal surgery, cryotherapy or ocular radiation, are substantial.  
In such eyes, inexorable progression of disease leads to blindness and phthisis bulbi. Serial 
ranibizumab injections alone do not lead to RCH regression or any consistent decrease in tumor 
exudation, but have shown a reasonable safety profile in a pilot study.21 There is a reasonable 
scientific rationale for the potential efficacy of combined VEGF and PDGF blockade in treatment 
of RCH, based on knowledge of the molecular biology of pVHL-defective cells and present 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 11 
understanding of angiogenesis in the setting of neoplasia. The investigational agent E10030 has 
not been studied in eyes with ocular VHL, but has shown a reasonable safety profile alone and in 
combination with ranibizumab or pegaptanib sodium in pre-clinical studies; furthermore, no 
significant safety concerns were apparent in phase I and phase II studies evaluating combination 
investigational treatment with E10030 and ranibizumab for NVAMD. 
Based on preliminary evidence for safety and efficacy in people with exudative AMD, and 
supportive evidence from animal studies, the 1.5 mg dose of E10030 has been selected for use in 
this phase 1/2 trial. The 0.5 mg dose of ranibizumab chosen for use in this trial is the same as that 
used in previous combinational therapy trials with E10030, and is the FDA-approved dose for 
treatment of neovascular AMD and macular edema following retinal vein occlusion. 
2.0 
STUDY OBJECTIVE 
The objective of this study is to investigate the safety and possible efficacy of combination 
investigational treatment with serial intravitreal injections of E10030, a PDGF-B antagonist and 
ranibizumab, a VEGF-A antagonist, in participants with severe ocular VHL disease. 
3.0 
PARTICIPANTS 
Three participants with severe ocular VHL disease who meet the eligibility criteria will receive 
the combination investigational treatment in one eye and will be followed for 104 weeks.  
Inclusion and exclusion criteria are listed below. 
3.1 
Participant Eligibility Criteria 
The participant must meet all of the eligibility criteria and none of the exclusion criteria below. 
3.1.1 Inclusion Criteria 
1. Participant must understand and sign the informed consent.  
2. Participant must be 18 years of age or older. 
3. Participant must have a diagnosis of VHL disease. In accordance with established 
criteria for diagnosis,48,49 any one of the following will be considered sufficient 
evidence that VHL disease is present: 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 12 
• 
A family history of VHL disease plus one or more of the following lesions: 
RCH, spinal or cerebellar hemangioblastoma, pheochromocytoma, multiple 
pancreatic cysts, epididymal or broad ligament cystadenomas, multiple renal 
cysts or renal cell carcinoma before age 60 years. 
• 
Presence of two or more hemangioblastomas of the retina or brain or a single 
hemangioblastoma in association with a visceral manifestation such as kidney 
or pancreatic cysts; renal cell carcinoma; adrenal or extra-adrenal 
pheochromocytomas; endolymphatic sac tumors; papillary cystadenomas of 
the epididymis or broad ligament; or neuroendocrine tumors of the pancreas. 
• 
Presence of a known disease-causing germline mutation in the VHL gene. 
4. Any female participant of childbearing potential (see Appendix 1 for definition) must 
not be pregnant or breast-feeding, must have a negative pregnancy test at screening and 
must be willing to undergo pregnancy testing immediately prior to each treatment. 
5. Any female participant of childbearing potential (see Appendix 1 for definition) and 
any male participant able to father children must have (or have a partner who has) had 
a hysterectomy or vasectomy, be completely abstinent from intercourse or must agree 
to practice two effective methods of contraception throughout the course of the study 
and for at least two months following the last administration of combination 
investigational treatment. Acceptable methods of contraception include:  
• hormonal contraception (i.e., birth control pills, injected hormones, dermal 
patch or vaginal ring),  
• intrauterine device,  
• barrier methods (diaphragm or condom) with spermicide, or  
• surgical sterilization (hysterectomy, tubal ligation or vasectomy). 
3.1.2 Exclusion Criteria 
1. Participant has a history or evidence of significant cardiac disease (for example, use of 
cardiac medications aside from agents to control blood pressure, past acute coronary 
syndrome, past myocardial infarction, past revascularization procedure or arrhythmias 
requiring past or present treatment). 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 13 
2. Participant 
has 
a 
history 
of 
stroke 
or 
transient 
ischemic 
attack.  
Note: cerebrovascular manifestations and/or complications of central nervous system 
hemangioblastomas are not exclusionary, in the absence of past stroke or transient 
ischemic attack. 
3. Participant has used systemic medication with significant anti-VEGF or anti-PDGF 
activity within 30 days of study entry or expects use of such a medication within  
12 months of study entry. 
4. Participant is medically unable to comply with study procedures or follow-up in the 
judgment of the investigator. 
5. Participant has a diagnosis of diabetic mellitus (type 1 or type 2). Any one of the 
following will be considered sufficient evidence that diabetes is present: 
• Current regular use of insulin for the treatment of diabetes, 
• Current regular use of oral anti-hyperglycemia agents for the treatment of 
diabetes, 
• Hemoglobin A1C of ≥ 6.5%, or 
• Documented diabetes by ADA and/or WHO criteria. 
3.2 
Study Eye Eligibility Criteria 
The participant must have at least one eye meeting all inclusion criteria and none of the exclusion 
criteria listed below. 
3.2.1 Inclusion Criteria 
1. Participant has at least one RCH secondary to VHL disease in the study eye that fulfills 
the following criteria:  
a. The RCH must exhibit growth potential with consequent threat to vision. 
Growth potential with consequent threat to vision is defined by AT LEAST ONE 
of the following:  
i. Associated intra- or sub-retinal exudation or lipid deposition that, in the 
judgment of the investigator, reflects ongoing vascular incompetence and is 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 14 
not solely reflective of residual changes following previous treatment or 
solely secondary to coexistent retinal traction.  
ii. Increased size of the tumor compared to a previous time point as assessed 
by fundus photography or FA. 
iii. Associated intra-, sub- or pre-retinal hemorrhage not secondary to previous 
treatment, as assessed by fundus photography or FA. 
iv. The presence of dilated and/or tortuous feeder vessels. 
v. Vitreous cell or haze indicative of vitreous exudation, in the absence of 
other ocular features potentially responsible for such findings. 
b. The RCH, in the judgment of the investigator, is NOT readily treatable using 
thermal laser because of its size, posterior location, poor previous response to 
conventional therapy, association with significant exudation, epiretinal 
proliferation, associated vascular abnormalities such as vascular proliferation or 
diffusely incompetent retinal vessels, or other factors predictive of a poor response 
to standard of care approaches. 
2. The study eye must have clarity of ocular media and degree of pupil dilation sufficient 
to permit adequate fundus photography. 
3.2.2 Exclusion Criteria 
1. The study eye has present or chronic ocular or periocular infection (including any 
history of ocular herpes zoster). 
2. The study eye has chronic glaucoma; OR has received anti-glaucoma medication at any 
time within 90 days of study entry; OR has significant ocular hypertension, defined as 
documented intraocular pressure of ≥ 28 mmHg on any occasion in the absence of  
self-limited acute glaucoma, OR ≥ 24 mmHg on at least two occasions in the absence 
of self-limited acute glaucoma. Note: History of self-limited acute glaucoma in a study 
eye, if now resolved and not expected to recur, is not exclusionary. History of glaucoma 
or ocular hypertension in the fellow eye, if not felt to significantly impact risk of 
glaucoma in the study eye, is not exclusionary. 
3. The study eye has undergone any surgical procedure within 60 days prior to study entry 
(inclusive of cryotherapy or thermal laser). 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 15 
4. The study eye has a history of intravitreal injection of an anti-VEGF agent (such as 
bevacizumab, ranibizumab or aflibercept) within 42 days prior to study entry. 
5. The study eye has a history of intravitreal or periocular injection of long-acting 
corticosteroids (such as triamcinolone acetonide) within 90 days of study entry or 
history of any sustained-release ocular drug delivery device with reasonable 
expectation of residual activity in the study eye. 
3.2.3 Choice of Study Eye in Cases of Bilateral Eligibility 
If both eyes of a participant meet the criteria described in Sections 3.2.1 and 3.2.2 above, the 
investigator will choose to enroll one eye in consultation with the participant. 
4.0 
STUDY DESIGN AND METHODS 
This is a phase I/II, single-center, prospective, open label, non randomized, uncontrolled, single 
group trial investigating the safety and potential efficacy of combined treatment of severe ocular 
VHL disease with serial intravitreal injections of E10030 and ranibizumab.  
4.1 
Recruitment 
Most of the participants for this study can be recruited from the current patient population with 
ocular VHL disease at the National Eye Institute (NEI) and other institutes within NIH, including 
the National Institute of Neurologic Disorders and Stroke (NINDS) and the National Cancer 
Institute (NCI). The study may also rely on referrals from outside physicians at Kaiser Permanente, 
the support group of the VHL Alliance and other national clinical sites. If any recruitment materials 
are used, IRB-approval will be obtained prior to distribution. It is anticipated that all participants 
will be recruited within 12 months of activation. 
4.2 
Screening 
Consent will be obtained before any study procedures are done, including any screening 
procedures that may be done under this current protocol. 
All potential participants will undergo a screening visit in the NEI ophthalmology clinic to 
determine whether they meet the eligibility criteria. Potential participants will be screened under 
the NEI screening protocol (08-EI-0102), NEI natural history protocols such as 08-EI-0169 or  


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 16 
12-EI-0042, or an NCI or NINDS natural history protocol to establish eligibility. Data collected 
under these protocols may be shared with the current protocol. Each potential participant must 
have an active signed consent for one of the above-mentioned protocols on file in order to allow 
for screening examination. Under these protocols, potential participants may undergo a 
medical/ophthalmic history, concomitant medication assessment, vital sign testing, physical 
examination, ophthalmic examination, visual acuity testing, color fundus photography, OCT, FA 
and laboratory testing to determine eligibility. Screening data may be used as baseline data if 
performed within one month (31 days) of the baseline visit. At any time during the screening 
process, the participant may enroll in this current protocol by signing the protocol’s consent form 
and may complete any remaining screening and baseline procedures under this protocol, with final 
determination of eligibility. Laboratory testing will include a complete blood count (CBC), 
hemoglobin A1C and acute care, hepatic and mineral panels, and may be done within one month 
(31 days) of the baseline visit. Women of childbearing potential (see Appendix 1 for definition) 
will have a pregnancy test to assess eligibility and must have a negative test within 24 hours prior 
to injection of any investigational product. If BCVA, concomitant medication assessment and vital 
sign testing were assessed on an earlier date under another protocol, these will be repeated as 
baseline examinations on the day of enrollment. All other screening procedures will not be 
repeated. These screening/baseline examinations are outlined in Appendix 2. Combination 
investigational treatment with E10030 and ranibizumab injections cannot occur until the 
participant has reviewed and signed this protocol’s consent form. 
4.3 
Study Design 
This study will examine the effect of multiple E10030 and ranibizumab injections in participants 
with severe ocular VHL disease. A single study eye in each participant will receive combination 
treatment consisting of intravitreal injections of E10030 (1.5 mg in 0.05 mL) and ranibizumab  
(0.5 mg in 0.05 mL) (given as separate injections during the same procedure, meaning that 
participants will receive two intravitreal injections per visit, see Appendix 3) every four weeks 
from baseline through Week 16 (totaling five treatments) and then every eight weeks through 
Week 48 (totaling nine treatments from baseline). The primary endpoint will be assessed by 
tabulation of AEs reported through Week 52. During the second year, all participants will be seen 
at Weeks 60, 72, 84 and 104. Starting after Week 52, participants may return for additional visits 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 17 
in the second year of the trial, as often as every four weeks, for evaluation and for administration 
of standard of care therapies, at investigator discretion. No further administration of investigational 
product will occur after the Week 48 visit. Participants will have a minimum of 14 study visits at 
the NEI outpatient clinic. The baseline study visit will require approximately five hours, and the 
subsequent visits will require approximately three to four hours each. 
Standard of care therapies will be considered for significant clinical worsening at any time during 
the study, for clinical improvement starting at Week 16 (as in a case where clinical improvement 
makes an eye more amenable to ablative or surgical treatment), and without restriction starting at 
Week 40 (in anticipation of unavailability of investigational product after Week 48).  
Any participants who discontinue combination investigational treatment will be asked to return for 
all study visits and will be included in the analyses at the end of the study. 
4.4 
Study Procedures 
The study will require a minimum of 14 visits (baseline and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 52, 
60, 72, 84 and 104). All visits must be conducted within a window of ± 7 days from the target day 
through Week 52 and ± 30 days thereafter. It is anticipated that the study duration will not exceed 
36 months if all participants are recruited within the first 12 months. Prior to treatment at each 
visit, the participant will undergo an AE assessment, concomitant medication review, vital sign 
check and ophthalmic evaluation. 
Over the course of the study, participants will undergo the following ocular and systemic 
evaluations as outlined in the study flowsheet (see Appendix 2). 
4.5 
Ocular and Systemic Evaluations 
1. Medical/Ophthalmic History  
2. Concomitant Medications Assessment  
3. Vital Signs 
4. Physical Examination  
5. AE Assessment  
6. Best-corrected visual acuity (BCVA) and Manifest Refraction using EVA Method   


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 18 
7. Slit Lamp Examination  
8. Dilated Fundus Examination  
9. Intraocular Pressure (IOP)  
10. Color Fundus Photography  
11. Optical Coherence Tomography (OCT)  
12. Fluorescein Angiography (FA) 
13. Complete Blood Count with Differential (CBC) 
14. Acute Care Panel 
15. Hepatic Panel 
16. Mineral Panel 
17. Hemoglobin A1C 
18. Pregnancy Test (for women of childbearing potential as defined in Appendix 1) 
It is expected that tests at any given visit can be completed in one day. The testing schedule varies 
with the visit. The evaluation and testing schedule is outlined in the study flowsheet (Appendix 2). 
4.5.1 Reporting of Expected Events 
It is anticipated that participants in this study will occasionally miss or fail to complete an 
assessment, procedure, or study visit. These omissions will be considered expected events and not 
protocol deviations provided they are infrequent and do not include data needed to assess safety 
or the primary study outcome. If such an event is identified, the PI will submit a report to the IRB 
within two weeks using PTMS.  
Cumulative proportions of these missed events in the study population will be presented to the 
IRB annually. In addition, these rates will be calculated and provided to the NEI SAE Review 
Committee regularly. The following are considered deviations: 
• An individual misses more than 15% of the required study assessments/procedures, 
• An individual misses more than 15% of the required study visits,  
• An individual completes more than 15% of the required study visits outside of the visit 
window, 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 19 
• Collectively, participants missed more than 15% of a specific assessment/procedure,  
• Collectively, participants missed more than 15% of the required study visits, or 
• Collectively, participants complete more than 15% of the required visits outside the visit 
window. 
If total number of items (study visits or study assessments/procedures) expected is less than 16, 
two or more missed is reportable. If the total number expected is greater than 16, then if more than 
15% are missed it is reportable. Missed items previously reported are not included in the 
subsequent tallies of missed items, but will be mentioned in future deviation reports. Once a 
deviation is identified, the PI will submit a report to the IRB within two weeks using PTMS. 
4.6 
Study Therapy and Concomitant Medications Administration 
4.6.1 E10030 Description 
E10030 is not a commercially available drug product, and will be provided by Ophthotech Corp. 
The drug product is provided as a sterile aqueous solution of E10030 at a concentration of 30 mg 
(oligo weight)/mL. The solution contains monobasic sodium phosphate monohydrate and dibasic 
sodium phosphate heptahydrate as buffering agents as well as sodium chloride as a tonicity 
adjuster. The intravitreal injection volume of E10030 is 50 µL, which correlates to 1.5 mg of dry 
E10030.  
4.6.2 E10030 Preparation and Administration 
The drug product is provided in a USP Type 1 glass vial with a halobutyl rubber stopper and an 
aluminum overseal. Included with E10030 solution is a filter needle for withdrawing the solution 
from the vial and appropriate syringes and needles for administration. 
E10030 will be administered according to the injection procedures outlined in Appendix 3.  
Each vial contains enough investigational product to inject one participant and each vial will be 
used one time only. 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 20 
4.6.3 Ranibizumab Description 
Ophthotech Corp. will be providing the commercially-available 10 mg/mL formulation of 
ranibizumab. Ranibizumab is formulated as a sterile solution (pH 5.5) with histidine, trehalose and 
polysorbate 20. The vial contains no preservative. Each vial contains 0.5 mL of 10 mg/mL 
ranibizumab aqueous solution. The intravitreal injection volume of ranibizumab is 50 µL, which 
correlates to 0.5 mg of dry ranibizumab. 
4.6.4 Ranibizumab Preparation and Administration 
Ranibizumab is supplied in aseptically filled, sterile, single use stoppered glass vials with blue 
caps. Included with each vial is a filter needle for withdrawing the solution from the vial and an 
appropriate needle for administration. 
Ranibizumab will be administered according to the Lucentis® prescribing information and the 
injection procedures outlined in Appendix 3. 
Each vial contains enough investigational product to inject one participant and each vial will be 
used one time only.  
4.6.5 Investigational Product Storage 
E10030 will be stored at 5°C (± 3°C) and protected from light, as recommended by the 
manufacturer. 
Ranibizumab should be refrigerated at 2°C - 8°C (36°F - 46°F). It must not be frozen or used after 
the expiration date. It must be protected from light.  
Storage temperature fluctuations that do not affect the stability of the investigational products will 
not be reported to the IRB. 
4.6.6 Drug Accountability 
The NIH Pharmacy is responsible for the accountability of all unused investigational products. 
Adequate drug accountability records include documentation of all investigational product 
shipped, received, stored and dispensed by the NIH Pharmacy. The NIH Pharmacy will dispose of 
unused investigational product once participants have completed through Week 48.  


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 21 
The investigator is responsible for the accountability for all used investigational product.  
Adequate drug accountability records include documentation of all investigational product 
administered and disposed of by the investigator. Used investigational product vials and supplies 
will be disposed in the hazardous waste disposal bins.  
4.6.7 Concomitant Medications or Treatments 
Any potential participant likely to need systemic treatment with an agent having significant  
anti-VEGF or anti-PDGF activity within 12 months of enrollment should not be entered in the 
study (see Section 3.2.2, Exclusion Criteria). However, once participants are enrolled in the study, 
concomitant therapies for non-ocular conditions are allowed without restriction. In the event that 
a participant requires systemic treatment with either anti-VEGF therapy or anti-PDGF therapy, 
interruption or discontinuation of combination investigational treatment will be considered and 
discussed with other treating physicians. 
Standard care therapies for VHL disease, including laser photocoagulation, cryotherapy, 
photodynamic therapy, surgery, ocular radiation and any medication use associated with these 
treatments (such as use of systemic corticosteroids to minimize exudation from RCH undergoing 
ablative treatment) will be considered for significant clinical worsening at any time during the 
study, for clinical improvement at any time starting at Week 16 (as in a case where clinical 
improvement makes an eye more amenable to ablative or surgical treatment), and without 
restriction starting at Week 40 (in anticipation of unavailability of investigational product after 
Week 48). 
Significant clinical worsening is defined as ANY OF THE FOLLOWING, assessed by clinical 
evaluation and /or clinical imaging with OCT, FA and fundus photography, as applicable,  
IF assessed to represent progression of ocular VHL disease in the judgment of the investigator:  
1. A decrease in BCVA of ≥ 15 letters; OR 
2. An increase in exudation, epiretinal proliferation or hemorrhage threatening vision in 
the judgment of the investigator; OR 
3. New or more extensive retinal detachment; OR 
4. Increase in size of RCH; OR 
5. Appearance of new RCH.  


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 22 
Clinical improvement is defined as ANY OF THE FOLLOWING, assessed by clinical evaluation 
and /or clinical imaging with OCT, FA and fundus photography, as applicable,  
IF associated with a significant improvement in chance of treatment success or significant 
reduction in treatment risk with standard of care therapies in the judgment of the investigator: 
1. A decrease in exudation, epiretinal proliferation or hemorrhage; OR 
2. Resolution or reduction of retinal detachment; OR 
3. Decrease in size of RCH; OR 
4. Disappearance of RCH. 
Any necessary treatment of a non-study eye will be allowed without restriction. 
4.7 
Follow-Up/Termination Procedures 
After the Week 104 study visit, follow-up care will be arranged with either an outside 
ophthalmologist or the participant will continue to be seen at the NIH under another protocol if the 
participant is eligible. The participants and their physicians will be informed of the participant’s 
disease status during this study. Clinical data obtained during participation will be shared with 
participants and, with written permission from the participants, with their private physicians. 
Results from the overall study will be shared once the data have been analyzed. 
5.0 
MANAGEMENT OF DATA AND SAMPLES 
No samples will be stored for this study. The clinical data will be stored in the NEI Electronic 
Medical Record, the Clinical Research Information System (CRIS) and The Emmes Corporation’s 
secure database. All individual data will remain confidential. 
Data will be maintained as specified in the informed consent document. The participant has a 
choice to limit data usage by selecting one of the following consent options: 
Please initial on the line below that reflects your choice: 
______YES, My data may be used for other research projects including those not related to VHL 
disease.  
______NO, I do not want my data used for other research projects. 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 23 
5.1 
Data Sharing Plan 
Data may be shared with collaborating laboratories at NIH or outside of NIH and/or submitted to 
NIH-designated 
repositories 
and 
databases 
if 
consent 
for 
sharing 
was 
obtained.  
Repositories receiving data from this protocol may be open-access or restricted access.  
Data will be stripped of identifiers and may be coded (“de-identified”) or unlinked from an 
identifying code (“anonymized”). When coded data is shared, the key to the code will not be 
provided to collaborators, but will remain at NIH. Data may be shared with investigators and 
institutions with a Federal Wide Assurance (FWA) or operating under the Declaration of Helsinki 
(DoH) and reported at the time of Continuing Review. Sharing with investigators without an FWA 
or not operating under the DoH will be submitted for prospective IRB approval. Submissions to 
NIH-sponsored or supported databases and repositories will be reported at the time of Continuing 
Review. Submission to non-NIH sponsored or supported databases and repositories will be 
submitted for prospective IRB approval. 
Required approvals from the collaborating institution will be obtained and materials will be 
shipped in accordance with NIH and federal regulations. 
6.0 
RISKS/DISCOMFORTS 
The anticipated discomforts and inconveniences of this protocol are those associated with the 
investigational products, intravitreal injections, the examination procedures and the time required 
for the participant to spend at the clinic. 
6.1 
Examination Risks 
Possible risks and discomforts associated with ocular examinations include: 
1. Dilating drops or anesthetic drops may sting. They can cause an allergic reaction, or if 
contaminated, can cause an infection, but neither of these problems is very likely to 
occur. Dilating drops can also cause a sudden increase of pressure (acute glaucoma) in 
eyes that are already predisposed to develop this condition. There is little risk of 
glaucoma being triggered in this way, but if it is, treatment is available.  
The participant’s intraocular pressure will be obtained at each ophthalmic examination 
to determine whether there is an increased risk of developing glaucoma. 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 24 
2. Color fundus photographs involve a bright flash to take pictures of the retina.  
This brief flash may cause temporary discomfort, but does not damage the eye. 
3. In rare instances, the cornea may be scratched during measurement of intraocular 
pressure or use of a fundoscopic contact lens. A corneal abrasion of this sort may be 
painful, but it will heal quickly with no lasting effects. 
4. The fluorescein dye used in fluorescein angiography can make a participant’s skin turn 
yellow for several hours. This yellow color is transient and usually disappears in one 
day. Because the dye undergoes renal excretion, the participant’s urine will turn dark 
orange for up to 24 hours after the examination. The study team will educate the 
participant regarding this urine color change. Some participants may be slightly 
nauseated during the examination, but their nausea usually lasts only a few seconds.  
If the dye extravasates during the injection, the skin around the injection site may feel 
mildly uncomfortable or become yellow. The discomfort usually lasts only a few 
minutes, and the yellow color fades in a few days. There is a chance of ecchymosis at 
the site of injection and a remote possibility of cellulitis from the needle track. In rare 
cases, participants may have an allergic reaction to the dye. Treatment typically 
consists of an oral antihistamine medication, but may require intravenous antihistamine 
administration if the symptoms are severe. Very rarely (less than one in one million 
people), a participant experiences anaphylaxis. This would be treated immediately by 
trained personnel with medications or, if necessary, intubation. 
5. OCT is a non-invasive test used to document and analyze retinal pathology and has no 
known medical risks. 
Possible risks and discomforts associated with non-ocular examinations include: 
1. Blood draws can cause discomfort and bleeding/bruising at the site of venous puncture. 
There is a remote risk of fainting or local infection. If any of these conditions arise, 
they will be treated. 
2. The medical/ophthalmic history, physical examination, vital sign testing and pregnancy 
testing entail no medical risk. 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 25 
6.2 
Potential Risks of E10030 
The following safety data for intravitreal use of E10030 are drawn from the attached Investigator 
Brochure (v5.0, February 29, 2016), furnished by Ophthotech Corp. Based on animal studies, 
injection-related risks appear to be limited to the risks of any intravitreal injection. 
Specifically, vitreous hemorrhage, retinal detachment, cataract, lens capsule pigmentation, fibrosis 
and retinal dysplasia were observed in some animals in multiple injection studies. 
Post-injection ocular inflammation may also be a risk of E10030 injection, although this reaction 
appears to be species-specific and has not been noted in human clinical trials. 
In beagle dogs, a single intravitreal injection of test article was associated with trace to 1+ cell 
transiently in some eyes in the 0.3 mg/eye, 1.0 mg/eye and 2.0 mg/eye dose groups. 
On pathologic examination of these eyes, the minimal inflammation noted microscopically at all 
dose levels was considered of little toxicological significance. These findings were not associated 
with major changes in retinal function, as assessed by electroretinography (ERG).  
No inflammatory reaction was noted in single dose testing of Dutch belted rabbits. 
Repeat injection studies were done in Dutch belted rabbits. The animals received bilateral 
injections every two weeks for six weeks and experienced no drug-related adverse effects.  
Several rabbits in the study and control groups sustained injection-related effects, including retinal 
detachment, cataract, lens capsule pigmentation, fibrosis and retinal dysplasia. 
Repeat E10030 injection studies were also done in beagle dogs. Like the animals in the single 
injection studies, intermittent vitreous cells (trace to 2+; suggestion of dose dependence) were 
detected. This was especially common in the group that was injected daily. Two animals also had 
anterior chamber cells. One dog that received E10030 at the 0.3 mg dose level developed marked 
ocular inflammation that was severe and persistent. Injection-related effects included vitreous 
hemorrhage in six eyes, of which four were in the control group. Three other eyes had retinal folds. 
One of these three was in the control group. ERG and histopathology studies revealed no  
E10030-related toxicity. 
New Zealand white rabbits that received multiple E10030/ranibizumab combined injections 
exhibited a species-specific ocular inflammatory reaction. Clinical signs of ocular inflammation 
included vitreous opacities, debris and infiltrating cells, fibrin and debris on the lens capsule. 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 26 
Inflammation was confirmed on histopathology. The incidence and severity of these findings 
tended to increase over time on study. The inflammation was attributed to the known 
immunogenicity of ranibizumab in rabbit eyes, and was not seen at the highest dose level of 
E10030 alone. No similar inflammation was seen in an identical study in beagle dogs. 
The maximum serum concentration of E10030 in the high intravitreal dose group (1.5 mg) was  
41 ng/mL. In rat studies, IV dosing (0.1, 1, 10 or 100 mg of E10030/kg/day IV over 14 or 90 days) 
has been associated with significant perturbations of hematology and clinical chemistry 
parameters, especially in the high-dose groups. Rats were found to have decreased leukocyte, 
hemoglobin, platelet and reticulocyte counts after IV administration. Prothrombin time and 
activated partial thromboplastin time were significantly increased at times during the study. 
Globulin levels were decreased by the end of the study, and there was a corresponding increase in 
albumin/globulin ratios. In the high-dose groups, serum cholesterol, ALT, total protein and AST, 
ALP, triglycerides and total bilirubin concentrations were all significantly decreased.  
Reductions in serum concentrations ranged from approximately 30 to 70%. Serum calcium was 
slightly but significantly reduced. Glucose and blood urea nitrogen concentrations were 
significantly increased, by as much as 55 and 75%, respectively. Increased liver weights and 
decreased spleen weights were also observed, and the significance of these findings is unclear. 
In the 14-day study, histopathology findings in the high-dose animals consisted of minimal to 
marked infiltration of histiocytes (macrophages) in multiple organs including the liver, spleen, 
lymph nodes and kidneys. In the 90-day study, histopathology findings in the high-dose animals 
consisted of cellular vacuolation in numerous tissues, including liver, spleen and lymph nodes.  
A dose response was evident, with increased severity and frequency of findings occurring in the  
high-dose group versus the mid-dose group. These histopathologic findings may reflect stages in 
the drug clearance process. 
No drug-specific adverse effects of E10030 have been identified in limited human use. The only 
serious AE in the phase 1 clinical trial of E10030 was new onset atrial fibrillation reported by a 
patient in the 0.3 mg dose group. The event was assessed as unrelated to study drugs or injection 
procedure. In the phase 1 clinical trial of E10030 and ranibizumab for choroidal neovascularization 
in age-related macular degeneration (n=23) (OPH1000), AEs were almost exclusively mild and 
related to the injection procedure. The most frequently occurring (≥ 3 subjects) AEs were all events 
that occurred in the study eye, including foreign body sensation in the eye, conjunctival 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 27 
hemorrhage, eye irritation and punctate keratitis. The only other ocular AEs reported in the study 
eye of more than one patient were conjunctival edema, anterior chamber cells (trace) and 
myodesopsia (floaters) (each reported in two patients, 9%). In a phase 2b randomized, prospective, 
double-masked, controlled trial of 449 patients with subfoveal neovascular lesions secondary to 
AMD (OPH1001), combination investigational treatment with E10030 and ranibizumab was well 
tolerated. Patients received six monthly intravitreous injections of E10030 given in combination 
with ranibizumab. In this randomized, sham-controlled, multicenter study, 449 patients were 
randomly assigned in a 1:1:1 ratio to the following dose groups: E10030 0.3 mg/eye + ranibizumab 
0.5 mg/eye, E10030 1.5 mg/eye + ranibizumab 0.5 mg/eye or E10030 sham + ranibizumab  
0.5 mg/eye. 
The most common ocular AEs were, as expected in intravitreal studies, related to the intravitreal 
preparation and injection procedure and not drug-related, e.g., conjunctival hemorrhage, punctate 
keratitis and eye pain. There were no events of endophthalmitis, retinal detachment, retinal tear or 
iatrogenic traumatic cataract after a total of 4,431 intravitreal injections (1,776 administrations of 
E10030 and 2,655 administrations of ranibizumab). As expected, the mean IOP increased after 
each intravitreal injection consistent with the volume effect. However, mean IOP in all arms 
returned to pre-injection level at the next visit, including at the end of the study. The systemic 
safety profile of E10030/ranibizumab was similar to that of ranibizumab alone. In the phase 2b 
trial above (OPH1001), the incidence of SAEs was similar among treatment arms. 
The percentage of subjects with at least one systemic SAE was 8.7% in the group getting E10030 
0.3 mg + ranibizumab 0.5 mg; 5.9% in the group getting E10030 1.5 mg + ranibizumab 0.5 mg; 
and 7.4% in the group getting sham + ranibizumab 0.5 mg. Systemic exposure to E10030 
following intravitreous injection is extremely low. Pharmacokinetic studies have been performed 
in rats, rabbits and dogs and are described in the Investigator Brochure, but the most meaningful 
data comes from a dose-escalating, multiple-dose phase 1 study involving 23 participants with 
exudative AMD involving three monthly injections of E10030 (0.03, 0.3, 1.5 and 3.0 mg) plus 
ranibizumab (0.5 mg). In this study, plasma levels of E10030 were measured at days 0, 1, 3 and  
7 and at week 4 and 8. E10030 was detectable in all participants receiving 1.5 mg or 3.0 mg doses. 
The mean maximum plasma concentration was calculated to be 15.9 ng/mL for those receiving 
1.5 mg and 34.4 ng/mL for those receiving 3.0 mg, with an estimated terminal half-life of  
8-14 days. By comparison, in animal studies, vitreous levels of E10030 were consistently more 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 28 
than 1000-fold higher than systemic values. Further information is contained in the Investigator 
Brochure. 
After intravitreal injection, transient increases in intraocular pressure should be anticipated in the 
immediate post-injection time period. Subjects should be cautioned on the potential risks 
associated with intravitreal injection procedures, which include retinal detachment, traumatic 
cataract, vitreous hemorrhage and intraocular infection, particularly endophthalmitis. 
Present cumulative experience in completed and ongoing human trials described in the Ophthotech 
Corp. Investigator Brochure involves use of E10030 in combination with an anti-VEGF agent 
(ranibizumab, bevacizumab or aflibercept) in approximately 1,245 subjects. To date, serious AEs 
have been reported in 225 participants, including four suspected unexpected serious adverse 
reactions: one case of uveitis in the OPH1001 trial; one case of cerebral hemorrhage in the 
OPH1002 trial; one case of retinal pigment epithelial tear in the OPH 1003 trial; and one case of 
left facial numbness with negative neurologic work-up, resolving within a day, in the OPH 1004 
trial, none of which has been considered to be likely to be related to E10030 administration by the 
Sponsor. Only one other case of uveitis (not designated a suspected unexpected SAE by 
investigators) has been reported across existing studies to date. 
No evidence was observed for a toxic or pharmacokinetic interaction between E10030 and the 
anti-VEGF agent ranibizumab when the combinations were administered by the intravitreal route 
to dogs and rabbits. Although no systematic studies of interactions have been conducted with other 
drugs to date, no interactions of E10030 with other drugs are anticipated. E10030 is metabolized 
by nucleases in vitreous humor and plasma; therefore, cytochrome P450- mediated drug 
interactions are unlikely. 
To date, no specific studies have been conducted to assess the effects of E10030 on the 
reproductive ability of adult animals or developmental parameters of fetuses or pups; therefore, 
E10030 must not be used during pregnancy or lactation. All women of childbearing potential must 
use two forms of effective contraception. 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 29 
6.3 
Potential Risks of Ranibizumab 
Ranibizumab (Lucentis®) is made by Genentech, Inc. and approved by the FDA as an intravitreal 
injection for the treatment of neovascular age-related macular degeneration, macular edema 
secondary to retinal vein occlusion, diabetic macular edema (DME) and diabetic retinopathy in 
people with DME. Ranibizumab may cause allergic reactions although, to date, none have been 
reported. Several thousand patients have been treated with ranibizumab for different therapeutic 
indications in clinical trials. Serious AEs possibly or probably attributed to intravitreal injection of 
ranibizumab include severe uveitis, endophthalmitis, retinal tears, retinal detachment, vitreous 
hemorrhage, lens damage and central retinal vein occlusion. Non-serious AEs possibly or probably 
attributed to intravitreal injection of ranibizumab include anterior chamber and vitreal 
inflammation, mild transient increases in IOP, posterior vitreal detachment, retinal hemorrhage, 
injection site pain, subconjunctival hemorrhage and transient decrease in visual acuity.  
Other ocular non-serious events included a foreign body sensation in the eye after intravitreal 
injection, conjunctivitis, dry eye and pruritus. Some of these ocular side effects may cause 
decreased vision and a possibility of causing blindness. Although there was a low rate of arterial 
thromboembolic events (ATEs) observed in the ranibizumab clinical trials, there is a potential risk 
of ATEs following intravitreal use of VEGF inhibitors. ATEs are defined as nonfatal stroke, 
nonfatal myocardial infarction or vascular death (including deaths of unknown cause). 
The safety of ranibizumab in pregnant or lactating women has not been tested.  
6.4 
Potential Risks of Any Intravitreal Injection 
Potential risks of any injection are related to the mechanics of manipulating the eye.  
Potential risks associated with intravitreal injection itself are similar to those associated with the 
injection of other approved drugs delivered via the same route and include endophthalmitis, retinal 
tear, retinal detachment, lens trauma, intraocular hemorrhage and elevated intraocular pressure. 
Such risks can lead to irreversible vision loss or blindness. These risks will be minimized by 
restricting performance of the treatment to clinicians with experience in intravitreal injection and 
by use of a standardized injection procedure. Appendix 3 describes the injection procedure that 
will be used. 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 30 
7.0 
PARTICIPANT SAFETY MONITORING 
Participants will be assessed for AEs during all study visits by the study investigators. At each 
visit, the participant will be asked about any new ocular or systemic symptoms including 
hospitalizations or new/changed medications. Participants will be instructed to contact a study 
investigator at any time if they experience any problems.  
Participants will be monitored at each visit for injection-related complications such as 
endophthalmitis, retinal tear/detachment, intraocular hemorrhage, cataract and glaucoma and for 
any progression of ocular VHL disease. They will also be monitored at each visit for intraocular 
inflammation (as assessed by presence of anterior chamber or vitreous cell on ophthalmoscopy), 
which was noted in some pre-clinical models using doses of E10030 higher than the human 
equivalent dose planned for this study. 
7.1 
Treatment of Endophthalmitis, Retinal Tear/Detachment, Intraocular Hemorrhage, 
 
Cataract and Glaucoma 
The decision to treat a participant for endophthalmitis, suspected endophthalmitis, retinal 
tear/detachment, intraocular hemorrhage, cataract or glaucoma will be guided by the clinical 
judgment of the investigator. Clinical management is also at the discretion of the investigator and 
should follow current standard practice patterns. A decision regarding whether discontinuation of 
combination investigational treatment is warranted will be made by the investigator in consultation 
with the participant. 
7.2 
Individual Withdrawal Criteria 
Participants may choose to withdraw from this study for any reason at any time without penalty, 
loss of benefits or prohibition from enrolling in other clinical protocols. Reasons for participant 
discontinuation of combination investigational product or withdrawal may include, but are not 
limited to, the following: 
• Visual acuity loss of ≥ 30 letters from baseline; 
• Investigator determination that it is not in the best medical interest of the participant to 
continue participation; 
• Findings in the course of the trial that may affect willingness to participate; 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 31 
• Inability to keep study visits or to comply with study requirements; 
• Participant requires ocular surgery which cannot safely be postponed until the end of the 
study; 
• Pregnancy; 
• An adverse reaction to the study treatment or a serious complication associated with or 
aggravated by continuation of one or both investigational products; 
• Cardiovascular event or stroke; or 
• Other safety concerns. 
Discontinuation of the combination investigational treatment does not necessitate study 
withdrawal. Whenever possible, investigators will ask study participants discontinuing 
combination investigational treatment to continue to return for study visits. 
7.3 
Pregnancy Monitoring 
If an investigator becomes aware that a female study participant has become pregnant during the 
study, no further intravitreal injections of combination investigational treatment will be 
administered. The investigator and participant will determine whether to continue any remaining 
study visits or to exit the study.  
If an investigator becomes aware that a male study participant has impregnated his partner during 
the study, the investigator will remind the participant of the potential risks to the unborn fetus.  
In either case of reported pregnancy, participant (or partner) will be referred to the NIH OB/GYN 
consultation service for evaluation and counseling. The investigator must follow the participant 
(or partner) until the pregnancy outcome.  
8.0 
OUTCOME MEASURES 
8.1 
Primary Outcome 
The primary outcome for the study will be safety of the combination investigational treatment, 
assessed by tabulation of AEs reported through Week 52. 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 32 
8.2 
Secondary Outcomes 
Secondary outcomes will include tabulation of AEs reported through Week 104 and the following 
measures in the study eye at Week 52 and 104: the proportion of participants experiencing 
reduction in size of at least one RCH in the absence of other ablative treatment (assessed by fundus 
photography and FA); the proportion of participants experiencing moderate vision loss (defined as 
a loss of ≥ 15 letters from baseline on EVA testing); mean change in visual acuity; change in size 
of RCH (measured by fundus photography and FA); change in exudation (measured by fundus 
photography, OCT and FA); change in epiretinal proliferation, fibrosis or retinal traction (assessed 
by OCT and fundus photography); proportion of participants undergoing ablative treatment of 
RCH or ocular surgery; proportion of participants with successful ablative treatment of RCH; and 
the proportion of participants with appearance of one or more new RCH.  
9.0 
STATISTICAL ANALYSIS 
All participants will be included in the analyses.  
9.1 
Primary Outcome Analysis 
In this open-label, prospective study, analyses will be primarily descriptive and by participant.  
All ocular and systemic AEs reported through Week 52 will be tabulated by participant.  
AE frequencies will be presented by body system, severity and whether they are considered related 
to the study treatment. 
9.2 
Secondary Outcome Analysis 
The proportion of participants experiencing reduction in size of at least one RCH, in the absence 
of other ablative treatment, will be assessed by fundus photography and FA images taken at  
Week 52 and 104 compared to baseline. OCT, fundus photograph and FA findings will be 
presented by participant to indicate increases/decreases in lesion size and exudation from baseline. 
Change in epiretinal proliferation, fibrosis or retinal traction will be assessed by fundus 
photography and OCT and will be reported descriptively for each participant. The proportion of 
participants experiencing moderate vision loss (defined as a loss of ≥ 15 letters from baseline on 
EVA testing); undergoing ablative treatment of RCH or ocular surgery; achieving successful 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 33 
ablative treatment of RCH; and showing appearance of one or more new RCH in the study eye 
will be reported. Mean change in visual acuity will be tabulated.  
9.3 
Sample Size/Accrual Rate 
The accrual goal is three participants. This is an appropriate sample size for the study objectives, 
since this preliminary investigation will not attempt to definitively determine the safety or efficacy 
of this treatment.  
10.0 
HUMAN PARTICIPANTS PROTECTION 
10.1 
Equitability 
Accrual will be equitable among patients with VHL disease meeting the enrollment criteria for 
this study.  
10.1.1 Justification for Exclusion of Children 
Children are not eligible for this study, as the safety of E10030 and ranibizumab has not been 
investigated in children. Furthermore, it is unlikely that young participants will be able to comply 
with all examinations and with intravitreal injections. 
10.1.2 Justification for Exclusion of Pregnant or Lactating Women 
Women who are pregnant or breastfeeding are excluded from this study because of the unknown 
risks of E10030 or ranibizumab on a fetus or nursing baby and the uncertainty with respect to 
whether E10030 or ranibizumab is excreted in human milk. Given the known and unknown effects 
on pregnancy outcomes, two forms of contraception will be required for female participants of 
childbearing potential (see Appendix 1 for definition). In addition, female participants of 
childbearing potential will undergo pregnancy tests throughout the study. 
10.1.3 Justification for Exclusion of Individuals without Consent Capacity 
Vulnerable subjects who lack consent capacity or are cognitively impaired are excluded from this 
study because they are frequently unable to cooperate with evaluation and testing in the manner 
standardized for other adult participants.  


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 34 
10.2 
Qualifications of Investigators 
The physicians who will be performing study procedures are experienced in caring for patients 
with VHL. In addition, they are experienced in conducting studies similar to this protocol. 
Credentialed NEI staff physicians and clinical fellows may also conduct procedures under the 
direction of these investigators. 
The Principal Investigator (PI) has verified that all individuals working on this protocol required 
to take HRPP training under OHSRP SOP 25 (Training requirements for the NIH Human Research 
Protections Program) have completed all required training, or will do so before assuming any 
duties for this protocol. 
Henry Wiley, MD, is the PI with the ability to obtain informed consent. He is responsible for the 
conduct and oversight of the study. Specifically, Dr. Wiley is responsible for obtaining medical 
history, performing ophthalmic examinations, administering combination investigational 
treatment, completing regulatory documentation and IRB submissions, generating clinical source 
documents, entering data and resolving data queries and overseeing the entire study. Dr. Wiley is 
a staff clinician, medical and surgical retina, at NEI with experience in clinical management of 
ocular VHL disease.  
Emily Chew, MD, is the Lead Associate Investigator with the ability to obtain informed consent. 
She is responsible for obtaining medical history, performing ophthalmic examinations, 
administering combination investigational treatment and generating clinical source documents.  
Dr. Chew is the deputy clinical director (CD) and director of the medical retina fellowship program 
at NEI. Dr. Chew has been PI on previous studies of ocular VHL disease and has written articles, 
contributed to book chapters and presented on VHL disease. 
Wai T. Wong, MD, PhD is an Associate Investigator with the ability to obtain informed consent. 
He is responsible for obtaining medical history, performing ophthalmic examinations, 
administering combination investigational treatment and generating clinical source documents.  
Dr. Wong is a staff clinician and the head of the unit of neuron-glial interactions in retinal diseases 
at NEI. He has written articles, contributed to book chapters and presented on VHL disease. 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 35 
Catherine Cukras, MD, PhD is an Associate Investigator with the ability to obtain informed 
consent. She is responsible for obtaining medical history, performing ophthalmic examinations, 
administering combination investigational treatment and generating clinical source documents.  
Dr. Cukras is a staff clinician at NEI and is a graduate of the medical retina fellowship program at 
NEI.  
Tiarnan Keenan, MD, PhD, Alexander Kaplan, MD, Munir Iqbal, MD, FRCSC, and Christopher 
Hwang, MD are Associate Investigators with the ability to obtain informed consent. They are 
responsible for obtaining medical history, performing ophthalmic examinations, administering 
combination investigational product and generating clinical source documents. They are clinical 
fellows at the NEI. 
Angela Kibiy, MPH, BSN, RN is an Associate Investigator and Referral Contact participating in 
the consent process but without the ability to obtain informed consent. She is responsible for 
assisting the PI with study visits, generating clinical source documents, entering data and resolving 
data queries. 
Prashant Chittiboina, MD, Karel Pacak, MD, PhD, DSc and W. Marston Linehan, MD are 
Associate Investigators without the ability to obtain informed consent. Dr. Chittiboina is a Clinical 
Investigator at the National Institute of Neurological Disorders and Stroke (NINDS).  
His laboratory focuses on neurosurgical disorders of the pituitary gland and inheritable tumor 
syndromes. Dr. Pacak is a Senior Investigator in Medical Neuroendocrinology at the National 
Institute of Child Health and Human Development (NICHD). His work focuses on the etiology, 
pathophysiology, genetics, diagnosis and treatment of pheochromocytoma and paraganglioma.  
Dr. Linehan is a Senior Investigator in the Urologic Oncology Branch of the National Cancer 
Institute (NCI). Dr. Linehan and his colleagues identified the VHL gene and his work has led to 
the development of new therapeutic strategies for kidney cancer associated with VHL disease. 
They are responsible for assisting the PI with the systemic evaluation of ER-VHL patients for 
screening and offering scientific input. 
 
 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 36 
11.0 
BENEFITS 
Participants may benefit directly from this study if combined E10030 and ranibizumab treatment 
causes regression of RCH and preserves visual acuity. The study will also lead to generalizable 
knowledge that will enhance our understanding of using E10030 and ranibizumab as treatment for 
patients with RCH associated with VHL. 
12.0 
SUMMARY/CLASSIFICATION OF RISK 
Risk is classified as more than minimal risk. The risks will be minimized with careful monitoring 
and are reasonable given that the participants are experiencing or are at risk of experiencing visual 
loss due to VHL disease. 
13.0 
CONSENT DOCUMENTS AND PROCESS 
Study investigators with consenting privileges will obtain informed consent. All NIH study 
investigators obtaining informed consent have completed the National Institute of Mental Health 
(NIMH) Human Subject’s Protection Unit (HSPU) “Elements of Successful Informed Consent” 
training. All participants will receive a verbal explanation in terms suited to their comprehension 
of the purposes, procedures and potential risks of the study. The participants must have the ability 
to understand and sign an informed consent form, which must be signed prior to enrollment.  
The participants will have an opportunity to carefully review the consent and ask questions 
regarding this study prior to signing, and they will be informed that they may withdraw from the 
study at any time without prejudice to themselves. 
If the participant requires the consent to be in larger font in order to read it well, this will be 
provided. If participants are visually impaired to the point of being unable to read the consent, they 
can take the consent back with them to read it over with a family member or with the use of 
magnifying devices. If the participant chooses, the investigator can also read the consent verbatim 
to the participant and answer any questions that may arise.  
An investigator present during the consent process will document the consent process in the 
participant’s medical record. A copy of the signed informed consent form will be provided to the 
participant to take home. 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 37 
13.1 
Unanticipated Enrollment of Non-English Speaking Participants 
If a non-English speaking participant is eligible for enrollment, the participant will be provided 
with the Clinical Center (CC) Short Written Consent Form for Non-English Speaking Research 
Subjects in the participant’s native language and a verbal explanation of the purpose, procedures 
and risks of the study. The IRB-approved English consent form will serve as basis for the verbal 
explanation of the study. The investigator will obtain an interpreter unless the investigator is fluent 
in the prospective participant’s language. Preferably, the interpreter will be someone who is not 
related to the participant (i.e., not a family member). Interpreters provided by the CC will be used 
whenever possible. The interpreters will interpret the IRB-approved English consent form and 
facilitate discussion between the participant and investigator.  
The IRB-approved English consent form will be signed by the investigator obtaining consent and 
a witness to the oral presentation. The CC Short Written Consent Form will be signed by the 
participant and a witness who observed the presentation of information. The interpreter may sign 
the consent documents as the witness and, in this case, will note “Interpreter” with his/her 
signature. If not also serving as the witness, the interpreter will be separately identified on the short 
form in the space provided. A copy of both signed forms (the long form serving as the script and 
the short form) will be provided to the participant. The short form process, including the use of an 
interpreter, will be documented in the medical record in accordance with NIH policy. 
All instances of use of the CC Short Written Consent Form will be reported to the IRB at the time 
of annual review. If the CC Short Written Consent Form is used three times or more for the same 
language within an IRB approval period, this will be reported to the IRB immediately. 
Interpreters will also be present for other protocol procedures as necessary. 
14.0 
DATA AND SAFETY MONITORING 
The NEI SAE Review Committee is responsible for monitoring data and safety, and will exercise 
oversight of the clinical investigation independently from the study investigators.  
 
 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 38 
14.1 
Coordinating Center  
The Emmes Corporation (Emmes) has been assigned as the Coordinating Center for this trial to 
conduct data collection, protocol monitoring, data analysis and reporting. The Coordinating Center 
provides routine monitoring of study participants’ data. More frequent monitoring visits will be 
performed at the beginning of the study when enrollment is open. Monitoring will decrease as 
enrollment closes and as participant follow-up continues. 
Although the Coordinating Center advises the NEI CD and PI on data and statistical activities, the 
Coordinating Center staff does not have direct access to or interaction with participants.  
14.2 
NEI Serious Adverse Event Review Committee 
The NEI SAE Review Committee, which consists of the NEI CD and three other NEI physicians, 
will be responsible for reviewing any reported serious safety events, if they occur under this 
protocol. The Committee will review data on a semiannual basis to determine whether the study 
should continue. If changes to the protocol are indicated, recommendations will be made to the 
NEI CD and Institutional Review Board (IRB) who will consider and act on such 
recommendations in a timely manner. Should any suspected serious adverse reactions occur, the 
NEI CD may, at his discretion, assemble the Committee before the scheduled date to consider if 
the study should go forward. In addition, if three or more participants experience non-serious 
suspected adverse reactions that require temporary or permanent cessation of the combination 
investigational treatment, the PI shall report this to the NEI CD. The NEI CD may convene the 
Committee before the scheduled time to consider the cessation of the study as a whole.  
14.3 
Criteria for Stopping the Study 
The NEI SAE Review Committee or IRB may recommend temporarily suspending or closing 
enrollment, or stopping the study at any time due to safety concerns, lack of efficacy or slow 
recruitment. 
15.0 
QUALITY ASSURANCE 
The NEI and Emmes maintain quality control by adhering to standard operating procedures  
(NEI QA program and NEIS standard operating procedures). These procedures cover the full 
protocol cycle beginning with staff credentialing and training, and protocol development and 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 39 
approval, through database development, data collection, monitoring and analysis and finally 
manuscript preparation at the conclusion of the study. Data quality assurance is of the utmost 
importance to the NEI and Emmes. The two groups use a quality assurance system that relies on 
real-time data checks and reports throughout the course of a study to ensure the accuracy of 
information. This system is a secure and confidential data management system that stores data and 
provides quality assurance and reporting. Emmes has developed a number of routine reports 
specifically designed for monitors (e.g., listings of SAEs, etc.). 
Additionally, Emmes has developed summary reports of discrepancies, as well as reports of the 
exceptions databases, which include requests and reasons for exceptions. The results of the reports 
are communicated back to site staff, and, along with protocol compliance issues, to the DSMC  
(if applicable).  
Following the monitoring plan for this study, Emmes will perform monitoring activities, including 
on-site audits, review of database entries and the resolution of study issues. In addition to 
monitoring, Emmes performs various detailed automated and manual data quality checks. 
The results from these checks and any protocol compliance issues are communicated back to site 
staff and to the NEI Project Officer, NEI CD and applicable regulatory bodies. 
16.0 
REPORTING OF UNANTICIPATED PROBLEMS, PROTOCOL DEVIATIONS AND ADVERSE 
 
EVENTS 
The PI is responsible for detecting, documenting and reporting unanticipated problems, AEs, 
including SAEs and deviations in accordance with NIH policy, IRB requirements and federal 
regulations. Relatedness to the research of all SAEs will be determined by the PI in consultation 
with the NEI CD. 
Serious unanticipated problems, SAEs (including deaths) that are not unanticipated problems and 
serious protocol deviations will be reported to the IRB and CD as soon as possible and in writing 
not more than seven days after the PI first learns of the event, unless immediate reporting is waived 
for specific SAEs as noted below. Not serious unanticipated problems and not serious deviations 
will be reported to the IRB and CD as soon as possible and in writing not more than 14 days after 
the PI first learns of the event. Written reports will be submitted in PTMS. 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 40 
All AEs, deviations and unanticipated problems will be summarized and reported at the time of 
Continuing Review. 
The PI will immediately report SAEs to the Sponsor according to the requirements of  
21 CFR 312.64(b). The PI will record non-serious AEs and report them to the Sponsor. 
Unexpected serious suspected adverse reactions will be reported to the FDA as soon as possible 
by facsimile or e-mail within seven days if life-threatening or resulting in death with a follow-up 
report within 15 days, and with a written report within 15 days otherwise.  
All SAEs or unanticipated problems will be reported to Ophthotech Corp. as soon as possible.  
17.0 
ALTERNATIVES TO PARTICIPATION  
Standard care for RCH in VHL ocular disease includes ablative therapies such as laser 
photocoagulation and trans-scleral cryotherapy. Other therapies include verteporfin photodynamic 
therapy, episcleral brachytherapy and external beam radiotherapy. Vitreoretinal surgery is used as 
an adjunct to ablative therapy in order to address vision-threatening epiretinal proliferation, 
tractional or rhegmatogenous retinal detachment or vitreous hemorrhage. 
Participants may receive standard care treatment for RCH (laser photocoagulation and 
cryotherapy) and complications of RCH (vitreoretinal surgery) when indicated for significant 
clinical worsening during this study. If a participant achieves clinical improvement during the 
study that allows for standard care treatment that was not previously feasible, this treatment may 
be administered anytime starting at the Week 16 visit. 
18.0 
PRIVACY 
All research activities will be conducted in as private a setting as possible. 
19.0 
CONFIDENTIALITY 
No blood, tissue or other samples will be stored in this study. All medical records will be kept 
confidential and will only be reviewed by the participating investigators. Data will be kept in 
password-protected computers held at the NEI and Emmes. Only study investigators and Emmes 
staff will have access to the study data. The participants’ names will not appear on any of the data 
forms reported to the Coordinating Center. A unique, coded identifier and study registration 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 41 
number will identify the participant if his or her information is shared with the Coordinating Center 
or Ophthotech Corp. for research purposes. Participants’ personal information will be kept as 
private as possible. However, records can be inspected by organizations for quality assurance and 
data analysis. These include the members of the IRB, the Coordinating Center and the NEI SAE 
Review Committee. Ophthotech Corp. will supply the investigational products, but will have 
neither control of the data nor access to identifiable information in order to ensure research 
integrity and participant privacy. 
20.0 
CONFLICT OF INTEREST 
The NIH guidelines were distributed to all of the investigators, and none of the investigators had 
conflicts of interest. Ophthotech Corp. will provide the investigational products and provide travel 
and per diem reimbursement. 
21.0 
TECHNOLOGY TRANSFER 
Ophthotech Corp. will provide the investigational products and provide travel and per diem 
reimbursement through a cooperative research and development agreement (CRADA) with the 
NEI. They will receive coded summary data after completion of the study as outlined in the 
CRADA. The company will receive any reports submitted to the FDA. 
22.0 
RESEARCH AND TRAVEL COMPENSATION 
There is no compensation for participation in this study. This protocol offers travel and per diem 
reimbursement for participants, paid by Ophthotech Corp.  


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 42 
23.0 
REFERENCES 
 
1. 
Singh AD, Shields CL, Shields JA: von Hippel-Lindau disease. Surv Ophthalmol 46:117-
142, 2001 
2. 
Calzada MJ: Von Hippel-Lindau syndrome: molecular mechanisms of the disease. Clin 
Transl Oncol 12:160-165,  
3. 
Kaelin WG, Jr.: Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer 
2:673-682, 2002 
4. 
Kaelin WG, Jr.: The von Hippel-Lindau tumour suppressor protein: O2 sensing and cancer. 
Nat Rev Cancer 8:865-873, 2008 
5. 
Roberts AM, Ohh M: Beyond the hypoxia-inducible factor-centric tumour suppressor model 
of von Hippel-Lindau. Curr Opin Oncol 20:83-89, 2008 
6. 
Wong WT, Chew EY: Ocular von Hippel-Lindau disease: clinical update and emerging 
treatments. Curr Opin Ophthalmol 19:213-217, 2008 
7. 
Sachdeva R, Dadgostar H, Kaiser PK, et al.: Verteporfin photodynamic therapy of six eyes 
with retinal capillary haemangioma. Acta Ophthalmol 88:e334-340, 2010 
8. 
Selver OB, Yaman A, Saatci AO: Temporary Exudative Retinal Detachment following 
Photodynamic Therapy in a Patient with Retinal Capillary Hemangioblastoma. Middle East 
Afr J Ophthalmol 18:246-248, 2011 
9. 
Rodriguez-Coleman H, Spaide RF, Yannuzzi LA: Treatment of angiomatous lesions of the 
retina with photodynamic therapy. Retina 22:228-232, 2002 
10. Gass JD, Braunstein R: Sessile and exophytic capillary angiomas of the juxtapapillary retina 
and optic nerve head. Arch Ophthalmol 98:1790-1797, 1980 
11. Siemeister G, Weindel K, Mohrs K, et al.: Reversion of deregulated expression of vascular 
endothelial growth factor in human renal carcinoma cells by von Hippel-Lindau tumor 
suppressor protein. Cancer Res 56:2299-2301, 1996 
12. Na X, Wu G, Ryan CK, et al.: Overproduction of vascular endothelial growth factor related 
to von Hippel-Lindau tumor suppressor gene mutations and hypoxia-inducible factor-1 alpha 
expression in renal cell carcinomas. J Urol 170:588-592, 2003 
13. George DJ, Kaelin WG, Jr.: The von Hippel-Lindau protein, vascular endothelial growth 
factor, and kidney cancer. N Engl J Med 349:419-421, 2003 
14. Yang JC, Haworth L, Sherry RM, et al.: A randomized trial of bevacizumab, an anti-vascular 
endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427-434, 
2003 
15. Haase VH, Glickman JN, Socolovsky M, Jaenisch R: Vascular tumors in livers with targeted 
inactivation of the von Hippel-Lindau tumor suppressor. Proc Natl Acad Sci U S A 98:1583-
1588, 2001 
16. Wizigmann-Voos S, Breier G, Risau W, Plate KH: Up-regulation of vascular endothelial 
growth factor and its receptors in von Hippel-Lindau disease-associated and sporadic 
hemangioblastomas. Cancer Res 55:1358-1364, 1995 
17. Chan CC, Collins AB, Chew EY: Molecular pathology of eyes with von Hippel-Lindau 
(VHL) Disease: a review. Retina 27:1-7, 2007 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 43 
18. Chan CC, Vortmeyer AO, Chew EY, et al.: VHL gene deletion and enhanced VEGF gene 
expression detected in the stromal cells of retinal angioma. Arch Ophthalmol 117:625-630, 
1999 
19. Benjamin LE, Keshet E: Conditional switching of vascular endothelial growth factor (VEGF) 
expression in tumors: induction of endothelial cell shedding and regression of 
hemangioblastoma-like vessels by VEGF withdrawal. Proc Natl Acad Sci U S A 94:8761-
8766, 1997 
20. Dahr SS, Cusick M, Rodriguez-Coleman H, et al.: Intravitreal anti-vascular endothelial 
growth factor therapy with pegaptanib for advanced von Hippel-Lindau disease of the retina. 
Retina 27:150-158, 2007 
21. Wong WT, Liang KJ, Hammel K, et al.: Intravitreal ranibizumab therapy for retinal capillary 
hemangioblastoma related to von Hippel-Lindau disease. Ophthalmology 115:1957-1964, 
2008 
22. Benjamin LE, Golijanin D, Itin A, et al.: Selective ablation of immature blood vessels in 
established human tumors follows vascular endothelial growth factor withdrawal. J Clin 
Invest 103:159-165, 1999 
23. Benjamin LE, Hemo I, Keshet E: A plasticity window for blood vessel remodelling is defined 
by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and 
VEGF. Development 125:1591-1598, 1998 
24. Gee MS, Procopio WN, Makonnen S, et al.: Tumor vessel development and maturation 
impose limits on the effectiveness of anti-vascular therapy. Am J Pathol 162:183-193, 2003 
25. Ballas MS, Chachoua A: Rationale for targeting VEGF, FGF, and PDGF for the treatment 
of NSCLC. Onco Targets Ther 4:43-58,  
26. Sennino B: Two is better than one: benefits of VEGF and PDGF inhibition in ovarian cancer. 
Cancer Biol Ther 9:183-185,  
27. Battegay EJ, Rupp J, Iruela-Arispe L, et al.: PDGF-BB modulates endothelial proliferation 
and angiogenesis in vitro via PDGF beta-receptors. J Cell Biol 125:917-928, 1994 
28. Carmeliet P, Jain RK: Molecular mechanisms and clinical applications of angiogenesis. 
Nature 473:298-307, 2011 
29. Magnusson PU, Looman C, Ahgren A, et al.: Platelet-derived growth factor receptor-beta 
constitutive activity promotes angiogenesis in vivo and in vitro. Arterioscler Thromb Vasc 
Biol 27:2142-2149, 2007 
30. Betsholtz C, Lindblom P, Bjarnegard M, et al.: Role of platelet-derived growth factor in 
mesangium development and vasculopathies: lessons from platelet-derived growth factor 
and platelet-derived growth factor receptor mutations in mice. Curr Opin Nephrol Hypertens 
13:45-52, 2004 
31. Enge M, Bjarnegard M, Gerhardt H, et al.: Endothelium-specific platelet-derived growth 
factor-B ablation mimics diabetic retinopathy. EMBO J 21:4307-4316, 2002 
32. Uemura A, Ogawa M, Hirashima M, et al.: Recombinant angiopoietin-1 restores higher-
order architecture of growing blood vessels in mice in the absence of mural cells. J Clin 
Invest 110:1619-1628, 2002 
33. Hickey MM, Simon MC: Regulation of angiogenesis by hypoxia and hypoxia-inducible 
factors. Curr Top Dev Biol 76:217-257, 2006 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 44 
34. Rafty LA, Khachigian LM: von Hippel-Lindau tumor suppressor protein represses platelet-
derived growth factor B-chain gene expression via the Sp1 binding element in the proximal 
PDGF-B promoter. J Cell Biochem 85:490-495, 2002 
35. Bohling T, Hatva E, Kujala M, et al.: Expression of growth factors and growth factor 
receptors in capillary hemangioblastoma. J Neuropathol Exp Neurol 55:522-527, 1996 
36. Darland DC, Massingham LJ, Smith SR, et al.: Pericyte production of cell-associated VEGF 
is differentiation-dependent and is associated with endothelial survival. Dev Biol 264:275-
288, 2003 
37. Brown EB, Campbell RB, Tsuzuki Y, et al.: In vivo measurement of gene expression, 
angiogenesis and physiological function in tumors using multiphoton laser scanning 
microscopy. Nat Med 7:864-868, 2001 
38. Fukumura D, Xavier R, Sugiura T, et al.: Tumor induction of VEGF promoter activity in 
stromal cells. Cell 94:715-725, 1998 
39. Bergers G, Song S, Meyer-Morse N, et al.: Benefits of targeting both pericytes and 
endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 111:1287-
1295, 2003 
40. Erber R, Thurnher A, Katsen AD, et al.: Combined inhibition of VEGF and PDGF signaling 
enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell 
survival mechanisms. FASEB J 18:338-340, 2004 
41. Jo N, Mailhos C, Ju M, et al.: Inhibition of platelet-derived growth factor B signaling 
enhances the efficacy of anti-vascular endothelial growth factor therapy in multiple models 
of ocular neovascularization. Am J Pathol 168:2036-2053, 2006 
42. Brown DM, Kaiser PK, Michels M, et al.: Ranibizumab versus verteporfin for neovascular 
age-related macular degeneration. N Engl J Med 355:1432-1444, 2006 
43. Brown DM, Michels M, Kaiser PK, et al.: Ranibizumab versus verteporfin photodynamic 
therapy for neovascular age-related macular degeneration: Two-year results of the ANCHOR 
study. Ophthalmology 116:57-65 e55, 2009 
44. Rosenfeld PJ, Brown DM, Heier JS, et al.: Ranibizumab for neovascular age-related macular 
degeneration. N Engl J Med 355:1419-1431, 2006 
45. Kaiser PK, Blodi BA, Shapiro H, Acharya NR: Angiographic and optical coherence 
tomographic results of the MARINA study of ranibizumab in neovascular age-related 
macular degeneration. Ophthalmology 114:1868-1875, 2007 
46. Rosenfeld PJ, Shapiro H, Tuomi L, et al.: Characteristics of patients losing vision after 2 
years of monthly dosing in the phase III ranibizumab clinical trials. Ophthalmology 118:523-
530, 2011 
47. Jaffe GJ, Eliott D, Wells JA, et al.: A Phase 1 Study of Intravitreous E10030 in Combination 
with Ranibizumab in Neovascular Age-Related Macular Degeneration. Ophthalmology 
123:78-85, 2016 
48. Schimke RN, Collins DL, Stolle CA. Von Hippel-Lindau Syndrome. In: Pagon RA, Bird 
TD, Dolan CR, eds. Gene Reviews. 2010/03/20 ed. Seattle: University of Washington; 1993. 
49. Melmon KL, Rosen SW. Lindau's disease. Review of the literature and study of a large 
kindred. Am J Med 1964;36:595-617. 
 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 45 
APPENDIX 1: DETERMINING CHILDBEARING POTENTIAL 
A female participant who is considered non-childbearing due to a medical condition  
(i.e., participant has previously undergone a hysterectomy) does not need a pregnancy test, 
Follicle-stimulating Hormone (FSH) test or contraception. 
If a female participant is considered non-childbearing due to menopause, it must be in accordance 
with 
the 
CNS 
IRB/NIH 
Ob-Gyn 
guidance 
on 
the 
definition 
of 
menopause. 
This guidance defines menopause as: 
• Women over age 55 who have not had a period for one year will be considered menopausal 
and do not need a pregnancy test, FSH test or contraception. 
• Women between 50 and 55, who have not had a period for one year, should have an FSH 
test. If their FSH level is ≥ 20 mIU/mL, they will be considered menopausal and do not 
need pregnancy testing or contraception. If their FSH level is < 20 mIU/mL, they will need 
pregnancy testing and contraception as required by the protocol. 
• Women between 45 and 50 who have not had a period for one year will need both an FSH 
test and a pregnancy test. If they are not pregnant and their FSH level is  
≥ 20 mIU/mL, they will be considered menopausal and will not require contraception or 
additional pregnancy testing. If their FSH test is < 20 mIU/mL, they will need pregnancy 
testing and contraception as required by the protocol. 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 46 
APPENDIX 2: STUDY FLOWSHEET 
 
VISIT SCHEDULE*  
0 
4 
8 
12 
16 
24 
32 
40 
48 
52 
Visit Number (week) 
000 004 008 012 016 024 032 040 048 052 
Target Day From Baseline 
0 
28 
56 
84 
112 168 224 280 336 364 
STUDY INTERVENTION 
 
Intravitreal injections of E10030 
and Ranibizumab 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
GENERAL ASSESSMENTS 
 
Medical/Ophthalmic History 
X2 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X2 
 
 
 
 
 
 
 
 
 
Adverse Event Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
OCULAR ASSESSMENTS (BOTH EYES)  
BCVA (EVA) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Manifest Refraction1 
X 
 
 
 
X 
 
 
 
 
X 
Slit Lamp Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dilated Fundus Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Intraocular Pressure (IOP) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Color Fundus Photography 
X2 
 
 
 
X 
 
 
 
 
X 
Optical Coherence Tomography 
(OCT) 
X2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fluorescein Angiography (FA) 
X2 
 
 
 
X 
 
 
 
 
X 
LABORATORY 
 
Complete Blood Count (CBC) 
X2 
 
 
 
X 
  
 
 
 
 
Acute Care Panel 
X2 
 
 
 
X 
 
 
 
 
 
Hepatic Panel 
X2 
 
 
 
X 
 
 
 
 
 
Mineral Panel 
X2 
 
 
 
X 
 
 
 
 
 
Hemoglobin A1C 
X2 
 
 
 
 
 
 
 
 
 
Pregnancy Test3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
*  All visits during the first year must be conducted within a window of ±7 days from the target visit day. After Week 
52, visits are conducted within a window of ±30 days from the target visit day.  
 
1 Manifest refraction must be performed when scheduled and when there is a change in visual acuity of ≥ 10  
E-ETDRS letters (≥ 0.20 logMAR) as compared with testing at the last visit.  


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 47 
2 These procedures may be completed under another NEI/NCI/NINDS protocol if performed within 31 days prior to 
the baseline visit. 
3 Only for women of childbearing potential. See Appendix 1 for guidance on determining whether a female is 
considered to be of childbearing potential. Some women may require a follicle-stimulating hormone (FSH) test to 
determine childbearing potential. Participants who meet this definition must have a negative test within 24 hours 
prior to injection of any investigational product.  


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 48 
APPENDIX 2: STUDY FLOWSHEET, CONTINUED: EXTENSION PHASE 
 
Visit Schedule* 
(Y2 Extra**) 
60 
72 
84 
104 
Visit Number (week) 
N/A 
060 
072 
084 
104 
Target Day From Baseline 
N/A 
420 
504 
588 
728 
GENERAL ASSESSMENTS 
 
Medical/Ophthalmic History 
 
 
 
 
 
Concomitant Medications 
Assessment 
X 
X 
X 
X 
X 
Vital Signs 
 
X 
X 
X 
X 
Physical Examination 
 
 
 
 
 
Adverse Event Assessment 
X 
X 
X 
X 
X 
OCULAR ASSESSMENTS (BOTH 
EYES) 
 
BCVA (EVA) 
X 
X 
X 
X 
X 
Manifest Refraction1 
 
 
 
 
 
Slit Lamp Examination 
X 
X 
X 
X 
X 
Dilated Fundus Examination 
X 
X 
X 
X 
X 
Intraocular Pressure (IOP) 
X 
X 
X 
X 
X 
Color Fundus Photography 
 
 
 
 
 
Optical Coherence Tomography 
(OCT) 
X 
X 
X 
X 
X 
Fluorescein Angiography (FA) 
 
 
 
 
 
LABORATORY 
 
Complete Blood Count (CBC) 
 
 
 
 
 
Acute Care Panel 
 
 
 
 
 
Hepatic Panel 
 
 
 
 
 
Mineral Panel 
 
 
 
 
 
Hemoglobin A1C 
 
 
 
 
 
 
* 
All visits during the first year must be conducted within a window of ±7 days from the target visit day. After 
Week 52, visits are conducted within a window of ±30 days from the target visit day.  
** Additional, discretionary visits may occur during the second year as often as every four weeks between Week 56 
and Week 104 
 
1 Manifest refraction must be performed when scheduled and when there is a change in visual acuity of ≥ 10  
E-ETDRS letters (≥ 0.20 logMAR) as compared with testing at the last visit.  
 
 
 


ER-VHL 
November 7, 2018 
Version 7.0 
CONFIDENTIAL 
Page 49 
Appendix 3: Injection Procedures for All Participants 
The following procedures will be implemented to minimize the risk of potential AEs associated 
with serial intravitreal injections (e.g., endophthalmitis). Aseptic technique will be observed by 
clinic staff involved in the injection tray assembly, anesthetic preparation and investigational 
product administration. In addition to the procedures outlined below, specific institutional policies 
associated with the safety of intravitreal injections will be observed. Included in these safety 
procedures are use of a mask and sterile gloves by staff preparing and administering intravitreal 
injections and instruction to the patient to minimize talking during preparation and administration 
of the injection. 
• The technician or nurse assembles the supplies and prepares a sterile field.  
• The investigator physician and/or nurse prepare the investigational product in sterile 
fashion as described in Section 4.6, with loading of ranibizumab and E10030 in separate, 
sterile, labeled syringes, with appropriate needles for injection affixed, on the sterile field. 
• The technician or nurse instills 1 drop of 0.5% tetracaine or proparacaine solution into the 
study eye. This is repeated one or two more times. 
• The technician or nurse instills 5% povidone iodine ophthalmic solution in the study eye. 
Anesthesia can be supplemented with additional drops of 0.5% tetracaine or proparacaine 
if the participant is uncomfortable. If additional topical anesthetic is delivered, then  
2-3 additional drops of 5% povidone iodine ophthalmic solution is instilled in the study 
eye. 
• The technician or nurse disinfects the periocular skin and eyelid of the study eye in 
preparation for injection. The technician or nurse cleanses the eyelid, lashes and periorbital 
skin with 10% povidone iodine swabs, starting with the eyelid and lashes and continuing 
with the surrounding periocular skin.  
• The investigator physician may opt to supplement the topical anesthetic regimen for the 
study eye with subconjunctival administration lidocaine 1% or 2%, in order to maximize 
comfort. Lidocaine 1% or 2% may be injected before or after the lid and periorbital 
preparation with povidone iodine and the insertion of the lid speculum described below, 
but only after pre-treatment with tetracaine or proparacaine and 5% povidone iodine on the 
ocular surface. A sterile cotton swab or sterile cotton pledget soaked in tetracaine or 
proparacaine may be used to supplement topical analgesia before the subconjunctival 
injection. Administration of lidocaine 1% or 2% consists of injecting between 0.1 and 
1.0 mL to raise a subconjunctival bleb in the quadrant of the study eye planned for 
injection, using a 30 gauge 0.5 inch needle, with care taken to maintain the needle as 
tangential to the globe as possible. 
• The investigator physician gloves and inserts an eye speculum into the study eye. 


ER-VHL 
November 7, 2018 
 
Version 7.0 
CONFIDENTIAL 
Page 50 
• The investigator physician saturates a sterile cotton-tipped applicator with 0.5% 
proparacaine or tetracaine drops and holds the swab against the planned intravitreal 
injection site for 20 to 40 seconds. Analgesia may be supplemented with 3.5% lidocaine 
gel at investigator discretion. If lidocaine gel is used, any additional 5% povidone iodine 
solution (see below) should be applied prior to gel application, and residual gel should be 
irrigated from the eye surface before the end of the procedure. 
• The investigator physician uses a caliper to mark the planned injection site, usually 3.5 to 
4 mm from the limbus.  
• The investigator physician applies another drop of 5% povidone iodine solution to the 
planned injection site. 
• The investigator physician injects 50 µL of ranibizumab using a 30-gauge 0.5-inch needle 
into the vitreous cavity and then removes the needle. 
• The investigator physician applies another drop of 5% povidone iodine solution to the 
injection site. 
• The investigator physician injects 50 µL of E10030 with a 27-gauge needle into the 
vitreous cavity and then removes the needle. 
• Sterile saline drops may be used in between steps above to keep the cornea lubricated as 
warranted, but should not be used immediately after application of povidone iodine 
solution. 
• The investigator physician removes the speculum. 
• The investigator physician performs pain assessment, visual testing (hand-motion testing) 
and assessment of retinal perfusion (by ophthalmoscopy) immediately after injections.  
Any severe pain, absence of hand-motion vision, or absence of perfusion of the retinal 
arterioles immediately following injection should prompt standard care assessment and 
intervention. Intraocular pressure should be measured and documented in such a 
circumstance, and should be treated with appropriate standard care options including 
medical management and/or surgical paracentesis when warranted. 
• Intraocular pressure is measured by Tono-Pen within 20 minutes after injection.  
Elevated intraocular pressure is monitored, and if necessary, managed using standard of 
care measures. A participant may be discharged from clinic when intraocular pressure 
measures ≤ 24 mmHg. 

SAP_001.pdf: 


ER-VHL SAP 
November 6, 2017 
 
TABLE OF CONTENTS 
Version 1.0 
Confidential 
Page i 
1.0 
INTRODUCTION ............................................................................................................................. 1 
1.1 
VHL Disease .................................................................................................................................. 1 
2.0 
DATA SOURCE ............................................................................................................................... 2 
3.0 
GENERAL REVIEW OF STUDY DESIGN ......................................................................................... 2 
3.1 
Study Design .................................................................................................................................. 2 
3.2 
Study Objective .............................................................................................................................. 3 
3.3 
Study Population ............................................................................................................................ 3 
3.3.1 
Inclusion Criteria ..................................................................................................................... 4 
3.3.2 
Exclusion Criteria .................................................................................................................... 5 
3.4 
Study Eye Eligibility Criteria ......................................................................................................... 5 
3.4.1 
Inclusion Criteria ..................................................................................................................... 5 
3.4.2 
Exclusion Criteria .................................................................................................................... 6 
3.4.3 
Choice of Study Eye in Cases of Bilateral Eligibility ............................................................. 7 
3.5 
Outcome Measures ......................................................................................................................... 7 
3.5.1 
Primary Study Outcome .......................................................................................................... 7 
3.5.2 
Secondary Study Outcomes .................................................................................................... 7 
4.0 
STATISTICAL CONSIDERATIONS .................................................................................................. 8 
4.1 
Sample Size .................................................................................................................................... 8 
4.2 
Analysis Population ........................................................................................................................ 8 
4.3 
Descriptive Statistics ...................................................................................................................... 8 
4.4 
Handling of Missing Values ........................................................................................................... 8 
4.5 
Adjustment for Multiplicity ............................................................................................................ 9 
4.6 
Software for Analyses .................................................................................................................... 9 
5.0 
DATA SUMMARIES ......................................................................................................................... 9 
5.1 
Accrual and Participant Characteristics .......................................................................................... 9 
5.2 
Medical and Ophthalmic History ................................................................................................... 9 
5.3 
Analysis of Protocol Compliance ................................................................................................... 9 
6.0 
TREATMENT ................................................................................................................................ 10 
7.0 
PRIMARY OUTCOMES ANALYSIS ................................................................................................ 10 
8.0 
SECONDARY OUTCOMES ANALYSIS ............................................................................................ 11 
8.1 
Adverse Events (AEs) .................................................................................................................. 11 
8.2 
Retinal Capillary Hemangioma(s) (RCH) .................................................................................... 11 
8.3 
Electronic Visual Acuity (EVA) .................................................................................................. 12 
9.0 
SAFETY ANALYSIS ....................................................................................................................... 12 
9.1 
Natural Progressions of the Disease ............................................................................................. 12 
9.2 
Post-Injection Evaluation ............................................................................................................. 12 
9.3 
Intraocular Pressure (IOP) ............................................................................................................ 13 
9.4 
EVA .............................................................................................................................................. 13 
9.5 
Other Ophthalmologic Assessments ............................................................................................. 13 
9.6 
Laboratory Assessments ............................................................................................................... 13 
9.7 
Treatment Discontinuation and Participant Withdrawal .............................................................. 13 
10.0 
QUALITY ASSURANCE PLANS ..................................................................................................... 13 
11.0 
REFERENCES ............................................................................................................................... 14 
12.0 
MOCK SHELLS ............................................................................................................................. 15 
12.1 Protocol Compliance .................................................................................................................... 15 
12.2 Primary Outcome Analysis ........................................................................................................... 16 


ER-VHL SAP 
November 6, 2017 
 
TABLE OF CONTENTS (CONTINUED) 
Version 1.0 
Confidential 
Page ii 
12.3 Secondary Outcome Analysis ....................................................................................................... 17 
12.4 Safety Analysis ............................................................................................................................. 21 
12.5 Listings ......................................................................................................................................... 24 
 
LIST OF TABLES 
 
Table 1: Missed Study Procedures .............................................................................................................................. 15 
Table 2: Missed and Out of Window Study Visits ...................................................................................................... 15 
Table 3: Summary of Adverse Events through Week 52 ............................................................................................. 16 
Table 4: Adverse Events through Week 52 by MedDRA System Organ Class........................................................... 17 
Table 5: Summary of Adverse Events through Week 104 ........................................................................................... 17 
Table 6: Adverse Events through Week 104 by MedDRA System Organ Class......................................................... 17 
Table 7: Analysis of Secondary Outcomes Relating to RCH ...................................................................................... 18 
Table 8: Analysis of Secondary Outcome of EVA ...................................................................................................... 20 
Table 9: Summary of Post-Injection Evaluations ........................................................................................................ 21 
Table 10: Summary of IOP Over Time ....................................................................................................................... 22 
Table 11: Summary of EVA Total Letters Read Over Time ....................................................................................... 24 
 
 


ER-VHL SAP 
November 6, 2017 
Version 1.0 
Confidential 
Page 1 
1.0 
INTRODUCTION 
This statistical analysis plan (SAP) provides the proposed analyses for ER-VHL protocol titled  
“A Phase I/II Trial for Intravitreous Treatment of Severe Ocular Von Hippel-Lindau Disease Using 
a Combination of the PDGF Antagonist E10030 and the VEGF Antagonist Ranibizumab”.  
This document contains eleven sections: (1) background of the study (2) data sources for analyses, 
(3) an overview of the study design, (4) statistical considerations, (5) baseline and protocol 
compliance summaries, (6) statistical analysis for the primary outcome, (7) statistical analyses for 
secondary outcomes, (8) review of safety analyses, (9) quality assurance plan, (10) references, and 
(11) mock shells. This document is based on version 5.0 of the protocol dated October 2, 2017. 
1.1 
VHL Disease 
Von Hippel-Lindau (VHL) disease is an autosomal dominant heritable disorder in which multiple 
benign and malignant neoplasms and cysts of specific histopathologies develop in the kidney, 
adrenal gland, pancreas, brain, spinal cord, eye, inner ear, epididymis and broad ligament.  
The disease affects about 7,000 individuals in the United States. Retinal capillary hemangiomas 
(RCH) are the most common and often the earliest manifestation of VHL disease and may lead to 
significant vision loss. In some such eyes, inexorable progression of RCH leads to blindness and 
phthisis bulbi despite aggressive treatment. Levels of vascular endothelial growth factor (VEGF), 
a potent mediator of angiogenesis and vascular permeability, have been shown to be elevated in 
multiple cell types deficient in the VHL protein (pVHL). Platelet-derived growth factor (PDGF), 
which has an important role in stabilization of immature new vessels during angiogenesis, is 
upregulated in pVHL-defective cell lines and expressed in other pVHL-defective tumors.  
Anti-VEGF therapy alone had no beneficial effect on ocular VHL disease in two previous phase 1 
studies. The objective of this study is to investigate the safety and possible efficacy of combination 
investigational treatment with serial intravitreal injections of E10030, a PDGF-B antagonist, and 
ranibizumab, a VEGF-A antagonist, in participants with severe ocular VHL disease. 


ER-VHL SAP 
November 6, 2017 
Version 1.0 
Confidential 
Page 2 
2.0 
DATA SOURCE 
Most of the data are collected using National Eye Institute’s (NEI) electronic data capture system 
(Electronic Medical Record [EMR]) and stored in EMR, the Clinical Research Information System 
(CRIS) and the Coordinating Center’s secure database. Additional outcome data not captured in 
EMR will be provided to the Coordinating Center in Excel spreadsheet or other formats as 
applicable. All individual data will remain confidential. 
3.0 
GENERAL REVIEW OF STUDY DESIGN 
3.1 
Study Design 
The ER-VHL study is a phase I/II, single-center, prospective, open label, non-randomized, 
uncontrolled, single group trial investigating the safety and potential efficacy of combined 
treatment of severe ocular VHL disease with serial intravitreal injections of E10030 and 
ranibizumab. 
The study will require a minimum of 14 visits (baseline and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 52, 
60, 72, 84 and 104). All visits must be conducted within a window of ± seven days from the target 
day through Week 52 and ± 30 days thereafter. Prior to treatment at each visit, the participant will 
undergo an AE assessment, concomitant medication review, vital sign check and ophthalmic 
evaluation. 
A single study eye in each participant will receive combination treatment consisting of intravitreal 
injections of E10030 (1.5 mg in 0.05 mL) and ranibizumab (0.5 mg in 0.05 mL) (given as separate 
injections during the same procedure, meaning that participants will receive two intravitreal 
injections per visit) every four weeks from baseline through Week 16 (totaling five treatments) 
and then every eight weeks through Week 48 (totaling nine treatments from baseline). The primary 
endpoint will be assessed by tabulation of AEs reported through Week 52. Starting after Week 52, 
participants may return for additional visits in the second year of the trial, as often as every  
4 weeks, for evaluation and for administration of standard of care therapies, at investigator 
discretion; all participants will be seen at Weeks 60, 72, 84 and 104. No further administration of 
investigational product will occur after the Week 48 visit.  


ER-VHL SAP 
November 6, 2017 
Version 1.0 
Confidential 
Page 3 
Participants will be monitored at each visit for injection-related complications such as 
endophthalmitis, retinal tear/detachment, intraocular hemorrhage, cataract and glaucoma and for 
any progression of ocular VHL disease; participants who develop such complications may be 
discontinued from receiving the combination treatment. They will also be monitored at each visit 
for intraocular inflammation (as assessed by presence of anterior chamber or vitreous cell on 
ophthalmoscopy). 
Concomitant therapies for non-ocular conditions are allowed without restriction. If systemic 
treatment with either anti-VEGF or anti-PDGF therapy is required, interruption or discontinuation 
of combination investigational treatment will be considered and discussed with other treating 
physicians. Any participant who discontinue study treatment will be asked to return for all future 
study visits.  
Standard care therapies for VHL disease, including laser photocoagulation, cryotherapy, 
photodynamic therapy, surgery, ocular radiation and any medication use associated with these 
treatments (such as use of systemic corticosteroids to minimize exudation from RCH undergoing 
ablative treatment) will be considered for significant clinical worsening at any time during the 
study, for clinical improvement at any time starting at Week 16 (as in a case where clinical 
improvement makes an eye more amenable to ablative or surgical treatment), and without 
restriction starting at Week 40 (in anticipation of unavailability of investigational product after 
Week 48). 
3.2 
Study Objective 
The objective of this study is to investigate the safety and possible efficacy of combination 
investigational treatment with serial intravitreal injections of E10030, a PDGF-B antagonist and 
ranibizumab, a VEGF-A antagonist, in participants with severe ocular VHL disease. 
3.3 
Study Population 
Three participants with severe ocular VHL disease who meet the eligibility criteria will receive 
the combination investigational treatment in one eye and will be followed for 104 weeks. Inclusion 
and exclusion criteria are listed below. 


ER-VHL SAP 
November 6, 2017 
Version 1.0 
Confidential 
Page 4 
3.3.1 Inclusion Criteria 
1. Participant must understand and sign the informed consent. 
2. Participant must be 18 years of age or older. 
3. Participant must have a diagnosis of VHL disease. In accordance with established 
criteria for diagnosis,1,2 any one of the following will be considered sufficient evidence 
that VHL disease is present: 
• 
A family history of VHL disease plus one or more of the following lesions: 
RCH, spinal or cerebellar hemangioblastoma, pheochromocytoma, multiple 
pancreatic cysts, epididymal or broad ligament cystadenomas, multiple renal 
cysts or renal cell carcinoma before age 60 years. 
• 
Presence of two or more hemangioblastomas of the retina or brain or a single 
hemangioblastoma in association with a visceral manifestation such as kidney 
or pancreatic cysts; renal cell carcinoma; adrenal or extra-adrenal 
pheochromocytomas; endolymphatic sac tumors; papillary cystadenomas of 
the epididymis or broad ligament; or neuroendocrine tumors of the pancreas. 
• 
Presence of a known disease-causing germline mutation in the VHL gene. 
4. Any female participant of childbearing potential must not be pregnant or  
breast-feeding, must have a negative pregnancy test at screening and must be willing 
to undergo pregnancy testing immediately prior to each treatment. 
5. Any female participant of childbearing potential and any male participant able to father 
children must have (or have a partner who has) had a hysterectomy or vasectomy, be 
completely abstinent from intercourse or must agree to practice two effective methods 
of contraception throughout the course of the study and for at least two months 
following the last administration of combination investigational treatment.  
Acceptable methods of contraception include: 
• hormonal contraception (i.e., birth control pills, injected hormones, dermal 
patch or vaginal ring), 
• intrauterine device, 
• barrier methods (diaphragm or condom) with spermicide, or 
• surgical sterilization (hysterectomy, tubal ligation or vasectomy). 


ER-VHL SAP 
November 6, 2017 
Version 1.0 
Confidential 
Page 5 
3.3.2 Exclusion Criteria 
1. Participant has a history or evidence of significant cardiac disease (for example, use of 
cardiac medications aside from agents to control blood pressure, past acute coronary 
syndrome, past myocardial infarction, past revascularization procedure or arrhythmias 
requiring past or present treatment). 
2. Participant 
has 
a 
history 
of 
stroke 
or 
transient 
ischemic 
attack.  
Note: cerebrovascular manifestations and/or complications of central nervous system 
hemangioblastomas are not exclusionary, in the absence of past stroke or transient 
ischemic attack. 
3. Participant has used systemic medication with significant anti-VEGF or anti-PDGF 
activity within 30 days of study entry or expects use of such a medication within  
12 months of study entry. 
4. Participant is medically unable to comply with study procedures or follow-up in the 
judgment of the investigator. 
5. Participant has a diagnosis of diabetic mellitus (type 1 or type 2). Any one of the 
following will be considered sufficient evidence that diabetes is present: 
• Current regular use of insulin for the treatment of diabetes, 
• Current regular use of oral anti-hyperglycemia agents for the treatment of 
diabetes, 
• Hemoglobin A1C of ≥ 6.5%, or 
• Documented diabetes by ADA and/or WHO criteria. 
3.4 
Study Eye Eligibility Criteria 
The participant must have at least one eye meeting all inclusion criteria and none of the exclusion 
criteria listed below. 
3.4.1  Inclusion Criteria 
1. Participant has at least one RCH secondary to VHL disease in the study eye that fulfills 
the following criteria: 


ER-VHL SAP 
November 6, 2017 
Version 1.0 
Confidential 
Page 6 
a. The RCH must exhibit growth potential with consequent threat to vision. 
Growth potential with consequent threat to vision is defined by AT LEAST ONE 
of the following: 
i. Associated intra- or sub-retinal exudation or lipid deposition that, in the 
judgment of the investigator, reflects ongoing vascular incompetence and is 
not solely reflective of residual changes following previous treatment or 
solely secondary to coexistent retinal traction. 
ii. Increased size of the tumor compared to a previous time point as assessed 
by fundus photography or fluorescein angiography (FA). 
iii. Associated intra-, sub- or pre-retinal hemorrhage not secondary to previous 
treatment, as assessed by fundus photography or FA. 
iv. The presence of dilated and/or tortuous feeder vessels. 
v. Vitreous cell or haze indicative of vitreous exudation, in the absence of 
other ocular features potentially responsible for such findings. 
b. The RCH, in the judgment of the investigator, is NOT readily treatable using 
thermal laser because of its size, posterior location, poor previous response to 
conventional therapy, association with significant exudation, epiretinal 
proliferation, associated vascular abnormalities such as vascular proliferation or 
diffusely incompetent retinal vessels, or other factors predictive of a poor response 
to standard of care approaches. 
2. The study eye must have clarity of ocular media and degree of pupil dilation sufficient 
to permit adequate fundus photography. 
3.4.2 Exclusion Criteria 
1. The study eye has present or chronic ocular or periocular infection (including any 
history of ocular herpes zoster). 
2. The study eye has chronic glaucoma; OR has received anti-glaucoma medication at any 
time within 90 days of study entry; OR has significant ocular hypertension, defined as 
documented intraocular pressure of ≥ 28 mmHg on any occasion in the absence of self-
limited acute glaucoma, OR ≥ 24 mmHg on at least two occasions in the absence of 
self-limited acute glaucoma. Note: History of self-limited acute glaucoma in a study 


ER-VHL SAP 
November 6, 2017 
Version 1.0 
Confidential 
Page 7 
eye, if now resolved and not expected to recur, is not exclusionary. History of glaucoma 
or ocular hypertension in the fellow eye, if not felt to significantly impact risk of 
glaucoma in the study eye, is not exclusionary. 
3. The study eye has undergone any surgical procedure within 60 days prior to study entry 
(inclusive of cryotherapy or thermal laser). 
4. The study eye has a history of intravitreal injection of an anti-VEGF agent (such as 
bevacizumab, ranibizumab or aflibercept) within 42 days prior to study entry. 
5. The study eye has a history of intravitreal or periocular injection of long-acting 
corticosteroids (such as triamcinolone acetonide) within 90 days of study entry or 
history of any sustained-release ocular drug delivery device with reasonable 
expectation of residual activity in the study eye. 
3.4.3 Choice of Study Eye in Cases of Bilateral Eligibility 
If both eyes of a participant meet the eligibility criteria, the investigator will choose to enroll one 
eye in consultation with the participant. 
3.5 
Outcome Measures 
3.5.1 Primary Study Outcome 
The primary outcome for the study is the safety of the combination investigational treatment, 
assessed by tabulation of adverse events (AEs) reported through Week 52. 
3.5.2 Secondary Study Outcomes 
Secondary outcomes include tabulation of AEs reported through Week 104 and the following 
measures in the study eye at Weeks 52 and 104: 
• the proportion of participants experiencing reduction in size of at least one RCH in the 
absence of other ablative treatment (assessed by fundus photography and FA); 
• the proportion of participants experiencing moderate vision loss (defined as a loss of  
≥ 15 letters from baseline on electronic visual acuity [EVA] testing); 
• mean change in visual acuity; 
• change in size of RCH (measured by fundus photography and FA); 


ER-VHL SAP 
November 6, 2017 
Version 1.0 
Confidential 
Page 8 
• change in exudation (measured by fundus photography, Optical Coherence Tomography 
[OCT] and FA); 
• change in epiretinal proliferation, fibrosis or retinal traction (assessed by OCT and fundus 
photography); 
• the proportion of participants undergoing ablative treatment of RCH or ocular surgery; 
• the proportion of participants with successful ablative treatment of RCH; and 
• the proportion of participants with appearance of one or more new RCH. 
4.0 
STATISTICAL CONSIDERATIONS 
Since this is a proof-of-principle study, all analyses will be exploratory in nature. 
4.1 
Sample Size 
The accrual goal is three participants. This is an appropriate sample size for the study objectives, 
since this preliminary investigation will not attempt to definitively determine the safety or efficacy 
of this treatment. 
4.2 
Analysis Population 
All enrolled participants who received at least one study treatment injection, regardless of whether 
they discontinued treatment prior to Week 52, will be included in the analysis population.  
All summaries and listings will be based on the primary analysis population. 
4.3 
Descriptive Statistics 
For continuous parameters, descriptive statistics will include number of observations, mean, 
standard deviation, median, minimum and maximum. For categorical parameters, frequency and 
percentage of participants will be summarized; percentages will be based on the number of 
participants in the primary analysis population. 
4.4 
Handling of Missing Values 
In general, missing observations will be excluded from analyses. 


ER-VHL SAP 
November 6, 2017 
Version 1.0 
Confidential 
Page 9 
4.5 
Adjustment for Multiplicity 
Since all analyses are exploratory in nature, no adjustments will be made for multiplicity in any 
statistical analyses performed. 
4.6 
Software for Analyses 
Statistical analyses will be performed using SAS version 9.4 or higher or R v3.3.1 or higher.  
All tables, listings and figures presented in the analysis will be created using either SAS v9.4 or 
Rv3.3.1 or higher. 
5.0 
DATA SUMMARIES 
5.1 
Accrual and Participant Characteristics 
Demographic data collected include baseline age, sex, race and ethnicity. Demographic data will 
be listed by participant and will include study registration date and information on study eye. 
5.2 
Medical and Ophthalmic History 
A listing of history of medical and ophthalmic conditions as well as any physical examination 
findings at baseline will be provided. 
5.3 
Analysis of Protocol Compliance 
Listings of participant-specific and non-participant-specific protocol deviations and unanticipated 
problems will be presented. 
Study Procedure Deviations 
This table will present the number of procedures not completed, the expected number of 
procedures completed, and the percentage of procedures missed for each individual participant and 
collectively for all participants, cumulatively throughout the study (Table 1). Number of 
procedures not completed is defined when the site reports a missed procedure or when the protcol 
monitors note missed procedures at a site, and will be presented as a sum. Expected number of 
procedures completed is defined based on the study flowsheet included in the protocol, and will 
also be presented as a sum. Percentage of procedures missed will be calculated as follows: 
(N procedures not completed / N expected procedures completed)*100 


ER-VHL SAP 
November 6, 2017 
Version 1.0 
Confidential 
Page 10 
The table will flag occurrences where collectively or individually, participants missed more than 
15% of the expected procedures if the number of expected procedures is > 16. Otherwise, if the 
number of expected procedures is 16 or less, the table will flag occurrences where collectively or 
individually, participants missed two or more procedures. 
Visit Schedule Deviations 
This table will present the number of expected visits, number of missed study visits, the percentage 
of missed study visits, the number of out of window visits, and the percentage of out of window 
visits for each individual participant and collectively for all participants, cumulatively throughout 
the study (Table 2). Number of expected, missed and out of window study visits will be calculated 
from the study flowsheet and will all be presented as sums. The percentage of missed study visits 
will be calculated as: 
(N visits missed / N expected visits)*100 
Similarily, the percentage of out of window study visits will be calculated as: 
(N visits out of window / N expected visits)*100 
If the number of expected visits is > 16, then the table will flag occurrences where collectively or 
individually participants missed more than 15% of the expected visits; similarly, the table will flag 
occurrences where collectively or individually participants completed more than 15% of the 
expected visits outside of the window. 
Otherwise, if the number of expected visits is 16 or less, then the table will flag occurrences where 
collectively or individually participants mised or completed out of window two or more visits. 
6.0 
TREATMENT 
Information related to injections administered at each visit will be listed. 
7.0 
PRIMARY OUTCOMES ANALYSIS 
The analysis of primary outcome will be considered exploratory; no formal statistical analysis will 
be performed. 
All treatment-emergent ocular and systemic AEs reported through Week 52 will be summarized. 
Treatment-emergent AEs are those events occurring at the time of or after administration of first 


ER-VHL SAP 
November 6, 2017 
Version 1.0 
Confidential 
Page 11 
dose of study drug. Frequency and percentage of particpants, total number of AEs and number of 
AEs experienced by each participant will be summarized by seriousness, severity of the AE, 
relatedness to the study treatment and Medical Dictionary for Regulatory Activities (MedDRA) 
System Organ Class (SOC); tabulations will also be provided by timing of occurrence of AEs 
(while on treatment vs. after discontinuaion of treatment) (Tables 3 and 4). 
8.0 
SECONDARY OUTCOMES ANALYSIS 
The analysis of secondary outcomes will be considered exploratory. Therefore, no formal 
statistical analysis will be performed. In addition to the data summaries detailed below, exploratory 
plots showing values over time for relevant measurements may be presented. 
8.1 
Adverse Events (AEs) 
All ocular and systemic AEs reported through Week 104 will be tabulated similar to the primary 
outcome (Tables 5 and 6). 
8.2 
Retinal Capillary Hemangioma(s) (RCH) 
The following will be assessed as secondary outcomes at Weeks 52 and 104 compared to baseline; 
information will also be presented for each participant separately (Table 7). 
• Frequency and percentage of participants with reduction in size of at least one RCH, in the 
absence of other ablative treatment assessed by fundus photography and FA; 
• Frequency and percentage of participants with increase, decrease, mixed effects and no 
change in size of RCH measured by fundus photography and FA; 
• Frequency and percentage of participants with increase, decrease, mixed effects and no 
change in exudation measured by fundus photography, OCT and FA; 
• Frequency and percentage of participants with increase, decrease, mixed effects and no 
change in epiretinal proliferation, fibrosis or retinal traction assessed by OCT and fundus 
photography; 
• Frequency and percentage of participants undergoing ablative treatment of RCH or ocular 
surgery; 
• Frequency and percentage of participants with successful ablative treatment of RCH; 
• Frequency and percentage of participants with appearance of one or more new RCH. 


ER-VHL SAP 
November 6, 2017 
Version 1.0 
Confidential 
Page 12 
8.3 
Electronic Visual Acuity (EVA) 
Binocular visual acuity measures and visual acuity measures for each eye will be obtained using 
an EVA algorithm. EVA with manifest refraction will be performed if a change in EVA  
≥ 10 E-ETDRS letters (≥ 0.20 logMAR) since previous visit is observed. 
Summary statistics for change in total letters read at Weeks 52 and 104 compared to baseline will 
be presented. Frequency and percentage of participants with moderate vision loss at Weeks 52 and 
104, defined as loss of ≥ 15 letters from baseline, will also be summarized (Table 8).  
Values from assessments performed with manifest refraction will be used for the analysis if 
available; otherwise, values from assessments performed without manifest refraction will be used. 
9.0 
SAFETY ANALYSIS 
In addition to the data summaries detailed below, exploratory plots showing values over time for 
relevant measurements may be presented. 
9.1 
Natural Progressions of the Disease 
All natural progressions of the disease reported through Week 104 will be listed. 
9.2 
Post-Injection Evaluation 
Intraocular pressure (IOP) in the injected eye is measured by Tono-Pen within 20 minutes after 
injection. Post-injection IOP and change from pre-injection measurement will be summarized for 
each visit (Table 10). Frequency and percentage of participants with the following will be 
presented for each visit: 
• > 24 mmHg IOP after injection in the treated eye (Table 10); 
• Severe pain, absence of hand-motion vision or absence of perfusion of the retinal arterioles 
following an injection (Table 9); 
• Intraocular inflammation as assessed by the presence of anterior chamber or vitreous cell 
on ophthalmoscopy by grade (Table 9); and 
• Any other complications following an injection (Table 9). 


ER-VHL SAP 
November 6, 2017 
Version 1.0 
Confidential 
Page 13 
9.3 
Intraocular Pressure (IOP) 
Summary statistics of baseline and change from baseline in IOP at each visit will be presented 
(Table 10). If study treatment is administered at a visit, then the pre-injection value will be used in 
the summaries. Post-injection values are summarized as described in Section 9.2. 
9.4 
EVA 
Summary statistics of baseline and change from baseline in total letters read at each visit will be 
presented (Table 11). 
9.5 
Other Ophthalmologic Assessments 
All ophthalmologic data collected will be descriptively summarized. If appropriate, exploratory 
plots may be presented. 
If sufficient data are available, frequency and percentage of participants who meet the definition 
of clinical improvement and time to clinical improvement will also be summarized; otherwise, the 
data will be listed. 
9.6 
Laboratory Assessments 
Laboratory testing includes a complete blood count (CBC), hemoglobin A1C and acute care, 
hepatic and mineral panels, and may be completed within one month (31 days) of the baseline 
visit. Laboratory testing excluding hemoglobin A1C will also occur at Weeks 16 and 104. 
A listing of all laboratory assessments and any abnormalities noted will be presented. 
9.7 
Treatment Discontinuation and Participant Withdrawal 
Participants who discontinue treatment early or withdraw from the study, including timing and 
reason for treatment discontinuation or withdrawal, will be listed. 
10.0 
QUALITY ASSURANCE PLANS 
To ensure accurate, reliable study results, two statisticians will separately analyze and compare the 
study outcomes. All SAS or R code use to generate primary and secondary outcomes  
will undergo a code validation by an independent statistician or SAS programmer.  


ER-VHL SAP 
November 6, 2017 
Version 1.0 
Confidential 
Page 14 
Documentation related to code validation audits will be maintained on file at the Coordinating 
Center. 
11.0 
REFERENCES 
1. Schimke RN, Collins DL, Stolle CA. Von Hippel-Lindau Syndrome. In: Pagon RA, Bird 
TD, Dolan CR, eds. Gene Reviews. 2010/03/20 ed. Seattle: University of Washington; 
1993. 
2. Melmon KL, Rosen SW. Lindau's disease. Review of the literature and study of a large 
kindred. Am J Med 1964;36:595-617. 


ER-VHL SAP 
November 6, 2017 
Version 1.0 
Confidential 
Page 15 
12.0 
MOCK SHELLS 
12.1 
Protocol Compliance 
Table 1: Missed Study Procedures 
Participant 
Number 
Number of Procedures 
Not Completed1 
Expected Number of 
Procedures Completed2 
Percentage of Procedures 
Missed (%) 
xxx 
xx 
xx 
x.x 
xxx 
xx 
xx 
x.x 
xxx 
xx 
xx 
x.x 
Total 
xx 
xx 
x.x 
1Procedures not completed are defined when the site reports a missed procedure or when the protocol monitors note missed 
procedures at a site visit. 
2Expected number of procedures is defined based on the study flowsheet included in the protocol. 
Highlighted cells indicate percentage of missed procedures above the protocol-defined threshold of 15%. 
Table 2: Missed and Out of Window Study Visits 
Participant 
Number 
Number of 
Missed 
Study 
Visits 
Number of 
Out 
of Window 
Study Visits 
Expected 
Number of 
Follow-up 
Visits 
Percentage 
of 
Visits 
Missed1 
Percentage 
of 
Visits Out 
of Window1 
Study Visits 
Missed or 
Out 
of Window 
xxx 
xx 
xx 
xx 
x.x 
x.x 
xxx 
xxx 
xx 
xx 
xx 
x.x 
x.x 
xxx 
xxx 
xx 
xx 
xx 
x.x 
x.x 
xxx 
Total 
xx 
xx 
xx 
x.x 
x.x 
xxx 
1The numbers in these cells reference the percentage of missed or out of window visits for all study participants because the 
protocol references the overall study visits threshold at 15% of missed or out of window study visits. 
Highlighted cells indicate percentage of missed or out of window visits above the protocol-defined threshold of 15%. 


ER-VHL SAP 
November 6, 2017 
Version 1.0 
Confidential 
Page 16 
12.2 
Primary Outcome Analysis 
Table 3: Summary of Adverse Events through Week 52 
 
Number of Events  
N 
While on Treatment 
After Discontinuation of 
Treatment 
Total 
Participant ID 
Participants 
with Events  
N (%)1 
Number 
of Events 
N 
Participants 
with Events  
N (%)1 
Number of 
Events 
N 
Participants 
with Events  
N (%)1 
Number of 
Events 
N 
XXX 
XXX 
XXX 
All AEs 
x 
x 
x 
x (x%) 
x 
x (x%) 
x 
x (x%) 
x 
Serious Adverse Events 
x 
x 
x 
x (x%) 
x 
x (x%) 
x 
x (x%) 
x 
 
 
 
 
 
 
 
 
 
 
Severity 
x 
x 
x 
x (x%) 
x 
x (x%) 
x 
x (x%) 
x 
 
Mild 
x 
x 
x 
x (x%) 
x 
x (x%) 
x 
x (x%) 
x 
 
Moderate 
x 
x 
x 
x (x%) 
x 
x (x%) 
x 
x (x%) 
x 
 
Severe 
x 
x 
x 
x (x%) 
x 
x (x%) 
x 
x (x%) 
x 
 
Life-threatening 
x 
x 
x 
x (x%) 
x 
x (x%) 
x 
x (x%) 
x 
 
Death 
x 
x 
x 
x (x%) 
x 
x (x%) 
x 
x (x%) 
x 
 
 
 
 
 
 
 
 
 
 
Ocular Specification 
x 
x 
x 
x (x%) 
x 
x (x%) 
x 
x (x%) 
x 
 
Non-ocular 
x 
x 
x 
x (x%) 
x 
x (x%) 
x 
x (x%) 
x 
 
Study Eye 
x 
x 
x 
x (x%) 
x 
x (x%) 
x 
x (x%) 
x 
 
Non-Study Eye 
x 
x 
x 
x (x%) 
x 
x (x%) 
x 
x (x%) 
x 
 
 
 
 
 
 
 
 
 
 
Relation to Treatment 
x 
x 
x 
x (x%) 
x 
x (x%) 
x 
x (x%) 
x 
 
Related 
x 
x 
x 
x (x%) 
x 
x (x%) 
x 
x (x%) 
x 
 
Not Related 
x 
x 
x 
x (x%) 
x 
x (x%) 
x 
x (x%) 
x 
1Denominators are the number of participants in the primary analysis population. 
 
 
 


ER-VHL SAP 
November 6, 2017 
Version 1.0 
Confidential 
Page 17 
Table 4: Adverse Events through Week 52 by MedDRA System Organ Class 
 
Number of Events  
N 
While on Treatment 
After Discontinuation of 
Treatment 
Total 
Participant ID 
Participants 
with Events  
N (%)1 
Number 
of Events 
N 
Participants 
with Events  
N (%)1 
Number 
of Events 
N 
Participants 
with Events  
N (%)1 
Number 
of Events 
N 
XXX 
XXX 
XXX 
System Organ Class 1 
x 
x 
x 
x (x%) 
x 
x (x%) 
x 
x (x%) 
x 
System Organ Class 2 
x 
x 
x 
x (x%) 
x 
x (x%) 
x 
x (x%) 
x 
System Organ Class 3 
x 
x 
x 
x (x%) 
x 
x (x%) 
x 
x (x%) 
x 
... 
x 
x 
x 
x (x%) 
x 
x (x%) 
x 
x (x%) 
x 
... 
x 
x 
x 
x (x%) 
x 
x (x%) 
x 
x (x%) 
x 
1Denominators are the number of participants in the primary analysis population. 
 
12.3 
Secondary Outcome Analysis 
Table 5: Summary of Adverse Events through Week 104 
This table will be similar to Table 3. 
Table 6: Adverse Events through Week 104 by MedDRA System Organ Class 
This table will be similar to Table 4. 


ER-VHL SAP 
November 6, 2017 
Version 1.0 
Confidential 
Page 18 
Table 7: Analysis of Secondary Outcomes Relating to RCH
 
 
Week 52 
Week 104 
Participant ID 
Total 
N (%)1 
Participant ID 
Total 
N (%)1 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
Reduction in Size of at 
least One RCH in the 
Absence of Other 
Ablative Treatment 
Yes/No 
Yes/No 
Yes/No 
x (x%) 
Yes/No 
Yes/No 
Yes/No 
x (x%) 
 
 
 
 
 
 
 
 
 
Change in Size of RCH 
from Baseline 
xxx 
xxx 
xxx 
 
xxx 
xxx 
xxx 
 
      Increase 
 
 
 
x (x%) 
 
 
 
x (x%) 
      Decrease 
 
 
 
x (x%) 
 
 
 
x (x%) 
      Mixed Effects 
 
 
 
x (x%) 
 
 
 
x (x%) 
      No Change 
 
 
 
x (x%) 
 
 
 
x (x%) 
 
 
 
 
 
 
 
 
 
Change in Exudation 
from Baseline 
xxx 
xxx 
xxx 
 
xxx 
xxx 
xxx 
 
      Increase 
 
 
 
x (x%) 
 
 
 
x (x%) 
      Decrease 
 
 
 
x (x%) 
 
 
 
x (x%) 
      Mixed Effects 
 
 
 
x (x%) 
 
 
 
x (x%) 
      No Change 
 
 
 
x (x%) 
 
 
 
x (x%) 
 
 
 
 
 
 
 
 
 
Change in Epiretinal 
Proliferation/ 
Fibrosis/Retinal Traction 
from Baseline 
xxx 
xxx 
xxx 
 
xxx 
xxx 
xxx 
 
      Increase 
 
 
 
x (x%) 
 
 
 
x (x%) 
      Decrease 
 
 
 
x (x%) 
 
 
 
x (x%) 
      Mixed Effects 
 
 
 
x (x%) 
 
 
 
 
      No Change 
 
 
 
x (x%) 
 
 
 
x (x%) 


ER-VHL SAP 
 
 
 
November 6, 2017 
 
Table 7: Analysis of Secondary Outcomes Relating to RCH (Continued) 
Version 1.0 
Confidential 
Page 19 
 
Week 52 
Week 104 
Participant ID 
Total 
N (%)1 
Participant ID 
Total 
N (%)1 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
Undergoing Ablative 
Treatment of RCH or 
Ocular Surgery 
Yes/No 
Yes/No 
Yes/No 
x (x%) 
Yes/No 
Yes/No 
Yes/No 
x (x%) 
 
 
 
 
 
 
 
 
 
Successful Ablative 
Treatment of RCH 
Yes/No 
Yes/No 
Yes/No 
x (x%) 
Yes/No 
Yes/No 
Yes/No 
x (x%) 
 
 
 
 
 
 
 
 
 
Appearance of One or 
More New RCH 
Yes/No 
Yes/No 
Yes/No 
x (x%) 
Yes/No 
Yes/No 
Yes/No 
x (x%) 
1Percentages are based on the number of participants in the primary analysis population. 


ER-VHL SAP 
November 6, 2017 
Version 1.0 
Confidential 
Page 20 
Table 8: Analysis of Secondary Outcome of EVA 
 
Baseline 
Change from Baseline 
Week 52 
Week 104 
EVA Total Letters Read 
 
 
 
 N 
x 
x 
x 
 Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 Median 
x 
x 
x 
 Range (Min, Max) 
x, x 
x, x 
x, x 
 
 
 
 
Participants with Moderate Vision Loss 
(Loss of ≥ 15 Letters Read from Baseline), 
N (%)1 
 
x (x%) 
x (x%) 
1Denominators are the number of participants in the primary analysis population. 


ER-VHL SAP 
November 6, 2017 
Version 1.0 
Confidential 
Page 21 
12.4 
Safety Analysis 
Table 9: Summary of Post-Injection Evaluations 
 
Anterior Chamber Cells 
N (%)1 
Vitreous Cells 
N (%)1 
Severe Pain, Absence of 
Hand Motion Vision or 
Absence of Perfusion of 
the Retinal Arterioles 
N (%)1 
Any Other  
Post-Injection 
Complications 
N (%)1 
Grade 
Grade 
0, 0.5 or T 
1-2 
3 
4 
0, T 
1-2 
3 
4 
At least Once 
During the Study 
 
 
 
 
 
 
 
 
 
 
 Study Eye 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 Non-Study Eye 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
 
 
 
 
 
 
 
 
 
 
 Study Eye 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 Non-Study Eye 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week 4 
 
 
 
 
 
 
 
 
 
 
 Study Eye 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 Non-Study Eye 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week XX 
 
 
 
 
 
 
 
 
 
 
 Study Eye 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 Non-Study Eye 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week 104 
 
 
 
 
 
 
 
 
 
 
 Study Eye 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
 
 Non-Study Eye 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
 
1Denominators are the number of participants in the primary analysis population. 


ER - VHL SAP 
November 6, 2017 
Version 1.0 
Confidential 
Page 22 
Table 10: Summary of IOP Over Time 
 
Pre-Injection IOP Measurements 
(mmHg) 
Post-Injection IOP 
Measurements 
(mmHg) 
Pre-Injection IOP 
Change from 
Baseline in Pre-
Injection 
Measurements 
Study Eye 
Study 
Eye 
Non-Study 
Eye 
Study 
Eye 
Non-Study 
Eye 
Post-
Injection 
IOP 
Change from 
Pre-Injection 
Measurement 
Baseline 
 
 
 
 
 
 
 N 
x 
x 
 
 
x 
x 
 Mean (SD) 
x.x (x.x) 
x.x (x.x) 
 
 
x.x (x.x) 
x.x (x.x) 
 Median 
x.x 
x.x 
 
 
x.x 
x.x 
 Range (Min, Max) 
x.x, x.x 
x.x, x.x 
 
 
x.x, x.x 
x.x, x.x 
 IOP > 24 mmHg, N 
(%)1 
 
 
 
 
x (x%) 
 
 
 
 
 
 
 
 
Week 4 
 
 
 
 
 
 
 N 
x 
x 
x 
x 
x 
x 
 Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 Median 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 Range (Min, Max) 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
 IOP > 24 mmHg, N 
(%)1 
 
 
 
 
x (x%) 
 
 
 
 
 
 
 
 
Week 8 
 
 
 
 
 
 
 N 
x 
x 
x 
x 
x 
x 
 Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 Median 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 Range (Min, Max) 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
 IOP > 24 mmHg, N 
(%)1 
 
 
 
 
x (x%) 
 
... 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week XX 
 
 
 
 
 
 
 N 
x 
x 
x 
x 
x 
x 
 Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 Median 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 Range (Min, Max) 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
 IOP > 24 mmHg, N 
(%)1 
 
 
 
 
x (x%) 
 
 
 
 
 
 
 
 
 
 


ER - VHL SAP 
November 6, 2017 
Table 10: Summary of IOP Over Time (Continued) 
Version 1.0 
Confidential 
Page 23 
 
Pre-Injection IOP Measurements 
(mmHg) 
Post-Injection IOP 
Measurements 
(mmHg) 
Pre-Injection IOP 
Change from 
Baseline in Pre-
Injection 
Measurements 
Study Eye 
Study 
Eye 
Non-Study 
Eye 
Study 
Eye 
Non-Study 
Eye 
Post-
Injection 
IOP 
Change from 
Pre-Injection 
Measurement 
Week 104 
 
 
 
 
 
 
 N 
x 
x 
x 
x 
 
 
 Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
 
 Median 
x.x 
x.x 
x.x 
x.x 
 
 
 Range (Min, Max) 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
 
 
1Denominators are the number of participants in the primary analysis population. 
 


ER-VHL SAP 
November 6, 2017 
 
Version 1.0 
Confidential 
Page 24 
Table 11: Summary of EVA Total Letters Read Over Time 
 
EVA Total Letters Read 
Change from Baseline  
 
Study Eye 
Non-Study Eye 
Study Eye 
Non-Study Eye 
Baseline 
 
 
 
 
 N 
x 
x 
 
 
 Mean (SD) 
x.x (x.x) 
x.x (x.x) 
 
 
 Median 
x.x 
x.x 
 
 
 Range (Min, Max) 
x.x, x.x 
x.x, x.x 
 
 
 
 
 
 
 
Week 4 
 
 
 
 
 N 
x 
x 
x 
x 
 Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 Median 
x.x 
x.x 
x.x 
x.x 
 Range (Min, Max) 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
 Loss of ≥ 15 Letters, N (%)1 
 
 
x (x%) 
x (x%) 
 
 
 
 
 
... 
 
 
 
 
... 
 
 
 
 
Week XX 
 
 
 
 
 N 
x 
x 
x 
x 
 Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 Median 
x.x 
x.x 
x.x 
x.x 
 Range (Min, Max) 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
 Loss of ≥ 15 Letters, N (%)1 
 
 
x (x%) 
x (x%) 
... 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
Week 104 
 
 
 
 
 N 
x 
x 
x 
x 
 Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 Median 
x.x 
x.x 
x.x 
x.x 
 Range (Min, Max) 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
 Loss of ≥ 15 Letters, N (%)1 
 
 
x (x%) 
x (x%) 
12.5 
Listings 
Listings will be by participant (except for non-participant specific protocol deviations and 
unanticipated problems) and will include all relevant raw data points captured and any relevant 
derived values.