Phase I/IIa, Open-Label, Dose-Escalation Study of Safety and Tolerability of Intravitreal RST-001 in Patients With Advanced Retinitis Pigmentosa (RP)
Phase: PHASE1
Conditions: Advanced Retinitis Pigmentosa
Sponsor: AbbVie

Allergan Confidential
Protocol RST-001-CP-0001 Amendment 4
1
ALLERGAN – CONFIDENTIAL
The following contains confidential, proprietary information
which is the property of Allergan, Inc.
Phase I/IIa, Open-Label, Dose-Escalation Study of 
Safety and Tolerability of Intravitreal RST-001 in 
Patients with Advanced Retinitis Pigmentosa (RP)
Protocol Number:  
RST-001-CP-0001, Amendment 4
Phase:
Phase 1/2a
Name of Investigational Product:
RST-001 (AGN-151597)
Sponsor:
Allergan, Inc.(an AbbVie 
Company)
2525 Dupont Drive
Irvine, California USA
92612
+1-714-246-4500
+1-800-347-4500
Emergency Telephone Number(s):
North America: Tel: +1-973-784-6402
Serious Adverse Event Reporting 
Fax Number(s):
+1-714-796-9504
(Back Up Fax No.: +1-714-246-5295)  
Allergan Medical Monitor
Contact Information:
MD
Tel (office): 
Tel (mobile)
Email:  
The following information can be found on United States FDA Form 1572 and/or study contacts 
page and/or the Trial Master File: Name and contact information of Allergan study personnel and 
Emergency Telephone Numbers; name, address, and statement of qualifications of each 
investigator; name of each subinvestigator working under the supervision of the investigator; 
name and address of each reviewing Institutional Review Board (IRB); US 21 CFR 312.23 
section 6(iii)b.
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INVESTIGATOR SIGNATURE PAGE
Investigator:
I agree to:

Implement and conduct this study diligently and in strict compliance with the protocol, 
good clinical practices and all applicable laws and regulations.

Maintain all information supplied by Allergan in confidence and, when this information 
is submitted to an Institutional Review Board (IRB), Independent Ethics Committee 
(IEC) or another group, it will be submitted with a designation that the material is 
confidential.

Ensure that all persons assisting with the study are adequately informed about the 
protocol, the investigational product(s), and their study-related duties and functions.
I have read this protocol in its entirety and I agree to all aspects.
Investigator Printed Name
Signature
Date
 
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1
Table of Contents
1
Table of Contents..........................................................................................................3
List of Tables ..............................................................................................................................6
List of Figures.............................................................................................................................6
2
Protocol Synopsis .........................................................................................................7
3
Introduction................................................................................................................10
3.1
Background and Rationale..........................................................................................10
3.1.1
Retinitis pigmentosa (RP)...........................................................................................10
3.1.2
Clinical features..........................................................................................................10
3.1.3
Cellular pathology ......................................................................................................10
3.1.4
Pathogenesis...............................................................................................................10
3.1.5
Treatment ...................................................................................................................11
3.2
Adeno-Associated Virus .............................................................................................11
3.3
Recombinant AAV Vectors..........................................................................................11
3.4
Human Clinical Experience with AAV2 Vectors..........................................................11
3.5
RST-001 .....................................................................................................................11
3.6
Nonclinical Studies with RST-001 ..............................................................................12
3.6.1
Pharmacology Studies.................................................................................................12
3.6.2
Toxicology and Biodistribution Studies ......................................................................13
3.6.3
Justification for Human Dose......................................................................................15
3.7
RST-001 Study Rationale: Optogenetic Therapy for Advanced Retinitis Pigmentosa ..15
3.7.1
Immunogenicity of RST-001.......................................................................................16
3.8
Treatment Administration ...........................................................................................16
3.9
Objectives of the Study...............................................................................................16
3.9.1
Primary Objective:......................................................................................................16
3.9.2
Secondary Objectives: ................................................................................................16
3.10
Study conduct and GCP Compliance Statement ..........................................................17
3.11
Risks and Benefits ......................................................................................................17
3.11.1
Potential Risks............................................................................................................17
3.12
Protection from Risks .................................................................................................17
3.13
Provisions for Injury...................................................................................................18
3.14
Potential Benefits........................................................................................................18
3.14.1
Risk Benefit Analysis .................................................................................................18
3.15
Study Overview..........................................................................................................18
3.15.1
Study Design ..............................................................................................................18
3.15.2
Study Population ........................................................................................................20
3.15.3
Eligibility Criteria.......................................................................................................21
3.15.4
Early Discontinuation of Patients................................................................................23
4
Treatments..................................................................................................................24
4.1
Identity of Investigational Product ..............................................................................24
4.2
Dosage and Administration.........................................................................................24
4.3
Method of Assigning Patients to Dose Groups ............................................................24
4.4
Dose Rationale ...........................................................................................................24
4.5
Patient and Investigator Masking ................................................................................25
 
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4.6
Packaging and Labeling..............................................................................................25
4.7
Handling and Storage .................................................................................................25
4.8
Study Treatment Preparation and Administration ........................................................26
4.9
Product Accountability ...............................................................................................26
4.10
Assessment of Compliance .........................................................................................26
4.11
Treatment of RST-001 Overdose.................................................................................26
4.12
Prior and Concomitant Therapy ..................................................................................26
5
Study Assessments and Intravitreal Injection ..............................................................27
5.1
Schedule of Procedures by Visit..................................................................................29
5.1.1
Informed Consent and Patient Privacy ........................................................................29
5.1.2
Screening Visit ...........................................................................................................29
5.1.3
Baseline Visit..............................................................................................................30
5.1.4
Treatment Visit (Day 0) ..............................................................................................31
5.1.5
Post Injection Visit (Day 1).........................................................................................31
5.1.6
Day 7..........................................................................................................................32
5.1.7
Month 1......................................................................................................................32
5.1.8
Month 3......................................................................................................................32
5.1.9
Month 6: Primary Endpoint ........................................................................................33
5.1.10
Month 9......................................................................................................................33
5.1.11
Month 12....................................................................................................................34
5.1.12
Month 18....................................................................................................................34
5.1.13
Month 24 (or Early Termination) Visit ........................................................................35
5.1.14
Long-term Follow-up Visits........................................................................................35
5.2
Description of Study Procedures.................................................................................36
5.2.1
Informed Consent .......................................................................................................36
5.2.2
Medical History (Review)...........................................................................................36
5.2.3
Concomitant Medications and Procedures...................................................................36
5.2.4
Adverse Event Review................................................................................................37
5.2.5
Physical Examination .................................................................................................37
5.2.6
Pregnancy Test............................................................................................................37
5.2.7
Blood Sample .............................................................................................................37
5.2.8
ECG (Electrocardiogram) ...........................................................................................37
5.2.9
Chest X-ray ................................................................................................................37
5.2.10
Visual Acuity..............................................................................................................38
5.2.11
Full Field Sensitivity Testing (FFST)..........................................................................38
5.2.12
Object Detection and Discrimination ..........................................................................38
5.2.13
Pupillometry (at Selected Sites) ..................................................................................38
5.2.14
Ambulation.................................................................................................................38
5.2.15
Complete Ophthalmic Examination ............................................................................38
5.2.16
Intraocular Pressure (IOP) ..........................................................................................39
5.2.17
Dilated Color Fundus Photography and Autofluorescence...........................................39
5.2.18
Spectral Domain Optical Coherence Tomography (SD-OCT) .....................................39
5.2.19
Electroretinography (ERG).........................................................................................39
5.2.20
Visual Evoked Potentials (VEP)..................................................................................39
5.2.21
Quality of Life Questionnaire (NEI VFQ-25)..............................................................39
5.3
Treatment Administration ...........................................................................................40
 
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5.3.1
Post Injection Medications..........................................................................................40
5.3.2
Management of Post Injection Intraocular Pressure.....................................................40
6
Safety Assessments.....................................................................................................40
6.1
Overview of Safety Assessments ................................................................................40
6.1.1
Ocular Safety Measurements ......................................................................................40
6.1.2
Systemic Safety Measurements...................................................................................42
6.2
Clinical Management of Safety Parameters.................................................................42
6.2.1
Intraocular Inflammation and Immunogenicity Related to RST-001............................43
6.2.2
Complications of the Intravitreal Injection..................................................................43
6.2.3
Occupational Safety....................................................................................................43
6.2.4
Pregnancy and Exposure to RST-001 In Utero ............................................................44
7
Data Safety Monitoring Committee (DSMC)..............................................................44
7.1
Composition ...............................................................................................................44
7.2
Role............................................................................................................................44
7.3
Responsibilities ..........................................................................................................44
7.4
Enrollment Stopping Rules .........................................................................................45
8
Adverse Events...........................................................................................................45
8.1
Definitions..................................................................................................................45
8.1.1
Adverse Event ............................................................................................................45
8.1.2
Serious Adverse Event................................................................................................46
8.1.3
Severity ......................................................................................................................47
8.1.4
Relationship to Study Drug or Study Procedure..........................................................47
8.2
Procedures for Reporting Adverse Events...................................................................47
8.3
Procedures for Reporting a Serious Adverse Event .....................................................48
9
Efficacy Assessments..................................................................................................49
10
Clinical Monitoring Structure .....................................................................................49
10.1
Monitoring .................................................................................................................49
10.2
Study and Site Closure................................................................................................49
11
Data Analysis and Statistical Considerations...............................................................49
11.1
Primary (Safety) Endpoint ..........................................................................................49
11.2
Secondary Endpoints ..................................................................................................50
11.2.1
Measures of Change in Visual function.......................................................................50
11.2.2
Anatomical Endpoints Relating to Retinal Integrity and Survival................................50
11.3
Statistical Analysis Plans ............................................................................................51
11.3.1
Power and Sample Size Considerations.......................................................................51
11.3.2
Baseline Characteristics..............................................................................................51
11.3.3
Safety Analysis...........................................................................................................51
11.3.4
Efficacy Analysis........................................................................................................51
11.3.5
Other Analysis ............................................................................................................52
11.3.6
Interim Analysis .........................................................................................................52
12
Investigator Responsibilities .......................................................................................52
13
Data Handling and Record Keeping............................................................................52
13.1
Data Management Responsibilities .............................................................................52
 
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13.1.1
Data Quality Assurance ..............................................................................................52
13.1.2
Source Documents......................................................................................................53
14
Study Termination ......................................................................................................53
15
Regulatory and Ethical Considerations........................................................................54
15.1
Ethical Conduct of the Study ......................................................................................54
16
Management of Protocol Amendments and Deviations ...............................................56
16.1
Protocol Amendments.................................................................................................56
17
Publication Policy.......................................................................................................57
18
Sponsor's Final Report................................................................................................57
19
References..................................................................................................................58
20
Appendices.................................................................................................................59
20.1
Appendix 1: Abbreviations .........................................................................................59
20.2
Appendix 2: Clinical Laboratory Tests........................................................................60
20.3
Protocol Amendment Summary Amendment 1............................................................62
20.4
Protocol Amendment Summary Amendment 2............................................................77
20.5
Protocol Amendment Summary Amendment 3............................................................87
20.6
Protocol Amendment Summary Amendment 4............................................................89
List of Tables
Table 1
Dose Escalation.......................................................................................................20
Table 2
Study Visit Schedule: Core Study Visits...................................................................28
Table 3
Study Visit Schedule: Long-term Follow-up Visits...................................................29
Table 4
Biomicroscopic Grading of Anterior Chamber Cells and Flare.................................41
List of Figures
Figure 1
Overview of the Treatment Schedule .......................................................................20
 
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2
Protocol Synopsis
Sponsor
Allergan, Inc.
Study Compound
RST-001 (AGN-151597)
Protocol Number
RST-001-CP-0001
Title
Phase I/IIa, Open-Label, Dose-Escalation Study of Safety and Tolerability of 
Intravitreal RST-001 in Patients with Advanced Retinitis Pigmentosa (RP)
Phase
1/2a
Indication
Advanced RP
Objective
To evaluate the safety, tolerability and preliminary efficacy of RST-001 in patients 
with advanced RP.  Preliminary efficacy data will be obtained through ocular 
evaluations.
Study Population
Up to approximately 21 patients will be enrolled in this study.  
Study Rationale

First-in-human (FIH) study, designed to evaluate whether RST-001 is safe and well 
tolerated in patients with advanced RP.

This is an open label dose-escalation study of three doses of RST-001

To provide further guidance toward the design of a pivotal efficacy study, the study 
also includes the option to expand, by up to approximately 21, the number of 
patients
Study Design

Structure: Open-label, dose-escalation, non-randomized study

Duration: 2 years (with an additional 3 years of long-term follow-up)

Treatment: Three doses of RST-001 (low, mid, and high, each group comprising of 
approximately but no less than three patients) will be evaluated by sequential dose 
escalation in Phase 1
Patients will receive a single 100 μL intravitreal injection of RST-001 in the study eye. 
In Phase 2a, approximately 6-12 patients may be enrolled and receive RST-001 at the 
maximum tolerated dose.
The doses used in the study have been calculated from the pre-clinical animal 
toxicology studies, as follows:

Low dose =
 vg/eye

Mid dose = 
vg/eye

High dose =
vg/eye
An independent Data Safety and Monitoring Committee (DSMC) will advise on 
dose-escalation and cohort expansion

Visit Schedule: 

Core study visits: Twelve visits are planned over 24 months including the 
Screening and Baseline visits, Day 0, Day 1, Day 7, and Months 1, 3, 6, 9, 12, 
18, and 24.

Long-term follow-up: After completion of the Month 24 visit, each patient 
will participate in a long-term follow-up study for an additional 3 years to 
monitor the long-term safety of RST-001. This includes a yearly visit for 
3 years (Months 36, 48, and 60). 
 
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Clinical Study 
progress
Patients will be enrolled sequentially. The decision to dose escalate will be determined 
with the DSMC upon review of adverse events (AE), clinical evaluations (ocular and 
systemic) and laboratory results.
Monitoring of safety 
and tolerability
Safety monitoring will include a combination of AE reporting, clinical evaluations 
(ocular and systemic), and laboratory results.
Ocular and systemic safety monitoring will include monitoring for signs of an immune 
response. 
Enrollment Stopping 
rules
Any Grade 3 (Common Terminology Criteria [CTC] for AEs v4.03) or greater AE 
considered related to the study treatment.
Primary endpoints: 
Assessment of safety
The primary endpoint is safety at 6 months from start of study treatment.
The therapy will be considered safe in the absence of any grade 3 or greater AE 
considered related to RST-001.
Secondary endpoints
The effect of intravitreal injection of RST-001 in improving visual function as 
measured by a series of psychophysical, electrophysiological and anatomical 
measures.
Analysis plan
The sample size for this study was chosen empirically; no formal sample size 
computations to meet power requirements were made. The sample size of 
approximately 3 patients for each dose group in Phase 1 are typical for dose escalation 
studies, an additional up to approximately 12 patients will be enrolled in Phase 2a for 
further safety and efficacy evaluation.
Summary tables and listings of data will be provided per Statistical Analysis Plan. All 
summaries of categorical data will present frequencies and percentages. All summaries 
of continuous data will present the number of non-missing values, mean, standard 
deviation, minimum, median and maximum.
 
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3
Introduction
3.1
Background and Rationale
3.1.1
Retinitis pigmentosa (RP)
Retinitis pigmentosa (RP) is a hereditary, slowly-progressive, neurodegenerative disease of the 
retina. It is estimated that the prevalence of RP in the United States (US) is approximately 
100,000 individuals (Sohocki et al., 2001) with 10-20% suffering severe vision loss from this 
condition. A similar prevalence rate is thought to occur worldwide. RP is most frequently 
inherited as an isolated ocular disease though it is a manifestation of many syndromes.
RP is genetically heterogeneous with more than forty causative genes and perhaps only 50% of 
genes have been identified. In the US, RP is most commonly inherited as an autosomal dominant 
trait.
3.1.2
Clinical features
Early disease manifests as night-blindness and peripheral visual field defects. As the disease 
progresses, the visual field constricts relatively symmetrically. Unless complicated by cystoid 
macula edema, visual acuity (VA) is preserved until advanced disease. A patient with advanced 
disease will have poor VA and minimal preserved visual field. In some instances, all vision is 
lost.
Examination findings include abnormal pigmentary changes in the retina, classically appearing 
as discrete bone-spicules, outer retinal atrophy, optic nerve pallor and retinal vascular 
attenuation.
3.1.3
Cellular pathology
RP is primarily a disease of the rod photoreceptors which are gradually lost as the disease 
progresses (Daiger et al., 2007). Cone photoreceptors subsequently degenerate, together with the 
retinal pigment epithelium. Loss of the photoreceptors results in changes in the inner retina, 
which include cell reorganization, disorganization and cell loss. Even in the advanced stages, 
retinal ganglion cells, which comprise the innermost layer of the retina, persist and maintain their 
connections with the brain.
3.1.4
Pathogenesis
Given the large number of causative genes and the diverse properties of the proteins they encode, 
the precise molecular pathology of RP remains elusive. It is likely that the molecular pathology 
stresses the photoreceptor cells eventually resulting in the activation of cell death pathways. 
 
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Photoreceptors and other neuronal cells of the retina have little or no replicative function and cell 
loss results therefore in progressive deficit.
3.1.5
Treatment
Currently, there is no approved drug treatment for RP. Supplemental doses of Vitamin A may 
reduce the rate of degeneration in certain individuals but the effects are insubstantial 
(Rayapudi et al., 2013). The Argus II retinal prosthesis (an opto-electronic implant developed by 
Second Sight Medical Products Inc., Sylmar, CA) has been approved by the FDA, on a 
humanitarian basis, for those most severely affected by RP (Dorn et al., 2013).
3.2
Adeno-Associated Virus
Adeno-associated virus (AAV) is a parvovirus with a single-stranded DNA genome 
(Muzyczka N, Berns KI, 2001). It requires a helper virus to complete its replication cycle in 
culture and in humans (Blacklow NR, Hoggan MD, 1967). AAV does not appear to integrate in 
humans (Schnepp BC, et al 2005) and has not been associated with human disease 
(Flotte TR, Carter BJ, 1995).
3.3
Recombinant AAV Vectors
Recombinant AAV (rAAV) vectors are composed of a transgene expression cassette between 
inverted terminal repeats (ITRs), which guide packaging of vector DNA into AAV capsids. rAAV 
vectors are non-toxic, highly efficient at transducing a wide variety of non-dividing cell types, 
and persist for long periods potentially leading to long-term expression of the transgene 
(Carter PJ, Samulski RJ 2000).
3.4
Human Clinical Experience with AAV2 Vectors
AAV2 is currently being used as the vector of choice in multiple clinical studies around the 
world setting a precedent as a safe delivery system for gene therapy. Specifically, AAV2 has been 
used as a vector in clinical studies within the United States since 2004. To date there are no 
approved products utilizing AAV2 but there are a number of clinical studies that either have been 
completed or are ongoing worldwide, some of which are in the area of ophthalmology, including 
indications like neovascular age-related macular degeneration, Leber Congenital Amaurosis 
(LCA), and choroideremia.
3.5
RST-001
RST-001 (AGN-151597) is a gene therapy product based on the light-gated ion channel, 
channelrhodopsin-2 (ChR2). RST-001 comprises a non-replicating recombinant 
 
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Adeno-Associated Virus serotype 
 containing the 
 
 
 
 
. RST-001 is manufactured in sterile conditions 
according to Good Manufacturing Practice (GMP) requirements, which includes screening and 
elimination of microbes.
3.6
Nonclinical Studies with RST-001
3.6.1
Pharmacology Studies
Two studies were conducted in mice, collectively covering a 10-fold range of dose exposure 
from the lowest (
 vg/eye) to the highest dose (
 vg/eye). The objective of these 
studies was to test the behavioral efficacy of a single-1 μL intravitreal injection in both eyes of 
RST-001 (dosing solutions (vg/mL): 
(Low); 
 (Mid); 
 (High)) on visual 
function in C3H/HeJ-Pde6brd1 mice (
 hereafter “C3H”). These mice are 
homozygous for the retinal degeneration 1 mutation (Pde6brd1), which causes blindness by 
weaning age. The sighted control mice were C3Sn.BLiA-Pde6b+/DnJ (
 
hereafter “C3Sn”). Behavioral assessments were done prior to AAV2-ChR2 (RST-001) (when 
mice are ~ 8 weeks old; hereafter “Baseline”), again starting at P120 (hereafter “Test 1”), and 
finally at 6 months post injection (hereafter “Test 2”). Viral injections were done around 
9 weeks old.
There were no injection-related complications and no animals died during the perioperative time 
period. At the two-month time point, there was evidence of improved visual function in rd1 mice 
treated with RST-001 at all doses (
 vg/eye, 
 vg/eye, and 
 vg/eye) 
evaluated as compared with vehicle injected mice, based upon optokinetic responses. The highest 
dose (
 vg/eye) also showed efficacy for visual placement responses. These effects were 
investigated in the high dose at 6 months post injection, but were not reproduced. However, 
electrophysiological measures appear to have verified ChR2-driven light responses at the 
ganglion cell layer 10 months post injection.
Non-GLP safety observations were also conducted in conjunction with this pharmacology study.  
RST-001 produced no signs of test article related effects on body weights, food consumption, 
clinical observations or during ophthalmic examinations. There were no gross lesions at terminal 
necropsy related to the test article treatment. Histological evaluations were conducted for 
animals in the control and highest dose group. No test item-related microscopic findings were 
 
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noted in the tissues examined (brain, epididymis, eye, heart, kidney, liver, lung, mandibular and 
mesenteric lymph nodes, optic nerve, parotid salivary gland, spleen and testis).
3.6.2
Toxicology and Biodistribution Studies
Two nonclinical GLP toxicology and biodistribution studies have been completed in two species, 
beagle dogs and mice. The objectives of both studies were to determine the potential ocular 
toxicity of RST-001 when given by a single intravitreal injection and to evaluate the potential 
reversibility of any findings within 99 days of treatment.
The following parameters and end points were evaluated: clinical signs, body weights, food 
consumption, ophthalmology, clinical pathology parameters (hematology, coagulation, clinical 
chemistry and bone marrow smear evaluation), immunogenicity 
, gross necropsy findings, organ weights, and histopathologic examinations, and 
biodistribution.
3.6.2.1
Dog Study
The dog study was conducted in healthy male and female animals 5-6 months of age. The dog 
was chosen as the animal model for this study as it is an accepted non-rodent species for 
preclinical ocular toxicity testing by regulatory agencies. There were 8 dogs per dose group and 
4 dose groups. Actual doses verified were vehicle (control); 
 (Low), 
 (Mid), 
and 
 (High) vg/eye of RST-001. Two dogs/sex/time point were administered, in the 
right eye, a single-
 μL intravitreal injection of vehicle or RST-001. Animals were sacrificed on 
Day 36 and Day 99.
No noteworthy adverse effects were observed in the body weight, food consumption, clinical 
pathology or organ weights following administration of RST-001 at any dose level. 
RST-001-related findings, consisting of ocular inflammation, were observed beginning at least 
5 weeks after administration with an increasing incidence and severity with dose at all dose 
levels.  Ophthalmic findings of anterior uveitis (anterior chamber cells, keratic precipitates 
and/or cell–like deposits on the corneal endothelium) were observed at Week 5 in 8/8 high dose 
eyes and 3/8 or 1/8 eyes for the mid and low doses, respectively. During the recovery period, 
findings generally remained stable or progressed.  Findings related to chronic inflammation, 
including the presence of perivascular retinal opacities in addition to findings in the anterior 
chamber, were present at all dose levels at the end of the recovery period.  In 2/8 high dose 
animals, the level of inflammation was greater when compared to other animals and was 
accompanied by anterior chamber flare, fibrin, corneal edema, pupil incomplete dilation, fundus 
hazy view, corneal vessels and/or lens opacities. These observations correlated with microscopic 
 
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findings. At the high dose, these consisted of minimal to marked mixed cell (lymphocytes, 
macrophages, and rarely, neutrophils) inflammation of the anterior chamber (iridocorneal angle), 
iris, ciliary body, vitreous body and/or retina.  At the mid and low dose, findings were limited to 
minimal to mild cell inflammation in the ciliary body, vitreous body and/or iris. There were no 
signs of overt tissue damage due to direct toxicity of the test item and no cellular or humoral 
immune response to RST-001 was detected at any dose level.
RST-001 DNA was detected predominantly in the spleen, with lower concentrations below the 
limit of quantitation (
 copies/μg of tissue) also detected within the mandibular lymph node, 
liver, lacrimal gland, and optic nerve. Preliminary immunohistochemistry evaluation of the dogs’ 
retina suggests ChR2 protein expression persistent throughout the 99 days of follow up.
In conclusion, administration of RST-001 by a single intravitreal injection at a 10-fold difference 
in nominal doses resulted in dose-related ocular inflammation, with no noteworthy adverse 
effects observed in the body weight, food consumption, clinical pathology, cellular immune 
response or organ weight. There were no signs of overt tissue damage due to direct toxicity of 
the test item and no cellular immune or humoral response to RST-001 was detected at any dose 
level. RST-001 had minimum biodistribution systemically and was expressed in the retina.
3.6.2.2
Mice Study
The purpose of this study was to evaluate the toxicity of the test article, RST-001, when given as 
a single 1 μL intravitreal injection in the right eye to C3H/HeJ-Pde6brd1 mice.
Mice historically have been used in safety evaluation studies and this particular strain is a disease 
model for advanced RP, the indication of RST-001.
There were 64 mice per dose group and 4 dose groups. Actual doses verified were: vehicle 
(control); 
 (Low), 
 (Mid), and 
 (High) vg/eye of RST-001.  After 
dosing, animals were observed post dose for at least 29 (interim sacrifice) or 89 days (terminal 
sacrifice). There were 16 animals/sex/group at each terminal sacrifice.
There are no signs of test article related effects on body weights, food consumption, and clinical 
observations or during ophthalmic examinations through Week 4 of the dosing phase. There were 
no gross lesions at any of the terminal necropsy intervals that appear to be related to the test 
article treatment.  There were no signs of overt tissue damage due to direct toxicity of the test 
item and no cellular immune or humoral response to RST-001 was detected at any dose level.
RST-001 was present at the highest level in the right eye and optic nerve of all animals tested. 
RST-001 was also detected just above the minimum level of detection (
 copies/μg of tissue) 
 
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within the hindbrain and spleen. Dose-dependent minimal to moderate ChR2 immunolabeling 
occurred in the right treated eye of animals given 
 vg/right eye; minimal ChR2 
immunolabeling was also present in the right optic nerve of some animals with ChR2 
immunolabeling in the right eye.
In conclusion, administration of RST-001 by a single intravitreal injection at a 10-fold difference 
in nominal doses resulted in no dose-related effects. RST-001 had minimum biodistribution 
systemically and was expressed in the retina.
3.6.3
Justification for Human Dose
The doses and injection volume have been calculated by allometric scaling from pre-clinical 
animal studies. Vitreous humor volume was the scaling factor across species. In general, scaling 
of the vitreous volume from mice and dogs to humans is 1:100 and 1:2, respectively.  
Two nonclinical toxicology studies were conducted in the dog and mouse. The safe intravitreal 
doses in the dog ranged from 
 to 
 vg/eye. For the mouse, the safe intravitreal 
doses ranged from 
 to 
 vg/eye. Two nonclinical pharmacology studies 
demonstrated efficacy and safety in the mouse at a dose range of 
 to 
 vg/eye in a 
dose range comparable to the toxicology study. Based on these studies, the expected safe dose 
range in humans is between 
 and 
 vg/eye. The dose range in this study 
(
 to 
1 vg/eye of RST-001) is based on the more conservative exposure in the dog, 
inclusion of potentially efficacious doses, the ability of the manufacturer to concentrate 
investigational product, and a safe injection volume of 100 μL per eye in humans.
3.7
RST-001 Study Rationale: Optogenetic Therapy for Advanced 
Retinitis Pigmentosa
RST-001 is a gene therapeutic treatment that renders cells in the retina sensitive to light. This 
light sensitivity is conveyed to the brain and is a photoreceptor substitute in conditions such as 
advanced RP where the normal light sensitive cells are lost.
The disease of advanced RP results in the irreversible loss of photoreceptors, which are the only 
cells in the retina that are able to convert the light entering the eye into an electrical signal that 
can be relayed to the brain and interpreted as vision. Although these cells degenerate, many of 
the other neuronal cell types that receive input from the photoreceptors persist. In particular, the 
innermost retinal cells, the retinal ganglion cells (RGCs) survive in significant numbers late into 
the disease and axons from these cells remain connected directly to the brain.
Direct electrical stimulation of the RGCs using surgically-implanted electronic devices have 
provided a proof of concept that vision can be mediated through these cells.
 
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RST-001 delivers a gene encoding a photo switch, channelrhodopsin-2, to the RGCs. When 
expressed, the channelrhodopsin-2 protein can depolarize in response to light thus generating a 
signal that is transmitted to the brain. The components of RST-001 are shown in detail above.
The study is composed of two phases. An initial dose-escalation study (Phase 1) is proposed 
whereby three dose levels of RST-001 will be studied in three separate groups of adult patients 
with advanced disease. Phase 1 is aimed at determining a single dose of the experimental 
treatment which is safe and well tolerated, to further evaluate in a fourth group of patients. If the 
Data Safety Monitoring Committee (DSMC) considers the safety and tolerability of RST-001 
satisfactory in the first phase, then the study may proceed to Phase 2a. Phase 2a is aimed at 
obtaining additional safety data at the maximum tolerated dose. An additional objective of 
Phase 2a is to provide important additional clinical data to guide the design of future efficacy 
studies.
3.7.1
Immunogenicity of RST-001
Preclinical data indicated that no cellular or humoral immune response to RST-001 was detected 
at doses up to 
 and 
 vg/eye in mice and dogs, respectively. In this study, 
evidence of an immune response to the product will be carefully assessed by monitoring for 
systemic measurement of humoral and cellular immunity. Local or systemic immune suppression 
may be initiated if clinically indicated.
3.8
Treatment Administration
RST-001 will be administered by intravitreal injection as specified in the Study Procedures 
Manual. The injection volume is 100 μL.
Prior to study treatment administration, the study eye of each patient will be prepared using a 
standard protocol as described in the Study Procedures Manual.
3.9
Objectives of the Study
3.9.1
Primary Objective:
To evaluate the safety of a single intravitreal injection of RST-001.
3.9.2
Secondary Objectives:
1.
To establish the maximum tolerated dose of RST-001.
2.
To evaluate the preliminary efficacy of RST-001 in patients with advanced RP.
 
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3.10
Study conduct and GCP Compliance Statement
This study will be conducted in compliance with the protocol approved by the Institutional 
Review Board (IRB), and according to Good Clinical Practice (GCP) standards.  No deviation 
from the protocol will be implemented without the prior review and approval of the IRB except 
where it may be necessary to eliminate an immediate hazard to a research patient.  In such case, 
the deviation will be reported to the IRB as soon as possible.
3.11
Risks and Benefits
3.11.1
Potential Risks
The risks associated with this study can be divided into those related to the intravitreal injection 
of RST-001, the RST-001 treatment and study procedures.
3.11.1.1
Intravitreal Injection
These risks are well recognized and include transient conjunctival hyperemia and hemorrhage at 
the injection site. Serious complications such as retinal tears/holes, retinal detachment, vitreous 
hemorrhage and endophthalmitis are uncommon or rare but may result in reduced vision and 
may require surgical intervention.
3.11.1.2
RST-001 Treatment
The risks of intravitreally-administered RST-001 are not known. Potential risks include an 
immune response, which may result in ocular inflammation and the associated consequences.
3.11.1.3
Study Procedures
The risk from the tests performed in this study carry minimal risks and mostly relate to the need 
for pupillary dilation, which typically results in temporary blurred vision and increased light 
sensitivity. On occasion, a corneal abrasion can result from the use of the ERG contact lens.
3.12
Protection from Risks
The RST-001 drug product has been manufactured in compliance with current Good 
Manufacturing Practice (cGMP). Extensive testing has been performed to ensure infective agents 
and pathogens are not present.
Intravitreal injection of RST-001 will be performed in the operating room under aseptic 
conditions by qualified staff in accordance with the Study Procedures Manual.
 
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After the procedure, each patient will be carefully monitored for complications. Evidence of an 
immune response to RST-001 will be monitored (refer to Section 6.2.1).
The conduct of this study will be overseen by the DSMC.
3.13
Provisions for Injury
Any complications arising post injection will be managed in accordance with the investigator’s 
standard of care.
It is not possible for RST-001 to be removed from the eye after injection.
3.14
Potential Benefits
Patients may not benefit directly from the study. It is theoretical at this time as to whether any 
visual benefit will be afforded by RST-001. The primary objective of this particular study is to 
establish safety of RST-001.
3.14.1
Risk Benefit Analysis
Since RST-001 has not yet been shown, in humans, to be efficacious, investigators and patients 
will need to weigh carefully the risks shown above with the theoretical possibility of improved or 
preserved visual function.
3.15
Study Overview
3.15.1
Study Design
This is an open-label, dose-escalation study to evaluate the safety and tolerability of RST-001 
administered as a single intravitreal injection in patients with advanced RP.
3.15.1.1
Enrollment Phase 1
Three groups of patients (A, B, C, each comprising of approximately but no less than three 
patients) will be enrolled in this study.
Approximately 3 patients in Group A will receive the lowest dose of RST-001 (LOW). The safety 
and tolerability of RST-001 will be assessed in the first patient for a minimum of one month 
(to include Month 1 Visit). If the DSMC considers the safety and tolerability of the first patient 
satisfactory and the enrollment stopping rules have not been met, then the remaining patients in 
Group A can be enrolled and receive treatment.
 
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If the DSMC considers the safety and tolerability of Group A satisfactory and the enrollment 
stopping rules have not been met after a minimum assessment of one month (to include Month 1 
Visit) from the last treatment group, then approximately 3 patients in Group B may be enrolled 
and receive a higher dose of RST-001 (MID) following the same guidelines and treatment 
schedule.
Similarly, if the DSMC considers the safety and tolerability of Group B satisfactory and the 
enrollment stopping rules have not been met after a minimum assessment of one month (to 
include Month 1 Visit) from the last treatment group, then approximately 3 patients in Group C 
may be enrolled and receive the highest dose of RST-001 (HIGH) following the same guidelines 
and treatment schedule.
After completion of the 2-year core study visits, each patient will be enrolled in a long-term 
follow-up for an additional 3 years to monitor the long-term safety of RST-001.
3.15.1.2
Enrollment Phase 2a 
If the DSMC considers the safety and tolerability satisfactory and the enrollment stopping rules 
have not been met after a minimum assessment of one month (to include Month 1 Visit) from 
treatment of the final patient in Groups A, B, or C, then the sponsor may elect to start enrollment 
in the second cohort of patients.  In Phase 2a, up to approximately 12 patients may be enrolled 
and receive RST-001 at the maximum tolerated dose.

If the DSMC considers the data from Phase 1, in their opinion, to be indicative of a 
treatment benefit for visual acuity/function, then approximately 6 patients will be 
enrolled in Phase 2a and follow the same eligibility criteria as Phase 1.

If the DSMC considers the data from Phase 1, in their opinion, to not be indicative of a 
treatment benefit, then approximately 12 patients will be enrolled in Phase 2a.
o
6 patients must have VA of no-better-than hand motion in the study eye.
o
6 patients must have VA in the study eye to range from no-worse-than count 
fingers to 20/200 vision.
A schematic providing an overview of the treatment schedule is illustrated in Figure 1, and the 
dose-escalation cohorts are illustrated in Table 1 below.
 
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Figure 1
Overview of the Treatment Schedule
Table 1
Dose Escalation
Phase
Group
Number of patientsa
Intravitreal Injection
Vector concentration
Volume
(µL)
1
A
3
LOW
100
B
3
MID
100
C
3
HIGH
100
2a
6-12b
Choice of dosec from groups A, B, or C
100
a Up to approximately 21 patients will be enrolled in this study.
b Number of patients is dependent upon whether or not the DSMC determines that, in their opinion, a treatment benefit for 
visual acuity/function has been observed in Phase 1.
c The maximum tolerated dose.
After completion of the 2-year core study visits, each patient will be enrolled in a long-term 
follow-up for an additional 3 years to monitor the long-term safety of RST-001.
3.15.2
Study Population
The study population consists of patients with advanced RP 
 
 
 
  
  
 
  
   
 
  
  
 
  
   
 
 
 
  
  
 
  
    
 
 
 
 
 
 
 
 
 
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 This patient group is considered to be a suitable population to assess 
safety and tolerability in this Phase 1 study. Furthermore, the presence of 
 
 will give a valuable opportunity to evaluate 
efficacy.
Up to approximately 21 patients will be enrolled in this study.
3.15.3
Eligibility Criteria
3.15.3.1
Inclusion Criteria
The following are requirements for entry in the study:
General Inclusion Criteria:
1. Male or female patients, ≥ 18 years of age at time of informed consent
2. Patient has provided written informed consent and written Authorization for Use and 
Release of Health and Research Study Information have been obtained prior to any study 
related procedures
3. Patient has the ability to understand and willingness to follow study instructions and is 
likely to complete all required visits and procedures
4. Women of childbearing potential must have a negative pregnancy test at Screening and at 
Baseline, and agree to use an effective form of contraception, or be surgically sterile or 
post menopausal (defined as last menstrual period greater than two years prior to 
Baseline). Acceptable methods of contraception include hormonal contraception 
(i.e., birth control pills, injected hormones, dermal patch or vaginal ring), intrauterine 
device, barrier methods (diaphragm, condom) with spermicide, or surgical sterilization 
(tubal ligation)
5. Males must use two forms of contraception (including one barrier method for three
months following study treatment administration if their partner is of child-bearing 
potential), or must be surgically sterile
 
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Ocular Inclusion Criteria:
Phase 1 and Phase 2a
1. Diagnosis of advanced RP defined as:
Phase 1
3. VA in the study eye of no-better-than hand motion
Phase 2a
4. If a treatment benefit is identified by the DSMC:
a.
VA eligibility criteria will match that of Phase 1.
5. If a treatment benefit is not identified by the DSMC:
a.
VA eligibility criteria will match that of Phase 1 for half of the enrolled patients.
b. VA criteria for the other half of the enrolled patients must range from no-worse-than 
count fingers to 20/200 vision in the study eye.
3.15.3.2
Exclusion Criteria
Patients will not be excluded if the molecular diagnosis underlying their RP is not known or if 
there is presence of macular edema due to advanced RP.
However, any one of the following will exclude patients from being enrolled into the study:
General Exclusion Criteria:
1. Participation in any investigational drug or device study within six months prior to Day 0;
2. Complicating systemic diseases or clinically significant abnormal baseline laboratory
values. Complicating systemic diseases include those in which the disease itself, or the 
treatment for the disease, can alter ocular function. Examples are malignancies whose
treatment could affect central nervous system function (i.e., radiation treatment of the 
orbit; leukemia with CNS/optic nerve involvement). For the procedure on establishing 
clinically significant abnormal baseline laboratory values, see Section 5.1.2.
 
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3. Immunocompromising diseases, such as hepatitis B, C and HIV, or use of 
immunosuppressive medications
4. Females who are pregnant, nursing, planning a pregnancy during the study or who are of 
childbearing potential not using a reliable method of contraception during their 
participation in the study
5. History or current evidence of hypersensitivity to any component of the study treatment, 
medications, or diagnostic agents used in the study
6. Immunogenicity assays show presence of neutralizing antibodies to AAV2 above 1:1000 
of dilution
7. Use of anti-platelets and anti-coagulants that may alter clotting within 28 days prior to 
study treatment administration
8. Any other condition that would not allow the potential patient to complete follow-up 
examinations during the course of the study and, in the opinion of the investigator, makes 
the prospective patient unsuitable for the study
Ocular Exclusion Criteria:
9. History of prior gene or stem cell therapy (ocular or other)
10. Pre-existing eye conditions that would preclude the planned treatment (i.e., injection) or 
interfere with the interpretation of study endpoints or surgical complications (examples 
include (but not limited to) glaucoma, diseases affecting the optic nerve causing 
significant visual field loss, active uveitis, corneal or lenticular opacities)
11. Cataract surgery, intraocular and/or peri-ocular injection in the study eye within six 
months prior to Day 0
12. Prior vitrectomy or aphakia in the study eye
3.15.4
Early Discontinuation of Patients
Patients may voluntarily withdraw from the study at any time or for the following reasons:
a)
Due to an adverse event (AE)
b)
If deemed necessary by the investigator or the sponsor that it is unsafe for the patient to 
continue in the study
When possible, the decision to withdraw a patient from study treatment or the study should be 
discussed with the sponsor. Notification of early patient discontinuation from the study and the 
 
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reason for discontinuation will be clearly documented on the appropriate Case Report Form 
(CRF).
In the case of a withdrawing patient, every reasonable attempt will be made to complete a final 
early termination visit (as shown in the study visit table). Patients who withdraw from the study 
prior to receiving the study treatment may be replaced.
4
Treatments
4.1
Identity of Investigational Product
The treatment in this study has been called RST-001. RST-001 constitutes a non-replicating 
recombinant Adeno-Associated Virus serotype 
 vector containing a gene encoding 
the channelrhodopsin-2 protein (ChR2 ORF) formulated in 
 
. RST-001 is 
provided as a sterile frozen liquid.
4.2
Dosage and Administration
The doses of RST-001 evaluated in this study will be:

LOW dose = 
 vg/eye

MID dose = 
 vg/eye

HIGH dose = 
vg/eye
4.3
Method of Assigning Patients to Dose Groups
This is a sequential dose-escalation study. In Phase 1, three groups comprising of approximately 
but no less than three patients, will be enrolled one after the other, receiving first the low dose, 
then the mid, and finally the high dose.
Escalation is dependent upon the enrollment stopping rules and DSMC recommendation.
In Phase 2a, up to approximately 12 patients may then be enrolled in parallel at the maximum 
tolerated dose.
4.4
Dose Rationale
The highest feasible concentration of RST-001 is constrained by manufacturing capabilities and 
product stability and has been determined to be approximately 
 vg/ml. The highest 
feasible dose is then limited by the volume that can be delivered to the human vitreous. Based 
upon estimated vitreous volumes and maximum feasible intravitreal dosing, this maximum 
 
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concentration was evaluated as the highest dose in our mouse pharmacology study (dose volume 
of 1 µl) and mouse (1 µl) and dog (
µl) toxicology and biodistribution studies. This dose was 
demonstrated to be efficacious and no dose-limiting toxicity was observed, respectively. Since 
the beagle dog vitreous has about half the vitreous volume of the human eye, the HIGH dose for 
the human study has been determined to be 
vg/eye given as a single 100 µl intravitreal 
injection. In order to be safe and conservative but also balanced with the potential for delivering 
an active dose, Allergan proposes that the LOW initial starting dose for the first-in-human study 
be 
of this dose, 
 vg/eye. The MID dose will be 
 of the HIGH dose, 
vg/eye.
Dose escalation will proceed according to Table 1, only after review by the DSMC (see Figure 1, 
above). Three doses have been chosen with the safety as the priority but will provide a good 
opportunity to observe biological effect.
The rationale for the dosing schedule is once again based primarily on patient safety. Thus, at 
each dose a single patient will receive treatment followed by an intensive period of observation 
for any evidence of AEs prior to dosing the remaining two patients in the group. The safety and 
tolerability and optimal single dose of RST-001 will therefore be established in Phase 1. Phase 2a 
patients will receive a single intravitreal injection of RST-001 at the maximum dose tolerated by 
Phase 1 patients.
4.5
Patient and Investigator Masking
This is an open-label study so that patients and investigators will know which eye is treated and 
what dose of RST-001 was given.
4.6
Packaging and Labeling
Correct product identity, labeling and patient specificity will be assured by the use of standard 
operating procedures in accordance with FDA regulations. These operating procedures will 
include identifiers to ensure correct labeling to identity study treatment throughout manufacture, 
handling and administration.
4.7
Handling and Storage
The study treatment RST-001 is provided as a sterile frozen liquid and must be stored at 
°C or 
below. Stability testing indicates RST-001 is stable for at least 
°C or below. Please 
refer to the Study Procedures Manual for additional information.
 
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4.8
Study Treatment Preparation and Administration
RST-001 must be prepared under aseptic conditions as described in the Study Procedures 
Manual. Keep residual study treatment separately from unused study vials.
Immediately prior to study treatment administration, the patient will be placed in the supine 
position and the patient’s eye will be prepared for injection in accordance with the description 
given in the Study Procedures Manual.
4.9
Product Accountability
Study treatment will be shipped to the site after receipt of required documents in accordance with 
applicable regulatory requirements. RST-001 study treatment will be handled in accordance with 
regulatory and institutional requirements.  RST-001 will only be administered to patients enrolled 
in the study who meet the eligibility criteria and who have signed the informed consent form. 
RST-001 will only be administered in accordance with the surgical procedure described in this 
document. Study treatment must be stored in a secure temperature-controlled area with access 
limited to the investigator and authorized study site personnel. The investigator or designated 
study site personnel is responsible for study treatment accountability, reconciliation and record 
maintenance. In accordance with all applicable regulatory requirements, the investigator or 
designated study site personnel must maintain study treatment accountability records throughout 
the course of the study.  All study treatment must be returned to Allergan or Allergan designee at 
the completion of patient enrollment.
4.10
Assessment of Compliance
Deviations with respect to dosage and administration will be documented by the investigator. 
Such deviations will be immediately reported to Allergan, the medical monitor, the institutional 
review board and the FDA, as appropriate.
4.11
Treatment of RST-001 Overdose
There is no known treatment in the event of an overdose of RST-001.
4.12
Prior and Concomitant Therapy
During the course of the study, patients will be allowed to continue taking prescribed and 
over-the-counter medications that are not excluded in the protocol (i.e., antiplatelets and 
anticoagulants prior to treatment, and immunosuppressive therapy).
 
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5
Study Assessments and Intravitreal Injection
Patients diagnosed with advanced RP and who are eligible based on inclusion and exclusion 
criteria will be invited to participate in this study. After obtaining informed consent and 
authorization, patients will undergo a complete physical examination and laboratory testing to 
assess eligibility for the study.
Patients who meet inclusion criteria will be considered eligible for study entry and will receive a 
single intravitreal injection of RST-001. Following RST-001 administration (Day 0) patients will 
be assessed on the first post injection day (Day 1).
The visit schedule includes:

Core study visits: Twelve visits are planned over 24 months, including Screening and 
Baseline visits, Day 0, Day 1, Day 7, and Months 1, 3, 6, 9, 12, 18, and 24.

Long-term follow-up: After completion of the Month 24 visit, each patient will 
participate in a long-term follow-up study for a total of an additional 3 years. These visits 
include yearly office visits for 3 years (Months 36, 48, and 60).
Core study visits are described in Table 2 and long-term follow-up visits are described in Table 3.
Study visits may be impacted due to the COVID-19 pandemic.  This may include changes such 
as telephone or virtual visits, visits at alternative locations, or changes in the visit frequency and 
timing of study procedures, among others.  Additional details are provided in the subsequent 
section.  Every effort is to be made to ensure the safety of subjects and site staff, while 
maintaining the integrity of the study.  If visits cannot be conducted onsite due to travel 
restrictions or other pandemic-related reasons, follow the updates below on how to proceed.
During the COVID-19 pandemic, if it is not possible for all study procedures to be performed as 
specified due to travel restrictions or other reasons, the following modifications are allowed with 
agreement from the sponsor:

If permitted by local regulations, the IRB/IEC, and the subject, postbaseline visits may be 
conducted virtually.

Study Visits and/or activities are to be performed as scheduled whenever possible.
 
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Table 2
Study Visit Schedule: Core Study Visits
Screeningb
Baselineb
Day
Month
Visit Windows (Days)a
-45 to -8
-7 to -1
0
1
7
± 1
1
± 7
3
± 7
6 
± 7
9
± 7
12 
± 30
18 
± 30
24c
± 30
Informed 
Consent/Authorization
X
Ophthalmic and 
Medical History
X
X
X
Concomitant 
medications and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events review
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
Pregnancy Test
X
X
Blood Sampled
X
X
Electrocardiogram 
(ECG)
X
Chest X-ray
X
Visual acuity 
X
X
Full Field Sensitivity 
Testing (FFST)
X
X
Object detection and 
discrimination
X
X
Pupillometry (at 
selected sites)
X
Ambulation
X
Complete Ophthalmic 
Examination
X
X
Intraocular Pressure 
(IOP)
X
X
Spectral Domain 
Optical Coherence 
Tomography 
(SD-OCT)
X
X
Color Fundus 
Photography and 
Autofluorescence
X
Electroretinography 
(ERG)
X
Visual Evoked 
Potentials (VEP)
X
Quality-of-life 
questionnaire
X
Study drug 
administrationf
a
Assessment administration may extend over more than one day.
b
If convenient, the Screening and Baseline visits may be combined.
c
Month 24 or early termination visit.
d
Blood samples will include hematology, chemistry and RST-001 immunogenicity testing: see Appendix 2 for details.
e
IOP measurements will be performed pre- and post-injection in the study eye only. After the intravitreal injection, the patient 
will remain in the supine position and (IOP) intraocular pressure will be monitored for at least 30 min. In the event that the 
IOP is 30 mmHg or above, this will be managed according to Section 5.3.2.
f
Topical corticosteroid treatment may be given to the injected eye according to the investigator’s standard of care.
 
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Table 3
Study Visit Schedule: Long-term Follow-up Visits
Months
Clinic Visits
Visit Windows (Month ± Days)
36 ± 30
48 ± 30
60 ± 30
Concomitant medications and 
procedures
X
X
X
Adverse Events review
X
X
X
Visual Acuity
X
X
X
Complete Ophthalmic Examination
X
X
X
5.1
Schedule of Procedures by Visit
Please refer to Table 2 and Table 3 for a schematic of the schedule of visits and procedures.
5.1.1
Informed Consent and Patient Privacy
The study will be discussed with the patient and patient’s impartial witness or legally acceptable 
representative. A patient wishing to participate must give informed consent and authorization 
prior to any study-related procedures. The patient must also give authorization (US only) and 
other written documentation in accordance with the relevant country and local privacy 
requirements (where applicable) prior to any study-related procedures or change in treatment. 
Each patient that provides informed consent and assent will be assigned a patient number that 
will be used on patient documentation throughout the study.
Due to the COVID-19 pandemic, it is possible that protocol modifications may become 
necessary.  If this situation arises, in addition to the study informed consent, additional verbal 
consent may be obtained prior to these adaptations or substantial changes in study conduct in 
accordance with local regulations.
5.1.2
Screening Visit 
Prospective patients will be screened for eligibility up to 45 days prior to enrollment and the 
procedures will be performed as specified below. If convenient, the Screening and Baseline visits 
may be combined.
It is the investigator’s responsibility to review the results of all laboratory tests as they become 
available. This review will be documented by the investigator’s dated signature on the laboratory 
report. For each abnormal laboratory test result in which the value of the test lies outside the 
normal range (see Appendix 2 for reference values), the investigator needs to ascertain if this is 
an abnormal (ie, clinically significant) result for the individual subject. The investigator may 
repeat the laboratory test or request additional tests to verify the results of the original laboratory 
 
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tests. If the laboratory value is determined by the investigator to be clinically significantly 
abnormal for that subject, the subject will be excluded from the study.
Records will be maintained of those individuals who are screened but do not meet the eligibility 
criteria for participation in the study.

Informed consent and authorization

Ophthalmic and medical history

Concomitant medications and procedures

Physical examination

Pregnancy test (blood)

Draw blood sample

ECG

Chest X-ray

Visual acuity 

FFST (full field sensitivity test)

Object detection and discrimination

Complete ophthalmic examination

IOP

SD-OCT 

ERG

AE review
5.1.3
Baseline Visit 

Confirm patient still consents

Ophthalmic and medical history

Concomitant medications and procedures

AE review

Pregnancy test (blood)

Draw blood sample 
 
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
Visual acuity 

FFST 

Object detection and discrimination

Pupillometry (at selected sites)

Ambulation

Complete ophthalmic examination

IOP

SD-OCT 

Dilated color fundus photography and autofluorescence 

VEP

Quality of life questionnaire
5.1.4
Treatment Visit (Day 0)

Ophthalmic and medical history (pre-injection)

Concomitant medications and procedures

AE review



5.1.5
Post Injection Visit (Day 1)

Concomitant medications and procedures

AE review



                                               
1 IOP measurements will be performed pre- and post-injection in the study eye only. After the intravitreal injection, 
the patient will remain in the supine position and IOP will be monitored for at least 30 min. In the event that the IOP 
is 30 mmHg or above, this will be managed according to Section 5.3.2.
 
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5.1.6
Day 7

Concomitant medications and procedures

AE review




5.1.7
Month 1

Concomitant medications and procedures

AE review








5.1.8
Month 3

Concomitant medications and procedures

AE review






 
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





5.1.9
Month 6: Primary Endpoint

Concomitant medications and procedures

AE review














5.1.10
Month 9

Concomitant medications and procedures

AE review

 
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





5.1.11
Month 12

Concomitant medications and procedures

AE review







5.1.12
Month 18

Concomitant medications and procedures

AE review







 
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5.1.13
Month 24 (or Early Termination) Visit

Concomitant medications and procedures

AE review















5.1.14
Long-term Follow-up Visits
Patients completing the Month 24 visit will participate in long-term follow-up visits. Patients 
will be asked to report any AEs that occur during this 3-year follow-up period. At Months 36, 48, 
and 60, patients will undergo the following study assessments conducted at yearly clinic visits:

Concomitant medications and procedures

AE review

Visual acuity 

Complete ophthalmic examination
 
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The procedures for these assessments will be the same as they were for the core study 
assessments.
5.2
Description of Study Procedures
5.2.1
Informed Consent
During the Screening visit, prospective patients will be invited to provide written informed 
consent prior to any screening evaluations. An investigator or study coordinator will provide a 
full explanation of the study, including potential risks of participation and that they may 
withdraw from the study at any time and for any reason without jeopardizing their future 
treatment, and an investigator will provide answers to all questions raised by the prospective 
patient. For those with low vision, a verbal consent will be read out. After ensuring that all 
questions have been answered, written documentation of the informed consent decision will be 
obtained and the consent form will be countersigned by a witness to indicate informed consent 
was obtained.
No study-related procedures will be performed until after informed consent/assent is obtained.
5.2.2
Medical History (Review)
These will comprise:

Documentation of presenting complaints, and history thereof

Ocular medical and surgical history

General medical and surgical history

Current medication use (ocular and other)
5.2.3
Concomitant Medications and Procedures
All medications and procedures will be recorded on the electronic case report form (eCRF). If 
the permissibility of a specific medication/treatment is in question, the investigator is to contact 
Allergan.  Given the ongoing COVID-19 pandemic, selected non-live vaccines (e.g., mRNA, 
non-replicating viral vector, protein subunit) to prevent Severe Acute Respiratory Syndrome 
Coronavirus 2 (SARS-CoV-2) infection may be administered during screening or the treatment 
period, as long as components of the vaccine are not contraindicated.
The decision to receive a locally available vaccine is to be based on local guidance and an 
individual discussion between the treating physician and the subject.
 
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The potential impact of RST-001 on SARS-CoV-2 vaccination is unknown.
5.2.4
Adverse Event Review
All AEs will be recorded at each study visit. COVID-19 infections should be reported as AEs.
5.2.5
Physical Examination
A complete physical examination will be performed at the Screening visit, 6 months, and at 
24 months (or early termination visit), to include vital signs (oral temperature, heart rate, 
respiratory rate and blood pressure), height, weight and examination of major organ systems 
(head/eyes/ears/nose/throat, neck, cardiovascular, respiratory, abdomen, 
musculoskeletal/extremities, skin, lymph nodes and neurological).
Symptom-specific examinations may be carried out and recorded during the study as needed.
5.2.6
Pregnancy Test
Women of childbearing potential will undergo blood serum beta-hCG testing, to be analyzed at 
the site’s preferred certified laboratory.
5.2.7
Blood Sample
A venous sample will be collected from a peripheral vein and laboratory tests will be conducted 
at the preferred certified laboratory.
Blood sample testing will include hematology (hemoglobin, hematocrit, white blood cell count 
with differential and platelet count), chemistry panel (sodium, potassium, chloride, total protein, 
albumin, calcium, phosphorous, glucose, blood urea nitrogen (BUN), creatinine, total bilirubin, 
alkaline phosphatase, lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and 
alanine aminotransferase (ALT)), liver function test panel, and RST-001 immunogenicity testing.  
Instructions for shipping venous blood for immunological analysis are detailed in the 
Study Procedures Manual.
5.2.8
ECG (Electrocardiogram)
A standard 12-lead ECG will be performed. An interpretation of the ECG will be performed by a 
qualified physician, and a signed report will be issued.
5.2.9
Chest X-ray
A standard posterior anterior (PA) chest x-ray will be performed.  An interpretation of the x-ray 
will be performed by a qualified physician, and a signed report will be issued.
 
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5.2.10
Visual Acuity
The visual acuity of each eye will be measured using an electronic visual acuity (EVA) Early 
Treatment for Diabetic Retinopathy Study (ETDRS) testing protocol, or low vision assessment of 
hand motion and light perception as described in the Study Procedures Manual.
5.2.11
Full Field Sensitivity Testing (FFST)
Full field sensitivity testing will be performed using the Espion ColorDomeTM LED full-field 
stimulator (Diagnosys LLC, Lowell, MA) (Klein M, Birch DG, 2009) according to the 
procedures outlined in the Study Procedures Manual.
5.2.12
Object Detection and Discrimination
Patients will perform these two tests concurrently, first identifying if a light displayed on an LED 
screen can be seen and then if a series of standard images (square, circle, triangle, or star) 
presented on the screen can be identified. The color of each shape will either be red or blue. For 
each image tested, the shape, color, and threshold intensity will be recorded.
5.2.13
Pupillometry (at Selected Sites)
The pupil responses of both eyes will be tested using a pupillometry system as described in the 
Study Procedures Manual.
5.2.14
Ambulation
A patient’s ability to navigate within a room will be evaluated according to the procedures 
outlined in the Study Procedures Manual.
5.2.15
Complete Ophthalmic Examination
A complete ophthalmic examination will be performed in both eyes at the Screening and 
Baseline visits and at each visit after study treatment administration.  The examination will 
include a slit lamp biomicroscopic evaluation of the conjunctiva, cornea, anterior chamber, iris, 
and lens. The posterior segment and fundus will also be evaluated through dilated pupils by 
indirect ophthalmoscopy. Intraocular pressure will be measured using Goldmann applanation 
tonometry or a hand held tonometer (using the same instrument for each patient throughout the 
study, when possible). If Goldmann applanation tonometry is used to measure IOP, then it must 
be performed after fundus photography and autofluoresence to prevent fluorescein dye from 
interfering with the images.
 
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5.2.16
Intraocular Pressure (IOP)
IOP measurements will be performed in both eyes at every study visit except on treatment day 
(Day 0), where there will be a pre- and post-injection IOP measurement in the study eye only. 
After the intravitreal injection, the patient will remain in the supine position and IOP will 
be monitored for at least 30 minutes. In the event that the intraocular pressure is 30 mmHg or 
above, it will be managed according to Section 5.3.2.
5.2.17
Dilated Color Fundus Photography and Autofluorescence
A standardized procedure for the collection of single, non-stereo images of the fundus of both 
eyes will be obtained. Color and autofluorescence images of the fundus will be maintained at the 
site until completion of Phase 2a.
5.2.18
Spectral Domain Optical Coherence Tomography (SD-OCT)
Retinal anatomy of both eyes will be evaluated by SD-OCT scans at the 
 
. Additional 
SD-OCT scans may be obtained at the discretion of the investigator. Each SD-OCT will be 
obtained using the site’s preferred macular scanning protocol. Use of the same instrument 
throughout the study for a given patient is recommended.
5.2.19
Electroretinography (ERG)
Electroretinography testing of both eyes will be performed using the full field procedures 
conducted in accordance with standard protocol provided by the ERG Standardization 
Committee of the International Society for Clinical Electrophysiology of Vision (ISCEV) 
standards. Electroretinography will be performed at the 
 
.
5.2.20
Visual Evoked Potentials (VEP)
The pattern of visual evoked potentials will be obtained from each eye using a VEP stimulator 
according to standard protocols as described in the Study Procedures Manual.
5.2.21
Quality of Life Questionnaire (NEI VFQ-25)
A member of the investigative team will administer the National Eye Institute (NEI) Visual 
Functioning Questionnaire (VFQ-25).
 
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5.3
Treatment Administration
RST-001 will be administered by intravitreal injection as specified in the Study Procedures 
Manual.
Prior to study treatment administration, the study eye of each patient will be prepared using the 
standard protocol as described in the Study Procedures Manual.
5.3.1
Post Injection Medications
Topical corticosteroid treatment may be given to the injected eye according to the investigator’s 
standard of care.
5.3.2
Management of Post Injection Intraocular Pressure
The investigator shall have the ability to determine the optimum management of a raised 
intraocular pressure and may use any combination of topical IOP-lowering medications, oral 
acetazolamide or anterior chamber paracentesis in order to normalize the intraocular pressure.
6
Safety Assessments
6.1
Overview of Safety Assessments
Safety assessments in this study can be divided into measures of ocular safety and measures of 
systemic safety.
6.1.1
Ocular Safety Measurements

Visual acuity as measured by low vision assessment of hand motion and light perception

Evaluation of ocular inflammation. Parameters of anterior segment, vitreous and 
retinal/choroidal inflammation will be very carefully monitored

Intraocular pressure measurement (IOP)

Full dilated slit lamp biomicroscopy

Color fundus photography and autofluorescence

Electroretinography (ERG) to ISCEV standards

Visual evoked potentials

Full field sensitivity testing

Spectral domain optical coherence tomography (SD-OCT) of the macula
 
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6.1.1.1
Visual Acuity

Visual acuity as measured by low vision of assessment of hand motion and light 
perception.
6.1.1.2
Ocular Inflammation
Owing to the potential for intraocular inflammation (as noted in the preclinical dog study) or 
immunogenicity, signs of ocular inflammation will be carefully monitored throughout the study 
and reported to the DSMC.  Active inflammation of the anterior chamber, vitreous and 
retina/choroid will be documented in the case report forms according to recognized international 
criteria shown in Table 4, below.  Additional investigations, such as OCT and fluorescein 
angiography, may be performed at the discretion of the investigator according to clinical findings 
and accepted standards of care.
Table 4
Biomicroscopic Grading of Anterior Chamber Cells and Flare 
This is compliant with the standardization of uveitis nomenclature [SUN] working group 
(Jabs et al., 2005).
(a) Anterior chamber cells
Grade 
Cells/1mm2
0+
< 1 cell
0.5+
1-5
1+
6-15
2+
16-25
3+
26-50
4+
>50
Anterior chamber flare
Grade 
Flare
0+
None
1+
Faint
2+
Moderate
3+
Marked
4+
Intense (including fibrin)
 
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Grading of Vitreous haze
Consistent with Nussenblatt RB, Palestine AG, Chan CC et al. Standardisation of vitreal 
inflammatory activity in intermediate and posterior uveitis (Nussenblatt et al, 1985).
Grade 
Vitreous flare
Vitreous 
Haze
Clinical finding
0
None
No haze
Clear view of optic nerve
1
Minimal
Trace
Slight blurring of optic disc margin
2
Mild
1+
Slightly blurred optic nerve and vessels
3
Moderate
2+
Moderately blurred optic nerve and vessels
4
Marked
3+
Optic nerve head border blurry but visible
5
Severe
4+
Optic nerve head obscured
6.1.2
Systemic Safety Measurements
1. Patient-reported and investigator-reported adverse events (AEs)
2. Physical examination findings including vital signs
3. Findings of blood and serum laboratory testing
4. Findings of immunological testing
5. ECG and Chest X-ray results
6. Other clinical and laboratory testing performed by the investigator(s) based upon clinical 
observation, such as:

Vital signs

Clinical safety laboratory parameters

Immune response to RST-001 administration as measured by the testing detailed in 
Section 6.2.1 below.
6.2
Clinical Management of Safety Parameters 
The need for additional clinical evaluations, assessments and visits shall be determined by the 
investigator(s) in accordance with accepted clinical practice and standards of care, where 
applicable. All activity will be recorded in the patient’s source documentation. 
Adverse events definitions and reporting requirements can be found in the Section 8.1 below.
 
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6.2.1
Intraocular Inflammation and Immunogenicity Related to 
RST-001
During the study, evidence of immune response to RST-001 will be monitored by systemic 
measurement of humoral and cellular immunity as follows:
These tests will be performed at several timepoints during the study: 
 
There is no diagnostic test available for ocular immunogenicity. Instead, clinical evidence 
suggestive of immunogenicity will be gathered. Examination findings such as reduced visual 
acuity in the study eye, intraocular inflammation, uveitis, retinal vasculitis, retinal edema, 
hemorrhage, exudation and/or detachment will also be gathered. Additional evaluations such as 
OCT and fluorescein angiography may also aid the clinical identification of an immune response.
Treatment of intraocular inflammation and immunogenicity
In the event that immunogenicity is suspected by the investigator, topical, local, intraocular or 
systemic corticosteroid, corticosteroid-sparing and immunomodulatory therapy may be initiated, 
usually in an escalating fashion, in accordance with the investigator’s practice, to control the 
inflammation. The patient will continue in the study and all additional assessments and visits will 
be documented in the source documents.
6.2.2
Complications of the Intravitreal Injection
The complications of intravitreal injection commonly include mild conjunctival hyperemia and 
subconjunctival hemorrhage. Other uncommon complications include endophthalmitis, retinal 
tears/breaks/detachment, choroidal, vitreous and retinal hemorrhage.
In all instances, management of these complications will be determined by the investigator in 
accordance with his/her practice and standard-of-care, where applicable.
6.2.3
Occupational Safety
The consequences of exposure of clinical personnel to the RST-001 drug are unknown. 
Precautions will be taken to avoid any exposure to the RST-001 product. No antidote is available 
for the RST-001 drug product.
 
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6.2.4
Pregnancy and Exposure to RST-001 In Utero
Females who are pregnant at the Screening and/or Baseline visit will be excluded from the study.  
Females of child-bearing potential are required to maintain contraception during their 
participation in the study.  In the event that a female becomes pregnant during the course of the 
study, the patient will continue to be followed in the study. The investigator should notify the 
sponsor within 24 hours of becoming aware that a female patient or female partner becomes 
pregnant during the course of the study.  Female patients of childbearing potential will require a 
pregnancy test at Month 24 or early termination visit.
The potential effects of in utero exposure to RST-001 are not known.
7
Data Safety Monitoring Committee (DSMC)
7.1
Composition
An independent Data Safety Monitoring Committee (DSMC) will be formed to monitor the data 
from the study. The members of the DSMC will comprise ophthalmologists, physicians and 
statistician(s) with experience in this field of research.
7.2
Role
The primary role of the DSMC is to ensure the protection and safety of patients participating in 
the study. The DSMC will review the general progress and conduct of the study and assist in 
resolving any issues that may arise. The composition and responsibilities, together with the 
agreed schedule for reviewing data will be detailed in the DSMC Charter.
7.3
Responsibilities
1. Monitor and review safety and AE data of patients participating in the study.
2. Advise on dose-escalation, Phase 2a sample size/study population, study suspension or 
termination, as appropriate.
3. Provide review and advice on protocol amendments and changes to the clinical protocol, as 
appropriate.
4. Provide advice on any other matters as deemed necessary for the safe conduct of the study.
5. Provide assessment as to whether treatment benefits have been observed in Phase 1 of the 
study.
 
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7.4
Enrollment Stopping Rules
Enrollment will be suspended pending a complete safety review by the sponsor of all patients 
including causality to determine the appropriateness of continuing dosing in the occurrence of 
the following events:
1. Any Grade 3 or greater AE related to RST-001 (according to Common Terminology 
Criteria for Adverse Events v4.03)
2. Occurrence of an intraocular infection related to contaminated RST-001 that required 
treatment would serve as a stopping rule
3. A safety issue has been identified that compromises the benefit or increases the risk 
balance
Dose-limiting toxicity (DLT) is defined as any adverse event of Grade 3 or higher that is 
expected to be related to the study treatment.
Dose escalation will stop if a DLT is observed, including:
4. Severe or persistent ocular inflammation
5. Other significant ocular toxicity (e.g., retinal detachment, evidence of direct toxicity)
8
Adverse Events
Adverse events occurring during the study will be recorded on an adverse event CRF.  If adverse 
events occur, the first concern will be the safety of the study participants.
8.1
Definitions
8.1.1
Adverse Event
An adverse event is any untoward medical occurrence in a subject or clinical investigation 
patient administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product.  In addition, during the screening period, adverse events will 
be assessed regardless of the administration of a pharmaceutical product.
Note:  Adverse events must be collected once informed consent has been obtained, regardless of
whether or not the patient has been administered study treatment.
 
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Progression of treatment indication including new or worsening of anticipated clinical signs or 
symptoms, which are collected as clinical efficacy variables and assessed as unequivocally 
associated with the disease progression and/or lack of efficacy, should NOT be reported as 
adverse events unless the disease progression is greater than anticipated in the natural course of 
the disease.
Adverse events will be assessed, documented, and recorded in the CRF throughout the study 
(ie, after informed consent has been obtained). At each visit, the investigator will begin by 
querying for adverse events by asking each patient a general, non-directed question such as 
“How have you been feeling since the last visit?” Directed questioning and examination will then 
be done as appropriate.  All reported adverse events will be documented on the appropriate CRF.
8.1.2
Serious Adverse Event
A serious adverse event is any adverse event occurring at any dose that results in any of the 
following outcomes:  death, congenital anomaly or birth defect, significant disability, 
hospitalization, or life threatening.  Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered a serious adverse event when, based 
upon appropriate medical judgment, they may jeopardize the patient or patient and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.
Allergan considers all cancer adverse events as serious adverse events. In addition, Allergan 
considers any abortion (spontaneous or nonspontaneous) as a serious adverse event.
Preplanned surgeries or procedures for pre-existing, known medical conditions for which a 
patient requires hospitalization is not reportable as a serious adverse event.
Any preplanned surgery or procedure should be clearly documented in the site source documents 
by the medically qualified investigator at the time of the patient’s entry into the study. If it has 
not been documented at the time of the patient’s entry into the study, then it should be 
documented as a serious adverse event and reported to Allergan.
 
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8.1.3
Severity
A clinical determination will be made of the intensity of an adverse event. The severity 
assessment for a clinical adverse event must be completed using the following definitions as 
guidelines:
Mild
Awareness of sign or symptom, but easily tolerated.
Moderate
Discomfort enough to cause interference with usual activity.
Severe
Incapacitating with inability to work or do usual activity.
8.1.4
Relationship to Study Drug or Study Procedure
A determination will be made of the relationship (if any) between an adverse event and the study 
drug or study procedure, as applicable.  A causal relationship is present if a determination is 
made that there is a reasonable possibility that the adverse event may have been caused by the 
drug or study procedure.
A study procedure occurring during the screening/baseline period can include a study required 
diagnostic procedure.
For treatment-related adverse events, the investigator will note on the CRF whether the event is 
related to the study drug, and/or the injection procedure.
8.2
Procedures for Reporting Adverse Events
Any adverse event must be recorded on the appropriate CRF.
SARS-CoV-2 infections are to be captured as AEs. If the event meets the criteria for a serious 
adverse event , then follow the serious adverse event reporting directions.
Reactions known to be associated with the SARS-CoV-2 vaccine are to be reported as AEs. If the 
event meets the criteria for a serious adverse event, then follow the serious adverse event
reporting directions.
All adverse events that are drug-related and unexpected (not listed as treatment-related in the 
current Investigator's Brochure) must be reported to the governing IRB as required by the IRB, 
local regulations, and the governing health authorities. Any adverse event that is marked 
“ongoing” at the exit visit must be followed-up as appropriate.
 
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8.3
Procedures for Reporting a Serious Adverse Event
Any serious adverse event occurring during the study period (beginning with informed consent) 
and for at least 28 days after study exit must be immediately reported but no later than 24 hours 
after learning of a serious adverse event. Serious adverse events must be reported to Allergan 
(or Agent of Allergan) as listed on the Allergan Study Contacts Sheet and recorded on the serious 
adverse event form. All patients with a serious adverse event must be followed up and the 
outcomes reported. The investigator must supply Allergan and the IRB with any additional 
requested information (eg, autopsy reports and discharge summaries). 
In the event of a serious adverse event, the investigator must:
1. Notify Allergan immediately by fax or email using the serious adverse event form 
(contact details can be found on page 1 of the serious adverse event form); phone 
numbers and relevant Allergan personnel contacts are also on the front page of protocol.
2. Obtain and maintain in his/her files all pertinent medical records, information, and 
medical judgments from colleagues who assisted in the treatment and follow-up of the 
patient.
3. Provide Allergan with a complete, written description of the adverse event(s) on the 
serious adverse event form describing the event chronologically, including any treatment 
given (eg, medications administered, procedures performed) for the adverse event(s).  
Summarize relevant clinical information about the event:  signs, symptoms, diagnosis, 
clinical course and relevant clinical laboratory tests, etc.  Include any additional or 
alternative explanation(s) for the causality which includes a statement as to whether the 
event was or was not related to the use of the investigational drug.
4. Promptly inform the governing IRB of the serious adverse event as required by the IRB, 
local regulations, and the governing health authorities.
Pregnancy
While not an AE, pregnancy in a study participant must be reported to Allergan within 
24 hours after the site becomes aware of the pregnancy.  If a pregnancy occurs in a study 
participant or in the partner of a study participant, information regarding the pregnancy and 
the outcome will be collected.
The pregnancy outcome of an elective or spontaneous abortion, stillbirth or congenital 
anomaly is considered a serious adverse event and must be reported to Allergan within 
24 hours after the site becomes aware of the event.
 
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9
Efficacy Assessments
A variety of parameters that encompass visual function will be evaluated in the study eye in 
order to identify a signal of efficacy, as follows:

Visual acuity 

Full field sensitivity 

Ambulation

Object detection and discrimination

Visual electrophysiological measures (visual evoked potentials)

Visual function (quality of life as measured by standardized questionnaire)
10
Clinical Monitoring Structure
10.1
Monitoring 
A representative of the sponsor will monitor the study on a periodic basis. The determination of 
the extent and nature of monitoring will be based on considerations such as the objective, 
purpose, design, complexity, blinding, size, and endpoints of the study. Authorized 
representatives of Allergan or regulatory authority representatives will conduct on-site visits to 
review, audit and copy study-related documents. These representatives will meet with the 
investigator(s) and appropriate staff at mutually convenient times to discuss study-related data 
and questions. During the COVID-19 pandemic, remote data review/verification may be 
employed if allowed by the local regulatory authority, IRB/IEC, and the study site.
10.2
Study and Site Closure
The study can be terminated at any time. The study will be considered complete after the final 
patient has completed study visits and assessments.
11
Data Analysis and Statistical Considerations
11.1
Primary (Safety) Endpoint
The primary endpoint is safety at 6 months, as assessed by
Visual function measures:

Change in visual acuity in the study eye

Change in full field sensitivity in the study eye
 
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
Change in ambulation

IOP measurements in the study eye

Changes in anatomical parameters as measured in the study eye by:
o
Fundus photography
o
Spectral domain-OCT (SD-OCT)
11.2
Secondary Endpoints
11.2.1
Measures of Change in Visual function
11.2.1.1
Change in Visual Acuity
Change in visual acuity in the study eye from Baseline (defined as last observed value prior to 
dosing) to 
11.2.1.2
Change in Full Field Sensitivity Testing
Change in retinal sensitivity in the study eye from Baseline to 
11.2.1.3
Change in Ambulation
Change in ambulation scores from Baseline to 
11.2.1.4
Change in Object Detection and Discrimination
Change in object detection and discrimination scores from Baseline to 
11.2.1.5
Change in Visual Evoked Potentials and Electroretinography
Change in VEP and ERG scores from Baseline to 
11.2.1.6
Change in Quality of Life
Change in composite score of NEI VFQ-25 scores from Baseline to 
11.2.2
Anatomical Endpoints Relating to Retinal Integrity and Survival
11.2.2.1
Fundus Photography
Qualitative assessment of the change in retinal appearance from Baseline to 
 
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11.2.2.2
Spectral Domain-OCT (SD-OCT)
Qualitative assessment of the change in retinal cross-sectional appearance from Baseline to 
 
11.3
Statistical Analysis Plans
Summary tables and listings of data will be provided per Statistical Analysis Plan. All summaries 
of categorical data will present frequencies and percentages. All summaries of continuous data 
will present the number of non-missing values, mean, standard deviation, minimum, median and 
maximum.
11.3.1
Power and Sample Size Considerations
The sample size for this study was chosen empirically; no formal sample size computations to 
meet power requirements were made. The sample size of approximately 3 patients for each dose 
group in Phase 1 are typical for dose escalation studies, an additional up to 
approximately12 patients will be enrolled in Phase 2a for further safety and efficacy evaluation.
11.3.2
Baseline Characteristics
Listings and descriptive statistics will be provided for baseline characteristics including 
demographics (race, ethnicity, age, sex) and baseline characteristics (height and body weight).
11.3.3
Safety Analysis
The Medical Dictionary for Regulatory Activities (MedDRA) nomenclature will be used to code 
AEs. Adverse events will be coded from the verbatim text into preferred term and system organ 
class (SOC). The number and percent of patients reporting treatment emergent AEs will be 
tabulated based on the primary SOC and preferred terms. Summary tables will be generated for 
all AEs regardless of causality as well as treatment-related AEs. Further details regarding the 
safety analyses will be presented in the Statistical Analysis Plan.
11.3.4
Efficacy Analysis
Efficacy will be measured by evaluation of visual acuity, full field sensitivity, ambulation, 
quality of life and electrophysiological measures (visual evoked potentials, electroretinography). 
Visual acuity data will be presented as the number of letters correctly identified at each time 
point and the calculated logMAR and Snellen equivalent values, or as count fingers, hand 
motion, and light perception. The Quality-of-life questionnaire will be scored using the NEI 
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11.3.5
Other Analysis
11.3.6
Interim Analysis
No interim analysis is planned. There will be one database lock for the final analysis. The final 
analysis will occur when all patients have completed the Month 60 visit or exited early from the 
study. The details of all analyses will be provided in the analysis plan, which will be finalized 
before database lock.
12
Investigator Responsibilities
In conducting clinical investigations of drugs, including biological products, under 21 CFR part 
312 and of medical devices under 21 CFR part 812, the investigator is responsible for: 

Ensuring that a clinical investigation is conducted according to the signed investigator 
statement for clinical investigations of drugs, including biological products, or agreement 
for clinical investigations of medical devices, the investigational plan, and applicable 
regulations

Protecting the rights, safety, and welfare of patients under the investigator’s care

Controlling drugs, biological products, and devices under investigation (21 CFR 312.60, 
21 CFR 812.100)
13
Data Handling and Record Keeping
Data must be collected in an accurate, consistent, complete and reliable manner in accordance 
with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use Good Clinical Practice (ICH GCP) guidelines.
13.1
Data Management Responsibilities
All clinical information including the results of genetic testing, if performed, will be stored in 
de-identified form on a database maintained by Allergan or Allergan designees.
13.1.1
Data Quality Assurance
All patient data relating to the study will be recorded on printed or electronic CRFs unless 
transmitted to the sponsor or designee electronically (e.g., laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the CRF.
 
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
The investigator must maintain accurate documentation (source documents) that supports 
the information entered in the CRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source documents.

The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.

Study monitors will perform ongoing source verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.

Records and documents, including signed informed consent forms (ICFs), pertaining to 
the conduct of this study must be retained by the investigator for 2 years after study 
completion unless local regulations or institutional policies require a longer retention
period. No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or party 
without written notification to the sponsor.
13.1.2
Source Documents

Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.

Source documents may include a patient’s medical records, hospital charts, clinic charts, 
the investigator’s and patient’s file, as well as the results of diagnostic tests such as x-rays
and laboratory tests.  The investigator’s copy of the CRFs serves as part of the 
investigator’s record of a patient’s study-related data.
14
Study Termination
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason.  Study sites will be closed upon study completion. A study site is considered 
closed when all required documents and study supplies have been collected and a study-site 
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The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB or 
local health authorities, the sponsor’s procedures, or GCP guidelines

Inadequate recruitment of patients by the investigator

Discontinuation of further study treatment development
15
Regulatory and Ethical Considerations
15.1
Ethical Conduct of the Study
This section has been extracted from the NIH guidance on Ethics in Clinical Research 
(http://clinicalcenter.nih.gov/recruit/ethics.html):
The goal of clinical research is to develop generalizable knowledge that improves human health 
or increases understanding of human biology. People who participate in clinical research make it 
possible to secure that knowledge. The path to finding out if a new drug or treatment is safe or 
effective, for example, is to test it on patient volunteers. But by placing some people at risk of 
harm for the good of others, clinical research has the potential to exploit patient volunteers. The 
purpose of ethical guidelines is both to protect patient volunteers and to preserve the integrity of 
the science.
The ethical guidelines in place today were primarily a response to past abuses, the most 
notorious of which in America was an experiment in Tuskegee, Alabama, in which treatment was 
withheld from 400 African American men with syphilis so that scientists could study the course 
of the disease. Various ethical guidelines were developed in the 20th century in response to such 
studies.
Some of the influential codes of ethics and regulations that guide ethical clinical research 
include:

Nuremberg Code (1947)

Declaration of Helsinki (2000)

Belmont Report (1979)
 
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
CIOMS (2002)

US Common Rule (1991)
Using these sources of guidance and others, seven main principles have been described as 
guiding the conduct of ethical research:

Social and clinical value

Scientific validity

Fair patient selection

Favorable risk-benefit ratio

Independent review

Informed consent

Respect for potential and enrolled patients
Social and clinical value
Every research study is designed to answer a specific question. Answering certain questions will 
have significant value for society or for present or future patients with a particular illness. An 
answer to the research question should be important or valuable enough to justify asking people 
to accept some risk or inconvenience for others. In other words, answers to the research question 
should contribute to scientific understanding of health or improve our ways of preventing, 
treating, or caring for people with a given disease. Only if society will gain useful knowledge —
which requires sharing results, both negative and positive — can exposing human patients to the 
risk and burden of research be justified.
Scientific validity
A study should be designed in a way that will get an understandable answer to the valuable 
research question. This includes considering whether the question researchers are asking is 
answerable, whether the research methods are valid and feasible, and whether the study is 
designed with a clear scientific objective and using accepted principles, methods, and reliable 
practices. It is also important that statistical plans be of sufficient power to definitively test the 
objective, for example, and for data analysis. Invalid research is unethical because it is a waste of 
resources and exposes people to risk for no purpose.
Fair patient selection
Who does the study need to include, to answer the question it is asking? The primary basis for 
recruiting and enrolling groups and individuals should be the scientific goals of the study — not 
vulnerability, privilege, or other factors unrelated to the purposes of the study. Consistent with 
 
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the scientific purpose, people should be chosen in a way that minimizes risks and enhances 
benefits to individuals and society. Groups and individuals who accept the risks and burdens of 
research should be in a position to enjoy its benefits, and those who may benefit should share 
some of the risks and burdens. Specific groups or individuals (for example, women or children) 
should not be excluded from the opportunity to participate in research without a good scientific 
reason or a particular susceptibility to risk.
Favorable risk-benefit ratio
Uncertainty about the degree of risks and benefits associated with a drug, device, or procedure 
being tested is inherent in clinical research — otherwise there would be little point to doing the 
research. And by definition, there is more uncertainty about risks and benefits in early-phase 
research than in later research. Depending on the particulars of a study, research risks might be 
trivial or serious, might cause transient discomfort or long-term changes. Risks can be physical
(death, disability, infection), psychological (depression, anxiety), economic (job loss), or social 
(for example, discrimination or stigma from participating in a certain study). Prior to initiating 
this study, reasonable efforts have been taken to minimize the risks and inconvenience to 
research patients, to maximize the potential benefits, and to determine that the potential benefits 
to individuals and society are proportionate to, or outweigh, the risks.
Independent review
To minimize potential conflicts of interest and make sure a study is ethically acceptable before it 
even starts, an independent review panel with no vested interest in the particular study should 
review the proposal and ask important questions, including: Are those conducting the study 
sufficiently free of bias? Is the study doing all it can to protect research volunteers? Has the study 
been ethically designed and is the risk–benefit ratio favorable? In the United States, independent 
evaluation of research projects is done through granting agencies, local institutional review 
boards (IRBs), and Data Safety Monitoring Committees. These groups also monitor a study 
while it is ongoing.
16
Management of Protocol Amendments and Deviations
16.1
Protocol Amendments
The investigator will conduct the study in accordance with this Clinical Study Protocol. 
Implementation of changes to the protocol will only be made following review and approval of 
Protocol Amendment(s) by the sponsor, investigator, Institutional Review Board and the FDA, as 
required.
 
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17
Publication Policy
Allergan as the sponsor, has proprietary interest in this study. Authorship and manuscript 
composition will reflect joint cooperation between multiple investigators and sites and Allergan 
personnel. Authorship will be established prior to the writing of the manuscript. As this study 
involves multiple centers, no individual publications will be allowed prior to completion of the 
final report of the multicenter study except as agreed with Allergan.
18
Sponsor's Final Report
A final report will be prepared by the sponsor.
 
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19
References
Blacklow NR, Hoggan MD and Rowe WP. Isolation of adeno virus-associated viruses from man. 
Proc Natl Acad Sci USA. 1967;58:1410-1415.
Carter PJ, Samulski RJ. Adeno-associated viral vectors as gene delivery vehicles. Int J Mol Med. 
2000;6:17-27.
Daiger SP, Bowne SJ, and Sullivan LS. Perspective on genes and mutations causing retinitis 
pigmentosa. Arch Ophthalmol. 2007;125:151-158.
Dorn JD, Ahuja AK, Caspi A, da Cruz L, Dagnelie G, Sahel JA, gus, I.I.S.G. The detection of 
motion by blind subjects with the epiretinal 60-electrode (argus II) retinal prosthesis. 
JAMA Ophthalmol. 2013;131:183-189.
Flotte TR, Carter BJ. Adeno-associated virus vectors for gene therapy. Gene Ther. 
1995;2:357-362.
Jabs DA, Nussenblatt RB, Rosenbaum JT, and Standardization of Uveitis Nomenclature 
Working, G. Standardization of uveitis nomenclature for reporting clinical data. Results of the 
First International Workshop. Am J Ophthalmol. 2005;140:509-516.
Klein M, Birch DG. Psychophysical assessment of low visual function in patients with retinal 
degenerative diseases (RDDs) with the Diagnosys full-field stimulus threshold (D-FST). 
Doc Ophthalmol. 2009;119:217–224.
Muzyczka N, Berns KI. Parvoviridae: the viruses and their replication. In: Knipe DM, Howley 
PM, eds. Fields Virology. Philadelphia: Lippincott Williams & Wilkins, 2001:2327-2359.
Nussenblatt RB, Palestine AG, Chan C, Roberge F. Standardization of vitreal inflammatory 
activity in intermediate and posterior uveitis. Ophthalmology. 1985;92:467-471.
Rayapudi S, Schwartz SG, Wang X, and Chavis P.  Vitamin A and fish oils for retinitis 
pigmentosa. 2013. Cochrane Database Syst Rev 12, CD008428.
Schnepp BC, Jensen RL, Chen CL, Johnson PR and Clark KR. Characterization of adeno 
associated virus genomes isolated from human tissues. J Virol. 2005;79:14793-14803.
Sohocki MM, Daiger SP, Bowne SJ, Rodriquez JA, Northrup H, Heckenlively JR, Sullivan LS. 
Prevalence of mutations causing retinitis pigmentosa and other inherited retinopathies. Hum 
Mutat. 2001;17:42-51.
 
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20
Appendices
20.1
Appendix 1: Abbreviations
AAV
Adeno-associated Virus
AE 
Adverse Event
ALT
Alanine Aminotransferase
AST
Aspartate aminotransferase
BCVA
Best Corrected Visual Acuity
oC
Degrees Celsius
CFR
Code of Federal Regulations
ChR2
Channelrhodopsin-2
COVID-19
Coronavirus disease - 2019
CRF
Case Report Form
CTC
Common Terminology Criteria for Adverse Events
DLT
Dose Limiting Toxicity
DNA
Deoxyribonucleic Acid
DSMC
Data Safety Monitoring Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
ERG
Electroretinography 
ETDRS
Early Treatment for Diabetic Retinopathy Study
EVA
Electronic Visual Acuity
FDA
Food and Drug Administration, USA
FIH
First-in-Human
FFST
Full Field Sensitivity Testing
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
GMP
Good Manufacturing Practice
IEC
Independent Ethics Committee
IND
Investigational New Drug
IOP
Intraocular Pressure
IRAE
Immediately Reportable Adverse Event
IRB
Institutional Review Board
ISCEV
International Society for Clinical Electrophysiology of Vision
mm
Millimeters
NEI
National Eye Institute
NIH
National Institutes of Health
OCT
Optical Coherence Tomography
QoL
Quality of Life
rAAV
Recombinant Adeno-associated Virus
RGC
Retinal Ganglion Cells
RP
Retinitis Pigmentosa
RST-001
RetroSense Therapeutics drug product (AGN-151597)
SARS-CoV-2
Severe Acute Respiratory Syndrome Coronavirus 2
SD-OCT
Spectral Domain - Optical Coherence Tomography
US
United States
VA
Visual Acuity
VEP
Visually Evoked Potential
VFQ
Visual Functioning Questionnaire
 
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20.2
Appendix 2: Clinical Laboratory Tests
Laboratory parameters for blood draws will evaluate the following, at a minimum:
CBC: complete blood count
Hemoglobin
Hematocrit
Red blood cell count
Mean Corpuscular Volume (MCV)
Mean Corpuscular Hemoglobin (MCH)
Mean Corpuscular Hemoglobin Concentration (MCHC)
White blood cell count with differential (neutrophils, lymphocytes, monocytes,
eosinophils, basophils
Platelet count
Chemistry panel
Sodium
Potassium
Blood Urea Nitrogen (BUN)
Creatinine
Glucose
Chloride
Liver function tests
Albumin
Bilirubin
Total protein
Calcium
Alkaline Phosphatase
AST (SGOT)
ALT (SGPT)
Triglycerides
 
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Serology
Human Immunodeficiency Viral Antibody
Hepatitis B and C Antibody
AAV2 antibody
Pregnancy test
Serology beta-hCG
RST-001 immunogenicity testing
 
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20.3
Protocol Amendment Summary Amendment 1
Title: Phase I/IIa, Open-Label, Dose-Escalation Study of Safety and Tolerability of Intravitreal 
RST-001 in Patients with Retinitis Pigmentosa (RP)
Protocol RST-001-CP-0001 Amendment 1: (March 2017)
Amendment Summary
This summary includes changes made to Protocol RST-001-CP-0001 (approved July 14, 2015). 
Allergan is taking over the sponsorship of Protocol RST-001-CP-0001. The main reasons for this 
amendment were to 1) replace Retrosense Therapeutics with Allergan, Inc. and 2) modify and 
update the protocol to align with Allergan SOPs.
Following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes. Minor editorial and document formatting 
revisions have not been summarized. Deleted text is indicated by strikethrough and added text is 
underlined, as appropriate. This summary provides a high-level list of changes to the document.
Section
Revision
Rationale
Title page 
Updated the title page information with Allergan personnel 
Administrative change
Title page 
Added Allergan signatory and the following text in underline:
The following information can be found on United States FDA 
Form 1572 and/or study contacts page and/or the Trial Master 
File: Name and contact information of Allergan study 
personnel and Emergency Telephone Numbers; name, address, 
and statement of qualifications of each investigator; name of 
each subinvestigator working under the supervision of the 
investigator; name and address of each reviewing Institutional 
Review Board (IRB); US 21 CFR 312.23 section 6(iii)b.
Administrative change
Investigator 
Signature Page 
Removed the investigator name David Birch, Ph.D.
Added spaces for additional investigator signatures and date
Updated section as per Allergan style.
Administrative change
Title page;
Protocol Synopsis;
Section 3.6.3;
Section 3.15.1;
Section 5.4;
Section 20.3
Removed the term “uniocular” 
Uniocular is not an 
Allergan term.  
Title page; Protocol 
Synposis and 
throughout protocol
Added the term “Advanced” before Retinitis Pigmentosa 
Added for consistency 
and clarity with regard 
to the study.
Protocol Synopsis
Objective
To evaluate the safety, tolerability and preliminary efficacy of 
RST-001 in patients with advanced RP. Preliminary efficacy 
data will be obtained through ocular evaluations.
Modified to provide 
clarity
 
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Section
Revision
Rationale
Protocol Synopsis 
Study Population
It expected that up to  Fifteen (15) patients with RP will be 
enrolled into this study. If cohorts need to be expanded this 
number may increase to 18.
Modified to provide 
better clarity to the 
sites and investigators. 
Protocol Synopsis
Study Design
• Structure: Open-label, dose-escalation, non-randomized 
study
• Duration: 2 years
• Treatment: Three doses of RST-001 will be evaluated by 
sequential dose escalation in three the first cohorts of three 
patients (groups A, B, C, each comprising three patients).
Patients will receive a single, uniocular, 100 μL intravitreal 
injection of RST-001 in the study eye. In Cohort 2, up to six 
patients may be enrolled and receive RST-001 at the highest
tolerated dose or any dose that has been previously evaluated 
that is both lower and safe.
• Visit Schedule: Eight visits (including the screening visit) are 
planned over 6 months including the Screening and Baseline 
visits, Day 0, Day 1, Day 7, and Months 1, 3, and 6) to reach 
the primary endpoint. Following the initial 6 months, four more 
visits are planned up to the end of the two year observation 
period patients will be followed for an additional 18 months 
across four visits (Months 9, 12, 18, and 24).
Modified to provide 
better clarity to the 
sites and investigators. 
Consolidated 
information from 
Length of Study and 
Study Visits and 
Assessments into Study 
Design section of 
Protocol Synopsis
Protocol Synopsis
Inclusion and 
Exclusion 
Criteria
Modified to include key inclusion and exclusion criteria
Modified as per 
Allergan style. A full 
list of inclusion and 
exclusion criteria is 
included in the 
Section 3.15.3.
Protocol Synopsis;
Section 6.2.3; 
Section 6.2.7;
Section 6.2.8;
Section 6.2.9;
Section 6.2.10;
Section 6.2.11;
Section 6.2.12;
Section 6.2.13;
Section 6.4.12
Pupillometry (at selected sites)
Modified to provide 
clarity.
Protocol Synopsis 
and Section 3.5
RST-001 (AGN-151597)
Added Allergan 
product code at first 
use 
Protocol Synopsis
Monitoring of 
Safety and 
Tolerability
Safety monitoring will include a combination of Adverse Event
AE reporting, clinical evaluations (systemic and ocular and 
systemic), and laboratory results testing. Specific oOcular and 
systemic safety monitoring will include monitoring for signs of 
an immune response. 
Evidence of systemic immune response will also be monitored.
Modified to provide 
clarity.
 
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Section
Revision
Rationale
Protocol Synopsis 
Clinical Study 
Progress
Participants Patients will be enrolled sequentially.
The dDecision to dose escalate will be determined with the 
Data Safety Monitoring Committee (DSMC) upon review of 
Adverse Event (AE), clinical evaluations (ocular and systemic 
and ocular) and laboratory results testing from enrolled 
participants.
Modified to provide 
clarity.
Protocol Synopsis
Stopping Rules  
Enrollment Stopping Rules 
Any Grade 3 (National Cancer Institute [NCI] grading system
Common Terminology Criteria [CTC] for AEs v4.03) or 
greater adverse event AE considered related to injection test 
article the study treatment.
Added to provide 
consistency throughout 
the document.
Modified for clarity.
List of 
Abbreviations
Moved from Section 3 to Section 20.1 (Appendix 1). All 
subsequent sections of the protocol were renumbered.
Moved for consistency 
with Allergan protocol 
template.
Section 3 
Key Roles Introduction
Removed all clinical site and investigator information
No longer applicable to 
Allergan protocol
Global change
Changed Study Manual of Operations to Study Procedures 
Manual
Modified to maintain 
consistency throughout 
the document.
Section 3.1.5
Removed the sentence: To date, there have been no human 
studies of optogenetic therapy for vision related disorders. 
ClinicalTrials.gov currently lists no other human optogenetic 
clinical trials.
Removed due to 
ongoing current 
Allergan study 
Section 3.7.1 
Retrosense Therapeutics’ preclinical data indicate that no local 
or systemic immunosuppression will be required. Preclinical 
data indicated that no cellular immune or humoral response to 
RST-001 was detected at doses up to 
 and 
 
vg/eye in mice and dogs, respectively. Throughout this study,
In this study, evidence of an immune response to the product 
will be carefully assessed by monitoring for systemic 
measurement of humoral and cellular immunity. Local or 
systemic immune suppression may be initiated if clinically 
indicated.
Modified preclinical 
text for clarity
Section 3.8 
Section renamed: Treatment Administration Surgical 
Procedure for the Delivery of RST 001
RST-001 will be administered delivered by intravitreal 
injection as specified in the Study Procedures Manual. The 
injection volume is 100 µL. through the pars plana, in the same 
fashion as other intravitreal agents in common clinical usage. 
The surgical procedure is detailed in Section 6.5, below.
Prior to study treatment administration, the study eye of each 
patient will be prepared using a standard protocol as described 
in the Study Procedures Manual.
Added to inform the 
site that further 
information can be 
found in the Study 
Procedures Manual for 
this topic.
 
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Section
Revision
Rationale
Section 3.12
The RST-001 drug product has been manufactured in 
compliance with current Good Manufacturing Practice 
(cGMP). Extensive testing has been performed to ensure 
infective agents and pathogens are not present.
Intravitreal Iinjection of RST-001 will be performed in the 
Ooperating Rroom under aseptic conditions by qualified staff 
in accordance with the Study Procedures Manual surgical team 
experienced in the performance of the technique.
After the procedure, Eeach patient will be carefully monitored 
post operatively for complications. Evidence of an immune 
response to RST-001 will be monitored (refer to Section 6.2.1).
Specific procedures are documented in this protocol in the 
event of immune reaction or ocular inflammation.
The conduct of this study will be overseen by the Data Safety 
Monitoring Committee (DSMC).
Administrative change
Section 3.13
Any complications arising post injection, as listed above will 
be managed in compliance with relevant standards of care and
in accordance with the investigator’s standard of care s’ and 
surgeons normal practices.
It is not possible for RST-001 to be removed from the eye after 
injection delivery.
Administrative change
Section 3.15.1.1
Enrollment Phase I (Cohort 1)
Three groups of patients (A, B, C, each comprising 3 patients) 
will be enrolled in recruited to this study. with advanced 
Retinitis Pigmentosa (RP) in accordance with the inclusion and 
exclusion criteria below.
Doses and cohorts are shown in the Table 1. A schematic 
providing an overview of the treatment schedule is also shown 
in Figure 1. Three Approximately 3 Group A patients in 
Group A will receive the lowest dose of RST-001 at the lowest 
dose level (LOW). The safety and tolerability of RST-001 will 
be assessed in the first patient for a minimum of one month 
(to include Month 1 Visit). If the DSMC considers the safety 
and tolerability of the first patient satisfactory and the 
enrollment stopping rules have not been met, then the 
remaining patients in Group A can be enrolled and receive 
treatment. An interval of 1 month (to include visit 6) between 
dosing the first and subsequent patients will be observed in 
order to assess the safety and tolerability of RST 001 in these 
patients.
If after a minimum interval of 1 month (to include visit 6) from 
treatment of the final Group A patient, the DSMC considers the 
safety and tolerability of Group A satisfactory, and the 
enrollment stopping rules have not been met after a minimum 
assessment of one month (to include Month 1 Visit) from the 
last treatment group, then three Group B approximately 
3 patients in Group B may also be enrolled and receive a 
higher dose of RST-001 (MID) following the same guidelines 
and treatment schedule.
Administrative change 
 
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Section
Revision
Rationale
Similarly, An interval of 1 month (to include visit 6) between 
dosing the first and subsequent patients will be observed. Iif 
after a minimum interval of 1 month (to include visit 6) from 
treatment of the final Group B patient, the DSMC considers the 
safety and tolerability of Group B satisfactory, and the 
enrollment stopping rules have not been met after a minimum 
assessment of one month (to include Month 1 Visit) from the 
last treatment group, then approximately 3 three Group C
patients in Group C may also be enrolled and receive the a
highestr dose of RST-001 (HIGH) following the same 
guidelines and treatment schedule. An interval of 1 month (to 
include visit 6) between dosing the first and subsequent 
patients will be observed.
Section 3.15.1.2
If after a minimum interval of 1 month (to include visit 6) from 
treatment of the final patient of any particular group and iIf the 
DSMC considers the safety and tolerability satisfactory and the 
enrollment stopping rules have not been met after a minimum 
assessment of one month (to include Month 1 Visit) from 
treatment of the final patient in Groups A, B, or C, then, the 
sponsor may elect to start enrollment in the second cohort of 
patients of Cohort 2 either at this highest tolerated dose or any 
dose that has been previously evaluated that is both lower and 
safe. In cCohort 2, up to six patients may be enrolled and 
receive RST-001 at this highest tolerated dose or any dose that 
has been previously evaluated that is both lower and safe.
A schematic providing an overview of the treatment schedule 
is illustrated in Figure 1, and the dose-escalation cohorts are 
illustrated in Table 1 below.
The primary endpoint of the study is safety at 6 months post 
RST 001 treatment up to which, participants will attend for 
12 scheduled visits. A further 6 visits are planned up to the end 
of the study at 2 years. 
At each visit, a battery of visual, ocular and systemic testing 
will rigorously evaluate the safety of RST 001. Ocular 
evaluations will also offer the opportunity to obtain potential 
preliminary efficacy data. Due to the nature of the study and 
the study drug, only summary statistics will be available and 
there is no opportunity to evaluate pharmacokinetics.
It is anticipated that enrollment will be completed after 
18 months.
Administrative change
Table 1 
Removed the Age column.
Added footnotes:
(a) Fifteen (15) patients will be enrolled in this study. 
(b) The highest tolerated dose or any dose that has been 
previously evaluated in Cohort 1 that is both lower and 
safe.
Modified to provide 
clarity.
Section 3.15.1.2 
(Figure 1)
Added title: Overview of the Treatment Schedule
Added title to include 
in table of contents
 
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3.15.2
Up to 15 participants A total of Fifteen (15) patients with RP 
can will be enrolled into this study. though if additional 
participants are added to groups A C, then this total may 
increase to 18.
Administrative change
3.15.3.1
Inclusion criteria displayed as general inclusion criteria and 
ocular inclusion criteria.
Modified for 
consistency with 
Allergan protocol 
template.
3.15.3.2
Exclusion criteria displayed as general exclusion criteria and 
ocular exclusion criteria.
Modified for 
consistency with 
Allergan protocol 
template.
3.15.4
Early Discontinuation Removal of pPatients from the study
Patients may voluntarily withdraw from the study at any time 
or for the following reasons:
a)
Voluntarily, at any time. Patients that withdraw may 
be replaced.
a)
Due to an adverse event (AE)
b)
At the request of If deemed necessary by the 
investigator or the sponsor that it is unsafe for the patient to 
continue in the study.
When possible, the decision to withdraw a patient from study 
treatment or the study should be discussed with the sponsor. 
Notification of early patient discontinuation from the study and 
the reason for discontinuation will be clearly documented on 
the appropriate Case Report Form (CRF).
In the case of a withdrawing patient, every reasonable attempt 
will be made to complete a final early-termination visit (as 
shown in the study visit table). Patients who withdraw from the 
study prior to receiving the study treatment agent may be 
replaced.
Administrative change
Section 4.8 
RST-001 must be prepared under aseptic conditions as 
described in the Study Procedures Manual.
Keep residual study treatment agent separately from unused 
study vials.
Modified to provide 
better clarity to the 
sites and investigators.
 
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Immediately prior to study agent treatment administration, the 
patient will be placed in the supine position and the 
participant’s eye will be prepared for injection in accordance 
with the description given in the Study Procedures Manual
Section 6.5
Section 4.9 
The investigator or designated study site personnel is 
responsible for study agent treatment accountability, 
reconciliation and record maintenance.
Removed sentence: “All unused study agent must be returned 
to Allergan or Allergan designee at the completion of the 
study.”
Added:  All study treatment must be returned to Allergan or 
Allergan designee at the completion of the study.
Modified to provide 
better clarity to the 
sites and investigators.
Language regarding the 
return of study drug 
was added to 
Section 4.9 
Section 4.12 
During the course of the study, participants patients will be 
allowed to continue taking all prescribed and non prescribed
over-the-counter medications that are not excluded in the 
protocol (i.e., anticoagulants and immunosuppressive therapy).
Administrative changes
Section 5 
Section 5: Study Assessments and Intravitreal Injection
Surgical Procedure
Only individuals who have been Patients diagnosed with 
advanced RP and who are eligible based on inclusion and 
exclusion criteria will be invited to participate in this clinical 
study trial. After obtaining informed consent and authorization, 
patients will undergo A complete physical examination and 
clinical chemistries will be performed at a pre treatment, 
screening evaluation laboratory testing to further determine to 
assess eligibility for the study. 
Subjects will be considered enrolled when they sign the 
Informed Consent.
Patients who meet inclusion criteria will be considered eligible 
for study entry and will receive a single intravitreal injection of 
RST-001. Following RST-001 administration (dDay 0) patients 
will be assessed on the first post injection day (dDay 1) and 
thereafter according to the table below:
Administrative changes
Section 5 (Table 2) 
Visit windows for Months 12, 18, and 24 were changed to 
± 30 days.
The following other changes were made:
Review of Ophthalmic and mMedical hHistory
A row was added for the Concomitant Medications and 
Procedures to match the same assessment time points for 
Ophthalmic and Medical History.
The row for Fundus autofluorescence was merged and renamed 
to Color Fundus Photography and Autofluorescence.
Modified to provide 
better clarity to the 
sites and investigators 
and maintain 
consistency throughout 
the document.
 
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Eye Complete Ophthalmic Examination
The following footnotes were added or edited:
(a) If convenient, the Screening and Baseline visits may be 
combined.
(b) Month 24 or early termination visit
(c) Any changes in ophthalmic and medical history will be 
noted post Screening.
(d) Blood draw studies samples will include hematology, 
chemistry and RST-001 immunogenicity testing: see 
Appendix 1 2 details.
(e) Topical corticosteroid treatment may be given to the 
injected eye according to the investigator’s standard of care.
(f) After the intravitreal injection, the patient will remain in the 
supine position and (IOP) intraocular pressure will be 
monitored for at least 30 min. In the event that the IOP is 
30 mmHg or above, this will be managed according to 
Section 5.4.2.
Section 5 (Table 2) 
Added Pregnancy testing at study exit or early termination visit
Added to comply with 
Allergan standards
Section 5.1 and 
5.1.1.
Screening Procedures and Screen Failures removed
Removed to comply 
with Allergan protocol 
template.
Section 5.1.1.
Added Section 5.1.1: Informed Consent and Patient Privacy
The study will be discussed with the patient and patient’s 
impartial witness or legally acceptable representative. A patient 
wishing to participate must give informed consent and 
authorization prior to any study-related procedures. The patient 
must also give authorization (U.S. only) and other written 
documentation in accordance with the relevant country and 
local privacy requirements (where applicable) prior to any 
study-related procedures or change in treatment. 
Each patient that provides informed consent and assent will be 
assigned a patient number that will be used on patient 
documentation throughout the study.
Removed section on visit windows
Administrative change
Repetitive information
Sections 5.1.2 to 
5.1.13.
The subheadings of each study timepoint were labeled using 
visit windows instead of visit number.
The following assessment titles were modified or added to the 
bulleted lists for consistency with Table 2 (Study Visit 
Schedule), where applicable:

Informed consent and authorization

Ophthalmic and Mmedical Hhistory, concomitant 
medications

Concomitant medications and procedures

AE review

Physical Eexamination
Administrative change
 
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
Pregnancy test (blood)

Draw Bblood sample Draw 

Object detection and discrimination

Visual acuity (BCVA, ETDRS)

Visual field testing 

Eye exam (full dilated ophthalmic exam) Complete 
ophthalmic examination

Fundus autofluorescence

Dilated color Ffundus photography and 
autofluorescence

Pattern VEP
Section 5.1.4 
Added endnote: After the intravitreal injection, the patient will 
remain in the supine position and IOP will be monitored for at 
least 30 min. In the event that the IOP is 30 mmHg or above, 
this will be managed according to Section 6.5.2
Added to maintain 
consistency throughout 
the document.
Section 5.1.13 
Added pregnancy test to study exit or early termination visit
Added to maintain 
consistency throughout 
the document
Section 5.3.1
For those with low vision, the a verbal consent form will be 
read out. 
Administrative change
Section 5.3.2 
Removed bullet: “Pertinent family and social history”
Modified for better 
clarity
Section 5.3.4 
Symptom-specific examinations may be carried out and 
recorded during the study as needed necessitated by medically 
significant events.
Modified to provide 
clarity.
Section 5.3.7
A Sstandard 12-lead ECG will be performed. An interpretation 
of the ECG will be performed by a qualified physician, 
cardiologist and a signed report will be issued.
Modified to provide 
better clarity.
Section 5.3.8
A standard posterior anterior (PA) chest Xx-ray will be 
performed.  An interpretation of the Xx-ray will be performed 
by a qualified physician radiologist, and a signed report will be 
issued.
Modified for better 
clarify
Section 5.3.9 
The best corrected visual acuity of each eye will be measured 
performed using the an electronic visual acuity (EVA) ETDRS
Early Treatment for Diabetic Retinopathy Study (ETDRS) 
testing protocol methodology, or low vision assessment of 
hand motion and light perception as described in the Study 
Procedures Manual.
Modified to provide 
more details and 
clarity. Details added to 
Study Procedures 
Manual.
Section 5.3.10 
Full field sensitivity testing FFST will be performed using the 
Espion ColorDomeTM LED full-field stimulator (Diagnosys 
LLC, Lowell, MA) (Klein M, Birch DG, 2009) according to 
the procedures outlined in the Study Procedures 
Manual.according to standard protocol.
Provided more details 
for clarity.
Section 5.3.11
Participants Patients will perform these two tests concurrently, 
first identifying the location of an LED wall mounted screen 
and then identifying a series of standard images (square, circle, 
triangle, or star) presented on the screen. The color of each 
shape will either be red or blue. For each image tested, the 
shape, color, and threshold intensity will be recorded.
Provided more details 
for clarity.
 
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Section 5.3.12
The pupil responses of both the treated and fellow eyes will be 
tested using a two semi automated pupillometry systems as 
described in the Study Procedures Manual.
Modified to provide 
clarity.
Section 5.3.14
A complete ophthalmic Ophthalmological examinations in 
both eyes will be performed at the Screening and Baseline 
visits and at each visit after study agent administration. These
examinations will include a slit lamp biomicroscopic 
evaluation of the conjunctiva, cornea, anterior chamber, iris, 
and lens. anterior segment examination, Goldmann tonometry,
The dilated posterior segment and fundus will also be 
evaluated through dilated pupils by indirect ophthalmoscopy. 
Intraocular pressure will be measured using Goldmann 
applanation tonometry or a hand held tonometer (using the 
same instrument for each patient throughout the study, when 
possible). If Goldmann applanation tonometry is used to 
measure IOP, then it must be performed after fundus 
photography and autofluoresence to prevent fluorescein dye 
from interfering with the images examination.
Modified to provide 
clarity.
Section 5.3.15
Dilated Color Fundus Photography and Autofluorescence
A standardized procedure for the collection of Ssingle, 
non-stereo images of the fundus of both eyes will be obtained. 
Color and autofluorescence images of the fundus will be kept 
at the site.
6.4.16
Fundus Autofluorescence
Autofluorescence images of the fundus of both eyes will be 
obtained.
Modified to provide 
clarity
Section 5.3.16
Added the sentence:
Use of the same instrument throughout the study for a given 
patient is recommended.
Added to provide clear 
directions to study site.
Section 5.3.17
Electroretinography testing of both eyes will be performed 
using the Ffull field procedures conducted in accordance with 
standard protocol provided by the ERG Standardization 
Committee of the electroretinography (to International Society 
for Clinical Electrophysiology of Vision [(ISCEV)] standards). 
Electroretinography will be performed at the Screening visit, 
6-months primary end point, and conclusion of the study at 
24 months (or early termination visit).
Modified to provide 
clarity.
Section 5.3.19
In the event that the patient is unable to complete the 
questionnaire on their own, the questionnaire will be read to 
the patient and their answers documented.
Removed to provide 
clarity.
Section 5.4
Eligible patients will be treated with a single intravitreal 
injection of RST-001 will be administered by intravitreal 
injection as specified in the Study Procedures Manual. 
Prior to study treatment administration, the study eye of each 
patient will be prepared using the standard protocol as 
described in the Study Procedures Manual.
The procedure will be undertaken by the retina trained faculty 
physician investigator, except where noted. 
Details removed and 
added to Procedure 
Manual
 
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Section 5.4.1 
Gtts Pred Forte will be given to the injected eye four times 
daily for two weeks and then twice daily for two weeks. 
Topical corticosteroid treatment may be given to the injected 
eye according to the investigator’s standard of care.
Modified for better 
clarity
Section 5.4.2 
The investigator shall have the ability to determine the 
optimum management of a raised intraocular pressure and may 
use any combination of topical IOP-lowering anti glaucoma 
medications, oral acetazolamide or anterior chamber 
paracentesis in order to normalize the intraocular pressure.
Modified to standard 
Allergan terminology
Section 6.1 
Moved all Ocular Safety Measurements prior to Systemic 
Safety Measurements to correct order of descriptions. The 
headings are as follows:
Section 6.1.1 Ocular Safety Measurements
Section 6.1.1.1 Visual Acuity
Section 6.1.1.2 Ocular Inflammation
Section 6.1.2 Systemic Safety Measurements
Modified for better 
clarity
Sections 6.1.1 and 
6.1.1.1
Best corrected visual acuity (BCVA) as measured by EVA 
modified ETDRS letter score, if possible, as measured or by
low vision of assessment of level of hand motion or and light 
perception.
Modified to provide 
consistency within the 
document.
Section 6.2
The following paragraph was modified:
The need for additional clinical evaluations, assessments and 
visits shall be determined by the investigator(s) in accordance 
with accepted clinical practice and standards-of-care, where 
applicable. All activity will be recorded in the patient’s source 
documentation. All adverse events will be monitored until 
resolution or stabilization.
Added clarity to study 
sites and following 
standard Allergan 
procedures
 
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Section 6.2.1 
Removed first sentence: “The immunogenicity of the RST 001 
product has been evaluated in animal models and it was 
determined that the doses proposed in this study fall below the 
Dose Limiting Toxicity.”
Modified for clarity. 
Sentence was not 
relevant for the section. 
Immunogenicity in 
animal models may not 
necessarily translate to 
humans.
Section 6.2.4
Modified the following sentence:
The Investigator should notify the and sponsor will be 
informed within 24 hours of becoming aware that a female 
patient or female partner becomes pregnant during the course 
of the study. Female patients of childbearing potential will 
require a pregnancy test at study exit (Month 24) or early 
termination visit.
Added to maintain 
consistency throughout 
the document
Sections 6.6 to 6.7.2 
(original protocol 
section numbers)
The following sections were removed because these topics are 
discussed in Section 7.4:
Sections 6.6, 6.7, 6.7.1, and 6.7.2.
Redundant Sections 
were removed to 
conform to Allergan 
template
Section 6.8 (original 
protocol section 
number)
Removed subheading Long-Term Follow-up Plan
Removed redundant 
sections within 
protocol to conform 
with Allergan template.
Section 7.2.5 
(Section number in 
original protocol)
Removed language regarding patient injury and financial 
compensation
This will be provided 
in further detail in the 
Informed Consent 
Form
Section 7.4 
Modified first paragraph:
Enrollment will be suspended pending a complete safety 
review of all patients including causality to determine the 
appropriateness of continuing dosing in the occurrence of the 
following events: immediately suspended in the event that one 
of the stopping rules below is met:
Removed line item #4:
“Failure to recruit participants in a practical timescale”
Added the following:
Dose-limiting toxicity (DLT) is defined as any adverse event of 
Grade 3 or higher that is possibly, probably or definitely 
related to the study treatment.  
Dosing will stop if a DLT is observed, including:
4.
Severe or persistent ocular inflammation
5.
Other significant ocular toxicity (e.g., retinal 
detachment, evidence of direct toxicity).
Modified to maintain 
consistency within the 
document.
Removed to provide 
clarity
Added text for clarity.
 
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Revision
Rationale
Section 8.1 
Added the following text: “AEs occurring during the study will 
be recorded on an AE case report form. If AEs occur, the first 
concern will be the safety of the study patients.
The investigator and any designees are responsible for 
detecting, documenting, and recording events that meet the 
definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the 
study treatment or study procedures, or that caused the patient 
to discontinue the study.  Phone and fax numbers of relevant 
Allergan personnel contacts are also on the front page of the 
protocol.”
Modified to align with 
Allergan standard 
language.
Section 8.2.3
Added below “or cancers”:
Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug 
dependency or drug abuse, or cancers.
Modified to align with 
Allergan standard 
language.
Section 8.3.1
Deleted the following sentence:
“When an AE occurs after written consent has been obtained 
but prior to the first dose of RST 001, the AE will be 
considered a non treatment emergent AE. An AE that occurs 
from the time the patient receives his/her first dose of RST 001 
until his/her last study visit will be considered a treatment
emergent AE.”
Sentence deleted to 
align with Allergan 
template.
Section 8.3.3
Added bullet point:
•
Allergan classifies all cancers as SAE’s
Added to maintain 
consistency throughout 
the document
Section 9
Modified bullet points:
•
Visual acuity (EVA ETDRS acuity) 
•
Full field Visual field sensitivity (full field sensitivity 
test)
•
Navigation and object detection (object detection and 
discrimination, ambulation) Ambulation
•
oObject detection and (object detection and
discrimination, ambulation)
Modified bullets to 
provide clarity and 
keep consistency 
within protocol.
Section 10.1 
Removed all text in Monitoring Section and replaced with 
Allergan standard language
Modified to align with 
Allergan standard 
SOPs
Section 11.1 
Added and modified the following:
•
Change in visual full field sensitivity
•
Change in ambulation and navigation
IOP measurements
Changes in Aanatomical parameters as measured by:
• RetinalFundus photography
Modified for clarity.
Will be including IOP 
measurements for 
safety.
Sections 11.2.1.1 to 
11.2.2.2
Removed the 6-month timepoint for the analyses of change in 
visual acuity, full field sensitivity, ambulation, Fundus 
photography, and spectral domain-OCT.
6-month time point was 
added as a secondary 
endpoint if not captured 
as a primary endpoint; 
modified for clarity and 
consistency.
 
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Section
Revision
Rationale
Section 11.2.1.4
Change in Object Detection and Discrimination
Change in object detection and discrimination scores from 
Baseline to
. Change in Quality of Life 
(QOL)
Modified to provide 
clarity.
Section 11.3.2
Listings and descriptive statistics will be provided for baseline 
characteristics including demographics (race, ethnicity, age, 
sex,), clinical variables  and baseline characteristics
(temperature, blood pressure, pulse, respiratory rate, height, 
and body weight), laboratory measurements (hematology, 
clinical chemistry parameters, and immunogenicity testing), 
and ocular variables (visual acuity, visual field sensitivity and 
size, visual function, electrophysiological and anatomical 
tests).
Data provided in other 
safety listings and not 
baseline characteristics
Section 11.3.3
Safety will be monitored by evaluation of ocular and non
ocular AEs, hematology and clinical chemistry parameters.
The Medical Dictionary for Regulatory Activities (MedDRA) 
nomenclature will be used to code AEs. Adverse events will be 
coded from the verbatim text into preferred term and system 
organ class (SOC). The number and percent of patients 
reporting treatment emergent AEs will be tabulated based on 
the primary SOC and preferred terms. Summary tables will be 
generated for all AEs regardless of causality as well as 
treatment-related AEs. Further details regarding the safety 
analyses will be presented in the Statistical Analysis Plan.
Adverse events will be coded into MedDRA preferred terms. 
The number and percentage of participantspatients within each 
treatment assignment experiencing each specific adverse 
experience will be tabulated by intensity and by relationship to 
treatment. For the calculations in these tables, each 
participant’spatient’s adverse experience will be counted once 
under the maximum intensity or the strongest recorded causal 
relationship to treatment. A complete listing of serious adverse 
experiences for each participantpatient will provide details 
including intensity, relationship to treatment, onset, duration 
and outcome. Listings and descriptive statistics will be 
provided for each time point for all laboratory parameters.
Modified for 
consistency throughout 
the document and to 
align with the Allergan 
template.
Section 11.3.6
Enrollment will begin with Group A in Phase 1 and will 
proceed to subsequent groups after satisfactory review of 
safety data by a DSMC. After completion of this first phase of 
the study, participants patients will be treated in Phase IIa part
of the study.
Before each DSMC review, the investigators and sponsor will 
prepare a summary of all available data. For DSMC reviews 
related to enrollment in subsequent groups, this summary will 
include data at least through a minimum of Month 1 visit 6 for 
all available participants patients.
Modified for clarity.
Section 13 and 
Section 14
Section 13: Data Handling and Record Keeping and Section 14 
Data Quality Control and Assurance
Sections were modified 
to Allergan standard 
language for clarity.
Section 15 
Removed language regarding informed consent and respect for 
potential and enrolled subjects. 
Deleted to align with 
Allergan template.
 
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Section
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Rationale
Section 16 
Removed language regarding protocol deviations.
Deleted to align with 
Allergan template.
Section 17 
Publication Policy section was revised with Allergan standard 
language
Updated to provide 
clarity to Investigator 
and study site
Section 19
Two references were removed: 
Blacklow et al, 1971 and Maclachlan et al, 2011 
Added reference: Klein M, Birch DG
These are not included 
in the protocol and 
have been removed 
from the reference 
section
Klein reference added 
to verify content.
Section 20
Added Appendix 1: Abbreviations
Added Appendix 2: Clinical Laboratory Tests from original 
protocol. No new information is added.
Removed Appendix 2 DSMB Charter, Appendix 3: 
Investigator Expectations, and Appendix 4: Good Clinical 
Practice Consolidated Guidance
Added appendix 2 at 
the end of the protocol 
as standard Allergan 
practice. 
Per Allergan SOPs, 
these are not necessary 
to include in the 
protocol
 
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20.4
Protocol Amendment Summary Amendment 2
Title: Phase I/IIa, Open-Label, Dose-Escalation Study of Safety and Tolerability of Intravitreal 
RST-001 in Patients with Retinitis Pigmentosa (RP)
Protocol RST-001-CP-0001 Amendment 2: (October 2017)
Amendment Summary
This summary includes changes made to Protocol RST-001-CP-0001 Amendment 1 (approved 
March 06, 2017). The main reasons for this amendment were to 1) incorporate the 13-year long-
term follow up period in this protocol, 2) specify that sample size and VA inclusion criteria in 
Phase 2a are dependent on a DSMC assessment as to whether treatment benefits have been 
observed in Phase 1, 3) add additional study measures, and 4) add protocol amendment changes 
made in August 2015 by RetroSense in response to FDA comments after initial protocol review.
Following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes. Minor editorial and document formatting 
revisions have not been summarized. Deleted text is indicated by strikethrough and added text is 
underlined, as appropriate. This summary provides a high-level list of changes to the document.
Section
Revision
Rationale
Protocol Synopsis
Study Population
Up to approximately 21Fifteen (15) patients will be 
enrolled in this study.  
Reflects a potentially 
larger sample size for 
Phase 2a
Protocol Synopsis
Study Rationale
To provide further guidance toward the design of a pivotal 
efficacy study, the study also includes the option to expand, 
by up to 6approximately 21, the number of patients
Reflects a potentially 
larger sample size for 
Phase2
Protocol Synopsis
Study Design
• Duration: 2 years (with an additional 13 years of long-
term follow-up)
• Treatment: Three doses of RST-001 (low, mid, and high, 
each group comprising of approximately but no less than 
three patients) will be evaluated by sequential dose 
escalation in the first cohort of patients (groups A, B, C, 
each comprising three patients. Phase 1. Patients will 
receive a single 100 µL intravitreal injection of RST-001 in 
the study eye. In Cohort 2, up to six In Phase 2a, 
approximately 6.-12 patients may be enrolled and receive 
RST-001 at the highest maximum tolerated dose or any 
dose that has been previously evaluated that is both lower 
and safe.
The doses used in the study have been calculated from the 
pre-clinical animal toxicology studies, as follows:

Low dose =
vg/eye

Mid dose = 
vg/eye

High dose =
 vg/eye
Changed to reflect 
incorporation of long-
term follow up visits 
into the existing 
protocol and to provide 
further clarity.
 
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• Visit Schedule:

Core Study Visits: Twelve eight visits are planned 
over 24 6 months including the Screening and 
Baseline visits, Day 0, Day 1, Day 7, and Months 
1, 3, and 6, 9, 12, 18, and 24.) to reach the primary 
endpoint.

Long-term follow-up: After completion of the 
Month 24 visit, each patient will participate in a 
long-term follow-up study for an additional 13 
years to monitor the long-term safety of RST 001. 
This includes a yearly visit for 5 years (Months 
36, 48, 60, 72, and 84). After 5 years, telephone 
interviews will be conducted over an 8-year period 
(Months 96, 108, 120, 132, 144, 156, 168, and 
180) for a total 13 years of long-term follow-up.
Protocol Synopsis
Inclusion Criteria
Phase 1 and Phase 2a:
1.
Male or female patients, ≥ 18 years of age at time 
of informed consent
2.
Diagnosis of advanced RP defined as:
Visual acuity (VA) in the study eye of no better
than hand motion
VA in the non study eye of no better than count 
fingers
3.
Phase 1:
4.
Visual acuity (VA) in the study eye of no-better-
than hand motion
Phase 2a:
5.
The DSMC will review the results from Phase 1 to 
determine if a documented treatment benefit was 
observed in the patients. If the DSMC identifies a 
treatment benefit, no changes will be made to the 
eligibility criteria. If the DSMC does not identify a 
treatment benefit, VA eligibility criteria will 
match that of Phase 1 for half of the enrolled 
patients. VA criteria for the other half of the 
enrolled patients must range from no-worse-than 
count fingers to 20/200 vision in the study eye.
Reflects the potential 
change in VA criteria 
for Phase IIa depending 
on results from Phase I
Protocol Synopsis
Exclusion Criteria
6.
Use of anti-platelet agentsand anti-coagulants that 
may alter coagulationclotting within 28 days prior 
to study treatment administration.
Provides further clarity
Protocol Synopsis
Primary endpoints
The primary endpoint is safety at 6 months from Baseline
start of study treatment.
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Protocol Synopsis
Analysis plan
NoThe sample size for this study was chosen empirically; 
no formal sample size computations to meet power 
requirements were made. The sample size for this study 
was chosen empirically, as reasonable to answer the 
primary safety objective. The sample size of approximately
3 patients per singlefor each dose cohortgroup in Phase 1 
are typical for Phase I/IIadose escalation studies of this 
type, , an additional up to approximately 12 patients will be 
enrolled in Phase 2a for further safety and are expected to 
provide a sufficient number of observations to meet the 
objectives of the studyefficacy evaluation.
Provides further clarity
Section 3.3
Recombinant AAV (rAAV) vectors insertare composed of 
a transgene expression cassette between the inverted 
terminal repeatrepeats (ITRs), which guide packaging theof 
vector DNA into AAV capsids.
Provides further clarity
Section 3.4
To date there are no approved products utilizing AAV2 but 
there are 43a number of clinical studies that either have 
been completed or are ongoing worldwide, 21 of these are 
in the United States, 8some of which are in the area of 
ophthalmology, including one inindications like
neovascular age-related macular degeneration, four in
Leber Congenital Amaurosis (LCA), and one in
choroideremia.
Removal of outdated 
information
Section 3.7
If the Data Safety Monitoring Committee (DSMC) 
considers the safety and tolerability of RST-001 
satisfactory in the first phase, then the study may proceed 
to the second phase. The second phase of the studyPhase 
2a. Phase 2a is aimed at obtaining additional safety data at 
the highestmaximum tolerated dose and providing. An 
additional objective of Phase 2a is to provide important 
additional clinical data to guide the design of future 
efficacy studies.
Provides further clarity
Section 3.15.1.1
Three groups of patients (A, B, C, each comprising 3of 
approximately but no less than three patients) will be 
enrolled in this study.
After completion of the 2-year core study visits, each 
patient will be enrolled in a long-term follow-up for an 
additional 13 years to monitor the long-term safety of RST 
001.
Changed to reflect 
incorporation of long-
term follow up visits 
into the existing 
protocol.
Section 3.15.1.2
In Cohort 2Phase 2a, up to sixapproximately 12 patients 
may be enrolled and receive RST-001 at this highestthe 
maximum tolerated dose. or any dose that has been 
previously evaluated that is both lower and safe.

If the DSMC considers the data from Phase 1, in 
their opinion, to be indicative of a treatment 
benefit for visual acuity/function, then 
approximately 6 patients will be enrolled in 
Phase 2a and follow the same eligibility criteria as 
Phase 1.
Reflects the potential 
change in VA criteria 
for Phase 2a depending 
on results from Phase 1. 
Long term follow up is 
no longer going to be a 
separate protocol, so 
that information has 
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Phase 2a
5.
If a treatment benefit is identified by the DSMC:
a.
VA eligibility criteria will match that of 
Phase 1.
6.
If a treatment benefit is not identified by the 
DSMC:
a.
VA eligibility criteria will match that of 
Phase I for half of the enrolled patients.
b.
VA criteria for the other half of the 
enrolled patients must range from no-
worse-than count fingers to 20/200 vision 
in the study eye.
7.
Presence of retinal ganglion cells and/or retinal 
nerve fiber layer on SD OCT testing
Section 3.15.3.2
1. Participation in any investigational drug or device study 
within six months prior to Baseline Day 0;
2. Complicating systemic diseases or clinically significant 
abnormal baseline laboratory values. Complicating 
systemic diseases include those in which the disease itself, 
or the treatment for the disease, can alter ocular function. 
Examples are malignancies whose treatment could affect 
central nervous system function (i.e., radiation treatment of 
the orbit; leukemia with CNS/optic nerve involvement). For
the procedure on establishing clinically significant 
abnormal baseline laboratory values, see Section 5.1.2.
11. Cataract surgery, intraocular and/or peri-ocular 
injection in the study eye within six months prior to 
Baseline Day 0
Incorporation of 
protocol amendments 
made by RetroSense in 
response to FDA 
comments in 2015
Section 4.2

Low dose =
vg/eye

Mid dose = 
vg/eye

High dose =
 vg/eye
Provide further clarity
Section 4.3
This is a sequential dose-escalation study. ThreeIn Phase 1, 
three groups, each comprising of approximately but no less 
than three patients, will be enrolled one after the other, 
receiving first the low dose, then the mid, and finally the 
high dose.
Escalation is dependent upon the enrollment stopping rules 
and DSMC recommendation.
In Phase 2a, up to an additional sixapproximately 
12 patients may then be enrolled in parallel at the 
maximum tolerated dose.
Reflects change in 
sample size and 
provides further clarity.
Section 4.4
The rationale for the dosing schedule is once again based 
primarily on patient safety. Thus, at each dose a single 
patient will receive treatment followed by an intensive 
period of observation for any evidence of AEs prior to 
dosing the remaining two patients in the group. The safety 
and tolerability and optimal single dose of RST-001 will 
therefore be established in the first three groups. The fourth 
dose groupPhase 1. Phase 2a patients will receive a single 
intravitreal injection of RST-001 at the highestmaximum
dose tolerated by the prior three groupsPhase 1 patients.
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Section 4.7
The study treatment RST-001 is provided as a sterile frozen 
liquid and must be stored at 
°C or below. Stability 
testing indicates RST-001 is stable for at least 
°C or below.
Change requested by 
CMC
Section 4.9
All study treatment must be returned to Allergan or 
Allergan designee at the completion of the study.patient 
enrollment.  
Changed to reflect the 
increased duration of 
the study.
Section 4.12
(i.e., antiplatelets and anticoagulants prior to treatment, and 
immunosuppressive therapy).
Provide further clarity
Section 5
Patients who meet inclusion criteria will be considered 
eligible for study entry and will receive a single intravitreal 
injection of RST-001. Following RST-001 administration 
(Day 0) patients will be assessed on the first post injection 
day (Day 1). and thereafter according to the table below 
(Table 2):
The visit schedule includes:

Core study visits: Twelve visits are planned over 
24 months, including Screening and Baseline 
visits, Day 0, Day 1, Day 7, and Months 1, 3, 6, 
9, 12, 18, and 24.

Long-term follow-up: After completion of the 
Month 24 visit, each patient will be invited to 
participate in a long-term follow-up study for an 
additional 13 years. These visits include yearly 
office visits for 5 years (Months 36, 48, 60, 72, 
and 84) and yearly teleconference interviews for 
8 years (Months 96. 108, 120, 132, 144, 156, 
168, and 180).
Core study visits are described in Table 2 and long-term 
follow-up visits are described in Table 3.
Changed to reflect 
incorporation of long-
term follow up visits 
into the existing 
protocol
Table 2
‘Core Study Visits’ added to title. Screening date range 
changed from -90 to -45. Ophthalmic and Medical History 
performed now at screening, baseline, and day 0. IOP 
measurement added to table. Footnotes edited.
Minor changes to visit 
schedule
Table 3
This table was added to show the study visit schedule for 
long-term follow-up visits.
Changed to reflect 
incorporation of long-
term follow-up visits in 
to this protocol.
Section 5.1
Please refer to Table 2 and Table 3 for a schematic of the 
schedule of visits and procedures.
IOP has been added to appropriate subheading visits. 
Ophthalmic and medical history has been removed from 
visits after Day 0 and replaced with concomitant 
medications and procedures.
Changed to reflect 
incorporation of long-
term follow-up visits 
and clarification of 
study visit procedures.
Section 5.1.2
Prospective patients will be screened for eligibility up to 
9045 days prior to enrollment and the procedures will be 
performed as specified below. If convenient, the Screening 
and Baseline visits may be combined.
It is the investigator’s responsibility to review the results of 
all laboratory tests as they become available. This review 
will be documented by the investigator’s dated signature on 
the laboratory report. For each abnormal laboratory test 
result in which the value of the test lies outside the normal 
Screening period has 
been shortened; 
Incorporation of 
protocol amendments 
made by RetroSense in 
response to FDA
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range (see Appendix 2 for reference values), the 
investigator needs to ascertain if this is an abnormal (ie, 
clinically significant) result for the individual subject. The 
investigator may repeat the laboratory test or request 
additional tests to verify the results of the original 
laboratory tests. If the laboratory value is determined by the 
investigator to be clinically significantly abnormal for that 
subject, the subject will be excluded from the study.
Section 5.1.13
5.1.13
Month 24 Exit (or Early Termination) Visit
Month 24 is no longer 
the exit visit
Section 5.1.14
5.25.1.14
Long-term Follow Up ProtocolVisits
This study will be conducted under a separate protocol. 
Patients completing the study will participate in a 13-year 
follow up study. Each Patients completing the Month 24 
visit will be asked to report any AEs that occur during this 
13-year follow up period. Additionally, from years 1 to 5At 
Months 36, 48, 60, 72, and 84, patients will undergo the 
following study assessments conducted at a single visit at 
the end of each yearyearly clinic visits:
•
Ophthalmic and medical history
•
Concomitant medications and procedures
•
AE review
•
Visual acuity 
•
Complete ophthalmic examination
During years 6 13,The procedures for these assessments 
will be the same as they were for the core study 
assessments.
At Months 96, 108, 120, 132, 144, 156, 168, and 180
patients will not be required to attend for study 
assessments. Instead, medical history review, concomitant 
medications and procedures and AE review will be 
conducted by telephone interview. Patients will continue to 
be evaluated by their ophthalmological provider and asked 
to release their medical records for these visits to the 
investigator at the site where they received the RST 001 
study drugvia annual teleconference interviews.
Changed to reflect 
incorporation of long-
term follow up visits 
into the existing 
protocol
Section 5.2.2
Medical History (Review) and Concomitant Medications
These will comprise (and be updated throughout the study):
Edited to separate 
medical history from 
concomitant 
medications
Section 5.2.3
Concomitant Medications and Procedures
All medications and procedures will be recorded on the 
eCRF. If the permissibility of a specific 
medication/treatment is in question, the investigator is to 
contact Allergan.
Added to separate 
medical history from 
concomitant 
medications
Section 5.2.12
Patients will perform these two tests concurrently, first 
identifying the location of if a light displayed on an LED 
screen can be seen and then identifyingif a series of 
standard images (square, circle, triangle, or star) presented 
on the screen can be identified.
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Section 5.2.16
Intraocular Pressure (IOP)
IOP measurements will be performed in both eyes at every 
study visit except on treatment day (Day 0), where there 
will be a pre- and post-injection IOP measurement in the 
study eye only. After the intravitreal injection, the patient 
will remain in the supine position and IOP will be 
monitored for at least 30 minutes. In the event that the 
intraocular pressure is 30 mmHg or above, it will be 
managed according to Section 5.3.2.
Added for clarity
Section 5.2.17
Color and autofluorescence images of the fundus will be 
keptmaintained at the site until completion of Phase 2a.
Provide further clarity
Section 5.2.18
Retinal anatomy of both eyes will be evaluated by SD-OCT 
scans at the Screening visit, Baseline visit, and each 
monthly visit after study treatment administration through 
Month 24.
Added for clarity, given 
SD-OCT will not be 
conducted during long-
term follow up.
Section 5.3
After the intravitreal injection, the patient will remain in the 
supine position and IOP will be monitored for at least 30 
minutes. In the event that the intraocular pressure is 30 
mmHg or above, it will be managed according to Section 
5.4.2.
Moved to Section 
5.2.16
Section 6.1.1.2
Owing to the potential for intraocular inflammation (as 
noted in the preclinical dog study) or immunogenicity, 
signs of ocular inflammation will be carefully monitored 
throughout the study and reported to the DSMC.  
Incorporation of 
protocol amendments 
made by RetroSense in 
response to FDA 
comments in 2015
Section 6.2.1
Intraocular Inflammation and Immunogenicity Related to 
RST-001
During the study, evidence of immune response to 
RST-001 will be monitored by systemic measurement of 
humoral and cellular immunity as follows:
These tests will be performed at several timepoints during 
the study: baseline (pre-dose)
 
Treatment of intraocular inflammation and immunogenicity
In the event that immunogenicity is suspected by the 
investigator, topical, local, intraocular or systemic 
corticosteroid, corticosteroid-sparing and 
immunomodulatory therapy may be initiated, usually in an 
escalating fashion, in accordance with the investigator’s 
practice, to control the inflammation. The patient will 
continue in the study and all additional assessments and 
visits will be documented in the source documents.
Incorporation of 
protocol amendments 
made by RetroSense in 
response to FDA 
comments in 2015
Section 6.2.4
Female patients of childbearing potential will require a 
pregnancy test at study exitMonth 24 or early termination 
visit.
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Section 7.3
2. Advise on dose-escalation, Phase 2a sample 
size/study population, study suspension or 
termination, as appropriate.
3. Provide review and advice on protocol 
amendments and changes to the clinical protocol, 
as appropriate.
4. Provide advice on any other matters as deemed 
necessary for the safe conduct of the study.
5. Provide assessment as to whether treatment 
benefits have been observed in Phase 1 of the 
study.
Reflects the 
responsibility of 
establishing the cohort 
size and eligibility for 
Phase 2a
Section 7.4
Enrollment will be suspended pending a complete safety 
review by the sponsor of all patients including causality to 
determine the appropriateness of continuing dosing in the 
occurrence of the following events: 
1.
Any Grade 3 or greater AE related to RST-001 
(according to Common Terminology Criteria for 
Adverse Events v4.03)
2.
Occurrence of an intraocular infection related to 
contaminated RST-001 that required treatment 
would serve as a stopping rule. Any evidence that 
the delivered product carries an infectious agent
3.
A safety issue has been identified that 
compromises the benefit or increases the risk 
balance
Dose-limiting toxicity (DLT) is defined as any adverse 
event of Grade 3 or higher that is possibly, probably or 
definitelyexpected to be related to the study treatment.  
DosingDose escalation will stop if a DLT is observed, 
including:
Incorporation of 
protocol amendments 
made by RetroSense in 
response to FDA 
comments in 2015
Section 8
The entire Adverse Events section has been removed and 
replaced with language that aligns with Allergan standards
Change to Allergan 
standards for
consistency in AE 
reporting
Section 11.2.1.1
Change in visual acuity in the treatedstudy eye from 
Baseline (defined as last observed value prior to dosing) to 
.
Edited for clarity.
Section 11.3.1
NoThe sample size for this study was chosen empirically; 
no formal sample size computations to meet power 
requirements were made. The sample size for this study 
was chosen empirically, as reasonable to answer the 
primary safety objective. The sample size of approximately
3 patients per single for each dose cohort and a total of 15 
patients group in Phase 1 are typical for Phase I/IIadose 
escalation studies of this type, and are expected to provide 
a sufficient number of observations to meet the objectives 
of the study, an additional up to approximately 12 patients 
will be enrolled in Phase 2a for further safety and efficacy 
evaluation.
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Section 3.15.1.2, 
Enrollment 
Phase 2a
After completion of the 2-year core study visits, each patient will be enrolled 
in a long-term follow-up for an additional 13 years to monitor the long-term 
safety of RST-001.
Reduce 
long-term 
follow-up
Section 5, Study 
Assessments 
and Intravitreal 
Injection
•
Long-term follow-up: After completion of the Month 24 visit, each 
patient will participate in a long-term follow-up study for a total of an 
additional 13 years. These visits include yearly office visits for 5 3 years 
(Months 36, 48, and 60, 72, and 84) and yearly teleconference interviews for 8 
years (Months 96, 108, 120, 132, 144, 156, 168, and 180).
Reduce 
long-term 
follow-up
Table 3:  Removed columns for Month 72 and 84 visits and all teleconference 
interviews
Section 5.1.14, 
Long-term
Follow-up Visits
Patients completing the Month 24 visit will participate in long-term follow-up 
visits. Patients will be asked to report any AEs that occur during this 13-year 
follow-up period. At Months 36, 48, and 60, 72, and 84, patients will undergo 
the following study assessments conducted at yearly clinic visits:
•
Concomitant medications and procedures
•
AE review
•
Visual acuity 
•
Complete ophthalmic examination
The procedures for these assessments will be the same as they were for the 
core study assessments.
At Months 96, 108, 120, 132, 144, 156, 168, and 180 patients will not be 
required to attend for study assessments. Instead, concomitant medications and 
procedures and AE review will be conducted via annual teleconference 
interviews.
Reduce 
long-term 
follow-up
Section 11.3.6, 
Interim Analysis
No interim analysis is planned. There will be three two database locks. The 
primary analysis will occur when all patients have completed the Month 6 24
visit, or exited earlier early from the study. The second analysis will occur 
when all patients have completed the Month 24 visit or exited early from the 
study.  The final analysis will occur when all patients have completed the long-
term follow-up or have been lost to follow-up. The details of all analyses will 
be provided in the analysis plan which will be finalized before database lock.
for the primary analysis at Month 6.
Reduce the 
database 
locks from 
three to two 
and revise 
the timing 
for the 
primary 
analysis
 
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20.6
Protocol Amendment Summary Amendment 4
Title: Phase I/IIa, Open-Label, Dose-Escalation Study of Safety and Tolerability of Intravitreal 
RST-001 in Patients with Advanced Retinitis Pigmentosa (RP)
Protocol RST-001-CP-0001 Amendment 4: (November 2022)
Amendment Summary
This summary includes changes made to Protocol RST-001-CP-0001 Amendment 4 (approved 
November 22, 2022). The main reason for this amendment was to include content related to 
virtual visits in case of COVID-19 and COVID-19 infection reporting, update contact 
information for AE reporting, and clarify timing for the final analysis.
Following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes. Minor editorial and document formatting 
revisions have not been summarized. Deleted text is indicated by strikethrough and added text is 
underlined, as appropriate. This summary provides a high-level list of changes to the document.
Section
Revision
Rationale
Section 5, Study 
Assessments 
and Intravitreal 
Injection
Study visits may be impacted due to the COVID-19 pandemic.  This may 
include changes such as telephone or virtual visits, visits at alternative 
locations, or changes in the visit frequency and timing of study procedures, 
among others.  Additional details are provided in the subsequent section.  
Every effort is to be made to ensure the safety of subjects and site staff, while 
maintaining the integrity of the study.  If visits cannot be conducted onsite due 
to travel restrictions or other pandemic-related reasons, follow the updates 
below on how to proceed.
During the COVID-19 pandemic, if it is not possible for all study procedures 
to be performed as specified due to travel restrictions or other reasons, the 
following modifications are allowed with agreement from the sponsor:

If permitted by local regulations, the IRB/IEC, and the subject, 
postbaseline visits may be conducted virtually.

Study Visits and/or activities are to be performed as scheduled 
whenever possible.
Provide 
content 
related to 
virtual visits 
in case of 
COVID-19
Section 5.1.1, 
Informed 
Consent and 
Patient Privacy
Due to the COVID-19 pandemic, it is possible that protocol modifications may 
become necessary.  If this situation arises, in addition to the study informed 
consent, additional verbal consent may be obtained prior to these adaptations 
or substantial changes in study conduct in accordance with local regulations.
Provide 
content 
related to 
virtual visits 
in case of 
COVID-19
 
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Rationale
Section 5.2.3, 
Concomitant 
Medications and 
Procedures
Given the ongoing COVID-19 pandemic, selected non-live vaccines (e.g., 
mRNA, non-replicating viral vector, protein subunit) to prevent Severe Acute 
Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection may be 
administered during screening or the treatment period, as long as components 
of the vaccine are not contraindicated.
The decision to receive a locally available vaccine is to be based on local 
guidance and an individual discussion between the treating physician and the 
subject.
The potential impact of RST-001 on SARS-CoV-2 vaccination is unknown.
Provide 
content 
related to 
the SARS-
CoV-2 
vaccination
Section 5.2.4, 
Adverse Event 
Review
COVID-19 infections should be reported as AEs.
Provide
content for 
reporting 
COVID-19 
infections
Section 8.2, 
Procedures for 
Reporting 
Adverse Events
SARS-CoV-2 infections are to be captured as AEs.  If the event meets the 
criteria for a serious adverse event, then follow the serious adverse event
reporting directions.
Reactions known to be associated with the SARS-CoV-2 vaccine are to be 
reported as AEs.  If the event meets the criteria for a serious adverse event, 
then follow the serious adverse event reporting directions.
Provide 
content for 
reporting 
COVID-19 
infections
Section 8.3, 
Procedures for 
Reporting a 
Serious Adverse 
Event
Pregnancy
While not an AE, pregnancy in a study participant must be reported to 
Allergan within 24 hours after the site becomes aware of the pregnancy.  If a 
pregnancy occurs in a study participant or in the partner of a study participant, 
information regarding the pregnancy and the outcome will be collected.
The pregnancy outcome of an elective or spontaneous abortion, stillbirth or 
congenital anomaly is considered a serious adverse event and must be reported 
to Allergan within 24 hours after the site becomes aware of the event.
Provide 
content for 
reporting 
pregnancies.
Section 10.1, 
Monitoring
During the COVID-19 pandemic, remote data review/verification may be 
employed if allowed by the local regulatory authority, IRB/IEC, and the study 
site.
Provide 
content for 
remote data 
review
Section 11.3.6, 
Interim Analysis
No interim analysis is planned. There will be twoone database locks for the 
final analysis. The primary analysis will occur when all patients have 
completed the Month 24 visit or exited early from the study. The final analysis 
will occur when all patients have completed the Month 60 visit or exited early 
from the studylong term follow up or have been lost to follow up. The details 
of all analyses will be provided in the analysis plan, which will be finalized 
before database lock.
Reduce the 
database 
lock from 
two to one 
and clarify 
the timing 
for the 
primary 
analysis
 
22Nov2022