Clinical trial NCT02556736
Conditions: Advanced Retinitis Pigmentosa
Keywords: gene therapy optogenetics channelrhodopsin retina retinitis pigmentosa
Sponsor: AbbVie
Start date: 2015-12-14; Completion date: 2024-10-21
Enrollment: 14 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Currently enrolling a total of 12 patients for Phase 2a of the study: 6 patients must have VA of no-better-than hand motion in the study eye, and 6 patients must have VA in the study eye to range from no-worse-than count fingers to 20/200 vision.

Detailed description:

Arms: arm 1: Single intravitreal injection of RST-001
Interventions: intervention 1: RST-001
Intervention descriptions: intervention 1: RST-001 is a gene therapeutic delivered by intravitreal injection

Protocol documents:
Prot_000.pdf: 
 
   
 
 
 
         NCT 02556736 
 
Study ID: 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) 
 
                                       Protocol Date: 19-Oct-2017 


 
 
Approval Date: 
 
19-Oct-2017
Allergan 
 
Protocol RST-001-CP-0001 Amendment 2
 
1 
ALLERGAN
 
 
 
The following contains 
 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 2 
Phase: 
Phase 1/2a 
Name of Investigational Product: 
RST-001 (AGN-151597) 
Sponsor: 
 
Allergan, Inc. 
2525 Dupont Drive 
Irvine, California USA 
92612 
+1-714-246-4500 
+1-800-347-4500 
 
Emergency Telephone Number(s): 
North America:
Serious Adverse Event Reporting 
Fax Number(s): 
Allergan Medical Safety Physician 
Contact Information: 


 
 
Approval Date: 
 
19-Oct-2017
Allergan 
 
Protocol RST-001-CP-0001 Amendment 2
 
2 
Allergan Signatory: 
Therapeutic Area Head 
Glaucoma and Retina 
Allergan – Global Drug Development  
Refer to the final page of this protocol for electronic signature 
and date of approval. 
 
 
 
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. 
 


 
 
Approval Date: 
 
19-Oct-2017
Allergan 
 
Protocol RST-001-CP-0001 Amendment 2
 
3 
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 
 
 


 
 
Approval Date: 
 
19-Oct-2017
Allergan 
 
 1
 1
List of T
List of F
 2
 3
3.1 
3.1.1 
3.1.2 
3.1.3 
3.1.4 
3.1.5 
3.2 
3.3 
3.4 
3.5 
3.6 
3.6.1 
3.6.2 
3.6.3 
3.7 
3.7.1 
3.8 
3.9 
3.9.1 
3.9.2 
3.10 
3.11 
3.11.1 
3.12 
3.13 
3.14 
3.14.1 
3.15 
3.15.1 
3.15.2 
3.15.3 
3.15.4 
 4
4.1 
4.2 
4.3 
4.4 
4.5 
Tabl
Table of C
ables ...........
igures .........
Protocol S
Introductio
Backgroun
Retinitis pi
Clinical fe
Cellular pa
Pathogenes
Treatment .
Adeno-Ass
Recombina
Human Cli
RST-001 ...
Nonclinica
Pharmacol
Toxicology 
Justificatio
RST-001 St
Immunoge
Treatment 
Objectives 
Primary O
Secondary 
Study cond
Risks and 
Potential R
Protection 
Provisions 
Potential B
Risk Bene
Study Ove
Study Desi
Study Pop
Eligibility 
Early Disc
Treatments 
Identity of 
Dosage an
Method of 
Dose Ratio
Patient and 
e of Conte
ontents ........
...................
...................
ynopsis........
n .................
d and Ration
gmentosa (R
atures ..........
thology .......
is ................
...................
ociated Viru
nt AAV Vect
nical Experie
...................
l Studies wit
ogy Studies .
and Biodist
n for Human
tudy Rationa
nicity of RST
Administrati
of the Study
bjective: ......
Objectives: 
uct and GCP
Benefits.......
isks ............
from Risks .
for Injury ...
enefits ........
fit Analysis ..
rview ..........
gn ...............
ulation .........
Criteria .......
ontinuation o
...................
Investigation
d Administra
Assigning Pa
nale ............
Investigator
ents 
....................
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nale ..............
RP) ...............
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us .................
tors .............
ence with AA
....................
th RST-001 ..
....................
tribution Stu
n Dose .........
ale: Optogen
T-001 ..........
on ...............
y ...................
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P Complianc
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of Patients ...
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nal Product ..
ation .............
atients to Do
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r Masking....
4 
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AV2 Vectors
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udies ............
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netic Therapy
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ce Statemen
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ment 2
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Approval Date: 
 
19-Oct-2017
Allergan 
 
4.6 
4.7 
4.8 
4.9 
4.10 
4.11 
4.12 
 5
5.1 
5.1.1 
5.1.2 
5.1.3 
5.1.4 
5.1.5 
5.1.6 
5.1.7 
5.1.8 
5.1.9 
5.1.10 
5.1.11 
5.1.12 
5.1.13 
5.1.14 
5.2 
5.2.1 
5.2.2 
5.2.3 
5.2.4 
5.2.5 
5.2.6 
5.2.7 
5.3 
Packaging 
Handling a
Study Trea
Product Ac
Assessmen
Treatment 
Prior and 
Study Asse
Schedule o
Informed 
Screening 
Baseline V
Treatment 
Post Injecti
Day 7 ........
Month 1 ....
Month 3 ....
Month 6: P
Month 9 ....
Month 12 ..
Month 18 ..
Month 24 (
Long-term 
Descriptio
Informed 
Medical Hi
Concomita
Adverse E
Physical E
Pregnancy 
Blood Sam
Treatment 
and Labeling
nd Storage ..
tment Prepar
countability
t of Complia
of RST-001 O
Concomitant 
ssments and
f Procedures
Consent and P
Visit ............
isit ..............
Visit (Day 0)
on Visit (Da
...................
...................
...................
rimary Endp
...................
...................
...................
or Early Ter
Follow-up V
n of Study Pr
Consent........
story (Revie
nt Medicatio
vent Review 
xamination..
Test ............
ple ..............
Administrati
g ..................
....................
ration and A
....................
ance .............
Overdose ....
Therapy ......
d Intravitreal 
s by Visit .....
Patient Priva
....................
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) ..................
ay 1) .............
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point ............
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mination) V
Visits ............
rocedures ....
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ew) ...............
ons and Proc
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on ...............
5 
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Administratio
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Injection ...
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acy .............
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Visit .............
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Protoco
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on ................
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ment 2
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.... 35 
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Approval Date: 
 
19-Oct-2017
Allergan 
 
5.3.1 
5.3.2 
 6
6.1 
6.1.1 
6.1.2 
6.2 
6.2.1 
6.2.2 
6.2.3 
6.2.4 
 7
7.1 
7.2 
7.3 
7.4 
 8
8.1 
8.1.1 
8.1.2 
8.1.3 
8.1.4 
8.2 
8.3 
 9
 
10
10.1 
10.2 
 
11
11.1 
11.2 
11.2.1 
11.2.2 
11.3 
11.3.1 
11.3.2 
11.3.3 
11.3.4 
11.3.5 
11.3.6 
 
12
 
13
13.1 
Post Injecti
Manageme
Safety Ass
Overview 
Ocular Saf
Systemic S
Clinical M
Intraocular 
Complicati
Occupatio
Pregnancy 
Data Safet
Compositi
Role ..........
Responsibi
Enrollment 
Adverse E
Definitions
Adverse E
Serious Ad
Severity ....
Relationshi
Procedures 
Procedures 
Efficacy A
Clinical M
Monitoring
Study and 
Data Analy
Primary (S
Secondary 
Measures o
Anatomica
Statistical 
Power and 
Baseline C
Safety Ana
Efficacy A
Other Anal
Interim An
Investigato
Data Hand
Data Mana
on Medicati
nt of Post Inj
essments .....
of Safety Ass
ety Measurem
afety Measu
anagement o
Inflammatio
ons of the In
nal Safety ....
and Exposur
y Monitoring
on ................
...................
lities ...........
Stopping Ru
vents ...........
...................
vent .............
verse Event 
...................
p to Study D
for Reportin
for Reportin
ssessments ..
onitoring Str
 ..................
Site Closure 
sis and Stati
afety) Endpo
Endpoints ..
f Change in 
l Endpoints R
Analysis Plan
Sample Size
haracteristics
lysis............
nalysis ........
ysis .............
alysis ..........
r Responsibi
ling and Rec
gement Resp
ons ..............
njection Intra
....................
sessments ....
ments ..........
urements ......
of Safety Par
on and Immu
ntravitreal Inj
....................
re to RST-00
g Committee
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ules .............
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Drug or Stud
ng Adverse E
ng a Serious 
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ructure .........
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istical Consid
oint ..............
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Visual func
Relating to R
ns ................
e Considerati
s ..................
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ilities ...........
cord Keeping
ponsibilities.
6 
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aocular Pres
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rameters ......
unogenicity 
njection .......
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01 In Utero .
e (DSMC) ...
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dy Procedur
Events ........
Adverse E
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derations ....
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tion ............
Retinal Inte
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Related to 
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grity and Su
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.....47 
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.... 48 
.....48 
.... 48 
.... 48 
.... 49 
.... 50 
.... 50 
.... 50 
.... 50 
.....51 
.....51 
.... 52 
.... 52 
.....52 
.... 52 
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Approval Date: 
 
19-Oct-2017
Allergan 
 
13.1.1 
13.1.2 
 
14
 
15
15.1 
 
16
16.1 
 
17
 
18
 
19
 
20
20.1 
20.2 
20.3 
20.4 
 
 
Data Quali
Source Do
Study Ter
Regulatory 
Ethical Co
Manageme
Protocol A
Publication
Sponsor's 
References 
Appendice
Appendix 
Appendix 
Protocol A
Protocol A
ty Assurance
cuments ......
mination .......
and Ethical 
nduct of the 
nt of Protoco
mendments .
 Policy .......
Final Report 
...................
s ..................
1: Abbreviati
2: Clinical La
mendment S
mendment S
e ...................
....................
....................
Considerati
Study ..........
ol Amendme
....................
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....................
....................
....................
ions .............
aboratory Te
ummary Am
ummary Am
7 
...................
...................
...................
ons .............
...................
ents and De
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ests .............
mendment 1 
mendment 2 
Protoco
...................
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viations .......
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l RST-001-CP
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ment 2
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.... 83 


 
 
Approval Date: 
 
19-Oct-2017
Allergan 
Protocol RST-001-CP-0001 Amendment 2
 
8 
List of Tables 
Table 1 
Dose Escalation .......................................................................................................... 23 
Table 2 
Study Visit Schedule: Core Study Visits .................................................................... 31 
Table 3 
Study Visit Schedule: Long-term Follow-up Visits .................................................... 32 
Table 4 
Biomicroscopic Grading of Anterior Chamber Cells and Flare ................................. 44 
 
 


 
 
Approval Date: 
 
19-Oct-2017
Allergan
Protocol RST-001-CP-0001 Amendment 2
 
9 
List of Figures 
Figure 1 
Overview of the Treatment Schedule ......................................................................... 23 
 
 






 
 
Approval Date: 
 
19-Oct-2017
Allergan 
Protocol RST-001-CP-0001 Amendment 2
 
12 
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. 
 


 
 
Approval Date: 
 
19-Oct-2017
Allergan 
 
 3
3.1 
3.1.1 
Retinitis 
retina. It 
100,000 
conditio
inherite
RP is ge
genes ha
dominan
3.1.2 
Early di
progress
macula 
disease 
lost. 
Examin
as discre
attenuatio
3.1.3 
RP is pri
progress
retinal p
which in
retinal g
connecti
3.1.4 
Given th
the preci
stresses 
Intr
Back
Reti
pigmentosa 
is estimate
individuals 
n. A similar 
d as an isolat
netically hete
ve been ide
t trait. 
Clin
sease manife
es, the visu
edema, visu
will have po
ation finding
te bone-spic
on.  
Cell
marily a dis
es (Daiger e
igment epit
clude cell r
anglion cell
ons with the 
Path
e large num
se molecula
the photorec
oduction 
kground an
nitis pigm
(RP) is a he
d that the pre
(Sohocki et a
prevalence r
ed ocular dis
erogeneous w
ntified. In the
ical featur
sts as night-
al field constr
al acuity (VA
or VA and m
s include abn
ules, outer r
ular patho
ease of the r
t al., 2007). 
helium. Loss 
eorganization
s, which com
brain. 
ogenesis 
ber of causat
r pathology 
eptor cells e
nd Ration
entosa (RP
ereditary, slo
evalence of R
al., 2001) wi
rate is though
sease though
with more th
e U.S., RP is
res 
blindness an
ricts relative
A) is preserve
minimal prese
normal pigm
retinal atroph
ology 
od photorece
Cone photor
of the photo
n, disorganiz
mprise the inn
tive genes an
of RP remai
eventually re
13 
nale 
P) 
owly-progre
RP in the U
ith 10-20% 
ht to occur w
h it is a man
han forty ca
s most com
nd peripher
ely symmetr
ed until adv
erved visual 
mentary chan
hy, optic ner
eptors whic
receptors su
oreceptors r
zation and ce
nermost lay
nd the diver
ns elusive. 
sulting in th
Protoco
ssive, neuro
nited States 
suffering se
worldwide. 
ifestation o  
usative gen
monly inheri
al visual field
ically. Unle
anced disea
field. In som
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ogy 


 
 
Approval Date: 
 
19-Oct-2017
Allergan 
Protocol RST-001-CP-0001 Amendment 2
 
14 
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 
 
 


 
 
Approval Date: 
 
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Allergan
Protocol RST-001-CP-0001 Amendment 2
 
15 
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 (
) to the highest dose (
). 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 
): 
(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 (
) 
evaluated as compared with vehicle injected mice, based upon optokinetic responses. The highest 
dose (
) 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 


 
 
Approval Date: 
 
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Allergan 
Protocol RST-001-CP-0001 Amendment 2
 
16 
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 
 
 
, gross necropsy findings, organ weights, and histopathologic examinations, and 
biodistribution.   


 
 
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Protocol RST-001-CP-0001 Amendment 2
 
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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


 
 
Approval Date: 
 
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Protocol RST-001-CP-0001 Amendment 2
 
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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 
; 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 
. For the mouse, the safe intravitreal doses 
ranged from 
.  Two nonclinical pharmacology studies demonstrated 
efficacy and safety in the mouse at a dose range of 
 in a dose range 
comparable to the toxicology study. Based on these studies, the expected safe dose range in 
humans is between 
 and 
. The dose range in this study (
to 
 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 
 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. 


 
 
Approval Date: 
 
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Protocol RST-001-CP-0001 Amendment 2
 
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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 
 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 
.  
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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Protocol RST-001-CP-0001 Amendment 2
 
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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 
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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Protocol RST-001-CP-0001 Amendment 2
 
21 
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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Protocol RST-001-CP-0001 Amendment 2
 
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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 13 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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Protocol RST-001-CP-0001 Amendment 2
 
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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 
 
1 
A 
3 
LOW  
 
B 
3 
MID  
 
C 
3 
HIGH  
 
2a 
 
6-12b 
Choice of dosec from 
groups A, B, or C  
 
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 13 years to monitor the long-term safety of RST-001. 


 
 
Approval Date: 
 
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Allergan
Protocol RST-001-CP-0001 Amendment 2
 
24 
3.15.2 
Study Population 
The study population consists of patients with advanced RP 
 
 
 This patient group is considered to be a suitable population to assess 
safety and tolerability in this Phase 1 study. 
 
 
  
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 


 
 
Approval Date: 
 
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Protocol RST-001-CP-0001 Amendment 2
 
25 
Ocular Inclusion Criteria: 
Phase 1 and Phase 2a 
1. Diagnosis of advanced RP defined as: 
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; 


 
 
Approval Date: 
 
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Protocol RST-001-CP-0001 Amendment 2
 
26 
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 
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  
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 
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. 




 
 
Approval Date: 
 
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Allergan 
 
Protocol RST-001-CP-0001 Amendment 2
 
28 
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, 
. The MID dose will be 
 of the HIGH dose, 
 
 
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 
 
Please 
refer to the Study Procedures Manual for additional information. 
4.8 
Study Treatment Preparation and Administration 


 
 
Approval Date: 
 
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Allergan 
 
4.9 
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onal 
to 


 
 
Approval Date: 
 
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Allergan 
 
Protocol RST-001-CP-0001 Amendment 2
 
30 
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 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. 


 
 
Approval Date: 
 
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Allergan 
 
Protocol RST-001-CP-0001 Amendment 2
 
31 
Table 2 
Study Visit Schedule: Core Study Visits 


 
 
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Protocol RST-001-CP-0001 Amendment 2
 
32 
Table 3 
Study Visit Schedule: Long-term Follow-up Visits 
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 (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. 
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 
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.  


 
 
Approval Date: 
 
19-Oct-2017
Allergan
Protocol RST-001-CP-0001 Amendment 2
 
33 
Records will be maintained of those individuals who are screened but do not meet the eligibility 
criteria for participation in the study. 


 
 
Approval Date: 
 
19-Oct-2017
Allergan 
Protocol RST-001-CP-0001 Amendment 2
 
34 
                                                 


 
 
Approval Date: 
 
19-Oct-2017
Allergan 
Protocol RST-001-CP-0001 Amendment 2
 
35 


 
 
Approval Date: 
 
19-Oct-2017
Allergan 
Protocol RST-001-CP-0001 Amendment 2
 
36 


 
 
Approval Date: 
 
19-Oct-2017
Allergan
Protocol RST-001-CP-0001 Amendment 2
 
37 


 
 
Approval Date: 
 
19-Oct-2017
Allergan
Protocol RST-001-CP-0001 Amendment 2
 
38 
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, 60, 72, and 84, patients will undergo the following study assessments conducted at yearly 
clinic visits: 


 
 
Approval Date: 
 
19-Oct-2017
Allergan 
Protocol RST-001-CP-0001 Amendment 2
 
39 
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) 


 
 
Approval Date: 
 
19-Oct-2017
Allergan
Protocol RST-001-CP-0001 Amendment 2
 
40 
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. 
5.2.4 
Adverse Event Review 
All AEs will be recorded at each study visit. 
5.2.5 
Physical Examination 
A complete physical examination will be performed 
 
 
 
 
 
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 
 
 
 
 
  
Instructions for shipping venous blood for immunological analysis are detailed in the Study 
Procedures Manual. 


 
 
Approval Date: 
 
19-Oct-2017
Allergan 
Protocol RST-001-CP-0001 Amendment 2
 
41 
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 
 
 
 
 
 


 
 
Approval Date: 
 
19-Oct-2017
Allergan 
Protocol RST-001-CP-0001 Amendment 2
 
42 


 
 
Approval Date: 
 
19-Oct-2017
Allergan 
 
5.3 
RST-001
Manual. 
Prior to 
standard 
5.3.1 
Topical 
standard 
5.3.2 
The inve
intraocu
acetazol
 6
6.1 
Safety a
systemic 
6.1.1 
Trea
 will be ad
 
study treatm
protocol as 
Post 
corticosteroi
of care. 
Man
stigator sha
lar pressure 
amide or ant
Safe
Ove
ssessments i
safety. 
Ocu
tment Adm
ministered by
ent administ
described in
Injection 
d treatment m
agement o
ll have the ab
and may use
erior chamb
ty Assessm
rview of Sa
n this study c
lar Safety 
ministrati
y intravitreal
tration, the s
n the Study P
Medicatio
may be give
of Post Inj
bility to dete
e any combin
er paracente
ments 
afety Asse
can be divid
Measurem
43 
on 
l injection a
tudy eye of 
Procedures 
ons 
en to the inje
jection In
ermine the o
nation of top
esis in order 
essments 
ded into mea
ments 
Protoco
s specified in
each patien
Manual.  
ected eye ac
traocular 
ptimum ma
pical IOP-lo
to normaliz
sures of oc
l RST-001-CP
n the Study P
t will be prep
cording to th
Pressure 
nagement of
wering medi
e the intraoc
ular safety an
-0001 Amendm
Procedures 
pared using t
he investigato
f a raised 
ications, oral
cular pressur
nd measures 
ment 2
the 
or’s 
l 
re. 
of 


 
 
Approval Date: 
 
19-Oct-2017
Allergan
Protocol RST-001-CP-0001 Amendment 2
 
44 
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, 
 
 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). 


 
 
Approval Date: 
 
19-Oct-2017
Allergan
Protocol RST-001-CP-0001 Amendment 2
 
45 
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 
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. 


 
 
Approval Date: 
 
19-Oct-2017
Allergan 
Protocol RST-001-CP-0001 Amendment 2
 
46 
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: 
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. 


 
 
Approval Date: 
 
19-Oct-2017
Allergan 
 
6.2.4 
Females 
Females 
participa
study, th
sponsor w
pregnant 
pregnan
The pote
 7
7.1 
An inde
from the 
statistici
7.2 
The pri
the stud
resolvin
agreed s
7.3 
Preg
who are pre
of child-be
tion in the s
e patient wil
within 24 h
during the 
cy test at M
ntial effects 
Dat
Co
pendent Dat
study. The 
an(s) with e
Role 
mary role of 
y. The DSM
g any issues 
chedule for 
Res
nancy and
gnant at the 
aring potentia
tudy.  In the 
l continue to
ours of becom
course of the
onth 24 or ea
of in utero e
a Safety M
mposition 
a Safety Mon
members of t
xperience in 
the DSMC is
C will review
that may ari
reviewing da
ponsibilitie
d Exposur
Screening a
al are requir
event that a 
o be followe
ming aware t
e study.  Fem
arly terminat
exposure to R
Monitoring 
nitoring Com
the DSMC w
this field of 
s to ensure th
w the genera
se. The com
ata will be de
es 
47 
re to RST-
and/or Basel
red to maint
female bec
d in the stu
that a femal
male patient
tion visit. 
RST-001 are
Committ
mmittee (D
will compri
f research. 
he protectio
al progress an
mposition an
etailed in the
Protoco
001 In Ute
ine visit wil
ain contrace
omes pregn
dy. The inves
e patient or f
s of childbea
e not known
ee (DSM
SMC) will b
se ophthalmo
n and safety 
nd conduct 
d responsibi
e DSMC C
l RST-001-CP
ero 
l be excluded
ption during
ant during th
stigator shou
female partn
aring potentia
. 
C) 
e formed to m
ologists, phy
 of patients p
of the study 
lities, togeth
harter. 
-0001 Amendm
d from the s
g their 
he course of t
uld notify the
ner becomes 
al will requir
monitor the 
ysicians and 
participating
and assist in
her with the 
ment 2
tudy.  
the 
e 
re a 
data 
g in 
n 


 
 
Approval Date: 
 
19-Oct-2017
Allergan 
 
7.4 
Enrollm
includin
the follow
 8
Adverse 
events o
8.1 
8.1.1 
An adve
patient a
relations
unintend
associat
medicin
be asses
Note:  A
whether 
Enr
ent will be s
g causality t
wing events
Adv
events occu
ccur, the firs
Defi
Adv
rse event is 
dministered 
hip with thi
ed sign (inc
ed with the 
al (investiga
sed regardle
dverse even
or not the p
ollment Sto
uspended pe
o determine 
:  
erse Event
rring during
t concern wi
nitions 
erse Event
any untowar
a pharmaceu
s treatment.  
luding an ab
use of a medi
tional) produ
ss of the adm
ts must be co
atient has be
opping Ru
ending a com
the appropri
ts 
 the study w
ill be the saf
t 
rd medical oc
utical produc
An adverse 
normal labo
icinal (inves
uct.  In addit
ministration o
ollected once
en administe
48 
ules  
mplete safety
iateness of 
will be recor
fety of the st
ccurrence i
ct and that 
event can t
oratory findi
tigational) p
tion, during 
of a pharma
e informed 
ered study t
Protoco
y review by t
continuing d
ded on an ad
udy partici
n a subject or
does not nece
herefore be 
ng), sympto
product, wh
the screenin
ceutical prod
consent has 
reatment. 
l RST-001-CP
the sponsor o
osing in the 
dverse event 
pants.  
r clinical inv
essarily have
any unfavora
m, or disease
ether or not r
g period, adv
duct.   
been obtaine
-0001 Amendm
of all patient
occurrence o
CRF.  If adv
vestigation 
e a causal 
able and 
e temporally
related to the
verse events
ed, regardles
ment 2
ts 
of 
verse 
y 
e 
s will 
ss of 


 
 
Approval Date: 
 
19-Oct-2017
Allergan 
Protocol RST-001-CP-0001 Amendment 2
 
49 
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. 


 
 
Approval Date: 
 
19-Oct-2017
Allergan
Protocol RST-001-CP-0001 Amendment 2
 
50 
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. 
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. 
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 


 
 
Approval Date: 
 
19-Oct-2017
Allergan 
 
outcome
requeste
In the ev
1. 
(
n
2. 
p
3. P
s
g
S
c
a
e
4. P
l
 9
A variety
order to 
s reported.  
d informatio
ent of a seri
Notify Aller
contact deta
umbers and 
Obtain and 
medical judg
atient. 
rovide Alle
erious adve
iven (eg, m
ummarize r
linical cour
lternative e
vent was or 
romptly inf
ocal regulati
Effic
y of paramet
identify a si
The investig
n (eg, autop
ous adverse 
gan immediat
ils can be fou
relevant All
maintain in hi
ments from c
rgan with a c
rse event form
edications ad
elevant clini
se and releva
xplanation(s)
was not rela
orm the gove
ons, and the 
cacy Asses
ers that enco
gnal of effica
gator must su
sy reports an
event, the in
tely by fax o
und on page
ergan person
is/her files a
colleagues w
complete, wr
m describing
dministered, 
cal informat
ant clinical la
) for the caus
ated to the us
erning IRB o
governing h
sments 
ompass visua
acy, as follow
51 
upply Allerg
nd discharge
nvestigator 
or email usi
e 1 of the se
nnel contacts
ll pertinent 
who assiste  
ritten descrip
g the event c
procedures 
tion about t
aboratory te
sality which 
se of the inv
of the seriou
health autho
al function 
ws: 
Protoco
an and the I
e summaries
must: 
ng the seriou
rious advers
s are also on
medical rec
d in the treatm
ption of the 
chronologic
performed) 
he event:  si
sts, etc.  Inc
 includes a s
estigational 
us adverse ev
rities. 
will be evalu
l RST-001-CP
RB with any
).  
us adverse ev
e event form
n the front pa
ords, informa
ment and fol
adverse even
ally, includin
for the adve
gns, symptom
lude any add
statement as 
drug. 
vent as requi
uated in the s
-0001 Amendm
y additional 
vent form 
m); phone 
age of protoc
ation, and 
llow-up of th
nt(s) on the 
ng any treatm
erse event(s)
ms, diagnosi
ditional or 
to whether t
ired by the IR
study eye in 
ment 2
col. 
he 
ment 
.  
is, 
the 
RB, 


 
 
Approval Date: 
 
19-Oct-2017
Allergan
 
 
10
10.1 
A represe
the exte
purpose, 
represen
review, 
investig
and ques
10.2 
The stud
patient h
 
11
11.1 
The pri
11.2 
11.2.1 
Clin
Mon
entative of t
nt and natur
design, co
tatives of Al
audit and cop
ator(s) and a
tions. 
Stu
y can be ter
as complete
Dat
Prim
mary endpoi
Seco
Mea
ical Monit
itoring  
he sponsor w
e of monitori
mplexity, blin
lergan or reg
py study-rela
ppropriate st
dy and Site
minated at an
d study visit
a Analysis 
mary (Safet
nt is safety a
ndary End
sures of C
toring Stru
will monitor 
ing will be b
nding, size, a
gulatory auth
ated docume
taff at mutua
e Closure
ny time. The
ts and assess
and Statis
ty) Endpo
t 6 months, a
dpoints 
Change in V
52 
ucture 
the study on
based on co
and endpoin
hority repres
ents. These re
ally conveni
e study will b
sments.  
stical Con
oint 
as assessed 
Visual fu
Protoco
n a periodic b
nsiderations s
ts of the stu
sentatives wi
epresentati
ent times to 
be consider
sideration
by 
nction  
l RST-001-CP
basis. The d
such as the o
dy. Authoriz
ill conduct o
ves will meet
discuss stud
ed complete 
ns 
-0001 Amendm
etermination
objective, 
ed 
on-site visits
t with the 
dy-related da
after the fin
ment 2
n of 
 to 
ata 
nal 


 
 
Approval Date: 
 
19-Oct-2017
Allergan 
Protocol RST-001-CP-0001 Amendment 2
 
53 
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. 






 
 
Approval Date: 
 
19-Oct-2017
Allergan 
 
13.1.2 
• S
i
 
14
The spo
for any r
closed w
closure 
The inve
and suffi
Reasons 
not limit
• F
l
• I
• 
Sou
ource docu
ntegrity of t
Stu
nsor designe
eason.  Stu
hen all requ
visit has bee
stigator ma
cient notice 
for the earl
ed to: 
ailure of th
ocal health 
nadequate r
Discontinuat
rce Docum
ments provid
he data colle
dy Termina
e reserves th
dy sites will b
ired docume
n performed.
y initiate stud
is given in a
y closure of a
e investigator
authorities, th
ecruitment of
ion of furthe
ments 
de evidence f
cted. Source
ation 
he right to clo
be closed up
ents and stud
. 
dy-site closu
advance of th
a study site b
r to comply 
he sponsor’s
f patients by
er study treat
56 
for the exist
e documents 
ose the stud
pon study co
dy supplies 
ure at any ti
he intended 
by the spons
with the pro
s procedures,
y the investi
tment develo
Protoco
ence of the 
are filed at 
y site or ter
mpletion. A 
have been c
me, provide
termination
sor or invest
otocol, the re
, or GCP gui
gator 
opment 
l RST-001-CP
patient and s
the investiga
minate the st
study site is
ollected and 
d there is rea
. 
igator may in
equirements 
idelines 
-0001 Amendm
substantiate t
ator’s site. 
tudy at any t
s considered 
a study-site 
asonable cau
nclude but a
of the IRB o
ment 2
the 
time 
use 
are 
or 


 
 
Approval Date: 
 
19-Oct-2017
Allergan
 
 
15
15.1 
This sec
(http://cl
The goal
or increa
possible 
effective
harm for 
purpose 
the scien
The ethi
notoriou
withheld 
of the di
studies. 
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the conduct 
ocial and cl
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air patient s
avorable ris
ulatory an
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nih.gov/recr
research is to
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le, is to test i
f others, clin
uidelines is b
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African Amer
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ial codes of 
Code (1947) 
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ort (1979) 
2) 
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of guidance 
of ethical res
inical value 
idity 
election 
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d Ethical 
uct of the S
from the NIH
ruit/ethics.ht
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man biology
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it on patient 
ical research
both to prote
oday were pr
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rican men wi
uidelines wer
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rimarily a re
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ith syphilis 
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ho participate
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sponse to p
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so that scie
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hat guide et
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l RST-001-CP
Clinical Res
that improve
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drug or treatm
ing some peo
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ave been des
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search 
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scribed as 
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alth 
ake it 
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Approval Date: 
 
19-Oct-2017
Allergan 
 
Protocol RST-001-CP-0001 Amendment 2
 
58 
• 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 
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 


 
 
Approval Date: 
 
19-Oct-2017
Allergan 
 
research 
trivial or 
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59 
n the particu
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Approval Date: 
 
19-Oct-2017
Allergan
 
 
19
Blacklow
Proc Nat
Carter P
2000;6:1
Daiger S
pigment
Dorn JD
motion 
Ophthal
Flotte T
1995;2:3
Jabs DA
Working
First Inte
Klein M,
degener
Ophthal
Muzycz
PM, eds.
Nussenb
activity i
Rayapu
pigment
Schnepp 
associat
Sohocki 
Prevalen
Mutat. 2
Refe
w NR, Hogg
l Acad Sci 
J, Samulski 
7-27. 
P, Bowne S
osa. Arch O
, Ahuja AK, 
by blind subj
mol. 2013;1
R, Carter BJ
57-362. 
, Nussenbla
, G. Standar
ernational 
, Birch DG. 
ative disease
mol. 2009;1
ka N, Berns 
 Fields Viro
latt RB, Pal
n intermedi
di S, Schwar
osa. 2013. C
BC, Jensen 
ed virus gen
MM, Daige
ce of mutati
001;17:42-5
rences 
an MD and R
USA. 1967;5
RJ. Adeno-a
J, and Sulliv
phthalmol. 2
Caspi A, da
ects with the
31:183-189. 
. Adeno-asso
tt RB, Rosen
dization of u
Workshop. Am
Psychophys
s (RDDs) wi
19:217–224. 
KI. Parvovir
logy. Philade
estine AG, C
ate and poste
tz SG, Wang
ochrane Dat
RL, Chen C
omes isolated
r SP, Bowne
ons causing 
1. 
Rowe WP. Is
58:1410-1415
associated vir
an LS. Persp
007;125:15
a Cruz L, Dag
e epiretinal 6
ociated virus
nbaum JT, an
uveitis nome
m J Ophthalm
ical assessm
ith the Diagn
ridae: the vir
elphia: Lipp
Chan C, Robe
erior uveitis.
g X, and Cha
tabase Syst R
CL, Johnson 
d from huma
 SJ, Rodriqu
retinitis pigm
60 
solation of 
5. 
ral vectors 
pective on ge
1-158. 
gnelie G, S
60-electrod
s vectors for 
nd Standardi
enclature fo  
mol. 2005;1
ment of low 
nosys full-fi
ruses and th
incott Willia
erge F. Stand
. Ophthalm
avis P.  Vitam
Rev 12, CD
PR and Clar
an tissues. J 
uez JA, Nort
mentosa an
Protoco
adeno virus-
as gene deli
enes and m
ahel JA, gus,
e (argus II) r
gene thera
ization of U
r reporting cl
40:509-516.
visual functi
eld stimulu
eir replicatio
ams & Wilk
dardization 
ology. 1985;9
min A and fis
008428. 
rk KR. Char
Virol. 2005
thrup H, He
d other inher
l RST-001-CP
associated vi
very vehicles
utations caus
, I.I.S.G. The
etinal prosth
py. Gene The
veitis Nomen
linical data. 
on in patient
s threshold (D
on. In: Knipe
ins, 2001:23
of vitreal inf
92:467–471.
sh oils for re
racterization 
;79:14793-1
ckenlively JR
rited retinopa
-0001 Amendm
iruses from m
s. Int J Mol M
sing retinitis 
e detection o
hesis. JAMA 
er. 
nclature 
Results of th
ts with retina
D-FST). Do
e DM, Howl
27-2359. 
flammatory 
. 
etinitis 
of adeno 
4803. 
R, Sullivan L
athies. Hum 
ment 2
man. 
Med. 
of 
A
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ley 
LS. 


 
 
Approval Date: 
 
19-Oct-2017
Allergan 
 
 
20
20.1 
AE  
AST 
BCVA 
oC 
CFR 
CRF 
CTC 
DLT 
DNA 
DSMC 
ETDRS 
FDA 
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Immediately
International
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United State
Visual Funct
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minotransferase
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Monitoring Co
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physiology of 
AGN-151597)
l RST-001-CP
Vision 
-0001 Amendment 2

SAP_001.pdf: 
 
   
 
 
 
         NCT 02556736 
 
Study ID: 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) 
 
                Statistical Analysis Plan Date: 22-FEB-2019 


1
 
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TITLE PA
STATISTIC
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CAL ANAL
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ST-001-CP-0
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ST-001 (AGN
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25 Dupont D
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on, 
hority 


Allergan 
 
 
Statistical Analysis Plan RST-001-CP-0001  
RST-001 (AGN-151597) 
2 
2.0 
TABLE OF CONTENTS 
1.0 
TITLE PAGE .................................................................................................................................... 1 
2.0 
TABLE OF CONTENTS .................................................................................................................. 2 
3.0 
LIST OF ABBREVIATIONS ........................................................................................................... 4 
4.0 
INTRODUCTION ............................................................................................................................ 5 
5.0 
OBJECTIVES AND ENDPOINTS .................................................................................................. 9 
6.0 
PATIENT POPULATIONS ............................................................................................................ 11 
6.1 
Enrolled Population .......................................................................................................... 11 
6.2 
Safety Population .............................................................................................................. 11 
7.0 
PATIENT DISPOSITION .............................................................................................................. 12 
8.0 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................................ 13 
9.0 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ................................................ 14 
9.1 
Extent of Exposure ........................................................................................................... 14 
9.2 
Measurement of Treatment Compliance ........................................................................... 14 
10.0 
EFFICACY ANALYSES ............................................................................................................... 15 
11.0 
SAFETY ANALYSES .................................................................................................................... 17 
11.1 
Adverse Events ................................................................................................................. 17 
11.2 
Primary Ocular Safety Measurements .............................................................................. 18 
11.3 
Secondary Ocular Safety Measurements .......................................................................... 19 
12.0 
INTERIM ANALYSIS ................................................................................................................... 27 
13.0 
DETERMINATION OF SAMPLE SIZE ....................................................................................... 28 
14.0 
STATISTICAL SOFTWARE ......................................................................................................... 29 
15.0 
DATA HANDLING CONVENTIONS .......................................................................................... 30 
15.1 
Summary Statistics ........................................................................................................... 30 
15.2 
Visit Time Windows ......................................................................................................... 30 
15.3 
Derived Variables ............................................................................................................. 31 
15.4 
Repeated or Unscheduled Assessments of Safety Parameters .......................................... 31 
15.5 
Missing Date of the Last Dose of Study Treatment .......................................................... 31 


Allergan 
 
 
Statistical Analysis Plan RST-001-CP-0001  
RST-001 (AGN-151597) 
3 
15.6 
Missing Severity Assessment for Adverse Events ............................................................ 32 
15.7 
Missing Causal Relationship to Study Drug for Adverse Events ..................................... 32 
15.8 
Missing Date Information for Adverse Events ................................................................. 32 
15.9 
Missing Date Information for Prior or Concomitant Medications .................................... 33 
15.9.1 
Incomplete Start Date ......................................................................................... 33 
15.9.2 
Incomplete Stop Date ......................................................................................... 34 
15.10 
Character Values of Clinical Laboratory Parameters ........................................................ 35 
16.0 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL .......................................................... 36 
17.0 
REFERENCES ............................................................................................................................... 37 
 


Allergan 
 
 
Statistical Analysis Plan RST-001-CP-0001  
RST-001 (AGN-151597) 
4 
3.0 
LIST OF ABBREVIATIONS  
AE 
adverse event 
eCRF 
electronic Case Report Form 
IOP 
Intraocular Pressure 
MedDRA 
Medical Dictionary for Regulatory Activities 
PCS 
potentially clinically significant 
PT 
Preferred Term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SI 
Le Système International d’Unités (International System of Units) 
SOC 
System Organ Class 
TEAE 
treatment-emergent adverse event 




a 
b 
c 
Allergan 
RST-001 (AGN
Figure 4–1. 
Table 
Phase 
1 
2a 
Up to approximately 2
Number of patients is d
Phase 1. 
The maximum tolerate
-151597) 
Overview
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Dos
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B 
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Allergan 
 
Statistical Analysis Plan RST-001-CP-0001  
RST-001 (AGN-151597) 
7 
Table 4–3. 
Study Visit Schedule: Core Study Visits 


Allergan 
 
Statistical Analysis Plan RST-001-CP-0001  
RST-001 (AGN-151597) 
8 
Table 4–4. 
Study Visit Schedule: Long-term Follow-up Visits 


Allergan
 
Statistical Analysis Plan RST-001-CP-0001  
RST-001 (AGN-151597) 
9 
5.0 
OBJECTIVES AND ENDPOINTS 
The primary objective of this study is to evaluate the safety of a single intravitreal 
injection of RST-001.  
The secondary objectives of this study are  
1. To establish the maximum tolerated dose of RST-001. 
2. To evaluate the preliminary efficacy of RST-001 in patients with advanced RP. 
The therapy will be considered safe in the absence of any grade 3 or greater AE 
considered related to RST-001.  
The secondary endpoints include the following efficacy measures of change in visual 
function:  


Allergan 
 
Statistical Analysis Plan RST-001-CP-0001  
RST-001 (AGN-151597) 
10 
 


Allergan 
 
 
Statistical Analysis Plan RST-001-CP-0001  
RST-001 (AGN-151597) 
11 
6.0 
PATIENT POPULATIONS 
6.1 
ENROLLED POPULATION 
The Enrolled Population will consist of all patients who signed the informed consent and 
receive a participant ID number.  
6.2 
SAFETY POPULATION 
The Safety Population will consist of all patients in the Enrolled Population who received 
at least 1 dose of study treatment. The safety analysis will be based on the actual 
treatment assigned.  
This population will be used for all analyses unless otherwise specified. 
 


Allergan 
 
 
Statistical Analysis Plan RST-001-CP-0001  
RST-001 (AGN-151597) 
12 
7.0 
PATIENT DISPOSITION 
Disposition will be summarized by the number and percentage of patients in each 
treatment group separately for each phase. The total number of patients screened will be 
summarized. 
Screen-failure patients (i.e., patients screened but not enrolled) and the associated reasons 
for fail to enroll will be tabulated for the all screened patients. The number and 
percentage of patients who complete each study phase (Phase 1 or 2a) and patients who 
prematurely discontinue during the same period will be presented for each treatment 
group and pooled across treatment groups separately for each phase. The reasons for 
premature discontinuation from the corresponding study phases will be summarized 
(number and percentage) by treatment group separately for each phase. All patients who 
prematurely discontinue during the corresponding study phases will be listed by 
discontinuation reason. 


Allergan 
 
 
Statistical Analysis Plan RST-001-CP-0001  
RST-001 (AGN-151597) 
13 
8.0 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
Demographic parameters (age; age group; race; ethnicity; sex), baseline characteristics 
(weight; height; and body mass index, calculated as weight [kg]/(height [m])2) will be 
summarized descriptively by treatment group separately for each phase.  
The number and percentage of patients with medical histories in each system organ class 
and preferred term will be summarized by treatment group separately for each phase. In 
addition, ocular medical history will be summarized for the study eye by treatment group 
separately for each phase.  
 
Concurrent procedure is defined as any procedure performed on or after the date of the 
first dose of study treatment. The number and percentage of patients with concomitant 
procedures in each system organ class and preferred term will be summarized by 
treatment group separately for each phase. In addition, ocular medical history will be 
summarized for the study eye by treatment group separately for each phase.  
 
Medical histories and concomitant procedures will be coded using the MedDRA, version 
21.0 or newer. 
 
Prior medication is defined as any medication taken before the date of the first dose of 
study treatment. Concomitant medication is defined as any medication taken on or after 
the date of the first dose of study treatment. The World Health Organization (WHO) 
Drug Dictionary Enhanced will be used to classify prior and concomitant medications by 
therapeutic class and drug name. 
The number and percentage of patients with prior medications will be summarized under 
each drug class and drug name by treatment group separately for each phase. A separate 
summary for prior ocular medications used in the study eye under each drug name by 
treatment group separately for each phase. If a patient took a specific medication multiple 
times or took multiple medications within a specific therapeutic class, that patient would 
be counted only once for the coded drug name or therapeutic class. Formulations 
(including salts, esters, etc.) containing the same active ingredient will be pooled under 
the coded drug name of the base compound. Medications containing multiple active 
ingredients of different coded drug names will be reviewed during the course of the study 
and may be pooled under a single coded drug name for analyses. 
Similarly, the number and percentage of patients with concomitant medications will be 
summarized under each drug class and drug name by treatment group separately for each 
phase separately for Core Study Visits and Long-term Follow-up Visits. A separate 
summary for concomitant ocular medications used by eye (study eye and fellow eye) 
under each drug name by treatment group separately for each phase separately for Core 
Study Visits and Long-term Follow-up Visits.  


Allergan 
 
 
Statistical Analysis Plan RST-001-CP-0001  
RST-001 (AGN-151597) 
14 
9.0 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
9.1 
EXTENT OF EXPOSURE 
Number and percent of patients exposed to the study treatment will be summarized by 
treatment group separately for each phase. 
9.2 
MEASUREMENT OF TREATMENT COMPLIANCE 
This is a single dose study and thus treatment compliance is not applicable. 
 
 


Allergan 
 
 
Statistical Analysis Plan RST-001-CP-0001  
RST-001 (AGN-151597) 
15 
10.0 
EFFICACY ANALYSES 


Allergan 
 
 
Statistical Analysis Plan RST-001-CP-0001  
RST-001 (AGN-151597) 
16 


Allergan 
 
 
Statistical Analysis Plan RST-001-CP-0001  
RST-001 (AGN-151597) 
17 
11.0 
SAFETY ANALYSES 
Safety assessments in this study are divided into measures of ocular safety and measures 
of systemic safety (Protocol Section 6.1). The safety parameters will include adverse 
events (AEs), ocular measurements, clinical laboratory tests including immunogenicity 
tests, vital signs, and 
. For each safety parameter, the last non-missing 
assessment before the first dose of study treatment will be used as the baseline for all 
analyses. 
11.1 
ADVERSE EVENTS 
Adverse events will be coded using MedDRA, version 21.0 or newer. 
An AE will be considered a treatment-emergent adverse event (TEAE) if it was present 
after the first dose of study treatment or was present before the date of the first dose of 
study treatment and increased in severity after the first dose of study treatment. If more 
than 1 AE was reported before the first dose of study treatment and coded to the same 
preferred term, the AE with the greatest severity will be used for comparison with the 
AEs occurring during the reporting periods.  
The number and percent of patients reporting TEAEs will be tabulated by treatment 
group in each phase separately during Core Study Visits and Long-term Follow-up Visits 
for the following categories:   
• All TEAEs 
• Treatment related TEAEs 
• Ocular TEAEs in the study eye 
• Non-ocular TEAEs 
• Treatment-related ocular TEAEs 
• Serious TEAEs 
• Deaths 
• AEs leading to study discontinuation 
The above categories will also be tabulated by SOC and PT, or by PT only for ocular 
related categories, with the number and percentage of patients by treatment group in each 
phase and separately during Core Study Visits and Long-term Follow-up Visits, except 
for the last 3 categories. 


Allergan 
 
 
Statistical Analysis Plan RST-001-CP-0001  
RST-001 (AGN-151597) 
18 
In addition, the number and percent of patients will be tabulated by SOC, PT, and 
severity, or by PT and severity only for ocular related categories, with the number and 
percentage of patients by treatment group in each phase and separately during Core Study 
Visits and Long-term Follow-up Visits for the following categories:  
• All TEAEs 
• Treatment related TEAEs 
• Ocular TEAEs in the study eye 
• Non-ocular TEAEs 
• Treatment-related ocular TEAEs 
If more than 1 AE is coded to the same PT for the same patient, the patient will be 
counted only once for that PT using the greatest severity and strictest causality for the 
summarization by severity and causal relationship. 
Separate tabular displays will be presented for patients who died, patients with SAEs, and 
patients with AEs leading to premature discontinuation.  
11.2 
PRIMARY OCULAR SAFETY MEASUREMENTS 
The following visual function measures at 6 months are considered primary safety 
endpoints. They will be listed and summarized by treatment group separately in each 
phase. 


Allergan 
 
 
Statistical Analysis Plan RST-001-CP-0001  
RST-001 (AGN-151597) 
19 
11.3 
SECONDARY OCULAR SAFETY MEASUREMENTS 


Allergan 
 
 
Statistical Analysis Plan RST-001-CP-0001  
RST-001 (AGN-151597) 
20 


Allergan 
 
 
Statistical Analysis Plan RST-001-CP-0001  
RST-001 (AGN-151597) 
21 


Allergan 
 
 
Statistical Analysis Plan RST-001-CP-0001  
RST-001 (AGN-151597) 
22 
11.5 
IMMUNOLOGICAL TESTS 
During the study, evidence of immune response to RST-001 will be monitored by 
systemic measurement of humoral and cellular immunity as follows: 
11.6 
CLINICAL LABORATORY PARAMETERS 
Descriptive statistics for clinical laboratory values (in SI units) and changes from the 
baseline values at each visit will be presented by treatment group separately for each 
phase for the following laboratory parameters as specified in the protocol amendment 2 
(Section 20.2). Only patients with clinical laboratory data at baseline and at least one 
Post-treatment visit will be included in the summary. 


Allergan 
 
 
Statistical Analysis Plan RST-001-CP-0001  
RST-001 (AGN-151597) 
23 


Allergan 
 
 
Statistical Analysis Plan RST-001-CP-0001  
RST-001 (AGN-151597) 
24 
Table 11.6–1. 
Criteria for Potentially Clinically Significant Laboratory Results 
11.7 
VITAL SIGNS 
Descriptive statistics for vital signs (respiratory rate, temperature, systolic and diastolic 
blood pressures, and pulse rate) and changes from baseline values at each visit will be 
presented by treatment group separately for each phase. 


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Vital sign values will be considered PCS if they meet both the observed-value criteria and 
the change-from-baseline criteria listed in Table 11.7–1. The number and percentage of 
patients with PCS Post-treatment values will be tabulated by treatment group separately 
for each phase. The percentages will be calculated relative to the number of patients with 
available non-PCS baseline values and at least 1 Post-treatment assessment. The 
numerator will be the total number of patients with available baseline values and at least 
1 PCS Post-treatment value. A supportive tabular display of patients with PCS Post-
treatment values will be provided, including the participant ID number, baseline and all 
Post-treatment (including non-PCS) values. 
 
Table 11.7–1. 
Criteria for Potentially Clinically Significant Vital Signs 
Parameter 
Flag 
Criteriaa 
Observed Value 
Change From Baseline 
Sitting systolic blood 
pressure, mm Hg 
High 
≥ 180 
Increase of ≥ 20 
Low 
≤ 90 
Decrease of ≥ 20 
Sitting diastolic blood 
pressure, mm Hg 
High 
≥ 105 
Increase of ≥ 15 
Low 
≤ 50 
Decrease of ≥ 15 
Sitting pulse rate, bpm 
High 
≥ 120 
Increase of ≥ 15 
Low 
≤ 50 
Decrease of ≥ 15 
Weight, kg 
High 
— 
Increase of ≥ 7% 
Low 
— 
Decrease of ≥ 7% 
a A Post-treatment value is considered potentially clinically significant if it meets both the observed-value 
and the change-from-baseline criteria. 
bpm = beats per minute. 


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11.9 
OTHER SAFETY PARAMETERS 
11.9.1 
Physical Examination 
The physical examination will be performed at screening visit, Month 6 and Month 12. 
Physical examination findings from screening visit will be recorded on the Medical and 
Surgical History eCRF.  Physical Examination findings at Month 6 or Month 12 or 
changes (worsening) since the previous physical examination, will be recorded on the 
Adverse Events eCRF. Summaries for medical/surgical history and adverse events are 
described in Sections 8.0 and 11.1, respectively.  
 
 
 


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12.0 
INTERIM ANALYSIS 
There will be three database locks. The primary analysis will occur when all patients 
have completed the Month 6 visit or exited earlier. 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.  


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13.0 
DETERMINATION OF SAMPLE SIZE 
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. 


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14.0 
STATISTICAL SOFTWARE 
Statistical analyses will be performed 
 
 
  


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15.0 
DATA HANDLING CONVENTIONS 
15.1 
SUMMARY STATISTICS 
The following statistical summaries will be presented for each type of data.  Further 
details are specified in the tables, figures, and listings shells. 
• Continuous variables will be summarized by descriptive statistics (number of 
patients, mean, standard deviation (SD), median, Q1, Q3, minimum, and 
maximum values).  
• Categorical variables will be summarized by frequency distributions (counts and 
percentages). 
• The results for ocular related assessments in the fellow eye will be summarized 
across the treatment groups, if applicable. 
15.2 
VISIT TIME WINDOWS 


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15.3 
DERIVED VARIABLES 
Analyses visits will be derived per Section 15.2. Observed data will be used for the 
primary and secondary objectives without derivation.  
15.4 
REPEATED OR UNSCHEDULED ASSESSMENTS OF SAFETY 
PARAMETERS 
If a patient has repeated assessments before the start of the first treatment, the results 
from the final non-missing assessment made prior to the start of the study treatment will 
be used as baseline. If end-of-study assessments are repeated or if unscheduled visits 
occur, the last non-missing Post-treatment assessment will be used as the end-of-study 
assessment for generating summary statistics. However, all Post-treatment assessments 
will be used for PCS value determinations, and all assessments will be presented in the 
data listings. 
15.5 
MISSING DATE OF THE LAST DOSE OF STUDY TREATMENT 
When the date of the last dose of study treatment is missing for a patient in the Safety 
Population, all efforts should be made to obtain the date from the Investigator. If after all 
efforts are made it is still missing, the last available dosing record date will be used as the 
last dose date. 


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15.6 
MISSING SEVERITY ASSESSMENT FOR ADVERSE EVENTS 
If severity is missing for an AE that started before the date of the first dose of study 
treatment, an intensity of mild will be assigned. If severity is missing for an AE that 
started on or after the date of the first dose of study treatment, an intensity of severe will 
be assigned. The imputed values for severity assessment will be used for the incidence 
summary; the values will be shown as missing in the data listings. 
15.7 
MISSING CAUSAL RELATIONSHIP TO STUDY DRUG FOR 
ADVERSE EVENTS 
If the causal relationship to the study treatment is missing for an AE that started on or 
after the date of the first dose of study treatment, a causality of yes will be assigned. The 
imputed values for causal relationship to study treatment will be used for the incidence 
summary; the values will be shown as missing in the data listings. 
15.8 
MISSING DATE INFORMATION FOR ADVERSE EVENTS 
The following imputation rules only apply to cases in which the start date for AEs is 
incomplete (i.e., partly missing). 


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15.9 
MISSING DATE INFORMATION FOR PRIOR OR 
CONCOMITANT MEDICATIONS 
For prior or concomitant medications, incomplete (i.e. partly missing) start dates and/or 
stop dates will be imputed. When the start date and the stop date are both incomplete for 
a patient, the start date will be imputed first. 
15.9.1 
Incomplete Start Date 
The following rules will be applied to impute the missing numeric fields for an 
incomplete prior or concomitant medication start date. If the stop date is complete (or 
imputed) and the imputed start date is after the stop date, the start date will be imputed 
using the stop date. 


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15.9.2 
Incomplete Stop Date 
The following rules will be applied to impute the missing numeric fields for an 
incomplete prior or concomitant medication stop date. If the date of the last dose of study 
treatment is missing, impute it as descripted in Section 15.4. If the imputed stop date is 
before the start date (imputed or non-imputed start date), the imputed stop date will be 
equal to the start date. 


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Missing month only 
• If only the month is missing, the day will be treated as missing and both the month 
and the day will be replaced according to the above procedure 
Missing day only 
• If the month and year of the incomplete stop date are the same as the month and year 
of the last dose of study treatment, the day of the last dose of study treatment will be 
assigned to the missing day 
• If either the year of the incomplete stop date is before the year of the date of the last 
dose of study treatment or if both years are the same but the month of the incomplete 
stop date is before the month of the date of the last dose of study treatment, the last 
day of the month will be assigned to the missing day 
• If either the year of the incomplete stop date is after the year of the date of the last 
dose of study treatment or if both years are the same but the month of the incomplete 
stop date is after the month of the date of the last dose of study treatment, the first day 
of the month will be assigned to the missing day 
15.10 
CHARACTER VALUES OF CLINICAL LABORATORY 
PARAMETERS 


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16.0 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
There are no changes to the analyses specified in the protocol Amendment 2 (dated 
19OCT2017).  
 


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17.0 
REFERENCES 
Not applicable. 


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DOCUMENT HISTORY PAGE 
Effect Date 
Revision 
Number 
Primary Author 
Description of Change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Date (DD/MMM/YYYY)/Time (PT) 
Signed by: 
Justification 
  
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
     
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
 
RST-001-CP-0001 Statistical Analysis Plan
21-Feb-2019 11:18 GMT-080
Medical Monitor Approval
21-Feb-2019 12:38 GMT-080
Management Approval
22-Feb-2019 08:00 GMT-080
Clinical Development Approval
22-Feb-2019 12:35 GMT-080
Biostatistics Approval
22-Feb-2019 12:54 GMT-080
Biostatistics Approval