Phase II, Multicenter, Open-label Safety Study of Bilateral NT-501 in Participants With Macular Telangiectasia Type 2
Phase: PHASE2
Conditions: Macular Telangiectasia Type 2
Sponsor: Neurotech Pharmaceuticals

NTMT-02B – Bilateral NT-501 Implant Phase 2 Study 
Protocol Version 4.0 (21 January 2022)
Confidential
Page 1 of 51
CLINICAL RESEARCH PROTOCOL
DRUG:
NT-501
STUDY NUMBER:
NTMT-02B
PROTOCOL TITLE:
Phase II, Multicenter, Open-label Safety Study of Bilateral 
NT-501 in Participants with Macular Telangiectasia Type 2
IND NUMBER:
10931
SPONSOR
Neurotech Pharmaceuticals, Inc
PROTOCOL VERSION
DATE
Version 4.0
January 21, 2022 (US and AUS)
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eurotech Ph
Version
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NTMT-02B – Bilateral NT-501 Implant Phase 2 Study
Protocol Version 4.0 (21 January 2022) 
Confidential
Page 2 of 51
CLINICAL PROTOCOL APPROVAL FORM
Phase II, Multicenter, Open-label Safety Study of Bilateral NT-501 in Participants with Macular Telangiectasia 
Type 2
Study No: NTMT-02B
Protocol Version/Date:
Version 1.0 / 20 January 2021
Version 2.0 / 18 March 2021 (US and AUS)
Version 3.0 / 16 July 2021 (US and AUS)
Version 4.0 / 21 January 2022 (US and AUS)
This study protocol was subject to critical review by the sponsor’s appropriate protocol review committee, and the 
signatures below document approval. The information contained in this protocol is consistent with:
1.
The current risk-benefit evaluation of the investigational product
2.
The moral, ethical and scientific principles governing clinical research as set out in the Declaration of Helsinki, 
and principles of Good Clinical Practice as described in the Code of Federal Regulations (CFR 21, parts 50, 54, 
56, and 312), and according to applicable local requirements
The investigator will be supplied with details of any significant or new findings, including adverse events, relating to 
treatment with the investigational product.
Name and Title
Signature
Date
Sponsor Representative:
Thomas Aaberg, MD
Chief Medical Officer
Neurotech Pharmaceuticals, Inc.
CRO Representative:
Joseph Sliman, MD
Global Medical Monitor, The Emmes 
Company, LLC
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I am approving this document.
01/21/2022 10:40 AM EST
Joseph  Sliman
Joseph Sliman
I am approving this document.
01/21/2022 01:18 PM
EST
Thomas Aaberg

NTMT-02B – Bilateral NT-501 Implant Phase 2 Study
Protocol Version 4.0 (21 January 2022) 
Confidential
Page 3 of 51
CONFIDENTIALITY AND INVESTIGATOR STATEMENT
The information contained in this protocol and all other information relevant to NT-501 are the confidential and 
proprietary information of Neurotech Pharmaceuticals, Inc., and except as may be required by federal, state, or 
local laws or regulations, may not be disclosed to others without prior written permission of Neurotech 
Pharmaceuticals, Inc.
I have read the protocol, including all appendices, and I agree that it contains all the necessary information for 
me and my personnel to conduct this study as described. I will conduct this study as outlined herein, in 
accordance with the regulations stated in the Federal Code of Regulations for Good Clinical Practices and 
International Conference on Harmonisation guidelines and will make a reasonable effort to complete the study 
within the time designated.
I will provide all study personnel under my supervision copies of the protocol and any amendments, and access 
to all information provided by Neurotech Pharmaceuticals, Inc., or specified designees. I will discuss the 
material with them to ensure that they are fully informed about NT-501 and the study.
Principal Investigator Name (printed)
Signature
Date
Site Number
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NTMT-02B – Bilateral NT-501 Implant Phase 2 Study
Protocol Version 4.0 (21 January 2022) 
Confidential
Page 4 of 51
PROTOCOL SYNOPSIS
Title of Study:
Phase II, Multicenter, Open-label Safety Study of Bilateral NT-501 in Participants
with Macular Telangiectasia Type 2
IND Number: 
10931
Sponsor:
Neurotech Pharmaceuticals, Inc.
Study Compound:
NT-501 is a combination of a sealed semipermeable hollow fiber membrane (HFM) 
capsule surrounding a scaffold of 6 strands of polyethylene terephthalate (PETP) 
yarn, and Ciliary Neurotrophic Factor (CNTF) secreting NTC-201.6A cells that 
adhere to the polyethylene terephthalate (PET) yarn. Using a surgical procedure, this 
implant is positioned into the vitreous and anchored to the sclera
Study Objectives
Primary Objective:
Assess the incidence and severity of adverse events following bilateral ocular
implantation of NT-501. Ocular safety will be assessed using ocular examinations, as 
well as best corrected visual acuity (BCVA) measurements using the Early Treatment 
Diabetic Retinopathy Study (ETDRS) visual acuity protocol. Systemic safety will be 
assessed based on the incidence and severity of systemic adverse events (AE)
Secondary Objectives:
Assess serum levels of CNTF, the immunogenicity of NT-501 with quantification of 
antibodies (Ab) to CNTF, neutralizing antibodies (Nab) to CNTF, and Ab to NTC-
201.6A cells, as well as Ab to dihydrofolate reductase (DFHR), in samples collected 
at the Baseline, Month 1, Month-3 and Month-6 study visits.
Study Design:
Clinical Study Sites:
Participants will be recruited from up to 10 clinical study sites. Clinical 
sites must have participated in the multicenter Phase 1/2 extension
study, NTMT-01/02E, or the Phase 3 (NTMT-03) study of NT-501 
in participants with Macular Telangiectas Type 2 (MacTel).
Number of Participants:
The goal is to have a minimum of 30 evaluable participants 
Structure:
Multicenter, Open-Label
Visit Schedule:
There will be a maximum of 7 visits over a study period of up to 7 months. These 
visits will include Visit 1, Screening (Day -28 to Day -1); Visit 2, Surgery; Visit 3, 
Post-Surgery Day 1; Visit 4, Post-Surgery Week 1; Visit 5, Post-Surgery Month 1; 
Visit 6, Post-Surgery Month 3; Visit 7, Post-Surgery Month 6 and Exit Visit.
Duration:
The study duration will be approximately 7 Months (screening period of up to 28 days 
plus a follow-up period of 6 months).
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NTMT-02B – Bilateral NT-501 Implant Phase 2 Study
Protocol Version 4.0 (21 January 2022) 
Confidential
Page 5 of 51
Study Description:
This is a multicenter, open-label, study to evaluate the safety of bilateral NT-501 
implants in a minimum of 30 study participants with MacTel type 2. All study 
subjects who have received a NT-501 implant in one eye through participation in the 
Phase 1/2 extension study, NTMT-01/02E, or the Phase 3 (NTMT-03) study and meet 
the eligibility criteria, will receive a NT-501 implant in their fellow eye and will be 
followed for 6 months following the NT-501 implantation. 
Inclusion Criteria:
Study eligibility is to be assessed at Visit 1 (Screening). To participate in this study, the 
potential participant must meet all the following criteria:
General Inclusion Criteria:
1.
Participants from the Phase 3 study must have completed the Month-24 visit
2.
Participant in the MacTel Phase 1/2 extension study or the Phase 3 study must 
exit these studies prior to entering the Bilateral Implant safety study (NTMT-02B)
3.
Participant must be willing and able to follow the study instructions and be 
willing and able to complete all required study procedures and visits
4.
Participant must be willing and able to provide a signed Informed Consent, as 
well as written documentation in accordance with the relevant country and local 
privacy requirements, e.g., written data protection consent
5.
Females of childbearing potential must consent to and complete a pregnancy test 
during the screening visit
6.
A participant’s refusal to allow the collection of blood samples for Ciliary 
neurotrophic factor (CNTF), Ab to CNTF, Nab to CNTF, Ab to NTC-201.6A 
cells, and Ab to DFHR will not exclude the participant from study participation 
Ocular Inclusion Criteria
1.
Participant must have a positive diagnosis of MacTel type 2, with evidence of 
fluorescein leakage typical of MacTel, and at least one of the other features that 
include hyperpigmentation that is outside of a 500-micron radius from the center 
of the fovea, retinal opacification, crystalline deposits, right-angle vessels, or 
inner/outer lamellar cavities in their study eyes
2.
Participant must have steady fixation in the foveal or parafoveal area in the study 
eye and sufficiently clear media for good quality photographs
3.
Participant must have a NT-501 implant in one eye and have completed the Phase 
1/2 extension study (NTMT-01/-2E) or the Month 24-visit of the Phase 3 study 
(NTMT-03)
Exclusion Criteria
Unless otherwise stated, eligibility assessments are to be performed at Visit 1 
(Screening). The following criteria will exclude participant from entry into the study. 
General Exclusion Criteria
1.
Females of childbearing potential (those who are not surgically sterilized or post-
menopausal, i.e., absence of menstruation for 12 months or longer) may not 
participate in the study if any of the following conditions exists:
o
Pregnant (positive pregnancy test at Visit 1 or intend to become 
pregnant during the study)
o
Nursing (lactating)
o
Do not agree to use adequate birth control methods for the duration of 
the study and until 90 days after the last administration of study drug 
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NTMT-02B – Bilateral NT-501 Implant Phase 2 Study
Protocol Version 4.0 (21 January 2022) 
Confidential
Page 6 of 51
(adequate birth control methods are: hormonal – oral, implantable, 
transdermal or injectable contraceptives; mechanical – spermicide in 
conjunction with a barrier such as condom or diaphragm, intrauterine 
device [IUD] or surgical sterilization of partner, or total sexual 
abstinence)
2.
Participant is too ill to likely complete the entire study, based on the 
investigator’s assessment
3.
Participant, in the opinion of the investigator, is not suitable for study 
participation
4.
Participant has any screening laboratory result (serum chemistry, hematology, 
urinalysis) that in the opinion of the investigator is not suitable for study 
participation
5.
History or current evidence of severe hypersensitivity to the NT-501 implant
6.
Participant has a history or current evidence of a medical condition (systemic or 
ophthalmic disease, metabolic dysfunction, physical examination finding or 
clinical laboratory finding) that may in the opinion of the investigator preclude 
the safe administration of the NT-501 or adherence to the scheduled study visits, 
safe participation in the study or affect the results of the study (e.g., unstable or 
progressive cardiovascular, cerebral vascular, pulmonary, Parkinson’s, liver or 
renal disease, depression, cancer, or dementia) 
Ocular Exclusion Criteria
1.
Participant has a history or evidence of the following surgeries/procedures in the 
study eye, as assessed at Visit 1, including:
o
Submacular surgery
o
Vitrectomy
o
Retinal detachment
o
Incisional glaucoma surgery
o
Trabeculectomy or trabeculoplasty
o
Cataract surgery or laser-assisted in situ keratomileusis (LASIK) 
performed in the previous 6 months
2.
Participant has uQFRQWUROOHGJODXFRPDRURFXODUK\SHUWHQVLRQLH,23 25 
mmHg in the study eye
3.
Participant has evidence of intraretinal or subretinal neovascularization or central 
serous chorio-retinopathy in the study eye
4.
Participant has evidence of ocular disorder(s) in the study eye of a severity that 
could confound the interpretation of study results, compromise visual acuity or 
require medical or surgical intervention during the study period, including retinal 
vascular occlusion, severe non-proliferative or proliferative diabetic retinopathy, 
retinal detachment, macular hole, geographic atrophy, intraretinal or subretinal 
neovascularization, central serous chorio-retinopathy, pathological myopia
5.
Participant has a vitreous hemorrhage in the study eye at Visit 1 (Screening)
6.
Participant has the spherical equivalent of refractive error in the study eye 
demonstrating more than 8 diopters of myopia
7.
Participant has a history or evidence of penetrating ocular trauma in the study eye 
8.
Participant has an anticipated need for cataract extraction in the study eye within 
6 months of Visit 1 (Screening) such as cortical opacity > standard 3, posterior 
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NTMT-02B – Bilateral NT-501 Implant Phase 2 Study
Protocol Version 4.0 (21 January 2022) 
Confidential
Page 7 of 51
subcapsular opacity > standard 2, or a nuclear opacity > standard 3 as measured 
on the Age-Related Eye Disease Study (AREDS) clinical lens grading system
9.
Participant has uveitis, history of uveitis in either eye or history of ocular herpes 
virus in either eye
10. Participant has undergone major surgery within the last 6 months (systemic or 
ocular in either eye) or participant who is likely to require major surgery within 6 
months of Visit 1 (Screening) 
11. Participant has a periocular or ocular/intraocular infection or inflammation in 
either eye (such as infectious conjunctivitis, keratitis, scleritis, endophthalmitis) 
within 3 months prior to Visit 1 (Screening)
12. Participant has ocular hypotension in either eye (<6 mmHg) that in the opinion of 
the Investigator would interfere with the NT-501 implantation
13. Participant has a history of scleritis, scleral thinning, periocular, ocular, or 
intraocular infection or inflammation, cicatrizing conjunctival diseases any other 
ocular conditions in the study eye that could interfere with the administration of 
NT-501
Response Measures
Safety Assessments:
x
Adverse Events after NT-501 Implantation Surgery 
x
General Physical Exam
x
Vital Signs 
x
Pregnancy Test
x
Complete ophthalmic exam (consisting of an external examination of the eye and 
adnexa, screening for eyelid/pupil responsiveness, slit lamp biomicroscopy, 
dilated fundus examination, indirect ophthalmoscopy, and IOP)
x
BCVA
x
SD-OCT
x
Serum chemistry, hematology, and urinalysis
x
Ab and Nab to CNTF, Ab to NTC-201.6A cells and Ab to DFHR (serum)
x
Blood sample collection for analysis of serum levels of CNTF
Safety Endpoints
Number and proportion of adverse events from day of surgery through post NT-501 
implantation follow-up
Number and proportion of severe adverse events from day of surgery through post 
NT-501 implantation follow-up
Number and proportion of ocular adverse events from day of surgery through post 
NT-501 implantation follow-up
Number and proportion of non-ocular adverse events from day of surgery through 
post NT-501 implantation follow-up
General Statistical Methods 
and Types of Analyses
Formal sample size calculations were not performed. The number of participants was 
chosen based on feasibility and is considered sufficient to meet the study objectives.
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phthalmic 
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creening fo
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BCVA
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SD
SD-OCT
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Serum chemi
Serum chemi
Ab
Ab and 
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NTMT-02B – Bilateral NT-501 Implant Phase 2 Study
Protocol Version 4.0 (21 January 2022) 
Confidential
Page 8 of 51
The general analytical approach for all endpoints is descriptive. No formal statistical 
hypothesis testing will be conducted.
Analysis Populations
Safety Population: Defined as participants who have a NT-501 implant in both eyes. 
This population will be used for all safety analysis. 
Safety Analysis
The primary objective of the study is to assess the safety and tolerability of bilateral 
NT-501 implants. Tolerance and safety will be based on the incidence and severity of 
treatment-emergent adverse events (TEAEs).
Sample size Calculations
Formal sample size calculations were not performed. The number of participants was 
chosen based on feasibility and is considered sufficient to meet the study objectives
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NTMT-02B – Bilateral NT-501 Implant Phase 2 Study
Protocol Version 4.0 (21 January 2022) 
Confidential
Page 9 of 51
Figure 1. Study Design
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NTMT-02B – Bilateral NT-501 Implant Phase 2 Study 
Protocol Version 4.0 (21 January 2022)
Confidential
Page 10 of 51
Table 1:  Schedule of Visits and Procedures in the Assessment of Safety in Participants with Bilateral NT-501 Implants
Procedures
Screening
Day 
-28 to -1
Surgery
Day 0
Post-
Surgery
Day 1
Post-
Surgery
Week 1
Post-
Surgery 
Month 1
Post-Surgery Month 
3
Post-
Surgery 
Month 
6
Visit Window 
±2 days
±7days
±14 days
±14 
days
Visit Number
1
2
3
4
5
6
7
STUDY DAY
-28 to -1
0
1
7
30
90
180
Informed Consent
X
Demographics
X
Medical & Ophthalmic 
History a
X
X
Concomitant Medications 
and non-study procedures
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
Vital Signs b
X
Inclusion/exclusion 
criteria
X
Eligibility Review
X
X
Medical evaluation c
X
X
Pregnancy Test d 
X
Serum Chemistry, 
Hematology & Urinalysis 
X
Visual Acuity (BCVA)
OUe
SEf
SEf
OU e
OU e
OU e
Measurement of pupil 
diameter
OU
OU
OU
OU
Complete Ophthalmic 
Exam g
OU
SE
SE
OU
OU
OU
Dilated Fundus 
Photography
OU
OU
SD-OCT h
OU
SE
OU
OU
OU
Fluorescein Angiography
OU
Serum concentrations of 
CNTF, Ab or Nab to 
CNTF, Ab to NTC-
201.6A cells; or Ab to 
DFHR (serum)
X
X
X
X
NT-501 implantation 
surgery
X
Post NT-501 implant 
assessment
SE
SE
OU
OU
OU
External photograph of 
conjunctiva over implant
OU
OU
OU
Complete Exit Form
X
Abbreviations: BCVA= Best Corrected Visual Acuity; SD-OCT = spectral domain optical coherence tomography, OU = 
both eyes, SE = study eye
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UR
S R
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SU
SU
S
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SS
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S
SS
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SS
$SS
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$SS
$SS
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$SS
SS
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NTMT-02B – Bilateral NT-501 Implant Phase 2 Study
Protocol Version 4.0 (21 January 2022) 
Confidential
Page 11 of 51
a
Demographic data includes height, weight, eye color and smoking history
b
Vital signs include body temperature, pulse rate, respiration rate and sitting blood pressure
c
The medical evaluation may be performed during screening 
or on the day of surgery; the evaluation is standard for any surgical procedure or anesthesia (the tests performed 
will be site-specific)
d
Females of childbearing potential only; additional pregnancy tests may be performed at any time/day during study
e
Manifest refraction will be performed prior to BCVA assessments except for the BCVA assessments performed 
prior to surgery and 1 week following surgery
f
Best-corrected visual acuity must be performed within 1 week prior to the day of surgery
g
h
Complete ophthalmic exam consists of an external examination of the eye and adnexa, screening for eyelid/pupil 
responsiveness, slit lamp biomicroscopy, dilated fundus examination, indirect ophthalmoscopy, and IOP 
assessment) Slit lamp biomicroscopy, indirect ophthalmoscopy and intraocular pressure (IOP). IOP measurements 
will be taken prior to pupil dilation. If possible, IOP measurements should take place at approximately the same 
time of the day at each visit and with the same equipment
The same SD-OCT instrument should be used for an individual participant throughout the entire study
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Protocol Version 4.0 (21 January 2022) 
Confidential
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LIST OF ABBREVIATIONS
Ab
antibodies
AE
adverse event
AREDS
Age-Related Eye Disease Study
AMD
age-related macular degeneration
BCVA
best-corrected visual acuity
CFR
Code of Federal Regulations
CNTF
ciliary neurotrophic factor
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
DHFR
dihydrofolate reductase
DSMC
data and safety monitoring committee
eCRF
electronic case report form
ECT
encapsulated cell therapy
EDC
electronic data capture
ETDRS
Early Treatment Diabetic Retinopathy Study
EZ
ellipsoid zone
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HFM
hollow fiber membrane
ICF
informed consent form
ICH
International Conference on Harmonisation
IDE
investigational device exemption
IEC
independent ethics committee
IND
investigational new drug
IOP
intraocular pressure
IRB
institutional review board
IReST
International Reading Speed Texts
IS/OS
inner segment/outer segment junction line
MacTel
macular telangiectasia type 2
MedDRA
Medical Dictionary for Regulatory Activities
Nab
Neutralizing antibodies
NEI-VFQ-25
National Eye Institute Visual Function Questionnaire-25 
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committee
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H
rm
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rapy
RY
pture
R
nt Diabetic R
iabetic Retinopa
eti
UR
one
SU
nd Drug Administrat
ug Administrat
SS
d Clinical Practice
d Clinical Practice
$S
ollow fiber membra
fiber membra
$S
ed consent
con
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NTMT-02B – Bilateral NT-501 Implant Phase 2 Study
Protocol Version 4.0 (21 January 2022) 
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NHOR
Natural History and Observation and Registry Study of Macular Telangiectasia Type 2
OCT
optical coherence tomography
ONL
outer nuclear layer
PET yarn
polyethylene terephthalate yarn
PSNS
parasympathetic nervous system
RP
retinitis pigmentosa
RPE
retinal pigment epithelium
SAE
serious adverse event
SD-OCT
spectral-domain optical coherence tomography
SE
standard error
SRNV
subretinal neovascularization
SUSAR
serious unexpected suspected adverse reaction
TEAEs
treatment-emergent AEs
US, USA
United States
VLDLR
very low-density lipoprotein receptor
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Table of Contents
CLINICAL PROTOCOL APPROVAL FORM..............................................................................................................................2
CONFIDENTIALITY AND INVESTIGATOR STATEMENT .....................................................................................................3
PROTOCOL SYNOPSIS.................................................................................................................................................................4
FIGURE 1. STUDY DESIGN ..........................................................................................................................................................9
1
INTRODUCTION AND RATIONALE..................................................................................................................................16
BACKGROUND..................................................................................................................................................................16
STUDY RATIONALE............................................................................................................................................................18
1.1.1
Pharmacokinetics.............................................................................................................................................................19
1.1.2
Preclinical Pharmacology.................................................................................................................................................19
1.1.3
Potential for Drug-Drug Interactions ...............................................................................................................................19
1.1.4
Clinical Adverse Event Profile ...........................................................................................................................................19
1.1.5
Elevations in Liver Function Tests.....................................................................................................................................20
1.1.6
Potential Risk of Testicular Injury.....................................................................................................................................20
1.1.7
Potential Risk to Fetal Development................................................................................................................................20
1.1.8
Dosing Regimen ...............................................................................................................................................................20
2
STUDY OBJECTIVES........................................................................................................................................................20
3
STUDY ENDPOINTS........................................................................................................................................................21
4
STUDY PLAN..................................................................................................................................................................21
STUDY DESIGN.................................................................................................................................................................21
SAFETY VARIABLES............................................................................................................................................................22
SAFETY ASSESSMENTS: ......................................................................................................................................................22
5
POPULATION.................................................................................................................................................................22
NUMBER OF PARTICIPANTS.................................................................................................................................................22
INCLUSION CRITERIA..........................................................................................................................................................22
EXCLUSION CRITERIA.........................................................................................................................................................23
PARTICIPANT SCREENING ...................................................................................................................................................25
DEVIATION FROM INCLUSION/EXCLUSION CRITERIA.................................................................................................................25
MASKING........................................................................................................................................................................25
6
STUDY CONDUCT...........................................................................................................................................................25
STUDY PROCEDURES BY TIME POINT.....................................................................................................................................26
DESCRIPTION OF THE STUDY PROCEDURES.............................................................................................................................26
6.2.1
Study Procedures..............................................................................................................................................................26
STUDY VISIT PROCEDURES..................................................................................................................................................27
6.3.1
Visit 1: Screening/Baseline Procedures ............................................................................................................................27
6.3.2
Visit 2: Enrollment and Surgery........................................................................................................................................28
6.3.3
Visit 3: 1 Day Post-surgery ...............................................................................................................................................29
6.3.4
Visit 4: 1 Week Post-surgery (+/- 2 days) .........................................................................................................................29
6.3.5
Visit 5:1-Month Post-surgery (+/- 7 days) ........................................................................................................................29
6.3.6
Visit 6: 3-Month Post-surgery (+/-14 days) ......................................................................................................................30
6.3.7
Visit 7: Six-Month Post-surgery (+/-14 days)....................................................................................................................30
CLINICAL LABORATORY TESTS..............................................................................................................................................31
STUDY LABORATORY TESTS.................................................................................................................................................31
PROTOCOL DEVIATIONS .....................................................................................................................................................32
7
INVESTIGATIONAL PRODUCT MANAGEMENT................................................................................................................32
DESCRIPTION...................................................................................................................................................................32
7.1.1
Formulation......................................................................................................................................................................32
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7.1.2
Storage.............................................................................................................................................................................32
PACKAGING AND SHIPMENT................................................................................................................................................32
DOSE AND ADMINISTRATION ..............................................................................................................................................33
ACCOUNTABILITY..............................................................................................................................................................33
8
CONCOMITANT MEDICATIONS AND PROCEDURES........................................................................................................34
CONCOMITANT MEDICATIONS ............................................................................................................................................34
CONCOMITANT PROCEDURES..............................................................................................................................................34
PROHIBITED CONCOMITANT THERAPY...................................................................................................................................34
9
ADVERSE EVENTS ..........................................................................................................................................................34
DOCUMENTING ADVERSE EVENTS........................................................................................................................................35
ASSESSMENT OF SEVERITY..................................................................................................................................................35
ASSESSMENT OF CAUSALITY................................................................................................................................................35
ADVERSE EVENT FOLLOW-UP..............................................................................................................................................36
REPORTING OF PREGNANCY................................................................................................................................................36
10
SERIOUS ADVERSE EVENT..............................................................................................................................................37
DEFINITION OF SERIOUS ADVERSE EVENT ..............................................................................................................................37
DEFINITION OF TERMS.......................................................................................................................................................37
REPORTING SERIOUS ADVERSE EVENTS.................................................................................................................................38
NOTIFYING FDA/REGULATORY AUTHORITIES.........................................................................................................................38
11
STATISTICS ....................................................................................................................................................................39
GENERAL PROCEDURES......................................................................................................................................................39
SAMPLE SIZE....................................................................................................................................................................39
STATISTICAL METHODS......................................................................................................................................................40
11.3.1
Analysis of Safety.........................................................................................................................................................40
11.3.2
Interim Analysis...........................................................................................................................................................40
12
STUDY RISKS..................................................................................................................................................................40
13
ETHICS AND RESPONSIBILITIES......................................................................................................................................43
14
COMPLIANCE.................................................................................................................................................................43
GOOD CLINICAL PRACTICE..................................................................................................................................................43
INFORMED CONSENT.........................................................................................................................................................44
15
AUDITING AND MONITORING.......................................................................................................................................45
COMMUNICATION WITH THE INSTITUTIONAL REVIEW BOARD OR INDEPENDENT ETHICS COMMITTEE ................................................45
STUDY MONITORING REQUIREMENTS...................................................................................................................................45
RECORDS MANAGEMENT...................................................................................................................................................46
DATA QUALITY ASSURANCE................................................................................................................................................46
SOURCE DOCUMENTATION.................................................................................................................................................46
STUDY FILES AND RECORD RETENTION..................................................................................................................................47
16
AMENDMENTS..............................................................................................................................................................48
17
STUDY REPORT AND PUBLICATIONS..............................................................................................................................48
18
STUDY DISCONTINUATION............................................................................................................................................48
PREMATURE DISCONTINUATION ..........................................................................................................................................49
19
CONFIDENTIALITY..........................................................................................................................................................49
20
REFERENCES..................................................................................................................................................................50
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Protocol Version 4.0 (21 January 2022) 
Confidential
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1
INTRODUCTION AND RATIONALE
Background
Idiopathic macular telangiectasia type 2 (MacTel) is a bilateral neuro/vascular/glial degenerative condition of 
unknown etiology with characteristic neurosensory atrophy, perifoveal telangiectatic vessels, and diffuse 
hyperfluorescence in the late phase of fluorescein angiography1. Other characteristic findings include loss of 
retinal transparency, crystalline deposits, a decrease or absence of macular pigment, and hyperplasia of the 
retinal pigment epithelium (RPE) in the macular area. Spectral-domain optical coherence tomography (SD-
OCT) assessments show disruption of the photoreceptor inner segment/outer segment junction line (IS/OS line) 
or ellipsoid zone (EZ)2, and hyporeflective cavities in both the inner and outer retina.
The natural course of MacTel is a gradual bilateral loss of vision with the progression of EZ loss, occasionally 
accompanied by development of a neovascular complex.1 Functional impairment may be mild with no 
impairment or only a slight reduction in binocular best-corrected visual acuity (BCVA) in the early stages of 
MacTel. However, loss of visual acuity in at least one eye is a frequently reported complaint1,3,4. Notably, even 
in the presence of deep paracentral scotomata and reduced reading ability, distance visual acuity may be 
relatively preserved.1,5,6 However, a decrease in visual acuity may eventually occur with disease progression. 
There appear to be essentially two different factors contributing to the decline of visual acuity.1,7,8. Initially, 
there may be a slow drop in visual acuity, usually not below ~20/50, which may be due to structural foveal 
changes, e.g., a low-grade chronic vascular leakage or degeneraWLYHK\SRUHÀHFWLYHFDYLWLHV in the inner retina. 
The second and more important factor for a decline in visual acuity is atrophy of the foveal photoreceptors, 
ZKLFKPD\UHVXOWLQHFFHQWULF¿[DWLRQDQGDYLVXDODFXLW\RIapproximately 20/200. Such photoreceptor dropout 
initially occurs temporal to the foveola causing the characteristic deep paracentral scotomata and may later 
spread centrally. If a relatively faster drop in visual acuity is observed, an associated macular hole, the 
development of a retinal pigment epithelial hypertrophy, or neovascular complex may be suspected. Visual 
acuity below 20/200 is rarely observed but there may be marked functional impairment in very late disease 
stages, with large central areas of photoreceptor atrophy or due to the development of a larger neovascular 
complex.1,4,9
There is significant evidence to support the use of ciliary neurotrophic factor (CNTF) as a potential therapy for 
retinal degenerative diseases. 10,11 Histopathologic studies in naturally occurring and genetically engineered 
animal models of photoreceptor dysfunction and death that phenotypically model retinitis pigmentosa (RP), 
have indicated the promise of CNTF as an effective therapeutic agent for reducing photoreceptor loss associated 
with degeneration of the cells of the outer retina. CNTF is one of several neurotrophic factors that are produced 
endogenously by neurons or Müller cells. CNTF has been demonstrated to be effective in retarding 
photoreceptor neuron loss in animal models of retinal degeneration of various forms12, including environmental 
light stress13. In two preclinical animal studies conducted by Neurotech Pharmaceuticals, Inc., CNTF-producing 
cells have been shown to have a protective effect on photoreceptors. In a rat model of RP, CNTF-producing 
cells delivered as an intravitreal injection appeared to have a protective effect on photoreceptors with treated 
eyes having 5 to 6 layers of photoreceptors in the ONL compared with 1 to 2 layers in the untreated eyes.12 In a 
dog model of RP, the NT-501 implant was also observed to have a protective effect on photoreceptors; the 
treated eyes had 5 to 6 layers in the ONL compared with 2 to 3 layers in the untreated eyes.12
Although CNTF is an attractive therapeutic candidate for neurodegenerative diseases, it is significantly 
handicapped by its extremely short half-life. Neurotech Pharmaceuticals, Inc. has developed the NT-501 
implant to treat retinal degenerative diseases. Human safety data is available from studies in participants with 
MacTel 13,14 RP15, atrophic age-related macular degeneration (AMD)16, and glaucoma (data on file). The NT-
501 implants are positioned into the vitreous cavity with a surgical procedure that may be performed under 
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NTMT-02B – Bilateral NT-501 Implant Phase 2 Study
Protocol Version 4.0 (21 January 2022) 
Confidential
Page 17 of 51
local/monitored anesthesia care. These implants consist of a sealed semipermeable hollow fiber membrane 
(HFM) capsule surrounding a scaffold of 6 strands of polyethylene terephthalate yarn, which have been loaded 
with CNTF-secreting NTC-201.6A cells.
Safety data have been collected from approximately 250 participants with retinitis pigmentosa (RP), 
achromatopsia, age-related macular degeneration (AMD) and macular telangiectasia, type 2, who have received 
the NT-501 implant producing a nominal dose of 20 ng/24 hours). In these subjects, adverse events (AEs) were 
generally limited to those related to the implant procedure.13,14,15,16 As noted previously, the natural history 
study of MacTel has demonstrated that photoreceptor loss is intrinsic to this disorder17,18 Although anti-vascular 
endothelial growth factor therapy reduced the vascular permeability, it did not influence the progression of 
photoreceptor cell loss or functional loss.19 A relatively small number of these participants have reported 
miosis , which is believed to be directly related to CNTF.15 During early development, a number of participants 
developed inflammation following implantation. This was subsequently found to be related to impurities in the 
membrane of the implant, which has since been replaced with a new membrane with fewer impurities. Trace to 
mild inflammation was seen postoperatively in a minority of participants and typically cleared by 3 months. In 
the Phase 2 study MacTel study, one episode of delayed inflammation (grade 3) was noted at 6 months and 
resolved by 12 months.
Studies of NT-501 in RP and AMD did not demonstrate any potential benefit. 15,16 However, in the NTMT-02 
study of 67 participants (99 eyes randomized 1:1) with MacTel, there was a statistically significant reduction in 
the rate of progression of MacTel in the eyes implanted with NT-501 as compared with the eyes that underwent 
the sham procedure.14. In the intent-to-treat population, mean (standard error [SE]) area of EZ break increased 
by 0.218 (0.049) mm2 in the implanted eyes and by 0.270 (0.050) mm2 in the sham eyes. The difference 
between groups in the increase of the MacTel lesion (0.052 mm2) was statistically significant (p = 0.039, 1-
sided). The mean change in retinal sensitivity as measured by microperimetry was not different between the 
treated and sham eyes. However, in a post hoc analysis of the per protocol population, when the aggregate 
retinal sensitivity (dB) was compared with the corresponding area affected by MacTel, a significant (P<0.002) 
difference between treated and sham eyes was detected. This difference was consistent with the slower growth 
of the MacTel lesion in the treated eyes. Additionally, there was a significant difference between treatment 
groups in reading speed at 24 months (13.5 words read per minute, p = 0.016). Specifically, the implanted eyes 
had not deteriorated from baseline (0.03 words read per minute), while the sham eyes showed impairment in 
reading speed relative to baseline (-13.5 words read per minute). The mean (SE) macular thickness was 
significantly increased in the treated population when compared with the sham group (NT-501: 
+5.45 [3.02] ȝPVKDP-4.97 [2.85] ȝPS = 0.007). The mean (SE) pupil size was also significantly reduced in 
the implanted eyes as compared with the sham eyes (difference between groups: 0.922 [0.13] mm, p < 0.0001).
As of September 2019, a total of 64 participants (94 study eyes) were consented in the Phase 1/2 Extension 
Study, and of those, 92 study eyes had EZ break grading at 36 months and 86 had EZ break grading at 48-
months (data on file). In post hoc analyses the mean (standard error [SE]) area of EZ break at 36 months was
0.149 (0.035) mm2 in the implanted eyes and 0.241 (0.032) mm2 in the sham eyes. The difference between 
groups in the increase of the MacTel lesion (0.092 mm2) was statistically significant (p = 0.022, 1-sided). The 
mean (standard error [SE]) area of EZ break at 48 months was 0.211 (0.059) mm2 in the implanted eyes and 
0.208 (0.056) mm2 in the sham eyes. The difference between groups in the increase of the MacTel lesion 
(0.077 mm2) did not meet statistical significance (p = 0.488, 1-sided). There was not a statistically significant 
difference between treatment groups in reading speed at 36 months (10.6 words read per minute, p = 0.093), or 
48 months (5.4 words read per minute, p = 0.202). The mean (SE) pupil size for all NTMT-02 Extension Study 
participants was reduced in the implanted eyes as compared with the sham eyes at 36 months (difference 
between groups: 0.805 [0.14] mm, p < 0.0001) and 48 months (difference between groups: 0.844 [0.15] mm, 
p < 0.0001).
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Consistent with the experience of the NT-501 implant in studies of RP and dry AMD, the implant was generally 
well tolerated in subjects with MacTel type 2. Of the 188 subjects receiving an NT-501 implant in the Phase 1, 
2 and 3 studies, there have been 4 study participants who have undergone implant removal after completing the 
24-month time point. In one of these subjects, the explant surgery was associated with a subsequent retinal 
detachment that was surgically reattached. 
In the ongoing Phase 3 studies, participants with a confirmed diagnosis of MacTel and an EZ break area of at 
least 0.16 mm2 and no greater than 2.00 mm2 were randomly assigned to 1 of 2 treatment groups: implantation 
of the NT-501 implant or sham surgery with no implant. A single NT-501 implant was inserted into the study 
eye for the duration of the study. The primary endpoint is the rate of change in the ellipsoid zone (EZ; inner 
segment/outer segment [IS/OS]) area loss over 24 months, as measured by study eye spectral-domain optical 
coherence tomography (SD-OCT). 
The current study is an open-label safety study to assess the safety and tolerance of bilateral NT-501 implants in 
participants with MacTel. Eligibility is open to study participants who received a NT-501 implant in one eye 
and completed either the MacTel Phase 1/2 extension study (NTMT-01/02E) or the Month 24 visit of the Phase 
3 (NRMt-03) study. Eligible participants who received an NT-501 in one eye and meet the eligibility criteria of 
the current study, NTMT-02B, will receive an NT-501 implant in the eye without an implant (study eye) and 
will be followed for 6-months after the surgical procedure. 
The study will be conducted in full compliance with the principles of the Declaration of Helsinki (as amended 
in Tokyo, Venice, Hong Kong, and South Africa), the guidelines set forth by the International Conference on 
Harmonisation (ICH), current Good Clinical Practice (GCP), and in compliance with local regulatory 
requirements and the applicable United States (US) Code of Federal Regulations (CFR), 21 CFR parts 50 and 
312.
Study Rationale
Historically, MacTel has been considered a vascular disorder of the retina. This concept was largely based on 
clinical observation and limited histopathology. With the initiation of a natural history study17 including over 
700 participants followed for more than 5 years, it has become apparent that MacTel may not be primarily a 
retinal vascular disease but, rather, one involving photoreceptor and glial cell abnormalities as well. The 
primary objectives of the MacTel natural history study are to enroll participants with MacTel and to document 
structural and functional changes over time using multiple real-time imaging modalities and functional 
assessments.
The most common retinal findings in patients with MacTel include retinal capillary dilatation associated with 
retinal vascular leakage, but without associated retinal thickening.1 Additional findings include superficial 
retinal crystalline deposits, retinal opacification, and right-angle venules. As the disease progresses, intraretinal 
pigment plaques and neovascular complexes may develop. Although individuals with MacTel are typically 
diagnosed in their fifth or sixth decade of life, it is likely that onset of clinical manifestations occurs earlier but 
go undetected until they become symptomatic. Both sexes are affected by this disease.1
As noted previously, the natural history study of MacTel has demonstrated that photoreceptor loss is intrinsic to 
this disorder17,18 Although anti-vascular endothelial growth factor (anti-VEGF) therapy has reduced the vascular 
permeability in subjects with MacTel type 2, anti-VEGF agents have not influenced the progression of 
photoreceptor cell loss or functional loss.19 A mouse model in which the very low-density lipoprotein receptor 
(VLDLR) has been knocked out (i.e., Vldlr-/- mice) mimics many of the characteristics of the human disease, 
including focal disruption of photoreceptors coincident with the abnormal outer retinal-penetrating vessels20. 
The new vessels observed in the human disease and the Vldlr-/- mouse exhibit relatively mild permeability 
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NTMT-02B – Bilateral NT-501 Implant Phase 2 Study
Protocol Version 4.0 (21 January 2022) 
Confidential
Page 19 of 51
defects and are accompanied by glial activation and disruption of the RPE. Thus, in the absence of clinically 
significant leakage or hemorrhage, neuronal cell death due to increased oxidative stress caused by proximity to 
the abnormal vessels is observed. Using the Vldlr-/- mouse model, it has been demonstrated that targeted 
delivery of a neurotrophic factor, neurotrophin-4, to sites of abnormal neovascularization significantly reduced 
photoreceptor degeneration and protected against visual dysfunction, even in the face of persistent 
microvascular abnormalities in these mice.21
Two postmortem donor eyes from elderly individuals with MacTel were analyzed histopathologically and 
immunohistochemically22, 23. Both eyes had extensive disruption of foveal anatomy and substantial reduction in 
Müller glial cell marker expression, as well as many other neural and glial abnormalities. Based on these 
observations, a knockout mouse was evaluated, in which Müller glial cells were depleted leading to 
photoreceptor apoptosis, vascular telangiectasis, blood-retinal barrier breakdown and, later, intraretinal 
neovascularization.24. In the mature retina, Müller glia are a major source of CNTF. Intravitreal CNTF had no 
effect on wildtype retinas, but significantly reduced both the area of cone outer segment loss and the number of 
apoptotic cells in the ONL between 7 and 10 days after tamoxifen-induced Müller cell ablation in transgenic 
mice. Functional rescue after CNTF administration was not assessed in this study.
Imaging using SD-OCT has recently demonstrated a neurodegenerative process in MacTel, with photoreceptor 
damage mapped to loss of vision. Similarly, adaptive optics scanning laser ophthalmoscopy (AOSLO) reveals 
unique dark regions in the cone mosaic and decreased cone density associated with decreased vision, even in 
areas with normal vasculature, which suggests that this feature represents early neuronal changes involved in 
the pathogenesis of MacTel.25 These studies, taken together with the clinical observations of MacTel, support 
the concept that delivery of neurotrophic molecules, such as CNTF, may prevent photoreceptor degeneration in 
diseases with outer retinal vascular abnormalities such as MacTel. Thus, we believe we have an established 
rationale for using CNTF delivered by NT-501 to treat MacTel.
1.1.1
Pharmacokinetics
CNTF is not detectable in the serum of study participants implanted with a single NT-501 implant. 
1.1.2
Preclinical Pharmacology
The half-life of CNTF in laboratory animals is extremely short and is measured in minutes.26
1.1.3
Potential for Drug-Drug Interactions
None.
1.1.4
Clinical Adverse Event Profile
Most AEs in the clinical studies of NT-501 have been related to the implantation procedure and were generally 
mild and well tolerated. The majority of these events resolved within a few days. Of the 188 subjects receiving 
an NT-501 implant in the Phase 1, 2 and 3 studies, there have been 4 study participants who have undergone 
implant removal after completing the 24-month time point, two from the NTMT-01/02 extension study and two 
from the NTMT-03 study. A small proportion of participants have reported miosis. No discontinuations due to 
this event have been reported in the MacTel clinical studies.
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NTMT-02B – Bilateral NT-501 Implant Phase 2 Study
Protocol Version 4.0 (21 January 2022) 
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1.1.5
Elevations in Liver Function Tests
No changes in aspartate aminotransferase, alanine aminotransferase, or serum bilirubin were seen in early 
studies of NT-501 in RP or atrophic AMD.
1.1.6
Potential Risk of Testicular Injury
There is no evidence from previous clinical trials or from preclinical toxicology studies to suggest a risk of 
testicular injury.
1.1.7
Potential Risk to Fetal Development
No embryo-fetal/teratogenicity studies have been conducted during the development of NT-501. Studies to 
support the systemic use of human CNTF from the treatment of amyotrophic lateral sclerosis were performed in 
rats and rabbits (Syntex Discovery Research, Palo Alto, USA). At doses up to 300 ȝJNJGD\QRHIIHFWVZHUH
observed on fertility in male and female rats. At doses up to 1000 ȝJNJGD\LQUDWVDQGȝJNJGD\LQUDEELWV
there was no evidence of fetal abnormality. The risk of these events in this trial is low, given the fact that the 
CNTF produced by the NTC-201-6A cell line is of human origin and there is no detectable CNTF in patient
plasma 13,15. CNTF has been extensively studied in animal and human neurological models and is considered a 
neuroprotectant.
1.1.8
Dosing Regimen
Study participants with MacTel who have previously received a NT-501 implant in one eye will be implanted 
with a NT-501 implant in their fellow eye. Only one configuration of the NT-501 implant will be used in this 
study, the configuration that delivers a nominal dose of CNTF, 20 ng/implant/day.
2
STUDY OBJECTIVES
The overall objective of this study is to evaluate the safety and tolerability of the NT-501 implant, when 
implanted in both eyes of participants with MacTel type 2.
Primary objective:
x
Assess the incidence and severity of adverse events following bilateral ocular implantation of NT-501. 
Ocular safety will be assessed using ocular examinations, as well as best corrected visual acuity (BCVA) 
measurements using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity protocol. 
Systemic safety will be assessed based on the incidence and severity of systemic adverse events (AE)
Secondary objective:
x
Assess serum levels of CNTF, the immunogenicity of NT-501 with quantification of antibodies (Ab) to 
CNTF, neutralizing antibodies (Nab) to CNTF, and Ab to NTC-201.6A cells, as well as Ab to 
dihydrofolate reductase (DFHR) in samples collected at the Baseline, Month 1, Month-3 and Month-6 
study visits.
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NTMT-02B – Bilateral NT-501 Implant Phase 2 Study
Protocol Version 4.0 (21 January 2022) 
Confidential
Page 21 of 51
3
STUDY ENDPOINTS
Primary Safety Endpoints
x
Number and proportion of adverse events from day of surgery through 6 months post implantation
x
Number and proportion of severe adverse events from day of surgery through 6 months post 
implantation
x
Number and proportion of ocular adverse events from day of surgery through 6 months post 
implantation
x
Number and proportion of non-ocular adverse events from day of surgery through 6 months post 
implantation
Secondary Safety Endpoints 
x
Number and proportion of participants with a loss in BCVA of 15 or more letters from baseline in the 
study eye using the Early Treatment Diabetic Retinopathy Study (ETDRS) distance chart
x
Number and proportion of participants with at least 1 treatment-emergent serious adverse event (SAE) 
x
Detectable serum levels of CNTF at Months 1, 3 and 6 post-implantations of NT-501
x
Number and proportion of participants with serum Ab or Nab to CNTF, Ab to NTC-201.6A cells and 
Ab to DFHR at Baseline and Months1, 3 and 6 post-implantation of NT-501
4
STUDY PLAN
Study Design
This is a multicenter, open-label, study to evaluate the safety of bilateral NT-501 implants in a minimum 
of 30 study participants with MacTel type 2. All study subjects who have received a NT-501 implant in 
one eye, completed either the Phase ½ extension study (NTMT-01/02E) or the Month-24 visit of the 
Phase 3 study (NTMT-03) and meet the eligibility criteria, will receive a NT-501 implant in their fellow 
eye and will be followed for 6 months following NT-501 implantation.
Study participants will have a screening period of up to 28 days. Participants who meet the 
inclusion/exclusion criteria will have implant surgery within 30 days of the Screening Visit. After the 
surgery, subjects receiving a NT-501 implant will return to the clinical center for assessments performed 
on Day 1, Week 1 (± 2 days), Month 1 (± 7 days), Month 3 (± 14 days) and Month 6 (± 14 days). Upon 
completion of the 6-month visit, these participants will exit the study. These participants may elect to be 
followed for safety and disease progression in a nested substudy of the existing Natural History and 
Observation and Registry Study of Macular Telangiectasia Type 2 (NHOR).17
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Protocol Version 4.0 (21 January 2022) 
Confidential
Page 22 of 51
Safety Variables
x
Safety will be evaluated by monitoring AEs and SAEs, complete ophthalmic exam (consisting of 
an external examination of the eye and adnexa, screening for pupil responsiveness, slit lamp 
biomicroscopy, dilated fundus examination, indirect ophthalmoscopy, and IOP), and
measurement of BCVA.
x
All AEs will be captured whether or not considered to be related to the surgical procedure, 
implant, or CNTF. An attempt will be made to differentiate between treatment-related AEs and 
AEs considered to be part of normal progression of the disease. In addition, for treatment-related 
AEs, an attempt will be made to differentiate those that the investigator believes are due to the 
implant itself, to CNTF, or to the implant procedure.
Safety Assessments:
The following safety assessments will be performed at the indicated timepoints:
x
Adverse Events
x
Vital Signs 
x
Pregnancy Test
x
Complete ophthalmic exam (consisting of an external examination of the eye and adnexa, 
screening for pupil responsiveness, slit lamp biomicroscopy, dilated fundus examination, indirect 
ophthalmoscopy, BCVA and IOP) 
x
SD-OCT
x
Serum chemistry, hematology, and urinalysis
x
Ab or Nab to CNTF, Ab to NTC-201.6A cells and Ab to DFHR (serum)
x
Serum levels of CNTF
5
POPULATION
All study subjects must have a diagnosis of bilateral MacTel type 2 in both eyes to be eligible for 
enrollment.
Number of Participants
The study will enroll a minimum of 30 participants who meet the inclusion and exclusion criteria.
Inclusion Criteria
Eligibility to participate in the NTMT-02B study is limited to participants with an NT-501 implant in 
one eye and have completed and exited from the NTMT-01/02 extension study or the Month 24 visit of 
the Phase 3 study (NTMT-03). No persons shall be excluded based on gender, race, or ethnicity. Study 
eligibility is to be assessed at Visit 1 (Screening). To participate in this study, the potential participant 
must meet all the following criteria:
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Protocol Version 4.0 (21 January 2022) 
Confidential
Page 23 of 51
General Inclusion Criteria
1. Participants from the Phase 3 study must have completed the Month-24 visit
2. Participant in the MacTel Phase 1/2 extension study or the Phase 3 study must exit these studies 
prior to entering the Bilateral Implant safety study (NTMT-02B)
3. Participant must be willing and able to follow the study instructions and be willing and able to 
complete all required study procedures and visits
4. Participant must be willing and able to provide a signed Informed Consent, as well as written 
documentation in accordance with the relevant country and local privacy requirements, e.g., 
written data protection consent
5. Females of childbearing potential must consent to a pregnancy test before entering the study 
6. A participant’s refusal to allow the collection of blood samples for analysis of serum CNTF, 
serum Ab or Nab to CNTF, Ab to NTC-201.6A cells and Ab to DFHR levelsin one eye will not 
exclude the participant from study participation
Ocular Inclusion Criteria
1. Participant must have a positive diagnosis of MacTel type 2 with evidence of fluorescein leakage 
typical of MacTel and at least one of the other features that include hyperpigmentation that is 
outside of a 500-micron radius from the center of the fovea, retinal opacification, crystalline 
deposits, right-angle vessels, or inner/outer lamellar cavities in the study eye
2. Participant must have steady fixation in the foveal or parafoveal area in the study eye and 
sufficiently clear media for good quality photographs
Exclusion Criteria
Unless otherwise stated, eligibility assessments are to be performed at Visit 1 (Screening). The 
following criteria will exclude participant from entry into the study.
General Exclusion Criteria
1. Females of childbearing potential (those who are not surgically sterilized or post- menopausal, 
i.e., absence of menstruation for 12 months or longer) may not participate in the study if any of 
the following conditions exists:
o
Pregnant (positive pregnancy test at Visit 1 or intend to become pregnant during the study)
o
Nursing (lactating)
o
Do not agree to use adequate birth control methods for the duration of the study and until 
90 days after the last administration of study drug (adequate birth control methods are: 
hormonal – oral, implantable, transdermal or injectable contraceptives; mechanical –
spermicide in conjunction with a barrier such as condom or diaphragm, intrauterine device 
[IUD] or surgical sterilization of partner, or total sexual abstinence)
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NTMT-02B – Bilateral NT-501 Implant Phase 2 Study
Protocol Version 4.0 (21 January 2022) 
Confidential
Page 24 of 51
2. Participant is too ill to likely complete the entire study, based on the investigator’s assessment
3. Participant, in the opinion of the investigator, is not suitable for study participation 
4. Participant with any screening laboratory finding (serum chemistry, hematology, urinalysis) that 
in the opinion of the investigator is not suitable for study participation 
5. Participant has a history or current evidence of severe hypersensitivity to the NT-501 implant
6. Participant has a history or current evidence of a medical condition (systemic or ophthalmic 
disease, metabolic dysfunction, physical examination finding or clinical laboratory finding) that 
may in the opinion of the investigator preclude the safe administration of the NT-501 implant or 
adherence to the scheduled study visits, safe participation in the study or affect the results of the 
study (e.g., unstable or progressive cardiovascular, cerebral vascular, pulmonary, Parkinson’s, 
liver or renal disease; depression, cancer, or dementia
Ocular Exclusion Criteria
1. Participant has a history or evidence of the following surgeries/procedures in the study eye, as 
assessed at Visit 1, including:
o
Submacular surgery
o
Vitrectomy
o
Retinal detachment
o
Incisional glaucoma surgery
o
Trabeculectomy or trabeculoplasty
o
Cataract surgery or laser-assisted in situ keratomileusis (LASIK) performed in the previous 
6 months
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3. Participant has evidence of intraretinal or subretinal neovascularization or central serous chorio-
retinopathy in the study eye
4. Participant has evidence of ocular disorder(s) in the study eye of a severity that could confound 
the interpretation of study results, compromise visual acuity or require medical or surgical 
intervention during the study period, including retinal vascular occlusion, severe non-
proliferative or proliferative diabetic retinopathy, retinal detachment, macular hole, geographic 
atrophy, intraretinal or subretinal neovascularization, central serous chorio-retinopathy, 
pathological myopia
5. Participant has a vitreous hemorrhage in the study eye at Visit 1 (Screening)
6. Participant has a spherical equivalent of the refractive error in the study eye demonstrating more 
than 8 diopters of myopia
7. Participant has a history or evidence of penetrating ocular trauma in the study eye 
8. Participant has an anticipated need for cataract extraction in the study eye within 6 months of 
Visit 1 (Screening) such as cortical opacity > standard 3, posterior subcapsular opacity > 
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NTMT-02B – Bilateral NT-501 Implant Phase 2 Study
Protocol Version 4.0 (21 January 2022) 
Confidential
Page 25 of 51
standard 2, or a nuclear opacity > standard 3 as measured on the Age-Related Eye Disease Study 
(AREDS) clinical lens grading system
9. Participant has uveitis, history of uveitis in either eye or history of ocular herpes virus in either 
eye
10. Participant has undergone major surgery within the last 6 months (systemic or ocular in either 
eye) or who are likely to require major surgery within 6 months of Visit 1 (Screening) 
11. Participant has periocular or ocular/intraocular infection or inflammation in either eye (such as 
infectious conjunctivitis, keratitis, scleritis, endophthalmitis) within 3 months prior to Visit 1 
(Screening)
12. Participant has ocular hypotension in either eye (<6 mmHg) that in the opinion of the 
Investigator would interfere with the NT-501 implant insertion
13. Participant has a history of scleritis, scleral thinning, periocular, ocular, or intraocular infection 
or inflammation, cicatrizing conjunctival diseases any other ocular conditions in the study eye 
that could interfere with or complicate the surgery associated with NT-501implant insertion
Participant Screening
Subjects from the NTMT-01/02 extension and have completed the study and subjects from the NTMT-
03 Phase 3 study who have completed the Month 24 visit and are interested in participating in the 
Bilateral Implant Safety Study, must exit from the these studies prior to participating in the Screening 
Visit for the Bilateral Implant Safety Study (NTMT-02B).
Potential participants will be consented prior to initiation of any screening procedures. All screening 
procedures may be completed in 1 day or may take place on more than 1 day if convenient for the 
participant or clinical site. All screening procedures should be completed within 28 days of signing the 
Informed Consent.
Deviation from Inclusion/Exclusion Criteria
No deviations from the stated inclusion/exclusion criteria will be allowed.
Masking
Participant, as well as treating and assessing investigators are unmasked to treatment.
6
STUDY CONDUCT
All potential participants will have a screening period of up to 28 days. In subjects who meet the 
inclusion/exclusion criteria, the implant surgery procedure in the study eye should be completed within 
one month of the Screening visit. 
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NTMT-02B – Bilateral NT-501 Implant Phase 2 Study
Protocol Version 4.0 (21 January 2022) 
Confidential
Page 26 of 51
Study Procedures by Time Point
Study eyes that receive a NT-501 implant will be assessed on post-operative Day 1, Week 1 (± 2 days), 
Month 1 (± 7 days), Month 3 (± 14 days), and Month 6 (± 14 days), where 1 month is defined as 30 
days. At baseline, SD-OCT and fluorescein angiography will be performed to confirm diagnosis and to 
exclude presence of a neovascular complex. BCVA, complete ophthalmic exams, dilated fundus 
photography and photographic assessment of the site of the implant surgery will be performed 
intermittently to assess the safety of the implant surgery and participant tolerance of the implant.
Description of the Study Procedures
6.2.1
Study Procedures
The following examinations are to be performed at the times indicated in the schedule of study 
procedures, where 1 month is defined as 30 days. Additional information related to these examinations 
is provided in the procedure specific instructions. All ocular evaluations/procedures will be completed 
only in the study eye unless otherwise indicated.
x
Medical evaluation, as would be standard for any surgical procedure and its associated anesthesia 
(the tests to be performed will be site-specific); evaluation may be performed during the 
screening period or on the day of surgery
x
Complete ophthalmic examination including:
o
External examination of the eye and adnexa
o
Pupil responsiveness
o
Manifest refraction
o
Slit lamp biomicroscopy
o
Dilated fundus examination
o
Indirect ophthalmoscopy
o
Goldmann applanation tonometry
o
BCVA (this assessment will be performed using the ETDRS visual acuity procedure, 
administered by a certified technician)
o
Measurement of undilated pupil diameter
x
Ophthalmic assessments including:
o
SD-OCT 
o
Fluorescein angiography
o
Color fundus photography
o
External photograph of conjunctiva over implant
x
Urine or blood pregnancy test for premenopausal female participants
x
Serum chemistry, hematology, and urinalysis
x
Serum analyses of CNTF, Ab and Nab to CNTF, Ab to NTC-201.6A cells and Ab to DFHR
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NTMT-02B – Bilateral NT-501 Implant Phase 2 Study
Protocol Version 4.0 (21 January 2022) 
Confidential
Page 27 of 51
Goldmann applanation tonometry, measurement of undilated pupil diameter, slit lamp biomicroscopy, 
dilated fundus examination, and urine or blood pregnancy testing will be performed following standard 
procedures at each site.
In the event of extenuating circumstances whereby an in-clinic follow-up visit cannot be conducted 
within the designated visit window, a Safety Check-In call should be performed, and an out of window 
in-clinic visit should be performed as soon as possible. Following a missed or out of window visit, every 
effort should be made to return the participant to the original protocol-specified visit schedule.
Study Visit Procedures
6.3.1
Visit 1: Screening/Baseline Procedures 
Subjects who have completed the NTMT-01/02 extension study and have an NT-501 implant are 
eligible for screening. Subjects who have completed the Month-24 visit of the Phase 3 study and wish to 
be considered for entry into the Bilateral Implant Safety Study, must exit the Phase 3 study prior to 
participating in the Screening Visit for the Bilateral Implant Safety Study. Participants who sign the 
consent form and begin screening will be assigned a participant identification number by the Advantage 
eClinical system. Screening procedures may be completed over more than 1 day to accommodate 
schedules and to lessen participant burden. All screening evaluations should be completed within 28 
days of signing the Informed Consent to establish eligibility.
Once the individual has indicated interest in participation, the principal investigator or appropriate 
designee must obtain the participant’s written consent. Once the consent is obtained, the investigator 
may initiate screening assessments. The results of all screening evaluations must be reviewed, and the 
participant must be found eligible prior to surgery. Once a participant is determined to be eligible for the 
study, surgery should be completed within approximately 30 days of the Screening visit.
The screening examinations and imaging must include the following:
x
Informed consent
x
Demographics; medical and ophthalmic history, including height, weight, eye color and smoking 
history
x
Concomitant medications and non-study procedures
x
Inclusion/exclusion criteria
x
Vital signs (body temperature, pulse rate, respiration rate and sitting blood pressure)
x
Medical evaluation, standard for any surgical procedure and its associated anesthesia (the 
specific tests to be ordered will be site-specific), may be performed during screening period or on 
the day of surgery
x
Blood and urine sample collection for serum chemistry, hematology, urinalysis
x
Urine or blood pregnancy exam for female participants of childbearing potential
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NTMT-02B – Bilateral NT-501 Implant Phase 2 Study
Protocol Version 4.0 (21 January 2022) 
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x
Blood sample collection for analysis of Ab and Nab to CNTF, Ab to NTC-201.6A cells and Ab 
to DFHR
x
Blood sample collection for analysis of serum levels of CNTF
x
BCVA following manifest refraction (both eyes)
x
Complete ophthalmic exam (consisting of an external examination of the eye and adnexa, 
screening for pupil responsiveness, slit lamp biomicroscopy, indirect ophthalmoscopy, and IOP) 
(both eyes)
x
Measurement of undilated pupil diameter (both eyes)\
x
Dilated fundus photography
x
SD-OCT (both eyes)
x
Fluorescein angiography (both eyes)
x
Color dilated fundus photography (both eyes)
The study investigator at each site will evaluate potential participants for study enrollment during the 
Screening Visit according to the inclusion and exclusion criteria as outlined in Sections 5.2 and 5.3.
6.3.2
Visit 2: Enrollment and Surgery
If the participant meets all study criteria and agrees to participate in the study, then the implant surgery 
date should be identified. The implant surgery procedure should be completed within one month of the 
Screening visit. 
On the date of the surgery, the investigator will confirm that no change in the participant’s general 
condition has occurred that would exclude study participation.
The following evaluations/procedures will be conducted during this visit:
x
Eligibility review
x
Medical evaluation that is standard for any surgical procedure and its associated anesthesia (the 
specific tests to be ordered will be site-specific), unless the medical evaluation was performed 
during screening period
x
Record any further medical/ophthalmic history 
x
Record any additional concomitant medications and non-study procedures
x
Perform AE assessment (from the time surgery begins)
x
Assess BCVA (may be performed within 1 week prior to the day of surgery or on the day of 
surgery, manifest refraction is not required)
x
NT-501 implant surgery
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NTMT-02B – Bilateral NT-501 Implant Phase 2 Study
Protocol Version 4.0 (21 January 2022) 
Confidential
Page 29 of 51
6.3.3
Visit 3: 1 Day Post-surgery 
Participants must return to the clinic 1-day post-surgery and will undergo the following procedures:
x
AE assessment
x
Review concomitant medications and non-study procedures
x
Complete ophthalmic exam of the study eye (consisting of an external examination of the eye 
and adnexa, screening for pupil responsiveness, slit lamp biomicroscopy, indirect 
ophthalmoscopy, and IOP) \
x
Implant site examination in study eye only
6.3.4
Visit 4: 1 Week Post-surgery (+/- 2 days)
Participants must return to the clinic 1-week post-surgery and will undergo the following procedures:
x
AE assessment
x
Review concomitant medications and non-study procedures
x
BCVA in study eye only (manifest refraction is not required) 
x
Complete ophthalmic exam of study eye (consisting of an external examination of the eye and 
adnexa, screening for pupil responsiveness, slit lamp biomicroscopy, indirect ophthalmoscopy, 
and IOP) in study eye only
x
SD-OCT in study eye only
x
Implant site examination in study eye only
6.3.5
Visit 5:1-Month Post-surgery (+/- 7 days)
Participants must return to the clinic 1-month post-surgery and will undergo the following procedures:
x
AE assessment
x
Review concomitant medications and non-study procedures
x
Blood sample collection for analysis of Ab and Nab to CNTF, Ab to NTC-201.6A cells and Ab 
to DFHR 
x
Blood sample collection for analysis of serum levels of CNTF
x
BCVA following manifest refraction (both eyes)
x
Complete ophthalmic exam (consisting of an external examination of the eye and adnexa, 
screening for pupil responsiveness, slit lamp biomicroscopy, dilated fundus examination, indirect 
ophthalmoscopy, and IOP) (both eyes)
x
Measurement of undilated pupil diameter (both eyes)
x
SD-OCT in both eyes
x
Implant site examination (both eyes)
x
External photograph of conjunctiva over implant (both eyes)
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NTMT-02B – Bilateral NT-501 Implant Phase 2 Study
Protocol Version 4.0 (21 January 2022) 
Confidential
Page 30 of 51
6.3.6
Visit 6: 3-Month Post-surgery (+/-14 days)
Participants must return to the clinic 3-months post-surgery and will undergo the following procedures: 
x
AE assessment
x
Review concomitant medications and concurrent non-study procedures
x
BCVA following manifest refraction (both eyes)
x
Blood sample collection for analysis of Ab and Nab to CNTF, Ab to NTC-201.6A cells and Ab 
to DFHR
x
Blood sample collection for analysis of serum levels of CNTF
x
Complete ophthalmic exam (consisting of an external examination of the eye and adnexa, 
screening for pupil responsiveness, slit lamp biomicroscopy, dilated fundus examination, indirect 
ophthalmoscopy, and IOP) (both eyes)
x
Measurement of undilated pupil diameter (both eyes)
x
SD-OCT in both eyes
x
Implant site examination (both eyes)
x
External photograph of conjunctiva over implant site examination (both eyes)
6.3.7
Visit 7: Six-Month Post-surgery (+/-14 days)
Participants must return to the clinic 6-months post-surgery and will undergo the following procedures: 
x
AE assessment
x
Review concomitant medications and concurrent non-study procedures
x
BCVA following manifest refraction (both eyes)
x
Blood sample collection for analysis of Ab and Nab to CNTF, Ab to NTC-201.6A cells and Ab 
to DFHR
x
Blood sample collection for analysis of serum levels of CNTF
x
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screening for pupil responsiveness, slit lamp biomicroscopy, dilated fundus examination, indirect 
ophthalmoscopy, and IOP) (both eyes)
x
Measurement of undilated pupil diameter (both eyes)
x
SD-OCT (both eyes)
x
Implant site examination (both eyes)
x
External photograph of conjunctiva over implant (both eyes)
x
Color digital fundus photography (both eyes)
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NTMT-02B – Bilateral NT-501 Implant Phase 2 Study
Protocol Version 4.0 (21 January 2022) 
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Clinical Laboratory Tests
All participants will undergo serum chemistry, hematology, and urinalysis examinations. In addition, 
premenopausal female participants will undergo a urine or blood pregnancy test at the screening visit 
and at other times if there is ever a question of possible pregnancy.
Blood for the chemistry and hematology analyses; and urine will be collected at the study site and 
analyzed at a local laboratory. Fasting prior to collection of these samples is not required. The results 
will be obtained by the investigator who will assess inclusion/exclusion criteria during the screening
period and/or prior to surgery at Visit 2 on Day 0.
The following clinical laboratory analyses will be performed:
x
Hematology: hematocrit, hemoglobin, red blood cell (RBC) count, white blood cell (WBC) 
count with differential (absolute and percentage of neutrophils, lymphocytes, monocyte, 
eosinophils, and basophils) and quantitative platelet count
x
Serum chemistries: blood urea nitrogen (BUN), serum creatinine, BUN/creatinine ratio, uric 
acid, cholesterol, triglycerides, albumin, total globulin, albumin/globulin ratio, total serum iron, 
total protein, serum electrolytes (sodium, potassium, bicarbonate, chloride, calcium, 
magnesium), phosphorus, glucose and the following liver function tests (LFT): serum aspartate 
transaminase (AST [SGOT]), serum alanine transaminase (ALT [SPGT]), alkaline phosphatase, 
gamma-glutamyl transpeptidase (GGT), total bilirubin, direct bilirubin, indirect bilirubin and 
lactate dehydrogenase (LDH), hemoglobin A1c
x
Urinalysis: specific gravity, pH, color, protein, glucose, blood, ketones, bilirubin, and 
microscopic examination (WBC, RBC, epithelial cells, bacteria, mucus, casts, crystals).
The investigator must review the results of the Screening visit clinical laboratory tests, including repeat 
analyses, prior to enrolling the participant into the surgical segment of the study. Participants with any 
clinically relevant laboratory values that may in the opinion of the investigator preclude the safe surgical 
implantation of the NT-501 implant, adherence to the scheduled study visits, safe participation in the 
study, or affect the results of the study, will not be eligible for study participation.
Study Laboratory Tests
All participants will undergo examinations of serum CNTF, Ab and Nab to CNTF, Ab to NTC-201.6A 
cells and Ab to DFHR (serum). Serum samples will be collected at the Screening Visit (Visit 1), Visit 5 
(Post-Surgery Month 1); Visit 6 (Post-surgery Month 3) and Visit 7 (Post-Surgery Month 6).
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Blood collected for these assessments will be collected at the study site and will be shipped to a 
Neurotech central laboratory for analysis. The laboratory will enter the results into the electronic data 
capture system. Fasting prior to collection of these samples is not required.
Protocol Deviations
Protocol deviations will be reported to the sponsor as they are discovered.
7
INVESTIGATIONAL PRODUCT MANAGEMENT
Description
7.1.1
Formulation
The study implant is the NT-501 implant, NTC-201.6A encapsulated cell therapy (ECT), delivering a 
nominal CNTF dose of 20 ng/implant/day.
7.1.2
Storage
The shipping container is to be stored at room temperature at the clinical or surgical center.  Room 
temperature LVQRWWRH[FHHG&)RUIDOOEHORZí&í). The implant must be used within 
the “use by” date. Storage of the box at temperatures outside this range could result in the internal 
temperature of the box and the implant exceeding the allowable range of 16°C to 37°C. If a planned 
implant surgical procedure is delayed such that the shipped investigational product will be in the 
shipping container for a period beyond the identified “use by” date, then Neurotech Pharmaceuticals,
Inc. must be notified, and an alternate/replacement shipment will be provided.
Packaging and Shipment
The NT-501 implant is contained within the primary packaging, which is comprised of a sealed clear 
plastic container that contains the transport medium. The NT-501 implant is suspended within the 
transport medium by a titanium clamp which, in turn, is held in position by a luer cap that is twisted onto 
the flange of the primary packaging. The inner surfaces of the primary packaging, the transport medium, 
and all other component surfaces are sterile. As long as the secondary packaging remains sealed, the 
exterior of the primary packaging within the secondary packaging is maintained sterile. Product labeling 
is located on the exterior, nonsterile side of the secondary packaging seal. This container is protected in 
an insulated transport carton.
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Dose and Administration
The study implant is the NT-501 implant, NTC-201.6A encapsulated cell therapy (ECT), delivering a 
nominal CNTF dose of 20 ng/implant/day. This implant will be implanted in the fellow eye of 
participants who received a NT-501 implant in an eye in an earlier MacTel study. All implants will 
remain in situ for the duration of the study. There are no plans to remove the implant, except in the case 
of participant intolerance or complications such as infection or inflammation. NT-501 implants can also 
be removed if requested by the study participant.
Accountability
All investigational product and supplies provided by the sponsor and used during this study must be 
maintained in a secure location. The investigator has overall responsibility for ensuring that the 
investigational product is stored in a safe, limited-access location under the specified appropriate storage 
conditions. Limited responsibility may be delegated to a nominated representative, but this delegation 
must be documented.
The investigator agrees to not supply the NT-501 implant to any person not enrolled in this study or to 
any person not delegated to perform investigational product handling.
The investigator/recipient will acknowledge receipt of the investigational product, indicating shipment 
content and condition. A record of the TempTale® readings must be kept for each shipment. Damaged 
supplies will be reported to the sponsor. Accurate records will be kept for all investigational products 
supplied and received. The date of implantation will be recorded.
Investigational product will not be returned to the sponsor except in an instance of implant inspection 
failure where the sponsor requests that the failed implant or a portion thereof should be returned for 
investigation.
All investigational product not implanted per protocol into enrolled study participants must be destroyed 
on site as dictated by the appropriate biohazardous waste standard operating or study specific procedure 
at the participating institution (if appropriate). Investigational products should only be destroyed after 
investigational product accountability has been performed and all investigational products are accounted 
for. Duplicate implants provided at the time of surgery that are not required for implantation should be 
marked in large letters “NOT FOR HUMAN USE” following successful implantation of the original 
implant, until the time of destruction.
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8
CONCOMITANT MEDICATIONS AND PROCEDURES
Concomitant Medications 
Any concomitant medications a participant is receiving at the start of the study or given for any reason 
during the study (except for routine medications given for ocular procedures required by the protocol, 
such as a topical anesthetic), including over the counter, supplements, and herbal formulas, must be 
recorded in the source document, including start and stop dates, dosing, route of administration, and 
indication information. Recording of concomitant medications on the case report forms (CRFs) must be 
done according to the instructions provided in the study regulatory binder. 
Concomitant Procedures
All ocular and non-ocular procedures (excluding study surgery and procedures) must also be recorded in 
the source document, including start and stop dates. Recording of procedures on the CRFs must be done 
according to the instructions provided in the study regulatory binder.
Prohibited Concomitant Therapy
Ocular administration of subconjunctival or intravitreal antibiotics is prohibited unless treating a sight 
threatening condition. The ocular administration of gentamicin or other aminoglycosides topically, peri-
ocularly, or by injection is prohibited unless treating a sight-threatening condition for which no other 
alternatives are appropriate. Systemic administration of aminoglycosides should also be avoided. 
Aminoglycosides are known to be toxic to RPE cells and ocular administration could harm the cells in 
the NT-501 implant. Anti-VEGF agents administered as intravitreal or intravenous injection are 
prohibited.
9
ADVERSE EVENTS
An AE is any untoward medical occurrence in humans, whether or not it is considered treatment- or 
procedure-related, which occurs during the conduct of a clinical trial. Any change in clinical status, 
ophthalmological assessments, etc., that is considered clinically significant by the study investigator and 
requires intervention is considered an AE. Medical conditions or diseases present before a participant 
starts study treatment are only considered AEs if they worsen after the participant starts study treatment 
(temporal association).
A suspected adverse reaction (related AE) is any event for which there is a reasonable possibility that 
the treatment caused the AE. A reasonable possibility implies that there is evidence that the treatment 
caused the event.
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Documenting Adverse Events
All AEs, either observed by the investigator or their medical collaborators, or reported by the participant 
spontaneously, or in response to direct questioning, will be reported. Any AE regardless of severity or 
potential association with the NT-501 implant, CNTF, or the study procedures must be documented in 
study records by the investigator and appropriately reported.
All AEs will be reported within the participant’s records and in the EDC system. All AEs should be 
entered into the data system as soon as possible after identification by the site personnel. All AEs will be 
recorded from the time of surgery through completion of the last study visit.
Assessment of Severity
Guidelines for Assessing Severity of an Adverse Event
The investigator should use the following definitions when assessing severity of an AE:
x
MILD: Transient (< 48 hours) or mild discomforts, no or minimal medical therapy or 
intervention required, hospitalization not necessary, no, or little limitation in normal activities
x
MODERATE: Mild to moderate limitation in activity, some assistance may be needed; possibly 
none but usually minimal intervention/therapy required; hospitalization possible
x
SEVERE: Marked limitation in activity, some assistance usually required; medical 
intervention/therapy required; hospitalization possible or likely
Assessment of Causality
Guidelines for Determining Causality of an Adverse Event
The investigator will answer the following question when assessing causality of an AE to study 
treatment: “Is there a reasonable possibility that the treatment caused the event?” A reasonable 
possibility implies there is evidence that the specific event was caused by the study treatment. An 
affirmative answer designates the event as a suspected adverse reaction, and the AE is therefore 
considered “related.” If the answer is no, then the AE is considered “unrelated.” For every related AE, 
the investigator will determine the causality in relation to the surgical procedure, to the NT-501 implant 
itself, and to CNTF.
Regarding relatedness of AEs, there are 3 possibilities. These include the following:
x
Related to surgical procedure:
Ocular events that occur immediately following the surgical procedure or later if they are directly 
related to the procedure
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x
Related to the NT-501 implant itself:
These would include malposition of the NT-501 implant with impingement of the participant’s 
visual field, inflammation of the vitreous, or visible deterioration of the NT-501 implant on 
inspection via the ophthalmoscope
x
Related to CNTF:
The known events related to CNTF release in the eye are clearly listed in the reference safety 
information of the investigator’s brochure
Adverse Event Follow-up
Until the participant reaches the final scheduled follow-up visit, any new AEs, as well as follow-up 
information for ongoing AEs, must be recorded. For participants who withdraw prematurely, AEs 
should be followed until 30 days after last study visit. 
Reporting of Pregnancy
Pregnancy, in and of itself, is not regarded as an AE. A confirmed pregnancy in a participant (by urine
or blood) test) should be reported in the EDC system as soon as the investigator has been made aware of 
the pregnancy. The decision on whether to remove the implant and withdraw the participant from the 
study will be made by the investigator and the participant following consultation with the sponsor. The 
investigator will use his/her expert judgment, based on an assessment of the potential benefit/risk to the 
participant, to determine if it is in the participant’s best interest to continue participation in the study.
A pregnancy in the partner of a participant should also be reported to the investigator who will in turn 
report in the EDC system as soon as possible.
The pregnancy should be followed until birth. The outcome of all such pregnancies (i.e., spontaneous 
miscarriage, elective termination, normal birth, or congenital abnormality) must be documented and 
followed-up in the EDC system. The pregnancy will be followed to term and the outcome, including any 
premature termination, must be reported in the EDC system. All live births must be followed for a 
minimum of 30 days or to the first well-baby visit. All reports of congenital abnormalities/birth defects 
and spontaneous abortions/miscarriages should be reported as an SAE for this study. Elective abortion 
procedures, without complications, should not be considered as AEs.
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10 SERIOUS ADVERSE EVENT
Definition of Serious Adverse Event
An SAE is any event that meets any of the following criteria:
x
Death
x
Life-threatening
x
Inpatient hospitalization or prolongation of existing hospitalization
x
Persistent or significant disability/incapacity
x
Congenital anomaly/birth defect in the offspring of a participant who received NT-501
x
Other: Important medical events that may not result in death, be life-threatening, or require 
hospitalization, may be considered an SAE when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.
Definition of Terms
Life-threatening: An AE is life-threatening if the participant is at immediate risk of death from the event 
as it occurred. The definition of a life-threatening AE does not include a reaction that if it had occurred 
in a more serious form might have caused death. For example, drug-induced hepatitis that resolved 
without evidence of hepatic failure would not be considered life-threatening even though drug-induced 
hepatitis can be fatal.
Hospitalization: AEs requiring hospitalization should be considered SAEs. Hospitalization for elective 
surgery or routine clinical procedures that are not the result of an AE (e.g., elective surgery for a pre-
existing condition that has not worsened) need not be reported as AEs or SAEs. If anything, untoward is 
reported during the procedure, that occurrence must be reported as an AE, either serious or nonserious 
according to the usual criteria.
In general, hospitalization signifies that the participant has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or outpatient setting. When in doubt as to whether 
‘hospitalization’ occurred or was necessary, the AE should be considered serious.
Disability/incapacity: An AE is disabling or incapacitating if the experience results in a substantial 
and/or permanent disruption of the participant’s ability to carry out normal life functions.
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Reporting Serious Adverse Events
The investigators will report data on all SAEs within 24 hours of site awareness of the event. If there are 
technical difficulties when entering the event into the EDC system, the SAE will be reported to the 
contract research organization (CRO) via fax communication or safety group email; the fax numbers and 
email address will be provided in the regulatory binder. All information reported by fax or email will 
need to be entered in the data system when it is available. All SAEs should be reported to local 
IRBs/independent ethics committees (IECs) per local IRB/IEC requirements.
The medical monitor will review each SAE report and will determine whether the SAE must be reported 
to the Food and Drug Administration (FDA)/regulatory authorities on an expedited basis. The final 
decision for disposition regarding reporting to the FDA and other regulatory authorities’ rests with the 
sponsor or their designee. The IND sponsor or their designee is responsible for submitting the SAE 
reports to FDA/regulatory authorities. The CRO will maintain copies of any SAE reports submitted to 
FDA/regulatory authorities by the sponsor.
The CRO will provide expedited reports to the principal investigator at each individual site to submit to 
their respective IRB/IEC. Events that are serious, related to therapy, and unexpected (serious unexpected 
suspected adverse reaction [SUSAR]) will be reported to FDA/regulatory authorities within 15 days or 
within 7 days for deaths and for events deemed life-threatening by the investigator (per 21 CFR 312.32).
All SAEs will be followed until resolution or until stability is reached. In rare instances, this may 
include following the participant after completion of the study. Every attempt must be made by the 
investigator to follow SAEs that are not resolved or medically stable within 30 days of the last study 
visit until they become resolved or medically stable.
Notifying FDA/Regulatory Authorities
After the SAE has been reported by the principal investigator and assessed by the IND sponsor, the IND 
sponsor or their designee must report the event to the appropriate regulatory authorities using 1 of these 
2 options:
x
Standard reporting (report in the annual report). This option applies if the AE is classified as one 
of the following:
o
Serious, expected, suspected adverse reaction (serious, expected, and related)
o
Serious and not a suspected adverse reaction (serious and not related)
x
Expedited reporting. This option applies if the AE is classified as SUSAR (serious, unexpected, 
and related).
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The sponsor must report an AE as a suspected adverse reaction (related AE) only if there is evidence to 
suggest a causal relationship between the study treatment and the AE, such as:
x
A single occurrence of an event that is uncommon and known to be strongly associated with 
study treatment
x
One or more occurrences of an event that is not commonly associated with study treatment, but 
is otherwise uncommon in the population exposed to the study treatment
x
Aggregate analysis of specific SAEs observed in a clinical trial (such as known consequences of 
the underlying disease or condition under investigation or other events that commonly occur in 
the study population independent of study treatment) that indicates those events occur more 
frequently in the study treatment group than in a concurrent or historical control group
x
Any findings from clinical or epidemiological studies, analysis of data pooled across multiple 
studies, published or unpublished scientific papers, or from animal or in vitro testing that would 
result in a safety-related change in the protocol, informed consent, general investigational plan 
section of the IND, or other aspects of the overall conduct of the trial
The investigator will ensure the timely dissemination of all AE information, including expedited reports, 
to the IRB and IEC in accordance with applicable local regulations and guidelines.
11 STATISTICS
General Procedures
This is an open-label Phase 2 study to evaluate safety of bilateral ocular NT-501 implants. The general 
analytical approach for all endpoints is descriptive. No formal statistical hypothesis testing will be 
conducted.
The safety population will include the data from all participants who receive a NT-501 implant in the 
study eye and have at least 1 safety measurement. No participant (or data) will be excluded from this 
dataset because of protocol violations that occur during the study.
Sample Size
Formal sample size calculations were not performed. The number of participants was chosen based on 
feasibility and is considered sufficient to meet the study objectives. 
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Statistical Methods
11.3.1 Analysis of Safety
Safety analyses will be performed on the safety population, which includes all participants who received 
an implant in the study eye. The assessment of safety will be based on the summary of ocular and non-
ocular treatment-emergent AEs (TEAEs) and ophthalmic examinations. The Medical Dictionary for 
Regulatory Activities (MedDRA) nomenclature will be used to code AEs.
Summaries for TEAEs will include the following: all TEAEs regardless of causality, treatment-related 
TEAEs, ocular TEAEs, treatment-related ocular TEAEs, TEAEs by intensity, SAEs, and TEAEs leading 
to discontinuation from the study.
The number and proportion of participants with a loss in BCVA of 15 or more letters from baseline in 
the study eye will be tabulated and presented. Summary tables will be supported with individual 
participant data listings.
Assessments of safety will also include measurements of systemic levels of CNTF, as well as the 
number of participants and the titer of antibodies to CNTF, neutralizing antibodies to CNTF and 
antibodies to NTC-201.6A that are observed at the 3-month time point and persist through the 6-month 
time point.
Descriptive statistics will be displayed to provide an overview of the safety results. For categorical 
parameters, these consists of the number and percent of participants in each category. The denominator 
for the percentages will be based on the number of participants appropriate for the purpose of the 
analysis. For continuous parameters, descriptive statistics includes n, mean standard deviation (SD), 
median, minimum, and maximum. Participants who prematurely discontinued the study will be 
evaluated on the basis of data collected at each visit attended.
11.3.2 Interim Analysis
No interim analysis will be performed in the study.
12 STUDY RISKS
Studies of intravitreal CNTF delivered by ECT at a nominal daily dose of 20 ng/implant/day have been 
performed in human participants and is being tested in the ongoing Phase 3 trial in participants with 
MacTel. 
Miosis: In the controlled clinical studies of AMD, RP, and MacTel (Phase 1 and Phase 2 studies), 40 of 
180 (22.2%) participants reported miosis as an AE. The prevalence of these findings was confirmed by 
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the DSMC in their review of the data. The DSMC in their review of these data confirmed that the 
potential benefit outweighed the risk of this event.  Miosis was not observed in 59 participants exposed 
to a lower dose of CNTF15.  
The intracellular mechanisms through which the trophic factor CNTF regulates cholinergic development 
were examined in sympathetic neuron cultures.27 Treatment with CNTF increased levels of choline 
acetyltransferase activity significantly, thus confirming the parasympathetic agonist effect of CNTF. 
Stimulation of the parasympathetic nervous system (PSNS) results in constriction of the pupillary 
muscles. Constriction of the pupil occurs when the circular muscle, controlled by the PSNS, contracts. 
This is the most likely mechanism for CNTF causing miosis. At lower doses in the Phase 2 studies of 
RP, this effect was not observed.
In addition, in the Phase 2 study of MacTel, pupil size was measured routinely throughout the duration 
of the study in all participants. The majority of eyes that received the implant had a reduction in the size 
of the pupil of approximately 1 mm. This effect was not seen in sham eyes but was present in over 90% 
of all treated eyes. The reason that only approximately 20% of the participants complained about the 
miosis is possibly related to the lack of any clinical symptoms and of noticeable effect for the 
participants. Certainly, no participant asked to have the implant removed as a result of noting this well-
described drug effect.
Delayed Dark Adaptation: This AE has only been reported in study participants with MacTel with 11 
cases out of the 55 (22%) implanted eyes in the Phase 1 and 2 studies. In the studies of participants with 
RP15 and atrophic AMD16 this AE was not reported. Additionally, this AE was not observed in 59 
participants exposed to a lower dose of CNTF15.  The cause of the delayed dark adaptation is not well 
understood, but a plausible explanation is that it is related to either miosis and/or the observed effect on 
photoreceptors following treatment with CNTF.10 CNTF treatment results in a change in rod 
photoreceptor nucleus phenotype, featuring an increase in euchromatin and an increase in nuclear size. 
Chronic stimulation of retinal cells with CNTF has been shown to affect gene expression in 
photoreceptors including reduction of phototransduction genes such as rhodopsin in animal models.28 As 
rod photoreceptors are more light sensitive than cone cells and are almost entirely responsible for night 
vision, it is possible that the CNTF-mediated changes in the rod photoreceptors may affect the 
participant’s ability to adapt to the dark. The reason why this AE is limited to a small subpopulation of 
the participants with MacTel is not well understood.
An increase in retinal thickness is observed in the majority of all eyes treated with CNTF at the dose 
proposed for study in Phase 3 and for this bilateral implant study. Taken together, the preclinical data in 
dogs and the fact that macular thickening is seen only in the treated eyes, suggest that the AE of delayed 
dark adaptation may well be a direct consequence of CNTF treatment.
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There are risks associated with the diagnostic procedures required for participants in this study. 
However, these are standard procedures that are performed as part of normal eye and medical 
examinations. Some of the discomforts associated with the ocular examination include the following:
x
Dilating drops or anesthetic drops may sting. They can cause an allergic reaction, or if 
contaminated, can cause an infection, but neither of these problems is very likely to occur.
x
Dilating drops can also cause a sudden increase of pressure (acute glaucoma) in eyes that are 
already predisposed to develop this condition. There is little risk of glaucoma being triggered in 
this way, but if it is, treatment is available.
x
In rare instances, the cornea may be abraded during measurement of IOP or the use of a contact 
lens (used for examination purpose only and not a contact lens used to correct a participants’ 
refractive error).
There are risks associated with the procedures required for participants in this study. The fluorescein 
angiogram requires injection of dye in the participant’s arm. Local subcutaneous infiltration of dye may 
create discomfort and temporary staining of the skin (< 5% risk). There is a chance of fainting,
ecchymosis at the site of injection, and a remote possibility of cellulitis from the needle track. After the 
dye injection, some participants (< 5%) may experience nausea that usually passes after a few seconds, 
and rarely, participants vomit.
Allergic reactions to fluorescein are uncommon; however, these reactions may cause hives and itching. 
These reactions are usually treated with oral or injectable antihistamines as needed. Anaphylaxis from 
fluorescein is extremely rare and may be life-threatening. Fluorescein dye routinely causes a 
yellowing/orange color to the skin and urine that generally passes in 24 hours.
Imaging using SD-OCT is an FDA-approved technique, which is not associated with any AEs.
Fundus photography is not associated with any AEs, although some participants may experience mild 
discomfort due to the bright lights.
NT-501 Implant Insertion or Removal Surgery:
There are risks associated with the eye surgery to insert or remove the NT-501 implant. Risks include
pain, infection, bleeding, miosis (small pupil), retinal detachment, cataract, vitritis (inflammation inside 
the eye), a change in the curvature of the front of the eye (astigmatism), decreased vision, blindness, or 
loss of the eye. Topical antibiotics and topical steroids are used to treat minor degrees of inflammation 
or infection. More serious infection or inflammation or development of retinal detachment may require 
additional procedures or surgery on the eye and possibly the need to remove or replace the implant. 
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A small sample (about 0.1 mL) of the vitreous along with the implant may be collected and shipped 
back to the sponsor for analysis. The risks of this procedure are same as those previously described for 
the explant procedure.
13
ETHICS AND RESPONSIBILITIES
Although disease progression of MacTel appears to be slow when assessed with standard methods, some 
participants report worsening visual function despite stable visual acuity measures. Functional 
evaluation of participants with MacTel using fundus-controlled perimetry (microperimetry) reveals 
characteristic small, deep, paracentral scotomata; these do not necessarily affect performance on single 
optotype visual acuity testing,5 but may affect reading and other visual tasks that require an intact 
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distance visual acuity testing alone correlate with such paracentral focal loss of macular sensitivity6. 
Moreover, longitudinal data from a recent interventional study showed progressive paracentral visual 
function loss in a subset of participants while visual acuity remained stable7, 29.
Currently there is no known therapy for MacTel. Previous clinical experience with the NT-501 implant
in human participants suggests that the implant is generally well tolerated. Importantly, the implant can 
be readily removed by explant procedure. Data from a significant number of human participants also 
suggest that the risks associated with the NT-501 implant are limited to those expected with the surgical 
procedure. 
14 COMPLIANCE
This study will be conducted in compliance with the protocol, ICH (International Council for 
Harmonization) guideline E6: GCP: Consolidated Guideline, and the applicable regulatory requirements 
from the US CFR, including but not limited to 45 CFR 46 (Human Subjects Protection), 21 CFR 312 
(Investigational New Drug [IND]), and 21 CFR 56 (institutional review board [IRB]). 
Good Clinical Practice
Participant medical information obtained by this study is confidential and may only be disclosed to third 
parties as permitted by the ICF (or separate authorization to use and disclose personal health 
information) signed by the participant, or unless permitted or required by law.
Medical information may be given to a participant’s physician or other appropriate medical personnel 
responsible for the participant’s welfare for treatment purposes. All active physician investigators are 
required to be experienced in the conduct of clinical trials and ophthalmologists with training in retinal 
surgery or retinal medicine. All physician investigators are trained specifically on the procedure for 
insertion of the NT-501 implant and the handling of the investigational product.
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Data generated by this study must be available for inspection upon request by representatives of the US 
FDA and other regulatory agencies, national and local health authorities, sponsor representatives, and 
the IRB/IEC for each site, if appropriate.
Informed Consent
All participants will receive a verbal explanation from the principal investigator or his/her appropriate 
designee in terms suited to their comprehension of the purposes, procedures, and potential risks of the 
study. In the opinion of the principal investigator or designee, the participants must be capable of 
comprehending the contents of the informed consent and able to sign an ICF, which must be obtained 
prior to enrollment. The participants will have an opportunity to review the ICF carefully and ask 
questions regarding this study prior to signing, and they will be informed that they may withdraw from 
the study at any time without prejudice to themselves.
A template ICF will be provided to each site. The sponsor, or their designee, must review and approve 
any proposed deviations from the provided ICF template or any alternate consent forms proposed by the 
site (collectively, the “consent forms”) before IRB/IEC submission. Participants must be reconsented per 
IRB/IEC requirements with the most current (updated) version of the respective consent form as 
applicable during their participation in the study. The final IRB/IEC-approved consent forms must be 
provided to the sponsor for regulatory purposes.
The consent forms must be dated and signed by the person obtaining consent and by the participant 
before his or her participation in the study. The case history for each participant shall document the
informed consent process and that written informed consent was obtained prior to participation in the 
study. A copy of each signed consent form must be provided to the participant.
All signed and dated ICFs must remain in each participant’s study file and must be available for 
verification by clinical research associates (CRAs) at any time.
The ICF should be revised whenever there are changes to the procedures outlined in the ICF or when 
new information becomes available that may affect the willingness of the participant to participate.
For any updated or revised ICFs, the case history for each participant shall document the informed 
consent process and that written informed consent was obtained for the updated/revised ICF for 
continued participation in the study. The final revised IRB/IEC-approved ICF must be provided to the 
sponsor for regulatory purposes.
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15 AUDITING AND MONITORING
This study will be conducted in accordance with GCP, using the guidance documents and practices 
offered by ICH and FDA, and in accordance with the Declaration of Helsinki. This study will also 
comply with the regulations 21 CFR parts 50, 54, 56, and 312 under an IND application authorized by 
FDA.
Communication with the Institutional Review Board or Independent Ethics Committee
This protocol, the ICFs, any information to be given to the participant and relevant supporting 
information must be submitted to the IRB/IEC by the principal investigator at each site for review and 
approval before the study is initiated. In addition, any participant recruitment materials must be 
approved by the IRB/IEC.
The principal investigator is responsible for providing written summaries of the status of the study to the 
IRB/IEC annually or more frequently in accordance with the regulatory requirements and policies and 
procedures established by the IRB/IEC. Investigators are also responsible for promptly informing the 
IRB/IEC of any protocol changes or amendments and of any unanticipated problems involving risk to 
human participants or others.
In addition to the requirements to report protocol-defined AEs to the sponsor, investigators are required 
to promptly report to their respective IRB/IEC all unanticipated problems involving risk to human 
participants. Some IRBs/IECs may want prompt notification of all SAEs, whereas others require 
notification only about events that are serious, assessed to be related to study treatments, and are 
unexpected. Investigators may receive written IND safety reports or other safety-related 
communications from the sponsor. Investigators are responsible for ensuring that such reports are 
reviewed and processed in accordance with regulatory requirements and with the policies and 
procedures established by their IRB/IEC and archived in the site’s study file.
Study Monitoring Requirements
To ensure compliance with GCP and all applicable regulatory requirements, the sponsor or their 
representative may conduct a quality assurance audit of the site records, and the regulatory agencies may 
conduct a regulatory inspection at any time during or after completion of the study. In the event of an 
audit or inspection, the principal investigator (and institution) must agree to grant the monitor(s) and 
inspector(s) direct access to all relevant documents and to allocate their time and the time of their 
personnel to discuss any findings/relevant issues. The principal investigator will permit the monitors, 
sponsor representatives, US FDA, other regulatory agencies, IRBs, and the respective national or local 
health authorities to inspect facilities and records relevant to this study.
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Records Management
The investigator will permit study-related monitoring, audits, and inspections by the IRB/IEC, the 
sponsor, government regulatory bodies, and compliance and quality assurance groups of all study-
related documents (e.g., source documents, regulatory documents, data collection instruments, study 
data). The investigator will ensure the capability for inspections of applicable study-related facilities 
(e.g., pharmacy, diagnostic laboratory). All authorized personnel, including health authority inspector(s), 
sponsor and designees, monitor(s), and auditor(s) will be given direct access to source data and 
documentation (e.g., medical records, laboratory results) for source data verification, provided that 
participant confidentiality is maintained in accordance with local requirements.
Data Quality Assurance
The CRO will have the primary responsibility for assuring that the data collected and reported in the 
study are of consistently high quality. Many factors contribute to the quality of the data, from the design 
and procedures of the trial to the analytic methods employed.
The major quality assurance features of the study are as follows:
x
Standard data collection forms and procedures
x
Common protocol for eligibility, examination, and follow-up of all participants at all sites
x
Data entry into EDC
x
Central, computer driven data editing for missing, invalid, and suspect responses
x
Regular reporting of performance of all sites
x
Monitoring visits to all sites
x
Certification of clinic personnel 
Source Documentation
All data relating to study procedures will be entered by trained site personnel into the electronic case 
report form (eCRF) around the time of study assessment collection. The eCRF exists within an EDC 
system with controlled access managed by the sponsor or its designee for this study. Study personnel 
will be appropriately trained in the use of eCRFs before the start of the study and prior to being given 
access to the EDC system. Original data and any changes to data will be recorded using the EDC 
system, with all changes tracked by the system and recorded in an electronic audit trail.
All eCRFs should be completed by designated, trained examining personnel, or the study coordinator as 
appropriate.
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The investigator will attest that the information contained in the eCRFs is true by providing electronic 
signature within the EDC system prior to database lock. After database lock, the investigator will 
receive a copy of the participant data for archiving at the site. At all times, the investigator has final 
responsibility for the accuracy and authenticity of all clinical data.
The CRAs will perform ongoing site visits to confirm that critical protocol data (i.e., source data) 
entered into the eCRFs by authorized site personnel are accurate, complete, and verifiable from source 
documents.
Source documents are where participant data are recorded and documented for the first time. They 
include, but are not limited to, hospital records, clinical and office charts, memoranda, evaluation 
checklists, recorded data from automated instruments, copies of transcriptions that are certified after 
verification as being accurate and complete, photographic negatives, magnetic media, and medico-
technical departments involved in the clinical trial.
To facilitate monitoring, the investigator(s) and institution(s) must provide the sponsor direct access to 
applicable source documents and reports for trial-related monitoring, sponsor audits and IRB/IEC 
review. The site must also allow inspection by applicable regulatory authorities.
When clinical observations are entered directly into the site’s computerized medical record system (i.e., 
in lieu of original hardcopy records), the electronic record can serve as the source document if the 
system has been validated in accordance with FDA requirements pertaining to computerized systems 
used in clinical research. An acceptable computerized data collection system (for clinical research 
purposes) would be one that (1) allows data entry only by authorized individuals, (2) prevents the 
deletion or alteration of previously entered data and provides an audit trail for such data changes (e.g., 
modifications of file), (3) protects the database from tampering and (4) ensures data preservation.
If a site’s computerized medical record system is not adequately validated for the purposes of clinical 
research (as opposed to general clinical practice), applicable hardcopy source documents must be 
maintained to ensure that critical protocol data entered into the eCRFs can be verified.
Study Files and Record Retention
The US FDA regulations (21 CFR §312.62[c]) and ICH Guideline for GCP (see Section 4.9 of the 
guideline) require that records and documents pertaining to the conduct of this study, including eCRFs 
and ICFs, must be retained by the principal investigator for 2 years after the last marketing application 
approval in an ICH region or after at least 2 years have elapsed since formal discontinuation of clinical 
development of the investigational product. All state and local laws for retention of records also apply.
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No records should be disposed of without the written approval of the sponsor. Written notification 
should be provided to the sponsor for transfer of any records to another party or moving them to another 
location.
For studies conducted outside the US under a US IND/IDE, the principal investigator must comply with 
the record retention requirements set forth in the US FDA IND/IDE regulations and the relevant national 
and local health authorities.
16 AMENDMENTS
Protocol modifications, except those intended to reduce immediate risk to study participants, may only 
be made by the sponsor. A protocol change intended to eliminate an apparent immediate hazard to 
participants may be implemented immediately, provided the IRB/IEC is notified within 5 days.
Any permanent change to the protocol must be handled as a protocol amendment. The written 
amendment must be submitted to the IRB/IEC and the investigator must await approval before 
implementing the changes. The sponsor or their designee will submit protocol amendments to the 
appropriate regulatory authorities for approval.
If in the judgment of the IRB/IEC, the investigator, and/or the sponsor, the amendment to the protocol 
substantially changes the study design and/or increases the potential risk to the participants, and/or has 
an impact on the participants’ involvement in the trial, the currently approved written ICF will require 
similar modification. In such cases, informed consent will be renewed for participants enrolled in the 
study and the new ICF signed before continued participation.
17 STUDY REPORT AND PUBLICATIONS
The sponsor or their designee is responsible for preparing and providing the appropriate regulatory 
authorities with clinical study reports according to the applicable regulatory requirements. The 
publication policy of the sponsor is discussed in the investigator’s clinical research agreement.
18
STUDY DISCONTINUATION 
Both the sponsor and the principal investigator reserve the right to terminate the study at the 
investigator’s site at any time. Should this be necessary, the sponsor or a specified designee will inform 
the appropriate regulatory authorities of the termination of the study and the reasons for its termination, 
and the principal investigator will inform the IRB/IEC of the same. If the decision is made to terminate 
the study, the sponsor and the principal investigator will assure that adequate consideration is given to 
the protection of the participants’ interests.
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The investigator may discontinue a participant from the study if warranted. The investigator and the 
sponsor may also request the withdrawal of a participant because of noncompliance (e.g., missed visits), 
administrative reasons, or any other valid and ethical reasons.
Reasons for participant discontinuation may include, but are not limited to, the following:
x
Investigator determination that it is not in the best interest of the participant to continue 
participation
x
Intercurrent illness
x
AE that is serious and unexpected
x
Worsening condition
x
Any other safety concerns
x
If a participant withdraws or is discontinued from the study, they should return for an exit visit. 
The schedule of assessments for this visit is the same as that for the 6-month visit. 
Premature Discontinuation
Premature discontinuation is not anticipated to be a frequent event based on the history of previous 
clinical trials with this implant. The investigator may discontinue a participant from the study if 
warranted and only after discussion with the medical monitor. If the participant discontinues study 
participation before completing the defined 6 months of follow-up, the principal investigator and study 
coordinator of the study site for the NHOR will be notified to ensure long-term follow-up.
If a participant requests explanation and withdrawal from the study, this can be readily arranged. The 
investigator should contact the sponsor’s medical monitor to discuss the reasons for the request and 
discuss the procedure for explanation. If a participant discontinues from the study, they will not be 
replaced once recruitment is complete.
If a participant requests explanation but does not wish to withdraw from the study, this is also 
acceptable. The participant would continue in the study with all planned follow-up visits and 
assessments. 
19 CONFIDENTIALITY
All information generated in this study is considered highly confidential and must not be disclosed to 
any person or entity not directly involved with the study unless prior written consent is gained from the 
sponsor. However, authorized regulatory officials, IRB/IEC personnel, and the sponsor and its 
authorized representatives are allowed full access to the records. The participants’ names will not appear 
on any of the data forms reported to the CRO. Participants will be identified by a study number. The 
date of birth of each participant will be collected in the data system. 
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20 REFERENCES
1.
Charbel Issa P, Gillies MC, Chew EY, Bird AC, Heeren TF, Peto T, et al. Macular telangiectasia 
type 2. Prog Retin Eye Res. 2013;34:49-77.
2.
Staurenghi G, Sadda S, Chakravarthy U, Spaide RF, International Nomenclature for Optical 
Coherence Tomography P. Proposed lexicon for anatomic landmarks in normal posterior segment 
spectral-domain optical coherence tomography: the IN*OCT consensus. Ophthalmology. 
2014;121(8):1572-8.
3.
Gass JD, Blodi BA. Idiopathic juxtafoveolar retinal telangiectasis. Update of classification and 
follow-up study. Ophthalmology. 1993;100(10):1536-46.
4.
Gass JD, Oyakawa RT. Idiopathic juxtafoveolar retinal telangiectasis. Arch Ophthalmol. 
1982;100(5):769-80.
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Charbel Issa P, Helb HM, Rohrschneider K, Holz FG, Scholl HP. Microperimetric assessment of 
patients with type 2 idiopathic macular telangiectasia. Invest Ophthalmol Vis Sci. 2007;48(8):3788-
95.
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Finger RP, Charbel Issa P, Fimmers R, Holz FG, Rubin GS, Scholl HP. Reading performance is 
reduced by parafoveal scotomas in patients with macular telangiectasia type 2. Invest Ophthalmol 
Vis Sci. 2009;50(3):1366-70.
7.
Charbel Issa P, Finger RP, Kruse K, Baumuller S, Scholl HP, Holz FG. Monthly ranibizumab for 
nonproliferative macular telangiectasia type 2: a 12-month prospective study. Am J Ophthalmol. 
2011;151(5):876-86 e1.
8.
Heeren TF, Clemons T, Scholl HP, Bird AC, Holz FG, Charbel Issa P. Progression of Vision Loss 
in Macular Telangiectasia Type 2. Invest Ophthalmol Vis Sci. 2015;56(6):3905-12.
9.
Yannuzzi LA, Bardal AM, Freund KB, Chen KJ, Eandi CM, Blodi B. Idiopathic macular 
telangiectasia. Arch Ophthalmol. 2006;124(4):450-60.
10. Bok D, Yasumura D, Matthes MT, Ruiz A, Duncan JL, Chappelow AV, et al. Effects of adeno-
associated virus-vectored ciliary neurotrophic factor on retinal structure and function in mice with a 
P216L rds/peripherin mutation. Exp Eye Res. 2002;74(6):719-35.
11. Rhee KD, Nusinowitz S, Chao K, Yu F, Bok D, Yang XJ. CNTF-mediated protection of 
photoreceptors requires initial activation of the cytokine receptor gp130 in Muller glial cells. Proc 
Natl Acad Sci U S A. 2013;110(47):E4520-9.
12. Tao W, Wen R, Goddard MB, Sherman SD, O'Rourke PJ, Stabila PF, et al. Encapsulated cell-based 
delivery of CNTF reduces photoreceptor degeneration in animal models of retinitis pigmentosa. 
Invest Ophthalmol Vis Sci. 2002;43(10):3292-8.
13. Chew EY, Clemons TE, Peto T, Sallo FB, Ingerman A, Tao W, Singerman L, Schwartz SD, 
Peachey NS, Bird AC, MacTel-CNTF Research Group. Ciliary Neurotrophic Factor (CNTF) for 
macular telangiectasia type 2 (MacTel): results from a phase 2 safety trial. Am J Ophthalmol. 
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