Clinical trial NCT01530659
Conditions: Retinitis Pigmentosa Usher Syndrome Type 2 Usher Syndrome Type 3
Keywords: Retinitis pigmentosa Usher syndrome type 2 Usher syndrome type 3 Cone photoreceptor Vision Blind
Sponsor: Neurotech Pharmaceuticals
Start date: 2012-01-01; Completion date: 2019-07-01
Enrollment: 22 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This clinical trial is a single-site, 30 patient study for participants who have early stage retinitis pigmentosa, or Usher syndrome (type 2 or 3). Funding Source - FDA OOPD and Foundation Fighting Blindness.

Detailed description:
This clinical trial is a prospective, randomized, double-masked, sham-controlled trial of 30 study participants who have early-stage retinitis pigmentosa, or Usher syndrome (type 2 or 3). The trial will be conducted at the University of California, San Francisco. Individuals with these diseases experience gradually worsening vision that ultimately may lead to blindness due to a genetic condition in which specialized cells in the eye's retina called photoreceptor cells cease functioning and/or die. The study is intended to use a relatively new, non-invasive technology called AOSLO (adaptive optics scanning laser ophthalmoscopy) in combination with a routine standard of care measurement called sdOCT (Spectral Domain Optical Coherence Tomography) to demonstrate that when a device that secretes an investigational drug called CNTF (Ciliary Neurotrophic Factor) is surgically placed in the patient's eye, one type of photoreceptor called "cone photoreceptors" is preserved such that the gradual loss of vision is halted.

Arms: arm 1: Encapsulated cell therapy that delivers ciliary neurotrophic factor to the retina arm 2: Sham surgery
Interventions: intervention 1: NT-501 intervention 2: Sham
Intervention descriptions: intervention 1: Study participants will undergo surgery to have an NT-501 Encapsulated Cell Therapy implant placed into the study eye. intervention 2: Non-penetrating sham procedure to mimic implant procedure in the other eye.

Protocol documents:
Prot_000.pdf: 
 
 
CNTF/UCSF, Version 2 
 
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Photoreceptor Structure in a Phase 2 Study of Encapsulated Human 
NTC-201 Cell Implants Releasing Ciliary Neurotrophic Factor 
(CNTF) for Participants with Retinitis Pigmentosa Using Rates of 
Change in Cone Spacing and Density as the Primary Outcome 
 
 
Neurotech USA, Inc. 
 
 
Protocol Designation: CNTF/UCSF 
 
 
IND – 10,931 
 
 
 
 
 
 
 
Investigator(s):  
 
 
Jacque Duncan, MD 
 
 
Institution(s):  
 
 
University of California, San Francisco 
 
 
Trial Sponsor:  
 
 
Neurotech USA, Inc. 
 
 
Chief Medical Officer:  
 
Charles Johnson MB ChB 
 
  
Date of Issue:  
 
 
26 October 2015 
 
 
 
Version: 
 
 
 
2.0 
 
 
 
Confidential: This document contains confidential information that is the property of 
Neurotech USA, Inc., and must not be disclosed to anyone other than the recipient clinical 
investigator(s) and their designees and members of the Institutional Review Board. This 
information must not be used for any purpose other than the evaluation or conduct of the 
clinical investigation without the prior written consent of Neurotech USA, Inc. 
 


 
 
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Study Administrative Structure 
 
 
Sponsor: 
 Neurotech USA, Inc. 
 
900 Highland Corporate, Suite 101 
 
Cumberland, RI 02864 USA  
 
Tel: 401-333-3880 
  
 
 
 
 
 
 
 
 
Neurotech Chief Medical Officer  
Contact Information: 
Charles Johnson, MB ChB 
Tel (office): 401.495.2395 
Tel (mobile) : 617.416.5453 
Fax: 401-333-3881 
Email: c.johnson@neurotechusa.com 
 
 
 
 
 
 
 
 
 
Contract Research Organization: 
N/A 
 
 
 
 
 
 
 
Clinical Investigator:  
Jacque Duncan, MD  
 
 
 
 
 


 
 
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Sponsor Protocol Approval Signature  
 
Protocol Title: 
Photoreceptor Structure in a Phase 2 Study of Encapsulated Human NTC-
201 Cell Implants Releasing Ciliary Neurotrophic Factor (CNTF) for Participants with Retinitis 
Pigmentosa Using Rates of Change in Cone Spacing and Density as the Primary Outcome 
 
Protocol Designation: 
CNTF/UCSF 
 
 
Authorized Sponsor Representative Signature 
Signature: 
  
Date: 27 October 2015 
 
 
Name: Charles Johnson MB ChB 
Title: Chief Medical Officer 


 
 
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Principal Investigator Signature Page 
 
Protocol Title: 
Photoreceptor Structure in a Phase 2 Study of Encapsulated Human NTC-
201 Cell Implants Releasing Ciliary Neurotrophic Factor (CNTF) for Participants with Retinitis 
Pigmentosa Using Rates of Change in Cone Spacing and Density as the Primary Outcome 
 
Protocol Designation: 
CNTF/UCSF 
 
I confirm that my staff and I have carefully read and understand this protocol. I agree to conduct 
this study according to this attached protocol. I also agree to conduct this study in compliance 
with Good Clinical Practice (GCP) International Conference on Harmonization (ICH) guidelines, 
and all applicable national and local laws and regulations, as well as with the requirements of the 
appropriate Institutional Review Board (IRB) and any other institutional requirements. No 
changes will be made to the study protocol without prior written approval of the Sponsor and the 
IRB. 
I have read, understand, and agree to abide by all conditions and instructions contained in this 
protocol. I confirm that I am qualified by training and experience as an appropriate expert to 
participate as principal investigator in this clinical study. I will provide copies of the study 
protocol and access to all study-related information to the study personnel at my site who are 
involved with this protocol. I will discuss with them this material and the material in the 
Investigator’s Brochure to ensure that they are fully informed about the study agent and 
understand the protocol. All documents will be kept in the confidence. 
 
Signature 
 
Signature:  
 
 
 
 
 
 
 
Date:  
 
 
Name: Jacque Duncan, MD 
University of California, San Francisco 
Department of Ophthalmology 
10 Koret Way, K129 
San Francisco, CA 94143-0730 
 
 
 


 
 
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Table of Contents 
 
Sponsor Protocol Approval Signature ................................................................................................................. iii 
Principal Investigator Signature Page ................................................................................................................. iv 
Protocol Summary .............................................................................................................................................. vii 
Table 1:  Visit Schedule ........................................................................................................................................ x 
1 
Background and Rationale ............................................................................................................................ 1 
2 
Scientific Rationale ....................................................................................................................................... 2 
2.1 
Encapsulated Cell Technology .................................................................................................................... 2 
2.2 
Rationale of ECT in Participants with RP .................................................................................................... 3 
2.3 
Rationale for Use of Sham Surgery ............................................................................................................. 3 
2.4 
Rationale for Excluding Participants Under 18 or Above 55 Years of Age .................................................. 4 
3 
Study Objectives ........................................................................................................................................... 4 
4 
Study Design and Methods ........................................................................................................................... 4 
4.1 
Outcomes .................................................................................................................................................... 5 
Primary Outcome: ................................................................................................................................................ 5 
Secondary Outcomes: .......................................................................................................................................... 6 
Safety Outcomes: ................................................................................................................................................. 6 
4.2 
Inclusion Criteria ......................................................................................................................................... 7 
4.3 
Exclusion Criteria ........................................................................................................................................ 8 
4.4 
Study and Concomitant Therapy Administration ...................................................................................... 10 
Study Treatment ................................................................................................................................................ 10 
Study/Follow-up Visit and Assessments ............................................................................................................ 11 
Prohibited Medications/Therapy ....................................................................................................................... 11 
4.5 
Investigational Product Packaging, Labeling, and Handling at Study Site ............................................... 11 
4.6 
Surgical Procedure .................................................................................................................................... 12 
4.6.1 
Subject Preparation, Implant and Sham Surgery ...................................................................................... 12 
4.6.2 
Post Surgical Observation Period .............................................................................................................. 16 
4.6.3 
Post-Op Implant Wound Care Recommendations .................................................................................... 16 
4.6.4 
Removal of Device .................................................................................................................................... 17 
4.7 
Examination Requirements ....................................................................................................................... 18 
4.8 
Enrollment, Randomization, Masking and Unmasking ............................................................................ 20 
5 
Safety Monitoring and Reporting ............................................................................................................... 22 
5.1 
Safety Monitoring Committee .................................................................................................................. 22 
5.2 
Adverse Experience Reporting .................................................................................................................. 22 
5.3 
Obligations of Site Investigators ............................................................................................................... 22 
5.4 
Obligations of Study Sponsor .................................................................................................................... 25 
5.5 
Adverse Events Defined ............................................................................................................................ 25 


 
 
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5.6 
Withdrawal Criteria .................................................................................................................................. 27 
6 
Statistical Considerations ........................................................................................................................... 28 
6.1 
Description of Trial.................................................................................................................................... 28 
6.2 
Analysis Populations ................................................................................................................................. 28 
6.3 
Efficacy and Safety Variables .................................................................................................................... 28 
6.4 
Sample Size Rationale ............................................................................................................................... 29 
6.5 
Statistical Analysis Plan ............................................................................................................................ 29 
6.6 
Interim Monitoring ................................................................................................................................... 29 
7 
Human Participant Protection .................................................................................................................... 29 
8 
Study Risk and Precautions ......................................................................................................................... 31 
8.1 
NT-501 Device Implant and Sham Surgery ............................................................................................... 31 
8.2 
CNTF and CNTF Producing Cells ................................................................................................................ 31 
8.3 
Dilation and Anesthetic Drops .................................................................................................................. 31 
8.4 
IOP Examination and ERG ......................................................................................................................... 31 
9 
Confidentiality and Access to Source Documents and Data ........................................................................ 31 
10 
Summary of GCP Compliance...................................................................................................................... 32 
10.1 
Investigator Responsibilities ..................................................................................................................... 32 
Institutional Review Board ................................................................................................................................. 33 
Review of Protocol, Consent and Recruitment Materials .................................................................................. 33 
10.2 
Data Handling and Record Keeping .......................................................................................................... 34 
10.3 
Protocol Amendments .............................................................................................................................. 34 
10.4 
Monitoring Plan ........................................................................................................................................ 35 
10.5 
Retention of Records ................................................................................................................................. 36 
11 
Certifications and Training Requirements ................................................................................................... 36 
11.1 
Certification for AOSLO Image Acquisition and Analysis ........................................................................ 36 
11.2 
Certification for Humphrey Visual Field Testing ....................................................................................... 38 
11.3 
Professional Licensure .............................................................................................................................. 38 
12 
References .................................................................................................................................................. 39 
13 
Appendix:  NT-501 Implant Accessories: Surgical Tool Information ............................................................ 43 
 


 
 
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Protocol Summary 
 
Protocol Title: 
Photoreceptor Structure in a Phase 2 Study of Encapsulated Human 
NTC-201 Cell Implants Releasing Ciliary Neurotrophic Factor 
(CNTF) for Participants with Retinitis Pigmentosa Using Rates of 
Change in Cone Spacing and Density as the Primary Outcome 
Protocol Designation: 
CNTF/UCSF 
Test Article: 
NT-501 Encapsulated cell intraocular implant; releasing CNTF.  
Primary Endpoint(s): 
The primary efficacy variable is the rate of change in cone spacing 
and cone density from baseline to 30 months.  
Secondary Endpoints(s):  Secondary efficacy variables will include: mean change from 
baseline value in Humphrey Visual Field Sensitivity (VFS) from 
baseline to 24 months, mean change in “5-point” VFS from baseline 
to 24 months (using the 5 retinal points with greatest average 
change), mean change from baseline in Best Corrected Visual Acuity 
(BCVA) at 12, 18, 24, 30 and 36 months, and changes in ERG, 
Optical Coherence Tomography (OCT), clinical grades of 
inflammation (anterior chamber cell and vitreous haze grades), and 
vision-related quality of life (NEI-VFQ25) at each visit.  
Safety Endpoint(s):   
Safety variables will include the incidence of adverse events, 
changes in vital signs, marked changes in clinical laboratory data, 
ECG abnormalities, and findings during physical examinations 
through 36 months 
# of Clinical Sites: 
This is a single investigator study; Retinal Degenerations Clinic at 
the University of California, San Francisco 
# of Study Subjects:  
Approximately 30 
Inclusion Criteria:   
1. Participant must be between 18 and 55 years of age. 
2. Participant must have a diagnosis of retinitis pigmentosa or Usher syndrome type 2 or 3. 
3. Participant must understand and sign the protocol informed consent. If the participant’s 
vision is impaired to the point where he/she cannot read the informed consent document, 
the document will be read to the participant in its entirety.  
4. Best-corrected visual acuity must be no worse than 20/63 (at least 59 letters). 
5. Participants must have clear natural lenses. 
6. Participants must have less than 6 diopters myopia. 
7. Participants must be medically able to undergo ophthalmic surgery for the NT-501 device 
insertion and able to undergo all assessments and tests associated with the protocol. 


 
 
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8. Females of childbearing potential (women with last menses <1 year prior to screening) 
must agree to use an effective form of birth control from study onset until they complete 
the study.  
9. Participants must have reproducible baseline AOSLO image montages at 2 baseline 
imaging sessions with quality suitable to identify a minimum of 7 regions of interest 
(ROIs) at which reliable cone spacing and/or density measures can be made over the 
central 5.7 degrees. 
10. Participants must have interocular symmetry of disease severity as measured by cone 
spacing, with a difference of less than 2 standard deviations in average cone spacing z-
scores at the selected ROIs between the 2 eyes. 
11. Participant’s clinical diagnosis must be consistent with retinal degeneration in the set of 
retinitis pigmentosa (RP) dystrophies characterized by the following features: 
a) clinical evidence of progressive photoreceptor cell dysfunction and 
degeneration of the outer retina; 
b) intraretinal ‘bone-spicule’-like pigment observed on clinical examination; 
c) peripheral visual field constriction documented on standard testing; 
d) symptomatic night blindness; 
e) reduction of both rod and cone electroretinogram (ERG) responses. 
For purposes of this study, individuals diagnosed with Retinitis Pigmentosa or Usher 
Syndrome Type 2 or Type 3 (without profound deafness or cochlear implants) who meet the 
inclusion criteria will be considered as potential candidates for this study.  A maximum of 4 
Usher Syndrome Type 2 or Type 3 participants may be enrolled in this trial. 
 
Exclusion Criteria: 
1. Participant is medically unable to comply with study procedures or follow-up visits. 
2. Participant who has any of the following lens opacities: cortical opacity > standard 3, 
posterior subcapsular opacity > standard 3, or a nuclear opacity > standard 3 as measured 
on the AREDS clinical lens grading system; or participant is pseudophakic or aphakic. 
3. Participant has history of corneal opacification or lack of optical clarity. 
4. Participant has undergone LASIK surgery or other refractive surgery for either eye. 
5. Participant has nystagmus. 
6. Participant has greater than 6 diopters myopia. 
7. Participant has cystoid macular edema with cysts present within 4 degrees of the foveal 
center. 
8. Participant has fewer than 7 ROIs present on 2 baseline AOSLO image montages. 
9. Participant has retinal vascular disease such as diabetic retinopathy or prior retinal 
vascular occlusive disease. 


 
 
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10. Participant has chronic requirement (e.g.,  4 weeks at a time) for ocular medications or 
has disease(s) that in the judgment of the examining physician are vision threatening, 
toxic to the lens, retina, or optic nerve or may affect the primary outcome. 
11. Participant has a requirement of acyclovir and/or related products during study duration. 
To be eligible for this study, the participant must discontinue use of these products prior 
to enrollment and must not continue with the products until after they have completed the 
study. 
12. Participant is receiving systemic steroids or other immunosuppressive medications. 
13. Participant is currently participating in or has participated in any other clinical trial of a 
drug by ocular or systemic administration within the last 6 months.  
14. Participant has previous exposure to an intra-ocular device or implant into the eye 
(excluding intra-ocular lens). 
15. Participant has uveitis or other retinal inflammatory disease. 
16. Participant has a history of myocardial infarction within the last 12 months. 
17. Participant is pregnant or lactating. 
18. Participant is considered immunodeficient or has a known history of HIV. A laboratory 
test for HIV will be performed, and a positive result is also an exclusion criterion. 
19. Participant with a history of ocular herpes zoster. 
20. Participant is on chemotherapy. 
21. Participant has a history of malignancy, except study participant with cancer treated 
successfully ≥5 years prior to inclusion in the trial. 
22.  Participant with severe hearing disabilities in both ears. 
23. Participant who has been diagnosed and treated for amblyopia as an infant. 
24. Participant who, in the opinion of the study doctor, will not be a good study subject. 
 
Visit Schedule of events and participant procedures is provided in Table 1 


 
 
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Table 1:  Visit Schedule 
1 Baseline 1 Screening will occur within 7 weeks of implant surgery; Baseline 2 Screening will occur within 4 weeks of Baseline 1. 
2 Baseline 3 will occur < 4 days prior to implant surgery  
3 ECG and pre-op laboratory testing should be performed within the timeframe mandated by the OR. 
4 Measurement or exams should be taken at any point within 7 weeks preceding implant surgery.  
5 Measurement at Baseline 1 must establish a minimum of 7 ROI’s; measurement at Baseline 2 must verify a minimum of 7 of the previously 
established ROI’s for measurement throughout the study period. 
6 Urine pregnancy test will only be performed on premenopausal women. 
7 Genetic testing will be offered to patients with diseases for which eyeGENE offers testing.  Separate consent is required and patients can 
refuse to submit blood for genetic testing but still participate in the present study. 
SCHEDULED VISIT WEEK 
 
Baseline 1 (Screening)1 
Baseline 2 (Screening)1 
Baseline 3 (<4 days pre-op)2 
Implant Surgery 
1 Day Post-Op 
1 Week (+ 3 days) 
1 Month (+ 3 days) 
6 Months (+7 days) 
12 months (+ 14 days) 
18 Months  - (+ 14 days) 
24 Months  - (+ 14 days) 
30 Months  - (+ 21 days) 
36 Months  - (+ 21 days) 
GENERAL ASSESSMENTS 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history, brief PE, and systems review 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs (BP, respiratory rate, temperature) 
X 
 
X3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
 
 
X3 
 
 
 
 
 
 
 
 
 
 
AE assessment 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Implant site clinical examination 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NEI-VFQ25 questionnaire 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
VISUAL SYSTEM EXAMS 
 
Manifest Refraction 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Best Corrected Visual Acuity, IOP 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Slit lamp exam and dilated fundus exam 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AOSLO 
X5 
X5 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Axial length, anterior chamber depth, corneal 
curvature  measurement [a-scan] 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
Humphrey 10-2 Visual Field 
X4 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Dark Adapted Fundus-Guided Microperimety 
X4 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Infrared Fundus Photographs 
X4 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Spectral domain OCT 
X4 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
ERG 
 
X4 
 
 
 
 
 
 
X 
 
X 
 
 
STUDY THERAPY 
 
Implant Surgery 
 
 
 
X 
 
 
 
 
 
 
 
 
 
LABORATORY 
 
Serum chemistry , hematology, urinalysis 
 
 
X3 
 
 
 
 
 
X 
 
X 
 
X 
Urine Pregnancy6 
 
 
X3 
 
 
 
 
 
X 
 
X 
 
X 
HIV testing 
 
 
X3 
 
 
 
 
 
 
 
 
 
 
Genetic testing through eyeGENE 
 
 
X7 
 
 
 
 
 
 
 
 
 
 
Serum for antibody/CNTF concentration 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 


 
 
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Photoreceptor Structure in a Phase 2 Study of Encapsulated Human 
NTC-201 Cell Implants Releasing Ciliary Neurotrophic Factor 
(CNTF) for Participants with Retinitis Pigmentosa Using Rates of 
Change in Cone Spacing and Density as the Primary Outcome 
 
 
1 
Background and Rationale 
Retinitis Pigmentosa (RP) is a group of hereditary disorders whose common feature is a 
progressive deterioration of the rod and cone photoreceptors in the retina, which results in the 
reduction and loss of both peripheral and central vision. Histopathologic studies in naturally 
occurring and genetically engineered animal models of photoreceptor dysfunction and death in 
the condition termed retinitis pigmentosa (RP) have indicated the promise of ciliary neurotrophic 
factor (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 supporting glial cells and has been demonstrated to be 
highly effective in retarding photoreceptor neuron loss in 12 animal RP models with various 
forms of retinal degeneration.  
One of the major challenges in the treatment of RP is to deliver therapeutic macro-molecules 
such as CNTF to the retina. The blood-retinal barrier effectively prevents the passage of large 
therapeutic molecules from the bloodstream into the tissues of the eye thus limiting systemic 
treatment approaches. Neurotech developed a form of encapsulated cell technology (ECT) 
specifically to overcome this challenge. This technology enables the controlled, continuous and 
long-term delivery of therapeutic macro-molecules, including a wide variety of neurotrophic 
factors and other proteins and compounds, directly into the vitreous cavity inside the eye.  
Due to RP’s slow progression and standard clinical imaging techniques that have, until recently, 
been unable to visualize individual photoreceptors due to optical imperfections in living eyes, it 
has been challenging to evaluate CNTF’s potential to treat RP. Natural history studies of retinal 
degeneration predict that significant changes in visual function may be measured reliably only 
after greater than 7 years, suggesting that significant photoreceptor loss is necessary before 
changes in visual function can be measured reliably (Fishman et al, 2007; Grover et al, 1997; 
Iannaccone et al, 2004).  However, adaptive optics (AO) ophthalmoscopy, including adaptive 


 
 
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optics scanning laser ophthalmoscopy (AOSLO), can produce images of individual cone 
photoreceptors non-invasively in living eyes (Liang et al, 1997; Roorda et al, 2002; Zhang et al, 
2006). Direct visualization of cones allows comparison of cone spacing and density, and in ideal 
situations, tracking of individual cones longitudinally. Cone spacing and density have been used 
to characterize normal eyes and eyes with retinal degeneration (Choi et al, 2006; Duncan et al, 
2007; Rossi et al, 2010). In addition, dark-adapted fundus-guided microperimetry has been used 
to study visual function reliably and provides insight into the function of both rods and cones in 
the macula of patients with retinal degeneration (Crossland et al, 2010).   
 
Preliminary studies using AOSLO to image cones in patients with retinal degenerations showed 
reduced rates of cone loss in eyes treated with CNTF compared to contralateral eyes that 
received sham treatment over 24-32 months, despite no significant changes in visual acuity or 
visual field (Talcott et al, 2010). These studies suggest that CNTF may be effective in slowing 
the rate of photoreceptor loss in eyes with retinitis pigmentosa and Usher syndrome, but that 
measures of visual function including visual acuity and visual field sensitivity are not sufficiently 
sensitive to identify a treatment effect over 24 months.  
 
2 
Scientific Rationale 
2.1 Encapsulated Cell Technology  
Encapsulated cell implants (NT-501) consist of cells encapsulated within supportive matrices 
and surrounded by a semi-permeable polymer membrane. The NT-501 implants consist of 
encapsulated NTC-201 cells.  The NTC-201 cells1, which produce ciliary neurotrophic factor 
(CNTF) in the NT-501 device, are derived by genetically modifying the NTC-200 cells using a 
proprietary plasmid vector containing the CNTF gene.  The NTC-200 cells are derived from a 
human retinal pigment epithelial cell line, ARPE-19 (ATCC # CRL-2302). This cell line is 
diploid, non-tumorigenic and meets established criteria for safety and freedom from microbial 
contaminants and adventitious viruses (Investigational New Drug Application BB-IND-10931). 
 
Two implant dosage forms, high (NT-501-6A.02) and low (NT-501-10.02) CNTF-secreting 
implants, were developed and employed in phase 1 and phase 2 studies to allow for the 
                                                 
1 A spontaneously immortalized human retinal pigment epithelial line derived from the ARPE-19 line (ATCC No. 
CRL-2302). 


 
 
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evaluation of different CNTF dosing regimens and their respective safety profiles in patients 
with RP.  Implants appeared identical, but differed in that they were loaded with either a high 
output (NTC-201-6A) or low output (NTC-201-10) CNTF-secreting cell line.   The CNTF-
specific productivity rate of the NTC-201-6A cell line is 800 ng CNTF per 1x106 cells per day. 
The NTC-201-6A cells are used to produce the CNTF secreting NT-501 implant that releases 
CNTF at 20 ng/day.  The NTC-201-10 cell line is a lower output line at 250 ng CNTF per 1x106 
cells per day are used to produce the CNTF secreting NT-501 implant that releases CNTF at ~5 
ng/day. 
 
Figure 1 
Schematic Representation of the NT-501 Implants 
 
 
 
 
 
2.2 Rationale of ECT in Participants with RP  
Currently, there are no treatments available for retinal degenerative disorders, and the clinical 
course for RP is very poor. RP symptoms usually manifest in patients between the ages of 7-30 
and the rate of progression varies among them. Most RP patients are legally blind by age 40. It 
has been hypothesized (Seiving et al, 2006) that CNTF implants improved the visual acuity of 
some of these participants who had both advanced RP and atrophic macular degeneration. 
2.3 Rationale for Use of Sham Surgery  
This Phase 2 study will explore the effect on cone spacing and cone density over a 24-month 
period of CNTF release by the NT-501 intravitreal device to establish whether CNTF delivered 
in this manner can improve cone photoreceptor survival or lessen the decline in cone density 
relative to the contralateral control eye. Measures of change in visual acuity, visual field 
sensitivity and disease modification will be collected over a total of 24 months as secondary 


 
 
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outcomes. Given this observation period to reach the primary outcome and the relatively small, 
absolute magnitude of improvement expected, a control sham treatment with minimal risk to the 
fellow eye is justified to qualify the chance that any observed differences are a result of a 
participant effort rather than from the treatment itself.   
2.4 Rationale for Excluding Participants Under 18 or Above 55 Years of Age 
The age limits were selected to maximize the homogeneity of the RP population under study. 
Participants younger than 18 or older than 55 may have a different clinical course of disease. 
3 
Study Objectives  
The objective of this study is to investigate whether CNTF improves or lessens the rate of cone 
photoreceptor loss, measured as increased cone spacing or decreased cone density, relative to the 
fellow control eye in participants with Retinitis Pigmentosa and Usher Syndrome types 2 and 3. 
4 
Study Design and Methods  
This is a prospective, randomized, double-masked, sham-controlled trial of approximately 30 
study participants with reduced vision in both eyes due to RP and Usher Syndrome types 2 and 3.  
This trial will be conducted at the Retinal Degenerations Clinic at the University of California, 
San Francisco.  The surgeon designated by the Principal Investigator will not be masked as to 
which eye received the implant and which eye received the sham.  The participants and the 
technicians will be masked regarding the sham versus implant eye.  
All participants will receive the implant after successfully completing baseline examinations 
during which participant’s eligibility to participate in the trial will be determined (see section 
4.6.1).   
Although implants containing the “high output” CNTF-secreting cell line are the intent of the 
study, a cohort of “low output” implants will also be studied:  The initial 9 participants will 
receive the high output implant; the subsequent 6 participants will receive the “low output” 
implant, and the remainder of subjects will receive the “high output” implant. 
Initial implantation of the investigational devices will be staggered over a 3-month period in 
order to permit a review of patient safety data by the SMC.  The 3-month staggered enrollment 


 
 
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will occur as follows.  Here, references to days, weeks and months are relative only to the first 
surgical procedure: 
 The first patient will undergo surgical implantation of the investigational product on day 
1 of week 1.   
 The one day, one week and one month post implant safety findings for the first patient 
will be forwarded to the Chairman of the SMC for review of the safety findings.  
Communicating the outcome of the SMC review will be accomplished prior to week 5.   
 Assuming a recommendation to continue enrollment results from the SMC’s review of 
safety data (up to one month post implant), the second patient will undergo surgical 
implantation of the investigational product during day’s 1 – 5 of week 5.   
 The 2-month post implant safety data for patients 1 and the one-month post-implant 
safety data for patient 2 will be supplied to the chairman of the SMC at the beginning of 
week 9.  
The SMC’s recommendation was to continue enrollment following the SMC review of safety 
data (up to two month post implant). The remaining patients will undergo surgical implantation 
of the investigational product in accordance with enrollment.  
 
Devices will not be explanted except in instances where it is medically advised due to an adverse 
event.  An examination for safety will occur one day following surgical implant and periodically 
thereafter.   
All participants will be followed clinically for 30 months. 
4.1 Outcomes 
Primary Outcome: 
The primary outcome is rate of change in cone spacing and rate of change in cone density as 
determined using AOSLO images of regions of interest (ROIs) preselected at baseline in eyes 
treated with CNTF compared to contralateral eyes treated with sham surgery over 30 months. 
Cone spacing and density will be measured by 3 independent graders who will remain fully 
masked to the treatment assignment throughout the duration of the trial. We will compare rates 
of change in cone spacing and cone density between CNTF-treated and contralateral sham-
treated eyes through 30-months using pooled linear regression.   


 
 
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Secondary Outcomes:  
Secondary outcome measures will involve comparing rates of change in standardized measures 
of visual function between CNTF- and sham-treated eyes. Secondary outcomes will include the 
following functional and structural assessments:  mean and median change in best spectacle-
corrected visual acuity (BCVA) using the ETDRS protocol, changes in visual field sensitivity 
and foveal sensitivity in decibels (dB) using automated static perimetry using the Humphrey 
visual field 10-2 protocol and rod and cone-mediated fundus-guided microperimetry using a 
modified Nidek MP1, changes in thickness of the outer nuclear layer (ONL) and outer segment 
plus RPE (OS+) layer thickness as measured using spectral-domain optical coherence 
tomography (SD-OCT), and changes in full-field ERG scotopic and photopic standard a- and b-
wave amplitudes and timing from baseline to 36 months. All parameters except full-field ERG 
will be measured at 6, 12, 18, 24, 30 and 36 months after implant surgery; standard full-field 
ERG will be performed according to ISCEV standards at baseline, 12, and 24 months. 
 
Safety Outcomes: 
Safety of the NT-501 ECT technology implant has been demonstrated in prior Phase 1 and Phase 
2 trials of the implant.  Separately from efficacy outcomes which demonstrate a reduction or 
increase in function, safety parameters will continue to be collected and assessed by the 
following outcomes (occurrence of these outcomes does not necessarily require explant): 
 Rejection or extrusion of the NT-501 device. 
 Protocol-related abnormal findings from serum chemistry, hematology, and 
urinalysis (those abnormal findings that are determined to be clinically significant 
by the Principal Investigator).  
 Peri-implant fibrosis, which either blocks the visual axis of the implanted eye or 
affects the lens or retina (minor/moderate fibrosis around the implant and/or the 
attachment point is an expected possibility and will be considered safe on ocular 
function).  Attention should focus on fibrosis that may detach the retina. 
 Development of choroidal neovascularization (CNV) in the implanted eye, in 
which case it may be considered a safety event and explant will be considered. 


 
 
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 Adverse events affecting ocular function, which are different from those expected 
in the normal course of RP or Usher Syndrome, which are thought to be 
potentially related to the implant. 
 Local or systemic toxicities considered serious adverse events that are potentially 
related to the implant. 
There are risks associated with the surgeries to implant and explant the device and with the sham 
surgery.  In general, the risks of intra-ocular surgery are very small. Some side effects could 
occur locally in the eye and could affect the participant’s vision. There may be pain or infection, 
a small amount of bleeding, cataract, vitritis, and/or mild astigmatism.  A retinal detachment 
could also possibly occur. Participants may experience a transient red eye from superficial 
bleeding and itching or a foreign body sensation in the corner of the eye from irritation of the 
suture itself.  These side effects are usually temporary and generally clear up in two weeks or 
less. In many cases, topical antibiotics and topical steroids can treat minor degrees of 
inflammation or infection. More serious infection or inflammation may require further surgery 
on the eye, likely with removal of the implant. 
In addition, all adverse events will be collected regardless of severity or potential relationship to 
the implant, CNTF, or surgical procedure. 
4.2 Inclusion Criteria 
 
1. Participant must be between 18 and 55 years of age. 
2. Participant must have a diagnosis of retinitis pigmentosa or Usher syndrome type 2 or 3. 
3. Participant must understand and sign the protocol informed consent. If the participant’s 
vision is impaired to the point where he/she cannot read the informed consent document, 
the document will be read to the participant in its entirety.  
4. Best-corrected visual acuity must be no worse than 20/63 (at least 59 letters). 
5. Participants must have clear natural lenses. 
6. Participants must have less than 6 diopters myopia. 
7. Participants must be medically able to undergo ophthalmic surgery for the NT-501 device 
insertion and be able to undergo all assessments and tests associated with the protocol. 


 
 
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8. Females of childbearing potential (women with last menses <1 year prior to screening) 
must agree to use an effective form of birth control from study onset until they complete 
the study.  
9. Participants must have reproducible baseline AOSLO image montages at 2 baseline 
imaging sessions with quality suitable to identify a minimum of 7 regions of interest 
(ROIs) at which reliable cone spacing and/or density measures can be made over the 
central 5.7 degrees. 
10. Participants must have interocular symmetry of disease severity as measured by cone 
spacing, with a difference of less than 2 standard deviations in average cone spacing z-
scores at the selected ROIs between the 2 eyes. 
11. Participant’s clinical diagnosis must be consistent with retinal degeneration in the set of 
retinitis pigmentosa (RP) dystrophies characterized by the following features: 
a) clinical evidence of progressive photoreceptor cell dysfunction and 
degeneration of the outer retina 
b) intraretinal ‘bone-spicule’-like pigment observed on clinical examination 
c) peripheral visual field constriction documented on standard testing 
d) symptomatic night blindness 
e) reduction of both rod and cone electroretinogram (ERG) responses. 
For purposes of this study, individuals diagnosed with Retinitis Pigmentosa or Usher 
Syndrome Type 2 or Type 3 (without profound deafness or cochlear implants) who meet the 
inclusion criteria will be considered as potential candidates for this study.  A maximum of 4 
Usher Syndrome Type 2 or Type 3 participants may be enrolled in this trial. 
4.3  Exclusion Criteria 
 
1. Participant is medically unable to comply with study procedures or follow-up 
visits. 
2. Participant who has any of the following lens opacities: cortical opacity > 
standard 3, posterior subcapsular opacity > standard 3, or a nuclear opacity > 
standard 3 as measured on the AREDS clinical lens grading system; or participant 
is pseudophakic or aphakic. 
3. Participant has history of corneal opacification or lack of optical clarity. 


 
 
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4. Participant has undergone LASIK surgery or other refractive surgery for either 
eye. 
5. Participant has nystagmus. 
6. Participant has greater than 6 diopters myopia. 
7. Participant has cystoid macular edema with cysts present within 4 degrees of the 
foveal center. 
8. Participant has fewer than 7 ROIs present on 2 baseline AOSLO image montages. 
9. Participant has retinal vascular disease such as diabetic retinopathy or prior retinal 
vascular occlusive disease. 
10. Participant has chronic requirement (e.g.,  4 weeks at a time) for ocular 
medications or has disease(s) that in the judgment of the examining physician are 
vision threatening, toxic to the lens, retina, or optic nerve or may affect the 
primary outcome. 
11. Participant has a requirement of acyclovir and/or related products during study 
duration. To be eligible for this study, the participant must discontinue use of 
these products prior to enrollment and must not continue with the products until 
after they have completed the study. 
12. Participant is receiving systemic steroids or other immunosuppressive 
medications. 
13. Participant is currently participating in or has participated in any other clinical 
trial of a drug by ocular or systemic administration within the last 6 months.  
14. Participant has previous exposure to an intra-ocular device or implant into the eye 
(excluding intra-ocular lens). 
15. Participant has uveitis or other retinal inflammatory disease. 
16. Participant has a history of myocardial infarction within the last 12 months. 
17. Participant is pregnant or lactating. 
18. Participant is considered immunodeficient or has a known history of HIV. A 
laboratory test for HIV will be performed, and a positive result is also an 
exclusion criterion. 
19. Participant with a history of ocular herpes zoster. 
20. Participant is on chemotherapy. 


 
 
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21. Participant has a history of malignancy, except study participant with cancer 
treated successfully ≥5 years prior to inclusion in the trial. 
22.  Participant with severe hearing disabilities in both ears. 
23. Participant who has been diagnosed and treated for amblyopia as an infant. 
24. Participant who, in the opinion of the study doctor, will not be a good study 
subject. 
 
4.4 Study and Concomitant Therapy Administration 
Study Treatment 
Each participant will be randomized to determine the study eye. The fellow eye will receive 
sham surgery and serve as the control. The surgeon will determine whether the sham or the 
implant surgery occurs first but it is recommended that the implant surgery be done first.   
The surgical procedure involves a small incision at the pars plana through the sclera, which is 
generally closed with three sutures. The titanium loop will be sutured beneath the sclera (using 
the Vitrasert technique) with the insertion site at the pars plana (Figure 2).   
Figure 2 
NT-501 (not to scale) with titanium anchor sutured beneath the sclera, secured by 
three sutures through the sclera (Vitrasert technique). Illustration shows site of device insertion 
through the pars plana, anterior to the neural retina, in the vitreous. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Study/Follow-up Visit and Assessments  
The Schedule of visits and procedures is provided in Table 1 (within the Protocol Summary). 
Prohibited Medications/Therapy 
The decision to administer a prohibited medication/treatment is done with the safety of the study 
participant as the primary consideration. When possible, Neurotech should be notified before the 
prohibited medication/treatment is administered. 
The use of systemic steroids and intraocular steroids in the study eye are prohibited unless 
required for the safety of the patient and should not be administered without consultation with 
the Sponsor, if possible.  
Administration of subconjunctival or intravitreal antibiotics is prohibited unless treating a sight-
threatening condition. Administration of gentamicin or other aminoglycosides is prohibited 
topically, periocularly or by injection unless treating a sight-threatening condition and no other 
alternatives are appropriate. Systemic administration of aminoglycosides should also be avoided, 
if possible. Aminoglycosides are known to be toxic to RPE cells and could harm the cells in the 
NT-501 investigational product. 
 
4.5 Investigational Product Packaging, Labeling, and Handling at Study Site  
 
All study therapy required for completion of this study will be provided by Neurotech 
Pharmaceuticals, Inc. The recipient will acknowledge receipt of the product indicating shipment 
content and condition.  Damaged supplies will be replaced.  Accurate records of all study product 
dispensed, used and returned will be maintained.   
The NT-501 implant is seated in a primary, sterile, inner container, called the primary package, 
which is protected by a secondary outer container, called the secondary package. The primary 
package is comprised of a sealed lower compartment that holds the maintenance medium and 
NT-501 implant, separated by a dry upper compartment allowing for access and ease of the 
removal of the implant from the lower compartment. The implant is suspended within the 
maintenance medium by a titanium clip that, in turn, is held in position by a luer locking cap that 
is twisted onto the flange of the packaging baffle, sealing and separating the lower from the 
upper compartment of the primary package. The primary and secondary packages are each 
hermetically sealed with a foil laminate barrier. The contents of the finished product package are 
sterile. 
Label: The product label for NT-501 will appear on the top of the finished package, centered on 
the top polymer-foil. The label will identify the implant investigational product is for clinical use 
only (CAUTON statement), the protocol number, lot number, and will comply with all regulatory 
requirements. The label will indicate the single use package contains 1 intraocular implant NT-


 
 
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501, is sterile if package is unopened, the intraocular implant is for surgical implantation only, to 
use only as directed by the study protocol, and storage temperature. 
Documentation: The Neurotech shipping/product receipt form is to be completed, and the 
product is inspected and documented, prior to use in accordance with Neurotech instructions. 
The completed form is to be provided to Neurotech. The investigational product is to be stored in 
the shipping box until surgery.  The IP must be used within the “Use By” date.   
All study therapy must be kept in a secure place under adequate storage conditions. The 
Investigator has overall responsibility for ensuring that study therapy is stored in a safe limited 
access location under the specified appropriate storage conditions.  The Investigator or designee 
will record dispensing of the study medication on a study medication accountability record.  
These records should include dates, quantities, lot numbers, expiration dates, and the unique 
code number assigned to the investigational product.  This record will be made available to 
clinical monitoring personnel for the purpose of accounting for the clinical study medication 
supply.  A study medication supply inspection for inventory purposes and assurance of proper 
storage will be conducted as necessary.  Any significant discrepancy will be recorded and 
reported to Neurotech Pharmaceuticals, Inc and a plan for resolution will be documented.  
Following surgical implantation, all unused product will be destroyed and documentation of 
destruction recorded. 
4.6 
Surgical Procedure 
All procedures must be performed by qualified retinal surgeons. All study surgeons will be 
trained by the Sponsor Neurotech. A general overview is provided below. Neurotech will provide 
surgical tools (ie, Sapphire Spearpoint Blade and incision dilators in an instrument 
tray). Additional information regarding the tools is provided in Appendix 13. 
4.6.1  Subject Preparation, Implant and Sham Surgery 
NT-501 Preparation Prior to Implantation  
1. Prior to scrubbing, perform a visual inspection of the implants.  Note that in most cases, > 
1 implant will be available for every study subject undergoing the implant procedure.  
Note the package labeling, expiration/Use By date and overall integrity of each of the 
implants including their packaging and media color. Choose one to open onto sterile 
field.  
2. Once in the sterile field, open the inner package and prepare to secure the implant for 
suturing. 


 
 
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3. Closely inspect the device for damage not visible while inside the package. If there is 
concern, discard and open the second device.  
4. Drying of the device must be minimized by limiting air exposure to < 2 minutes. BSS 
rinse can be applied if needed to maintain the device moist. 
Patient Preparation Prior to Implantation Procedure  
1. Prior to transfer to the surgical suite, the participant’s general condition will be recorded.  
2. Establish an IV line for administration of medications.   
3. Dilate pupils with a minimum of two drops each of phenylephrine hydrochloride (2.5%) 
and cyclopentolate hydrochloride (1%).   
4. Transfer the study subject to the operating room and onto the operating table in a supine 
position.   
5. Monitor the participant for oxygen saturation, heart rate, temperature, blood pressure and 
ECG throughout the implant and sham procedures. 
6. It is recommended that the implant eye surgery will be performed prior to sham surgery. 
 
NT-501 Implant Surgery 
1. The surgeon has the option of bilateral peribulbar or subtenon anesthesia.  If the option of 
peribulbar is used, administer the block to the implant eye at this point using bupivacaine 
0.5% with lidocaine 2% 1:1. 
 
Prep with anesthetic and iodine-based solution(s) and drape in standard sterile 
fashion. For example, scrub/prep the periocular region with 10% iodophor and the 
exposed surface of the eye and the conjunctiva will be rinsed with 5% iodophor 
solution.  
 
Placing corneal shield or alternative to avoid direct illumination of the macula is 
recommended 
2. Secure sterile drapes.   
3. Retract the eyelids with a lid speculum.   
4. Under microscopic visualization, perform an inferior limbal conjunctiva peritomy using 
scissors.   
5. If the option of subtenon injection is selected, then administer the subtenon injection to 
the implant eye at this point using bupivacaine 0.5% with lidocaine 2% 1:1. 


 
 
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6. Make a 2.0 mm sclerotomy 3.75 mm posterior to the limbus in the inferotemporal 
quadrant. An alternative quadrant may be selected if the vitreo-retinal surgeon determines 
that the implant should not be inserted in the inferotemporal quadrant.   
7. Using the custom dilator tool, dilate the opening made by the scleral incision. 
8. Remove the NT-501 implant from its packaging.  NOTE:  Drying of the device must be 
minimized by limiting air exposure to < 2 minutes. BSS rinse can be applied if 
needed to maintain the device moist. Rinse the implant with a stream of sterile BSS and 
insert the implant into through the scleral incision and into the vitreous, being careful the 
keep the titanium loop visible above the sclera. 
9. Release the device from the titanium clip using forceps or needle holders. 
10. Feed the 9-0 Prolene suture through the implant’s titanium clip and secure it with 2 single 
knots. 
11.  Pass each arm of the suture through either side of the wound at a depth of nine-tenths 
thickness through the sclera.  Anchor the implant to the sclera with a triple throw knot 
followed by 2 single throws.  It is important to leave the tails of the suture long to 
facilitate the following steps.  
12. Place interrupted 9-0 nylon sutures over the tails of the anchoring suture to ensure closure 
of the wound; an attempt to bury the knots will be made for comfort.  The tails on the 
anchoring sutures can be left slightly long, but should be trimmed so that they lie flat on 
the sclera.  If necessary, additional 9-0 sutured knots may be used to further close the 
incision site. 
13. Close or reappose the conjunctiva with 7-0 vicryl suture for complete coverage of the 
wound.  
14. Examine the eye with an indirect ophthalmoscope to confirm placement of the device 
into the vitreous.  Sterile bacitracin will be applied and the eye will be patched during the 
post surgical observation period. 
15. Examine the eyes with an indirect ophthalmoscope to confirm placement of the device 
into the vitreous 
16. Day of Surgery Wound Care Recommendations:  
1. At the end of surgery, administer subconjunctival dexamethasone (2mg/0.5 ml 
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anticipated in the opinion of the investigator, a higher dose of dexamethasone 
(0.5cc of 10mg/ml or comparable) may be used. 
2. Apply Vigamox® (moxifloxacin) to eye prior to patching 
3. Patch eye during the post surgical observation period as deemed necessary 
Post-Op Implant Wound Care:  Starting the next day, the participant will self-administer the 
following medications is provided in section 4.6.3 
Sham Implant Surgery 
1. These instructions assume that the surgeon completed the implant eye surgery first and 
operates on the sham eye immediately upon completion of the implant surgery.  
2. If the peribulbar anesthesia was used in implant surgery, either administer the peribulbar 
block to the sham eye at this point using bupivacaine 0.5% with lidocaine 2% 1:1, or 
perform a small skin puncture using small gauge needle, to simulate the skin puncture in 
the fellow eye, without the actual block being placed. 
3. Prep with anesthetic and iodine-based solution(s) and drape in the usual sterile fashion. 
For example, scrub/prep the periocular region with 10% iodophor and rinse the exposed 
surface of the eye and the conjunctiva with 5% iodophor solution.  Note that the sham 
eye may be scrub prepped at the time of implant eye preparation. 
4. Placing corneal shield or alternative to avoid direct illumination of the macula is 
recommended 
5. Secure the sterile drapes.   
6. Retract the eyelids with a lid speculum.   
7. Perform an inferior limbal conjunctiva peritomy under microscopic visualization using 
scissors.   
8. If a subtenon block will be used, then apply it at this point to the sham eye using 
bupivacaine 0.5% with lidocaine 2% 1:1 (unless the surgeon prefers the peribulbar block 
(see above)). 
9. Apply pressure for two seconds at 3.75 mm posterior to the limbus in the inferotemporal 
quadrant. Select an alternative quadrant if the vitreo-retinal surgeon determines that the 
pressure should not be applied in the inferotemporal quadrant.   
10. Close the conjunctiva with 7-0 vicryl suture. 
11. Day of Surgery Wound Care Recommendations:  


 
 
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a. At the end of surgery, administer subconjunctival dexamethasone (2mg/0.5 ml 
(4mg/ml), or comparable; If the case is complicated and excess inflammation is 
anticipated in the opinion of the investigator, a higher dose of dexamethasone 
(0.5cc of 10mg/ml or comparable) may be used. 
b. Apply Vigamox® (moxifloxacin) to eye prior to patching 
c. Patch eye during the post surgical observation period as deemed necessary 
Post-Op Implant Wound Care:  Starting the next day, the participant will self-administer the 
following medications is provided in section 4.6.3   
12. Examine the eye will with an indirect ophthalmoscope.  
At the completion of the exampatch the eyes for the post surgical observation periodas 
deemed necessary. 
 
4.6.2  Post Surgical Observation Period 
1. After the post surgical observation period, send the participant with instructions to return 
to the clinic for examinations and evaluations the next day and at one week (+3 days).   
2. Provide post-operative care instructions to the study subject and instruct him/her to 
contact the center in the event of any adverse event.  
3. Provide post operative wound care medications to self administer per section 4.6.4. 
4. Perform routine post-surgery check-ups 1 day, 1 week, and 1 month after the 
implantation (visual acuity, IOP, slit lamp exam, indirect ophthalmoscopy, and AE 
assessment per the Visit Schedule in Table 1).  
 
4.6.3 Post-Op Implant Wound Care Recommendations 
Starting the next day, the participant will self-administer the following medications as follows: 
1. Vigamox (moxifloxacin) one drop 4 times a day to both eyes for 7 days 
2. PredForte to both eyes 
 1 drop every 2 hours for 5 days (while awake) 
 Then 1 drop 4 times a day for 7 days 
 Then 1 drop 3 times a day for 7 days 
 Then 1 drop 2 times a day for 7 days 
 Then 1 drop daily for 7 days 
 


 
 
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4.6.4 Removal of Device  
The NT-501 implant may be explanted for significant safety or tolerability concerns, but should 
not be removed without prior consultation with the sponsor, if possible.  Once removed, the 
implant is to be returned to the sponsor if possible, using handling and shipping instructions 
provided by the sponsor prior to explantation.   
A sample of the vitreous will be collected if feasible during the explant procedure, to measure 
CNTF concentration.  Surgical Explantation Procedure 
The sponsor will review with the surgeon the instructions for surgical removal and handling of 
the ECT investigational product prior to the explants surgery.  A general summary is provided. 
Patient preparation:  
 Prep with anesthetic and iodine-based solution(s) and drape in the usual sterile fashion 
 After draping the eye, the eyelids will be retracted with a lid speculum.  
 Under microscopic visualization a peritomy will be performed at the site of the previous 
implant. 
 Placing corneal shield or alternative to avoid direct illumination of the macula is 
recommended 
 Attention is then placed to implant removal. Bipolar wetfield cautery may be applied as 
needed to control bleeding  
 The previously placed prolene sutures will be identified.  
 The two lateral nylon sutures will be removed.  
 A supersharpblade will then be used to create approximately a 1 mm sclerotomy on either 
side of the anchoring 9-0 prolene suture along the original incision.  
 Bleeding from the pars plana sclerotomy will be controlled with a 23 gauge tapered 
bipolar cautery.  
 Care will be taken to ensure the scleral wound lips are not cauterized. The edges of the 
sclerotomy will be gently spread and micro forceps will be used to grasp the anchoring 
loop on the implant.  
 The sclerotomy may have to be enlarged to adequately visualize the implant. 
Implant removal: 
 Once grasped, the implant will be steadied while the sclerotomy is completed (joining 
adjacent sclerotomies) using the supersharpblade. The anchoring prolene knot will be 
transected by this maneuver.  
 An attempt will then be made to gently remove the implant using the micro forceps.  
 If resistance is encountered, the sclerotomy will be inspected and adhesions will be 
transected using thesupersharp blade or micro scissors. 
 Handling instructions for the explanted ECT will be provided separately. 
 A vitreous sample may be collected. Handling instructions will be provided separately. 
Closure: 


 
 
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 Once the implant has been removed the sclerotomy will be closed with 7-0 vicryl suture 
and the retina inspected for tears or bleeding using indirect ophthalmoscopy.  
 The conjunctiva will be closed.  
4.7 Examination Requirements  
At scheduled visits, participants will undergo a medical evaluation and an ophthalmic 
examination, which includes eye photography and vision measurements and laboratory tests. 
Scheduled visits are approximated with windows as defined in section 4.4.1 Study/Follow-up 
Visit and Assessment Schedule. 
The following are examinations to be performed at the times indicated in section 4.4.1.  
1. Medical evaluation including: 
 Demographic data 
 Medical history, including confirmation of RP diagnosis 
 Vital signs (blood pressure, respiration, and temperature) 
 Brief physical examination with body system review 
 Herpes zoster history 
 Adverse Event assessment 
 ECG (once prior to surgery) 
2. Complete ophthalmic examination including: 
 Slit Lamp Exam including AREDS Clinical Lens Grading2  
 Implant site clinical examination 
 Ophthalmoscopic Exam 
 Manifest refraction 
 BCVA (using the ETDRS methods for refraction and EVA)  
 IOP 
 Humphrey 10-2 Visual Field Testing 
 Dark Adapted Fundus Guided Microperimetry using red and blue targets at 2 
degree intervals across a horizontal line extending 10 degrees with a 
Goldmann V, 200 ms target using a 4-2-1 threshold strategy to assess rod and 
cone-mediated function 
                                                 
2 The AREDS clinical lens grading protocol will be used for protocol scoring purposes (using slit lamp without any 
photographs). 


 
 
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 Full Field ERG using ISCEV standard protocol (Marmor et al, 2009) 
3. Photography and measurements including: 
 Axial length, corneal curvature, anterior chamber depth measures using the 
IOL master (Carl Zeiss Meditech, Inc.) 
 Adaptive Optics Scanning Laser Ophthalmoscopy (AOSLO): AOSLO will be 
performed to image each eye of each subject at 2 baseline imaging sessions 
separated by no more than 1 month. During the first baseline session 37 
fixation points will be imaged, each with a 1.2 degree field size, to yield a 5.7-
degree diameter, roughly circular, montage of the central retina. The montage 
will be analyzed over the subsequent 2-3 weeks. Regions of interest (ROIs) in 
which unambiguous cone mosaics can be identified will be pre-specified in 
each eye, with the goal to identify at least 1 ROI per degree within 2.85 
degrees radius of the anatomic fovea. Requirements for enrollment include the 
following:  
o At least 7 ROIs must be present in each eye of each patient,  
o ROIs must be located at similar distances from the fovea in each eye 
o There must be less than 2 standard deviations difference between average 
cone spacing z-scores (standard deviations from the mean at the 
eccentricity of the ROI) between the 2 eyes.  
o Cone spacing will be quantified in the ROIs by 3 independent graders, all 
of whom will remain fully masked to the treatment assignment throughout 
the duration of the study. A second baseline session performed within 1 
month of the first session will focus exclusively on the ROIs identified at 
baseline visit 1.  After at least 7 ROIs at 1 degree intervals within 2.85 
degrees radius of the fovea in each eye have been identified on 2 baseline 
visits, the subject is eligible to enroll in the study. The PI will review 
AOSLO montages from each eye of each subject after each session to 
ensure the imaging features are indistinguishable before and after surgery 
between eyes randomized to receive CNTF and sham treatment. Although 
the PI will not be masked to treatment since she will be examining eyes 
post-operatively, the Co-Investigator and all study personnel responsible 
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randomization and treatment assignment throughout the trial. 
 Spectral Domain Optical Coherence Tomography (SD-OCT, 20 degree 
horizontal and vertical scans plus 20 x 15 degree volume scans; Spectralis 
HRA+OCT, Heidelberg Instruments, Inc.) 
 Infrared Fundus photographs (Spectralis HRA+OCT, Heidelberg Instruments, 
Inc.) 
4. Laboratory tests including: 
 Serum chemistry 
 Hematology with CBC, PTT, and APT 
 Urine pregnancy tests (females of childbearing age or potential only) 
 Urinalysis 
 HIV test 
 Whole blood collected for genetic testing through the eyeGENE research 
consortium, as applicable, for patients with autosomal dominant RP and other 
retinal degenerations that are included on the list of conditions tested by 
eyeGENE.                                       
For consideration of eligibility, study participants will be screened to ensure eligibility.  Some 
screening evaluations will not be completed on the initial screening day, however all screening 
evaluations, which are completed within 1 month of the initial screening visit, can be used to 
establish eligibility.  
4.8  Enrollment, Randomization, Masking and Unmasking  
Enrollment and Randomization: 
To determine eligibility, prospective participants will be screened per the screening examination 
cited in Section 4 and Table 1 at the time of their routine visit for RP evaluation.   
Participants will be enrolled and randomized in two stages. In the first stage, if the participant 
appears to be a likely candidate (based upon the patient’s known medical history), the PI or a 
delegate will obtain the participant’s informed consent.  After receiving the participant’s consent, 
the clinic will complete screening assessments during the Baseline 1 visit(s). AOSLO images 
will not be taken until the Principal Investigator or qualified designee has reviewed all non-
AOSLO inclusion and exclusion criteria carefully.  Once the patient is determined to be eligible 


 
 
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to participate based on all non-AOSLO criteria, a montage of AOSLO images will be acquired 
from the central 5.7 degrees surrounding fixation in each eye.  AOSLO images will be analyzed 
and evaluated for selection of at least 7 ROIs in each eye, located at similar distances from the 
fovea and with less than 2 standard deviations difference between average cone spacing z-scores 
between the 2 eyes.  The patient will return for a second baseline visit during which AOSLO 
images will be acquired again, but this time focusing on the ROIs that were identified during 
baseline visit 1.  If the second set of AOSLO images of at least 7 ROIS are suitable for cone 
spacing and density measures in each eye (as determined by the Principal Investigator), and the 
patient continues to express interest to participate in the study, then the patient will be 
randomized.  Upon randomization, the patient (now referred to as the “study subject” or 
“subject”) is considered enrolled into the study and will then be qualified for surgery.  The 
subject will proceed to the Baseline 2 and Baseline 3 visits prior to surgery.  The timing for each 
Baseline visit is as follows: 
 
Baseline 1 will occur within  approximately 7 weeks (21 days) of implant surgery; 
 Baseline 2 will occur within approximately 4 weeks of Baseline 1;  
 Baseline 3 will occur at the time of medical evaluation for surgery which will occur 
within  4 days before device surgical implant. 
Masking: 
The participants, vision examiners and AOSLO graders will be masked as to which eye receives 
the implant and which is the sham control eye.  All other clinic staff will remain masked to the 
maximum extent possible. Personnel involved in AOSLO image acquisition and analysis, visual 
acuity and visual field examiners must not have access to implant surgery records, unless visual 
acuity is assessed by clinical coordinator for safety only. The surgeon designated by the Principal 
Investigator will be unmasked and will be responsible for performing the NT-501 and sham 
surgery procedures.    
Unmasking: 
Participants will be told which eye received the implant at the end of the study. 


 
 
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Unmasking prior to the end of study visit, or explant surgery visit (if necessary) should only be 
considered when knowing the randomization code would change the treatment decisions for a 
participant.  Requests for unmasking should be referred to the Medical Monitor who will consult 
with the Safety Monitoring Committee (SMC) Chair prior to disclosing any treatment 
assignments. All incidences of premature unmasking without prior permission from the Medical 
Monitor and SMC Chair will be considered protocol deviations and should immediately be 
reported to the sponsor.   
5 
Safety Monitoring and Reporting 
5.1 Safety Monitoring Committee 
The SMC will be convened prior to trial initiation to review the protocol and will review 
accumulated data during the staggered implantation phase (see section 4.0) and on a regular basis 
during the trial. The Committee will also meet ad hoc to address any problems of significance 
related to participant safety brought to its attention. The committee will consider whether a 
protocol modification is indicated. If changes in the protocol are indicated, recommendations 
will be made to the sponsor who will act on such recommendations in a timely manner.  
5.2 Adverse Experience Reporting 
All adverse events, either observed by the Investigator or one of his/her medical collaborators, or 
reported by the participant spontaneously, or in response to direct questioning, will be reported.  
Any adverse event regardless of severity or potential association with the test article (considered 
to be the implant or CNTF) or study procedures must be documented in study records by the 
Investigator and promptly reported to the sponsor.  
5.3 Obligations of Site Investigators 
The Principal Investigator is obligated to promptly report to the sponsor any adverse event that 
may reasonably be regarded as caused by, or probably caused by the test article or study 
procedures. This protocol additionally requires the Investigator to report all other adverse events 
regardless of their severity or potential association with the test article or treatment procedures.  
When reporting an adverse event, the Investigator must assign a severity grade to each event and 
declare an opinion on the relatedness of the event to the study test article or procedure. 


 
 
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For any serious or unexpected adverse event, the sponsor must be notified within 24 hours of 
when the Investigator first learns of the occurrence of the event.  Expedited reporting 
requirements for serious adverse events are described below (see Section 5.2.1.1). Adequate 
information must be collected with supporting documentation to complete a standard MedWatch 
Form FDA 3500A for submission to the sponsor. 
For adverse events considered non-serious, expected or routine and where the specific event type 
is explicitly tracked on study case report forms, timely recording is considered acceptable when 
the data are reported on the schedule established for regular case report forms in the study 
Manual of Procedures.  
If the participant reaches the final scheduled follow-up visit, any new adverse events, as well as 
follow-up information for ongoing adverse events, must be recorded.  For participants who 
withdraw prematurely, adverse events should be followed until resolved or 30 days after the final 
study visit.  In any case, serious adverse events that are not resolved or considered to be chronic 
within 30 days of the final study visit must be followed by the investigator until they become 
resolved or are considered to be chronic (stabilized for at least 30 days). 
5.3.1 Expedited Reporting Responsibilities of the Site 
When expedited reporting of a serious adverse event (SAE) is required (or expected to be 
required) for event types described in Sections 5.2.3.1 or 5.2.3.2, the Investigator (or the Study 
Coordinator) will promptly: 
 Notify the medical monitor and SMC chair of any SAE within 24 hours of the 
knowledge of the occurrence of the SAE and fax a SAER Form to the medical 
monitor at 401-333-3881. 
 Assess and report the causality of the event. 
 If applicable, provide the Medical Monitor with immediate follow-up 
information necessary to make an initial assessment of the event, in order to 
meet reporting obligations. 


 
 
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 Provide the medical monitor with subsequent follow-up information to 
finalize the SAE (in the form of a follow-up SAER, answered SAE query 
form, discharge summary, laboratory reports, etc. as applicable). 
5.3.2 Submitting an Expedited Safety Report to the Local IRB 
Once the medical monitor receives all supporting documentation for the reported event, the 
Medical Monitor will determine if the safety report is eligible for expedited review. The medical 
monitor will log the initial event within 1 day after initial receipt.  The Medical Monitor will 
complete the review of the event and will create a MedWatch form. This form, as well as other 
supporting documentation, will be forwarded to the Medical Monitor for review.  The Medical 
Monitor will finalize the report for distribution within 2 days after initial receipt. When 
expedited safety reporting to regulatory authorities is indeed required, the Investigator should 
review and update any newly available materials at once.  
Each expedited safety report will routinely include a brief cover memorandum, the completed 
MedWatch Form FDA 3500A, and any additional pertinent information recommended by the 
sponsor, or study Medical Monitor. Once the report is assembled, the Principal Investigator must 
submit the expedited safety report to the local IRB within the required reporting timeframe.  
Follow-up reports should be submitted when requested or when pertinent information becomes 
available.  
5.3.3 Submitting Adverse Events Report to IRBs 
When the Principal Investigator receives an expedited safety report from the medical monitor or 
the sponsor detailing adverse events occurring under this protocol or in other studies using the 
same test article, it must be promptly submitted to the site’s IRB.  The Principal Investigator 
must retain a copy of such reports as submitted to their IRB. 
5.3.4 Contacting the Medical Monitor 
When contacting the medical monitor, the protocol number and location of the study should be 
clearly noted.  If necessary, back-up personnel and procedures are in place to assure adverse 
events are adequately handled and reported correctly.  Neurotech Safety contact is provided on 
the protocol cover page. 


 
 
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5.4 Obligations of Study Sponsor 
Neurotech is the IND holder with the FDA and hence is the legal sponsor of this study.  The 
protocol was designed by the sponsor in collaboration with participating study investigators.   
Neurotech must immediately investigate each reported adverse event.  The sponsor has 15 days 
to submit a report to the FDA of any reported adverse experience that is associated with the use 
of the test article that is both serious and unexpected.  
5.5 Adverse Events Defined 
An adverse event includes any unfavorable and unintended sign (including a clinically 
significant abnormal laboratory finding), symptom, or disease temporally associated with the use 
of the medicinal product, whether or not related to the investigational product or device.  
Medical conditions or diseases present before a participant starts study treatment are only 
considered adverse events if they worsen after the participant starts study treatment (temporal 
association). 
For 
adverse 
events 
that 
result 
in 
persistent 
or 
significant 
disability/incapacity, 
disability/incapacity refers to a substantial disruption of a participant’s ability to carry out normal 
life functions. 
Non-serious adverse events that are expected according to previous experience with the test 
article (as described in the protocol, investigator’s brochure and consent materials) can be 
collected in a routine manner using case report forms. If an expected event is observed to occur 
during the study at a greater frequency or severity than previously described, it may become an 
unexpected event that requires further investigation and reporting as an unexpected adverse 
event. Serious or unexpected adverse events, or any other events not specifically listed on case 
report forms as expected events, must be promptly reported to the Medical Monitor as noted 
above. This permits immediate investigation by the Medical Monitor and sponsor to determine 
the reporting requirements to regulatory authorities.  


 
 
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A hospitalization that is scheduled prior to enrollment for an elective or cosmetic procedure, that 
is unrelated to the medical condition under study, or is for a procedure scheduled under this 
protocol, is excluded from this definition of an adverse event. 
5.5.1 Serious Adverse Events Defined 
A serious adverse event (SAE) [may also be termed a Serious Suspected Adverse Drug Reaction 
– Serious SADR; or in device studies, a serious unanticipated device effect – Serious UADE] is 
defined for this protocol as an adverse event or experience that meets one or more of the 
following criteria: 
A. A death occurring during the study or which comes to the attention of the Investigator 
within 6 months of the end of the protocol-defined follow-up period, whether 
considered treatment-related. 
B. A life-threatening event. 
C. An adverse event requiring in-patient hospitalization or prolonged hospitalization due 
to the adverse event. 
D. An adverse event resulting in a significant, persistent, or permanent change, 
impairment, damage or disruption in the participant’s body function or structure, 
physical activities or quality of life.   As part of the outcome-measure of these studies, 
any progression in disease will be identified through routine scheduled visual 
assessments.  Natural progression of disease alone (e.g., worsening of vision) is not to 
be considered a serious adverse event (SAE).  Any disease progression that is deemed 
by the Investigator as beyond the natural progression of disease will be reported as an 
SAE.      
E. A congenital anomaly or birth defect, where exposure to the test articles prior to 
conception or during pregnancy is suspected in resulting in an adverse outcome in the 
child. 
F. An event that otherwise required a medical or surgical intervention to preclude 
permanent impairment or damage (excluding unrelated elective or cosmetic 
procedures). 
Hospitalization scheduled before a participant enrolls in the study is not the result of a treatment-
emergent AE, and therefore events leading to such hospitalization will not be considered study 


 
 
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AEs or SAEs. During the study, if a participant has elective surgery for a pre-existing condition 
and the condition did not worsen during the study, the reason for elective surgery (and resulting 
hospitalization, if applicable) should not be considered or reported as an SAE. Surgery or 
hospitalization should always be reported as an outcome of an adverse event. In the case of 
surgery for a pre-existing condition, the surgery or hospitalization itself does not merit an SAE 
report. 
5.5.2 Unexpected Events Defined 
An unexpected event is any adverse drug experience or unanticipated adverse device effect, the 
specificity or severity of which is not consistent with the current approved product labeling 
(package insert) for the test article, the Investigator’s Brochure, or as described in the clinical 
protocol and consent materials. This includes an increase in the frequency or severity of a 
previously reported adverse event that is significantly above the rates known from previous 
experience with the test article. 
5.5.3 Relatedness of Event to Test Article or Procedure 
The Investigator (or an authorized study physician) must submit an attribution for the relatedness 
of the reported adverse event to the test article or procedure.  
The attribution should take into account both the temporal association and any known physical, 
physiological or toxicological information regarding the test article that could reasonably infer 
causality. Relatedness should only be considered for the experimental test article and not for any 
standard study examination or diagnostic procedures. The five attribution categories are: 
  Definite—Clearly related to test article or procedure. 
  Probable—Likely related to test article or procedure. 
  Possible—May be related to test article or procedure. 
  Remotely—Unlikely related to test article or procedure. 
  Unrelated—Clearly NOT related to test article or procedure. 
5.6  Withdrawal Criteria 
Participants may choose to withdraw from this study for any reason at any time without penalty 
or prohibition from enrolling in other clinical protocols.   


 
 
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If a participant withdraws from the study completely, they should return for a safety visit at least 
1 month after withdrawing.  All 30-month assessments/examinations should be included in the 
safety visit. 
6 
Statistical Considerations  
6.1 Description of Trial 
10 subjects will be enrolled into the study.  Both eyes of each participant will be evaluated in this 
study. There are, thus, a minimum of 10 participants and a minimum of 20 eyes in the trial. One 
eye of each participant will be randomly assigned to receive CNTF, and the fellow eye will 
receive sham surgery.  AOSLO montages will be acquired at baseline 1 covering the central 5.7 
degrees to identify at least 7 ROIs where unambiguous cone mosaics are visualized. AOSLO 
images will be acquired at Baseline 2 within 1 month of Baseline 1 and focused on the ROIs. 
Humphrey visual field sensitivity of each eye will be measured at baseline, month 6, month 12, 
month 18, month 24 and month 30.  The total score for the entire retina, averaged across 
replicates, will serve as the unit of analysis for baseline qualifications and efficacy outcomes.  In 
addition, the 5 points of the visual field with the greatest change during treatment will serve as a 
key secondary efficacy variable.  Pupil size will be recorded during HVF assessment. 
6.2 Analysis Populations  
Efficacy and safety analyses will be based on all randomized patients, in accordance with the 
intent-to-treat principle.  Secondary analyses will be performed in the subgroup of patients who 
are in full compliance with protocol, have a favorable surgical outcome and no evidence of 
cataracts at 30 months.   
6.3 Efficacy and Safety Variables 
The primary efficacy variable is the rate of change in cone spacing and cone density from 
baseline to 24 months. Secondary efficacy variables will include: mean change from baseline 
value in Humphrey Visual Field Sensitivity (VFS) from baseline to 24 months, mean change in 
“5-point” VFS from baseline to month 24 (using the 5 retinal points with greatest average 
change), mean change from baseline in Best Corrected Visual Acuity (BCVA) at 12, 18, and 24 
months, and changes in ERG, Optical Coherence Tomography (OCT), clinical grades of 


 
 
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inflammation (anterior chamber cell and vitreous haze grades), and vision-related quality of life 
(NEI-VFQ25) at each visit.   
The mean change in VFS will be calculated using the sum of all points at baseline and each 
follow-up visit.  Likewise, the 5 points with greatest change from baseline will be selected for 
each patient based on the average score per point across replicates at baseline and at month 24; 
the mean of these 5 points will be used to compute the change from baseline in “5-point” VFS.    
Safety variables will include the incidence of adverse events, changes in vital signs, marked 
changes in clinical laboratory data, ECG abnormalities, and findings during physical 
examinations.   
6.4 Sample Size Rationale 
The primary analysis will compare the mean rate of change in cone spacing and cone density 
between CNTF-treated and control eyes over the 24-month study period using pooled linear 
regression.  With a minimum 10 patients the sample size will provide in excess of 80% power to 
detect a difference of 0.084 arcminutes in cone spacing (twice the effect reported per year in 
preliminary studies (Talcott et al, 2010), assuming a within-region standard deviation of 0.11 
(based on preliminary data, and using a paired-subjects t-test as a basis for power calculations).   
6.5  Statistical Analysis Plan 
Prior to the statistical analysis of the data resulting from this study, the Statistical Analysis Plan 
(SAP) will be developed by an appropriate statistician, and approved by both the Principal 
Investigator and the Sponsor.  The SAP will include, at a minimum, a discussion on the analysis 
and presentation of baseline and demographic data, efficacy analysis and safety analysis. 
6.6 Interim Monitoring 
The SMC will review safety summaries on a periodic basis throughout the trial. Data summaries 
will be provided by the study statistician in advance of all SMC meetings. 
7 
Human Participant Protection 
All participants will receive a verbal explanation by the Principal Investigator or qualified 
designee, or as designated by state or local law in terms suited to their comprehension of the 


 
 
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purposes, procedures, and potential risks of the study. The participants must have the ability to 
understand and sign an informed consent form, which must be obtained prior to enrollment. The 
participants will have an opportunity to carefully review the consent and ask questions regarding 
this study prior to signing, and they will be informed that they may withdraw from the study at 
any time without prejudice to themselves. 
The participants’ names will not appear on any of the data forms reported to the sponsor. 
Participants will be identified by a name code and a study registration number.  The information 
collected will remain confidential. 
There are risks associated with the examination procedures required for participants in this study. 
However, these are all standard procedures that are performed as part of a normal eye and 
medical exam. The procedures associated with the implant/explant of the device employ standard 
surgical techniques but the device itself is experimental. Some of the discomforts associated with 
the ocular exam include the following: 
1. Dilating drops or anesthetic drops may sting. They can cause an allergic reaction, or 
if contaminated, can cause an infection, but neither of these problems is very likely to 
occur. 
2. 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. 
3. In rare instances, the cornea may be abraded during measurement of intra-ocular 
pressure or use of a contact lens (used for examination purpose only and not a contact 
lens used to correct one's refractive error). A corneal abrasion of this sort may be 
painful, but it heals quickly with no lasting effects. 
 
There are also risks associated with the surgeries to implant and explant the device and with the 
sham surgery.  In general, the risks of intra-ocular surgery are very small and are described 
below. 


 
 
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8 
Study Risk and Precautions 
8.1 NT-501 Device Implant and Sham Surgery 
The risks associated with surgery to implant the NT-501 device are very small.  They include 
pain, infection, bleeding and mild astigmatism.  These side effects are usually temporary and 
generally resolve within two weeks. In many cases, topical antibiotics and topical steroids can 
treat minor degrees of infection or inflammation. More serious infection or inflammation may 
require further surgery on the eye and likely will include removal of the implant. 
8.2 CNTF and CNTF Producing Cells 
Based on data collected from NT-501 clinical trials, no serum levels of antibodies to NT501 or to 
CNTF have been demonstrated.  In the rare event of a device rupture, surgery may be required to 
remove the implant. The NTC-201 cells are non-tumorigenic in nude mice, so it will not lead to 
tumor formation. 
8.3 Dilation and Anesthetic Drops 
Dilating or anesthetic drops may sting and can trigger an allergic reaction.  An additional risk is a 
sudden increase of pressure (acute glaucoma) in eyes that are already predisposed to develop this 
condition.  In the rare event that the drops are contaminated, an infection could also occur.   
8.4  IOP Examination and ERG 
In rare instances, the cornea may be abraded during measurement of intra-ocular pressure or use 
of a contact lens electrode. An abrasion like this may be painful, but it heals quickly with no 
lasting effects. In the event that a participant experiences a corneal abrasion, ointment should be 
administered and an eye patch or gauze should be placed over the eye.   
9 
Confidentiality and Access to Source Documents and Data 
The Investigators and study staff must maintain the highest degree of confidentiality permitted 
for the information obtained from participants in this clinical study.  Although medical and 
research records should be maintained in the strictest confidence, as part of the quality assurance 
and legal responsibilities of an investigator, the site must permit authorized representatives of the 
sponsor, SMC, and regulatory agencies to examine (and when permitted or required by 
applicable law, to copy) clinical records for the purposes of quality assurance reviews, audits and 


 
 
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evaluation of the study safety and progress. Unless required by the law, no copying of records 
with personally identifying information will be permitted. Only the coded identity associated 
with documents or other participant data may be copied (obscuring any personally identifying 
information) or transmitted to the sponsor. Authorized representatives as noted above are bound 
to maintain the strict confidentiality of medical and research information that may be linked to 
identified individuals.  
10 
Summary of GCP Compliance 
This trial will be conducted in accordance with Good Clinical Practice (GCP) using the guidance 
documents and practices offered by ICH and FDA, and in accordance with the Declarations of 
Helsinki.  This study will also comply with the regulations under 21 CFR Parts 50, 54, 56, and 
312 under an IND application authorized by FDA.  
10.1 Investigator Responsibilities 
A Statement of Investigator (Form FDA-1572) including the names of the all sub-investigators 
and pertinent, key study personnel directly involved in the study will be completed and signed by 
the Principal Investigator;. The general responsibilities of the Investigator as acknowledged on 
the Form FDA-1572 are governed under the regulations in 21 CFR Parts 50, 54, 56, and 312. All 
study Investigators will be required to disclose all of their financial interests in the study test 
therapies or study sponsors per 21 CFR 54 – Financial Disclosure by Clinical Investigators, 
Subsection 4 – Certification and Disclosure Requirement. The investigational test article may be 
administered only in accordance with the approved protocol and under the supervision of the 
Investigator or a sub-investigator listed on this form. The Investigator must maintain accurate 
and complete study records, including records for disposition of the test article, and an accurate 
and complete record of all submissions made to and received from the IRB, including a copy of 
all reports and documents submitted. Adverse experiences that are reported to the FDA as IND 
Safety Reports or as described must be submitted promptly to the local IRB. 
Progress reports must be submitted by the Investigator to the IRB at least once per year and to 
the study sponsor.  The IRB must be promptly notified of completion or termination of the study.  


 
 
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The curriculum vitae (CV) or a résumé for each Investigator, sub-investigator, and key study 
personnel must also be supplied if named on the FDA Form 1572. This form and related CVs 
must be supplied to the sponsor prior to initiating the trial at each site. When necessary due to 
personnel changes, updated versions of the Form FDA-1572 must be forwarded to the sponsor 
and copies of all versions maintained in study records at each site. Any CV or résumé collected 
at the beginning of a study should be current.  These documents should be updated in the event 
that substantial changes or additions are warranted (e.g., change of position or affiliation, 
certifications or licensure, or significant new publications relevant to the study protocol). 
Institutional Review Board 
The UCSF Institutional Review Board will operate in accordance with the regulations under 21 
CFR Part 56 and authorized by the institution to review and approve materials for this trial. A list 
of IRB voting members, their titles or occupations, and their institutional affiliations, as well as a 
copy of the Assurance of Compliance, must be kept in the regulatory binder and made available 
by the institution for inspection and copying by authorized study monitors, auditors, and 
regulatory officials. 
Review of Protocol, Consent and Recruitment Materials 
The clinical protocol, consent materials and any participant recruitment materials specific to this 
study must be reviewed and approved by the IRB in accordance with local procedures and 
21 CFR Parts 50, 56, and 312. Any amendments to the protocol or consent materials, or any 
revised materials used for the recruitment of participants in this study must also be approved in 
advance of their use by the local IRB/IEC. Before initiation of the study, the Investigator will 
develop a consent form in compliance with 21 CFR Part 50 for this trial that must be submitted 
for review and approved by the local IRB. 
Written approval of the protocol and the consent form(s) must be obtained from the IRB/IEC and 
transmitted to the sponsor prior to enrollment of participants. Written approvals must specify 
which components (i.e., protocol, consent and/or recruitment materials) are being approved, and 
explicitly indicate the study title (or short title) and the protocol code number and date (and/or 
version number, if used) on the cover page of the protocol or any amendments. Written 
approvals should explicitly state the duration of the approval, or preferably the expiration date of 


 
 
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the approval, and the date when application for continuing approval is required. In accordance 
with 21 CFR Part 56, a written notification by an IRB that modifications are required to secure 
IRB approval for the protocol, consents or recruitment materials is not considered adequate 
documentation of final approval, even if the modifications have been made. In such a case, it is 
required that the site Principal Investigator receives written final approval from the IRB 
acknowledging the completion of the required modifications. At least once per year, the local 
IRB must review and give written approval to continue the study. 
10.2 Data Handling and Record Keeping 
The Principal Investigator is responsible for maintaining adequate clinical records documenting 
the medical history, condition, and test results for each study participant throughout the study. 
Source documentation may consist of written and/or electronic records and supporting data 
maintained by the Investigator and/or the institution. The preliminary case histories or medical 
records for each participant shall document that informed consent was obtained prior to 
participation in the study. 
Case Report Forms:  
Clinical data will be entered onto Case Report Forms (CRFs).  Data on CRFs must correspond to 
and be supported by source documentation maintained at the investigational site. All study forms 
and records must carry only coded identifiers such that personally identifying information is not 
transmitted. 
10.3 Protocol Amendments 
The Investigator will not modify the protocol or alter the research activity without first obtaining 
permission from the local IRB and the sponsor. Protocol modifications that have an impact on 
participant safety, the scientific soundness or validity of the investigation, or the rights and 
welfare of study participants must be submitted in advance for approval by the SMC and 
approved by the local IRB and sponsor prior to implementation. The sponsor will forward 
protocol amendments and related documentation to all the participating sites, the SMC and the 
FDA as appropriate. 


 
 
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10.4 Monitoring Plan 
The study sponsor, PI and UCSF will follow standard operating procedures for monitoring this 
study in accordance with GCP recommendations and FDA regulatory requirements.  A 
monitoring plan will be developed prior to enrollment of the first study subject.  This monitoring 
plan will describe, at a minimum, each of the items mentioned below. 
 
Planned Site Visits: 
Participating sites will have at a minimum a study site initiation visit, one or more annual routine 
monitoring visits and a study closeout visit conducted by experienced monitoring personnel from 
Neurotech, Inc. Additional monitoring visits may be performed for cause or if the volume of 
information to be reviewed cannot be easily completed in a single visit. Study visits will 
normally be scheduled well in advance so that necessary site staff and appropriate records will be 
available during the monitoring visit. 
Items Reviewed at Site Visits: 
Each monitoring visit will utilize a standardized checklist of elements to be reviewed at the site, 
tailored to the specific requirements of this study. Site monitoring visits will routinely review the 
participating site staff roster; study administrative and financial documents; required regulatory 
documentation; status of IRB/IEC approvals; changes or actions taken since any previous visit; 
participant recruitment status, screening, enrollment, and follow-up visit records; documentation 
of informed consent for each participant; review of adverse events; test article storage conditions, 
inventory, expiration dates and accountability; biological specimens or photographs awaiting 
transport or assessments; outstanding data clarifications and a review of selected data elements 
against source documentation. Site visits will follow standard procedures and a report will be 
prepared for study records. 
Regulatory Binder: 
Each site will maintain a confidential regulatory binder that contains site-specific and study-wide 
documentation. The Principal Investigator is required to maintain this documentation and make it 
available for review by authorized study monitors, auditors and regulatory authorities.  Both 
current and outdated study documents must be maintained. The regulatory binder will contain all 
relevant information required for this trial in compliance with US regulations. 


 
 
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Clinical Data: 
Selected clinical data will be reviewed at monitoring visits according to the Monitoring Plan that 
will be developed and finalized prior to the enrollment of the first study subject.  During a 
monitoring visit, data discrepancies noted by the monitor will be recorded and the list of 
discrepancies reported to the Principal Investigator and/or Coordinator. An audit of as much as 
100% of study data elements may be performed for one or more participant records. Depending 
on the observed data discrepancy rate (number of discrepancies / total number of data elements 
reviewed), additional clinical data may be scrutinized at a more or less rigorous level than the 
initial plan, either during the same visit or at subsequent monitoring visits. Higher discrepancy 
rates will cause an increased level of review. All observed discrepancies will be corrected if 
possible during the monitoring visit. Any outstanding discrepancies may be resolved later and 
reported in accordance with standard procedures.  
Monitoring Visit Report: 
The monitor will prepare written reports for each monitoring visit. Reports will summarize the 
site administrative and regulatory status, detail data discrepancies observed and corrected, and 
list outstanding deficiencies that still require correction. 
10.5 Retention of Records 
The Principal Investigator is responsible for maintaining intact study records for a period of at 
least 2 years following the date of approval of a marketing application for the test article with the 
indication for which this study is conducted. If an application is not filed or approved for that 
indication, the Principal Investigator must maintain these records for at least 2 years after the 
investigation is discontinued and FDA is notified. Local policies for records retention may 
require longer periods, or the sponsor may request a longer retention period. When retention of 
trial-related records is no longer required, the study sponsor should inform the 
Investigator/institution in writing. 
11 
Certifications and Training Requirements 
11.1 Certification for AOSLO Image Acquisition and Analysis 
Quality control of AOSLO study data will be ensured with the following requirements. The exact 
field size and any scanning distortions will be carefully measured prior to each AOSLO imaging 


 
 
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session by recording a video of a model eye with a calibration scale in place of the retina. For 
each patient, trial lenses may be necessary to remove high refractive errors prior to AO 
correction. The exact location of the trial lenses with respect to the eye will be recorded for each 
session and additional corrections to the image scale will be made. After correction, scaling or 
field distortion errors are estimated to be < 1% across the image.   
Metrics have been developed for quantitative cone assessment and all research assistants 
involved in the imaging and analyses have been trained and certified by the PI and/or appropriate 
delegate. The PI or delegate will evaluate the quality and selection of the ROIs at baseline visits 
1 and 2 and will determine whether the subject is eligible for enrollment and randomization. All 
AOSLO images will be de-identified and coded. Trained readers will be fully masked to subject 
identifiers and treatment assignment. Three independent readers will analyze the coded AOSLO 
montage and obtain quantitative measures of cone parameters in each ROI according to the 
protocol described below:  
Cone Identification: For cone density and spacing analyses, the cones are identified by hand. We 
have developed automated tools to aid in this process but final decisions on the cone locations 
are made manually. To confidently identify cones, images of cones must meet the following 
criteria: 
1.  Cones must form a close-packed array of distinct bright spots in the image; 
2.  An intact external limiting membrane and inner segment/outer segment junction must be 
present on SD-OCT images at that location. 
Cone Spacing: To measure cone spacing, not all cones must be visualized, but a sufficient 
number (> 30 cones) of neighboring cones must be identified within a ROI to yield an average 
cone spacing measurement. Cone spacing is a more conservative measure than cone density, and 
we anticipate that cone spacing at each ROI will be obtained at each visit.  
Cone Density: To track cone density, ROIs in which all cones are visualized are required. We 
will require ROIs with a region of > 50 cones in which every cone can be unambiguously 
identified for use in cone density measurements. Cone reflectivity is known to change over time, 
so high-resolution, high signal-to-noise images are required to see all cones, including those that 


 
 
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are weakly reflecting. Normal variation in image quality may result in fewer ROIs being used to 
track for cone density at all time points than can be used for cone spacing measures.  
To ensure the cone spacing and density measures are made in an unbiased manner, each ROI will 
be evaluated by 3 independent graders masked to treatment assignment.  
11.2 Certification for Humphrey Visual Field Testing 
Specific certification in techniques for Humphrey Visual Field is required for this study. 
Certification involves a practicum and testing in the competent use of the equipment. Each 
person (e.g., physician, optometry professional, ophthalmic technician and/or nurse) that 
performs this testing on study participants must be certified.  Training and certification for the 
Humphrey Visual Field Testing will be provided prior to study initiation.   
11.3 Professional Licensure 
All study physicians must provide evidence of current medical licensure applicable to the study 
location(s) if they are practicing medicine, diagnosing and/or treating participants.  This includes 
physicians who perform the NT-501 implant / sham / explant surgeries. A physician who is a site 
Principal Investigator must also provide satisfactory evidence of ophthalmology training before 
study initiation. 


 
 
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12 
References 
 
Aebischer, P. et al. Intrathecal delivery of CNTF using encapsulated genetically modified 
xenogeneic cells in amyotrophic lateral sclerosis patients [published erratum appears in Nat 
Med 1996 Sep;2(9):1041]. Nat Med 1996;2: 696-9. 
 
Aebischer, P. & Kato, A.C. Treatment of amyotrophic lateral sclerosis using a gene therapy 
approach. Eur Neurol 1995;35: 65-8. 
 
Bok, D. 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: 
719-35. 
 
Bush, R.A., Lei, B., Tao, W., Raz, D., Chan, C-C., Cox, T.A., Santos-Muffley, M., and Sieving, 
P.A. Encapsulated cell-based intraocular delivery of ciliary neurotrophic factor (CNTF) in 
normal rabbit: dose dependent effects on ERG and retinal histology. IOVS. 2004. 45(7):2420-
30. 
 
Cayouette, M., Behn, D., Sendtner, M., Lachapelle, P. & Gravel, C. Intraocular gene transfer of 
ciliary neurotrophic factor prevents death and increases responsiveness of rod photoreceptors 
in the retinal degeneration slow mouse. J Neurosci 1998;18: 9282-93. 
 
Cayouette, M. & Gravel, C. Adenovirus-mediated gene transfer of ciliary neurotrophic factor can 
prevent photoreceptor degeneration in the retinal degeneration (rd) mouse. Hum Gene Ther 
1997;8: 423-30. 
 
Cedarbaum, J. M. (1995a). The pharmacokinetics of subcutaneously administered recombinant 
human ciliary neurotrophic factor (rHCNTF) in patients with amyotrophic lateral sclerosis: 
relation to parameters of the acute-phase response.  The ALS CNTF Treatment Study 
(ACTS) Phase I-II Study Group. Clin Neuropharmacol 18, 500-514. 
 
Cedarbaum, J. M. (1995b). A phase I study of recombinant human ciliary neurotrophic factor 
(rHCNTF) in patients with amyotrophic lateral sclerosis.  The ALS CNTF Treatment Study 
(ACTS) Phase I-II Study Group. Clin Neuropharmacol 18, 515-532. 
 
Choi, S.S., Doble, N., Hardy, J.L., et al. In vivo imaging of the photoreceptor mosaic in retinal 
dystrophies and correlations with visual function. Invest Ophthalmol Vis Sci 2006;47:2080-
2092. 
 
Chong, N.H. et al. Repeated injections of a ciliary neurotrophic factor analogue leading to long 
term photoreceptor survival in hereditary retinal degeneration. Invest Ophthalmol Vis Sci 
1999;40: 1298-305. 
 
Crossland, M.D., et al. Invest Ophthalmol Vis Sci 2010 ; 51 : ARVO E-Abstract 3640. 
 


 
 
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de Almeida, L.P., Zala, D., Aebischer, P. & Deglon, N. Neuroprotective effect of a CNTF-
expressing lentiviral vector in the quinolinic acid rat model of Huntington's disease. 
Neurobiol Dis 2001;8: 433-46. 
 
Duncan, J.L., Zhang, Y., Gandhi, J., et al. High-resolution imaging with adaptive optics in 
patients with inherited retinal degeneration. Invest Ophthalmol Vis Sci 2007;48:3283-3291. 
 
Emerich, D.F. et al. Implants of encapsulated human CNTF-producing fibroblasts prevent 
behavioral deficits and striatal degeneration in a rodent model of Huntington's disease. J 
Neurosci 1996;16: 5168-81. 
 
Emerich, D.F. et al. Protective effect of encapsulated cells producing neurotrophic factor CNTF 
in a monkey model of Huntington's disease. Nature 1997;386: 395-9. 
 
Fishman, G.A., Bozbeyoglu, S., Massof, R.W., Kimberling, W. Natural course of visual field 
loss in patients with Type 2 Usher syndrome. Retina 2007;27:601-608. 
 
Grover, S., Fishman, G.A., Anderson, R.J., Alexander, K.R., Derlacki, D.J. Rate of visual field 
loss in retinitis pigmentosa. Ophthalmology 1997;104:460-465. 
 
Iannaccone, A., Kritchevsky, S.B., Ciccarelli, M.L., et al. Kinetics of visual field loss in Usher 
syndrome Type II. Invest Ophthalmol Vis Sci 2004;45:784-792. 
 
Investigational New Drug Application BB-IND-10931; NT-501; Allogeneic Retinal Pigment 
Epithelial Cells Transfected with DNA Plasmid Vector (pNUT-IgSP-hCNTF), Expressing 
Ciliary Neurotrophic Factor (CNTF), Encapsulated in a Hollow Fiber Membrane, Original 
Submission (000). 
 
LaVail, M.M. et al. Protection of mouse photoreceptors by survival factors in retinal 
degenerations. Invest Ophthalmol Vis Sci 1998;39: 592-602. 
 
LaVail, M.M. et al. Multiple growth factors, cytokines, and neurotrophins rescue photoreceptors 
from the damaging effects of constant light. Proc Natl Acad Sci U S A 1992;89: 11249-53. 
 
Liang, F.Q. et al. AAV-mediated delivery of ciliary neurotrophic factor prolongs photoreceptor 
survival in the rhodopsin knockout mouse. Mol Ther 2001;3: 241-8. 
 
Liang, F.Q. et al. Long-term protection of retinal structure but not function using RAAV.CNTF 
in animal models of retinitis pigmentosa. Mol Ther 2001;4: 461-72. 
 
Liang, J., Williams, D.R., Miller, D.T. Supernormal vision and high-resolution retinal imaging 
through adaptive optics. J Opt Soc Am A Opt Image Sci Vis 1997;14:2884-2892. 
 
 
Lindsay, R.M. Neurotrophic growth factors and neurodegenerative diseases: therapeutic potential 
of the neurotrophins and ciliary neurotrophic factor. Neurobiol Aging 1994;15: 249-51. 
 


 
 
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Marmor, M.F., Fulton, A.B., Holder, G.E., Miyake, Y., Brigell, M., Bach, M. ISCEV Standard 
for full-field clinical electroretinography (2008 update). Doc Ophthalmol 2009;118:69-77. 
Mittoux, V. et al. Restoration of cognitive and motor functions by ciliary neurotrophic factor in a 
primate model of Huntington's disease. Hum Gene Ther 2000;11: 1177-87. 
 
Moke, P.S., Turpin, A.H., Beck, R.W., et al.  A computerized method of visual acuity testing: 
adaptation of the amblyopia treatment study visual acuity testing protocol.  Am J Ophthalmol  
2001; 132:903-14.  
 
Penn, R.D., Kroin, J.S., York, M.M. & Cedarbaum, J.M. Intrathecal ciliary neurotrophic factor 
delivery for treatment of amyotrophic lateral sclerosis (phase I trial). Neurosurgery 1997;40: 
94-9; discussion 99-100. 
 
Peterson, W.M., Wang, Q., Tzekova, R. & Wiegand, S.J. Ciliary neurotrophic factor and stress 
stimuli activate the Jak-STAT pathway in retinal neurons and glia. J Neurosci 2000;20: 
4081-90. 
 
Regulier, E., Pereira de Almeida, L., Sommer, B., Aebischer, P. & Deglon, N. Dose-dependent 
neuroprotective effect of ciliary neurotrophic factor delivered via tetracycline-regulated 
lentiviral vectors in the quinolinic acid rat model of Huntington's disease. Hum Gene Ther 
2002;13: 1981-90. 
 
Roorda, A., Romero-Borja, F., Donnelly III, W., Queener, H., Hebert, T., Campbell, M. 
Adaptive optics scanning laser ophthalmoscopy. Opt Express 2002;10:405-412. 
 
Rossi, E.A., Roorda, A. The relationship between visual resolution and cone spacing in the 
human fovea. Nat Neurosci 2010;13:156-157. 
 
Saggio, I., Gloaguen, I., Poiana, G. & Laufer, R. CNTF variants with increased biological 
potency and receptor selectivity define a functional site of receptor interaction. Embo J 
1995;14: 3045-54. 
 
Sagot, Y. et al. Polymer encapsulated cell lines genetically engineered to release ciliary 
neurotrophic factor can slow down progressive motor neuronopathy in the mouse. Eur J 
Neurosci 1995;7: 1313-22. 
 
Sieving, P.A., Caruso, R.C., Tao, W., Coleman, H.R., Thompson, D.J.S., Fullmer, K.R., Bush, 
R.A.   CNTF for Human Retinal Degeneration: Phase I Trial of Ciliary Neurotrophic Factor 
Delivered by Encapsulated Cell Intraocular Implants.  Proc Natl Acad Sci USA 2006;103:  
3896-3901 . 
 
Sieving, P.A., “Chapter 108: Retinitis Pigmentosa and Related Disorders.” Eds: Yanoff M, 
Duker JS. Ophthalmology, 2: Elsevier Science, 2003:1652.  
 
Talcott, K.E., Ratnam, K., Sundquist, S.M., Lucero, A.S., Lujan, B., Tao, W., Porco, T.C., 
Roorda, A., Duncan, J.L. Longitudinal study of cone photoreceptors during retinal 


 
 
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degeneration and in response to ciliary neurotrophic factor treatment. [published online ahead 
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Tao, W. et al. Encapsulated cell-based delivery of CNTF reduces photoreceptor degeneration in 
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13 
Appendix:  NT-501 Implant Accessories: Surgical Tool Information 
 
1.0 NT-501, 2.0 mm Sapphire Spearpoint Blade Tool 
 
The NT-501 2.0 mm Sapphire Spearpoint Blade Tool is an ophthalmic knife used to create the 
incision for implantation of the NT-501 Implant. The knife is equipped with a spring-loaded 
retractable 2.0 mm Sapphire Spearpoint Blade on the distal end. The NT-501, 2.0 mm Sapphire 
Spearpoint Blade Tool is a Class I ophthalmic device per regulation 21 CFR 886.4350.  
 
Materials  
The handle of the NT-501, 2.0 mm Sapphire Spearpoint Blade is made of titanium. The 2.0 mm 
Sapphire blade is made of 9 Mohs hardness Sapphire. Both blade and handle are manufactured 
by Shaanxi Xingmao Industry Co., Ltd., an FDA registered medical device manufacturer.  
 
Description of Use  
The NT-501, 2.0 mm Sapphire Spearpoint Blade Tool is intended for use in ophthalmic surgical 
applications by trained physicians and personnel only. The knife is packaged in a sterilization 
container with the blade in the retracted position. The knife is to be cleaned and sterilized prior to 
use in accordance with NT-501 Surgical Instrument Handling Instructions provided to each 
investigator. Immediately prior to use, trained personnel should expose the blade from the handle 
by releasing the spring-loading mechanism on proximal end of the handle. The blade should be 
retracted immediately after use.  
“Prior to each use, the blade should be thoroughly inspected for damage, sharpness and 
cleanliness. A blade showing signs of overuse, wear, damage or soil that cannot be removed with 
cleaning should be replaced.” 
 
Classifying Regulation and Product Code:  
Regulation: 21 CFR 886.4350  
FDA Classification Name: Knife, Ophthalmic  
Product Code: HNN  
 
Device Registration and Listing:  
Device distributed by Robbins Instruments, Inc.  
Registration number: 2221941  
Neurotech Assigned Part Number (8.ZTC-186 Sapphire Spearpoint Blade Tool): 0346 
Robbins Instruments Assigned Part Number: 8.ZTC-186 
Device Manufactured by Shaanxi Xingmao Industry Co., Ltd.  
Registration Number: 3004027120 
 
Packaging  
The NT-501, 2.0 mm Sapphire Spearpoint Blade Tool is packaged within a diamond knife plastic 
sterilization tray, 2 1/2" W x 6" L x 3/4" H, distributed by Ambler Surgical. The sterilization tray 
(RM 0334) is an off-the-shelf part that is etched with the Neurotech logo prior to use.  
 
Packaging Registration and Listing Information:  
Sterilization Tray Distributed by Ambler Surgical, LLC  
Registration Number: 3005528784 


 
 
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2.0 NT-501 1.55mm Incision Dilator  
 
The NT-501 1.55 mm Incision Dilator (RM 0347) is a manual ophthalmic instrument for use in 
maintaining a properly sized incision site for implantation of the NT-501 Implant. The dilator is 
a single instrument consisting of a 5.0mm long dulled point dilator of specified width (1.55 mm) 
connected via a widened, rounded chamfer to a proximal handle region. The NT-501 1.55 mm 
Incision Dilator is a Class I exempt investigational device.  
 
Materials  
The NT-501 1.55 mm Incision Dilator is made of ASTM F136 standard 6Al4V Titanium, 
received from AllVAC (Monroe, NC) per RM 0347 Material Certificate of Test. 
 
Description of Use  
NT-501 1.55 mm Incision Dilator is intended for use in ophthalmic surgical applications by 
trained physicians and personnel only. After an incision is made for implantation of the NT-501 
Investigational Device using the NT-501 2.0 mm Sapphire Spearpoint Blade Tool, the 1.55 mm 
Incision Dilator is inserted within the incision site to dilate the scleral wound to adequately 
accommodate the NT-501 Investigational Device. Dilators should be cleaned and sterilized prior 
to use in accordance with NT-501 Surgical Instrument Handling Instructions, within the Manual 
of Procedures provided to each investigator.  
“Prior to each use, dilator plugs should be thoroughly inspected for damage, surface roughness 
and cleanliness. If a dilator shows signs of wear, damage, surface roughness or soils that have 
not been removed with cleaning, it should not be used within the surgical field.” 
 
Classifying Regulation  
Regulation: 21 CFR 886.4350  
FDA Classification Name: Manual ophthalmic surgical instrument  
 
Packaging  
The NT-501 1.55 mm Incision Dilator is packaged within a diamond knife plastic sterilization 
tray, 2 1/2" W x 6" L x 3/4" H, distributed by Ambler Surgical. The sterilization tray (RM 0334) 
is an off-the-shelf part that is etched with the Neurotech logo prior to use.   
 
Packaging Registration and Listing Information:  
Sterilization Tray Distributed by Ambler Surgical, LLC  
Registration Number: 3005528784 
 
 
3.0 NT-501 Surgical Kit Assembly 
Following release from quality management system, one NT-501, 2.0 mm Sapphire Spearpoint 
Blade Tool and one NT-501 1.55 mm Incision Dilator are fitted into one sterilization tray with 
cover (RM0334).   The sterilization tray including one NT-501, 2.0 mm Sapphire Spearpoint 
Blade Tool and one NT-501 1.55 mm Incision Dilator  is designated NT-501 Surgical Kit 
Assembly (RM 0343). 

SAP_001.pdf: 
 
 
Photoreceptor Structure in a Phase 2 Study 
of Encapsulated Human NTC-201 Cell 
Implants Releasing Ciliary Neurotrophic 
Factor (CNTF) for Participants with Retinitis 
Pigmentosa Using Rates of Change in Cone 
Spacing and Density as the Primary Outcome 
 
Statistical Analysis Plan 
Confidential 
Version 2.0 dated 20APR2022 
 
Prepared by:  
Travis C. Porco, PhD, MPH 
Division of Preventive Medicine and Public Health 
Department of Epidemiology and Biostatistics 
490 Illinois St., Floor 2, Box 0944 
San Francisco, CA 94107 
University of California, San Francisco 
San Francisco, California 94143-0412 
Telephone: (415) 476-4101 
Email: travis.porco@ucsf.edu 


 
 
1  Introduction 
This document (Statistical Analysis Plan, SAP) describes the planned analysis and reporting for 
the clinical trial entitled, “Photoreceptor Structure in a Phase 2 Study of Encapsulated Human 
NTC-201 Cell Implants Releasing Ciliary Neurotrophic Factor (CNTF) for Participants with 
Retinitis Pigmentosa Using Rates of Change in Cone Spacing and Density as the Primary 
Outcome”, University of California, San Francisco (J. Duncan, PI). It includes specifications for 
the statistical analyses and tables to be prepared for the final Clinical Study Report.  
The proposed trial is a Phase II clinical trial to estimate the effects of an implant which 
delivers sustained release CNTF (ciliary neurotrophic factor) to the retina (Neurotech USA) in 
treating retinitis pigmentosa and Usher Syndrome Types 2 and 3. The trial will also collect safety 
data. 
The content of this Statistical Analysis Plan (see McCulloch, 2007) meets the requirements 
stated by the US Food and Drug Administration (Department of Health and Human Services, 
Food and Drug Administration, 1998) and conforms to the American Statistical Association’s 
Ethical Guidelines (American Statistical Association, 1999).  
The following documents were reviewed in preparation of this Statistical Analysis Plan:  
• Proposal for “Photoreceptor Structure in a Phase 2 Study of Encapsulated Human NTC-
201 Cell Implants Releasing Ciliary Neurotrophic Factor (CNTF) for Participants with 
Retinitis Pigmentosa Using Rates of Change in Cone Spacing and Density as the Primary 
Outcome” 
• ICH Guidance on Statistical Principles for Clinical Trials (Department of Health and 
Human Services, Food and Drug Administration, 1998)   
The planned analyses described in this Statistical Analysis Plan will be included in future 
manuscripts. Note, however, that exploratory analyses not necessarily identified in this Statistical 
Analysis Plan may be performed to support the analysis. All post-hoc or unplanned analyses which 
have not been delineated in this Statistical Analysis Plan will be clearly documented as such in the 
final Clinical Study Report, manuscripts, or any other document or submission. 


 
 
2  Investigational Plan 
2.1  Study Design 
The trial, Photoreceptor Structure in a Phase 2 Study of Encapsulated Human NTC-201 Cell 
Implants Releasing Ciliary Neurotrophic Factor (CNTF) for Participants with Retinitis 
Pigmentosa Using Rates of Change in Cone Spacing and Density as the Primary Outcome 
(“CNTF Implant Trial”), is a Phase 2 clinical trial to determine whether treatment with a 
sustained-release CNTF implant (NT-501, Neurotech, USA) is safe and effective in reducing the 
rate of cone photoreceptor loss in eyes with RP and Usher syndrome types 2 and 3.  The Specific 
Aims and rationale are indicated in the clinical trial Proposal. 
2.2  Study Population 
The study population is described in detail in Duncan (2010). Full details of the exclusion criteria 
are provided in that document. 
2.3  Study Objectives and Endpoints 
2.3.1  Primary Objective 
The objectives of the study are to assess safety and efficacy of the sustained-release CNTF 
implant, based on cone spacing and density measures, supplemented with additional 
measurements. 
The primary outcome measure for hypothesis testing is cone photoreceptor spacing, 
measured using AOSLO imaging in preselected regions of interest (ROI).  Specifically, regions 
of interest are identified at baseline prior to randomization and followed longitudinally.  
Untreated, progression of disease exhibits continued longitudinal increase in cone spacing.  Our 
objective is to compare the change in cone spacing in eyes treated with the CNTF implant with 
the change in cone spacing in contralateral eyes receiving sham surgery. 
     An additional primary outcome measure is cone spacing.  Cone spacing increases 
progressively in untreated patients, and we wish to compare changes in cone density over time in 
eyes receiving CNTF implant with contralateral sham-treated eyes. 
     The study period will be 36 months. 
     Procedures for evaluating cone density and spacing using raters trained in grading images will 
be discussed below. 
Additionally, we propose to evaluate the incidence of adverse events following application of 
the investigational product in all subjects. 
The primary hypothesis test will be two-sided.  If cone photoreceptor spacing increases 
(indicating a greater loss or thinning of cone cells) more in the treatment eyes than the control eyes, 
then this will provide evidence against the safety of the implant.  However, safety will also be 
assessed using other laboratory measurements. (see §7.4 for further discussion).  Similarly, if cone 
photoreceptor spacing decreases less in the treatment eyes than the control eyes, this will provide 
evidence of efficacy.   


 
 
2.3.2  Secondary Objectives 
Secondary outcome measures will compare rates of change in standardized measures of visual 
function between CNTF- and sham-treated eyes. Secondary outcomes will include functional and 
structural assessments: 
• 
Mean and median change in best spectacle-corrected visual acuity (BCVA) using the ETDRS 
protocol,  
• 
Changes in visual field sensitivity and foveal sensitivity in decibels (dB) using automated 
static perimetry using the Humphrey visual field 10-2 protocol and rod and cone-mediated 
fundus-guided microperimetry using a modified Nidek MP1 (see attached protocol, Appendix 
5),  
• 
Changes in ONL (outer nuclear layer) and OS+ (outer segment) layer thickness, and 
• Changes in full-field ERG (electroretinogram) scotopic and photopic standard a- and b-wave 
amplitudes and timing from baseline to 36 months.  
All parameters except full-field ERG will be measured every six months.  
3  Study Design 
3.1  Sample Size Planning 
3.1.1  Alpha level 
The study hypotheses are listed as bidirectional effects; we will never conduct one sided tests. All 
hypothesis tests proposed for the CNTF Implant Trial are two-sided. 
Results will be judged significant using a two-tailed  of 0.05.  
3.1.2  Power 
We plan recruitment of sufficient subjects for an 80% power to detect an effect size of 0.084 
arcminutes over two years.  
3.1.3  Statistical Properties of the Primary Outcome 
Based on our preliminary study, we expect the standard deviation in the difference between the 
regression slopes to be approximately 0.11 arcminutes. 
3.1.4  Withdrawals and expected loss to follow-up 
We conservatively allow for a 15% loss to follow-up based on prior studies. 
3.1.5  Sample size calculation methodology 
We used a simplified version of the analysis we plan in order to estimate the power for the more 
complex analysis.  This reduces the analysis to a paired T-test.  More specifically, we determined 
the rate of change over time of the cone spacing in our pilot patients, and computed a pooled 
standard deviation over all these regions (in untreated persons) from which we derived an 
expected standard deviation of the difference in the total change in cone spacing after two years 
of approximately 0.11.  Using the standard formula for the sample size of a one-sample T-test 


 
 
(e.g. Chow et al, 2007, formula 3.1.2), we find we would need a total of 17 individuals per group, 
or 20 adjusting for loss to follow-up.   
3.2  Secondary outcomes 
The sample size was determined with respect to the single prespecified primary outcome variable 
for hypothesis testing, cone spacing.  
     For the second primary outcome variable, cone density, we calculate the effect size for which 
our power is 80% as follows (although we will perform hypothesis tests here, this analysis is strictly 
secondary).  We fitted a linear regression (ordinary least squares) to cone density over time in each 
region of interest in a small subset of patients (Talcott et al, 2011); we estimated the standard 
deviation of the regression slopes, and used this to estimate the standard deviation in the difference 
in the change at 2 years.  Using this in the sample size formula for a one-sample T-test (Chow et 
al, 2007) yields an effect size of approximately 5% of the baseline value of cone density over two 
years.  Expressed differently, if the true effect of the implant is to result in 5% more cones relative 
to baseline than the control eyes, we have 80% power to detect this effect.  Assuming our standard 
deviation estimate is too optimistic, with the true value being 30% higher, we have power to detect 
a difference of 7% in cone density relative to baseline at 2 years. 
     For visual acuity, we have 80% power to detect a standardized effect size of 1.02 (using the 
standard formula for a one-sample T-test cited above), considering the outcome to be the change 
in the difference in acuity between the treatment and control (sham-implant) eyes.  Using a standard 
deviation for the signed visual acuity difference between two eyes at baseline of 0.05 logMAR 
(e.g. Brown and Yap, 1995) and assuming independence of changes, we would expect greater than 
80% power to detect an effect size of 0.1 logMAR in the change in the difference between two 
eyes.  We do not have adequate information at this time regarding the standard deviation of the 
visual acuity difference between the eyes in our patient population or of the expected correlation 
between two time points assuming no treatment effect.   
     For changes in visual field sensitivity, foveal sensitivity, outer nuclear layer, outer segment 
thickness, and changes in ERG measurements, we will be able to obtain variance information 
which will be useful in planning future studies.  We will report confidence intervals for estimated 
effects. Note that the trial will also provide information needed to plan further studies of retinal 
function and cone spacing/density. 
     Covariates, including age, gender, and diagnosis, will be used in selected exploratory or 
supplemental analyses. 
3.3  Randomization 
Each patient will receive a unique identifier.  Each patient will be randomized to receive the 
implant in the right or left eye (with the sham in the other eye). T. Porco will generate the 
randomization list using the statistical package R, creating an Excel® spreadsheet in which each 
unique identifier is listed on a row next to a treatment assignment.  The name of the file will clearly 
identify it as a randomization list.  TP will maintain a hard copy of the randomization list in a 
locked cabinet in a locked room, and will communicate the randomization lists to the Study 
Surgeon in person (or using secure encrypted email if absolutely necessary).  To ensure against 


 
 
information loss due to unforeseen circumstances, a backup copy of the randomization list will be 
maintained by the Safety Monitoring Committee Chair in a locked cabinet stored away from the 
main UCSF site, and also a backup copy of the randomization list will be maintained on an 
encrypted partition on the REDCap server; these copies would not be accessible to the PI or to any 
study personnel.  Our procedures are designed to maintain absolute confidentiality of the list while 
ensuring integrity. 
The randomization protocol is as follows. First, a seed integer for the random number generator 
will be chosen prior to any collection of data; the choice of the seed is arbitrary, but it determines 
the pseudorandom sequence generated by the algorithm, and it will be recorded in a sealed 
envelope and kept confidential.  The algorithm will be the default algorithm used by the R statistics 
package.  Ten assignments for the right eye and ten for the left eye will then be produced by 
randomly shuffling a sequence of ten “R” and ten “L” characters using the sample command 
from R.  These assignments will be presented in a spreadsheet to the surgeon using a hand-
delivered hard copy.  Each line of the spreadsheet will contain a randomization code for each 
patient and an assignment 
3.4  Masking 
Masking procedures and procedures designed to maintain masking are discussed in Appendix 2 
and the grant Proposal. 
4  Analysis Populations 
4.1  Summary 
The following analysis populations are planned for this study:  
• The screening population, which is to include all subjects who provide (a) baseline 
screening (including any demographic, visual acuity, or photographic data), and (b) informed 
consent.  
• The safety population, which is to include all patients who receive the investigational 
intervention.  
• The intent-to-treat efficacy population, which is to include all patients who are 
randomized. This is the primary population for the efficacy analyses.  
• The per-protocol efficacy population, which is to include all patients in the intent-to-treat 
efficacy population, excluding patients with major protocol deviations.  
4.2  Major protocol deviations 
The incidence of deviations from the inclusion and exclusion criteria will be summarized using 
counts and percentages, and the treatment groups compared for the overall frequency of deviations 
using a 2N Fisher’s exact test. Similar deviations will be grouped into general categories of 
deviations for a more condensed summary. A listing of deviations by participant will also be 
produced. Any major deviations from the protocol will be listed and/or summarized, including, but 
not limited to, participants who:  


 
 
• never received the intervention  
• were subsequently found to be ineligible for the study  
• never returned for a follow-up visit  
• have follow-up visits outside any prescribed visit window  
The number and percentage of randomized subjects actually receiving study medication will be 
summarized. The treatment groups will be analyzed for the proportion of and reason for study 
discontinuation using the chi-square test. A summary of volunteer status at the end of the study 
period will also be generated with categories including lost to follow-up.  
5  Data Collection and Quality Assurance 
Data collection and quality assurance is described in Appendix 2 and the grant Proposal. 
6  Human Subjects 
6.1  Summary of final dispositions 
All subjects who provide informed consent will be accounted for in this study. The frequency of 
subjects in each population will be presented. We will also present the frequency of subjects in 
each subgroup, the frequency of withdrawal and loss to follow-up, and any major protocol 
violations. 
6.2  Safety Monitoring Committee 
6.2.1  Scope 
A Safety Monitoring Committee (SMC) will be empaneled. The committee will meet by 
teleconference at study initiation and will convene biannual teleconferences for progress reports. 
Ad hoc meetings as needed may also be convened. All study protocols will be subject to review 
and approval by Institutional Review Boards at the UCSF and by the SMC.   
No planned interim efficacy analysis is planned.  
6.2.2  Meetings 
All teleconference meetings of the SMC and study personnel will consist of (a) “open” sessions, 
which may be attended as needed by masked study personnel, and (b) “closed” sessions, which 
may only be attended by unmasked study personnel (TP). Care will be taken so that no treatment 
assignments, data which would allow treatment assignments to be determined, or outcome data 
based on treatment assignments will be revealed during the open sessions. 
Interim reports for the SMC will be prepared by study biostatistician (TP). These reports will 
include (a) recruitment overall, and by study site, (b) compliance, and (c) retention. The reports 
will also list study outcomes, and all adverse outcomes, including mortality and perforations. The 
SMC will determine the database closure dates for each report in advance; archival copies of the 
(a) main SQL database, and (b) study analysis file as they exist at the time of each report will be 
maintained. All reports will be sent using secure email to the members of the SMC two weeks prior 


 
 
to each meeting. Each interim report will be labeled clearly as confidential, printed in binding so 
that the contents are not visible from the outside, and labeled with the name of each person 
authorized to receive it. In addition, redacted versions of the interim reports will be prepared which 
contain no masked study information, and which are suitable for restricted distribution to other 
personnel on an as-needed basis. All hard copies will be destroyed at the end of each meeting, 
except for a copy to be kept in a locked file cabinet accessible only to TP. 
6.2.3  Decisions 
     The SMC will make nonbinding recommendations.  Guidelines will be agreed upon at the initial 
meeting, and are expected to include (a) safety, (b) effect of baseline covariates, or (c) validity. 
Benefits.  In this relatively small Phase II trial, we do not propose unmasked interim analyses 
to determine whether or not sufficient evidence has accumulated to justify stopping the trial 
because one treatment is clearly superior (and therefore should be extended to all future cases). 
Such interim analyses may, however, be requested by the SMC, in which case we will utilize 
available procedures.  If needed, a flexible alpha spending function will be prespecified at the 
beginning of the trial and included in version 2.0 of this SAP. 
Harm.  Stopping for harm may be recommended. Several endpoints will be examined, 
including (a) visual acuity, (b) cone density and spacing as measured by an AOSLO, (c) visual 
sensitivity measurements, (d) adverse events, and especially (e) serious adverse events, including 
mortality. While the analysis would consider maldistribution of predictive factors such as baseline 
visual function in the treatment eye and underlying medical history, it is recognized that ethical 
considerations require careful considerations of statistical tests as well as qualitative judgments in 
the light of experience. Any additional analyses required by the SMC will be conducted by TP as 
needed. 
Note that serious adverse events (SAE) are reported directly to the SMC Chair with 24 hours 
of the time the study site learns of them. The SMC Chair receives notification of the event, the 
timing of the event, a medical narrative from the medical monitor, the site, the patient identification 
number. The statistician reports the study treatment assignment to the SMC Chair.  
We do not anticipate any difficulties with respect to safety, because the implant device has been 
studied in previous clinical trials and no safety issues have been observed.  Nevertheless, if the 
CNTF implant use results in an unacceptable increase in the risk of adverse outcomes, then the 
study will be stopped. It is difficult to fully prescribe boundaries for monitoring safety because 
there need not be strong evidence to discontinue the study if it appears that the treatment is harmful. 
Futility.  For our Phase II trial, we are not proposing decision rules for early discontinuation 
due to the unlikeliness of significant findings conditional on interim results. Should the SMC 
recommend such procedures, we would propose to use available procedures for conducting 
unmasked interim analysis together with sample size re-estimation. 


 
 
7  Statistical Analysis 
7.1  Summary and Descriptive Statistics 
7.1.1  Demographics and Patient History 
All demographic and history variables determined at presentation or enrollment will be 
summarized by counts and percentages tabulated by treatment assignment. In particular, we 
propose to collect age, sex, eye involved, previous surgery, visual acuity, cone spacing, cone 
density, all current medications, and all current medical problems.  Laboratory measurements are 
reviewed in §2.3.2 and in detail in the study Proposal. 
7.1.2  Prior and concurrent medication 
We will present the percentage taking any ophthalmic medications at baseline. 
7.1.3  Baseline comorbidities and history 
Clinical variables at baseline will be presented by gender and age. We will also tabulate the baseline 
visual function measures and laboratory measurements.  Measurements of physiological function 
(i.e.,  Humphrey visual field measurements, and all other measurements outlined in §2.3.2) will be 
tabulated by treatment assignment (note that treatment assignment is random, independent of these 
measurements).  In addition, the mean distance from the fovea of all prospectively identified 
regions of interest in each eye will be calculated (i.e., if Dijk is the mean distance to the fovea of 
region k in eye j of person i, we compute D ij  1
nij
Dijk
k 1
nij
¦
, where nij is the number of regions of 
interest in eye j of person i) and tabulated by subsequent treatment assignment of the eye.  Note 
that the mean foveal distance of the regions of interest is independent of treatment assignment; this 
tabulation is designed to provide insight into whether the randomization process yielded any 
substantial imbalance in this factor. 
7.2  Accrual 
We anticipate accruing sufficient patients within 15 months following the beginning of the study. 
Details are given in the Proposal.   
7.3  Interim and Final Analysis 
     As indicated earlier, no formal prespecified interim analysis of efficacy is planned. We expect, 
however, to report results to the SMC during the progress of the trial. 
     Stopping guidelines for harm are at the discretion of the medical monitor and/or the SMC. In 
this trial (a small phase II trial), we propose no formal stopping rules for benefit or futility (see 
Section 7.2).  Any rules or guidelines would be determined at the first meeting of the SMC (see 
Section 7.2). 
     All final, planned analyses identified in this Statistical Analysis Plan will be performed only 
when the last patient has completed the final visit.  The final analysis will be conducted by 
statistician TP. 


 
 
7.4  Safety and Efficacy Outcomes 
     The primary outcome variable (cone spacing) will be analyzed using a two-sided test with 
symmetric rejection regions on each side.  An relative increase in cone spacing in the treatment 
group will provide evidence of lack of safety; a relative decrease in cone spacing in the treatment 
group (the treatment group loses fewer cones than the control group) will provide evidence for 
efficacy.   
     While (as discussed in the proposal) the CNTF implant has been found safe in previous 
clinical trials, it is understood that failure to find evidence of harm does not demonstrate safety. 
Our purpose has been to refine these earlier safety assessments using more refined 
measurements.  We recognize that multiple measures may be needed, together with clinical 
assessment by experts, to form a complete judgment; we note that we are not powered to detect 
unlikely events.  Our reporting on safety will always reflect these considerations.  Adjustments, 
such as an asymmetric rejection region for the primary outcome variable or the use of 
noninferiority procedures, may be requested by the SMC, and would be prespecified in this SAP 
prior to enrolling patients.   
7.5  Hypothesis Tests 
7.5.1  Analysis of primary outcome 
We describe an analysis template for continuous outcomes which will be repeated as indicated. 
7.5.1.1  Primary analysis 
     While we consider both cone spacing and density to be primary outcome measures, for the 
purpose of formal hypothesis testing for the efficacy aims of the trial, we chose the outcome 
variable to be cone spacing.  We will analyze cone spacing as the primary prespecified outcome, 
but also conduct an analogous analysis of cone density.  Cone spacing as well as cone density will 
be measured longitudinally in regions of interest selected prior to randomization and surgery and 
followed over time.  Specifically, as detailed in the flow sheet of examination procedures in the 
Protocol, we will consider acquiring measurements at the following times: 
  Baseline 1, within 7 weeks of implant surgery 
  Baseline 2, within 4 weeks of baseline 1 
  Six months (plus or minus 7 days) 
  Twelve months (plus or minus 14 days) 
  Eighteen months (plus or minus 14 days) 
  Twenty-four months (plus or minus 14 days) 
  Thirty months (plus or minus 14 days) 
  Thirty-six months (plus or minus 14 days)—this measurement is the primary outcome and 
is required 
A minimum of seven regions of interest per eye will ideally be established from the Baseline 1 
images. These specific regions will be followed longitudinally.  Note that if outcome data were 
not available at a specific visit due to inability to acquire images from patients, the study could 


 
 
optionally be continued at the discretion of the DSMC. Such decisions would be made 
independent (masked to) all outcome data. 
     The primary hypothesis test uses the 36-month observations.   
     We use the following notation.  The data are hierarchical, with region nested within eye and 
eye nested within person.  Let each region within each eye be labeled k, k=1, ..., nij, where nij is 
the number of regions of interest identified within eye j of person i. We denote the control eye by 
j=0, and the treatment eye by j=1. We denote the study time by ℓ, with ℓ=0 representing baseline, 
and ℓ=1 representing the final followup. We let Yijkℓmg denote the outcome variable for person i, 
eye j, region k, time ℓ, repetition m, and grader g  In the case of the baseline visit, m=1, 2; for the 
followup, m=1; grader g=1,2 identifies the two graders. We denote the foveal distance of each 
region of interest as Dijk; each region of interest is prospectively identified and followed over 
time, and these distances are therefore constant over time. 
     Z scores will be used as the prespecified outcome variable, based on analysis of normal 
subjects. Spacing is determined by analysis of images, by two independent graders. 
     The baseline score for a region of interest for each grader is  (Yijk01g+ Yijk02g)/2. The change 
score for each region of interest for grader g is ijkg = Yijkℓ1g-(Yijk01g+ Yijk02g)/2. The mean change 
score (averaging over graders) is ijk=(ijk1+ ijk2)/2. The average change score for each eye is 
ij=(k ijk)/nij. The difference between the treatment and control eyes for person i is Ui= i1- i0. 
     Under the null hypothesis, the differences U in change between treatment and control should 
have mean 0. We test this hypothesis using the Wilcoxon rank sum test. 
     Additional analyses may be reported. In each case, we will distinguish between such 
supplementary analyses and the primary analysis. 
• The grader-specific difference in change scores, analyzed using Rosner’s clustered 
version of the Wilcoxon rank sum test 
• Analyses of covariance, in which the baseline is used as a regressor and the outcome 
variable is the final value. These models will be at the level of the individual ROI, 
clustering on eye and person. 
• Subset analyses in which the analysis is restricted to regions of interest in which both 
graders’ results are available at all visits. Note that this does not eliminate bias, since 
missingness of follow-up data occur post-randomization. 
7.5.1.2  Cone spacing 
     The analytic template in §7.5.1.1 (and in §7.5.1.3 below) will be applied to the cone spacing 
measurements.  Inferentially, we consider cone spacing as a secondary outcome.   
 
7.5.1.3  Longitudinal analysis 
     As a complement to the above analysis, we will also model the clinical trial data using linear 
mixed models (e.g. Yasui et al, 2004), a modeling approach we have used in analysis of cone 
spacing and density data in the pilot study (Talcott et al., 2011)—provided interim observations 
are available. 


 
 
7.5.1.4  Image grading 
The outcome variables above will be derived by averaging cone spacing and cone density 
measurements for independent graders.  These graders will be masked to the treatment during the 
entire trial.   
     The linear mixed model framework may be expanded to model the ratings individually by 
including a rater-specific random effect.   
7.5.2  Secondary efficacy variables 
The following methods will be used to assess secondary endpoints, as indicated.  While we will 
report Holm-corrected p-values (correcting for six hypothesis tests), we note that such procedures 
are conservative and reduce our power to detect lack of safety.  We emphasize that safety cannot 
be assessed by means of these hypothesis tests, that alternative lower bounds may be of interest to 
the SMC, and that a full assessment must take into account multiple factors and clinical judgment.  
As with the primary outcome variable, the analytic results in this section are relevant both to safety 
(when results are worse in the treated eye), and to efficacy (when the results are better). 
7.5.2.1 Visual acuity   
     The template of §7.5.1.1 will be used here, except that we will simply model the difference in 
visual acuity between the eyes (regions of interest play no role, and we do not have multiple 
graders). We will test the hypothesis that the difference in visual acuity between the treatment and 
control eyes is constant in time, using a two-sided alpha of 0.05 (following Holm correction). 
Models including the covariates (such as age and diagnosis) will be explored.   
7.5.2.2 Visual field sensitivity   
     As above, we will follow the template in §7.5.1.1, using visual field sensitivity in each quadrant 
to produce an overall measure for each eye. A two-sided alpha of 0.05 will be used (following 
Holm correction). 
7.5.2.3 Foveal sensitivity   
     Foveal sensitivity will be examined in the same way as visual acuity (one measurement per 
eye), using the same strategy as in §7.5.2.1.  A two-sided alpha of 0.05 will be used (following 
Holm correction). 
7.5.2.4 Outer nuclear layer  
     Outer nuclear layer measurements will also be examined in the same way as visual acuity (one 
measurement per eye), using the same strategy as in §7.5.2.1. A two-sided alpha of 0.05 will be 
used (following Holm correction). 
7.5.2.5 Outer segment thickness  
     Outer segment thickness will also be examined in the same way as visual acuity (one 
measurement per eye), using the same strategy as in §7.5.2.1. A two-sided alpha of 0.05 will be 
used (following Holm correction). 
7.5.2.6 ERG measurements 
     We will model photopic b-wave measurements at the baseline, 12, 24, and 36 month times using 
the template of §7.5.1.1.  This will be conducted at a two sided alpha of 0.05 (following Holm 
correction for multiple comparisons).  Scotopic b-wave, as well as photopic and scotopic a-wave 


 
 
measurements, will be reported descriptively and will provide additional information which can 
guide assessments of safety. 
7.5.2.7 Other outcomes 
     For the incidence of adverse events following application of the investigational product in all 
subjects, we propose to use Poisson or negative binomial random-effects regression (extending to 
a more general hidden Markov model in the event of poor fit of the simpler models). Specifically, 
we will test the hypothesis that the underlying event rate per unit time is the same in the treatment 
and sham eyes. As a secondary analysis, we will analyze the time to first adverse event in each 
group using Cox proportional hazards regression (using baseline medical history as well as time 
since last treatment as covariates). We emphasize that while the statistical fit may be informative, 
decisions about drug safety (or trial continuation) will not be based solely on statistical criteria. 
7.5.2.8 Other analyses 
     We will also explore multivariate models (using many variables as outcomes), and explore the 
correlation structure between these variables cross-sectionally and longitudinally. 
     Plots of the average cone spacing in the treatment eye as a function of average cone spacing in 
the treatment eye will also be examined, adjusting for mean distance to the fovea (and likewise for 
density, and all other ocular measurements).  Exploratory models in which the spacing in the 
control eye is used as a predictor of the spacing in the treatment eye may be examined to provide 
additional statistical insight, but not as formal hypothesis tests. 
7.6  Additional statistical considerations 
7.6.1  Software 
The standard software package R version 2.11 or later (http://www.r-project.org) for 
the MacIntosh OS X will be used for all descriptive and inferential analyses.  SAS PROC MIXED 
(SAS Institute, Cary, North Carolina, USA) will be used in addition to R for fitting linear mixed 
models. 
7.6.2  Missing data and loss to follow-up 
     Missing values of cone spacing or density will be handled by regression-based multiple 
imputation in several steps.  
• Missing values for one grader at a baseline visit, when observations at the same visit are 
available from the other grader 
• Missing values for both graders at a baseline visit, when observations at the other baseline 
visit are available 
• Missing values for one grader at a follow-up visit, when observations are available at the 
same follow-up visit from the other grader 
• Missing values for both graders at a follow-up visit, when values other regions of interest 
from that eye are available at that visit 
• Missing values for all regions of interest for a given eye at the follow-up visit 


 
 
Complete case analyses will be included in reports. We will report multiple imputation results 
when we impute baseline visits based on other baseline visits. We will then report multiple 
imputation results when we extend to impute follow-up data for regions of interest when the second 
grader is imputed from the first. We will finally report multiple imputation results when we impute 
outcome data for regions of interest for which no follow-up data are available. 
     The latter is the primary outcome for the trial, and will be sharply distinguished from other 
analyses. We note that complete case analyses are biased. 
     Subsidiary analyses will be conducted to assess the role of image quality on missingness. 
Results may be biased because of treatment-related loss of image quality. 
7.6.3  Transformations and model adequacy 
Because the legitimacy of the hypothesis test being conducted depends on the assumptions (i.e. 
normality and homoskedasticity for linear models, proportional hazards for Cox regression), the 
adequacy of the statistical model must be checked. Methods which will be employed will include 
(a) residual plots (vs. baseline value, vs. predicted values, and Q-Q plots), (b) jackknife influence 
estimates, and (c) tests for normality (including the Anderson-Darling and Shapiro-Wilk 
procedures). 
7.6.4  Multiple comparisons 
An alpha of 0.05 will be used for the primary efficacy analysis. For pre-specified secondary 
analyses, we will report both the P-value and the number of pre-specified analyses performed. Note 
that the results of secondary analyses are not independent events, making a Bonferroni correction 
very conservative.  
7.7  Safety and tolerability 
The analysis of safety in this study will include summaries of the following:  
•   Exposure  
•   Adverse events  
     • 
Adverse events and serious adverse events  
     • 
Adverse events leading to withdrawal  
     • 
Any deaths  
The incidence of adverse events will be compared between treatment and sham eyes using the 
McNemar test. 
     Additional considerations are given in §7.4.   
7.7.1  Exposure 
Individual eyes are assumed to have exposure to the intervention assigned to the arm they were 
randomized to. 


 
 
7.7.2  Adverse Events 
7.7.2.1  Individual events 
The proportion of subjects with at least one of the following safety-related events will be compared 
using Fisher’s Exact Test. Non-serious adverse events (not requiring narrative form) are list here: 
irritation or infection from dilation drops, bruising from blood work. 
Serious ocular adverse events (which must be reported within 24 hours and which require a 
narrative form) are list here:  acute angle closure glaucoma precipitated by dilation, corneal 
abrasion after tonometry or electroretinography, risks associated with implantation surgery 
(cataract, retinal detachment, infection, bleeding). 
In addition, we will compare the rate of each of the adverse events during the follow-up period 
using Poisson regression, which can take into account multiple instances of adverse events within 
a single subject. 
7.7.2.2  Pooled adverse events 
Adverse events will be analyzed according to four main categories:  
• Proportion of subjects with any ocular adverse event  
• Proportion of subjects with any serious ocular adverse event  
• Proportion of subjects with any non-ocular serious adverse event  
• Proportion of subjects with any non-ocular adverse event  
The proportion of subjects with these events will be compared between the arms using Fisher’s 
Exact Test. Poisson regression will be applied to compare the rates of overall adverse events, 
including recurrent events. 
8  Reporting conventions 
• All tables and data listings will be presented in landscape orientation, unless presented as 
part of the text of the final report.  
• Figures will be presented in landscape orientation, unless the information is substantially 
easier to interpret in portrait orientation.  
• Direct annotation of figures will be preferred to legends. All figures with more than one 
variable or item will contain either direct annotation or legends. All annotation will be 
unambiguously identifiable as such.  
• Color will be used in figures only when needed to enhance clarity of communication. All 
color schemes will be evaluated for visual clarity for individuals with diminished color 
vision. All color encodings will be identified. Redundant encodings (such as the use of 
different plot symbols or line dash patterns) will be used in addition to color, so that all 
figures are interpretable after monochrome reproduction at 100 dots per inch. All dash 
patterns and line widths will be adequate to be distinguishable after monochrome 
reproduction at 100 dots per inch. Any distinction between plot symbols (circles, filled 
circles, diamonds, etc.) will remain clear after monochrome reproduction at 100 dots per 
inch.  


 
 
• Sans serif fonts will be used for all labeling (Helvetica, Arial, Futura, or Computer Modern 
Sans Serif (CMSS)).  
• Boldface and italics will not be used unless substantial value is added.  
• Decorative fonts and enhancements, including borders and shading, will not be used. 
Decorative presentation methods, such as ribbon graphs, will never be used.  
• All information given in figures will also be presented in summary tables (perhaps only 
included in an Appendix or in supplementary materials).  
• Only standard characters will be used in tables and data listings.  
• All titles will be centered. The first title line will be the number of the table, figure, or listing. 
The second and possibly third lines will be the description of the table, figure, or data listing. 
The ICH numbering convention will be used for all.  
• All footnotes will be left justified and at the page bottom. Footnotes will be used sparingly. 
Reference footnotes will be complete enough to locate any reference based on the 
information provided (Author, Journal, Pages, Date, or PubMed accession number).  
• Missing values for numeric or character variables will be unambiguously identified as such 
using the special string NA (not available) in all settings; NA is the standard missing value 
code for our software. Each figure or table caption in which NA is used will indicate the 
meaning of NA in that figure or table. The abbreviation NA will never be used for any other 
purpose.  
• All date values will presented in the form DDmmmYYYY format (e.g. 01jan2008), using 
four digit years. June will be encoded as jne (otherwise jan and jun would differ by only 
a single character), and July as jly (so that the lowercase letter l, easily confused with the 
digit 1, will not be adjacent to any numerals).  
• All tables, figures, and data listings will have the name of the program and a date/time stamp 
on the bottom of the output.  


 
 
9  Abbreviations and acronyms 
AES Advanced Encryption Standard  
AOSLO Adaptive Optics Scanning Laser Ophthalmoscope 
BCVA, BSCVA Best spectacle-corrected visual acuity 
CAR(1)  continuous autoregression process of order 1 (Ornstein-Uhlenbeck process) 
CNTF  Ciliary Neurotrophic Factor  
CNTF Implant Trial  The trial discussed in this SAP; official title: Photoreceptor Structure in a 
Phase 2 Study of Encapsulated Human NTC-201 Cell Implants Releasing Ciliary 
Neurotrophic Factor (CNTF) for Participants with Retinitis Pigmentosa Using Rates of 
Change in Cone Spacing and Density as the Primary Outcome 
DSMC Data and Safety Monitoring Committee  
ERG Electroretinography 
ETDRS Early Treatment of Diabetic Retinopathy Study 
FDA U.S. Food and Drug Administration  
FIPS Federal Information Processing Standard  
JD Jacque Duncan  
NIST National Institute of Standards and Technology  
PI Principal Investigator  
ROI region of interest  
SAP  Statistical Analysis Plan 
SMC  Safety Monitoring Committee 
TP T. Porco  
UCSF University of California, San Francisco  


 
 
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