A Multicentre Longitudinal, Observational Natural History Study to Evaluate Disease Progression in Subjects With Usher Syndrome Type 1B (USH1B)
Conditions: Usher Syndrome, Type 1B
Sponsor: Fondazione Telethon

 
 
 
 
 
PROTOCOL: TIGEM3-UshTher-NHS 
TITLE: 
A Multicentre, Prospective, Longitudinal, Observational Natural History 
Study to Evaluate Disease Progression in Subjects with Usher 
Syndrome type 1B (USH1B) 
 
DRUG: 
N/A 
 
 
EUDRACT NO.: 
Non-EUDRACT 
 
SPONSOR: 
Fondazione Telethon 
 
PRINCIPAL/ 
COORDINATING 
INVESTIGATOR: 
Francesca Simonelli 
University of Campania Luigi Vanvitelli 
Naples, Italy 
 
PROTOCOL  
HISTORY: 
16 March 2018 
 Version 1.1
 
 
 
 
 
 
 
 
 
This document contains confidential and proprietary information of the UshTher Consortium and is disclosed pursuant 
to confidentiality and non-disclosure obligations. This information should be used solely for the purposes for which 
it was provided and should not be copied, shared with, or disclosed to any third party without the express written 
consent of Telethon. 
 
 
 
 

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SIGNATURE PAGE 
 
 
CLINICAL PROTOCOL NUMBER: TIGEM3-UshTher-NHS 
 
Principal Investigator at Administration Site: 
 
STUDY TITLE  
A Multicentre, Prospective, Longitudinal, Observational Natural History Study to Evaluate Disease 
Progression in Subjects with Usher Syndrome type 1B (USH1B) 
 
Sponsor: Fondazione Telethon 
Sponsor Address: Via Varese 16B, 00185 Rome, Italy 
 
SponsorÕs Representative: Dr. Stefano Zancan 
 
On behalf of the Sponsor I agree to this protocol: 
 
 
____________________________ 
 
 
________________ 
 
Sponsor signature 
 
 
 
 
 
Date 
 
 
 
Investigator Name:  
Investigator Address:  
 
My signature below confirms that I have read and approved this protocol, and assures that this clinical study 
will be conducted according to all of the requirements in this protocol, the Declaration of Helsinki (1991), ICH 
Guideline for Good Clinical Practice and all applicable regulatory requirements.  
 
 
 
________________________________               ______________________ 
Principal Investigator signature 
 
 
Date:  
 
 
 

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TABLE OF CONTENTS 
 
TABLE OF CONTENTS ................................................................................................................... 3 
STUDY SYNOPSIS .......................................................................................................................... 5 
Table 1: 
Study Schedule of Events ............................................................................................ 7 
1 
BACKGROUND INFORMATION ........................................................................................... 8 
1.1 Indication and Current Treatment Options ................................................................................. 8 
2 
STUDY OBJECTIVES AND PURPOSE .................................................................................. 8 
2.1 Rationale for the Study ............................................................................................................... 8 
2.2 Study Objectives ......................................................................................................................... 8 
2.2.1 
Primary Objectives ....................................................................................................... 8 
2.2.2 
Secondary Objectives ................................................................................................... 8 
3 
STUDY DESIGN ....................................................................................................................... 9 
3.1 Study Design .............................................................................................................................. 9 
3.2 Duration and Study Completion Definition ............................................................................... 9 
3.3 Sites and Regions ....................................................................................................................... 9 
4 
STUDY POPULATION ........................................................................................................... 10 
4.1 Inclusion Criteria ...................................................................................................................... 10 
4.2 Exclusion Criteria ..................................................................................................................... 10 
4.3 Reproductive Potential ............................................................................................................. 11 
4.4 Discontinuation of Subjects ...................................................................................................... 11 
4.4.1 
Reasons for Discontinuation ...................................................................................... 11 
4.4.2 
Subjects ÒLost to Follow-upÓ Prior to Last Scheduled Visit ..................................... 11 
5 
PRIOR AND CONCOMITANT TREATMENT ..................................................................... 12 
5.1 Prior Treatment ......................................................................................................................... 12 
5.2 Concomitant Treatment ............................................................................................................ 12 
5.2.1 
Permitted Treatment ................................................................................................... 12 
5.2.2 
Not recommended Treatment ..................................................................................... 12 
6 
INVESTIGATIONAL PRODUCT .......................................................................................... 13 
7 
STUDY PROCEDURES .......................................................................................................... 13 
7.1 Study Schedule ......................................................................................................................... 13 
7.1.2 
Baseline visit .............................................................................................................. 13 
7.1.3 
1 year and 2 year follow-up visit ................................................................................ 13 
7.1.4 
Additional Care of Subjects after the Study .............................................................. 14 
7.2 Study Evaluations and Procedures ............................................................................................ 14 
7.2.1 
Demographic and Other Baseline Characteristics ...................................................... 14 
7.2.1.1 
Demographics ............................................................................................................ 14 
7.2.1.2 
Medical history ........................................................................................................... 14 
7.2.1.3 
Concurret Medical Conditions ................................................................................... 14 
7.2.2 
Measures of Disease Progression ............................................................................... 14 
7.2.2.1 
Refraction and Best Corrected Visual Acuity ............................................................ 14 
7.2.2.2 
Visual Field Assessments .......................................................................................... 14 

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7.2.2.3 
Clinical ophthalmic examination ............................................................................... 15 
7.2.2.4 
Microperimetry .......................................................................................................... 15 
7.2.2.5 
Fundus photography ................................................................................................... 15 
7.2.2.6 
Fundus autofluorescence ............................................................................................ 15 
7.2.2.7 
Ocular Coherence Tomography ................................................................................. 15 
7.2.2.8 
Multifocal electroretinogram ..................................................................................... 15 
7.2.2.9 
Electroretinography .................................................................................................... 15 
7.3 Patient Reported Outcomes ...................................................................................................... 16 
8 
DATA MANAGEMENT AND STATISTICAL METHODS ................................................. 17 
8.1 Data Collection and source data ............................................................................................... 17 
8.2 Statistical Analysis Process ...................................................................................................... 17 
8.3 Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee ...................... 17 
8.4 Sample Size Calculation and Power Considerations ................................................................ 17 
8.5 Study Population ...................................................................................................................... 17 
9 
SPONSORÕS AND INVESTIGATORÕS RESPONSIBILITIES ............................................. 18 
9.1 SponsorÕs Responsibilities ....................................................................................................... 18 
9.1.1 
Good Clinical Practice Compliance ........................................................................... 18 
9.1.2 
Indemnity/Liability and Insurance ............................................................................. 18 
9.1.3 
Public Posting of Study Information .......................................................................... 18 
9.2 InvestigatorÕs Responsibilities ................................................................................................. 18 
9.2.1 
Good Clinical Practice Compliance ........................................................................... 18 
9.2.2 
Protocol Adherence and Investigator Agreement ...................................................... 19 
9.2.3 
Audit/Inspection ......................................................................................................... 19 
9.3 Ethical Considerations .............................................................................................................. 19 
9.3.1 
Informed Consent ....................................................................................................... 19 
9.3.2 
Institutional Review Board or Ethics Committee ...................................................... 20 
9.4 Privacy and Confidentiality ...................................................................................................... 20 
9.5 Study Results/Publication Policy ............................................................................................. 20 
10 REFERENCES ......................................................................................................................... 22 
11 APPENDICES .......................................................................................................................... 23 
APPENDIX 1 PROTOCOL HISTORY ............................................................................................. 23 
APPENDIX 2 SCALES AND ASSESSMENTS ............................................................................... 24 
 

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STUDY SYNOPSIS 
 
Protocol number: TIGEM3-UshTher-NHS 
Disease under study: Usher Sydrome type 1B 
Title of the study: A Multicentre Longitudinal, Observational Natural History Study to Evaluate Disease 
Progression in Subjects with Usher Syndrome type 1B (USH1B) 
Number of subjects (total): 
Approximately 50 subjects are planned to be enrolled in the recruitment period. 
Investigator(s): Multicenter study 
Site(s) and Region(s): Italy, Spain and The Netherland  
Study period (planned): 
2018-2021 
Clinical phase: 
NA 
Objectives: 
Primary: The primary objective of this study is to evaluate the natural progression of disease over time in 
USHIB patients using visual field testing and best corrected visual acuity.  
Secondary: The secondary objectives of this study are to evaluate the progression of disease over time in 
USHIB patients through additional assessments:  
¥ 
Microperimetry (only in selected centres) 
¥ 
Fundus autofluorescence (FAF)  
¥ 
Optical Coherence Tomography (OCT) 
¥ 
Full-field Electroretinogram (ERG), 
¥ 
Multifocal Electroretinogram,  
¥ 
Vision-related function and quality of life, as measured by the 25-Item National Eye Institute Visual 
Function Questionnaire (NEI VFQ-25) 
Rationale: 
This natural history study is being conducted to understand the progression of disease in USH1B patients as 
measured by visual acuity and visual field testing and a number of other vision-related assessments.  
Investigational product, dose, and mode of administration: N/A 
Methodology: 
This is a multicenter longitudinal, observational study designed to evaluate the rate of progression in USH1B 
subjects by visual acuity and visual field measurements and a number of other vision-related assessments. 
Inclusion and exclusion criteria: 
Inclusion Criteria: 
 

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The study population consists of 50 subjects with clinical and genetic diagnosis of USH1 due to MYO7A 
mutations showing Retinitis Pigmentosa.  
Male and female subjects of any ethnic group are eligible for participation in this study, providing they 
meet the following criteria: 
1. 
Must be willing to adhere to protocol for long-term follow-up as evidenced by written informed consent 
or parental permission and subject assent. 
2. 
Subjects diagnosed with USH1. 
3. 
Molecular diagnosis of USH1B due to MYO7A mutations (homozygotes or compound heterozygotes). 
4. 
Age eight years old or older at the time of baseline. 
5. 
Visual acuity g 20/640 in at least one eye 
 
Exclusion Criteria: 
Subjects are excluded from the study if any of the following exclusion criteria are met: 
1. 
Unable or unwilling to meet requirements of the study. 
2. 
Unable to communicate with suitable verbal/auditory and/or tactile sign language (in the opinion of the 
investigator) 
3. 
Participation in a clinical study with an investigational drug in the past six months. 
4. 
Pre-existing eye conditions that would interfere with the interpretation of study endpoints (for example, 
glaucoma, corneal or significant lenticular opacities, cystoid macular oedema, macular hole). 
5. 
Complicating systemic diseases in which the disease itself, or the treatment for the disease, can alter ocular 
function. Examples are malignancies whose treatment could affect central nervous system function (for 
example, radiation treatment of the orbit; leukemia with CNS/optic nerve involvement). Also excluded 
would be subjects with immuno- compromising diseases, as there could be susceptibility to opportunistic 
infection [such as cytomegalovirus (CMV) retinitis].  
6. 
Subjects with diabetes or sickle cell disease would be excluded if they had any manifestation of advanced 
retinopathy (e.g. macular edema or proliferative changes).  
7. 
Prior ocular surgery within three months. 
8. 
Any other condition that would not allow the potential subject to complete follow-up examinations during 
the course of the study and, in the opinion of the investigator, makes the potential subject unsuitable for 
the study. 
Subjects will not be excluded based on their gender, race or ethnicity. 
 
 
Maximum duration of subject involvement in the study: 
¥ 
Planned duration of enrollment period: 18 months 
¥ 
Planned duration of assessment period: 24 months 
Statistical analysis: 
Continuous variables at each scheduled visit will be summarized using descriptive statistics (n, mean, quartiles, 
standard deviation, minimum and maximum). For categorical variables, tabular summaries will consist of 
presenting the number and percentage in each category, including missing category, if applicable. The annual 
rate of progression of each endpoint will be estimated by means of regression models for the analysis of 
longitudinal data, as appropriate. 

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Table 1: 
Study Schedule of Events 
Evaluationa 
 
Baseline  
1 year follow-up 
2 year follow-up 
Informed Consentb 
¥ 
Eligibility Criteria 
¥ 
 
 
Demographics 
¥ 
 
 
Medical History/Review of Systemsc 
¥ 
 
 
NEI VFQ-25=25-Item National Eye Institute 
Visual Functioning Questionnaire d 
¥ 
¥ 
¥ 
Concurret Medical Conditions \ Disease 
progression  
¥ 
¥ 
¥ 
Pregnancy or nursering status 
¥ 
¥ 
¥ 
Medication/Nutritional 
Supplements/Therapies/Procedures   
¥ 
¥ 
¥ 
Ophthalmic examinatione 
¥ 
¥ 
¥ 
Refraction and Best corrected visual acuity 
¥ 
¥ 
¥ 
Visual Field Assessments (Kinetic and Static) 
¥ 
¥ 
¥ 
Microperimetry 
¥ 
¥ 
¥ 
Fundus Photography* 
¥ 
¥ 
¥ 
Fundus autofluorescence* 
¥ 
¥ 
¥ 
Optical Coherence Tomography* 
¥ 
¥ 
¥ 
Multifocal electroretinogramf** 
¥ 
¥ 
¥ 
Full field electroretinogramg** 
¥ 
¥ 
¥ 
Notes: 
a 
It may take approximately 2 days to complete all required assessments. 
b 
Informed consent will be obtained  
c 
Includes family history, vision-related medical history, vision-related family history and abstracting of all previous available 
tests and examination. 
d 
The NEI VFQ-25 will be administered at the start of the scheduled visit so that any interaction between physician and 
subject will not influence the subjectÕs responses to the questionnaires. 
e 
Clinical ophthalmic examination will include slit lamp examination, direct and/or indirect ophthalmoscopy, and cataract 
grading. 
f 
To be performed only in patients with stable fixation 
g 
If a patient has a non-detectible ERG response at previous visit, ERG assessments will not be performed at 
subsequent study visits. 
*    to be performed without dilation in pregnant subjects 
**  to be not performed in pregnant subjects 

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1 
BACKGROUND INFORMATION 
 
1.1 
Indication and Current Treatment Options 
 
With an overall prevalence of 1 in 6000 (Kimberling, Hildebrand et al. 2010), the autosomal 
recessive Usher syndrome (USH) is the most common combination of genetic deafness and 
blindness due to Retinitis Pigmentosa (RP) (Gregory-Evans, Pennesi et al. 2013). USH type I 
which accounts for approximately 40% of all USH cases (Rosenberg, Haim et al. 1997) is the 
most severe form with the RP onset in childhood (Gregory-Evans, Pennesi et al. 2013). USH 
type IB (USHIB) accounts for 35-50% of USHI [(Ouyang, Yan et al. 2005), 1 in 30-42000 
individuals] and is caused by mutations in MYO7A. While hearing loss in USH can be 
counteracted by cochlear implantation, RP remains untreatable. 
 
2 
STUDY OBJECTIVES AND PURPOSE 
 
2.1 
Rationale for the Study 
 
Drug development in non-syndromic and syndromic RP has proved to be challenging, also due 
to the difficulty in applying endpoints commonly used in ophthalmology clinical trials. For 
instance, BCVA, which is used as a registration endpoint in many ophthalmologic clinical trials, 
may be not a viable endpoint for use in this slowly progressing disease. In addition, due to the 
slow progression of RP and the large amount of variability inherent to visual function 
assessments, some assessments have insufficient sensitivity for quantifying clinically 
meaningful changes in photoreceptor loss in a time frame desirable for clinical trials. 
This natural history study (NHS) is being conducted to understand the progression of disease in 
USH1B patients as measured by a number of vision-related assessments. Disease progression 
will be evaluated as change over time in these measures, and associations between the endpoints 
will be examined.  
 
2.2 
Study Objectives 
 
2.2.1 
Primary Objectives 
The primary objective of this study is to evaluate the natural progression of disease over time in 
USHIB patients using best corrected visual acuity and visual field testing. 
 
2.2.2 
Secondary Objectives 
The secondary objectives of this study are to evaluate the progression of disease over time in 
USHIB patients through additional assessments:  
¥ 
Microperimetry (only in selected centres) 
¥ 
Fundus autofluorescence (FAF)  
¥ 
Optical Coherence Tomography (OCT) 
¥ 
Full-field Electroretinogram (ERG), 
¥ 
Multifocal Electroretinogram,  
¥ 
Vision-related function and quality of life, as measured by the 25-Item National Eye Institute 
Visual Function Questionnaire (NEI VFQ-25). 

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3 
STUDY DESIGN 
 
3.1 
Study Design  
This is a multicentre longitudinal, observational study designed to evaluate disease progression 
in in subjects with USHB1 by several vision-related assessments.  
After informed consent (and assent, if applicable) is obtained from the subject or his/her 
parent(s) or legally authorized guardian(s), initial eligibility will be based on a confirmed 
clinical and molecular diagnosis of USH1B.  
 
Subjects will be assessed using the following schedule: 
 
¥ Baseline visit 
 
¥ 1 year follow-up visit 
 
¥ 2 year follow-up visit  
 
 
This is an observational study; no treatment for USH1B with an investigational medicinal 
product will be provided. Subjects who are eligible to enroll into this study are not obligated to 
participate. Once enrolled, subjects may withdraw at any time and for any reason without 
prejudice to any future medical care or research opportunities. A subjectÕs participation in this 
observational study does not guarantee participation in future interventional studies. 
The evaluation performed in the course of this study  are part of the standard clinical care of 
USHIB patients.  The study does not require any  additional test or administration of any 
drugs.
 
3.2 
Duration and Study Completion Definition 
 
The subjectÕs maximum duration of participation is expected to be approximately 24 months.  
Recruitment period is 18 months. 
The study will be completed in approximately 3.5 years. 
 
The Study Completion Date is defined as the date the final subject, across all sites, completes 
their final protocol-defined assessment. The Study Completion Date is used to ascertain timing 
for posting and reporting of study results. 
 
3.3 
Sites and Regions 
 
The study is planned to be conducted at 3 sites: the Eye Clinic of the University of Campania 
Luigi Vanvitelli, Naples, Italy, as Coordinating Centre, the Instituto de Investigacion Sanitaria 
de la Fundacion Jimenez Diaz, Madrid, Spain and the Stichting Oogziekenhuis Rotterdam, 
Rotterdam, The Netherland.

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4 
STUDY POPULATION 
 
It is expected that approximately 50 patients may be recruited into the study  during the 
recruitment period. 
Each subject must participate in the informed consent process and provide written informed 
consent/assent before any procedures specified in the protocol are performed. 
 
4.1 
Inclusion Criteria 
 
Male and female subjects of any ethnic group are eligible for participation in this study, providing 
they meet the following criteria: 
 
1. Must be willing to adhere to protocol for long-term follow-up as evidenced by written 
informed consent or parental permission and subject assent. 
2. Subjects diagnosed with USH1. 
3. Molecular diagnosis of USH1B due to MYO7A mutations (homozygotes or compound 
heterozygotes). 
4. Age eight years old or older at the time of baseline. 
5. Visual acuity g 20/640 in at least one eye 
 
4.2 
Exclusion Criteria 
 
Subjects are excluded from the study if any of the following exclusion criteria are met: 
 
1. Unable or unwilling to meet requirements of the study. 
2. Unable to communicate with suitable verbal/auditory and/or tactile sign language (in the 
opinion of the investigator) 
3. Participation in a clinical study with an investigational drug in the past six months. 
4. Pre-existing ocular conditions that would interfere with the interpretation of study 
endpoints (for example, glaucoma, corneal or significant lenticular opacities, moderate / 
severe cystoid macular oedema, macular hole) in both eyes. 
5. Complicating systemic diseases in which the disease itself, or the treatment for the disease, 
can alter ocular function. Examples are malignancies whose treatment could affect central 
nervous system function (for example, radiation treatment of the orbit; leukemia with 
CNS/optic nerve involvement).  
6. Subjects with diabetes or sickle cell disease would be excluded if they had any 
manifestation of advanced retinopathy (e.g. macular edema or proliferative changes).  
7. Prior ocular surgery within three months. 
8. Any other condition that would not allow the potential subject to complete follow-up 
examinations during the course of the study and, in the opinion of the investigator, makes 
the potential subject unsuitable for the study. 
 
Subjects will not be excluded based on their gender, race or ethnicity. 

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4.3 
Reproductive Potential 
 
Pregnant or nursering patient will not be excluded. Subjects who become pregnant while on 
study may continue participation in the study. Pregnancy information, including outcome, as 
reported by the patient will be recorded . Pregnant and nursing subjects will undergo study 
assessments without instillation of ocular drops for the duration of their pregnancy and nursing. 
All study assessments which cannot be done without ocular drops will be omitted while the 
subject is pregnant and nursing. 
 
4.4 
Discontinuation of Subjects 
 
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). 
 
Comments (spontaneous or elicited) or complaints made by the subject must be recorded in the 
source documents.  
 
Subjects who withdraw or are discontinued from participation in the study may be replaced at the 
discretion of the sponsor. 
 
4.4.1 
Reasons for Discontinuation 
The reason for withdrawal must be determined by the investigator and recorded in the subjectÕs 
medical record. If a subject is withdrawn for more than 1 reason, each reason should be 
documented in the source document. 
 
Reasons for discontinuation include but are not limited to: 
 
 
¥ Protocol deviation 
 
¥ Withdrawal by subject/parent/guardian 
 
¥ Lost to follow-up 
 
¥ Physician decision 
 
¥ Unwilling or unable to comply with protocol 
 
¥ Study terminated by sponsor 
 
¥ Site terminated by sponsor 
 
¥ Other (must be specified by investigator) 
 
4.4.2 
Subjects ÒLost to Follow-upÓ Prior to Last Scheduled Visit 
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point before withdrawing him\ her from the study. 

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5 
PRIOR AND CONCOMITANT TREATMENT 
 
 
5.1 
Prior Treatment 
 
Prior treatment (medications/nutritional supplements/therapies/procedures) includes all treatment 
(pharmacologic and non-pharmacologic) received within 90 days prior to obtaining IC. Prior 
treatment information must be recorded. 
 
5.2 
Concomitant Treatment 
 
Concomitant treatment (medications/nutritional supplements/therapies/procedures) refers to all 
treatment taken between the dates of obtaining IC and the final protocol-defined assessment. 
Concomitant treatment information must be recorded. 
 
5.2.1 
Permitted Treatment 
Treatments not specifically listed in Section 5.2.2 are permitted. 
 
5.2.2 
Not recommended Treatment 
The  patient is asked to notify the investigator in case he\she takes any of the following not 
recommended  mediciation  in the course of the study: 
: 
 
¥ Plaquenil 
 
¥ Thioridazine 
 
¥ Clofazimine 
 
¥ Deferoxamine 
 
¥ Phenothiazine 
 
¥ Chlorpromazine 
 
¥ Cisplatin 
 
¥ Valproic acid 
 
¥ Any other drugs with known visual side effects 

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6 
INVESTIGATIONAL PRODUCT 
 
Not applicable. This is a natural history study, and no investigational product will be 
administered. 
 
7 
STUDY PROCEDURES 
 
7.1 
Study Schedule 
 
See Table 1 for study procedures. 
 
The 1 year and 2 year follow-up visit assessments may be performed within a ± 30-day window. 
 
7.1.2 
Baseline visit 
The following procedures will be performed: 
 
¥ Obtaining written IC (and assent if applicable) by subject, and/or the subjectÕs parent(s) or 
legally authorized guardian(s) 
¥ Assessment of eligibility according to the inclusion/exclusion criteria 
¥ Collection of medical history, including subjectÕs ocular history, previous medications, and 
previous test and examination 
¥ NEI VFQ-25 plus its additional items 
¥ Concurret Medical Conditions   
¥ Pregnancy or nursering status 
¥ Concomitant treatment (medications/nutritional supplements/therapies/procedures) 
¥ Refraction and BCVA 
¥ Visual field assessments (kinetic and static) 
¥ Clinical ophthalmic examination 
¥ Microperimetry 
¥ Fundus Photography 
¥ Fundus autofluorescence 
¥ Optical Coherence Tomography 
¥ Confirmation of eligibility according to the inclusion/exclusion criteria 
¥ Multifocal electroretinogram 
¥ Full field electroretinogram 
 
7.1.3 
1 year and 2 year follow-up visit 
The following procedures will be performed: 
 
¥ NEI VFQ-25 plus its additional items 
¥ Concurret Medical Conditions \ Disease progression  
¥ Pregnancy or nursering status 
¥ Concomitant treatment (medications/nutritional supplements/therapies/procedures) 
¥ Refraction and BCVA 
¥ Visual field assessments (kinetic and static) 

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¥ Clinical ophthalmic examination 
¥ Microperimetry 
¥ Fundus Photography 
¥ Fundus autofluorescence 
¥ Optical Coherence Tomography 
¥ Multifocal electroretinogram 
¥ Full field electroretinogram 
 
 
7.1.4 
Additional Care of Subjects after the Study 
No after care is planned for this study.  
 
7.2 
Study Evaluations and Procedures 
 
7.2.1 
Demographic and Other Baseline Characteristics 
7.2.1.1 
Demographics 
Subject demographic information including sex, age, race, and ethnicity will be collected. 
 
7.2.1.2 
Medical history 
Medical history, including subjectÕs ocular history, previous medications, and previous test and 
examination  will be collected at baseline. 
 On this visit, if the patient has been previously visited at the  clinical centre, the available historical  
data on  visual related assessments as described in section 7.2.2  will be collected  and  will form 
the retrospective data.  
 
 
7.2.1.3 
Concurret Medical Conditions   
Any clinically significant medical condition will be recorded. 
Deafness severity or grade will also be recorded 
 
 
7.2.2 
Measures of Disease Progression 
The study procedures described in this section must be performed by trained site personnel. 
 
7.2.2.1 
Refraction and Best Corrected Visual Acuity 
Visual acuity with manifest refraction will be assessed in both eyes using a standardized ETDRS 
protocol. Following complete refraction of both eyes by a trained refractionist, BCVA 
measurements will be obtained for each eye. Subjects will be allowed as much time as necessary 
and will be encouraged to read each letter. If they are unsure about a letter, they will be asked to 
guess. Details are provided in the Technical Manual of Procedures. 
 
7.2.2.2 
Visual Field Assessments 
Visual field measurements will be made in both eyes using the Octopus 900 (Haag-Streit 
International) with the semiautomatic kinetic perimetry module and a full field static perimetry 
protocol as defined in the Technical Manual of Procedures. Visual field measurements will be 

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evaluated by the Coordinating center. 
 
7.2.2.3 
Clinical ophthalmic examination 
Clinical ophthalmic examination includes: 
External Ocular Examination: to assess the motility of the extraocular muscles and the 
appearance and function  of  the  eyelids  before the instillation  of  any  dilating  or anesthetic 
eye drops;  
Slit Lamp Examination (SLE) (biomicroscopy), to assess eyelids, lashes, conjunctiva, cornea, 
lens, iris and anterior chamber. SLE must be performed before the instillation of any dilating or 
anesthetic eye drops or the fluorescein agent. 
Intraocular Pressure (IOP) measurement, performed using either Goldmann applanation 
tonometry or   a   handheld   applanation   tonometer   (e.g.   Tonopen)   after instillation of a 
topical anesthetic. 
Dilated Fundus Ophthalmoscopy, performed after dilation of the pupil, in order to assess the 
retina, macula, choroid and optic nerve head. 
 
7.2.2.4 
Microperimetry 
Microperimetry will be performed using the MP-1 or Maia to more accurately access the central 
visual field by tracking fundus movements while the patient looks steadily at the fixation target.  
 
7.2.2.5 
Fundus photography 
Non-stereo images of macula and eight non-stereoscopic photographic fields surrounding the 
macula will be taken  through  a  dilated  pupil  to document the appearance of the posterior pole. 
 
7.2.2.6 
Fundus autofluorescence 
Infrared reflectance and FAF (blue) imaging covering 30¡ degree and centred on the macula will 
be obtained using the Spectralis (Heidelberg Engineering) or other sponsor-approved FAF 
machine. Details are provided in the Technical Manual of Procedures 
 
7.2.2.7 
Ocular Coherence Tomography 
A volume scan capturing a 30 x 25 degree region of the posterior pole of the retina of both eyes 
will be obtained using the Spectralis (Heidelberg Engineering) or other  sponsor-approved OCT 
machine. Details are provided in the Technical Manual of Procedures. 
 
7.2.2.8 
Multifocal electroretinogram 
Multifocal electroretinograms will be performed in both eyes (monocular stimulation) using a 
Reticom (Roland Consultant) or Espion D15 (Diagnosis) equipment according to the 
International Society for Clinical Electrophysiology of Vision standards(Hood, Bach et al. 2012).  
Details are provided in the Technical Manual of Procedures.  
 
7.2.2.9 
Electroretinography 
Full field electroretinograms will be performed in both eyes using a Reticom (Roland Consultant) 
or Espion D15 (Diagnosis) equipment according to the International Society for Clinical 
Electrophysiology of Vision standards(McCulloch, Marmor et al. 2015). Scotopic and photopic 
assessments will be performed as follows: 

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¥ Dark-adapted (40 minutes) 
 
¥ Rod response (0.01 ERG) 
 
¥ Maximal combined rod/cone response (3 ERG) 
 
¥ Light-adapted (10 minutes) 
 
¥ Cone response (3 ERG) 
 
¥ Response to flicker (30 Hz flicker ERG) 
 
Details are provided in the Technical Manual of Procedures.  
If a patient has a non-detectible ERG response to all stimuli at previous visit (or as assessed 
by medical history), ERG assessments will not be performed at subsequent study visits. 
 
7.3 
Patient Reported Outcomes 
Patient reported outcome assessments will not be administered to subjects less than 16 years old. 
 
25-ITEM NATIONAL EYE INSTITUTE VISUAL FUNCTIONING QUESTIONNAIRE AND ITS 
ADDITIONAL ITEMS 
 
Vision-related function and QOL will be assessed using the NEI VFQ-25 and its additional 
items, a valid and reliable questionnaire developed to measure the influence of visual impairment 
on QOL due to chronic eye diseases/conditions (Mangione, Lee et al. 2001). The questionnaire 
will be administered by an interviewer (interviewer-administered format) during the scheduled 
visits so that any interaction between subject and physician will not influence the subjectÕs 
responses to the questionnaire. On average, it takes approximately 10 minutes to administer. 
 
The NEI VFQ-25 includes 25 items plus 1 general health item and an appendix of 13 
supplementary items (additional items) that are used to expand the scales. These additional items 
enhance the reliability of the specific scales and are likely to improve responsiveness of the 
sub-scale to changes over time. The NEI VFQ-25 and its additional items result in 11 vision- 
related constructs/scales (37 items) assessing global vision, difficulty with near vision activities, 
difficulty with distance vision activities, limitations in social functioning due to vision, role 
limitations due to vision, dependency on others due to vision, mental health symptoms due to 
vision, driving difficulties, limitations with peripheral vision, limitations with color vision, and 
ocular pain and a general health scale (2 items).There is limited information on the performance 
of the NEI VFQ-25 in subjects with Usher Syndrome; therefore the SF-12v2 and PGI-S (see 
below) will also be assessed to establish the psychometric properties (validity, reliability, and 
sensitivity) of the NEI VFQ-25 and its additional items in this patient population. 
 
Questionnaire will be provided in the patient language  and administrated with the help of a sign 
language interpreter,  as required / recommended by national law or local procedures 
 
 
 

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8 
DATA MANAGEMENT AND STATISTICAL METHODS 
 
8.1 
Data Collection and source data  
 
The investigatorsÕ authorized site personnel must enter the information required by the protocol 
in the Clinical Record Form (CRF)  
 
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto CRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log. 
 
 All key data must be recorded in the subjectÕs medical records. 
Original source data will include, but are not limited to subjectÕs medical file, including all visual 
assessments. 
 
All data sent to the sponsor must be endorsed by the investigator. 
 
A study monitor will verify the contents against the source data per the monitoring plan. If the 
data are unclear or contradictory, queries are sent for corrections or verification of data. 
 
Essential documents must be maintained according to ICH GCP requirements .  
 
8.2 
Statistical Analysis Process 
 
Continuous variables at each scheduled visit will be summarized using descriptive statistics (n, 
mean, quartiles, standard deviation, minimum and maximum). For categorical variables, tabular 
summaries will consist of presenting the number and percentage in each category, including 
missing category, if applicable. The annual rate of progression of each endpoint will be estimated 
by means of regression models for the analysis of longitudinal data, as appropriate.  
The main analysis will be done on data collected prospectively, but a secondary analysis will be 
performed considering also the retrospective data recovered in patients medical history. 
 
8.3 
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee 
 
One interim analysis is planned when all patients recruited within in the first six months will 
have the 1-year follow-up visit.  Data will be reviewed and a longitudinal analysis exploring the 
annual rate of progression of the main endpoints will be performed to help future clinical 
development planning. 
 
8.4 
Sample Size Calculation and Power Considerations 
 
No formal sample size computation was performed. Approximately 50 subjects will be enrolled 
in this study. 
 
8.5 
Study Population 
 
The Enrolled Set will consist of all subjects who have signed an informed consent and study 
procedures have begun. 
 
All safety and disease progression data will be assessed using the Enrolled Set. 
 

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9 
SPONSORÕS AND INVESTIGATORÕS RESPONSIBILITIES 
 
This study is conducted in accordance with current applicable regulations, the International 
Conference on Harmonisation (ICH), European Union (EU) Directive 2001/20/EC and its 
updates, and local ethical and legal requirements. 
 
9.1 
SponsorÕs Responsibilities 
 
9.1.1 Good Clinical Practice Compliance 
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH GCP Guideline E6 (1996), EU Directive 2001/20/EC, as 
well as all applicable national and local laws and regulations. 
 
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjectsÕ 
medical records, and CRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities. 
 
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required. 
 
9.1.2 Indemnity/Liability and Insurance 
No insurance policy is in place  for this study, being an observational one.  
 
9.1.3 Public Posting of Study Information 
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigatorsÕ names 
and contact information. 
9.2 
InvestigatorÕs Responsibilities 
 
9.2.1 Good Clinical Practice Compliance 
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines. 
 
It is the investigatorÕs responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period. 
 
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study. 
 
If a potential research subject has a primary care physician, the investigator should, with the 
subjectÕs consent, inform them of the subjectÕs participation in the study. 
 

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A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the signed 
and dated signature of the principal investigator (single-site study) or coordinating principal 
investigator (multicenter study), in compliance with Directive 2001/83/EC as amended by 
Directive 2003/63/EC and ICH Guidance E3 (1995). 
 
9.2.2 Protocol Adherence and Investigator Agreement 
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met all of 
the protocol-defined eligibility criteria.  
 
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. Upon 
study completion, the investigator will provide the sponsor, IRB/EC, and regulatory agency with 
final reports and summaries as required by (inter)national regulations. 
 
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, or investigator, according to national 
provisions and will be documented in the investigator agreement. 
 
9.2.3 Audit/Inspection 
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the EMA, the Medicines and 
Healthcare products Regulatory Agency, other regulatory authorities, the sponsor or its 
representatives, and the IRB/EC for each site. 
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media. 
 
The study monitor (and auditors, IRB/EC, or regulatory inspectors) may check the CRF entries 
against the source documents. The consent form includes a statement by which the subject agrees 
to the monitor/auditor from the sponsor or its representatives, national or local regulatory 
authorities, or the IRB/EC, having access to source data (eg, subjectÕs medical file, appointment 
books, original laboratory reports, X-rays, etc.). Non-study site personnel will not disclose any 
personal information or personal medical information. 
 
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, European 
Medicines Agency [EMA]) or an auditor. 
 
9.3 
Ethical Considerations 
 
9.3.1 Informed Consent 
It is the responsibility of the investigator to obtain written IC and assent, where applicable, from 
all study subjects prior to any study-related procedures. All consent and assent documentation 
must be in accordance with applicable regulations and GCP. Each subject or the subjectÕs legally 
authorized representative, as applicable, is requested to sign and date the subject IC form after 
the subject has received and read (or been read) the written subject information and received an 
explanation of what the study involves, including but not limited to the objectives, potential 
benefits and risk, inconveniences, and subjectÕs rights and responsibilities. A copy of the IC and 
assent documentation (ie, a complete set of subject information sheets and fully executed 

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signature pages) must be given to the subject or the subjectÕs legally authorized representative, 
as applicable. This document may require translation into the local language. Signed consent 
forms must remain in each subjectÕs study file and must be available for verification at any time. 
 
The principal investigator provides the sponsor with a copy of the consent form and assent form 
where applicable which was reviewed by the IRB/EC and which received their favorable 
opinion/approval. A copy of the IRBÕs/ECÕs written favorable opinion/approval of these 
documents must be provided to the sponsor prior to the start of the study unless it is agreed to 
and documented (abiding by regulatory guidelines and national provisions) prior to study start 
that another party (ie, sponsor or coordinating principal investigator) is responsible for this 
action. Additionally, if the IRB/EC requires modification of the sample subject information and 
consent document provided by the sponsor, the documentation supporting this requirement must 
be provided to the sponsor. 
 
9.3.2 Institutional Review Board or Ethics Committee 
 
The  study will be submitted  by the investigator to the competent  Ethics Committee  to seek EC 
approval to the study. 
A copy of the IRBÕs/ECÕs written favorable opinion/approval of the study must be provided to 
the sponsor prior to the start of the study 
 
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all IC documents and amendments to the protocol unless there is a subject safety 
issue. 
 
The sponsor will provide a summary of the clinical study report to the EC and will inform the EC 
in case of early termination of the study 
 
 
9.4 
Privacy and Confidentiality 
 
Subject  will  be assigned a unique alphanumeric code and all subject data will be identified  
by that code. Only the cinical centre staff wll have access to the patient identity. 
 
 The  patientsÕ data may, in addition, be reviewed by the sponsor delegated staff, the monitor and 
others, including auditors and third parties involved in the UshtTer Consorium; national or local 
regulatory authorities; and the IRB(s)/EC(s) which gave approval for the study to proceed. The 
sponsor and/or its representatives accessing the records and data will take all reasonable 
precautions in accordance with applicable laws, regulations, and guidelines to maintain the 
confidentiality of subjectsÕ identities. 
 
The results of studies, containing subjectsÕ unique identifying numbers and relevant medical 
records, may be transferred to and used in other countries which may not afford the same level of 
protection that applies within the countries where this study is conducted. The purpose of any 
such transfer would include to support regulatory submissions, to conduct new data analyses to 
publish or present the study results, or to answer questions asked by regulatory or health 
authorities. 
 
9.5 
Study Results/Publication Policy 
 
The term ÒpublicationÓ refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 

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letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form. 
 
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsorÕs 
confidential information shall be submitted for publication without the sponsorÕs prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication.  
 
Since the study is part of a multicenter study, the first publication of the study results shall be 
made by the sponsor in conjunction with the sponsorÕs presentation of a joint, multicenter 
publication of the compiled and analyzed study results. If such a multicenter publication is not 
submitted to a journal for publication by the sponsor within an 18-month period after conclusion, 
abandonment, or termination of the study at all sites, or after the sponsor confirms there shall be 
no multicenterstudy publication of the study results, an investigator may individually publish the 
study results from the specific site in accordance with this section. The investigator must, 
however, acknowledge in the publication the limitations of the single-site data being presented. 
 
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
current standards. Participation as an investigator does not confer any rights to authorship of 
publications. 

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10 
REFERENCES 
 
Gregory-Evans, K., M. E. Pennesi and R. G. Weleber (2013). Retinitis Pigmentosa and Allied 
Disorders. Retina. S. J. Ryan, Elsevier. 2: 761-835. 
Hood, D. C., M. Bach, M. Brigell, D. Keating, M. Kondo, J. S. Lyons, M. F. Marmor, D. L. 
McCulloch, A. M. Palmowski-Wolfe and V. International Society For Clinical Electrophysiology of 
(2012). "ISCEV standard for clinical multifocal electroretinography (mfERG) (2011 edition)." Doc 
Ophthalmol 124(1): 1-13. 
Kimberling, W. J., M. S. Hildebrand, A. E. Shearer, M. L. Jensen, J. A. Halder, K. Trzupek, E. S. 
Cohn, R. G. Weleber, E. M. Stone and R. J. Smith (2010). "Frequency of Usher syndrome in two 
pediatric populations: Implications for genetic screening of deaf and hard of hearing children." 
Genet Med 12(8): 512-516. 
Mangione, C. M., P. P. Lee, P. R. Gutierrez, K. Spritzer, S. Berry, R. D. Hays and I. National Eye 
Institute Visual Function Questionnaire Field Test (2001). "Development of the 25-item National 
Eye Institute Visual Function Questionnaire." Arch Ophthalmol 119(7): 1050-1058. 
McCulloch, D. L., M. F. Marmor, M. G. Brigell, R. Hamilton, G. E. Holder, R. Tzekov and M. 
Bach (2015). "ISCEV Standard for full-field clinical electroretinography (2015 update)." Doc 
Ophthalmol 130(1): 1-12. 
Ouyang, X. M., D. Yan, L. L. Du, J. F. Hejtmancik, S. G. Jacobson, W. E. Nance, A. R. Li, S. 
Angeli, M. Kaiser, V. Newton, S. D. Brown, T. Balkany and X. Z. Liu (2005). "Characterization of 
Usher syndrome type I gene mutations in an Usher syndrome patient population." Hum Genet 
116(4): 292-299. 
Rosenberg, T., M. Haim, A. M. Hauch and A. Parving (1997). "The prevalence of Usher syndrome 
and other retinal dystrophy-hearing impairment associations." Clin Genet 51(5): 314-321. 

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11 
APPENDICES 
 
 
APPENDIX 1 PROTOCOL HISTORY 
 
Document 
Date 
Global/Country/Site Specific 
Original Protocol 
31 Jan 2018 
Global 
Version 1.1 
16 March 2018 
Spain, Netherland 
 
 
SUMMARY OF CHANGES FROM PREVIOUS VERSION 
 
In the section 4.1.1 Reasons for Discontinuation Adverse Event was removed from the list of 
reason for Discontinuation, as not applicable for an observational study. 
Since the current study is an observational study, the therapy listed in the paragraph 5.2.2 should 
be nonrecommended instead of prohibited. 
In the section 7.2.2.4 Microperimetry, the use of Maia instrumentation was included. 
 
  
 
 
 
 

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APPENDIX 2 SCALES AND ASSESSMENTS 
The following scales/assessments will be utilized in this study: 
 
Full Title of Scale/Assessment 
Version Number 
25-Item National Eye Institute Visual Functioning 
Questionnaire (NEI VFQ-25) and its Additional Items 
NEI VFQ-25 
 
 
A separate master file containing each scale/assessment listed above will be provided to the site. 
Updates to scales/assessments during the study (if applicable) will be documented in the table 
above, and a new master file containing the revised scale/assessment will be provided to the site.