Conditions: Retinitis Pigmentosa Usher Syndrome Type 2 Deaf Blind Retinal Disease Eye Diseases Eye Diseases, Hereditary Eye Disorders Congenital Vision Disorders
Keywords: Retinitis Pigmentosa USH2A RP exon 13 RNA therapies antisense oligonucleotide exon skipping Sirius IVT mutations in exon 13 of the USH2A gene NSRP Non-Syndromic RP Inherited Retinal Disorders Usher Syndrome Intravitreal Injection ultevursen
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 7
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy safety and tolerability of ultevursen administered via intravitreal injection (IVT) in subjects with Retinitis Pigmentosa (RP) due to mutations in exon 13 of the USH2A gene.

Detailed description:
The purpose of this study is to evaluate the efficacy safety and tolerability of ultevursen administered via intravitreal injection (IVT) in subjects with Retinitis Pigmentosa (RP) due to mutations in exon 13 of the USH2A gene.

The below dose levels of ultevursen will be evaluated with the loading dose administered at Day 1 and maintenance dose administered at Month 3 and every 6 months thereafter:

1. Loading dose of 60 µg, maintenance dose of 60 µg
2. Loading dose of 180 µg, maintenance dose of 60 µg

Dose levels will include subjects randomized to sham-procedure or treatment with ultevursen.

Arms:
arm 1: 60 µg loading dose administered on Day 1, 60 µg maintenance dose administered at Month 3 and every 6 months thereafter arm 2: 180 µg loading dose administered on Day 1, 60 µg maintenance dose administered at Month 3 and every 6 months thereafter arm 3: Sham-procedure (no experimental drug administered) on Day 1, Month 3 and every 6 months thereafter

Interventions: intervention 1: Ultevursen intervention 2: Sham-procedure
Intervention descriptions: intervention 1: RNA antisense oligonucleotide for intravitreal injection intervention 2: Sham-procedure (no experimental drug administered)

Protocol document:
Prot_000.pdf: 
 
 
 
 
Investigational Product: Ultevursen 
Protocol No. PQ-421a-003 (Version 3) 
 
 
CLINICAL STUDY PROTOCOL 
A DOUBLE-MASKED, RANDOMIZED, CONTROLLED, MULTIPLE-DOSE STUDY 
TO EVALUATE THE EFFICACY, SAFETY, AND TOLERABILITY OF ULTEVURSEN 
IN SUBJECTS WITH RETINITIS PIGMENTOSA (RP) DUE TO MUTATIONS IN 
EXON 13 OF THE USH2A GENE (SIRIUS) 
 
 
 
Protocol No. 
PQ-421a-003  
Protocol/Amendment Date: 
14 June 2022 
Protocol Version:  
3.0 
Supersedes Version: 
2.0 
EudraCT/IND Number 
2021-002729-74 
IND 137660 
Sponsor: 
ProQR Therapeutics  
Zernikedreef 9 
2333 CK Leiden 
The Netherlands 
 
 


 
 
 
 
Investigational Product: Ultevursen 
Protocol No. PQ-421a-003 (Version 3) 
 
ProQR Therapeutics 
 
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14 June 2022 
INVESTIGATOR SIGNATURE PAGE 
PRINCIPAL INVESTIGATOR COMMITMENT: 
I will provide copies of the protocol, any subsequent protocol amendments and access to all 
information provided by the Sponsor to the study personnel under my supervision. I will discuss 
this material with them to ensure that they are fully informed about the study drug and the study 
protocol. 
I agree to conduct this clinical study according to the attached protocol, except when mutually 
agreed to in writing. I also agree to conduct this study in compliance with all applicable local 
regulations, Good Clinical Practices (GCP), as well as with the requirements of the appropriate 
Institutional Review Board(s) (IRB)/Ethics Committee(s) (EC) and any other Institutional 
requirements. 
 
 
Printed Name of Principal Investigator 
 
Signature of Principal Investigator 
 
Date 
 
Institution 
 
Address of Institution 
 
Phone Number of Investigator 
 


 
 
 
 
Investigational Product: Ultevursen 
Protocol No. PQ-421a-003 (Version 3) 
 
ProQR Therapeutics 
 
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14 June 2022 
PROTOCOL APPROVAL PAGE 
A Double-Masked, Randomized, Controlled, Multiple-Dose Study to Evaluate the Efficacy, 
Safety and Tolerability of Ultevursen in Subjects with Retinitis Pigmentosa (RP) due to 
Mutations in Exon 13 of the USH2A Gene (SIRIUS) 
Protocol No. PQ-421a-003 
Protocol/Amendment Date: 14 June 2022 
Protocol Version: 3.0 
Sponsor: ProQR Therapeutics 
Zernikedreef 9 
2333 CK Leiden 
The Netherlands 
 
 
 
 
 
 
ProQR Therapeutics 
 
Date 
 
 
 


 
 
 
 
Investigational Product: Ultevursen 
Protocol No. PQ-421a-003 (Version 3) 
 
ProQR Therapeutics 
 
Page 4 of 68
 
 
14 June 2022 
1.0 
SYNOPSIS 
 
Name of the Sponsor: 
ProQR Therapeutics 
Individual Study Table Referring to Part of the 
Dossier: 
Volume: NA 
Page: NA 
For National Authority 
Use Only 
Name of Study Drug: 
QR-421a (henceforth 
ultevursen) Solution for 
Intravitreal Injection 
Name of Active Ingredient: 
Ultevursen  
Title of Study:  
A Double-Masked, Randomized, Controlled, Multiple-Dose Study to Evaluate the 
Efficacy, Safety and Tolerability of Ultevursen in Subjects with Retinitis 
Pigmentosa (RP) due to Mutations in Exon 13 of the USH2A Gene (SIRIUS) 
Phase of Development: 
Phase 2/3 
Study Period: 
Anticipated to be approximately 34 months 
Duration of Subject 
Participation: 
Approximately 27 months (up to 12 weeks screening; 24 months on-study) 
Rationale:  
There are currently no approved therapies for the treatment of RP due to mutations 
in exon 13 of the USH2A gene, and disease management is supportive; therefore, a 
large unmet medical need exists in this sight-threatening condition. 
 
 
 
 
 
 
 
 
 
 
Study PQ-421a-003 will investigate the efficacy and safety of 2 dose regimens of 
ultevursen in subjects with RP due to mutations in exon 13 of the USH2A gene. 
Objectives: 
Primary  
• 
To evaluate the efficacy of ultevursen 
Endpoints: 
Primary endpoint 
• 
Mean change from baseline in best corrected visual 
acuity (BCVA) (based on the Early Treatment 
Diabetic Retinopathy Study (ETDRS) chart) at 
18 months of treatment versus sham-procedure  


 
 
 
 
Investigational Product: Ultevursen 
Protocol No. PQ-421a-003 (Version 3) 
 
ProQR Therapeutics 
 
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Secondary 
• 
To further evaluate the efficacy of ultevursen 
• 
To evaluate the safety and tolerability of ultevursen  
• 
To evaluate changes in Patient-Reported Outcome 
(PRO) measures in subjects treated with ultevursen 
• 
To evaluate systemic exposure of ultevursen 
Key Secondary Endpoint (Efficacy) 
• Proportion of subjects who maintain vision defined by 
BCVA loss less than 15 Letters (based on ETDRS) 
Other Secondary Endpoints (Efficacy) 
• 
Change from baseline in the following outcome 
measures: 
o 
Other analyses of BCVA  
o 
Ellipsoid zone (EZ) area and width as imaged by 
Spectral domain optical coherence tomography 
(SD-OCT) 
o 
Low Luminance Visual Acuity (LLVA) 
o 
Microperimetry 
o 
Full-field Stimulus Threshold (FST) 
Secondary Endpoints (Safety and Tolerability) 
• 
Ocular and non-ocular adverse events (AEs) 
Secondary Endpoints (PRO) 
• 
Change from baseline in PRO measures, as assessed 
by: 
o 
Veterans Affairs Low Vision Visual Functioning 
Questionnaire (VA LV VFQ-20) 
o 
Patient Global Impressions of Severity (PGI-S) 
o 
Patient Global Impressions of Change (PGI-C) 
Secondary Endpoints (Systemic Exposure) 
• 
Exposure of ultevursen in serum 
Number of Subjects 
(planned): 
Approximately 81 subjects  
 
Study Design 
PQ-421a-003 is a double-masked, randomized, controlled, multiple-dose study to 
evaluate the efficacy, safety and tolerability of ultevursen in subjects with RP due 
to mutations in exon 13 of the USH2A gene.  
At study start subjects will be randomized to one of the following treatment 
groups: 
1) Group 1: Ultevursen 180/60 µg (180 µg loading dose administered on Day 1, 
60 µg maintenance dose administered at Month 3 and every 6 months 
thereafter; n = 27) 
2) Group 2: Ultevursen 60/60 µg (60 µg loading dose administered on Day 1, 
60 µg maintenance dose administered at Month 3 and every 6 months 
thereafter; n = 27) 
3) Group 3: Sham-procedure (administered on Day 1, Month 3 and every 
6 months thereafter; n = 27) 
The primary endpoint will be assessed at 18 months of treatment. Analysis of all 
other efficacy and safety parameters will also be reported at that time point. All 
efficacy and safety parameters will continue to be followed during the 24-month 
study period. 
Study Plan 
The study includes screening period of up to 12 weeks. Screening will take place 
over at least 2 days. The treatment visit (Day 1) should be performed as soon as 
possible after Screening, where feasible. 


 
 
 
 
Investigational Product: Ultevursen 
Protocol No. PQ-421a-003 (Version 3) 
 
ProQR Therapeutics 
 
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During the screening period, subjects will be assessed according to the eligibility 
criteria. 
 
 
 It is recommended that screening will be conducted in a stepwise 
manner, so that eligibility is confirmed first with less intensive assessments and 
more intensive assessments are conducted after eligibility by all other criteria have 
been confirmed.  
Subjects who meet all eligibility criteria will be enrolled and randomized into the 
study and will receive their dose of study treatment on Day 1. Ultevursen will be 
administered via intravitreal (IVT) injection into the subject’s study eye (i.e., 
treated eye or henceforth TE; see Section 4.2.1.2 for selection of the TE) in 
accordance with the procedures outlined in the Study Reference Manual. Subjects 
receiving the sham-procedure will undergo a procedure that will closely mimic the 
active injection, but there will be no penetration of the globe. Administration of 
study treatment, as well as clinical monitoring of the subject during and right after 
administration of study treatment, will be performed by an unmasked physician. 
All other clinical assessments will be performed by a separate, masked physician, 
or by masked study personnel.  
After each administration of study treatment subjects will be monitored clinically 
for safety, including intraocular pressure (IOP) and signs of inflammation. 
Frequent study visits and safety monitoring by the Investigator will be in place, 
together with oversight by the Medical Monitor and the Data Monitoring 
Committee (DMC) (see Section 9.1). The Investigator or the Medical Monitor (in 
consultation with the DMC, as appropriate) may decide to hold (delay or skip) or 
discontinue study treatment for an individual subject. Stopping criteria are 
described in Section 4.2.3. Subjects who discontinue study treatment will continue 
to be followed for safety and efficacy. 
Efficacy and safety assessments, including retinal structure changes, functional 
assessments of vision and PRO measures will be performed at selected study visits 
as indicated in the Schedule of Events (SOE) 
 All assessments will 
be performed on both eyes. A central reading center will grade structural and 
functional exams in a masked way. Any assessment may be repeated if the results 
are considered unreliable or of unacceptable quality by the Investigator or the 
reading center.  
Samples for systemic exposure analysis will be collected as indicated in the SOE 
 
Assessments can be completed over multiple non-consecutive days. 
Diagnosis and Main Criteria 
for Eligibility Relating to 
Study Initiation: 
Inclusion Criteria Relating to Study Initiation: 
The subject is eligible for the study and thus eligible to receive ultevursen or 
sham-procedure in the TE if all the following inclusion criteria apply at 
Screening/Day 1: 
1. An adult (≥ 18 years) willing and able to provide informed consent for 
participation prior to performing any study related procedures, and suitable 
verbal, auditory, written and/or tactile sign language communication as to 
allow informed consent to be obtained, in the opinion of the Investigator. 
OR 
A minor (12 to < 18 years) with a parent or legal guardian willing and able to 
provide written permission for the subject’s participation prior to performing 
any study related procedures and pediatric subjects able to provide age 
appropriate assent for study participation. The lower age limit for pediatric 


 
 
 
 
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Protocol No. PQ-421a-003 (Version 3) 
 
ProQR Therapeutics 
 
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14 June 2022 
populations is subject to local regulatory and ethics committee requirements 
(e.g., 16 to <18 for Norway). 
2. An adult willing to comply with the protocol, follow study instructions, attend 
study visits as required and willing and able to complete all study 
assessments.  
OR  
A minor able to complete all study assessments and comply with the protocol 
and has a parent or caregiver willing and able to follow study instructions, and 
attend study visits with the subject as required. 
3. Clinical presentation consistent with RP with Usher syndrome type 2 or non-
syndromic form of RP (NSRP), based on ophthalmic, audiologic, and 
vestibular examinations. 
4. A molecular diagnosis of homozygosity or compound heterozygosity for 1 or 
more pathogenic exon 13 mutations in the USH2A gene, based on genetic 
analysis at screening.  
5. BCVA between ≥30 and ≤68 letters (approximate Snellen equivalent 20/250 – 
20/50) in the TE, using the mean BCVA reading at Screening (see Section 
8.1) and based on the ETDRS. Subjects with a mean BCVA between >68 and 
≤73 letters will be allowed with documented historic evidence of a BCVA 
equivalent decline of >5 letters in both eyes (i.e., >1 line decline using Snellen 
or >0.1 LogMAR) anytime within the last 18 months relative to Screening. 
6. BCVA between ≥30 and ≤73 letters (approximate Snellen equivalent 20/250 – 
20/40) in the contralateral eye (CE), using the mean BCVA reading at 
Screening (see Section 8.1) and based on the ETDRS.  
7. A difference in mean BCVA readings at Screening between the TE and CE of 
≤10 letters (based on ETDRS). BCVA differences between eyes that are 
greater than 10 letters may be allowed however, the Investigator should 
discuss the case with the Medical Monitor.  
8. Stable BCVA in the TE and CE, defined as 2 separate BCVA measurements 
at Screening that fall within ≤ 5 letters (based on the ETDRS) for each 
respective eye. See Section 8.1 of the protocol. 
9. A visible EZ layer on SD-OCT in the TE, as determined by the Investigator. 
10. No limitations to SD-OCT image collection that would prevent high quality, 
reliable images from being obtained in both eyes, as determined by the 
Investigator. 
11. Reliable BCVA, perimetry, and other measurements in both eyes, as 
described in the Study Reference Manual and Imaging Manual and 
determined by the Investigator.  
12. No visually significant ocular media opacities and adequate pupillary dilation 
to permit good quality retinal imaging in both eyes, as assessed by the 
Investigator.  


 
 
 
 
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Protocol No. PQ-421a-003 (Version 3) 
 
ProQR Therapeutics 
 
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Exclusion Criteria Relating to Study Initiation: 
The subject is ineligible for the study if any of the following criteria apply at 
Screening/Day 1: 
1. Presence of additional non-exon 13 USH2A pathogenic mutation(s) on the 
USH2A allele carrying the exon 13 mutation in subjects who have mono-
allelic exon-13 mutations. 
2. Presence of non-exon 13 USH2A pathogenic mutation(s) on both USH2A 
alleles in subjects who have biallelic exon 13 mutations. 
3. Presence of pathogenic mutations in genes (other than the USH2A gene) 
associated with Usher syndrome Type 2 or NSRP, or other inherited retinal 
degenerative diseases or syndromes.  
Note: The confirmed presence of homozygous or compound heterozygous 
known disease-causing mutations in other genes involved in recessive retinal 
dystrophies (RD), or the confirmed presence of known disease-causing 
mutations in genes involved in dominant or X-linked retinal dystrophies is 
exclusionary. 
4. Presence of any significant ocular (in either eye) or non-ocular 
disease/disorder (or medication and/or laboratory test abnormalities) which, in 
the opinion of the Investigator and with concurrence of the Medical Monitor, 
may either put the subject at risk because of participation in the study, may 
influence the results of the study, or the subject’s ability to participate in the 
study. This includes but is not limited to a subject who has uncontrolled 
cystoid macular edema (CME). CME is permissible if stable for 3 months 
(with or without treatment). Past CME is permissible if resolved for more than 
1 month. 
5. History or presence of ocular herpetic diseases (including herpes simplex 
virus, varicella zoster or cytomegalovirus) in either eye. 
6. Presence of any suspected active ocular or periocular infection in either eye. 
7. Presence of any of the following lens opacities in either eye based on the age-
related eye diseases study (AREDS) lens grading scale: cortical opacity ≥ +2, 
posterior subcapsular opacity ≥ +2, or a nuclear sclerosis ≥ +2, and which are: 
1) clinically significant in the opinion of the Investigator, 2) would adequately 
prevent clinical and photographic evaluation of the retina. 
8. History of amblyopia in either eye that resulted in significant vision loss, in 
the opinion of the Investigator.  
9. Receipt within 3 months prior to Screening of any intraocular or periocular 
surgery (including refractive surgery), or an IVT injection, or planned 
intraocular surgery or procedure in either eye during the course of the study.  
For YAG laser treatment of a posterior capsular opacity, receipt within 1 
month prior to Screening or planned procedure in either eye during the course 
of the study. 
10. Current treatment or treatment within the past 12 months with therapies 
known to influence the immune system (including but not limited to steroid 
implants, cytostatics, interferons, tumor necrosis factor (TNF)-binding 
proteins, drugs acting on immunophilins, or antibodies with known impact on 
the immune system). Subjects that have been treated with systemic steroids 
within the past 12 months or that require intermittent use of topical steroids 
may be considered for inclusion following approval by the Medical Monitor. 
11. A history of glaucoma or an IOP greater than 21 mmHg in either eye that is 
not controlled with medication or surgery. IOP measurements between 21 and 
24 mmHg may be allowed however, the Investigator should discuss the case 
with the Medical Monitor. 


 
 
 
 
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Protocol No. PQ-421a-003 (Version 3) 
 
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12. Use of any investigational drug or device within 90 days or 5 half-lives 
preceding the first dose of study medication, whichever is longer, or plans to 
participate in another study of an investigational drug or device during the 
course of the study. 
13. Any prior treatment with genetic or stem-cell therapy for ocular or non-ocular 
disease. 
14. History of malignancy within 2 years prior to Screening, except adequately 
treated squamous or basal cell carcinoma of the skin or carcinoma in situ of 
the cervix that has been successfully treated. 
15. Known hypersensitivity to antisense oligonucleotides or any constituents of 
the injection. 
16. Pregnant and breastfeeding subjects. Females of childbearing potential and 
males must comply with using highly effective methods of contraception as 
defined in Section 6.2.2. Women of non-childbearing potential may be 
included without the use of adequate birth control, provided they meet the 
criteria in the protocol (see Section 6.2.2). 
Study Drug, Dosage and Mode 
of Administration: 
 
Two dose regimens will be tested: 
1. 180 µg loading dose, and 60 µg maintenance doses (180/60 g)  
2. 60 µg loading dose, and 60 µg maintenance doses (60/60 g) 
Duration of Treatment: 
24 months 
The Sponsor plans on providing access to ultevursen drug after the end of study 
(EOS) in an open-label extension study. 
Reference Therapy, Dosage 
and Mode of Administration: 
Sham procedure 
Statistical Methods: 
 
 
  
 
  
 
 
 
 
 
 


 
 
 
 
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TABLE OF CONTENTS 
 
CLINICAL STUDY PROTOCOL ...............................................................................................1 
INVESTIGATOR SIGNATURE PAGE......................................................................................2 
PROTOCOL APPROVAL PAGE ...............................................................................................3 
1.0 
SYNOPSIS ..........................................................................................................................4 
TABLE OF CONTENTS ............................................................................................................10 
LIST OF FIGURES .....................................................................................................................14 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................15 
2.0 
INTRODUCTION............................................................................................................18 
2.1 
Retinitis Pigmentosa ..............................................................................................18 
2.2 
Ultevursen for the Treatment of RP due to Mutations in Exon 13 of the 
USH2A Gene ..........................................................................................................19 
2.3 
Benefit Risk Assessment........................................................................................20 
2.4 
Study Rationale ......................................................................................................22 
2.5 
Measures to Minimize Bias ...................................................................................22 
2.6 
Dose Selection .......................................................................................................23 
2.7 
Study Population ....................................................................................................24 
3.0 
STUDY OBJECTIVES ....................................................................................................25 
3.1 
Primary Objective ..................................................................................................25 
3.2 
Secondary Objective ..............................................................................................25 
4.0 
STUDY OVERVIEW ......................................................................................................25 
4.1 
Criteria for Evaluation ...........................................................................................25 
4.1.1 
Primary Endpoints .................................................................................25 
4.1.2 
Secondary Endpoints .............................................................................25 
4.2 
Study Design ..........................................................................................................26 
4.2.1 
Study Plan .............................................................................................27 
4.2.2 
Emergency Unmasking Procedure ........................................................28 
4.2.3 
Stopping Criteria ...................................................................................28 
4.2.4 
Discontinuation of the Study .................................................................29 
5.0 
SELECTION OF STUDY POPULATION ...................................................................29 
5.1 
Study Population ....................................................................................................29 
5.2 
Selection of Subjects ..............................................................................................29 
5.3 
Eligibility Criteria ..................................................................................................30 
5.3.1 
Inclusion Criteria Relating to Study Initiation ......................................30 


 
 
 
 
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5.3.2 
Exclusion Criteria Relating to Study Initiation .....................................31 
6.0 
STUDY DRUG AND CONCOMITANT THERAPIES ...............................................32 
6.1 
Study Drug .............................................................................................................32 
6.1.1 
Study Drug Description and Supply .....................................................32 
6.1.2 
Placebo ..................................................................................................32 
6.1.3 
Study Drug Shipment and Storage ........................................................33 
6.1.4 
Study Drug Accountability and Reconciliation ....................................33 
6.1.5 
Dosage and Administration ...................................................................33 
6.2 
Concomitant Medications and Auxiliary Therapy .................................................34 
6.2.1 
Prohibited Concomitant Medications ....................................................34 
6.2.2 
Adequate Forms of Birth Control .........................................................34 
7.0 
STUDY VISITS ................................................................................................................35 
7.1 
Visit and Assessment Windows .............................................................................35 
7.2 
Screening................................................................................................................36 
7.3 
Dosing and Follow-up Visits .................................................................................37 
7.4 
End of Study Visit & Roll Over to Open Label Extension Study .........................37 
8.0 
STUDY ASSESSMENT PROCEDURES ......................................................................38 
8.1 
Efficacy ..................................................................................................................38 
8.2 
Safety .....................................................................................................................40 
8.2.1 
Adverse Events......................................................................................40 
8.2.2 
Laboratory Evaluations .........................................................................40 
8.2.3 
Ophthalmic Examinations .....................................................................41 
8.2.4 
Spectral Domain Optical Coherence Tomography ...............................41 
8.3 
Systemic Exposure .................................................................................................41 
8.4 
Immunogenicity .....................................................................................................41 
8.5 
Gene Sequencing ...................................................................................................42 
9.0 
ASSESSMENT OF SAFETY, ADVERSE EVENTS AND SERIOUS ADVERSE 
EVENTS............................................................................................................................42 
9.1 
Data Monitoring Committee ..................................................................................42 
9.2 
Definitions of Adverse Event, Serious Adverse Event, and Suspected 
Unexpected Serious Adverse Event .......................................................................42 
9.2.1 
Adverse Events......................................................................................42 
9.2.2 
Serious Adverse Events.........................................................................43 
9.2.3 
Suspected Unexpected Serious Adverse Reaction Definition ..............44 
9.2.4 
Adverse Events of Special Interest .......................................................44 
9.3 
Assessment of Adverse Events ..............................................................................45 


 
 
 
 
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9.3.1 
Assessment of Severity (Intensity) of Adverse Events .........................45 
9.3.2 
Assessment of the Relationship of Adverse Events to Study Drug ......45 
9.3.3 
Assessment of the Outcome of Adverse Events ...................................46 
9.4 
Reporting of Adverse Events .................................................................................46 
9.4.1 
Adverse Event Reporting Period ...........................................................46 
9.4.2 
Eliciting Adverse Events .......................................................................47 
9.4.3 
Recording Adverse Events and Serious Adverse Events ......................47 
9.5 
AESIs and Serious Adverse Events Notification ...................................................49 
9.6 
Expedited Reporting of Suspected Unexpected Serious Adverse Reactions .........50 
10.0 
STATISTICAL METHODOLOGY...............................................................................51 
10.1 
General Considerations ..........................................................................................51 
10.2 
Determination of Sample Size ...............................................................................51 
10.3 
Randomization and Masking .................................................................................52 
10.4 
Replacement of Subjects ........................................................................................52 
10.5 
Analysis Populations ..............................................................................................52 
10.6 
Subject Disposition, Demographics and Baseline Disease Characteristics ...........53 
10.7 
Treatment Compliance ...........................................................................................53 
10.8 
Efficacy Analyses ..................................................................................................53 
10.9 
Safety Analyses ......................................................................................................54 
10.9.1 
Treatment Emergent Adverse Events....................................................54 
10.9.2 
Other Safety Assessments .....................................................................54 
10.10 18-Month Primary Analysis and 24-Month/EOS Analysis ...................................54 
10.11 Multiplicity Considerations ...................................................................................55 
10.12 Subgroup Analyses ................................................................................................55 
10.13 Systemic Exposure Analyses .................................................................................55 
11.0 
QUALITY CONTROL AND QUALITY ASSURANCE .............................................55 
11.1 
Data Collection ......................................................................................................55 
11.2 
Data Quality Control ..............................................................................................56 
11.3 
Monitoring .............................................................................................................56 
11.4 
Audits and Inspections ...........................................................................................57 
12.0 
ETHICAL AND REGULATORY OBLIGATIONS ....................................................57 
12.1 
Ethical Considerations ...........................................................................................57 
12.2 
Informed Consent...................................................................................................57 
12.3 
Ethics and Regulatory Review ...............................................................................57 
12.4 
Subject Confidentiality ..........................................................................................58 
13.0 
STUDY ADMINISTRATION ........................................................................................59 


 
 
 
 
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13.1 
Investigator’s Brochure ..........................................................................................59 
13.2 
Protocol Amendments ............................................................................................59 
13.3 
Study Termination and Procedure .........................................................................59 
13.4 
Study Documentation and Storage .........................................................................60 
13.5 
Use of Information .................................................................................................60 
13.6 
End of Study and Final Report...............................................................................61 
13.7 
Financing and Insurance ........................................................................................61 
13.8 
Publication Policy ..................................................................................................61 
14.0 
REFERENCES .................................................................................................................62 
15.0 
PROTOCOL SUMMARY OF CHANGES ...................................................................64 
16.0 
APPENDICES ..................................................................................................................65 
 
16.2 
Appendix 2: Clinical Laboratory Tests ..................................................................68 
 


 
 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
Abbreviation 
Definition 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of covariance 
AON 
Antisense Oligonucleotide 
AREDS 
Age-Related Eye Diseases Study 
AST 
Aspartate Aminotransferase 
BCVA 
Best Corrected Visual Acuity 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CE 
Contralateral Eye 
CFR 
Code of Federal Regulations 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CME 
Cystoid Macular Edema 
CRP 
C-Reactive Protein 
CSR 
Clinical Study Report 
DHA 
Docosahexaenoic Acid 
DMC 
Data Monitoring Committee 
DP 
Drug Product 
EC 
Ethics Committee 
EZ 
Ellipsoid Zone 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
eGFR 
Estimated Glomerular Filtration Rate 
EOS 
End of Study 
ERG 
Electroretinogram 
FAS 
Full-Analysis Set 
FDA 
Food and Drug Administration 
FIH 
First-in-human 
FST 
Full-field Stimulus Threshold  
GCP 
Good Clinical Practice 


 
 
 
 
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Abbreviation 
Definition 
γGT 
Gamma-Glutamyl Transferase 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation  
INR 
International Normalized Ratio 
IOP 
Intraocular Pressure 
iPSC 
Induced Pluripotent Stem Cells 
IRB 
Institutional Review Board 
IVT 
Intravitreal 
IWRS 
Interactive Web Response System 
LDH 
Lactic Dehydrogenase 
LLVA 
Low Luminance Visual Acuity 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRNA 
Messenger Ribonucleic Acid 
NSRP 
Non-syndromic Retinitis Pigmentosa 
PBS 
Phosphate buffered saline 
PGI-C 
Patient Global Impressions of Change 
PGI-S 
Patient Global Impressions of Severity 
PRO 
Patient Reported Outcome 
ProQR 
ProQR Therapeutics 
PT 
Preferred Term 
RNA 
Ribonucleic Acid 
RD 
Retinal Dystrophies 
RP 
Retinitis Pigmentosa 
RTU 
Ready to Use 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD-OCT 
Spectral Domain Optical Coherence Tomography 
SMP 
Safety Management Plan 
SOC 
System Organ Class 
SOE 
Schedule of Events 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TE 
Treated Eye 
TEAE 
Treatment Emergent Adverse Event 


 
 
 
 
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Abbreviation 
Definition 
TLF 
Table Listing Figure format 
TNF 
Tumor Necrosis Factor 
US 
United States 
VA LV VFQ-20 
Veterans Affairs Low Vision Visual Functioning Questionnaire 
VF 
Visual Field 
WBC 
White Blood Cell 
WOCBP 
Women of Childbearing Potential 
 
 


 
 
 
 
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2.0 
INTRODUCTION 
ProQR Therapeutics (ProQR) is developing an oligonucleotide product, ultevursen, for the 
treatment of patients with retinitis pigmentosa (RP) caused by mutations in exon 13 of the 
USH2A gene. The primary goal of the development plan for ultevursen is to provide treatment to 
overcome the genetic defect in patients with pathogenic mutations in exon 13 of the USH2A 
gene, resulting in functional vision restoration or preservation. The intended route of 
administration is intravitreal (IVT) injection. 
2.1 
Retinitis Pigmentosa 
Retinitis pigmentosa is a clinically and genetically heterogeneous condition and mutations in 
over 100 genes have been implicated. USH2A mutations represent the most common cause of 
autosomal recessive RP (Hartong 2006).  
Pathogenic mutations in the USH2A gene disrupt the production of usherin, a protein expressed 
in photoreceptors where it is required for their maintenance (Liu 2007). In the eye, defects in 
usherin cause RP. Usherin is also expressed in the ear, where it is required for normal 
development of cochlear hair cells and hence, normal hearing.  
Mutations in exon 13 of the USH2A gene result in both non-syndromic and syndromic forms of 
RP. In the NSRP, RP is not associated with other signs and symptoms as part of a genetic 
syndrome. In the syndromic form, known as Usher syndrome type 2, patients present with 
congenital moderate to severe hearing loss, and later detection of the retinal disease (i.e., RP). 
Affected patients first experience defective dark adaption, with decreased night vision, around 
the second decade of life, and subsequent loss of peripheral visual field (VF) when photoreceptor 
degeneration progresses, eventually leading to only a residual central island of vision, which 
ultimately progresses to complete blindness. Early onset deafness is attributable to genetic causes 
in at least 50% of cases (Marazita 1993). 
The number of patients with RP due to mutations in exon 13 of the USH2A gene is estimated to 
be around 16,000 in the Western World (United States, Canada, Europe, and Australia) from 
gene databases. While the hearing deficit in patients with Usher syndrome can be at least 
partially restored using hearing aids or cochlear implants, there is no approved treatment for the 
retinal disease in NSRP or RP in Usher syndrome type 2 and disease management is supportive. 
Vitamin A and docosahexaenoic acid (DHA) supplementations have been proposed as 
pharmacological treatment options. Both therapies showed a good safety profile but limited 
clinical benefit. 


 
 
 
 
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2.2 
Ultevursen for the Treatment of RP due to Mutations in Exon 13 of the USH2A 
Gene 
The primary goal of the development plan for ultevursen is to provide treatment to overcome the 
genetic defect in patients with pathogenic mutations in exon 13 of the USH2A gene, resulting in 
functional vision restoration or preservation. 
 
 
 
 
 
 
 
. Reference is made to the IB for further details. 


 
 
 
 
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2.3 
Benefit Risk Assessment 
Retinitis Pigmentosa is a group of inherited eye disorders causing slow photoreceptor 
degeneration, leading to progressive vision loss. Affected patients first experience defective dark 
adaption, peripheral visual field loss when photoreceptor degeneration progresses, and eventually 
have only a residual central island of vision, which ultimately progresses to complete blindness. 
There are currently no approved therapies for the treatment of RP patients with mutations in 
exon 13 of the USH2A gene and disease management is supportive. They may receive adaptive 
support, when necessary. In addition, patients usually receive genetic counselling on the risks of 
passing the condition on to their children and regular medical follow up. A significant unmet 
medical need exists in this sight-threatening condition. 
The design of this study has been selected to provide a sufficient benefit-risk ratio to justify the 
participation of subjects. Planned doses are expected to result in retinal concentrations in the 
efficacious range. In addition, multiple measures are incorporated to ensure the safety of 
participating subjects. 


 
 
 
 
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To address the potential risks defined in the toxicology studies, the reported risks from 
oligonucleotides administered by IVT injection, and the risks associated with the IVT injection 
procedure, extensive monitoring to protect subject safety is incorporated in this study. This will 
include assessments of subjects’ ophthalmic function and anatomy, in particular, monitoring of 
anterior, intermediate and posterior segment inflammation by slit-lamp biomicroscopy, clinical 
lens grading using the Age-Related Eye Diseases Study (AREDS) Clinical Lens Grading 
System, and monitoring for retinal changes by OCT and dilated fundus examinations. This 
extensive clinical monitoring provides a means to allow early detection of potential AEs, such as 
macular edema, changes in BCVA and IOP, detection of intraocular inflammation, lens 
opacities, and retinal structural modifications. In addition, the visit schedule is designed to 
monitor subjects one day following IVT injection and a second time within 1 week of IVT 
injection to monitor for signs of endophthalmitis and intraocular inflammation, consistent with 
guidelines for IVT injections (Avery 2014).  


 
 
 
 
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While the number of subjects is small, these results, and the positive benefit-risk assessment 
support continued clinical testing of ultevursen.  
Detailed information about benefits and potential risks of ultevursen, as well as information on 
nucleotide AONs as a class of therapeutics can be found in the IB.  
There is a risk with the ongoing COVID-19 pandemic, that subjects may be exposed and contract 
COVID-19 while attending the clinic for scheduled visits, or unable to attend the clinic due to 
regional restrictions associated with pandemic response measures. COVID-19 exposure 
mitigation strategies, in accordance with local regulatory and site standard of care medical 
practices will be in place to minimize exposure risk. Extensions of the visit window or alterations 
in the SOE can be approved by the Medical Monitor, where required. Any modifications will be 
in accordance with applicable local regulatory guidelines and documented as a deviation. 
2.4 
Study Rationale 
There are currently no approved therapies for the treatment of RP due to mutations in exon 13 of 
the USH2A gene and disease management is supportive; therefore, an important unmet medical 
need exists in this condition. 
Study PQ-421a-003 aims to define safety and quantify the treatment effect of ultevursen 
administered via IVT injection in subjects with RP due to mutations in exon 13 of the USH2A 
gene, relative to masked, untreated control subjects, at 2 dose regimens of ultevursen. 
2.5 
Measures to Minimize Bias  
To facilitate interpretation of clinical data, inclusion of randomized, concurrent parallel control 
groups is recommended for clinical studies whenever possible. Masking of participating subjects, 
treating physicians and study staff is of particular importance when subject effort or perception 


 
 
 
 
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could bias evaluation of study endpoints, such as for measurement of visual acuity (Glassman 
2012).  
IVT injection is a well-established route of administration within ophthalmic indications that 
permits targeting of the therapeutic agent to the eye, while minimizing systemic absorption. IVT 
injection is used in several products for the chronic treatment of ophthalmic diseases 
(e.g., Lucentis®, Eylea™, Macugen®) and the risk of complications is low when injections are 
performed by trained ophthalmologists (AAO 2015, Avery 2014). 
However, potentially severe complications to IVT injections exist, including endophthalmitis, 
intraocular inflammation, cataract, retinal detachment, and vitreous hemorrhage. Although the 
risk of severe complications is small, it is well documented (Jager 2004). Therefore, while IVT 
injection of the vehicle alone is theoretically feasible as a placebo control, it is not considered 
ethical since the physical properties of such an injection do not have potential therapeutic 
benefit. Hence, placebo injections will not be administered in this study to preserve subject 
safety.  
Other possibilities than placebo injections to effect masking include alternative dosing regimens, 
alternative dose levels, and existing products approved for the indication being sought. There are 
no existing approved products for the indication under investigation. 
Use of sham-procedures (i.e., no penetration of the globe) to mask subjects to treatment 
assignment in studies of products administered via IVT injections eliminates the risk of 
complications due to injection in the control arm. The sham-procedure, which closely mimics the 
injection procedure used for product delivery can effectively mask participants to treatment 
assignment; however, the masking effect is less pronounced in the case that a single subject 
receives both the real and sham injections in their 2 eyes (Glassman 2012). 
To reduce bias due to effort and subjectivity, masking will be achieved by use of a sham- 
procedure (see Study Reference Manual for details) as well as testing of 2 different dose levels, 
and no subject will receive both ultevursen and sham injection.  
Drug administration, as well as clinical monitoring of the subject during and right after 
administration of study treatment, will be performed by a separate, unmasked physician (see 
Section 4.2.1.3), and clinical assessments (including efficacy and safety assessments) will be 
performed by a masked physician. A masked central reading center will be used for 
ophthalmologic assessments including microperimetry, FST, and SD-OCT.  
2.6 
Dose Selection 


 
 
 
 
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The target regimen of ultevursen will consist of a loading dose of 180 µg, followed by 
maintenance doses of 60 µg after 3 months, and at 6 monthly intervals thereafter. The use of a 
loading dose followed by maintenance doses aims at reaching steady state (efficacious) levels in 
the retina from the first injection, to maximize clinical response and the potential to provide 
benefit to the subject. A second arm will test the efficacy and safety of a dose regimen of 
ultevursen without a high loading dose (i.e., 60 µg loading dose, followed by 60 µg maintenance 
dose at month 3, and every 6 months thereafter). 
As AONs are readily distributed to all eye tissues, and the vitreous is not acting as a drug 
reservoir, the axial length and overall eye volume are considered the most important parameter 
for determining the ultevursen dose and the highest recommended IVT injection volume. At 
around 3 years of age, the human eye is fully developed, and the compartmental volume is 90% 
of that in adulthood (Fledelius 2014, Vinekar 2015). The axial length of the eye changes from 
approximately 16 to 18 mm at birth, 19.5 mm in infants, 23 mm in 3-year-olds, until 22 to 24 
mm in adults (Hellstrom 1997).
 
 
2.7 
Study Population 
Eligible subjects will be 12 years of age or older and have a molecular diagnosis of either 
homozygosity or compound heterozygosity for at least one pathogenic mutation in exon 13 of the 
USH2A gene. All subjects must be free of confounding non-exon 13 USH2A mutations and/or 
other pathologies that may interfere with the interpretation of study results, with participation 
and/or compliance in the study, or put the subject at increased risk due to participation.  
At the time of screening, to determine eligibility, subjects will undergo anatomical and structural 
assessments of both eyes and must exhibit a clinical presentation consistent with RP due to 
Usher syndrome type 2 or NSRP, as assessed by the Investigator.  
Reference is made to Section 5.3 for specific eligibility requirements. 


 
 
 
 
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3.0 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of ultevursen. 
3.2 
Secondary Objective 
The secondary objectives of the study are: 
• To further evaluate the efficacy of ultevursen 
• To evaluate the safety and tolerability of ultevursen  
• To evaluate changes in PRO measures in subjects treated with ultevursen 
• To evaluate the systemic exposure of ultevursen  
4.0 
STUDY OVERVIEW 
4.1 
Criteria for Evaluation 
The primary endpoint will be assessed at 18 months of treatment. All other efficacy and safety 
parameters will also be reported at that time point. All efficacy and safety assessments will 
continue to be followed up until Month 24. 
4.1.1 
Primary Endpoints 
• Mean change from baseline in BCVA (based on ETDRS chart) at 18 months of 
treatment versus sham-procedure  
4.1.2 
Secondary Endpoints 
The order in which the secondary endpoints will be analysed will be defined in the SAP. 
 
Key Secondary Endpoints (Efficacy) 
o Proportion of subjects who maintain vision defined by BCVA loss less than 
15 Letters (based on ETDRS) 
Other Secondary Endpoints (Efficacy) 
o Other analyses of BCVA  
o EZ area and width as imaged by SD-OCT 
o LLVA 
o Microperimetry 
o FST 
Secondary Endpoints (Safety and Tolerability) 


 
 
 
 
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• Ocular and non-ocular AEs 
Secondary Endpoints (PROs) 
• Change from baseline in PRO measures, as assessed by: 
o Veterans Affairs Low Vision Visual Functioning Questionnaire (VA LV 
VFQ-20) (Stelmack 2007) 
o Patient Global Impressions of Severity (PGI-S) 
o Patient Global Impressions of Change (PGI-C) 
Secondary Endpoints (Systemic Exposure) 
• Exposure of ultevursen in serum 
4.2 
Study Design 
PQ-421a-003 is a double-masked, randomized, controlled, multiple-dose study to evaluate the 
efficacy, safety, and tolerability of ultevursen in subjects with RP due to mutations in exon 13 of 
the USH2A gene.  
At study start subjects will be randomized to one of the following treatment groups: 
• Group 1: Ultevursen 180/60 µg (180 µg loading dose administered on Day 1, 60 µg 
maintenance dose administered at Month 3 and every 6 months thereafter; n = 27) 
• Group 2: Ultevursen 60/60 µg (60 µg loading dose administered on Day 1, 60 µg 
maintenance dose administered at Month 3 and every 6 months thereafter; n = 27) 
• Group 3: Sham-procedure (administered on Day 1, Month 3 and every 6 months 
thereafter; n = 27) 
The primary endpoint will be assessed at 18 months of treatment. Analysis of all other efficacy 
and safety parameters will also be reported at that time point. All efficacy and safety parameters 
will continue to be followed until Month 24.  
The same safety monitoring protocol and efficacy assessments will apply to both eyes.  
Dosing will be only in the TE (i.e., study eye). The CE will not be dosed. 
Changes to the above-described treatment plan may be warranted and will be guided by the 
ongoing assessment of benefit-risk, with concurrence from the Medical Monitor. 


 
 
 
 
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4.2.1 
Study Plan  
4.2.1.1 
Screening 
During the screening period, subjects will be assessed according to the eligibility criteria. 
Subjects who meet all eligibility criteria will be enrolled into the study. Reference is made to 
Section 7.2 for more details on the screening process.  
Assessments can be completed over multiple, non-consecutive days instead of 1 full day, at the 
discretion of the Investigator. 
4.2.1.2 
Study Drug Administration 
Subjects will receive study drug via IVT injection in accordance with the procedures outlined by 
the current international guidelines (AAO 2015; Avery 2014) and as outlined in the Study 
Reference Manual.  
Administration of study treatment, as well as clinical monitoring and evaluation of subject’s 
safety during and right after administration of study treatment, will be performed by an 
unmasked physician, but clinical assessments (including efficacy and safety assessments) will be 
performed by a separate, masked physician. Specific study drug and sham-procedure 
administration procedures can be found in the Study Reference Manual. 
After each dosing, subjects will be assessed for safety and tolerability at follow-up visits. 
4.2.1.3 
Assessments and Follow-up 
On the dosing days post study treatment, subjects will be monitored for safety, including IOP, 
optic nerve swelling and signs of inflammation. An unmasked physician will administer the 
study treatment and monitor right after administration. The clinical monitoring and evaluation of 
subject’s safety by the unmasked physician during and right after administration of the study 
treatment include e.g., IOP, verification that the retina is attached, and checking for hemorrhage 
and signs of intraocular inflammation.
  


 
 
 
 
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The frequency of all assessments is presented in the SOE 
. See Section 7.2  for 
details on dosing and follow-up visit procedures. More frequent evaluation may be undertaken 
for an individual subject to monitor safety at the discretion of the Investigator. Data for all 
unscheduled visits should be recorded in the electronic case report form (eCRF). 
Assessments can be completed over multiple, non-consecutive days instead of 1 full day, at the 
discretion of the Investigator. 
All ophthalmic assessments will be performed on both the TE and CE. 
The primary endpoint will be assessed at 18 months of treatment. Available data on other 
efficacy and safety parameters will also be reported at that time point. All efficacy and safety 
parameters will continue to be followed up until Month 24
 For subjects 
completing the study, the Sponsor plans on providing access to study drug and/or continued 
follow up after the EOS visit, in an open-label extension study. 
4.2.2 
Emergency Unmasking Procedure 
In the event of a medical emergency, when knowledge of treatment assignment is needed for 
immediate medical management of the subject’s health, the Investigator can obtain unmasked 
treatment assignment through the centralized Interactive Web Response System (IWRS) at any 
time. Instructions on how to unmask subjects will be provided in the eCRF completion 
guidelines. Thorough documentation of the rationale for unmasking is required along with 
prompt notification to the Medical Monitor that unmasking has taken place, however this should 
not delay the unmasking. 
4.2.3 
Stopping Criteria 
4.2.3.1 
Stopping Criteria for Individual Subjects 
 
 
The Investigator may also discontinue a subject from study treatment for other reasons 
 
 Reference is made to 
Section 9.4.1 for required follow-up by the Investigator in case of ongoing (serious) AEs at the 
time of study treatment discontinuation. Any subject discontinued from study treatment is to 
have the reason recorded in the eCRF.   


 
 
 
 
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If a subject is discontinued from the study, his/her subject number cannot be reused. 
  
4.2.3.2 
Subject Withdrawal 
Subjects are free to withdraw from the study at any time. However, subjects will be encouraged 
to remain in the study for safety follow-up whenever possible through the EOS visit. A subject 
who withdraws consent will always be asked about the reason(s) and the presence of any AEs. 
The Investigator should make every attempt to encourage the subject to remain in the study for 
observation (at least) through the Month 24 Visit (see also Section 9.4.1). The Investigator 
should follow up on AEs outside of the clinical study to ensure subject safety; however, no data 
on such events will be collected for study purposes. 
4.2.4 
Discontinuation of the Study 
4.2.4.1 
Efficacy 
The final inferential analyses will be performed at the planned primary time point at Month 18. 
Analyses at other (earlier or later) time points will be considered as exploratory. Hence, there are 
no planned inferential interim analyses (i.e., for either a futility or efficacy claim) and therefore 
no associated stopping rules. 
4.2.4.2 
Safety 
The DMC and Medical Monitor will evaluate the safety and tolerability data at pre-specified 
time points (defined in the DMC charter, Section 9.1) and on an ad hoc basis as needed (Section 
4.2.3), leading to a recommendation (by the DMC) and subsequently a decision (by the Sponsor) 
if the study should continue or cease, or if any modifications should be made as to how subjects 
are treated or managed. Reference is also made to Section 13.3. 
5.0 
SELECTION OF STUDY POPULATION  
5.1 
Study Population 
Subjects with a diagnosis of RP due to mutations in exon 13 of the USH2A gene who meet all 
eligibility criteria will be eligible for participation in this study. 
5.2 
Selection of Subjects 
Screening of subjects will be performed within 12 weeks prior to dosing. Screening will take 
place over at least 2 days. The treatment visit (Day 1) should be performed as soon as possible 
after Screening, where feasible.  
Subjects will be evaluated against all eligibility criteria as presented in the SOE 
 If a subject would not be eligible in the opinion of the Sponsor’s Medical Monitor, after 


 
 
 
 
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discussion with the Investigator, it may be decided that the subject cannot participate in the 
study.  
Results of assessments for all eligibility criteria must be available and reviewed prior to the 
subject’s dose of study treatment. 
5.3 
Eligibility Criteria 
5.3.1 
Inclusion Criteria Relating to Study Initiation 
The subject is eligible for the study and thus eligible to receive ultevursen or sham-procedure in 
the TE if all the following inclusion criteria apply at Screening/Day 1: 
1. An adult (≥ 18 years) willing and able to provide informed consent for participation prior to 
performing any study related procedures, and suitable verbal, auditory, written and/or tactile 
sign language communication as to allow informed consent to be obtained, in the opinion of 
the Investigator. 
OR 
A minor (12 to < 18 years) with a parent or legal guardian willing and able to provide written 
permission for the subject’s participation prior to performing any study related procedures 
and pediatric subjects able to provide age appropriate assent for study participation. The 
lower age limit for pediatric populations is subject to local regulatory and ethics committee 
requirements (e.g., 16 to <18 for Norway). 
2. An adult willing to comply with the protocol, follow study instructions, attend study visits as 
required and willing and able to complete all study assessments.  
OR  
A minor able to complete all study assessments and comply with the protocol, and has a 
parent or caregiver willing and able to follow study instructions, and attend study visits with 
the subject as required. 
3. Clinical presentation consistent with RP with Usher syndrome type 2 or non-syndromic form 
of RP (NSRP), based on ophthalmic, audiologic, and vestibular examinations. 
4. A molecular diagnosis of homozygosity or compound heterozygosity for 1 or more 
pathogenic exon 13 mutations in the USH2A gene, based on genetic analysis at screening.  
5. BCVA between ≥30 and ≤68 letters (approximate Snellen equivalent 20/250 – 20/50) in the 
TE, using the mean BCVA reading at Screening (see Section 8.1) and based on ETDRS. 
Subjects with a mean BCVA between >68 and ≤73 letters will be allowed with documented 
historic evidence of a BCVA equivalent decline of >5 letters in both eyes (i.e., >1 line 
decline using Snellen or >0.1 LogMAR) anytime within the last 18 months relative to 
Screening. 
6. BCVA between ≥30 and ≤73 letters (approximate Snellen equivalent 20/250 – 20/40) in the 
CE, using the mean BCVA reading at Screening (see Section 8.1) and based on the ETDRS.  
7. A difference in mean BCVA readings at Screening between the TE and CE of ≤10 letters 
(based on ETDRS). BCVA differences between eyes that are greater than 10 letters may be 
allowed however, the Investigator should discuss the case with the Medical Monitor.  


 
 
 
 
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8. Stable BCVA in the TE and CE, defined as 2 separate BCVA measurements at Screening 
that fall within ≤ 5 letters (based on the ETDRS) for each respective eye. See Section 8.1 of 
the protocol. 
9. A visible EZ layer on SD-OCT in the TE, as determined by the Investigator. 
10. No limitations to SD-OCT image collection that would prevent high quality, reliable images 
from being obtained in both eyes, as determined by the Investigator. 
11. Reliable BCVA, perimetry, and other measurements in both eyes, as described in the Study 
Reference Manual and Imaging Manual and determined by the Investigator.  
12. No visually significant ocular media opacities and adequate pupillary dilation to permit good 
quality retinal imaging in both eyes, as assessed by the Investigator. 
 
5.3.2 
Exclusion Criteria Relating to Study Initiation 
The subject is ineligible for the study if any of the following criteria apply at Screening/Day 1: 
1. Presence of additional non-exon 13 USH2A pathogenic mutation(s) on the USH2A allele 
carrying the exon 13 mutation in subjects who have mono-allelic exon-13 mutations. 
2. Presence of non-exon 13 USH2A pathogenic mutation(s) on both USH2A alleles in subjects 
who have biallelic exon 13 mutations. 
3. Presence of pathogenic mutations in genes (other than the USH2A gene) associated with 
Usher syndrome Type 2 or NSRP, or other inherited retinal degenerative diseases or 
syndromes.  
Note: The confirmed presence of homozygous or compound heterozygous known disease-
causing mutations in other genes involved in recessive retinal dystrophies (RD), or the 
confirmed presence of known disease-causing mutations in genes involved in dominant or X-
linked retinal dystrophies is exclusionary. 
4. Presence of any significant ocular (in either eye) or non-ocular disease/disorder (or 
medication and/or laboratory test abnormalities) which, in the opinion of the Investigator and 
with concurrence of the Medical Monitor, may either put the subject at risk because of 
participation in the study, may influence the results of the study, or the subject’s ability to 
participate in the study. This includes but is not limited to a subject who has uncontrolled 
cystoid macular edema (CME). CME is permissible if stable for 3 months (with or without 
treatment). Past CME is permissible if resolved for more than 1 month. 
5. History or presence of ocular herpetic diseases (including herpes simplex virus, varicella 
zoster or cytomegalovirus) in either eye. 
6. Presence of any suspected or active ocular or periocular infection in either eye. 
7. Presence of any of the following lens opacities in either eye based on the age-related eye 
diseases study (AREDS) lens grading scale: cortical opacity ≥ +2, posterior subcapsular 
opacity ≥ +2, or a nuclear sclerosis ≥ +2, and which are: 1) clinically significant in the 
opinion of the Investigator, 2) would adequately prevent clinical and photographic evaluation 
of the retina. 
8. History of amblyopia in either eye that resulted in significant vision loss, in the opinion of 
the Investigator.  


 
 
 
 
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9. Receipt within 3 months prior to Screening of any intraocular or periocular surgery 
(including refractive surgery), or an IVT injection other or planned intraocular surgery or 
procedure in either eye during the course of the study. For YAG laser treatment of a posterior 
capsular opacity, receipt within 1 month prior to Screening or planned procedure in either 
eye during the course of the study. 
10. Current treatment or treatment within the past 12 months with therapies known to influence 
the immune system (including but not limited to steroid implants, cytostatics, interferons, 
tumor necrosis factor (TNF)-binding proteins, drugs acting on immunophilins, or antibodies 
with known impact on the immune system). Subjects that have been treated with systemic 
steroids within the past 12 months or that require intermittent use of topical steroids may be 
considered for inclusion following approval by the Medical Monitor. 
11. A history of glaucoma or an IOP greater than 21 mmHg in either eye that is not controlled 
with medication or surgery. IOP measurements between 21 and 24 mmHg may be allowed 
however, the Investigator should discuss the case with the Medical Monitor. 
12. Use of any investigational drug or device within 90 days or 5 half-lives preceding the first 
dose of study medication, whichever is longer, or plans to participate in another study of an 
investigational drug or device during the course of the study. 
13. Any prior treatment with genetic or stem-cell therapy for ocular or non-ocular disease. 
14. History of malignancy within 2 years prior to Screening, except adequately treated squamous 
or basal cell carcinoma of the skin or carcinoma in situ of the cervix that has been 
successfully treated. 
15. Known hypersensitivity to antisense oligonucleotides or any constituents of the injection. 
16. Pregnant and breastfeeding subjects. Females of childbearing potential and males must 
comply with using highly effective methods of contraception as defined in Section 6.2.2. 
Women of non-childbearing potential may be included without the use of adequate birth 
control, provided they meet the criteria in the protocol (see Section 6.2.2). 
 
6.0 
STUDY DRUG AND CONCOMITANT THERAPIES 
6.1 
Study Drug 
6.1.1 
Study Drug Description and Supply 
The ultevursen study drug is a solution for IVT injection. 
  
Please refer to the Pharmacy Manual and Study Reference Manual for additional details. 
6.1.2 
Placebo 
No placebo is used.  


 
 
 
 
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6.1.3 
Study Drug Shipment and Storage 
Please refer to the Pharmacy Manual for details on shipment, storage, handling and dose 
preparation. For administration, please refer to the Study Reference Manual. 
6.1.4 
Study Drug Accountability and Reconciliation 
The Investigator must designate a research pharmacist or other staff member to maintain an 
inventory record of drugs received and dispensed. Additional details on study drug 
accountability are provided in the Pharmacy Manual and the Study Reference Manual.  
Forms are provided to facilitate the inventory control. These forms must be used unless the 
Investigator (or designee) has previously established a system that complies with local 
regulations and is approved by the Sponsor. The study drug must be dispensed only at the 
institution(s) specified on form Food and Drug Administration (FDA) 1572 or Statement of 
Investigator (as applicable). 
Upon completion or termination of the study and after inventory by a Sponsor representative 
(monitor), it will be determined if unopened study drug vials are to be sent to the Sponsor in the 
original containers or are to be destroyed at the study center.  
6.1.5 
Dosage and Administration 
Two dose regimens of ultevursen will be tested: 
1. 180 µg loading dose, 60 µg maintenance dose (180/60 g)  
2. 60 µg loading dose, 60 µg maintenance dose (60/60 g) 
 
 The physician administering study treatment will be unmasked to assignment of 
study drug or sham-procedure but will be masked to the dose of study drug. Treatment 
assignment will be through the centralized IWRS for the study. The physician performing the 
clinical assessments will be masked. All subjects will be masked to study treatment assignment. 
Subjects will receive ultevursen via IVT injection or will undergo a sham-procedure. 
Administration of ultevursen and the sham-procedure will only be performed by qualified 
ophthalmologists in an in-clinic setting. No other medications should be mixed with ultevursen.  
Reference is made to the Study Reference Manual and Pharmacy Manual for detailed 
instructions on the IVT injection and the sham-procedure. 


 
 
 
 
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6.2 
Concomitant Medications and Auxiliary Therapy 
The medications usually used in ophthalmology care are permitted, including but not limited to: 
topical anesthetic agents, carbonic anhydrase inhibitors (intravenous, oral, topical), alpha 
agonists ophthalmic drops, rho kinase inhibitor ophthalmic drops, beta blocker ophthalmic 
solutions, prostaglandin analog ophthalmic solutions, ophthalmic solutions/gels of 
corticosteroids, non-steroidal anti-inflammatory ophthalmic drops, antibiotics and antiseptics, 
topical agents for pupillary dilatation, artificial tears and anti-allergic ophthalmic solutions, in 
accordance with the approved Label or Summary of Product Characteristics of the products. Use 
of topical steroids should be initiated only when other treatments have been deemed 
ineffective/unsafe for the subject.   
The concomitant medications recommended for IVT injection are detailed in the Study 
Reference Manual.  
There are no medicinal products classified as auxiliary in this clinical trial. 
6.2.1 
Prohibited Concomitant Medications 
The use of any investigational drug or device within 90 days or 5 half-lives of the drug at Day 1, 
whichever is longer, or plans to participate in another clinical study during the study period is 
prohibited. Medications that are known to be toxic to the lens, retina, or optic nerve are 
prohibited. These may include, but are not limited to: systemic/intraocular steroids, amiodarone, 
deferoxamine, chloroquine/hydroxychloroquine sulfate, tamoxifen, phenothiazines, and 
ethambutol, pentosan polysulfate, etc. Topical steroids are not prohibited but should only be used 
following consultation with the Medical Monitor (see Section 6.2). 
During the study, use of any new medication or change in the dose of a medication that may 
have side effects on vision will need to be reviewed and approved by the Medical Monitor. 
6.2.2 
Adequate Forms of Birth Control 
Women of childbearing potential (WOCBP; i.e., fertile, following menarche and until becoming 
postmenopausal unless permanently sterile) and fertile male subjects (i.e., after puberty unless 
permanently sterile) must either practice true abstinence in accordance with their preferred and 
usual lifestyle, 
 A postmenopausal state is defined as no menses for 12 
months without an alternative medical cause. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A man is considered fertile 
unless permanently sterile by bilateral orchiectomy or has undergone vasectomy and received 
medical assessment of surgical success. 
Highly effective methods of birth control include: 


 
 
 
 
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• Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal, transdermal) 
• Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable, implantable) 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized partner (provided that the partner is the sole sexual partner and has 
received medical assessment of the surgical success) 
• Sexual abstinence: sexual abstinence must be true abstinence which is the preferred and 
usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods), declaration of abstinence for the duration of the 
study, and withdrawal are not acceptable methods of contraception 
Double barrier methods (a combination of condom with cap, diaphragm, or sponge with 
spermicide) are not considered highly effective. 
Women of non-childbearing potential (i.e., not fertile, before menarche, postmenopausal, or 
permanently sterilized) may be included without the use of adequate birth control, provided they 
meet the criteria in the protocol.  
Birth control measures must be employed during the time of participation (beginning at the 
Screening Visit) in this study and must be continued
  
A man who is fertile should use a condom during treatment and until 
 
7.0 
STUDY VISITS 
All study visits, assessments and procedures should be completed as indicated per the SOE 
 
  
7.1 
Visit and Assessment Windows 
For those procedures for which a specific time point post dose is required (e.g., systemic 
exposure blood draws), the protocol refers to nominal times. Actual times for such assessments 
are to be recorded in the source documentation and in the eCRFs, and if any time points are 


 
 
 
 
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missed, the reasons are also to be recorded. For more details, please refer to the case report form 
completion guidelines. 
 
Visits and/or assessments can be completed over multiple, non-consecutive days.  
 
All efforts should be made to prevent missing data. Therefore, deviations from the treatment 
cycle (and subsequent assessments) may be justified in some cases (e.g., if an AE makes 
treatment impossible at the schedule dosing day). In exceptional cases, e.g., related to the 
significant restrictions in site activities or subject’s ability to travel to sites for visits as occurring 
related to the COVID-19 pandemic, extensions of the visit window or alterations in the SOE can 
be approved by the Medical Monitor. Such extensions of the visit window will be documented as 
protocol deviations. Still, sites should make every reasonable effort to complete scheduled visits 
within the time windows defined in this protocol. 
7.2 
Screening 
Prior to or at the first Screening visit a sample for gene sequencing analysis will be obtained (see 
Section 8.5 for further details). In case the sample for gene sequencing analysis will be obtained 
prior to the first Screening visit, a separate Informed Consent Form (ICF) and/or assent is 
available for this purpose (see Section 12.2).
 
 
During the screening period, subjects will be assessed according to the eligibility criteria and 
specified assessments conducted, as presented in the SOE 
 Subjects who have 
been identified as screen failure may be rescreened if, in the opinion of the Investigator, there is 
a reasonable chance that the subject may become eligible at a later timepoint. If the decision is 
taken to rescreen a subject, the subject will need to be re-consented and will obtain a new subject 
number. 


 
 
 
 
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For all subjects, screening should be conducted in a stepwise manner so that eligibility is 
confirmed first by less intensive assessments. More intensive assessments are to be conducted 
once eligibility by other criteria have been confirmed to minimize risk and burden.  
7.3 
Dosing and Follow-up Visits 
The timing of dosing and follow-up visits is outlined in the SOE 
 Study treatment 
will be administered by unmasked qualified ophthalmologists. 
 
 
 
All follow-up study visits, assessments and procedures should be completed as indicated per the 
SOE 
 All efforts should be taken to prevent missing data. Deviations from the 
treatment cycle (and subsequent assessments) may be justified in some cases (e.g., if an AE 
makes treatment impossible at the scheduled dosing day [see also Section 7.1]). Subjects will be 
assessed for safety, tolerability, and efficacy at follow-up visits with all ophthalmic assessments 
performed on both the TE and CE.  
7.4 
End of Study Visit & Roll Over to Open Label Extension Study 
 
 
 
 
 


 
 
 
 
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8.0 
STUDY ASSESSMENT PROCEDURES 
All clinical assessments (including all efficacy and safety assessments) will be performed by 
masked staff. Clinical monitoring during and right after administration of study treatment will be 
performed by an unmasked IVT physician (see also Section 4.2.1.3). 
Eligible subjects must complete all Screening examinations. If a subject is unable to complete a 
specific assessment, this should be recorded in the eCRF and the subject’s ability reassessed at 
the next specified visit. All attempts at performing assessments should be recorded in the eCRF. 
Any assessment may be repeated if the results are considered unreliable or of unacceptable 
quality by the Investigator. 
8.1 
Efficacy 
Efficacy assessments include BCVA, LLVA, SD-OCT, microperimetry, FST and PROs. A 
central reading center, utilizing evaluators masked to treatment assignment, will assess 
microperimetry, FST, and SD-OCT. See the Study Reference Manual and Imaging Procedure 
Manual for further information on these assessments. 
 
 
 
 
 
 
 
  


 
 
 
 
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Subject’s assessment of disease severity will be assessed by PGI-S, and assessment of any 
improvement or decline in clinical status will be assessed by PGI-C.  
8.2 
Safety 
Safety assessments to monitor for AEs include ophthalmic examinations, laboratory evaluations, 
and SD-OCTs. Assessments will be conducted as indicated by the SOE 
 
8.2.1 
Adverse Events 
Information regarding occurrence of AEs will be captured throughout the study. Duration (start 
and stop dates), severity/grade, outcome, treatment, and relationship to study drug will be 
recorded. Refer to Section 9.0 for further details. 
8.2.2 
Laboratory Evaluations 
All laboratory evaluations will be conducted at a central laboratory. Reference ranges for all 
laboratory parameters are provided in the Laboratory Manual. See Appendix 2 for a list of 
laboratory tests to be conducted. 
Serum chemistries will include sodium, potassium, chloride, bicarbonate, blood urea nitrogen 
(BUN), creatinine, glucose, calcium, phosphorus, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), gamma-glutamyl transferase (γGT), C-reactive protein (CRP), alkaline 
phosphatase (ALP), total and direct bilirubin, lactic dehydrogenase (LDH), albumin, and total 
protein. Estimated glomerular filtration rate (eGFR) is to be calculated using the Chronic Kidney 
Disease Epidemiology- Collaboration Creatinine Equation 2009 calculation for adult subjects 
and the Bedside Schwartz equation, according to the recommendation from National Institutes of 
Health/National Institute of Diabetes and Digestive and Kidney Diseases, for pediatric subjects. 
Hematology will include a complete blood count (CBC): CBC with absolute differential 
(hematocrit, hemoglobin, white blood cell count [WBCs], red blood cell count, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count). 
Coagulation panel: prothrombin time and International Normalized Ratio (INR).  
Approximately 80 mL of blood will be drawn over the course of the entire study for laboratory 
evaluations, systemic exposure and immunogenicity.   
For female subjects of childbearing potential, a pregnancy test will be performed as indicated by 
the SOE
 and is recommended at any visit that may warrant a pregnancy test.  
Eligibility of the subject to participate in the study is based in part on safety signals that may be 
indicated by laboratory values.  


 
 
 
 
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Repeat laboratory tests are permitted to confirm potentially spurious values or false positive 
results, at the discretion of the Investigator. Repeat analysis results for any laboratory 
assessments that are eligibility criteria should be discussed with the Medical Monitor prior to 
subject inclusion. 
8.2.3 
Ophthalmic Examinations 
Ophthalmic examinations include slit lamp biomicroscopy, intraocular pressure, and dilated 
fundus examination and will be performed as indicated per the SOE 
 
 
 
 
 
Further details on the procedures for ophthalmic examinations are in the Study Reference 
Manual.   
8.2.4 
Spectral Domain Optical Coherence Tomography  
Changes in SD-OCT findings, 
 All SD-OCT scans should be performed in 
accordance with the procedures outlined in the Imaging Procedure Manual.  
8.3 
Systemic Exposure 
Blood samples for systemic exposure analysis of ultevursen will be collected from all subjects as 
indicated per the SOE (see Section 8.2.2 
8.4 
Immunogenicity 
Blood samples for assessment of immunogenicity will be taken as indicated per the SOE (see 
Section 8.2.2
 and stored for potential later quantification.  


 
 
 
 
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8.5 
Gene Sequencing  
A genotyping report is required for eligibility.
 Separate informed consent may need to be obtained per 
local requirements. A blood or saliva sample for genotyping and gene sequencing should be 
obtained at or prior to the Screening Visit. In case the sample for gene sequencing analysis will 
be obtained prior to the first Screening Visit, a separate ICF and/or assent is available for this 
purpose (see Section 12.2). 
 
 
 
9.0 
ASSESSMENT OF SAFETY, ADVERSE EVENTS AND SERIOUS ADVERSE 
EVENTS 
All subjects who receive study treatment will be assessed for safety.  
Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting the Sponsor regarding any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the subject. The Investigator is responsible for appropriate 
medical care of subjects during the study and may add unscheduled visits, additional exams/tests 
for safety purposes. 
9.1 
Data Monitoring Committee 
An independent DMC will provide safety oversight for the study. A DMC operational charter 
will be finalized, and an initial organizational meeting held prior to screening of the first subject.  
Reference is also made to Sections 4.2.3 and 4.2.4. 
9.2 
Definitions of Adverse Event, Serious Adverse Event, and Suspected Unexpected 
Serious Adverse Event 
9.2.1 
Adverse Events  
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
considered drug related or not. Adverse events can include any unfavorable, noxious, unintended 
sign, symptom, or disease temporally associated with use of a study drug or other protocol-
imposed intervention, regardless of attribution. Adverse events may be spontaneously reported 


 
 
 
 
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by the subject, discovered by Investigator questioning, or detected through laboratory test, or 
other means. 
Adverse events include: 
• Pre-existing medical conditions judged by the Investigator to have worsened in 
severity or frequency or changed in character during the protocol-specified AE 
reporting period (as specified in Section 9.4.1) 
• Adverse events not previously observed in the subject that emerge during the 
protocol-specified AE reporting period (as specified in Section 9.4.1)  
• Complications that occur as a result of protocol-mandated interventions  
• Adverse events that occur prior to study treatment that are related to a 
protocol-mandated intervention (e.g., invasive procedures such as blood draws, 
sedation prior to IVT injection) 
9.2.2 
Serious Adverse Events 
An AE is considered “serious” if, in the view of Investigator, it results in any of the following 
outcomes: 
• Death 
• Life-threatening AE. This definition implies that the subject, in the view of the 
Investigator, is at immediate risk of death from the event as it occurred. It does 
not include an event that, had it occurred in a more severe form, might have 
caused death 
• Inpatient hospitalization or prolongs existing hospitalization, except for planned 
hospitalization  
• Persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions) 
• Congenital anomaly or birth defect. This serious criterion applies if a congenital 
anomaly/birth defect is diagnosed in a child born to a female subject, or a female 
partner of a male subject exposed to the study drug 
• Other important medical events. Medical and scientific judgment should 
determine whether an AE should be classified as serious in other situations, such 
as important medical events that may not be immediately life threatening or result 
in death or hospitalization but may jeopardize the subject or require intervention 
to prevent one of the outcomes listed in the definition above.  
All AEs that do not meet any of the criteria for serious should be regarded as non-serious AEs. 
Surgery for lens opacity removal (lens replacement) is not considered a serious AE as it does not 
require the subject be admitted to a hospital unit based on the nature of the surgery. Even in the 


 
 
 
 
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case where the subject may be hospitalized for convenience, or a subject is too frail to make the 
commute back and forth to the surgical center, it is still not a Serious AE. The terms “severe” 
and “serious” are not synonymous. Severity refers to the intensity of an AE (as in mild, 
moderate, or severe pain); the event itself may be of relatively minor medical significance (such 
as severe headache) (see Section 9.3.1). “Serious” is a regulatory definition and is based on 
subject or event outcome or action criteria usually associated with events that pose a threat to a 
subject’s life or vital functions. Seriousness (not severity) serves as the guide for defining 
regulatory reporting obligations. 
Severity and seriousness should be independently assessed when recording AEs and serious 
adverse events (SAEs) on the AE eCRF and SAE form. 
9.2.3 
Suspected Unexpected Serious Adverse Reaction Definition 
In order to be qualified as a suspected unexpected serious adverse reaction (SUSAR), the AE 
must meet 3 criteria: the event is serious, there is a certain degree of probability that the event is 
a reaction to the study drug being researched and the nature and severity of the reaction are not in 
agreement with the product information (i.e., the reaction is unexpected as per the reference 
safety information). All SUSARs will be reported as required to the Competent Authorities and 
to the Ethics Committee (EC)/Institutional Review Boards (IRBs) of the countries and centers 
concerned. 
9.2.4 
Adverse Events of Special Interest 


 
 
 
 
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9.3 
Assessment of Adverse Events  
The Investigator is responsible for assessing the severity and causality of AEs. 
9.3.1 
Assessment of Severity (Intensity) of Adverse Events 
On the AE eCRF, the Investigator will use the adjectives MILD, MODERATE, or SEVERE to 
describe the maximum intensity of the AE. For purposes of consistency, these intensity grades 
are defined as follows:  
• MILD: Awareness of sign, symptom, or event, but easily tolerated. Does not 
interfere with subject’s usual function. 
• MODERATE: Discomfort enough to cause interference to some extent with 
subject’s usual function and may warrant intervention. 
• SEVERE: Incapacitating and interferes significantly with subject’s usual function 
and warrants intervention. 
As described previously in Section 9.2.2, note the distinction between the severity and the 
seriousness of an AE. A severe event is not necessarily a serious event and may not meet the 
regulatory definition of serious. For example, a headache may be severe (interferes significantly 
with subject’s usual function) but would not be classified as a serious AE unless it met one of the 
regulatory criteria for SAEs, listed above in Section 9.2.2. 
Any change in severity should be noted in the eCRF, e.g., a change from mild to severe or a 
change from severe to moderate should be noted with the start and stop dates for each intensity. 
9.3.2 
Assessment of the Relationship of Adverse Events to Study Drug 
The Investigator will make a causality assessment about the relationship of each AE to study 
drug. Assessment of causality is based on considering associative connections (time or place), 
pharmacological explanations, previous knowledge of the study drug, presence of characteristic 
clinical or pathological phenomena, underlying conditions in the study population, exclusion of 
other causes, and/or absence of alternative explanations. To ensure consistency of AE and SAE 
causality assessments, Investigators should apply the following general guideline: 
Not Related: The AE has an etiology other than the study drug (e.g., preexisting medical 
condition, underlying disease, intercurrent illness, or concomitant medication); and/or the AE has 
no plausible temporal relationship to administration of the study drug (e.g., cancer diagnosed 
2 days after dose of study drug).  
Related: An AE that is related to the study drug or its administration (i.e., an event that follows a 
reasonable temporal sequence from administration of the study intervention, follows a known or 


 
 
 
 
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expected response pattern to the suspected intervention, that could not be reasonably explained 
by the known characteristics of the subject’s clinical state). 
For all AEs and SAEs, Investigators will make separate assessments of causality about the 
relationship of the event to study drug and to study procedures (i.e., IVT injection). 
Note: The Investigator’s assessment of causality for individual AE reports is part of the study 
documentation process and will be recorded in the subject’s medical record, AE eCRF, and SAE 
form if applicable. Adverse events recorded without the Investigator’s assessment of the 
relationship to study drug will be followed up until causality is assigned. 
9.3.3 
Assessment of the Outcome of Adverse Events 
The Investigator will record the outcome of AEs and SAEs using the following criteria: 
• Recovered/resolved: The subject has fully recovered from the event, with no 
residual effects observable. 
• Recovered/resolved with sequelae: The subject has recovered from the event, 
but with residual sequelae effects observable. 
• Not recovered/resolved: Effects of the event are still present. 
• Recovering/resolving: The subject has improved but has not fully recovered 
from the event. 
• Fatal: The death is related to the event. 
• Unknown: The outcome of the event is unknown to the reporter (e.g., subject was 
lost to follow-up). 
9.4 
Reporting of Adverse Events 
The Investigator is responsible for ensuring that all AEs and SAEs are recorded in the subject’s 
medical record, AE eCRF, and/or SAE form, and reported to the Sponsor in accordance with 
protocol instructions. The AE eCRF can be used to report both AEs and SAEs. If necessary, 
e.g., in case of failure of the Electronic Data Capture (EDC) system or for logistical reasons, a 
paper AESI/SAE/Special Situation reporting form may be used instead. 
9.4.1 
Adverse Event Reporting Period 
After signing of the Informed Consent all significant medical conditions including 
signs/symptoms of the underlying disease and known pre-existing medical conditions found 
during the screening period and up to initiation of dosing will be captured as medical history. 
Any event/condition, including those related to participation in the study or study procedures, 
those not related to underlying disease or pre-existing medical conditions already part of medical 


 
 
 
 
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history, and occurring before first dose of study treatment will be captured as a non-treatment 
emergent AE. 
Any event/condition noted once the subject receives their dose of study drug will be captured as 
a treatment emergent AE. All AEs and SAEs regardless of attribution will be collected until at 
least 90 days following the last administration of study drug or the subject’s EOS visit, 
whichever is later. At the last scheduled visit, the Investigator should instruct each subject to 
report to the Investigator any subsequent AEs/SAEs that the subject’s personal physician 
believes could be related to prior study treatment.  
SAEs unrelated to study treatment and non-serious AEs are to be followed until the last 
scheduled study visit (EOS visit), with the outcome at that point of time to be recorded in the 
eCRF. SAEs related to study treatment (Serious Adverse Drug Reactions) are to be followed 
until resolution or until they return to baseline, stabilize, or the subject is lost to follow-up. 
Resolution of AEs and SAEs (with dates) should be documented on the AE eCRF and SAE form 
(if applicable) and in the subject’s medical record to facilitate source data verification. For some 
SAEs, the Sponsor or its designee may follow up by telephone, facsimile, electronic mail, and/or 
a monitoring visit to obtain additional case details deemed necessary to appropriately evaluate 
the SAE report (e.g., hospital discharge summary, consultant report, or autopsy report).  
9.4.2 
Eliciting Adverse Events 
A consistent methodology of non-directive questioning for eliciting AEs at all subject evaluation 
time points should be adopted. Examples of non-directive questions include: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last here?” 
9.4.3 
Recording Adverse Events and Serious Adverse Events  
Investigators should use correct medical terminology/concepts when recording AEs or SAEs on 
the eCRF and/or AESI/SAE/Special Situation reporting form. Colloquialisms and abbreviations 
should be avoided. Serious AEs must also be recorded on the AE eCRF or AESI/SAE/Special 
Situation reporting form. Only 1 medical concept should be recorded in the event field on the AE 
eCRF and AESI/SAE/Special Situation reporting form (if applicable). 
a. 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (e.g., cascade events or clinical sequelae) 
should also be entered as separate AEs. For example, if severe diarrhea is known to have resulted 
in dehydration, both diarrhea and dehydration should be entered as AEs on the eCRF, and if also 
serious, as SAE on AE eCFR and AESI/SAE/Special Situation reporting form (if applicable).  


 
 
 
 
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b 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution between subject evaluation 
time points. Such events should only be recorded once in the eCRF unless their severity 
increases. If a persistent AE becomes more severe or occurs more frequently, it should be 
recorded again on the AE eCRF with the increased severity grading.  
A recurrent AE is one that occurs and resolves between subject evaluation time points and 
subsequently recurs. All recurrent AEs should be recorded individually on the AE eCRF. 
c. 
Abnormal Laboratory Values 
Only clinically significant laboratory abnormalities will be recorded as AEs on the eCRF and 
SAE form (if applicable).  
If the laboratory abnormality can be characterized by a precise clinical term, the clinical term 
should be recorded as the AE or SAE. For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as “hyperkalemia”. 
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs on the eCRF and SAE form (if applicable), unless their 
severity, seriousness, or etiology changes.  
d. 
Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section 9.4.1), 
regardless of attribution, will be recorded on the AE eCRF and SAE form and reported to the 
Sponsor within 24 hours of event knowledge.  
When recording a death, the event or condition that caused or contributed to the fatal outcome 
should be recorded as a single medical concept. For example, if death resulted from respiratory 
failure, the AE recorded should be “Respiratory Failure”, and the outcome of the AE would be 
“Death”. If the cause of death is unknown and cannot be ascertained at the time of reporting, 
record “unexplained death” on the AE eCRF and SAE form. 
e. 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. Such conditions 
should be recorded on the Medical History eCRF. 
A preexisting medical condition should be recorded as an AE or SAE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such events on 
an AE eCRF and SAE form (if applicable), it is important to convey the concept that the 
preexisting condition has changed by including applicable descriptors (e.g., “more frequent 
headaches”). 


 
 
 
 
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f. 
Hospitalization, Prolonged Hospitalization or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE unless specifically instructed otherwise in this protocol.  
g. 
Pregnancy 
If a female subject or a female partner of a male subject becomes pregnant during study 
participation of the female subject or the male partner, a Pregnancy Report form should be 
completed and faxed to the Sponsor within 24 hours of learning of the pregnancy, using the fax 
numbers listed in the Study Reference Manual. 
Abortion, whether therapeutic or spontaneous, will also be reported on a Pregnancy Report form 
and faxed to the Sponsor. Refer to the Study Reference Manual for forms and complementary 
reporting information. If the abortion meets seriousness criteria (see Section 9.2.2, Serious 
Adverse Event Definition), this information will be captured on the AE eCRF and SAE form (if 
applicable). 
Pregnancy should be followed up until after delivery, and any events to 3 months post-partum or 
termination of the pregnancy. Any congenital anomaly/birth defect in a child born to a female 
subject or to a female partner of a male subject exposed to the study drug should be recorded and 
reported as an SAE. 
h. 
Special Situations Reporting 
Medication errors and uses outside what is foreseen in the protocol, including overdose and 
occupational exposure must be reported to the Sponsor within 24 hours from awareness on an 
paper AESI/SAE/Special Situation reporting form (if applicable) for tracking purposes and will 
be considered a protocol deviation. Overdose is defined as any study drug dose administered 
above the intended dose for the cohort assignment. Additional instructions for reporting special 
situation information will be provided by the Sponsor at the time of notification. 
9.5 
AESIs and Serious Adverse Events Notification  
For all AESI and SAEs, regardless of suspected causality, a completed AESI/SAE/Special 
Situation reporting form must be sent within 24 hours of discovery of the event immediately 
(without undue delay) to: 
DRUG SAFETY 
See Study Reference Manual  
Any fatal or life-threatening (i.e., imminent risk of death) event that is attributed by the 
Investigator to the study drug must be immediately telephoned to: 


 
 
 
 
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DRUG SAFETY  
Phone: See Study Reference Manual for phone number  
followed by submission of written case details on an AESI/SAE/Special Situation reporting 
form within 24 hours. 
Serious AEs occurring any time after study participation that are considered by the Investigator 
to be possibly related to study drug must also be reported. The following are important points to 
remember when completing the SAE form: 
• If complete information is not available, at a minimum, subject identifier, suspect 
drug, study center identifier, event or outcome, and Investigator assessment of causal 
relationship to study drug should be provided. 
• A rationale for the causality assessment of an SAE should always be included, so that 
a better understanding of the event can be compiled. 
• Follow-up information, such as laboratory reports, discharge summaries, autopsy 
reports, and information concerning outcome of the event should be submitted by 
revising the SAE form as soon as the information becomes available. Copies of 
source documents, with subject identifiers redacted, should be submitted only when 
they are written in English. If source documents are not in English, the Investigator 
must summarize the source documents, providing a complete English narrative that 
includes a description of the events as it evolved, the results of all diagnostic 
procedures performed, treatments administered, and outcome of the event. A query 
regarding a follow-up report should be answered within 5 working days from receipt 
of the query. 
• Appropriate diagnostic tests and therapeutic measures are to be performed as 
necessary and reported on the SAE form. 
• All SAEs must be reported to the IRB/EC, if applicable. See the International Council 
for Harmonisation (ICH) GCP E6 (R2), Section 4.11.1 (ICH 2016). 
9.6 
Expedited Reporting of Suspected Unexpected Serious Adverse Reactions 
The Sponsor or designee will fulfil reporting obligations as defined in the Safety Management 
Plan (SMP). The SMP details the responsibilities, processes and timelines for expedited 
reporting and aggregate periodic reporting to relevant recipients (e.g. Competent Authorities, 
Central ECs/Central IRB, Investigators etc.) across sites within the study. The SMP ensures a 
systematic approach to safety monitoring and promotes early issue detection to help mitigate any 
safety risks in clinical trial subjects. 


 
 
 
 
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• The Sponsor or its designee is responsible for notifying the study centers of all 
expedited SAEs that occur during any clinical studies that are using the study drug. 
The Sponsor or its designee shall also notify Central ECs and Central IRB of 
SUSARs or significant risks to subjects, per country requirements. All SUSARs will 
be reported as required to the Competent Authorities of all involved participating 
countries. 
• The Investigator will notify local IRB/EC of SUSARs or significant risks to subjects, 
per local country requirements. The Investigator must keep copies of all AE 
information, including correspondence with the Sponsor or local IRB/EC on file.  
• The Sponsor will inform Investigators of any emerging safety issues as soon as 
possible, and at least prior to any planned dosing, following which the Investigator 
will subsequently inform participants. 
• All studies that are conducted within any European country will comply with the 
European Clinical Trial Directive 2005/28/EC, the Clinical Trial Directive 
2001/20/EC, and the Detailed Guidance CT-3 (2011/C 172/01) and Regulation 
536/2014. 
10.0 
STATISTICAL METHODOLOGY 
10.1 
General Considerations 
A comprehensive SAP specifies the statistical methodology, and table, listing and figure (TLF) 
formats for all aspects of the planned analyses. The SAP supports the completion of the Clinical 
Study Report (CSR) for this protocol. All AEs will be considered in determining the safety 
profile of ultevursen. Exploratory analyses not necessarily identified in the SAP may be 
performed to support the clinical development program. Any post-hoc, or unplanned, analyses 
not identified in the SAP will be clearly identified in the CSR, in accordance with applicable 
Standard Operating Procedures of the Sponsor.  
10.2 
Determination of Sample Size 
This is a Phase 2/3 study designed to evaluate efficacy, safety, and tolerability of ultevursen in 
subjects with RP due to mutations in exon 13 of the USH2A gene 


 
 
 
 
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10.3 
Randomization and Masking 
Subjects, treating physicians and study staff are masked. The physician administering study 
treatment will be unmasked to assignment of study drug or sham-procedure but will be masked 
to the dose of study drug. 
The randomization procedure used to assign study treatment to eligible subjects will be through a 
centralized IWRS, utilizing the randomization schedule generated by the designated unmasked 
statistician. Subjects will be sequentially assigned according to a computer generated 
randomization list in the appropriate randomization ratio to 1 of 3 treatment groups and the TE 
will be treated accordingly (see Section 10.2 and Section 4.2). Subjects will be stratified at 
randomization based on clinical presentation (i.e., syndromic/non-syndromic RP). 
10.4 
Replacement of Subjects 
10.5 
Analysis Populations 
All Screened Subjects: All subjects who provided informed consent to participate in the study. 
Intent to Treat Population: All subjects who were randomized. 
Safety Population: All subjects who were randomized and received at least one dose of study 
treatment. 
Full Analysis Set (FAS) Population: All subjects who received at least one dose of study 
treatment and had at least 1 baseline BCVA observation or measurement.  
Per Protocol Efficacy Population: All subjects in the FAS Population with the exception of 
subjects with major protocol deviations. The list of major protocol deviations selected for 
exclusion from this population will be completed prior to database lock.  
Systemic Exposure Set: All subjects who received ultevursen and have at least one 
pharmacokinetic sample taken. 


 
 
 
 
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10.6 
Subject Disposition, Demographics and Baseline Disease Characteristics 
Subject disposition will be summarized for All Screened Subjects population by dose group.  
The number and percentage of subjects who receive ultevursen or the sham-procedure will be 
tabulated by the number of doses and the treatment group.  
Subject demographics and baseline characteristics will be summarized for each treatment group 
and for all subjects combined. Subject characteristics at baseline include age, race, body weight, 
and height. Baseline disease characteristics include ophthalmic examinations, measurements and 
tests, as previously described.  
10.7 
Treatment Compliance 
All doses are observed and administered by study staff. Treatment compliance will be 
determined by source records documenting treatment observations and summarized. 
10.8 
Efficacy Analyses 
The efficacy evaluations will include evaluations of the endpoints listed in Section 4.1.  
Descriptive statistics of clinical efficacy will be tabulated by dose group, and if appropriate, for 
dose groups combined.  
All continuous endpoints will be summarized using the following descriptive statistics: number 
of subjects, mean, standard deviation, standard error, median, minimum, maximum and 95% 
confidence intervals for the mean. Categorical endpoints will be summarized using the 
following: number of subjects, frequency, percentages and 95% confidence intervals. If data 
appear highly skewed, natural log or other transformation may be used to compute summary 
statistics. 
Continuous efficacy endpoints will be summarized and may be analyzed using appropriate 
parametric and/or nonparametric inference tests.  


 
 
 
 
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10.9 
Safety Analyses 
10.9.1 
Treatment Emergent Adverse Events 
A treatment-emergent AE (TEAE) is defined as an event that was not present prior to 
administration of the first dose of study treatment and present after the first administration or if it 
represents the exacerbation of an event that was present prior to the first administration. 
Adverse events noted during the study will be coded to system organ classes (SOCs) and 
preferred terms (PTs) using the Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary. The overall incidence of TEAEs will be summarized by treatment group and 
classified by SOC and PT. Deaths, AE severity, serious AEs, relationship to study treatment and 
study discontinuation due to AE will also be tabulated by treatment group. An AE will be 
considered related to study treatment if the Investigator indicated the event is at least “possibly” 
related or if the relationship is missing. Adverse events with missing start dates, but with stop 
dates overlapping into the treatment period will be counted as treatment emergent. All AEs will 
be listed in subject listings and summarized by numbers and percentages of subjects by treatment 
group.  
10.9.2 
Other Safety Assessments 
Other safety assessments, such as ophthalmic examinations and SD-OCT will be summarized 
and listed as specified in the SAP. 
10.10 18-Month Primary Analysis and 24-Month/EOS Analysis 
18-Month Primary Analysis 


 
 
 
 
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After all randomized subjects have completed their Month 18 visit or discontinued the study 
prior to this visit, the primary analysis will be conducted, i.e., analysis of the primary and 
secondary efficacy endpoints at Month 18. Follow-up data beyond 18 months, and available data 
from other endpoints will be analyzed as well. 
24-Month /EOS Analysis 
Follow-up data collected post the 18-month treatment period will be presented based on an 
analysis to be performed after the database is locked once all subjects have reached Month 24.  
10.11 Multiplicity Considerations 
 
  
 
10.12 Subgroup Analyses 
 
10.13 Systemic Exposure Analyses 
Systemic exposure analyses will be performed as outlined in the SAP. 
11.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 
Data Collection 
The Investigator will prepare and maintain adequate and accurate source documents (including 
medical records) designed to record all observations and other pertinent data for each subject 
treated with the study treatment. Study center staff at each study center will enter data from 
source documents corresponding to a subject’s visit into the protocol-specific eCRF. Subjects 
will not be identified by name in the study database or on any study documents to be collected by 
the Sponsor (or designee) but will be identified by a study center number and subject number, 
which will be completed in the Screening and Enrollment Log. This number will be used for the 
duration of their participation in the study. The subject Screening number cannot be re-used if a 
subject withdraws consent or is a screening fail. 
Study center staff will be trained and authorized to use the system in compliance with the Code 
of Federal Regulations (CFR) 21CFR Part 11, International Council for Harmonisation (ICH) - 
Good Clinical Practice (GCP) and local regulations, before recording data on eCRFs. All 
corrections to eCRFs will be made by authorized users, and the changes will be automatically 
logged in the audit trail of the system (time and date stamps and the user entering or updating 


 
 
 
 
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data). Electronic CRFs should be completed for every subject screened or enrolled in the study. 
At the study’s conclusion, a Portable Document Format file will be created for each study center 
containing their subjects’ data submitted on eCRFs. A copy of the eCRF will remain at the study 
center at the completion of the study. 
The Investigator is responsible for all information collected on subjects enrolled in this study and 
shall ensure that the eCRFs are accurate, complete and completed in a timely fashion. All data 
collected during the course of this study must be reviewed and verified for completeness and 
accuracy by the Investigator. The Investigator will ensure that the eCRFs are accurate, complete, 
and completed in a timely fashion. The Investigator will ensure that source documents that are 
required to verify the validity and completeness of data transcribed on the eCRFs are retained 
according to storage guidelines (Section 13.4). Separate source records are required to support all 
eCRF entries. The eCRF is not to be used to document data without prior written or electronic 
records. The Investigator will electronically sign and date in the required places in the eCRF. 
These signatures will indicate that the Investigator inspected or reviewed the data on the eCRF 
and agrees with the content. 
11.2 
Data Quality Control 
To ensure the quality of clinical data across all subjects and study centers, a clinical data 
management review will be performed on subject data. During this review, subject data will be 
checked for consistency, omissions, and any apparent discrepancies. In addition, the data will be 
reviewed for adherence to the protocol and ICH GCP. To resolve any questions arising from the 
clinical data management review process, data queries will be sent to the study center. 
Corrections or updates to the data resulting from queries should be made on the eCRF. All 
changes will be automatically documented in the software’s audit trail, including the reason for 
change. 
11.3 
Monitoring 
A Sponsor representative (monitor) will contact the Investigator(s) at periodic intervals by 
telephone or on-site visit for the purpose of monitoring the facilities and assessing the progress 
of the study. Electronic CRFs and subject records will be reviewed at on-site visits at regular 
intervals throughout the study to verify adherence to the protocol, completeness, accuracy, and 
consistency of the data, and adherence to local regulations on the conduct of clinical research. 
The monitor should have access to subject medical records and other study-related records 
needed to verify the entries on the eCRF. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected 
during these monitoring visits, including delays in completing eCRFs, are resolved. 
Monitoring of study center facilities (e.g., pharmacy, drug storage areas, laboratories) and review 
of study-related records will occur to evaluate the study conduct and compliance with the 


 
 
 
 
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protocol, ICH GCP, and applicable regulatory requirements. Study drug dispensing and 
accountability will also be assessed. 
11.4 
Audits and Inspections 
Authorized representatives of the Sponsor, a regulatory authority, or an IRB/EC may perform 
audits or inspections at the study center, including source data verification. The purpose of an 
audit or inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, ICH GCP, and applicable regulatory 
requirements. The Investigator will contact the Sponsor immediately if contacted by a regulatory 
agency about an inspection at the study center. 
12.0 
ETHICAL AND REGULATORY OBLIGATIONS 
12.1 
Ethical Considerations 
The Investigator agrees to conduct this study in accordance with ethical principles that have their 
origin in the Declaration of Helsinki and are consistent with ICH GCP. The Investigator will 
conduct all aspects of this study in compliance with the protocol, ICH GCP and applicable 
regulatory requirements. 
12.2 
Informed Consent 
Before the start of required study procedures, the Investigator or his/her associate must obtain 
informed consent from each study participant (or the subject’s legal representative) in 
accordance with ICH GCP, and country authority requirements. Age-appropriate assent and 
permission from a minor subject’s parent or legal guardian is required for pediatric subjects. The 
subject or his/her legal representative must sign the current version of the written, IRB/EC- 
approved Informed Consent Form in the presence of a witness and be given a copy. The 
Investigator will ensure that a copy of the signed consent is kept with the subject’s records. 
In accordance with ICH GCP and country authority requirements, an IRB/EC must review and 
approve this protocol and the ICF prior to initiation of the study.  
12.3 
Ethics and Regulatory Review 
An IRB/EC should approve the final study protocol, including the final version of the ICF, assent 
forms and any other written information and/or materials to be provided to the subjects. The 
Investigator will ensure the distribution of these documents to the applicable IRB/EC, and to the 
study center staff. 
The opinion of the IRB/EC should be given in writing. The Investigator should submit the 
written approval to Sponsor before enrollment of any subject into the study.  


 
 
 
 
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The IRB/EC should approve all advertising used to recruit subjects for the study. 
The Sponsor should approve any modifications to the ICF that are needed to meet local 
requirements. 
If required by local regulations, the protocol should be re-approved by the IRB/EC annually. 
Before enrollment of any subject into the study, the final study protocol, including the final 
version of the ICF, is approved by the national regulatory authority or a notification to the 
national regulatory authority is done, according to local regulations. 
The Sponsor will handle the distribution of any of these documents to the national regulatory 
authorities. 
The Sponsor will provide Regulatory Authorities, IRB/ECs and Investigators with safety 
updates/reports according to local requirements. 
Each Investigator is responsible for providing the IRB/EC with reports of any serious and 
unexpected adverse drug reactions from any other study conducted with the study drug. The 
Sponsor will provide this information to the Investigator so that he/she can meet these reporting 
requirements. 
12.4 
Subject Confidentiality 
The Investigator and the Sponsor must ensure that the subject’s confidentiality is maintained, in 
accordance with GCP and local regulations. On the eCRFs or other documents submitted to the 
Sponsor, subjects should be identified by their age and subject number only. Documents that are 
not for submission to the Sponsor (e.g., signed ICF), should be kept in strict confidence by the 
Investigator.  
The Investigator and the Sponsor will ensure that all clinical trial information shall be recorded, 
processed, handled, and stored, in such a way that it can be accurately reported, interpreted and 
verified while the confidentiality, integrity and availability of records and the personal data of 
the subjects remain protected in accordance with the applicable (local) laws on personal data 
protection. Measures taken to ensure all of the above include, but are not limited to, encryption, 
anonymization, multifactor authentication, Intrusion Protection, segregation of authentication. 
In compliance with applicable regulations, it is required that the Investigator and institution 
permit authorized representatives of the Sponsor, the United States (US) Food and Drug 
Administration (FDA), other regulatory authorities (e.g., European Union/European Economic 
Area Member State inspector), and the IRB/EC direct access to review the subject’s original 
medical records for verification of study-related procedures and data. Direct access includes 
examining, analyzing, verifying, and reproducing any or all records and reports that are 
important to the evaluation of this study. The Investigator is obligated to inform and obtain the 


 
 
 
 
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consent of the subject to permit named representatives to have access to the study-related records 
without violating the confidentiality of the subject. 
The sponsor will notify the Member States concerned about a serious data security breach at the 
time of the breach without undue delay but not later than 7 days of becoming aware of that 
breach. Measures that will be implemented to mitigate the possible adverse effects of a serious 
data security breach include, but are not limited to, back-ups including remote location, high 
availability systems for critical environments, and a security incident response plan. 
13.0 
STUDY ADMINISTRATION 
13.1 
Investigator’s Brochure 
Before the study begins, the Investigator will receive the ultevursen IB describing all known 
nonclinical data, contraindications, warnings, precautions, and adverse reactions associated with 
the administration of the study drug. If such information is revised while the study is in progress, 
the IB will be amended or revised, and the Sponsor will provide the most current version to the 
Investigator. 
13.2 
Protocol Amendments 
If there are any substantial changes to the study protocol, these changes will be documented in a 
protocol amendment and in a new version of the protocol. The Sponsor will inform the 
Investigator in writing of any amendment to the protocol. The Investigator must submit the 
protocol modifications and any ICF modifications to the IRB/EC, and approval must be obtained 
before the modifications are implemented. The Investigator must send a copy of the approval 
letter from the IRB/EC to the Sponsor for review. The Investigator may implement a deviation 
from, or a change of, the protocol to eliminate an immediate hazard(s) to trial subjects without 
prior IRB/IEC approval/favorable opinion. In this case, as soon as possible, the implemented 
deviation or change, the reasons for it, and, if appropriate, the proposed protocol amendment(s) 
should be submitted to the sponsor, IRB/EC and if applicable the regulatory authority. 
13.3 
Study Termination and Procedure 
Both the Sponsor and the Investigator reserve the right to terminate the study according to the 
study contract. The Investigator should notify the IRB/EC in writing of the study’s completion or 
early termination and send a copy of the notification to the Sponsor. 
If the Sponsor, Medical Monitor or designee, study center monitor, or appropriate regulatory 
officials discover conditions arising during the study that indicate that the study should be halted 
or that a study center should be terminated, this action may be taken after appropriate 
consultation. Termination may occur in accordance with the clauses contained in the study 
center’s executed clinical study agreement. The Sponsor reserves the right to discontinue the 


 
 
 
 
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study prior to enrollment of the intended number of subjects but intends only to exercise this 
right for valid scientific reasons. 
If the clinical development of ultevursen is discontinued, the Sponsor shall immediately inform 
all Investigators/institutions and regulatory authorities. Study termination and follow-up will be 
performed in compliance with the conditions set forth in the ICH Guidelines S7A (ICH 2000) 
and local regulatory requirements. 
13.4 
Study Documentation and Storage 
The Sponsor will provide the Investigator with records of drug shipments, eCRFs, and other 
forms as necessary. The Investigator and study staff are responsible for maintaining a 
comprehensive and centralized filing system of all study-related documentation, suitable for 
inspection at any time by representatives from the Sponsor and/or applicable regulatory 
authorities. Elements should include, but are not limited to: 
• Subject files containing ICFs and supporting originals of source documentation.  
• Study files containing the protocol with all amendments, IB, copies of pre-study 
documentation, and all correspondence to and from the IRB/EC, applicable 
country authorities, and the Sponsor. 
• Records of drug accountability and all drug-related documentation.  
In addition, all original source documents supporting entries in the eCRFs must be maintained 
and be readily available.  
Upon the request of the Sponsor, designees, or the regulatory authorities, the Investigator will 
make all study records available for inspection, including source documents. This information 
will be treated as confidential. 
No study document is to be destroyed without prior written agreement between Sponsor and the 
Investigator. Should the Investigator wish to assign the study records to another party or move 
them to another location, he/she must notify the Sponsor in writing of the new responsible person 
and/or the new location. 
13.5 
Use of Information 
All personal data pertaining to the subjects in this study and in any subsequent reports will be 
kept confidential. Subjects will be identified only by their month and year of birth and a subject 
number. It is the responsibility of the Investigator to keep a subject listing for cross-referencing.  


 
 
 
 
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The sponsor will notify the Member States concerned about a serious data security breach at the 
time of the breach without undue delay but not later than 7 days of becoming aware of that 
breach. Measures that will be implemented to mitigate the possible adverse effects of a serious 
data security breach include, but are not limited to, back-ups including remote location, high 
availability systems for critical environments, and a security incident response plan. 
The Investigator understands that the information developed in the clinical study will be used by 
the Sponsor in connection with the development of the study drug. This information may be 
disclosed to other clinical Investigators, to the US FDA, and to other government agencies. 
The Sponsor will ensure that personal data transfers and bodily materials transfer comply with 
Data Protection Laws of the EU, i.e., the General Data Protection Regulation 2016/679. To that 
end, all parties/vendors involved in this study will have been assessed and qualified by the 
Sponsor to ensure data privacy protection is at an adequate level. Appropriate contractual 
arrangements (Standard Contractual Clauses) will be in place and sufficient supplement technical 
measures will be implemented by the parties involved in the study.  
13.6 
End of Study and Final Report 
The end of the study is defined as the date of the last visit of the last subject in the study globally. 
The Investigator or delegate must notify the IRB/EC upon study completion or termination in 
compliance with local regulations.  
The Sponsor or its designee will provide a final report and/or synopsis to the Investigators, the 
IRB/EC and Regulatory Authorities in accordance with local requirements.  
13.7 
Financing and Insurance 
Financing and Insurance are addressed separately in the Clinical Study Agreement. 
13.8 
Publication Policy 
Publication policy is addressed separately in the Clinical Study Agreement. 
Reporting of clinical study results will be performed in accordance with local Competent 
Authority regulatory requirements and obligations (e.g., trial data uploaded to EudraCT database 
within one year following end of the trial). 


 
 
 
 
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14.0 
REFERENCES 
American Academy of Ophthalmology. Clinical Statement. Intravitreal Injections. AAO Hoskins 
Center for Quality Eye Care. March 2015. Available at: https://www.aao.org/clinical-
statement/intravitreal-injections-statement. 
Avery RL, Bakri SJ, Blumenkranz MS, Brucker AJ; Cunningham ET; DʼAmico DJ, et al. 
Intravitreal injection technique and monitoring: updated guidelines of an expert panel. Retina. 
2014; 34:S1–S18.  
Brunner, E., and Munzel, U. (2000), “The Nonparametric Behrens-Fisher Problem: Asymptotic 
Theory and a Small-Sample Approximation,” Biometrical Journal, 42, 17–25. 
Childrens and Womens Health Centre of British Columbia Research Ethics Board, “Pediatric 
Blood Draw Guidance,” Version 3.2 – February 19, 2013. Available at 
http://www.phsa.ca/research/Documents/pediatric-blood-draw-guidance.pdf. 
EC Directive 2001/20/EC. Ethical Considerations for clinical trials on medicinal products with 
the paediatric population. Recommendations of the Ad hoc group for the development of 
implementing guidelines for Directive 2001/20/EC. 2008. Available at 
http://ec.europa.eu/health//sites/health/files/files/eudralex/vol-10/ethical_considerations_en.pdf. 
EC Clinical Trial Directive 2005/28/EC. Commission directive 2005/28/EC of 8 April 2005 
2005. Available at http://ec.europa.eu/health//sites/health/files/files/eudralex/vol-
1/dir_2005_28/dir_2005_28_en.pdf. 
EC Communication from the Commission — Detailed guidance on the collection, verification 
and presentation of adverse event/reaction reports arising from clinical trials on medicinal 
products for human use (‘CT-3’) (2011/C 172/01) 2011. Available at 
http://ec.europa.eu/health//sites/health/files/files/eudralex/vol-
10/2011_c172_01/2011_c172_01_en.pdf. 
Fledelius HC, Christensen AS, Fledelius C. Juvenile eye growth, when completed? An 
evaluation based on IOL-Master axial length data, cross-sectional and longitudinal. Acta 
Ophthalmol. 2014 May;92(3):259-64. doi: 10.1111/aos.12107.  
General Data Protection Regulation (EU) 2016/679 of the European Parliament and of the 
Council of 27 April 2016 on the protection of natural persons with regard to the processing of 
personal data and on the free movement of such data. Available at: https://eur-
lex.europa.eu/eli/reg/2016/679/oj. 
Glassman AR, Stockdale CR, Beck RW, Baker C, Bressler NM. Evaluation of study participant 
masking of intravitreal injections in a randomized clinical trial. Arch Ophthalmol. 2012 Feb; 
130(2):190–94. 


 
 
 
 
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Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. Lancet 2006; 368(9549):1795-809.  
Hellström A, Svensson E, Strömland K. Eye size in healthy Swedish children and in children 
with fetal alcohol syndrome. Acta Ophthalmol Scand. 1997 Aug;75(4):423-8. doi: 
10.1111/j.1600-0420.1997.tb00406.x. 
ICH Harmonised Tripartite Guideline: Safety pharmacology studies for human pharmaceuticals 
S7A 2000. Available at: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S7A/Step4/S7
A_Guideline.pdf 
ICH Harmonized Tripartite Guideline: Guideline for good clinical practice E6(R2) 2016. 
Available at: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__
Step_4_2016_1109.pdf  
Jager RD, Aiello LP, Patel SC, Cunningham ET Jr. Risks of intravitreous injection: a 
comprehensive review. Retina. 2004 Oct;24(5):676-98. 
Liu X, Bulgakov OV, Darrow KN, Pawlyk B, Adamian M, Liberman MC, et al. Usherin is 
required for maintenance of retinal photoreceptors and normal development of cochlear hair 
cells. Proc Natl Acad Sci USA. 2007; 104(11):4413-8.  
Marazita ML, Ploughman LM, Rowlings, B, Remington E, Arnos KS, Nance WE. Genetic 
epidemiological studies of early-onset deafness in the U.S. school-age population. Am J Med 
Genet. 1993 Jun 15; 46(5):486-91. doi: 10.1002/ajmg.1320460504 
Roman AJ, Cideciyan AV, Aleman TS, Jacobson SG. Fullfield stimulus testing (FST) to 
quantify visual perception in severely blind candidates for treatment trials. Physiol Meas 
2007;28:N51–N56. 
Stelmack JA, RW Massof. Using the VA LV VFQ-48 and LV VFQ-20 in low vision 
rehabilitation. Optom Vis Sci. 2007 Aug; 84(8):705-9.  
Sunness JS, Rubin GS, Broman A, Applegate CA, Bressler NM, Hawkins BS. Low luminance 
visual dysfunction as a predictor of subsequent visual acuity loss from geographic atrophy in 
age-related macular degeneration. Ophthalmology. 2008;115(9):1480-8, 1488.e1-2. 
Vinekar A, Mangalesh S, Jayadev C, Maldonado RS, Bauer N, Toth CA. Retinal Imaging of 
Infants on Spectral Domain Optical Coherence Tomography. Biomed Res Int. Hindawi 
Publishing Corporation BioMed Research International Volume 2015, 2015;2015:782420. doi: 
10.1155/2015/782420. Epub 2015 Jul 6. 


 
 
 
 
Investigational Product: Ultevursen 
Protocol No. PQ-421a-003 (Version 3) 
 
ProQR Therapeutics 
 
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15.0 
PROTOCOL SUMMARY OF CHANGES 
 


 
 
 
 
Investigational Product: Ultevursen 
Protocol No. PQ-421a-003 (Version 3) 
 
ProQR Therapeutics 
 
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16.0 
APPENDICES 
 


Investigational Product: Ultevursen 
Protocol No. PQ-421a-003 (Version 3.0) 
 
ProQR Therapeutics 
 
Page 66 of 68 
 
14 June 2022 


Investigational Product: Ultevursen 
Protocol No. PQ-421a-003 (Version 3.0) 
 
ProQR Therapeutics 
 
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14 June 2022 


Investigational Product: Ultevursen 
Protocol No. PQ-421a-003 (Version 3.0) 
 
ProQR Therapeutics 
 
Page 68 of 68 
 
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16.2 
Appendix 2: Clinical Laboratory Tests 
 
Chemistry 
Hematology 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Blood urea nitrogen (BUN)  
Creatinine 
Glucose 
Calcium 
Phosphorus 
Albumin 
Total protein 
Alkaline phosphatase (ALP) 
Aspartate aminotransferase (AST)  
Alanine aminotransferase (ALT) 
Gamma-glutamyl transferase (ɣGT) 
Total and direct bilirubin 
Lactic dehydrogenase (LDH) 
Creatinine clearance (eGFR by CKD-EPI 
or Bedside Schwartz)* 
C-reactive protein (CRP) 
Hematocrit 
Hemoglobin 
Red blood cells 
White blood cells (WBCs) 
Neutrophils  
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Platelets 
 
Other Tests 
Coagulation 
Pregnancy testing 
INR 
Prothrombin time 
* Estimated glomerular filtration rate (eGFR) is to be calculated using the CKD-Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) Creatinine Equation 2009 calculation for calculation for adult subjects and Bedside Schwartz 
equation, according to the recommendation from National Institutes of Health/National Institute of Diabetes and Digestive 
and Kidney Diseases, for pediatric subjects. 

SAP_001.pdf: 
  
PQ-421a-003
Abbreviated SAP version: 1.0
Date: 03-Nov-2022
 
 
 
Cover page 
 
 
 
Protocol PQ-421a-003 (SIRIUS) 
A DOUBLE-MASKED, RANDOMIZED, CONTROLLED, MULTIPLE-DOSE STUDY TO 
EVALUATE THE EFFICACY, SAFETY, AND TOLERABILITY OF QR-421a IN SUBJECTS 
WITH RETINITIS PIGMENTOSA (RP) DUE TO MUTATIONS IN EXON 13 OF THE USH2A 
GENE  
NCT number: NCT05158296 
 


  
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Page 1 of 20 
 
STATISTICAL ANALYSIS PLAN 
Protocol PQ-421a-003 (SIRIUS) 
 
A DOUBLE-MASKED, RANDOMIZED, CONTROLLED, 
MULTIPLE-DOSE STUDY TO EVALUATE THE EFFICACY, SAFETY, 
AND TOLERABILITY OF ULTEVURSEN IN SUBJECTS WITH 
RETINITIS PIGMENTOSA (RP) DUE TO MUTATIONS IN EXON 13 OF 
THE USH2A GENE (SIRIUS) 
Protocol Number: 
(Version Date) 
PQ-421a-003 
Name of Test Drug: 
Ultevursen (QR-421a)  
Phase: 
2/3 
Methodology: 
Double-masked, Randomized, Controlled, Multiple-dose 
Sponsor: 
ProQR Therapeutics 
Zernikedreef 9 
2333 CK Leiden  
The Netherlands 
Sponsor Representative: 
Document Date: 
03-Nov-2022 
Document Version: 
1.0 FINAL 
 
SIGNATURE PAGE 


  
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Page 2 of 20 
 
Protocol Title: 
SIRIUS - A Double-Masked, Randomized, Controlled, 
Multiple-Dose Study to Evaluate the Efficacy, Safety, 
and Tolerability of Ultevursen in Subjects with 
Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 
of the USH2A Gene 
Sponsor: 
ProQR Therapeutics 
Zernikedreef 9  
2333 CK Leiden 
The Netherlands 
Protocol Number: 
PQ-421a-003 
Document Date: 
03-Nov-2022 
Version: 
1.0 FINAL 
Author: 
 
 
Signature:__________________________________ 
 
Date:______________________________________ 
 
 
 


  
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Page 3 of 20 
Sponsor Approval 
By signing this document, I acknowledge that I have read the document and approve of the 
planned statistical analyses described herein.  I agree that the planned statistical analyses are 
appropriate for this prematurely terminated study. 
I have discussed any questions I have regarding the contents of this document with the 
statistical author. 
Sponsor Signatory: 
 
ProQR Therapeutics 
Zernikedreef 9  
2333 CK Leiden 
The Netherlands 
 
 
Signature:___________________________________ 
 
Date:_______________________________________ 
 
 
 
 


  
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Page 4 of 20 
MODIFICATION HISTORY 
Current 
Version 
Date 
Amended 
by 
Summary of Changes from 
Previous Version 
Reason 
1.0 
03-Nov-2022 
N/A 
Original document  
N/A 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
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TABLE OF CONTENTS 
1. 
ABBREVIATIONS ...................................................................................................................... 6 
2. 
INTRODUCTION AND STUDY OBJECTIVES...................................................................... 7 
2.1. 
INTRODUCTION ........................................................................................................................... 7 
2.2. 
STUDY TERMINATION ............................................................................................................... 7 
3. 
STUDY DESIGN .......................................................................................................................... 8 
3.1. 
SYNOPSIS OF STUDY DESIGN .................................................................................................. 8 
3.2. 
RANDOMIZATION METHODOLOGY ....................................................................................... 8 
3.3. 
STUDY PROCEDURES ................................................................................................................. 9 
3.4. 
UNMASKING ................................................................................................................................. 9 
4. 
POPULATIONS DEFINITIONS .............................................................................................. 10 
5. 
STATISTICAL METHODS ...................................................................................................... 11 
5.1. 
COMPUTING ENVIRONMENT ................................................................................................. 11 
5.2. 
DEFINITION OF BASELINE ...................................................................................................... 11 
5.3. 
DATA HANDLING ...................................................................................................................... 11 
5.3.1. 
GENERAL ................................................................................................................... 11 
5.4. 
GENERAL STATISTICAL METHODS ...................................................................................... 11 
5.5. 
STUDY POPULATION ................................................................................................................ 12 
5.5.1. 
SUBJECT DISPOSITION ............................................................................................ 12 
5.5.2. 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS .......................................... 12 
5.6. 
SAFETY – ADVERSE EVENTS ................................................................................................. 12 
5.6.1. 
PARTIAL AND MISSING DATE/TIME FOR ADVERSE EVENTS ............................. 13 
5.7. 
OTHER DATA LISTINGS TO BE GENERATED ...................................................................... 15 
6. 
CHANGES TO PLANNED ANALYSES ................................................................................. 17 
7. 
REFERENCES ........................................................................................................................... 18 
8. 
APPENDICES ............................................................................................................................ 19 
 


  
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1. 
ABBREVIATIONS 
Abbreviation 
Definition 
AD 
Analysis Description 
AE 
Adverse Events 
AESI 
Adverse Event of Special Interest 
BCVA 
Best Corrected Visual Acuity 
CE 
Contralateral Eye 
CSR 
Clinical Study Report 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FST 
Full-field Stimulus Testing 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonization 
IRT 
Interactive Response Technology 
IVT 
Intravitreal 
LLVA 
Low Luminance Visual Acuity 
MedDRA 
Medical Dictionary for Regulatory Activities 
MH 
Medical History 
PT 
Preferred Term 
RP 
Retinitis Pigmentosa 
RTF 
Rich Text Format 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD-OCT 
Spectral Domain Optical Coherence Tomography 
SOC 
System Organ Class 
TE 
Treated Eye 
TEAE 
Treatment Emergent Adverse Event 
TLF 
Table Listing Figure format 
WHO 
World Health Organization 
 
 


  
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2. 
INTRODUCTION AND STUDY OBJECTIVES  
2.1. 
Introduction 
Study PQ-421a-003 (Sirius) aimed to define safety and quantify the treatment effect of ultevursen 
administered via intravitreal (IVT) injection in subjects with retinitis pigmentosa (RP) due to 
mutations in exon 13 of the USH2A gene, relative to masked, untreated sham-control subjects, at 
2 dose regimens of ultevursen. 
2.2. 
Study Termination 
 
In this context, the Analysis Description (AD) is abbreviated and describes the populations for 
analysis, data handling rules, statistical methods, and formats for data presentation that will be 
required for the close out of the study, after all randomized subjects have completed the end of 
study visit and the database is locked.  
The summary tabulations and listings that will be produced for the close out of the study, will 
provide the basis for the appropriate sections of the abbreviated clinical study report (CSR) or 
equivalent document. 


  
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3. 
STUDY DESIGN  
3.1. 
Synopsis of Study Design 
PQ-421a-003 is a double-masked, randomized, controlled, multiple-dose study to evaluate the 
efficacy, safety and tolerability of ultevursen in subjects with RP due to mutations in exon 13 of 
the USH2A gene. 
At study start, subjects are randomized to one of the following treatment groups: 
• 
Group 1: Ultevursen 180/60 μg (180 μg loading dose administered on Day 1, 60 μg 
maintenance dose administered at Month 3, and every 6 months thereafter; n = 27) 
• 
Group 2: Ultevursen 60/60 μg (60 μg loading dose administered on Day 1, 60 μg 
maintenance dose administered at Month 3, and every 6 months thereafter; n = 27) 
• 
Group 3: Sham-procedure (administered on Day 1, Month 3, and every 6 months thereafter; 
n = 27)  
Please refer to Section 4.2 of the study protocol for details regarding the study design. 
3.2. 
Randomization Methodology 
The randomization procedure used to assign study treatment to eligible subjects/eye was through 
a centralized Interactive Response Technology (IRT), utilizing the randomization schedule 
generated by the designated unmasked statistician.  
Two periods of randomization were planned:  
 
Subjects who satisfy all eligibility criteria at Day 1 were randomized in a 1:1:1 ratio to one of the 
following groups: 
o Ultevursen 180/60 μg 
o Ultevursen 60/60 μg  
o Sham-procedure 
 
 
 


  
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The randomization in both periods was stratified at Day 1 on one single factor, collected during 
the Day 1 visit: Syndromic subjects versus Non-Syndromic subjects. 
3.3. 
Study Procedures 
Please refer to Section 8.0 of the study protocol for details regarding the study procedures. 
3.4. 
Unmasking 
 
 


  
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4. 
POPULATIONS DEFINITIONS 
The following analysis sets will be evaluated and used for presentation and analysis of the data.  
Analysis sets defined by eye will be respect to each eye. For example, the Safety Analysis Set for 
the CE will be determined by measurements taken on the CE. The subject-level analysis sets 
consist of subjects who meet the criteria in at least one of the eye-level analysis sets.  
Screening Analysis Set: Includes all subjects who signed the informed consent form. 
Safety Analysis Set (SAF): All screened subjects who were randomized and received at least one 
dose of study treatment. 
The disposition data will be presented for all screened subjects. The SAF will be the primary set 
for the analysis of the safety parameters. The SAF will also be used for descriptive summaries of 
demographics, baseline characteristics, and ocular/non-ocular medical history.  


  
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5. 
STATISTICAL METHODS 
5.1. 
Computing Environment 
All information and analyses in the tables and listings provided will be performed using SAS 
statistical software Version 9.4 or later, unless otherwise noted. The Medical History (MH) and 
Adverse Events (AEs) will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) version 24.1. The Prior and Concomitant Medications will be coded using World 
Health Organization (WHO) Drug version Global B3 September 2021.  
5.2. 
Definition of Baseline 
Baseline BCVA for the TE is defined as the mean of all BCVA assessments collected during the 
screening period.  
Baseline BCVA for the CE is defined as the mean of all BCVA assessments collected during the 
screening period.  
5.3. 
Data Handling 
5.3.1. 
General 
Unless otherwise noted, the data reported in the listings will be as reported on the electronic case 
report form. 
5.4. 
General Statistical Methods  
All output will be incorporated into Rich Text Format (RTF) files and bookmarked PDFs, sorted 
and labeled according to the International Conference on Harmonisation (ICH) recommendations, 
and formatted to the appropriate page size(s). 
Tabulations will be produced for appropriate disposition and demographic characteristics. 
For measurements of continuous variables, summary statistics of absolute values will be reported 
and will include n, mean, standard deviation, median, and minimum and maximum values. The 
number of missing values will be displayed in parenthesis next to ‘n’. Mean, standard deviation, 
median, will be presented with one more decimal place compared to the raw data, and minimum 
and maximum will be presented with the same number of decimal places as the raw data. 
For categorical variables, summary tabulations of the number and percentage within each 
category of the parameter will be presented (as well as the number for missing data). 
Denominator for percentages is column N. Percentages will be rounded to one decimal place. 


  
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Therefore, there may be cases where for instance the total of the percentages does not exactly 
equal 100%.  
Where appropriate, data will be listed by eye (i.e., TE, CE). 
In summary tables the study treatments will be presented in the following order: ‘Ultevursen 
180/60 μg’, Ultevursen 60/60 μg’, and ‘All Subjects’. 
5.5. 
Study Population 
5.5.1. 
Subject Disposition 
Subject disposition, including the number of screened subjects, the number of subjects failed 
screening, the number of randomized subjects, the number of subjects who received study 
treatment in the TE, the number of subjects who received study treatment in the CE, who 
completed the study and the number of subjects who discontinued from the study, along with the 
reasons will be summarized by treatment group.  
A listing of subject disposition will be generated, including the reason for premature study or 
treatment discontinuation, if applicable.  
A listing of screen failure data will also be provided. 
5.5.2. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics, including age as collected, age category (Adult >=18 
years, Children <18 years), gender, race, ethnicity, body weight (kg), height (cm), genotype 
(homozygous, heterozygous), and baseline BCVA (ETDRS letter score for both TE and CE), will 
be summarized for the Safety Population by treatment group using descriptive statistics.   
5.6. 
Safety – Adverse events 
A treatment-emergent AE (TEAE) is defined as an event that was not present prior to 
administration of the dose of study drug (ultevursen or sham-procedure) and present after the 
dose or if it represents the exacerbation of an event that was present prior to the dose. 
Adverse events will be summarized by treatment group separately as follows: 
• For non-ocular AE:  
o by subject, therefore, in any tabulation, a subject contributes only once to 
the count for a given adverse event (System Organ Class [SOC] or 
Preferred Term [PT])  
o and during the overall study period (i.e., up to the last visit for the last 
subject). 


  
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o Time to onset will be calculated in hours, relative to the last dose received, 
irrespective of which eye received the last dose (i.e., TE or CE). 
• For ocular AE:  
o by eye frequencies, separately for the TE and the CE, therefore, in any tabulation, 
an eye contributes only once to the count for a given AE (by SOC or PT). AEs that 
are reported in both eyes (i.e., OU) will be reported individually by eye in the 
tabular summaries. 
o and during the overall study period (i.e., up to the last visit for the last subject). 
o Time to onset will be calculated in hours, relative to the last dose received in the 
eye experiencing the ocular AE. 
Unless otherwise stated, any summary of any type of TEAEs which includes the SOC and PT of 
the events will order the SOC and the PTs within the SOC by descending incidence of PT. 
The following summary tables will be produced separately according to the type of AEs 
(ocular/non-ocular where applicable) as defined above: 
• Overview of Ocular Adverse Events for Treatment Eye during the overall study period 
(Safety Population)  
• Overview of Ocular Adverse Events for Contralateral Eye during the overall study period 
(Safety Population)  
• Overview of Non-Ocular Adverse Events during the overall study period (Safety 
Population) 
• Summary of Ocular Treatment-Emergent Adverse Events for Treatment Eye during the 
overall study period by MedDRA System Organ Class and Preferred Term (Safety 
Population) 
• Summary of Ocular Treatment-Emergent Adverse Events for Contralateral Eye during the 
overall study period by MedDRA System Organ Class and Preferred Term (Safety 
Population). 
• SAEs 
• AESIs 
5.6.1. 
Partial and Missing Date/Time for Adverse Events 
Imputation of missing/partial AE date/time will be done only to identify TEAEs. 
AE onset dates 


  
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• Partially missing onset date/time will be imputed as follows: 
o When only Day is missing: 
▪ If Month & Year of the onset date are the same as Month & Year of the 
first administration date, the imputed onset date will be imputed as the 
minimum of the first administration date/time and the AE resolution date 
(imputed if needed). 
▪ Otherwise, the missing day will be replaced by “1.” 
o When Day & Month are missing: 
▪ If Year of the onset date is the same as Year of the first administration 
date, the imputed onset date will be imputed as the minimum of the first 
administration date/time and the AE end date (imputed if needed). 
▪ Otherwise, the missing Day & Month will be replaced by “01 JAN.” 
o If a partial AE start date is consistent with the actual start date being on Day 1, and 
either the AE end date information is completely missing, or the complete or 
imputed AE end date/time information indicates that the AE did not end before 
Day 1, the imputed AE start date will be Day 1 in the following scenarios:  
▪ The AE start time is missing (the AE will be flagged as treatment-
emergent following the first dose of study treatment) 
▪ The AE start time is after the date/time of first dosing of study treatment 
on Day 1 (the AE will be flagged as treatment-emergent following the first 
dose of study treatment) 
▪ The AE start time is before the time of first dosing of study treatment on 
Day 1, and imputing the AE start date as Day 2 instead of Day 1 would be 
inconsistent with the partially recorded AE start date (e.g., the calendar 
month for Day 2 is not the same as for Day 1), or with the complete or 
imputed AE end date/time (in this case, the AE will not be flagged as 
treatment-emergent following the first dose of study treatment). 
o Missing start time will be imputed with the time of administration if the day of AE 
start date and administration are identical, or with 00:00 otherwise. 
• Completely missing onset dates for AEs will be imputed by the first administration date 
and the AE will be considered as treatment-emergent unless the end date/time of the AE 
(imputed if needed) or the end year of the AE (if day and month are missing) is entered 


  
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and is before the first administration date. If the end date/time is before the first 
administration date, the AE will not be considered as treatment-emergent. 
AE end dates 
• If Day only is missing, incomplete end dates will be replaced by the last day of the month 
if it is not resulting in a date later than the date of the subject’s last visit. In the latter case, 
the date of the subject’s last visit will be used to impute the incomplete end date. 
• If Day & Month are missing, Day & Month will be replaced by 31DEC if it is not 
resulting in a date later than the date of the subject’s last visit. In the latter case, the date 
of the subject’s last visit will be used to impute the incomplete end date. 
• If the AE end date is completely missing, the AE will be assumed to be ongoing on the 
date of the subject’s last visit and the incomplete end date will not be imputed. 
5.7. 
Other Data Listings to be Generated 
The following by-subject data listings for the Safety Population will be provided: 
• Subject Disposition  
• Screen Failures (All Screened Subjects)  
• Demographic and Baseline Characteristics (Safety Population) 
• Non-Ocular Medical History (Safety Population) 
• Ocular Medical History (Safety Population) 
• Study Drug Administration of the TE (Safety Population) 
• Study Drug Administration of the CE (Safety Population) 
• BCVA Based on ETDRS (Safety Population) 
• Low Luminance Visual Acuity (LLVA) (Safety Population) 
• Spectral Domain Optical Coherence Tomography (SD-OCT) (Safety Population) 
• Static Perimetry (Safety Population) 
• Microperimetry (Safety Population) 
• Full Field Stimulus Threshold (FST; Safety Population) 
• Patient Global Impressions of Severity (PGI-S) and Patient Global Impressions of Change 
(PGI-C) (Safety Population) 


  
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• Veterans Affairs Low-Vision Visual Functioning Questionnaire – 20 (Safety Population) 
• Ophthalmic exam (Safety Population) 
• Non-Ocular Adverse Events (Safety Population) 
• Ocular Adverse Events (Safety Population) 
• Prior and/or Concomitant Medications (Safety Population)  
• Laboratory results: Hematology, Coagulation, and Chemistry (Safety Population)  


  
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6. 
CHANGES TO PLANNED ANALYSES 
As the study is prematurely stopped by Sponsor’s decision, no formal statistical analysis will be 
produced. Only disposition, demographic and baseline characteristics, and overview of AEs will 
be summarized in tables. By-subjects data listings will be produced based on raw data.  
 


  
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7. 
REFERENCES 
1. International Council on Harmonization, Statistical Principles for Clinical Trials (ICH E9)  


  
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8. 
APPENDICES  
The shells of planned outputs are provided in a separate document (PQ-421a-003_List of Planned 
Outputs_Final_V1.0 (2022-11-03)).