An Open-Label Extension Study to Evaluate the Safety and Tolerability of QR 421a in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene (Helia)
Phase: PHASE2
Conditions: Retinitis Pigmentosa, Usher Syndrome Type 2
Sponsor: Laboratoires Thea

Investigational Product: QR-421a 
Protocol No. PQ-421a-002 (Version 4) 
 
ProQR Therapeutics 
 
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24 May 2022 
 
CLINICAL STUDY PROTOCOL 
AN OPEN-LABEL EXTENSION STUDY TO EVALUATE THE SAFETY AND 
TOLERABILITY OF QR-421a IN SUBJECTS WITH RETINITIS PIGMENTOSA (RP) 
DUE TO MUTATIONS IN EXON 13 OF THE USH2A GENE 
 
 
Protocol No. 
PQ-421a-002  
Protocol/Amendment Date: 
24 May 2022 
Protocol/Amendment No.: 
3.0 
Protocol Version:  
4.0 
Supersedes: 
3.0 
EudraCT/IND Number 
2021-002070-93 
IND 137660 
Sponsor: 
ProQR Therapeutics  
Zernikedreef 9 
2333 CK Leiden 
The Netherlands 
 
 
 

 
 
 
 
Investigational Product: QR-421a 
Protocol No. PQ-421a-002 (Version 4) 
 
ProQR Therapeutics 
 
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24 May 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 (DD Month Year) 
 

 
 
 
 
Investigational Product: QR-421a 
Protocol No. PQ-421a-002 (Version 4) 
 
ProQR Therapeutics 
 
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24 May 2022 
PROTOCOL APPROVAL PAGE 
An Open-Label Extension Study to Evaluate the Safety and Tolerability of QR-421a in Subjects 
with Retinitis Pigmentosa (RP) due to Mutations in Exon 13 of the USH2A Gene  
Protocol No. PQ-421a-002 
Protocol/Amendment Date: 24 May 2022 
Protocol/Amendment No.: 3.0 
Protocol Version: 4.0 
Sponsor: ProQR Therapeutics 
Zernikedreef 9 
2333 CK Leiden 
The Netherlands 
 
 
 
 
 
 
 
 
ProQR Therapeutics 
 
Date 
 
 
 

 
 
 
 
Investigational Product: QR-421a 
Protocol No. PQ-421a-002 (Version 4) 
 
ProQR Therapeutics 
 
Page 4 of 65
 
 
24 May 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 Solution for 
Intravitreal Injection 
Name of Active Ingredient: 
QR-421a 
Title of Study:  
An Open-Label Extension Study to Evaluate the Safety and Tolerability of 
QR-421a in Subjects with Retinitis Pigmentosa (RP) due to Mutations in Exon 13 
of the USH2A Gene  
Phase of Development: 
Phase 2 
Study Period: 
Anticipated to be 24 months, or until provision of continued treatment by other 
means is available.  
Duration of Subject 
Participation: 
Until provision of continued treatment by other means is available, provided the 
subject’s benefit-risk assessment remains positive.  
Subject participation is expected to be 12 months for subjects who will only 
receive follow up in this study (i.e., chosen not to have any treatment 
administered). 
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 
significant unmet medical need exists in this sight-threatening condition. 
QR-421a is designed to target mutations in exon 13 of USH2A gene specifically. 
Hybridization of QR-421a to the pre-messenger ribonucleic acid (pre-mRNA) 
molecule modulates the ribonucleic acid (RNA) splicing process, which leads to 
exclusion of exon 13 from the mRNA. The exclusion of exon 13 results in the 
production of a functional (shorter) usherin protein. It is hypothesized that the 
production of usherin protein restores the outer segments of the photoreceptors and 
prevents their degeneration. 
 Subjects that have participated 
in QR-421a clinical studies, including study PQ-421a-001, will be given the 
opportunity to enroll into this extension study for continued dosing and/or follow 
up. 
Study PQ-421a-002 will provide long-term safety, tolerability, and efficacy data of 
QR-421a. 
Objectives: 
Primary  
• 
To evaluate long-term safety and tolerability of 
QR-421a  
Endpoints: 
Primary endpoints 
• 
Incidence and severity of ocular adverse events (AEs) 
• 
Incidence and severity of non-ocular AEs  
Secondary 
• 
To evaluate long-term efficacy of QR-421a  
Secondary endpoints 
• 
Change from baseline in the following outcome 
measures: 

 
 
 
 
Investigational Product: QR-421a 
Protocol No. PQ-421a-002 (Version 4) 
 
ProQR Therapeutics 
 
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24 May 2022 
• 
To evaluate long-term systemic exposure of 
QR-421a  
 
o 
Best Corrected Visual Acuity (BCVA)  
o 
Low Luminance Visual Acuity (LLVA) 
o 
Ellipsoid Zone (EZ) area/width by spectral domain 
optical coherence tomography (SD-OCT) 
o 
Static perimetry  
o 
Microperimetry 
• 
Exposure of QR-421a in serum 
Exploratory 
 
 
 
Exploratory efficacy endpoints 
 
  
 
 
 
 
Number of Subjects 
(planned): 
The number of subjects is dependent on the number of eligible subjects that have 
participated in preceding clinical studies with QR-421a, including 20 subjects 
from study PQ-421a-001.   
Study Design 
PQ-421a-002 is an open-label extension study to evaluate the safety, tolerability, 
and efficacy of QR-421a in subjects with RP due to mutations in exon 13 of the 
USH2A gene.  
Subjects who have participated in QR-421a clinical studies, including study PQ-
421a-001, will be allowed to enrol in this extension study for (continued) dosing, 
provided the subject’s benefit-risk assessment is positive, or for additional follow 
up. In consultation and agreement with the Medical Monitor, the Investigator will 
decide on the subject’s enrollment upon assessment of the subject’s benefit-risk.  
In consultation and agreement with the Medical Monitor, the Investigator will 
decide on dosing both eyes. Continued subject treatment in this study will be 
pursued provided that the benefit-risk balance is positive for the individual 
subject, as discussed and agreed upon with the Medical Monitor.  
The same safety monitoring protocol and efficacy assessments will apply to both 
eyes.  
Baseline functional and structural measurements for the study and fellow eye will 
be those from the Screening/Day 1 visit of PQ-421a-002 study. Baseline 
functional and structural measurements from a previous QR-421a study or 
historical clinical data may also be used as part of the long-term safety and 
efficacy analysis. 
Study Plan 
Subjects in the preceding QR-421a study who have completed the End of Study 
(EOS) visit as part of study completion/early termination procedures may have the 
Screening/Day 1 visit for study PQ-421a-002 combined with the EOS visit. All 
Screening/Day 1 assessments should take place during the EOS visit of the 
preceding study. If this is not possible, a separate Day 1 should be performed 
within 12 weeks of the EOS visit. If more than 12 weeks elapse from the EOS visit 
in the preceding study, a new Screening and Day 1 visit must be performed. 
Screening and Day 1 may be conducted as a single visit or as two separate visits, 
(within 12 weeks) as per the Investigator’s discretion. 

 
 
 
 
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Protocol No. PQ-421a-002 (Version 4) 
 
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Subjects in a preceding QR-421a study who did not complete an EOS visit must 
have a Screening and Day 1 visit performed as part of PQ-421a-002. Screening 
and Day 1 may be conducted as a single visit or two separate visits (within 12 
weeks), as per the Investigator’s discretion.  
Assessments can be completed over multiple, non-consecutive days. 
Subjects who do not meet stopping criteria prior to their next scheduled injection 
will receive their planned dose. Subjects who meet stopping criteria will be 
discontinued from dosing and will be followed for safety and efficacy. The 
Sponsor, in consultation with the Investigator, may decide to modify the dose, the 
dosing interval for repeat injections in one eye or both eyes, hold the dose (delay 
or skip), or discontinue the study drug for an individual subject based on emerging 
safety and efficacy data and if it is anticipated to be in the best interest of the 
subject. Stopping criteria are described in Section 4.2.2. 
Subjects who discontinue study drug in both eyes or who will only receive follow 
up in this study will be encouraged to remain in the study for observation for at 
least 12 months post last dose (or post-study initiation for subjects who will only 
receive follow up). During these 12 months post last dose (or post-study 
initiation), visits will be planned at 6-month intervals. For subjects who 
discontinue treatment in one eye, the visits will be reduced to once every 6-month, 
rather than once every 3 months. 
After each administration of study treatment, subjects will be monitored clinically 
for safety, including intraocular pressure (IOP), optic nerve swelling, and signs of 
inflammation. 
Efficacy and safety assessments will be performed at selected study visits as 
indicated in the Schedule of Events (SOE) 
 All ophthalmic 
assessments will be performed on both eyes. 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 
 
Diagnosis and Main Criteria 
for Eligibility: 
Inclusion Criteria: 
1. Subjects who have participated in a preceding QR-421a study and who may 
derive benefit from (continued) treatment with QR-421a, and/or continued 
follow up, as assessed by the Investigator, in consultation and agreement with 
the Medical Monitor (Section 4.2.1.1). 
2. 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) able to provide age-appropriate assent for study 
participation, and 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. 
3. 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.  

 
 
 
 
Investigational Product: QR-421a 
Protocol No. PQ-421a-002 (Version 4) 
 
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4. Reliable BCVA, perimetry, and other measurements in both eyes, as 
described in the Study Reference Manual and Imaging Manual and 
determined by the Investigator.  
5. Clear ocular media and adequate pupillary dilation to permit good quality 
retinal imaging, as assessed by the Investigator. 
 
Exclusion Criteria: 
1. Presence of any significant ocular 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) in the treatment eye. CME is permissible if stable for 3 months (with 
or without treatment). Past CME is permissible if resolved for more than 1 
month. 
2. 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 during the course of the study. 
3. Safety issue during preceding QR-421a study that may compromise subject 
safety when continued dosing, as determined by the Investigator and in 
consultation with the Medical Monitor. 
a. 
Subjects with existing safety events from the preceding QR-421a 
study may be included as determined by the Investigator and in 
consultation with the Medical Monitor. 
4. 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. 
5. Use of any investigational drug (other than QR-421a) 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 PQ-421a-002 study period. 
6. Any prior treatment with genetic or stem-cell therapy for ocular or non-ocular 
disease. 
7. Known hypersensitivity to antisense oligonucleotides or any constituents of 
the injection. 
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 
adequate birth control, provided they meet the criteria in the protocol (Section 
6.2.2). 
Study Drug, Dosage and Mode 
of Administration: 
QR-421a Solution for IVT injection and solvent; 180 µg loading dose followed by 
60 µg maintenance doses at 6-month intervals; IVT injection 
  
Fellow eye is defined as follows: For subjects previously treated (active or sham) 
in the preceding QR-421a study: the eye that was not selected as the study eye. 

 
 
 
 
Investigational Product: QR-421a 
Protocol No. PQ-421a-002 (Version 4) 
 
ProQR Therapeutics 
 
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For subjects that were not treated at all: the eye with the worst BCVA at Helia 
Screening/Day1. 
Study eye is defined as follows: For subjects previously dosed (active or sham) in 
the preceding QR-421a study: the eye that was selected as the study eye. 
For subjects that were not dosed at all: the eye with the best BCVA at Helia 
Screening/Day1. 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
The Sponsor, in consultation with the Investigator, may decide to modify the dose, 
the dosing interval for repeat injections in one eye or both eyes, hold the dose 
(delay or skip), or discontinue the study drug for an individual subject based on 
the emerging safety and efficacy data and if it is anticipated to be in the best 
interest of the subject. Stopping criteria are described in Section 4.2.2. 
Duration of Treatment: 
Anticipated to be 24 months, or until provision of continued treatment by other 
means is available, provided the subject’s benefit-risk determination remains 
positive. 
Reference Therapy, Dosage 
and Mode of Administration: 
Not applicable 
Statistical Methods: 
Analyses will generally be descriptive.  
A comprehensive Statistical Analysis Plan (SAP) will specify the statistical 
methodology, including interim data reviews (if conducted) and table, listing, and 
figure (TLF) formats for all aspects of the planned analyses. 
 
 

 
 
 
 
Investigational Product: QR-421a 
Protocol No. PQ-421a-002 (Version 4) 
 
ProQR Therapeutics 
 
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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 ..............................................................................................................9 
LIST OF FIGURES .....................................................................................................................13 
LIST OF TABLES .......................................................................................................................13 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................14 
2.0 
INTRODUCTION............................................................................................................16 
2.1 
Retinitis Pigmentosa ..............................................................................................16 
2.2 
QR-421a for the Treatment of RP due to Mutations in Exon 13 of the USH2A 
Gene .......................................................................................................................16 
2.2.1 
Nonclinical Experience .........................................................................18 
2.2.2 
Clinical Experience ...............................................................................19 
2.3 
Benefit Risk Assessment........................................................................................19 
2.4 
Study Rationale ......................................................................................................21 
2.5 
Dose Selection .......................................................................................................21 
2.6 
Study Population ....................................................................................................23 
3.0 
STUDY OBJECTIVES ....................................................................................................23 
3.1 
Primary Objective ..................................................................................................23 
3.2 
Secondary Objective ..............................................................................................23 
3.3 
Exploratory Objectives ..........................................................................................23 
4.0 
STUDY OVERVIEW ......................................................................................................23 
4.1 
Criteria for Evaluation ...........................................................................................23 
4.1.1 
Primary Endpoints .................................................................................23 
4.1.2 
Secondary Endpoints .............................................................................23 
4.1.3 
Exploratory Endpoints ..........................................................................24 
4.2 
Study Design ..........................................................................................................24 
4.2.1 
Study Plan .............................................................................................25 
4.2.2 
Stopping Criteria ...................................................................................27 
4.2.3 
Discontinuation of the Study .................................................................28 
5.0 
SELECTION OF STUDY POPULATION ...................................................................28 
5.1 
Study Population ....................................................................................................28 
5.2 
Selection of Subjects ..............................................................................................28 

 
 
 
 
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5.3 
Eligibility Criteria ..................................................................................................28 
5.3.1 
Inclusion Criteria ...................................................................................28 
5.3.2 
Exclusion Criteria..................................................................................29 
6.0 
STUDY DRUG AND CONCOMITANT THERAPIES ...............................................30 
6.1 
Study Drug .............................................................................................................30 
6.1.1 
Study Drug Description and Supply .....................................................30 
6.1.2 
Placebo ..................................................................................................30 
6.1.3 
Study Drug Shipment and Storage ........................................................30 
6.1.4 
Study Drug Accountability and Reconciliation ....................................30 
6.1.5 
Dosage and Administration ...................................................................30 
6.2 
Concomitant Medications and Auxiliary Therapy .................................................33 
6.2.1 
Prohibited Concomitant Medications ....................................................33 
6.2.2 
Adequate Forms of Birth Control .........................................................33 
7.0 
STUDY VISITS ................................................................................................................34 
7.1 
Visit and Assessment Windows .............................................................................34 
7.2 
Dosing and Follow-up Visits .................................................................................35 
7.3 
End of Study Visit ..................................................................................................36 
8.0 
STUDY ASSESSMENT PROCEDURES ......................................................................36 
8.1 
Adverse Events ......................................................................................................36 
8.2 
Laboratory Evaluations ..........................................................................................36 
8.3 
Systemic exposure .................................................................................................37 
8.4 
Ophthalmic Examinations ......................................................................................37 
8.5 
Spectral Domain Optical Coherence Tomography ................................................38 
8.6 
Efficacy Assessments.............................................................................................38 
8.7 
Retinitis Pigmentosa Medical History ...................................................................38 
9.0 
ASSESSMENT OF SAFETY OR ADVERSE EVENTS AND SERIOUS 
ADVERSE EVENTS .......................................................................................................38 
9.1 
Definitions of Adverse Event, Serious Adverse Event, and Suspected 
Unexpected Serious Adverse Event .......................................................................39 
9.1.1 
Adverse Events......................................................................................39 
9.1.2 
Serious Adverse Events.........................................................................39 
9.1.3 
Suspected Unexpected Serious Adverse Reaction Definition ..............40 
9.1.4 
Adverse Events of Special Interest .......................................................41 
9.2 
Assessment of Adverse Events ..............................................................................41 
9.2.1 
Assessment of Severity (Intensity) of Adverse Events .........................41 
9.2.2 
Assessment of the Relationship of Adverse Events to Study Drug ......42 

 
 
 
 
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9.2.3 
Assessment of the Outcome of Adverse Events ...................................42 
9.3 
Reporting of Adverse Events .................................................................................43 
9.3.1 
Adverse Event Reporting Period ...........................................................43 
9.3.2 
Eliciting Adverse Events .......................................................................43 
9.3.3 
Recording Adverse and Serious Adverse Events ..................................44 
9.4 
Serious Adverse Events Notification .....................................................................46 
9.5 
Expedited Reporting of Suspected Unexpected Serious Adverse Reactions .........47 
10.0 
STATISTICAL METHODOLOGY...............................................................................47 
10.1 
General Considerations ..........................................................................................47 
10.2 
Determination of Sample Size ...............................................................................47 
10.3 
Randomization and Masking .................................................................................47 
10.4 
Replacement of Subjects ........................................................................................48 
10.5 
Analysis Populations ..............................................................................................48 
10.6 
Subject Disposition, Demographics and Baseline Disease Characteristics ...........48 
10.7 
Treatment Compliance ...........................................................................................48 
10.8 
Safety Analyses ......................................................................................................48 
10.8.1 
Treatment Emergent Adverse Events....................................................48 
10.8.2 
Other Safety Assessments .....................................................................49 
10.9 
Systemic Exposure Analyses .................................................................................49 
10.10 Efficacy Analyses ..................................................................................................49 
10.11 Interim Analysis .....................................................................................................49 
10.12 Subgroup Analyses.................................................................................................49 
11.0 
QUALITY CONTROL AND QUALITY ASSURANCE .............................................49 
11.1 
Data Collection ......................................................................................................49 
11.2 
Data Quality Control ..............................................................................................50 
11.3 
Monitoring .............................................................................................................50 
11.4 
Audits and Inspections ...........................................................................................51 
12.0 
ETHICAL AND REGULATORY OBLIGATIONS ....................................................51 
12.1 
Ethical Considerations ...........................................................................................51 
12.2 
Informed Consent...................................................................................................51 
12.3 
Ethics and Regulatory Review ...............................................................................52 
12.4 
Subject Confidentiality ..........................................................................................52 
13.0 
STUDY ADMINISTRATION ........................................................................................53 
13.1 
Investigator’s Brochure ..........................................................................................53 
13.2 
Protocol Amendments ............................................................................................53 
13.3 
Study Termination .................................................................................................54 

 
 
 
 
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13.4 
Study Documentation and Storage .........................................................................54 
13.5 
Use of Information .................................................................................................55 
13.6 
End of Study and Final Report...............................................................................55 
13.7 
Financing and Insurance ........................................................................................55 
13.8 
Publication Policy ..................................................................................................56 
14.0 
REFERENCES .................................................................................................................57 
15.0 
PROTOCOL SUMMARY OF CHANGES ...................................................................60 
16.0 
APPENDICES ..................................................................................................................61 
 
16.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ...........................................65 
 

 
 
 
 
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LIST OF FIGURES 
 
 
LIST OF TABLES 
 
 

 
 
 
 
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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 
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 
CFR 
Code of Federal Regulations 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CME 
Cystoid Macular Edema 
CRP 
C-Reactive Protein 
CSR 
Clinical Study Report 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
eGFR 
Estimated Glomerular Filtration Rate 
EOS 
End of Study 
ERG 
Electroretinogram 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
EZ 
Ellipsoid Zone 
DP 
Drug Product 
FDA 
Food and Drug Administration 
FIH 
First In Human 
GCP 
Good Clinical Practice 
γGT 
Gamma-Glutamyl Transferase 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation  
INR 
International Normalized Ratio 
IOP 
Intraocular Pressure 

 
 
 
 
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Abbreviation 
Definition 
IRB 
Institutional Review Board 
iPSCs 
Induced pluripotent stem cells 
IVT 
Intravitreal 
LCA 
Leber’s Congenital Amaurosis 
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 
PD 
Pharmacodynamic 
 
 
 
ProQR 
ProQR Therapeutics 
PT 
Preferred Term 
RNA 
Ribonucleic Acid 
RP 
Retinitis Pigmentosa 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD-OCT 
Spectral Domain Optical Coherence Tomography 
SOC 
System Organ Class 
SOE 
Schedule of Events 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment Emergent Adverse Event 
TLF 
Table Listing Figure format 
TNF 
Tumor Necrosis Factor 
US 
United States 
 
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, QR-421a, 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 QR-421a 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 non-syndromic form of RP (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 (ie, 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 supplementations have been proposed as pharmacological 
treatment options. Both therapies showed a good safety profile but limited clinical benefit. 
2.2 
QR-421a for the Treatment of RP due to Mutations in Exon 13 of the USH2A Gene 
The primary goal of the development plan for QR-421a 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. 

 
 
 
 
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2.2.1 
Nonclinical Experience 

 
 
 
 
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2.2.2 
Clinical Experience 
The clinical development program started in the first half of 2019 with the first-in-human (FIH) 
clinical study (PQ-421a-001), a Phase 1b/2, double-masked, sham-controlled, dose-escalation 
study to evaluate the safety and tolerability of QR-421a. An interim analysis was performed in 
March 2021 and the final participant visit was in Q4 2021. The study is undergoing final 
analyses and reporting.  
Available safety and efficacy data from study PQ-421a-001 support the therapeutic potential 
observed in the nonclinical studies. Reference is made to the IB for further details. 
2.3 
Benefit Risk Assessment 
RP is a group of inherited eye disorders causing 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. In addition, these patients usually receive 
genetic counselling on the risks of passing the condition on to their children and regular medical 
follow up. They also may receive adaptive support when necessary. Therefore, a significant 
unmet medical need exists in this sight-threatening condition. 
The high unmet medical need in this orphan, sight-threatening condition warrants therapeutic 
intervention in those patients with usually preserved central vision. In addition, subjects with 
sufficient residual retinal photoreceptors translated in preserved central VF may derive a clinical 
benefit (see inclusion criteria of clinical study protocol). 
The design of this study has been selected to provide a sufficient benefit-risk ratio to justify the 
participation of patients. 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. 
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 and 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 

 
 
 
 
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System, monitoring for retinal changes by OCT, and VF testing to monitor changes in retinal 
sensitivity. This extensive clinical monitoring provides a means to allow early detection and/or 
prevention of potential AEs such as early signs of macular edema appearance or worsening, 
decrease in BCVA, the elevation of IOP, 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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Detailed information about benefits and potential risks of QR-421a, as well as information on 
nucleotide AONs as a class of therapeutics can be found in the IB.  
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. 
Available safety and efficacy data from study PQ-421a-001 support the therapeutic potential 
observed in the nonclinical studies and warrant the initiation of the additional clinical studies to 
confirm benefit-risk. 
This extension study allows subjects having participated in QR-421a clinical studies, including 
study PQ-421a-001, to continue to receive treatment, or follow up, and to observe the long-term 
safety, tolerability, systemic exposure, and efficacy of treatment with QR-421a. Additionally, 
this extension study allows for the treatment of the previously untreated fellow/contralateral eye 
for subjects from study PQ-421a-001. 
2.5 
Dose Selection 
The FIH study PQ-421a-001 evaluated 50, 100 and 200 µg single doses. Safety and efficacy data 
from 20 subjects followed up for 3 to 24 months have been taken into consideration in the dose 
selection for the current study. The safety profile of these dose levels did not differ. Available 
efficacy data confirmed the potential therapeutic value of these dose levels. No clear dose-
response was observed. Hence, simulations including nonclinical data were performed to select a 
dose regimen that will provide exposure levels that maintain a wide safety margin, while at the 

 
 
 
 
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same time maximizing pharmacodynamic effects. Additional details on the dose selection are 
provided in the IB.  
TE and FE in Helia are defined in Section 4.2. 
 
QR-421a will be first administered to the fellow eye (as defined in the preceding study) and will 
be repeated every 6-month. Treatment of the study eye (as defined in the preceding study) can 
commence 9 months after the treatment of the fellow eye has been initiated and will be repeated 
every 6-month as well. QR-421a will be administered as a loading dose, followed by 
maintenance doses at 6-month intervals. 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. For subjects from 
study PQ-421a-001 who were administered 50 and 100 µg doses, the loading dose will be 
180 µg and the maintenance dose will be 60 µg. The same dosing regimen applies to the fellow 
eye of subjects from study PQ-421a-001 who were administered 200 µg doses. However, the 
study eye of these subjects will have a dosing regimen without loading dose and will therefore 
receive 60 µg in the study eye at Month 9, and every 6-month thereafter, to account for 
remaining exposure to QR-421a from their initial dose as part of study PQ-421a-001.  

 
 
 
 
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2.6 
Study Population 
Subjects who have participated in a preceding QR-421a study and who may derive benefit from 
(continued) treatment with QR-421a, and/or continued follow up, as assessed by the Investigator, 
in consultation and agreement with the Medical Monitor (Section 4.2.1.1). 
Reference is made to Section 5.3 for specific eligibility requirements. 
3.0 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of the study is to evaluate the long-term safety and tolerability of 
QR-421a. 
3.2 
Secondary Objective 
The secondary objectives of the study are: 
• To evaluate the long-term efficacy of QR-421a  
• To evaluate the systemic exposure of QR-421a  
3.3 
Exploratory Objectives 
  
 
4.0 
STUDY OVERVIEW 
4.1 
Criteria for Evaluation 
4.1.1 
Primary Endpoints 
• Incidence and severity of ocular adverse events (AEs)  
• Incidence and severity of non-ocular AEs  
4.1.2 
Secondary Endpoints 
• Change from baseline in the following outcome measures: 
o Best Corrected Visual Acuity (BCVA)  

 
 
 
 
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o Low Luminance Visual Acuity (LLVA) 
o Static perimetry  
o Ellipsoid Zone (EZ) area/width by spectral domain optical coherence 
tomography (SD-OCT) 
o Microperimetry 
• Exposure of QR-421a in serum 
4.1.3 
Exploratory Endpoints 
 
 
 
 
 
 
4.2 
Study Design 
PQ-421a-002 is an open-label, extension study to evaluate the safety, tolerability, and efficacy of 
QR-421a in subjects with RP due to mutations in exon 13 of the USH2A gene.  
Subjects that have participated in preceding QR-421a clinical studies, including study PQ-421a-
001, will be given the opportunity to enroll into this extension study for continued dosing, 
provided the subject’s benefit-risk assessment is positive, or for additional follow up. The 
Investigator, in consultation and agreement with the Medical Monitor, will decide on subject’s 
enrollment upon assessment of subject’s benefit-risk.  
QR-421a will be first administered to the fellow eye and will be repeated every 6-month. 
Treatment of the study eye can commence as outlined in Section 6.1.5 and 
 based 
on the participant and when they completed their participation in the previous QR-421a study. 
The Investigator, in consultation and agreement with the Medical Monitor, will decide on dosing 
of both eyes. Continued subject treatment in this study will be pursued provided that the benefit-
risk is positive for the individual subject, as discussed and agreed upon with the Medical 
Monitor.  
The Sponsor, in consultation with the Investigator, may decide to modify the dose, the dosing 
interval for repeat injections in one eye or both eyes, hold the dose (delay or skip), or discontinue 
study drug for an individual subject, based on emerging safety and efficacy data and if it is 
anticipated to be in the best interest of the subject. 
The same safety monitoring protocol and efficacy assessments will apply to both eyes.  

 
 
 
 
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Baseline functional and structural measurements for the study and fellow eye will be those from 
the Screening/Day 1 visit of the current study. Baseline functional and structural measurements 
from the previous QR-421a study, or historical clinical data, may also be used as part of the 
long-term safety and efficacy analysis. 
Definition of Study Eye and Fellow Eye in Helia 
Fellow eye is defined as follows: For subjects previously dosed (active or sham) in the preceding 
QR-421a study: the eye that was not selected as the study eye. For subjects that were not dosed 
at all: the eye with the worst BCVA at Helia Screening/Day1. 
Study eye is defined as follows: For subjects previously dosed (active or sham) in the preceding 
QR-421a study: the eye that was selected as the study eye. For subjects that were not dosed at 
all: the eye with the best BCVA at Helia Screening/Day1. 
4.2.1 
Study Plan  
4.2.1.1 
Screening 
Subjects in the preceding QR-421a study who have completed the End of Study (EOS) visit as 
part of study completion/early termination procedures may have the Screening/Day 1 visit for 
this study combined with the EOS visit. All Screening/Day 1 assessments should take place 
during the EOS visit of the preceding study. If this is not possible, a separate Day 1 should be 
performed within 12 weeks of the EOS visit. If more than 12 weeks elapse from the EOS visit in 
the preceding study, a new Screening and Day 1 visit must be performed. Screening and Day 1 
may be conducted as single visit or as two separate visits (within 12 weeks), as per the 
Investigator’s discretion. 
Subjects in a preceding QR-421a study who did not complete an EOS visit must have a 
Screening and Day 1 visit performed as part of PQ-421a-002. Screening and Day 1 may be 
conducted as a single visit or as two separate visits (within 12 weeks), as per the Investigator’s 
discretion.  
During the Screening/Day 1 visit, subjects will be assessed according to the eligibility criteria.  
Assessments can be completed over multiple, non-consecutive days instead of 1 full day, at the 
discretion of the Investigator. 
The Investigator, in consultation and agreement with the Medical Monitor, will decide on 
subject’s enrollment upon assessment of subject’s benefit-risk and the subject’s meeting of 
eligibility criteria. Continued subject treatment in this study is desirable, but cannot be 
guaranteed, since it will depend on the risks and benefit of further treatment on a case-by-case 
basis, as discussed and agreed upon with the Medical Monitor. 

 
 
 
 
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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.  
Subjects who do not meet stopping criteria prior to their next scheduled injection will receive 
their planned dose. Subjects who meet stopping criteria will be discontinued from dosing and 
will be followed for safety and efficacy. The Sponsor, in consultation with the Investigator, may 
decide to modify the dose, the dosing interval, hold a specific dose (delay or skip), or discontinue 
study drug for an individual subject, based on emerging safety and efficacy data and if it is 
anticipated to be in the best interest of the subject. The Investigator and/or the Sponsor may 
decide to stop treatment for an individual subject due to an AE. Stopping criteria are described in 
Section 4.2.2. 
Subjects who discontinue study drug in both eyes, or who will only receive follow up in this 
study, will be encouraged to remain in the study for observation for at least 12 months post last 
dose (or post study initiation for subjects who will only receive follow up). During these 12 
months post last dose (or post study initiation), visits will be planned at 6-month intervals.  
For subjects who discontinue treatment in one eye, the visit frequency will be reduced to once 
every 6-month, rather than once every 3 months. 
4.2.1.3 
Assessments and Follow-up 
On the dosing days post study treatment, subjects will be monitored for safety, including in 
intraocular pressure (IOP), optic nerve swelling and signs of inflammation. Both post-dose visits 
(i.e., 1 day after dosing and 7 days after dosing) will be a phone call from the site to the subject, 
and do not need to be planned if no dosing took place. 
All ophthalmic assessments will be performed on both eyes. 
The frequency of all assessments is presented in the Schedule of Events (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. 

 
 
 
 
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4.2.2 
Stopping Criteria 
4.2.2.1 
Stopping Criteria for Individual Subjects 
The Investigator or the Medical Monitor may stop treatment for an individual subject due to an 
AE (see Section 8.1). The severity of the event(s), as well as the temporal relationship to study 
drug administration, potential for worsening of the event(s) with continued QR-421a treatment 
and association with other safety signals or laboratory values should be considered in the 
decision to stop treatment. The Medical Monitor must be notified of any subject who stops 
treatment due to an AE. Adverse events considered to be related to the study drug should be 
taken into account in the benefit-risk assessment. 
The Medical Monitor, in consultation with the Investigator, may decide to modify the dose, the 
dosing interval, hold a specific dose (delay or skip), or discontinue study drug for an individual 
subject, based on emerging safety and efficacy data and if it is anticipated to be in the best 
interest of the subject. 
Subjects who discontinue study drug in both eyes will be encouraged to remain in the study for 
observation for at least 12 months post last dose. During these 12 months post last dose, visits 
can be planned at 6-month intervals.  
The Medical Monitor will perform ongoing safety reviews of systemic and ophthalmic safety 
data and AEs to identify any safety signal.
 
 
 
 
The Investigator and/or the Sponsor may also decide to stop treatment for both eyes, based on 
the AE in the first eye. 
4.2.2.2 
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 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. 

 
 
 
 
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4.2.3 
Discontinuation of the Study 
The Medical Monitor will evaluate the safety and tolerability data as described in Section 
2.2.2 and thereafter on an ongoing basis to recommend if the study should continue or cease, or 
if any modifications should be made as to how subjects are treated or managed. 
5.0 
SELECTION OF STUDY POPULATION  
5.1 
Study Population 
Subjects who have participated in a preceding QR-421a study and who may derive benefit from 
(continued) treatment with QR-421a, and/or continued follow up, as assessed by the Investigator, 
in consultation and agreement with the Medical Monitor, and meet all eligibility requirements, 
are eligible to participate in this extension study. 
5.2 
Selection of Subjects 
Subjects will be evaluated against all eligibility criteria as presented in the SOE
 
Final approval from the Sponsor’s medical monitor on subject eligibility is required prior to 
dosing of subjects. 
Results of assessments for all eligibility criteria must be available and reviewed prior to the 
subject’s first dose of study treatment. 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 time point (for example, when awaiting a 3-month window after 
intraocular surgery). 
5.3 
Eligibility Criteria 
5.3.1 
Inclusion Criteria 
The subject is eligible for the study if all the following inclusion criteria apply at baseline: 
1. Subjects who have participated in a preceding QR-421a study and who may derive benefit 
from continued treatment with QR-421a, and/or continued follow up, as assessed by the 
Investigator, in consultation and agreement with the Medical Monitor (Section 4.2.1.1). 
2. 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) able to provide age-appropriate assent for study participation, and 
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. 

 
 
 
 
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3. 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.  
4. Reliable BCVA, perimetry, and other measurements in both eyes, as described in the Study 
Reference Manual and Imaging Manual and determined by the Investigator.  
5. Clear ocular media and adequate pupillary dilation to permit good quality retinal imaging, as 
assessed by the Investigator. 
5.3.2 
Exclusion Criteria 
The subject is ineligible for the study if any of the following criteria apply at Screening: 
1) Presence of any significant ocular 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) in the treatment eye. CME is permissible if stable for 3 months (with or 
without treatment). Past CME is permissible if resolved for more than 1 month. 
2) 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 during the course of the study. 
3) Safety issue during preceding QR-421a study that may compromise subject safety when 
continued dosing, as determined by the Investigator, and in consultation with the Medical 
Monitor. 
a) Subjects with existing safety events from the preceding QR-421a study may be included 
as determined by the Investigator and in consultation with the Medical Monitor. 
4) 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. 
5) Use of any investigational drug (other than QR-421a) 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 PQ-421a-002 study period. 
6) Any prior treatment with genetic or stem-cell therapy for ocular or non-ocular disease. 

 
 
 
 
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7) Known hypersensitivity to antisense oligonucleotides or any constituents of the injection. 
8) 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 (Section 6.2.2). 
6.0 
STUDY DRUG AND CONCOMITANT THERAPIES 
6.1 
Study Drug 
6.1.1 
Study Drug Description and Supply 
The QR-421a 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.  
6.1.3 
Study Drug Shipment and Storage 
Please refer to the Pharmacy Manual and Study Reference Manual for details on shipment, 
storage, handling, preparation, and administration. 
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 handling are 
provided in the Pharmacy Manual and the Study Reference Manual.  
6.1.5 
Dosage and Administration 
The study eye is the study/treatment eye as defined in the preceding QR-421a study; the fellow 
eye is the fellow/contralateral eye as defined in the preceding QR-421a study. In general, 
QR-421a will be administered as a 180 µg loading dose on day 1, followed by 60 µg 
maintenance doses at 6-month intervals. Modifications for individual participants, defined based 
on the dosing and/or timing of their participation completion in the previous QR-421a study are 
outlined below. 
 

 
 
 
 
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QR-421a will be administered via IVT injection in accordance with the procedures outlined by 
the American Academy of Ophthalmology (Avery 2014). The pharmacist (or other personnel 
qualified to prepare study drug for administration) at each study center will receive study drug 
and will prepare and/or dilute the study drug with sterile solvent (PBS) when necessary, 
according to the Pharmacy Manual for each administration. 
 
Administration of study drug will only be performed by qualified ophthalmologists in an in-
clinic setting. No other medications should be mixed with study drug. Reference is made to the 
Pharmacy Manual and Study Reference Manual for detailed instructions on the IVT injection.  
6.2 
Concomitant Medications and Auxiliary Therapy 
6.2.1 
Prohibited Concomitant Medications 
The use of any investigational drug (other than QR-421a) 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, etc. Topical steroids are not prohibited but should only be used following 
consultation with the Medical Monitor. 
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; ie fertile, following menarche and until becoming 
postmenopausal unless permanently sterile) and fertile male subjects (ie, after puberty unless 
permanently sterile) must either practice true abstinence in accordance with their preferred and 
usual lifestyle, or agree to use highly effective methods of contraception for up to 24 months 
following their last dose of QR-421a. 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 (eg, 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 (ie, 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 
 
A man who is fertile should use a condom during treatment 
 
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 (eg, 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 missed, the 

 
 
 
 
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reasons are also to be recorded. For more details, please refer to the case report form completion 
guidelines. 
Subjects in the preceding QR-421a study who have completed the EOS visit as part of study 
completion/early termination procedures may have the Screening/Day 1 visit for this study 
combined with the EOS visit. All Screening/Day 1 assessments should take place during the 
EOS visit of the preceding study. If this is not possible, a separate Day 1 should be performed 
within 12 weeks of the EOS visit. If more than 12 weeks elapse from the EOS visit in the 
preceding study, a new Screening and Day 1 visit must be performed. Screening and Day 1 may 
be conducted as a single visit or as two separate visits (within 12 weeks), as per the 
Investigator’s discretion. 
Subjects in a preceding QR-421a study who did not complete an EOS visit must have a 
Screening and Day 1 visit performed as part of PQ-421a-002. Screening and Day 1 may be 
conducted as a single visit or as two separate visits (within 12 weeks), as per the Investigator’s 
discretion.  
During the Screening/Day 1 visit, subjects will be assessed according to the eligibility criteria.  
Dosing day visits have a visit window of ± 30 days. Study center phone calls to the subjects will 
occur 1 and 7 (±3) days post-IVT injection. All visits and/or assessments can be completed over 
multiple, non-consecutive days.  
All visit windows should be calculated from Day 1 in this study.  
7.2 
Dosing and Follow-up Visits 
Dosing visits occur on Day 1, and then every 6-month for the fellow eye. Dosing visits for the 
study eye will begin at Month 3 or Month 9 (see Section 6.1.5 on dosing schema by participant 
and preceding QR-421a study), and then every 6-month. The (eventual) between-eye interval of 
every 3 months could be adapted in agreement with the Medical Monitor if safety data are 
supportive, and for logistic reasons.  
Subjects should be monitored for safety, including IOP, optic nerve swelling and signs of 
inflammation during the post-injection period. 
Study center phone calls to the subjects will occur 1 day and 7 (±3) days post-IVT injection. 
These calls are only required if the subject received a dose. 
All follow-up study visits, assessments and procedures should be completed as indicated per the 
SOE
 Subjects will be assessed for safety, tolerability, and efficacy at follow-
up visits with all ophthalmic assessments performed on both eyes.  
Subjects who discontinue study drug in both eyes, or who will only receive follow up in this 
study, will be encouraged to remain in the study for observation for at least 12 months post last 

 
 
 
 
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dose (or post study initiation for subjects who will only receive follow up). During these 12 
months post last dose (or post study initiation), visits can be planned at 6-month intervals.  
For subjects who discontinue treatment in one eye, the visit frequency can be reduced to once 
every 6-month, rather than once every 3 months. 
7.3 
End of Study Visit  
The EOS visit occurs 12 months after the last dose of study drug for a subject.  
Subjects who discontinue study treatment but do not withdraw consent will be encouraged to 
remain in the study for observation for at least 12 months post last dose.  
8.0 
STUDY ASSESSMENT PROCEDURES 
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. Any assessment may be repeated if the results are considered unreliable or of 
unacceptable quality by the Investigator. 
All assessments will be conducted as indicated by the SOE 
. 
8.1 
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, Assessment of Safety or Adverse Events and Serious Adverse 
Events, for further details. 
8.2 
Laboratory Evaluations 
At Screening, laboratory results from the preceding QR421a study will be reviewed (if within the 
12-week window), or a new local or central laboratory test, including a urine dipstick, will be 
performed to review for any abnormal laboratory values that may indicate a safety signal that 
would affect eligibility.  
Subsequent laboratory evaluations will be conducted at a central laboratory and include serum 
chemistries, hematology and urinalysis. 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 

 
 
 
 
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protein. Estimated glomerular filtration rate (eGFR) is to be calculated using the CKD-EPI 
Creatinine Equation 2009 calculation.  
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).  
Urinalysis (by visual inspection and dipstick) will include color and appearance, specific gravity, 
pH, protein, glucose, blood (erythrocytes), leukocytes, bilirubin, ketones, nitrite, and 
urobilinogen.  
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 may affect eligibility should be discussed with the Medical Monitor prior to 
subject inclusion. 
For female subjects of childbearing potential, pregnancy testing will be performed per the SOE 
 
8.3 
Systemic exposure 
Samples for systemic exposure analysis of QR-421a will be collected from all subjects as 
indicated per the SOE
 
8.4 
Ophthalmic Examinations 
Ophthalmic examinations include slit lamp biomicroscopy, intraocular pressure, and dilated 
fundus examination and will be performed according to the SOE
 
Biomicroscopic examination includes pupillary examination, and examination of the external 
adnexa, conjunctiva, sclera, cornea, anterior chamber flare and cell score, iris, lens grading using 
the Age-Related Eye Diseases Study (AREDS) lens grading system, and vitreous examination. 
Intraocular pressure will preferably be assessed using Goldmann applanation tonometry. The 
same equipment should be used consistently throughout the study for a particular subject. 
Funduscopic examination (dilated) includes evaluation of optic nerve, macula, retinal vessels, 
and retinal periphery.  
Following administration of study treatment, intraocular pressure and perfusion of the optic 
nerve head should be monitored and managed appropriately. Subjects should also be monitored 
for signs of inflammation during the post dosing period.  
Further details on the procedures for ophthalmic examinations are in the Study Reference 
Manual.   

 
 
 
 
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8.5 
Spectral Domain Optical Coherence Tomography  
Spectral domain optical coherence tomography (SD-OCT) will be performed according to the 
SOE 
.  Changes in SD-OCT findings are of relevance to the safety and efficacy 
profile of QR-421a. All SD-OCT scans should be performed in accordance with the procedures 
outlined in the Imaging Manual.  
8.6 
Efficacy Assessments  
Efficacy assessments include static and microperimetry, SD-OCT, BCVA, and LLVA, and will 
be performed at selected study visits as indicated in the SOE
 See the Study 
Reference Manual and Imaging Manual for further information on these assessments. All 
ophthalmic assessments will be performed on both the study and fellow eye. A central reading 
center will be used for several of the ophthalmologic assessments, including SD-OCT. 
BCVA and LLVA will be assessed using the Early Treatment Diabetic Retinopathy Study 
(ETDRS) vision chart. LLVA will be measured by reading an ETDRS chart under normal 
lighting with a 2.0-log-unit neutral density filter placed in front of the best lens correction 
(Sunness 2008). 
8.7 
Retinitis Pigmentosa Medical History 
The following information related to subjects RP due to mutations in exon 13 of the USH2A 
gene will be collected: 
9.0 
ASSESSMENT OF SAFETY OR 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 

 
 
 
 
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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 
Definitions of Adverse Event, Serious Adverse Event, and Suspected Unexpected 
Serious Adverse Event 
9.1.1 
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 
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 9.3.1) 
• Adverse events not previously observed in the subject that emerge during the 
protocol-specified AE reporting period (as specified in Section 9.3.1)  
• 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) 
9.1.2 
Serious Adverse Events 
An AE or suspected adverse reaction is considered “serious” if, in the view of either the 
Investigator or Sponsor, 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) 

 
 
 
 
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• 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 
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 (SAE). 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 9.2.1). “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 SAEs on the 
AE eCRF and SAE form. 
9.1.3 
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. 

 
 
 
 
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9.1.4 
Adverse Events of Special Interest 
9.2 
Assessment of Adverse Events  
The Investigator is responsible for assessing the seriousness, severity and causality of AEs. 
9.2.1 
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: Does not interfere with subject’s usual function. 
• MODERATE: Interferes to some extent with subject’s usual function. 
• SEVERE: Interferes significantly with subject’s usual function. 
As described previously in Section 9.1.2, 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 9.1.2. 

 
 
 
 
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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. 
9.2.2 
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. 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 
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, or paper 
AESI/SAE/Special Situation 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. 
9.2.3 
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 (eg, subject was 
lost to follow-up). 

 
 
 
 
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9.3 
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, or paper AESI/SAE/Special Situation 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 form may be used instead. 
9.3.1 
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. 
This includes (ongoing) AEs from the preceding study. 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 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 
an 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 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 or paper AESI/SAE/Special Situation 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 (eg, hospital discharge summary, consultant report, or autopsy report).  
9.3.2 
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?” 

 
 
 
 
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9.3.3 
Recording Adverse and Serious Adverse Events  
Investigators should use correct medical terminology/concepts when recording AEs or SAEs on 
the eCRF or paper AESI/SAE/Special Situation form. Colloquialisms and abbreviations should 
be avoided. Serious AEs must also be recorded on the AE eCRF or paper AESI/SAE/Special 
Situation form. Only 1 medical concept should be recorded in the event field on the AE eCRF or 
paper AESI/SAE/Special Situation 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 or paper AESI/SAE/Special Situation form (if applicable).  
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 or 
paper AESI/SAE/Special Situation 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 or paper AESI/SAE/special situation 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 9.3.1), 
regardless of attribution, will be recorded on the AE eCRF or paper AESI/SAE/Special Situation 
form and reported to the Sponsor within 24 hours of event knowledge.  

 
 
 
 
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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 or paper AESI/SAE/Special Situation 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 or paper AESI/SAE/Special Situation form (if applicable), it is important to convey 
the concept that the preexisting condition has changed by including applicable descriptors 
(eg, “more frequent headaches”). 
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 9.1.2, Serious 
Adverse Event Definition), this information will be captured on the AE eCRF or paper 
AESI/SAE/Special Situation form (if applicable). 
Pregnancy should be followed up until after delivery 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 a 
paper AESI/SAE/Special Situation Form and an AE eCRF for tracking purposes and will be 
considered a protocol deviation. Overdose is defined as any study drug dose administered above 

 
 
 
 
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the intended dose. Additional instructions for reporting special situation information will be 
provided by the Sponsor at the time of notification. 
9.4 
Serious Adverse Events Notification  
For all SAEs, regardless of suspected causality, a completed AESI/SAE/Special Situation form 
must be sent within 24 hours of discovery of the event to: 
DRUG SAFETY 
See Study Reference Manual  
Any fatal or life-threatening (ie, imminent risk of death) event that is attributed by the 
Investigator to the study drug must be immediately telephoned to: 
DRUG SAFETY  
Phone: See Study Reference Manual for phone number  
followed by submission of written case details on an AESI/SAE/Special Situation 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 AESI/SAE/Special Situation 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 AESI/SAE/Special Situation 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 AESI/SAE/Special Situation form. 

 
 
 
 
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• 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). 
9.5 
Expedited Reporting of Suspected Unexpected Serious Adverse Reactions 
• 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.  
• 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 Statistical Analysis Plan (SAP) will specify the statistical methodology, 
including interim data reviews (if conducted) 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 QR-421a. As an early phase 
clinical study, exploratory analyses not necessarily identified in the SAP may be performed to 
support the clinical development program. Any p values that will be calculated according to the 
analysis plan will be interpreted in view of the exploratory nature of the study. 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 
The sample size is determined by the number of subjects completing preceding QR-421a studies, 
including PQ-421a-001, who meet the inclusion and exclusion criteria and provide informed 
consent. 
10.3 
Randomization and Masking 
This is an open-label study; randomization and masking are not required. 

 
 
 
 
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10.4 
Replacement of Subjects 
Not applicable as this is an extension study. 
10.5 
Analysis Populations 
All Screened Subjects: All subjects who provided informed consent to participate in the study. 
Safety Population: the population for safety analysis will consist of all subjects who receive any 
QR-421a. 
Efficacy Evaluable Population: All subjects who received at least one dose of study treatment 
and had at least 1 baseline observation or measurement. The Efficacy Evaluable Population will 
be defined separately for each endpoint, based on availability of at least 1 baseline measurement 
of that endpoint. 
Per Protocol Efficacy Population: All subjects in the Efficacy Evaluable Population except for 
subjects with major protocol deviations. The list of major protocol deviations selected for 
exclusion from this population will be completed prior to database lock. The Per Protocol 
Population will also be defined separately for each endpoint. 
10.6 
Subject Disposition, Demographics and Baseline Disease Characteristics 
Subject disposition, baseline demographics and disease characteristics will be summarized for all 
subjects combined, and potentially grouped by baseline characteristics. Such grouping of subject 
disposition, demographics and disease characteristics by baseline characteristics will be 
described in the SAP.  
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 
Safety Analyses 
10.8.1 
Treatment Emergent 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 and present after the dose or if it represents the 
exacerbation of an event that was present prior to the dose. 
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.  

 
 
 
 
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The overall incidence of TEAEs will be classified by SOC and PT, and potentially summarized 
by groups based on baseline characteristics. Deaths, AE severity, seriousness, relationship to 
study drug will also be tabulated, potentially by groups based on baseline characteristics. If 
included, grouping based on baseline characteristics will be described in the SAP. 
Ocular AEs will be presented separately for the study eye and the fellow eye. 
10.8.2 
Other Safety Assessments 
Ophthalmology findings will also be summarized using descriptive statistics, frequencies, and 
percentages, and shifts from baseline, as appropriate. The number of subjects with a 10- and 
15-letter decrease from baseline in BCVA will be tabulated. 
10.9 
Systemic Exposure Analyses 
Systemic exposure will be estimated using standard methodology, if adequate serum 
concentrations of QR-421a are detected. 
10.10 Efficacy Analyses 
The efficacy evaluations will include evaluations of the endpoints listed in Section 4.1.  
Descriptive statistics of clinical efficacy will be presented for study eye and fellow eye and will 
potentially be tabulated by groups based on baseline characteristics.  
Further detail about the analysis and reporting of study data will be provided in the SAP. 
10.11 Interim Analysis 
Ongoing review of safety and efficacy data will be conducted to inform the program. Interim 
analyses may be performed, e.g., yearly, or at key time points during clinical development.   
10.12 Subgroup Analyses 
Exploratory analyses may be carried out for subgroups based on age, baseline visual acuity, and 
other factors identified 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 

 
 
 
 
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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 
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 

 
 
 
 
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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 (eg, pharmacy, drug storage areas, laboratories) and review 
of study-related records will occur to evaluate the study conduct and compliance with the 
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 examine all study-related activities and documents systematically and 
independently, 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 subject in accordance with ICH GCP, and country authority 
requirements.  
Age-appropriate assent and permission from a minor (12 to < 18 years) subject’s parent or legal 
guardian is required for pediatric subjects. The subject must sign the current version of the 
written, IRB/EC-approved Informed Consent Form (ICF) 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.  

 
 
 
 
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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.  
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 (eg, signed ICF), should be kept in strict confidence by the 
Investigator.  
The Investigator and the Sponsor will ensure that all clinical study 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 

 
 
 
 
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protection. Measures taken to ensure all 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 (ie, European Union/European Economic 
Area member state, Q&A: Good clinical practice (GCP) | European Medicines Agency 
(europa.eu), 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 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 QR-421a 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 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. 

 
 
 
 
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13.3 
Study Termination 
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 
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 QR-421a 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. 

 
 
 
 
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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.  
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. 
Biological samples remaining after the tests described in this protocol are completed, may be 
used for additional research purposes. This additional research may be done by or on behalf of 
the Sponsor, to increase overall knowledge on QR-421a, and the effects of QR-421a on RP due 
to exon 13 mutations of the USH2A gene as well as the effect on other diseases. The samples 
may be stored or used for as long as they last or are needed for research. 
The Sponsor will ensure that personal data transfers and bodily materials transfer comply with 
Data Protection Laws of the EU, ie, 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 
Last Patient Last Visit defines the date that the last subject completed the study. The End of the 
Study is the date of the Last Patient Last Visit. 
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. 

 
 
 
 
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13.8 
Publication Policy 
Publication policy is addressed separately in the Clinical Study Agreement. 

 
 
 
 
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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.  
Collin RW, den Hollander AI, van der Velde-Visser SD, Bennicelli J, Bennett J, Cremers FP. 
Antisense Oligonucleotide (AON)-based therapy for Leber congenital amaurosis caused by a 
frequent mutation in CEP290. Mol Ther Nucleic Acids. 2012; 1:e14. doi:10.1038/mtna.2012.3. 
Den Hollander, A. I., R. K. Koenekoop, S. Yzer, I. Lopez, M. L. Arends, K. E. Voesenek, M. N. 
Zonneveld, T. M. Strom, T. Meitinger, H. G. Brunner, C. B. Hoyng, L. I. van den Born, K. 
Rohrschneider and F. P. Cremers (2006). "Mutations in the CEP290 (NPHP6) gene are a 
frequent cause of Leber congenital amaurosis." Am J Hum Genet 79(3): 556-561. 
EC Clinical Trial 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 Directive 2005/28/EC. Commission directive 2005/28/EC of 8 April 2005. Available at 
http://ec.europa.eu/health//sites/health/files/files/eudralex/vol-
1/dir_2005_28/dir_2005_28_en.pdf. 
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. 
Exondys 51 FDA Review. 2016. Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/206488_TOC.cfm  
Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, et al. Nusinersen versus 
sham control in infantile-onset spinal muscular atrophy. N Engl J Med 2017; 377:1723-32. 
doi: 10.1056/NEJMoa1702752 
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. 

 
 
 
 
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Gerard X, Perrault I, Hanein S, et al. AON-mediated exon skipping restores ciliation in 
fibroblasts harboring the common Leber congenital amaurosis CEP290 mutation. Mol Ther 
Nucleic Acids. 2012; 1(6):e29. doi: 10.1038/mtna.2012.21. 
Gerard X, Garanto A, Rozet JM, Collin RW. Antisense oligonucleotide therapy for inherited 
retinal dystrophies. Adv Exp Med Biol. 2016; 854:517-24. doi: 10.1007/978-3-319-17121-0_69. 
Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. Lancet 2006; 368(9549):1795-809. 
ICH Harmonised Tripartite Guideline: Safety pharmacology studies for human pharmaceuticals 
S7A 2000. Available at: GUIDELINE FOR GOOD CLINICAL PRACTICE (ich.org). 
ICH Harmonized Tripartite Guideline: Guideline for good clinical practice E6(R2) 2016. 
Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-
clinical-practice-e6r2-4-step-2b_en.pdf. 
Lacy GD, et al. The Michigan Retinal Degeneration Questionnaire: A Patient-Reported Outcome 
Instrument for Inherited Retinal Degenerations. Am J Ophthalmol . 2021 Feb;222:60-68. 
Littink, K. W., J. W. Pott, R. W. Collin, H. Y. Kroes, J. B. Verheij, E. A. Blokland, M. de Castro 
Miro, C. B. Hoyng, C. C. Klaver, R. K. Koenekoop, K. Rohrschneider, F. P. Cremers, L. I. van 
den Born and A. I. den Hollander (2010). "A novel nonsense mutation in CEP290 induces exon 
skipping and leads to a relatively mild retinal phenotype." Invest Ophthalmol Vis Sci 51(7): 
3646-3652. 
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 
Perrault, I., N. Delphin, S. Hanein, S. Gerber, J. L. Dufier, O. Roche, S. Defoort-Dhellemmes, H. 
Dollfus, E. Fazzi, A. Munnich, J. Kaplan and J. M. Rozet (2007). "Spectrum of NPHP6/CEP290 
mutations in Leber congenital amaurosis and delineation of the associated phenotype." Hum 
Mutat 28(4): 416. 
Regulation EU No 536/2014 on clinical trials on medicinal products for human use, and 
repealing Directive 2001/20/EC, available at: 
https://ec.europa.eu/health/human-use/clinical-trials/regulation_en  
 

 
 
 
 
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Stone, E. M. (2007). "Leber congenital amaurosis - a model for efficient genetic testing of 
heterogeneous disorders: LXIV Edward Jackson Memorial Lecture." Am J Ophthalmol 144(6): 
791-811. 
Spinraza® (nusinersen) FDA Pharmacology Review, 2016. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/209531Orig1s000PharmR.pdf 
[Accessed 12 December 2020]. 
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. 
Whittaker SG, Scheiman M, Sokol-McKay DA. Low Vision Rehabilitation: A Practical Guide 
for Occupational Therapists, Second Edition. © 2016 SLACK Incorporated. 
 
 

 
 
 
 
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15.0 
PROTOCOL SUMMARY OF CHANGES 

 
 
 
 
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16.0 
APPENDICES 
 
 
 
 
 

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16.2 
APPENDIX 2: CLINICAL LABORATORY TESTS 
 
Chemistry 
Hematology 
Urinalysis (dipstick) 
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)* 
C-reactive protein (CRP) 
Hematocrit 
Hemoglobin 
Red blood cells 
White blood cells (WBCs) 
Neutrophils  
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Platelets 
 
Color and appearance 
Specific gravity 
pH 
Protein 
Glucose 
Blood (erythrocytes) 
Leukocytes 
Bilirubin 
Ketones 
Nitrite 
Urobilinogen 
 
Other Tests 
 
Coagulation 
Pregnancy testing 
 
INR 
Prothrombin time 
* Estimated eGFR is to be calculated using the Chronic Kidney Disease Epidemiology Collaboration CKD-EPI Creatinine 
Equation 2009 calculation for adult subjects and Schwartz equation, according to the recommendation from National 
Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases, for pediatric subjects