A Double-Masked, Randomized, Controlled, Multiple-Dose Study to Evaluate the Efficacy, Safety and Tolerability of QR-421a in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene With Early to Moderate Vision Loss
Phase: PHASE2
Conditions: Retinitis Pigmentosa, Usher Syndrome Type 2, Deaf Blind, Retinal Disease, Eye Diseases, Eye Diseases, Hereditary, Eye Disorders Congenital, Vision Disorders
Sponsor: Laboratoires Thea

Investigational Product: QR-421a 
Protocol No. PQ-421a-004 (Version 2.0) 
 
ProQR Therapeutics 
 
Page 1 of 67
 
 
29 October 2021 
CLINICAL STUDY PROTOCOL 
A DOUBLE-MASKED, RANDOMIZED, CONTROLLED, MULTIPLE-DOSE STUDY 
TO EVALUATE THE EFFICACY, SAFETY, AND TOLERABILITY OF QR-421a IN 
SUBJECTS WITH RETINITIS PIGMENTOSA (RP) DUE TO MUTATIONS IN 
EXON 13 OF THE USH2A GENE WITH EARLY TO MODERATE VISION LOSS 
 
 
 
Protocol No. 
PQ-421a-004  
Protocol/Amendment Date: 
29 October 2021 
Protocol/Amendment No.: 
1 
Protocol Version:  
2.0 
Supersedes: 
1.0 
EudraCT/IND Number 
2021-002728-19 
IND 137660 
Sponsor: 
ProQR Therapeutics  
Zernikedreef 9 
2333 CK Leiden 
The Netherlands 
 
 

 
 
 
 
Investigational Product: QR-421a 
Protocol No. PQ-421a-004 (Version 2.0) 
 
ProQR Therapeutics 
 
Page 2 of 67
 
 
29 October 2021 
INVESTIGATOR SIGNATURE PAGE 
PRINCIPAL INVESTIGATOR COMMITMENT: 
I will provide copies of the protocol, any subsequent protocol amendments and access to all 
information provided by the Sponsor to the study personnel under my supervision. I will discuss 
this material with them to ensure that they are fully informed about the study drug and the study 
protocol. 
I agree to conduct this clinical study according to the attached protocol, except when mutually 
agreed to in writing. I also agree to conduct this study in compliance with all applicable local 
regulations, Good Clinical Practices (GCP), as well as with the requirements of the appropriate 
Institutional Review Board(s) (IRB)/Ethics Committee(s) (EC) and any other Institutional 
requirements. 
 
 
Printed Name of Principal Investigator 
 
Signature of Principal Investigator 
 
Date 
 
Institution 
 
Address of Institution 
 
Phone Number of Investigator 
 

 
 
 
 
Investigational Product: QR-421a 
Protocol No. PQ-421a-004 (Version 2.0) 
 
ProQR Therapeutics 
 
Page 3 of 67
 
 
29 October 2021 
PROTOCOL APPROVAL PAGE 
A Double-Masked, Randomized, Controlled, Multiple-Dose Study to Evaluate the Efficacy, 
Safety and Tolerability of QR-421a in Subjects with Retinitis Pigmentosa (RP) due to Mutations 
in Exon 13 of the USH2A Gene with Early to Moderate Vision Loss 
Protocol No. PQ-421a-004 
Protocol/Amendment Date: 29 October 2021 
Protocol/Amendment No.: 1 
Protocol Version: 2.0 
Sponsor: ProQR Therapeutics 
Zernikedreef 9 
2333 CK Leiden 
The Netherlands 
 
 
 
 
 
 
ProQR Therapeutics 
 
Date 
 
 
 

 
 
 
 
Investigational Product: QR-421a 
Protocol No. PQ-421a-004 (Version 2.0) 
 
ProQR Therapeutics 
 
Page 4 of 67
 
 
29 October 2021 
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:  
A Double-Masked, Randomized, Controlled, Multiple-Dose Study to Evaluate the 
Efficacy, Safety and Tolerability of QR-421a in Subjects with Retinitis Pigmentosa 
(RP) due to Mutations in Exon 13 of the USH2A Gene with Early to Moderate 
Vision Loss 
Phase of Development: 
Phase 2/3 
Study Period: 
Anticipated to be approximately 34 months 
Duration of Subject 
Participation: 
Approximately 27 months (up to 12 weeks screening; 24 months treatment) 
Rationale:  
There are currently no approved therapies for the treatment of RP due to mutations 
in exon 13 of the USH2A gene and disease management is supportive; therefore, a 
large unmet medical need exists in this sight-threatening condition. 
Study PQ-421a-004 will investigate the efficacy and safety of 2 dose regimens of 
QR-421a in subjects with early to moderate vision loss. 
Objectives: 
Primary  
• 
To evaluate the efficacy of QR-421a 
Endpoints: 
Primary endpoint 
• 
Change from baseline in mean sensitivity (based on 
static perimetry) at 12 months of treatment versus 
sham-procedure  

 
 
 
 
Investigational Product: QR-421a 
Protocol No. PQ-421a-004 (Version 2.0) 
 
ProQR Therapeutics 
 
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29 October 2021 
Secondary 
• 
To further evaluate efficacy of QR-421a 
• 
To evaluate the safety and tolerability of QR-421a  
• 
To evaluate changes in Patient-Reported Outcome 
(PRO) measures in subjects treated with QR-421a 
• 
To evaluate systemic exposure of QR-421a 
Key Secondary endpoints 
• 
Ellipzoid Zone area (EZ) as measured by Spectral 
Domain optical coherence tomography SD-OCT 
Other Secondary endpoints 
• 
Change from baseline in the following outcome 
measures: 
o 
BCVA  
o 
Spectral domain optical coherence tomography 
(SD-OCT) (other measures) 
o 
Low Luminance Visual Acuity (LLVA) 
o 
Other measures of static perimetry  
o 
Full-field Stimulus Threshold (FST) 
• 
Change from baseline in PRO measures, as assessed 
by: 
o 
Michigan Retinal Degeneration Questionnaire 
(MRDQ) (Lacy 2021) 
o 
Patient Global Impressions of Severity (PGI-S) 
o 
Patient Global Impressions of Change (PGI-C) 
• 
Ocular and non-ocular adverse events (AEs) 
• 
Exposure of QR-421a in serum 
Exploratory  
To evaluate the effects of QR-421a on mobility course 
performance 
Exploratory endpoints 
• 
Change from baseline in mobility course score 
Number of Subjects 
(planned): 
Approximately 120 subjects  
 
Study Design 
PQ-421a-004 is a double-masked, randomized, controlled, multiple-dose study to 
evaluate the efficacy, safety and tolerability of QR-421a in subjects with RP due 
to mutations in exon 13 of the USH2A gene with early to moderate vision loss.  
At study start subjects will be randomized to one of the following treatment 
groups: 
1) Group 1: QR-421a 180/60 µg (180 µg loading dose administered on Day 1, 
60 µg maintenance dose administered at Month 3 and every 6 months 
thereafter; n = 40) 
2) Group 2: QR-421a 60/60 µg (60 µg loading dose administered on Day 1, 
60 µg maintenance dose administered at Month 3 and every 6 months 
thereafter; n = 40) 
3) Group 3: Sham-procedure (administered on Day 1, Month 3 and every 
6 months thereafter; n = 40) 
The primary endpoint will be assessed at 12 months of treatment. Analysis of all 
other efficacy and safety parameters will also be reported at that time point. All 
efficacy and safety parameters will continue to be followed during the 24-month 
treatment period. 

 
 
 
 
Investigational Product: QR-421a 
Protocol No. PQ-421a-004 (Version 2.0) 
 
ProQR Therapeutics 
 
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Study Plan 
The study includes screening period of up to 12 weeks.  
During the screening period, subjects will be assessed according to the eligibility 
criteria.
 
 
 It is 
recommended that screening will be conducted in a stepwise manner, so that 
eligibility is confirmed first with less intensive assessments and more intensive 
assessments are conducted after eligibility by all other criteria have been 
confirmed.  
Subjects who meet all eligibility criteria will be enrolled into the study and will 
receive their dose of study treatment on Day 1. QR-421a will be administered via 
intravitreal (IVT) injection into the subject’s study eye (ie, the first eye to be 
treated, see section 4.2.1.2 for selection of the study eye) in accordance with the 
procedures outlined in the Study Reference Manual. Subjects receiving the sham-
procedure will undergo a procedure that will closely mimic the active injection, 
but there will be no penetration of the globe. Administration of study treatment, as 
well as clinical monitoring of the subject during and right after administration of 
study treatment, will be performed by an unmasked physician. All other clinical 
assessments will be performed by a separate, masked physician, or by masked 
study personnel.  
After each administration of study treatment subjects will be monitored clinically 
for safety, including intraocular pressure (IOP) and signs of inflammation. 
Frequent study visits and safety monitoring by the Investigator will be in place, 
together with oversight by the Medical Monitor and the Data Monitoring 
Committee (DMC) (see Section 9.1). The Investigator or the Medical Monitor (in 
consultation with the DMC) may decide to hold (delay or skip) or discontinue 
study treatment for an individual subject. Stopping criteria are described in 
Section 4.2.2. Subjects who discontinue study treatment will continue to be 
followed for safety and efficacy. 
Efficacy and safety assessments, including retinal structure changes and functional 
assessments of vision and patient-reported outcome (PRO) measures will be 
performed at selected study visits as indicated in the Schedule of Events (SOE) 
 All assessments will be performed on both eyes. A central reading 
center will grade structural and functional exams in a masked way. Any 
assessment may be repeated if the results are considered unreliable or of 
unacceptable quality by the Investigator or the reading center.  
Samples for systemic exposure analysis will be collected as indicated in the SOE 
Assessments can be completed over multiple non-consecutive days. 
Diagnosis and Main Criteria 
for Eligibility Relating to 
Study Initiation: 
Inclusion Criteria Relating to Study Initiation: 
The subject is eligible for the study and thus eligible to receive QR-421a or sham-
procedure in the study eye if all the following inclusion criteria apply at 
Screening/Day 1: 
1. An adult (≥ 18 years) willing and able to provide informed consent for 
participation prior to performing any study related procedures, and suitable 
verbal, auditory, written and/or tactile sign language communication as to 
allow informed consent to be obtained, in the opinion of the Investigator. 
OR 
A minor (12 to < 18 years) with a parent or legal guardian willing and able to 
provide written permission for the subject’s participation prior to performing 

 
 
 
 
Investigational Product: QR-421a 
Protocol No. PQ-421a-004 (Version 2.0) 
 
ProQR Therapeutics 
 
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29 October 2021 
any study related procedures and pediatric subjects able to provide age 
appropriate assent for study participation. 
2. An adult willing to comply with the protocol, follow study instructions, attend 
study visits as required and willing and able to complete all study 
assessments.  
OR  
A minor able to complete all study assessments and comply with the protocol 
and has a parent or caregiver willing and able to follow study instructions, and 
attend study visits with the subject as required. 
3. Clinical presentation consistent with RP with Usher syndrome type 2 or non-
syndromic form of RP (NSRP), based on ophthalmic, audiologic, and 
vestibular examinations. 
4. A molecular diagnosis of homozygosity or compound heterozygosity for 1 or 
more pathogenic exon 13 mutations in the USH2A gene, based on genetic 
analysis at screening. 
 
 
5. BCVA better than ≥69 letters (approximate Snellen equivalent 20/40) in the 
study eye, using the best BCVA reading at Screening (see Section 8.1) and 
based on the Early Treatment Diabetic Retinopathy Study (ETDRS). 
6. Impairment of Visual Field (VF) in the opinion of the Investigator as 
determined by perimetry, with a continuous area of central field greater than 
or equal to 10 degrees diameter in each meridian as measured by a size V4e 
target, and a mean defect of ≥ 10 dB, 
 
 in the study eye.  
7. Clearly visible and measurable ellipsoid zone (EZ) width and/or area on SD-
OCT, per investigator judgement. 
8. No limitations to SD-OCT image collection that would prevent high quality, 
reliable images from being obtained in both eyes, as determined by the 
Investigator. 
9. Reliable BCVA, perimetry, and other measurements in both eyes, as 
described in the Study Reference Manual and Imaging Manual and 
determined by the Investigator.  
10. No visually significant ocular media opacities and adequate pupillary dilation 
to permit good quality retinal imaging, as assessed by the Investigator.  

 
 
 
 
Investigational Product: QR-421a 
Protocol No. PQ-421a-004 (Version 2.0) 
 
ProQR Therapeutics 
 
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29 October 2021 
 
Exclusion Criteria Relating to Study Initiation: 
The subject is ineligible for the study if any of the following criteria apply at 
Screening/Day 1: 
1. Presence of additional non-exon 13 USH2A pathogenic mutation(s) on the 
USH2A allele carrying the exon 13 mutation in subjects who have mono-
allelic exon-13 mutations. 
2. Presence of non-exon 13 USH2A pathogenic mutation(s) on both USH2A 
alleles in subjects who have biallelic exon 13 mutations. 
3. Presence of pathogenic mutations in genes (other than the USH2A gene) 
associated with Usher syndrome Type 2 or NSRP, or other inherited retinal 
degenerative diseases or syndromes.  
Note: The confirmed presence of homozygous or compound heterozygous 
known disease-causing mutations in other genes involved in recessive retinal 
dystrophies (RD), or the confirmed presence of known disease-causing 
mutations in genes involved in dominant or X-linked retinal dystrophies is 
exclusionary. 
4. Presence of any significant ocular 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 study eye. CME is permissible if stable for 3 months (with or 
without treatment). Past CME is permissible if resolved for more than 1 
month. 
5. History or presence of ocular herpetic diseases (including herpes simplex 
virus, varicella zoster or cytomegalovirus) in either eye. 
6. Presence of any active ocular infection in either eye. 
7. Presence of any of the following lens opacities in the study eye based on the 
age-related eye diseases study (AREDS) lens grading scale: cortical opacity ≥ 
+2, posterior subcapsular opacity ≥ +2, or a nuclear sclerosis ≥ +2, and which 
are: 1) clinically significant in the opinion of the Investigator, 2) would 
adequately prevent clinical and photographic evaluation of the retina. 
8. History of amblyopia in the study eye that resulted in significant vision loss, 
in the opinion of the Investigator.  
9. Receipt within 3 months prior to Screening of any intraocular or periocular 
surgery (including refractive surgery), or an IVT injection other or planned 
intraocular surgery or procedure during the course of the study. 
10. Current treatment or treatment within the past 12 months with therapies 
known to influence the immune system (including but not limited to steroid 
implants, cytostatics, interferons, tumor necrosis factor (TNF)-binding 
proteins, drugs acting on immunophilins, or antibodies with known impact on 
the immune system). Subjects that have been treated with systemic steroids 
within the past 12 months or that require intermittent use of topical steroids 
may be considered for inclusion following approval by the Medical Monitor. 
11. A history of glaucoma or an IOP greater than 24 mmHg in either eye that is 
not controlled with medication or surgery. 
12. Use of any investigational drug or device within 90 days or 5 half-lives 
preceding the first dose of study medication, whichever is longer, or plans to 
participate in another study of an investigational drug or device during the 
course of the study. 

 
 
 
 
Investigational Product: QR-421a 
Protocol No. PQ-421a-004 (Version 2.0) 
 
ProQR Therapeutics 
 
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29 October 2021 
13. Any prior treatment with genetic or stem-cell therapy for ocular or non-ocular 
disease. 
14. History of malignancy within 2 years prior to Screening, except adequately 
treated squamous or basal cell carcinoma of the skin or carcinoma in situ of 
the cervix that has been successfully treated. 
15. Known hypersensitivity to antisense oligonucleotides or any constituents of 
the injection. 
16. Pregnant and breastfeeding subjects. Females of childbearing potential and 
males must comply with using highly effective methods of contraception as 
defined in Section 6.2.2. Women of non-childbearing potential may be 
included without the use of adequate birth control, provided they meet the 
criteria in the protocol (see Section 6.2.2). 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 

 
 
 
 
Investigational Product: QR-421a 
Protocol No. PQ-421a-004 (Version 2.0) 
 
ProQR Therapeutics 
 
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29 October 2021 
Study Drug, Dosage and Mode 
of Administration: 
 
Two dose regimens will be tested: 
1. 180 µg loading dose, 60 µg maintenance dose (180/60 g)  
2. 60 µg loading dose, 60 µg maintenance dose (60/60 g) 
Duration of Treatment: 
24 months 
The Sponsor plans on providing access to study drug after the end of study (EOS) 
in an open-label extension study. 
Reference Therapy, Dosage 
and Mode of Administration: 
Sham procedure 
Statistical Methods: 
The primary endpoint for efficacy will be mean change from baseline in retinal 
sensitivity in a pre-specified area with at least 5 loci at Month 12 between QR-
421a-treated and sham-treated eyes. Hypothesis testing of the mean treatment 
effect between QR-421a treatment and sham procedure will be performed using an 
ANCOVA model at a one-sided significance level of alpha=0.025. Since two QR-
421a doses are being tested, Type I error will be controlled for multiplicity using 
appropriate methods.
 
 
 
 

 
 
 
 
Investigational Product: QR-421a 
Protocol No. PQ-421a-004 (Version 2.0) 
 
ProQR Therapeutics 
 
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29 October 2021 
TABLE OF CONTENTS 
 
CLINICAL STUDY PROTOCOL ...............................................................................................1 
INVESTIGATOR SIGNATURE PAGE......................................................................................2 
PROTOCOL APPROVAL PAGE ...............................................................................................3 
1.0 
SYNOPSIS ..........................................................................................................................4 
TABLE OF CONTENTS ............................................................................................................11 
LIST OF FIGURES .....................................................................................................................15 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................16 
2.0 
INTRODUCTION............................................................................................................19 
2.1 
Retinitis Pigmentosa ..............................................................................................19 
2.2 
QR-421a for the Treatment of RP due to Mutations in Exon 13 of the USH2A 
Gene .......................................................................................................................19 
2.3 
Benefit Risk Assessment........................................................................................21 
2.4 
Study Rationale ......................................................................................................21 
2.5 
Measures to Minimize Bias ...................................................................................21 
2.6 
Dose Selection .......................................................................................................22 
2.7 
Study Population ....................................................................................................23 
3.0 
STUDY OBJECTIVES ....................................................................................................23 
3.1 
Primary Objective ..................................................................................................23 
3.2 
Secondary Objective ..............................................................................................23 
3.3 
Exploratory ............................................................................................................24 
4.0 
STUDY OVERVIEW ......................................................................................................24 
4.1 
Criteria for Evaluation ...........................................................................................24 
4.1.1 
Primary Endpoints .................................................................................24 
4.1.2 
Secondary Endpoints .............................................................................24 
4.1.3 
Exploratory Endpoints ..........................................................................25 
4.2 
Study Design ..........................................................................................................25 
4.2.1 
Study Plan .............................................................................................26 
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 
5.3 
Eligibility Criteria ..................................................................................................29 

 
 
 
 
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5.3.1 
Inclusion Criteria Relating to Study Initiation ......................................29 
5.3.2 
Exclusion Criteria Relating to Study Initiation .....................................30 
 
 
6.0 
STUDY DRUG AND CONCOMITANT THERAPIES ...............................................32 
6.1 
Study Drug .............................................................................................................32 
6.1.1 
Study Drug Description and Supply .....................................................32 
6.1.2 
Placebo ..................................................................................................32 
6.1.3 
Study Drug Shipment and Storage ........................................................32 
6.1.4 
Study Drug Accountability and Reconciliation ....................................32 
6.1.5 
Dosage and Administration ...................................................................33 
6.2 
Concomitant Medications and Auxiliary Therapy .................................................33 
6.2.1 
Prohibited Concomitant Medications ....................................................33 
6.2.2 
Adequate Forms of Birth Control .........................................................34 
7.0 
STUDY VISITS ................................................................................................................35 
7.1 
Visit and Assessment Windows .............................................................................35 
7.2 
Screening................................................................................................................35 
7.3 
Dosing and Follow-up Visits .................................................................................36 
7.4 
End of Study Visit & Roll Over to Open Label Extension Study .........................36 
8.0 
STUDY ASSESSMENT PROCEDURES ......................................................................36 
8.1 
Efficacy ..................................................................................................................37 
8.2 
Safety .....................................................................................................................37 
8.2.1 
Adverse Events......................................................................................37 
8.2.2 
Laboratory Evaluations .........................................................................38 
8.2.3 
Ophthalmic Examinations .....................................................................38 
8.2.4 
Spectral Domain Optical Coherence Tomography ...............................39 
8.3 
Systemic Exposure .................................................................................................39 
8.4 
Immunogenicity .....................................................................................................39 
8.5 
Gene Sequencing ...................................................................................................39 
9.0 
ASSESSMENT OF SAFETY, ADVERSE EVENTS AND SERIOUS ADVERSE 
EVENTS............................................................................................................................39 
9.1 
Data Monitoring Committee ..................................................................................40 
9.2 
Definitions of Adverse Event, Serious Adverse Event, and Suspected 
Unexpected Serious Adverse Event .......................................................................40 
9.2.1 
Adverse Events......................................................................................40 
9.2.2 
Serious Adverse Events.........................................................................40 

 
 
 
 
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9.2.3 
Suspected Unexpected Serious Adverse Reaction Definition ..............41 
9.2.4 
Adverse Events of Special Interest .......................................................42 
9.3 
Assessment of Adverse Events ..............................................................................42 
9.3.1 
Assessment of Severity (Intensity) of Adverse Events .........................42 
9.3.2 
Assessment of the Relationship of Adverse Events to Study Drug ......43 
9.3.3 
Assessment of the Outcome of Adverse Events ...................................43 
9.4 
Reporting of Adverse Events .................................................................................44 
9.4.1 
Adverse Event Reporting Period ...........................................................44 
9.4.2 
Eliciting Adverse Events .......................................................................45 
9.4.3 
Recording Adverse Events and Serious Adverse Events ......................45 
9.5 
AESIs and Serious Adverse Events Notification ...................................................47 
9.6 
Expedited Reporting of Suspected Unexpected Serious Adverse Reactions .........48 
10.0 
STATISTICAL METHODOLOGY...............................................................................48 
10.1 
General Considerations ..........................................................................................48 
10.2 
Determination of Sample Size ...............................................................................49 
10.3 
Randomization and Masking .................................................................................49 
10.4 
Replacement of Subjects ........................................................................................49 
10.5 
Analysis Populations ..............................................................................................49 
10.6 
Subject Disposition, Demographics and Baseline Disease Characteristics ...........50 
10.7 
Treatment Compliance ...........................................................................................50 
10.8 
Efficacy Analyses ..................................................................................................50 
10.9 
Safety Analyses ......................................................................................................51 
10.9.1 
Treatment Emergent Adverse Events....................................................51 
10.9.2 
Other Safety Assessments .....................................................................52 
10.10 12-Month Primary Analysis and 24-Month/EOS Analysis ...................................52 
10.11 Multiplicity Considerations ...................................................................................52 
10.12 Subgroup Analyses ................................................................................................52 
10.13 Systemic Exposure Analyses .................................................................................52 
11.0 
QUALITY CONTROL AND QUALITY ASSURANCE .............................................52 
11.1 
Data Collection ......................................................................................................52 
11.2 
Data Quality Control ..............................................................................................53 
11.3 
Monitoring .............................................................................................................54 
11.4 
Audits and Inspections ...........................................................................................54 
12.0 
ETHICAL AND REGULATORY OBLIGATIONS ....................................................54 
12.1 
Ethical Considerations ...........................................................................................54 
12.2 
Informed Consent...................................................................................................54 

 
 
 
 
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12.3 
Ethics and Regulatory Review ...............................................................................55 
12.4 
Subject Confidentiality ..........................................................................................55 
13.0 
STUDY ADMINISTRATION ........................................................................................56 
13.1 
Investigator’s Brochure ..........................................................................................56 
13.2 
Protocol Amendments ............................................................................................56 
13.3 
Study Termination .................................................................................................57 
13.4 
Study Documentation and Storage .........................................................................57 
13.5 
Use of Information .................................................................................................58 
13.6 
End of Study and Final Report...............................................................................58 
13.7 
Financing and Insurance ........................................................................................59 
13.8 
Publication Policy ..................................................................................................59 
14.0 
REFERENCES .................................................................................................................60 
15.0 
PROTOCOL SUMMARY OF CHANGES ...................................................................62 
16.0 
APPENDICES ..................................................................................................................63 
 
16.2 
Appendix 2: Clinical Laboratory Tests ..................................................................66 
 
 

 
 
 
 
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29 October 2021 
LIST OF FIGURES 
 
 
 
 

 
 
 
 
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Protocol No. PQ-421a-004 (Version 2.0) 
 
ProQR Therapeutics 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
Abbreviation 
Definition 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of covariance 
AON 
Antisense Oligonucleotide 
AREDS 
Age-Related Eye Diseases Study 
AST 
Aspartate Aminotransferase 
BCVA 
Best Corrected Visual Acuity 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CME 
Cystoid Macular Edema 
CRP 
C-Reactive Protein 
CSR 
Clinical Study Report 
DAC 
Dark Adapted Chromatic 
DHA 
Docosahexaenoic Acid 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
eGFR 
Estimated Glomerular Filtration Rate 
EOS 
End of Study 
ERG 
Electroretinogram 
EZ 
Ellipsoid Zone 
FDA 
Food and Drug Administration 
FIH 
First-in-human 
FST 
Full-field Stimulus Threshold  
GCP 
Good Clinical Practice 
γGT 
Gamma-Glutamyl Transferase 
IB 
Investigator’s Brochure 

 
 
 
 
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Protocol No. PQ-421a-004 (Version 2.0) 
 
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29 October 2021 
Abbreviation 
Definition 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation  
INR 
International Normalized Ratio 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
IVT 
Intravitreal 
IWRS 
Interactive Web Response System 
LDH 
Lactic Dehydrogenase 
LLVA 
Low Luminance Visual Acuity 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRDQ 
Michigan Retinal Degeneration Questionnaire 
mRNA 
Messenger Ribonucleic Acid 
NSRP 
Non-syndromic Retinitis Pigmentosa 
PBS 
Phosphate buffered saline 
PGI-C 
Patient Global Impressions of Change 
PGI-S 
Patient Global Impressions of Severity 
PRO 
Patient Reported Outcome 
ProQR 
ProQR Therapeutics 
PT 
Preferred Term 
RNA 
Ribonucleic Acid 
RD 
Retinal Dystrophies 
RP 
Retinitis Pigmentosa 
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 

 
 
 
 
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Abbreviation 
Definition 
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 (DHA) 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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2.3 
Benefit Risk Assessment 
 
 
Detailed information about benefits and potential risks of QR-421a, as well as information on 
nucleotide antisense oligonucleotides (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. 
Study PQ-421a-004 aims to define safety and quantify the treatment effect of QR-421a 
administered via IVT injection in subjects with RP due to mutations in exon 13 of the USH2A 
gene with early to moderate loss of vision, relative to masked, untreated control subjects, at 
2 dose regimens of QR-421a. 
2.5 
Measures to Minimize Bias  
To facilitate interpretation of clinical data, inclusion of randomized, concurrent parallel control 
groups is recommended for clinical studies whenever possible. Masking of participating subjects, 
treating physicians and study staff is of particular importance when subject effort or perception 
could bias evaluation of study endpoints, such as for measurement of visual acuity (Glassman 
2012).  
IVT injection is a well-established route of administration within ophthalmic indications that 
permits targeting of the therapeutic agent to the eye, while minimizing systemic absorption. IVT 
injection is used in several products for the chronic treatment of ophthalmic diseases (eg, 
Lucentis®, Eylea™, Macugen®) and the risk of complications is low when injections are 
performed by trained ophthalmologists (AAO 2015, Avery 2014). 
However, potentially severe complications to IVT injections exist, including endophthalmitis, 
intraocular inflammation, cataract, retinal detachment, and vitreous hemorrhage. Although the 
risk of severe complications is small, it is well documented (Jager 2004). Therefore, while IVT 
injection of the vehicle alone is theoretically feasible as a placebo control, it is not considered 
ethical since the physical properties of such an injection do not have potential therapeutic 
benefit. Hence, placebo injections will not be administered in this study to preserve subject 
safety.  
Other possibilities than placebo injections to effect masking include alternative dosing regimens, 
alternative dose levels, and existing products approved for the indication being sought. There are 
no existing approved products for the indication under investigation. 

 
 
 
 
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Use of sham-procedures (ie, no penetration of the globe) to mask subjects to treatment 
assignment in studies of products administered via IVT injections eliminates the risk of 
complications due to injection in the control arm. The sham-procedure, which closely mimics the 
injection procedure used for product delivery can effectively mask participants to treatment 
assignment; however, the masking effect is less pronounced in the case that a single subject 
receives both the real and sham injections in their 2 eyes (Glassman 2012). 
To reduce bias due to effort and subjectivity, masking will be achieved by use of a sham- 
procedure (see Study Reference Manual for details) as well as testing of 2 different dose levels.  
Drug administration, as well as clinical monitoring of the subject during and right after 
administration of study treatment, will be performed by a separate, unmasked physician (see 
Section 4.2.1.3), and clinical assessments (including efficacy and safety assessments) will be 
performed by a masked physician. A masked central reading center will be used for 
ophthalmologic assessments including static perimetry, full-field stimulus threshold testing 
(FST), spectral domain optical coherence tomography (SD-OCT) and mobility course scoring 
(for subjects/sites participating in the mobility course substudy).  
2.6 
Dose Selection 
 
 
 
 
The target regimen of QR-421a will consist of a loading dose of 180 µg, followed by 
maintenance doses of 60 µg after 3 months, and at 6 monthly intervals thereafter. The use of a 
loading dose followed by maintenance doses aims at reaching steady state (efficacious) levels in 
the retina from the first injection, to maximize clinical response and the potential to provide 
benefit to the subject. A second arm will test the efficacy and safety of a dose regimen of QR-
421a without a high loading dose (ie, 60 µg loading dose, followed by 60 µg maintenance dose 
at month 3, and every 6 months thereafter). 
As AONs are readily distributed to all eye tissues, and the vitreous is not acting as a drug 
reservoir, the axial length and overall eye volume are considered the most important parameter 
for determining the QR-421a dose and the highest recommended IVT injection volume. At 
around 3 years of age, the human eye is fully developed, and the compartmental volume is 90% 
of that in adulthood (Fledelius 2014, Vinekar 2015). The axial length of the eye changes from 
approximately 16 to 18 mm at birth, 19.5 mm in infants, 23 mm in 3-year-olds, until 22 to 24 
mm in adults (Hellstrom 1997).

 
 
 
 
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2.7 
Study Population 
Eligible subjects will have mutations in exon 13 of the USH2A gene, impaired visual field with a 
mean defect of at least 10 dB, a remaining central continuous visual field of at least 10 degrees 
diameter, evidence of functioning rods, and best-corrected visual acuity (BCVA) better than ≥69 
letters in the study eye, based on the Early Treatment Diabetic Retinopathy Study (ETDRS).  
An impairment of the visual field is a prerequisite to detect improvements in the sensitivity of the 
visual field. 
 
 
 
 
 
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 efficacy of QR-421a. 
3.2 
Secondary Objective 
The secondary objectives of the study are: 
• To evaluate the safety and tolerability of QR-421a  
• To evaluate changes in Patient-Reported Outcome (PRO) measures in subjects 
treated with QR-421a 
• To evaluate the systemic exposure of QR-421a  

 
 
 
 
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3.3 
Exploratory  
• To evaluate the effects of QR-421a on mobility course performance 
4.0 
STUDY OVERVIEW 
4.1 
Criteria for Evaluation 
The primary endpoint will be assessed at 12 months of treatment. All other efficacy and safety 
parameters will also be reported at that time point. All efficacy and safety assessments will 
continue to be followed up during the 24-month treatment period. 
4.1.1 
Primary Endpoints 
• Change from baseline in mean sensitivity (based on static perimetry) at 12 months 
of treatment versus sham-procedure  
4.1.2 
Secondary Endpoints 
The order in which the secondary endpoints will be analysed will be defined in the Statistical 
Analysis Plan (SAP). 
 
Key Secondary Endpoint  
• Ellipzoid Zone area (EZ) as measured by Spectral Domain optical coherence tomography 
SD-OCT 
 
Other Secondary Endpoints 
• Change from baseline in the following outcome measures: 
o BCVA  
o Spectral domain optical coherence tomography (SD-OCT) (other measures) 
o Low Luminance Visual Acuity (LLVA) 
o Other measures of static perimetry  
o Full-field Stimulus Threshold (FST) 
• Change from baseline in PRO measures, as assessed by: 
o Michigan Retinal Degeneration Questionnaire (MRDQ) (Lacy 2021) 
o Patient Global Impressions of Severity (PGI-S) 
o Patient Global Impressions of Change (PGI-C) 
• Ocular and non-ocular adverse events (AEs) 

 
 
 
 
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• Exposure of QR-421a in serum 
4.1.3 
Exploratory Endpoints 
• Change from baseline in mobility course score 
4.2 
Study Design 
PQ-421a-004 is a double-masked, randomized, controlled, multiple-dose study to evaluate the 
efficacy, safety, and tolerability of QR-421a in subjects with RP due to mutations in exon 13 of 
the USH2A gene with early to moderate vision loss.  
At study start subjects will be randomized to one of the following treatment groups: 
• Group 1: QR-421a 180/60 µg (180 µg loading dose administered on Day 1, 60 µg 
maintenance dose administered at Month 3 and every 6 months thereafter; n = 40) 
• Group 2: QR-421a 60/60 µg (60 µg loading dose administered on Day 1, 60 µg 
maintenance dose administered at Month 3 and every 6 months thereafter; n = 40) 
• Group 3: Sham-procedure (administered on Day 1, Month 3 and every 6 months 
thereafter; n = 40) 
The primary endpoint will be assessed at 12 months of treatment. Analysis of all other efficacy 
and safety parameters will also be reported at that time point. All efficacy and safety parameters 
will continue to be followed during the 24-month treatment period.  
The same safety monitoring protocol and efficacy assessments will apply to both eyes.  
 
 
 

 
 
 
 
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4.2.1 
Study Plan  
4.2.1.1 
Screening 
During the screening period, subjects will be assessed according to the eligibility criteria. 
Subjects who meet all eligibility criteria will be enrolled into the study. Reference is made to 
Section 7.2 for more details on the screening process.  
Assessments can be completed over multiple, non-consecutive days instead of 1 full day, at the 
discretion of the Investigator. 
4.2.1.2 
Study Drug Administration 
Subjects will receive study drug via IVT injection in accordance with the procedures outlined by 
the current international guidelines (AAO 2015; Avery 2014) and as outlined in the Study 
Reference Manual.  
Administration of study treatment, as well as clinical monitoring and evaluation of subject’s 
safety during and right after administration of study treatment, will be performed by an 
unmasked physician, but clinical assessments (including efficacy and safety assessments) will be 
performed by a separate, masked physician. Specific study drug and sham-procedure 
administration procedures can be found in the Study Reference Manual. 

 
 
 
 
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After each dosing subjects will be assessed for safety and tolerability at follow-up visits. 
4.2.1.3 
Assessments and Follow-up 
On the dosing days post study treatment, subjects will be monitored for safety, including in 
intraocular pressure (IOP), optic nerve swelling and signs of inflammation. An unmasked IVT 
physician will administer the study treatment and monitor right after administration. The clinical 
monitoring and evaluation of subject’s safety by the unmasked IVT physician during and right 
after administration of the study treatment include eg, IOP, verification that the retina is attached, 
and checking for hemorrhage and signs of intraocular inflammation.
 
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. 
All ophthalmic assessments will be performed on both the study eye and fellow eye. 
The primary endpoint will be assessed at 12 months of treatment. Available data on other 
efficacy and safety parameters will also be reported at that time point. All efficacy and safety 
parameters will continue to be followed up during the 24 months treatment period 
 For subjects completing the study, the Sponsor plans on providing access to study drug and/or 
continued follow up after the End of Study (EOS) visit, in an open-label extension study. 
4.2.2 
Stopping Criteria 
4.2.2.1 
Stopping Criteria for Individual Subjects 

 
 
 
 
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The Investigator may also discontinue a subject from study treatment for other reasons 
 
 Reference is made to Section 
9.4.1 for required follow-up by the Investigator in case of ongoing (serious) AEs at the time of 
study treatment discontinuation. Any subject discontinued from study treatment is to have the 
reason recorded in the eCRF.   
If a subject is discontinued from the study, his/her subject number cannot be reused. 
  
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 make every attempt to encourage the subject to remain in the study for 
observation (at least) through the Month 24 Visit (see also Section 9.4.1). The Investigator 
should follow up on AEs outside of the clinical study to ensure subject safety; however, no data 
on such events will be collected for study purposes. 
4.2.3 
Discontinuation of the Study 
The DMC and Medical Monitor will evaluate the safety and tolerability data at pre-specified 
time points (defined in the DMC charter, Section 9.1) and on an ad hoc basis as needed (Section 
4.2.2), leading to a recommendation (by the DMC) and subsequently a decision (by the Sponsor) 
if the study should continue or cease, or if any modifications should be made as to how subjects 
are treated or managed. Reference is also made to Section 13.3. 
5.0 
SELECTION OF STUDY POPULATION  
5.1 
Study Population 
Subjects with a diagnosis of RP due to mutations in exon 13 of the USH2A gene who meet all 
eligibility criteria will be eligible for participation in this study. 
5.2 
Selection of Subjects 
Screening of subjects will be performed within 12 weeks prior to dosing.  

 
 
 
 
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Subjects will be evaluated against all eligibility criteria as presented in the SOE
 If a subject would not be eligible in the opinion of the Sponsor’s Medical Monitor, after 
discussion with the investigator it may be decided that the subject cannot participate in the study.  
Results of assessments for all eligibility criteria must be available and reviewed prior to the 
subject’s dose of study treatment. 
5.3 
Eligibility Criteria 
5.3.1 
Inclusion Criteria Relating to Study Initiation 
The subject is eligible for the study and thus eligible to receive QR-421a or sham-procedure in 
the study eye if all the following inclusion criteria apply at Screening/Day 1: 
1. An adult (≥ 18 years) willing and able to provide informed consent for participation prior to 
performing any study related procedures, and suitable verbal, auditory, written and/or tactile 
sign language communication as to allow informed consent to be obtained, in the opinion of 
the Investigator. 
OR 
A minor (12 to < 18 years) with a parent or legal guardian willing and able to provide written 
permission for the subject’s participation prior to performing any study related procedures 
and pediatric subjects able to provide age appropriate assent for study participation. 
2. An adult willing to comply with the protocol, follow study instructions, attend study visits as 
required and willing and able to complete all study assessments.  
OR  
A minor able to complete all study assessments and comply with the protocol, and has a 
parent or caregiver willing and able to follow study instructions, and attend study visits with 
the subject as required. 
3. Clinical presentation consistent with RP with Usher syndrome type 2 or non-syndromic form 
of RP (NSRP), based on ophthalmic, audiologic, and vestibular examinations. 
4. A molecular diagnosis of homozygosity or compound heterozygosity for 1 or more 
pathogenic exon 13 mutations in the USH2A gene, based on genetic analysis at screening. 
 
5. BCVA better than ≥69 letters (approximate Snellen equivalent 20/40) in the study eye, using 
the best BCVA reading at Screening (see Section 8.1)  
and based on the Early Treatment Diabetic Retinopathy Study (ETDRS). 
6. Impairment of Visual Field (VF) in the opinion of the Investigator as determined by 
perimetry, with a continuous area of central field greater than or equal to 10 degrees diameter 
in each meridian as measured by a size V4e target, and a mean defect of ≥ 10 dB,
in the study eye.  
7. Clearly visible and measurable ellipsoid zone (EZ) width and/or area on SD-OCT, per 
investigator judgement. 
8. No limitations to SD-OCT image collection that would prevent high quality, reliable images 
from being obtained in both eyes, as determined by the Investigator. 

 
 
 
 
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9. Reliable BCVA, perimetry, and other measurements in both eyes, as described in the Study 
Reference Manual and Imaging Manual, and determined by the Investigator.  
10. No visually significant ocular media opacities and adequate pupillary dilation to permit good 
quality retinal imaging, as assessed by the Investigator. 
5.3.2 
Exclusion Criteria Relating to Study Initiation 
The subject is ineligible for the study if any of the following criteria apply at Screening/Day 1: 
1. Presence of additional non-exon 13 USH2A pathogenic mutation(s) on the USH2A allele 
carrying the exon 13 mutation in subjects who have mono-allelic exon-13 mutations. 
2. Presence of non-exon 13 USH2A pathogenic mutation(s) on both USH2A alleles in subjects 
who have biallelic exon 13 mutations. 
3. Presence of pathogenic mutations in genes (other than the USH2A gene) associated with 
Usher syndrome Type 2 or NSRP, or other inherited retinal degenerative diseases or 
syndromes.  
Note: The confirmed presence of homozygous or compound heterozygous known disease-
causing mutations in other genes involved in recessive retinal dystrophies (RD), or the 
confirmed presence of known disease-causing mutations in genes involved in dominant or X-
linked retinal dystrophies is exclusionary. 
4. Presence of any significant ocular 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 study eye. CME is permissible if stable for 3 months (with or without 
treatment). Past CME is permissible if resolved for more than 1 month. 
5. History or presence of ocular herpetic diseases (including herpes simplex virus, varicella 
zoster or cytomegalovirus) in either eye. 
6. Presence of any active ocular infection in either eye. 
7. Presence of any of the following lens opacities in the study eye based on the age-related eye 
diseases study (AREDS) lens grading scale: cortical opacity ≥ +2, posterior subcapsular 
opacity ≥ +2, or a nuclear sclerosis ≥ +2, and which are: 1) clinically significant in the 
opinion of the Investigator, 2) would adequately prevent clinical and photographic evaluation 
of the retina. 
8. History of amblyopia in the study eye that resulted in significant vision loss, in the opinion of 
the Investigator.  
9. Receipt within 3 months prior to Screening of any intraocular or periocular surgery 
(including refractive surgery), or an IVT injection other or planned intraocular surgery or 
procedure during the course of the study. 
10. Current treatment or treatment within the past 12 months with therapies known to influence 
the immune system (including but not limited to steroid implants, cytostatics, interferons, 
tumor necrosis factor (TNF)-binding proteins, drugs acting on immunophilins, or antibodies 
with known impact on the immune system). Subjects that have been treated with systemic 

 
 
 
 
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steroids within the past 12 months or that require intermittent use of topical steroids may be 
considered for inclusion following approval by the Medical Monitor. 
11. A history of glaucoma or an IOP greater than 24 mmHg in either eye that is not controlled 
with medication or surgery. 
12. Use of any investigational drug or device within 90 days or 5 half-lives preceding the first 
dose of study medication, whichever is longer, or plans to participate in another study of an 
investigational drug or device during the course of the study. 
13. Any prior treatment with genetic or stem-cell therapy for ocular or non-ocular disease. 
14. History of malignancy within 2 years prior to Screening, except adequately treated squamous 
or basal cell carcinoma of the skin or carcinoma in situ of the cervix that has been 
successfully treated. 
15. Known hypersensitivity to antisense oligonucleotides or any constituents of the injection. 
16. Pregnant and breastfeeding subjects. Females of childbearing potential and males must 
comply with using highly effective methods of contraception as defined in Section 6.2.2. 
Women of non-childbearing potential may be included without the use of adequate birth 
control, provided they meet the criteria in the protocol (see Section 6.2.2). 
 

 
 
 
 
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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 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 
accountability are provided in the Pharmacy Manual and the Study Reference Manual.  
Forms are provided to facilitate the inventory control. These forms must be used unless the 
Investigator (or designee) has previously established a system that complies with local 
regulations and is approved by the Sponsor. The study drug must be dispensed only at the 
institution(s) specified on form Food and Drug Administration (FDA) 1572 or Statement of 
Investigator (as applicable). 

 
 
 
 
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Upon completion or termination of the study and after inventory by a Sponsor representative 
(monitor), it will be determined if unopened study drug vials are to be sent to the Sponsor in the 
original containers or are to be destroyed at the study center.  
6.1.5 
Dosage and Administration 
Two dose regimens of QR-421a will be tested: 
1. 180 µg loading dose, 60 µg maintenance dose (180/60 g)  
2. 60 µg loading dose, 60 µg maintenance dose (60/60 g) 
 
 The physician administering study treatment will be unmasked to assignment of 
study drug or sham-procedure but will be masked to the dose of study drug. Treatment 
assignment will be through the centralized Interactive Web Response System (IWRS) for the 
study. The physician performing the clinical assessments will be masked. All subjects will be 
masked to study treatment assignment. 
Subjects will receive QR-421a via IVT injection or will undergo a sham-procedure. 
Administration of QR-421a and the sham-procedure will only be performed by qualified 
ophthalmologists in an in-clinic setting. No other medications should be mixed with QR-421a.  
Reference is made to the Study Reference Manual and Pharmacy Manual for detailed 
instructions on the IVT injection and the sham-procedure. 
6.2 
Concomitant Medications and Auxiliary Therapy 
There are no medicinal products classified as auxiliary in this clinical trial. 
6.2.1 
Prohibited Concomitant Medications 
The use of any investigational drug or device within 90 days or 5 half-lives of the drug at Day 1, 
whichever is longer, or plans to participate in another clinical study during the study period is 
prohibited. Medications that are known to be toxic to the lens, retina, or optic nerve are 
prohibited. These may include, but are not limited to systemic/intraocular steroids, amiodarone, 
deferoxamine, chloroquine/hydroxychloroquine sulfate, tamoxifen, phenothiazines, and 
ethambutol, pentosan polysulfate, etc. Topical steroids are not prohibited but should only be used 
following consultation with the Medical Monitor. 
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. 

 
 
 
 
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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: 
• 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 and must be continued
  

 
 
 
 
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A man who is fertile should use a condom during treatment and until 
 
7.0 
STUDY VISITS 
All study visits, assessments and procedures should be completed as indicated per the SOE 
 
  
7.1 
Visit and Assessment Windows 
For those procedures for which a specific time point post dose is required (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 
reasons are also to be recorded. For more details, please refer to the case report form completion 
guidelines. 
 
Visits and/or assessments can be completed over multiple, non-consecutive days.  
 
All efforts should be taken to prevent missing data. Therefore, deviations from the treatment 
cycle (and subsequent assessments) may be justified in some cases, eg. if an AE makes treatment 
impossible at the schedule dosing day. In exceptional cases, eg, related to the significant 
restrictions in site activities or subject’s ability to travel to sites for visits as occurring related to 
the COVID-19 pandemic, extensions of the visit window or alterations in the SOE can be 
approved by the Medical Monitor. Such extensions of the visit window will be documented as 
protocol deviations. Still, sites should make every reasonable effort to complete scheduled visits 
within the time windows defined in this protocol. 
7.2 
Screening 
 
  
Prior to or at the first Screening visit a sample for gene sequencing analysis will be obtained (see 
Section 8.55 for further details). In case the sample for gene sequencing analysis will be obtained 
prior to the first Screening visit, a separate Informed Consent Form (ICF) and/or assent is 
available for this purpose (see Section 12.2). 
  

 
 
 
 
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During the screening period, subjects will be assessed according to the eligibility criteria and 
specified assessments conducted, as presented in the SOE
 Subjects who have 
been identified as screen failure may be rescreened if, in the opinion of the Investigator, there is 
a reasonable chance that the subject may become eligible at a later timepoint. If the decision is 
taken to rescreen a subject, the subject will need to be re-consented and will obtain a new subject 
number. 
For all subjects, screening should be conducted in a stepwise manner so that eligibility is 
confirmed first by less intensive assessments. More intensive assessments are to be conducted 
once eligibility by other criteria have been confirmed to minimize risk and burden.  
7.3 
Dosing and Follow-up Visits 
The timing of dosing and follow-up visits is outlined in the SOE 
. Study treatment 
will be administered by unmasked qualified ophthalmologists. 
 
 
 
All follow-up study visits, assessments and procedures should be completed as indicated per the 
SOE
 All efforts should be taken to prevent missing data. Deviations from the 
treatment cycle (and subsequent assessments) may be justified in some cases, eg. if an AE makes 
treatment impossible at the scheduled dosing day (see also Section 7.1). Subjects will be assessed 
for safety, tolerability, and efficacy at follow-up visits with all ophthalmic assessments 
performed on both the study eye and fellow eye.  
7.4 
End of Study Visit & Roll Over to Open Label Extension Study 
8.0 
STUDY ASSESSMENT PROCEDURES 
All clinical assessments (including all efficacy and safety assessments) will be performed by 
masked staff. Clinical monitoring during and right after administration of study treatment will be 
performed by an unmasked IVT physician (see also Section 4.2.1.3). 

 
 
 
 
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Eligible subjects must complete all Screening examinations. If a subject is unable to complete a 
specific assessment, this should be recorded in the eCRF and the subject’s ability reassessed at 
the next specified visit. All attempts at performing assessments should be recorded in the eCRF. 
Any assessment may be repeated if the results are considered unreliable or of unacceptable 
quality by the Investigator. 
8.1 
Efficacy 
Efficacy assessments include BCVA, LLVA, SD-OCT, static perimetry, FST, mobility course (at 
selected sites) and PROs. A central reading center, utilizing evaluators masked to treatment 
assignment, will assess static perimetry, FST, and SD-OCT. Mobility course scoring will also be 
reviewed and calculated by a masked evaluator. See the Study Reference Manual, Imaging 
Procedure Manual and Mobility Course Manual for further information on these assessments. 
Subjects’ assessment of the impact of their visual disability on general health-related outcomes 
as well as specific vision-related outcomes of daily living will be assessed by the MRDQ (at 
selected sites) (Lacy 2021). 
Subjects’ assessment of disease severity will be assessed by PGI-S, and assessment of any 
improvement or decline in clinical status will be assessed by PGI-C.  
8.2 
Safety 
Safety assessments to monitor for AEs include ophthalmic examinations, laboratory evaluations, 
and SD-OCTs. Assessments will be conducted as indicated by the SOE 
 
8.2.1 
Adverse Events 
Information regarding occurrence of AEs will be captured throughout the study. Duration (start 
and stop dates), severity/grade, outcome, treatment, and relationship to study drug will be 

 
 
 
 
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recorded. Refer to Section 9.0, Assessment of Safety or Adverse Events and Serious Adverse 
Events, for further details. 
8.2.2 
Laboratory Evaluations 
All laboratory evaluations will be conducted at a central laboratory. Reference ranges for all 
laboratory parameters are provided in the Laboratory Manual. See Appendix 2 for a list of 
laboratory tests to be conducted. 
Serum chemistries will include sodium, potassium, chloride, bicarbonate, blood urea nitrogen 
(BUN), creatinine, glucose, calcium, phosphorus, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), gamma-glutamyl transferase (γGT), C-reactive protein (CRP), alkaline 
phosphatase (ALP), total and direct bilirubin, lactic dehydrogenase (LDH), albumin, and total 
protein. Estimated glomerular filtration rate (eGFR) is to be calculated using the 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).  
For female subjects of childbearing potential, a pregnancy test will be performed as indicated by 
the SOE
 and is recommended at any visit that may warrant a pregnancy test.  
Eligibility of the subject to participate in the study is based in part on safety signals that may be 
indicated by laboratory values.  
Repeat laboratory tests are permitted to confirm potentially spurious values or false positive 
results, at the discretion of the Investigator. Repeat analysis results for any laboratory 
assessments that are eligibility criteria should be discussed with the Medical Monitor prior to 
subject inclusion. 
8.2.3 
Ophthalmic Examinations 
Ophthalmic examinations include slit lamp biomicroscopy, intraocular pressure, and dilated 
fundus examination and will be performed as indicated per the SOE
 

 
 
 
 
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Further details on the procedures for ophthalmic examinations are in the Study Reference 
Manual.   
8.2.4 
Spectral Domain Optical Coherence Tomography  
Changes in SD-OCT findings,
. All SD-OCT scans should be performed in 
accordance with the procedures outlined in the Imaging Procedure Manual.  
8.3 
Systemic Exposure 
Blood samples for systemic exposure analysis of QR-421a will be collected from all subjects as 
indicated per the SOE 
 
8.4 
Immunogenicity 
Blood samples for assessment of immunogenicity will be taken as indicated per the SOE 
and stored for potential later quantification.  
8.5 
Gene Sequencing  
A genotyping report (either historic or at screening) is required for eligibility.
 A blood or saliva sample for genotyping and 
gene sequencing should be obtained at or prior to the Screening Visit. In case the sample for 
gene sequencing analysis will be obtained prior to the first Screening Visit, a separate Informed 
 
 
 
9.0 
ASSESSMENT OF SAFETY, ADVERSE EVENTS AND SERIOUS ADVERSE 
EVENTS 
All subjects who receive study treatment will be assessed for safety.  

 
 
 
 
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Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting the Sponsor regarding any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the subject. The Investigator is responsible for appropriate 
medical care of subjects during the study and may add unscheduled visits, additional exams/tests 
for safety purposes. 
9.1 
Data Monitoring Committee 
An independent DMC will provide safety oversight for the study. A DMC operational charter 
will be finalized, and an initial organizational meeting held prior to screening of the first subject.  
Reference is also made to Sections 4.2.2 and 4.2.3. 
9.2 
Definitions of Adverse Event, Serious Adverse Event, and Suspected Unexpected 
Serious Adverse Event 
9.2.1 
Adverse Events  
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
considered drug related or not. Adverse events can include any unfavorable, noxious, unintended 
sign, symptom, or disease temporally associated with use of a study drug or other protocol-
imposed intervention, regardless of attribution. Adverse events may be spontaneously reported 
by the subject, discovered by Investigator questioning, or detected through laboratory test, or 
other means. 
Adverse events include: 
• Pre-existing medical conditions judged by the Investigator to have worsened in 
severity or frequency or changed in character during the protocol-specified AE 
reporting period (as specified in Section 9.4.1) 
• Adverse events not previously observed in the subject that emerge during the 
protocol-specified AE reporting period (as specified in Section 9.4.1)  
• Complications that occur as a result of protocol-mandated interventions  
• Adverse events that occur prior to study treatment that are related to a 
protocol-mandated intervention (eg, invasive procedures such as blood draws, 
sedation prior to IVT injection) 
9.2.2 
Serious Adverse Events 
An AE is considered “serious” if, in the view of Investigator, it results in any of the following 
outcomes: 
• Death 

 
 
 
 
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• 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 (ie, the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions) 
• Congenital anomaly or birth defect. This serious criterion applies if a congenital 
anomaly/birth defect is diagnosed in a child born to a female subject, or a female 
partner of a male subject exposed to the study drug 
• Other important medical events. Medical and scientific judgment should 
determine whether an AE should be classified as serious in other situations, such 
as important medical events that may not be immediately life threatening or result 
in death or hospitalization but may jeopardize the subject or require intervention 
to prevent one of the outcomes listed in the definition above.  
All AEs that do not meet any of the criteria for serious should be regarded as non-serious AEs. 
Surgery for lens opacity removal (lens replacement) is not considered a serious AE as it does not 
require the subject be admitted to a hospital unit based on the nature of the surgery. Even in the 
case where the subject may be hospitalized for convenience, or a subject is too frail to make the 
commute back and forth to the surgical center, it is still not a Serious AE. The terms “severe” 
and “serious” are not synonymous. Severity refers to the intensity of an AE (as in mild, 
moderate, or severe pain); the event itself may be of relatively minor medical significance (such 
as severe headache) (see Section 9.3.1). “Serious” is a regulatory definition and is based on 
subject or event outcome or action criteria usually associated with events that pose a threat to a 
subject’s life or vital functions. Seriousness (not severity) serves as the guide for defining 
regulatory reporting obligations. 
Severity and seriousness should be independently assessed when recording AEs and serious 
adverse events (SAEs) on the AE eCRF and SAE form. 
9.2.3 
Suspected Unexpected Serious Adverse Reaction Definition 
In order to be qualified as a suspected unexpected serious adverse reaction (SUSAR), the AE 
must meet 3 criteria: the event is serious, there is a certain degree of probability that the event is 
a reaction to the study drug being researched and the nature and severity of the reaction are not in 
agreement with the product information (ie, 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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9.2.4 
Adverse Events of Special Interest 
9.3 
Assessment of Adverse Events  
The Investigator is responsible for assessing the severity and causality of AEs. 
9.3.1 
Assessment of Severity (Intensity) of Adverse Events 
On the AE eCRF, the Investigator will use the adjectives MILD, MODERATE, or SEVERE to 
describe the maximum intensity of the AE. For purposes of consistency, these intensity grades 
are defined as follows:  
• MILD: Awareness of sign, symptom, or event, but easily tolerated. Does not 
interfere with subject’s usual function. 
• MODERATE: Discomfort enough to cause interference to some extent with 
subject’s usual function and may warrant intervention. 
• SEVERE: Incapacitating and interferes significantly with subject’s usual function 
and warrants intervention. 

 
 
 
 
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As described previously in Section 9.2.2, note the distinction between the severity and the 
seriousness of an AE. A severe event is not necessarily a serious event and may not meet the 
regulatory definition of serious. For example, a headache may be severe (interferes significantly 
with subject’s usual function) but would not be classified as a serious AE unless it met one of the 
regulatory criteria for SAEs, listed above in Section 9.2.2. 
Any change in severity should be noted in the eCRF, eg, a change from mild to severe or a 
change from severe to moderate should be noted with the start and stop dates for each intensity. 
9.3.2 
Assessment of the Relationship of Adverse Events to Study Drug 
The Investigator will make a causality assessment about the relationship of each AE to study 
drug. Assessment of causality is based on considering associative connections (time or place), 
pharmacological explanations, previous knowledge of the study drug, presence of characteristic 
clinical or pathological phenomena, underlying conditions in the study population, exclusion of 
other causes, and/or absence of alternative explanations. To ensure consistency of AE and SAE 
causality assessments, Investigators should apply the following general guideline: 
Not Related: The AE has an etiology other than the study drug (eg, 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 (eg, cancer diagnosed 
2 days after dose of study drug).  
Related: An AE that is related to the study drug or its administration (ie, 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 (ie, IVT injection). 
Note: The Investigator’s assessment of causality for individual AE reports is part of the study 
documentation process and will be recorded in the subject’s medical record, AE eCRF, and SAE 
form if applicable. Adverse events recorded without the Investigator’s assessment of the 
relationship to study drug will be followed up until causality is assigned. 
9.3.3 
Assessment of the Outcome of Adverse Events 
The Investigator will record the outcome of AEs and SAEs using the following criteria: 
• Recovered/resolved: The subject has fully recovered from the event, with no 
residual effects observable. 
• Recovered/resolved with sequelae: The subject has recovered from the event, 
but with residual sequelae effects observable. 

 
 
 
 
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• 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). 
9.4 
Reporting of Adverse Events 
The Investigator is responsible for ensuring that all AEs and SAEs are recorded in the subject’s 
medical record, AE eCRF, and/or SAE form, and reported to the Sponsor in accordance with 
protocol instructions. The AE eCRF can be used to report both AEs and SAEs. If necessary, 
eg, in case of failure of the Electronic Data Capture (EDC) system or for logistical reasons, a 
paper AESI/SAE/Special Situation reporting form may be used instead. 
9.4.1 
Adverse Event Reporting Period 
After signing of the Informed Consent all significant medical conditions including 
signs/symptoms of the underlying disease and known pre-existing medical conditions found 
during the screening period and up to initiation of dosing will be captured as medical history. 
Any event/condition, including those related to participation in the study or study procedures, 
those not related to underlying disease or pre-existing medical conditions already part of medical 
history, and occurring before first dose of study treatment will be captured as a non-treatment 
emergent AE. 
Any event/condition noted once the subject receives their dose of study drug will be captured as 
a treatment emergent AE. All AEs and SAEs regardless of attribution will be collected until at 
least 90 days following the last administration of study drug or the subject’s EOS visit, 
whichever is later. At the last scheduled visit, the Investigator should instruct each subject to 
report to the Investigator any subsequent AEs/SAEs that the subject’s personal physician 
believes could be related to prior study treatment.  
SAEs unrelated to study treatment and non-serious AEs are to be followed until the last 
scheduled study visit (EOS visit), with the outcome at that point of time to be recorded in the 
eCRF. SAEs related to study treatment (Serious Adverse drug Reactions) are to be followed until 
resolution or until they return to baseline, stabilize, or the subject is lost to follow-up. Resolution 
of AEs and SAEs (with dates) should be documented on the AE eCRF and SAE form (if 
applicable) and in the subject’s medical record to facilitate source data verification. For some 
SAEs, the Sponsor or its designee may follow up by telephone, facsimile, electronic mail, and/or 
a monitoring visit to obtain additional case details deemed necessary to appropriately evaluate 
the SAE report (eg, hospital discharge summary, consultant report, or autopsy report).  

 
 
 
 
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9.4.2 
Eliciting Adverse Events 
A consistent methodology of non-directive questioning for eliciting AEs at all subject evaluation 
time points should be adopted. Examples of non-directive questions include: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last here?” 
9.4.3 
Recording Adverse Events and Serious Adverse Events  
Investigators should use correct medical terminology/concepts when recording AEs or SAEs on 
the eCRF and/or AESI/SAE/Special Situation reporting form. Colloquialisms and abbreviations 
should be avoided. Serious AEs must also be recorded on the AE eCRF or AESI/SAE/Special 
Situation reporting form. Only 1 medical concept should be recorded in the event field on the AE 
eCRF and AESI/SAE/Special Situation reporting form (if applicable). 
a. 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (eg, cascade events or clinical sequelae) 
should also be entered as separate AEs. For example, if severe diarrhea is known to have resulted 
in dehydration, both diarrhea and dehydration should be entered as AEs on the eCRF, and if also 
serious, as SAE on AE eCFR and AESI/SAE/Special Situation reporting form (if applicable).  
b 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution between subject evaluation 
time points. Such events should only be recorded once in the eCRF unless their severity 
increases. If a persistent AE becomes more severe or occurs more frequently, it should be 
recorded again on the AE eCRF with the increased severity grading.  
A recurrent AE is one that occurs and resolves between subject evaluation time points and 
subsequently recurs. All recurrent AEs should be recorded individually on the AE eCRF. 
c. 
Abnormal Laboratory Values 
Only clinically significant laboratory abnormalities will be recorded as AEs on the eCRF and 
SAE form (if applicable).  
If the laboratory abnormality can be characterized by a precise clinical term, the clinical term 
should be recorded as the AE or SAE. For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as “hyperkalemia”. 

 
 
 
 
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Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs on the eCRF and SAE form (if applicable), unless their 
severity, seriousness, or etiology changes.  
d. 
Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section 9.4.1), 
regardless of attribution, will be recorded on the AE eCRF and SAE form and reported to the 
Sponsor within 24 hours of event knowledge.  
When recording a death, the event or condition that caused or contributed to the fatal outcome 
should be recorded as a single medical concept. For example, if death resulted from respiratory 
failure, the AE recorded should be “Respiratory Failure”, and the outcome of the AE would be 
“Death”. If the cause of death is unknown and cannot be ascertained at the time of reporting, 
record “unexplained death” on the AE eCRF and SAE form. 
e. 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. Such conditions 
should be recorded on the Medical History eCRF. 
A preexisting medical condition should be recorded as an AE or SAE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such events on 
an AE eCRF and SAE form (if applicable), it is important to convey the concept that the 
preexisting condition has changed by including applicable descriptors (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 9.2.2, Serious 
Adverse Event Definition), this information will be captured on the AE eCRF and SAE form (if 
applicable). 

 
 
 
 
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Pregnancy should be followed up until after delivery, and any events to 3 months post-partum or 
termination of the pregnancy. Any congenital anomaly/birth defect in a child born to a female 
subject or to a female partner of a male subject exposed to the study drug should be recorded and 
reported as an SAE. 
h. 
Special Situations Reporting 
Medication errors and uses outside what is foreseen in the protocol, including overdose and 
occupational exposure must be reported to the Sponsor within 24 hours from awareness on an 
paper AESI/SAE/Special Situation reporting form (if applicable) for tracking purposes and will 
be considered a protocol deviation. Overdose is defined as any study drug dose administered 
above the intended dose for the cohort assignment. Additional instructions for reporting special 
situation information will be provided by the Sponsor at the time of notification. 
9.5 
AESIs and Serious Adverse Events Notification  
For all AESI and SAEs, regardless of suspected causality, a completed AESI/SAE/Special 
Situation reporting form must be sent within 24 hours of discovery of the event 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 reporting 
form within 24 hours. 
Serious AEs occurring any time after study participation that are considered by the Investigator 
to be possibly related to study drug must also be reported. The following are important points to 
remember when completing the SAE form: 
• If complete information is not available, at a minimum, subject identifier, suspect 
drug, study center identifier, event or outcome, and Investigator assessment of causal 
relationship to study drug should be provided. 
• A rationale for the causality assessment of an SAE should always be included, so that 
a better understanding of the event can be compiled. 

 
 
 
 
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• Follow-up information, such as laboratory reports, discharge summaries, autopsy 
reports, and information concerning outcome of the event should be submitted by 
revising the SAE form as soon as the information becomes available. Copies of 
source documents, with subject identifiers redacted, should be submitted only when 
they are written in English. If source documents are not in English, the Investigator 
must summarize the source documents, providing a complete English narrative that 
includes a description of the events as it evolved, the results of all diagnostic 
procedures performed, treatments administered, and outcome of the event. A query 
regarding a follow-up report should be answered within 5 working days from receipt 
of the query. 
• Appropriate diagnostic tests and therapeutic measures are to be performed as 
necessary and reported on the SAE form. 
• All SAEs must be reported to the IRB/EC, if applicable. See the International Council 
for Harmonisation (ICH) GCP E6 (R2), Section 4.11.1 (ICH 2016). 
9.6 
Expedited Reporting of Suspected Unexpected Serious Adverse Reactions 
• The Sponsor or 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 SAP specifies the statistical methodology, and table, listing and figure (TLF) 
formats for all aspects of the planned analyses. The SAP supports the completion of the Clinical 
Study Report (CSR) for this protocol. All AEs will be considered in determining the safety 
profile of QR-421a. Exploratory analyses not necessarily identified in the SAP may be 
performed to support the clinical development program. Any post-hoc, or unplanned, analyses 
not identified in the SAP will be clearly identified in the CSR, in accordance with applicable 
Standard Operating Procedures of the sponsor.  

 
 
 
 
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10.2 
Determination of Sample Size 
This is a Phase 2/3 study designed to evaluate efficacy, safety, and tolerability of QR-421a in 
subjects with early to moderate vision loss.  
 
10.3 
Randomization and Masking 
Subjects, treating physicians and study staff are masked. The physician administering study 
treatment will be unmasked to assignment of study drug or sham-procedure but will be masked 
to the dose of study drug. 
The randomization procedure used to assign study treatment to eligible subjects will be through a 
centralized IWRS, utilizing the randomization schedule generated by the designated unmasked 
statistician. Subjects will be sequentially assigned according to a computer-generated 
randomization list in the appropriate randomization ratio to 1 of 3 treatment groups and the 
eligible eye will be treated accordingly (see Section 10.2 and Section 4.2). Stratification for 
baseline characteristics (when included) will be described in the SAP. 
10.4 
Replacement of Subjects 
10.5 
Analysis Populations 
All Screened Subjects: All subjects who provided informed consent to participate in the study. 
Intent to Treat Set: All subjects who were randomized. 
Safety Set: All subjects who were randomized and received at least one dose of study treatment. 
Full Analysis Set: 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 

 
 
 
 
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separately for each endpoint, based on availability of at least 1 baseline measurement of that 
endpoint. 
Per Protocol Efficacy Set: All subjects in the Efficacy Evaluable Population with the exception 
of subjects with major protocol deviations. The list of major protocol deviations selected for 
exclusion from this population will be completed prior to database lock. The Per Protocol 
Population will also be defined separately for each endpoint. 
Systemic Exposure Population: All subjects who received QR-421a and who have measurable 
drug concentrations in blood samples. 
10.6 
Subject Disposition, Demographics and Baseline Disease Characteristics 
Subject disposition will be summarized for All Screened Subjects population by dose group.  
The number and percentage of subjects who receive QR-421a or the sham-procedure will be 
tabulated by the number of doses and the treatment group.  
Subject demographics and baseline characteristics will be summarized for each treatment group 
and for all subjects combined. Subject characteristics at baseline include age, race, body weight, 
and height. Baseline disease characteristics include ophthalmic examinations, measurements, and 
tests, as previously described.  
10.7 
Treatment Compliance 
All doses are observed and administered by study staff. Treatment compliance will be 
determined by source records documenting treatment observations and summarized. 
10.8 
Efficacy Analyses 
The efficacy evaluations will include evaluations of the endpoints listed in Section 4.1.  
Descriptive statistics of clinical efficacy will be tabulated by dose group, and if appropriate, for 
dose groups combined.  
All continuous endpoints will be summarized using the following descriptive statistics: number 
of subjects, mean, standard deviation, standard error, median, minimum, maximum and 95% 
confidence intervals for the mean. Categorical endpoints will be summarized using the 
following: number of subjects, frequency, percentages and 95% confidence intervals. If data 
appear highly skewed, natural log or other transformation may be used to compute summary 
statistics. 
Continuous efficacy endpoints will be summarized and may be analyzed using appropriate 
parametric or nonparametric inference tests.  

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

 
 
 
 
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10.9.2 
Other Safety Assessments 
Other safety assessments, such as ophthalmic examinations and SD-OCT will be summarized 
and listed as specified in the SAP. 
10.10 12-Month Primary Analysis and 24-Month/EOS Analysis 
12-Month Primary Analysis 
After all randomized subjects have completed their Month 12 visit or discontinued the study 
prior to this visit, the primary analysis will be conducted, ie, analysis of the primary and 
secondary efficacy endpoints at Month 12. Follow-up data beyond 12 months, and available data 
from other endpoints will be analyzed as well. 
24-Month /EOS Analysis 
Follow-up data collected post the 18-month treatment period will be presented based on an 
analysis to be performed after the database is locked once all subjects have reached Month 24.  
10.11 Multiplicity Considerations 
10.12 Subgroup Analyses 
10.13 Systemic Exposure Analyses 
Systemic exposure analyses will be performed as outlined in the SAP. 
11.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 
Data Collection 
The Investigator will prepare and maintain adequate and accurate source documents (including 
medical records) designed to record all observations and other pertinent data for each subject 

 
 
 
 
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treated with the study treatment. Study center staff at each study center will enter data from 
source documents corresponding to a subject’s visit into the protocol-specific eCRF. Subjects 
will not be identified by name in the study database or on any study documents to be collected by 
the Sponsor (or designee) but will be identified by a study center number and subject number, 
which will be completed in the Screening and Enrollment Log. This number will be used for the 
duration of their participation in the study. The subject Screening number cannot be re-used if a 
subject withdraws consent or is a screening fail. 
Study center staff will be trained and authorized to use the system in compliance with the Code 
of Federal Regulations (CFR) 21CFR Part 11, International Council for Harmonisation (ICH) - 
Good Clinical Practice (GCP) and local regulations, before recording data on eCRFs. All 
corrections to eCRFs will be made by authorized users, and the changes will be automatically 
logged in the audit trail of the system (time and date stamps and the user entering or updating 
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. 

 
 
 
 
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11.3 
Monitoring 
A Sponsor representative (monitor) will contact the Investigator(s) at periodic intervals by 
telephone or on-site visit for the purpose of monitoring the facilities and assessing the progress 
of the study. Electronic CRFs and subject records will be reviewed at on-site visits at regular 
intervals throughout the study to verify adherence to the protocol, completeness, accuracy, and 
consistency of the data, and adherence to local regulations on the conduct of clinical research. 
The monitor should have access to subject medical records and other study-related records 
needed to verify the entries on the eCRF. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected 
during these monitoring visits, including delays in completing eCRFs, are resolved. 
Monitoring of study center facilities (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 systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, ICH GCP, and applicable regulatory 
requirements. The Investigator will contact the Sponsor immediately if contacted by a regulatory 
agency about an inspection at the study center. 
12.0 
ETHICAL AND REGULATORY OBLIGATIONS 
12.1 
Ethical Considerations 
The Investigator agrees to conduct this study in accordance with ethical principles that have their 
origin in the Declaration of Helsinki and are consistent with ICH GCP. The Investigator will 
conduct all aspects of this study in compliance with the protocol, ICH GCP and applicable 
regulatory requirements. 
12.2 
Informed Consent 
Before the start of required study procedures, the Investigator or his/her associate must obtain 
informed consent from each study participant (or the subject’s legal representative) in 
accordance with ICH GCP, and country authority requirements. Age-appropriate assent and 
permission from a minor subject’s parent or legal guardian is required for pediatric subjects. The 
subject or his/her legal representative must sign the current version of the written, IRB/EC- 

 
 
 
 
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approved Informed Consent Form in the presence of a witness and be given a copy. The 
Investigator will ensure that a copy of the signed consent is kept with the subject’s records. 
In accordance with ICH GCP and country authority requirements, an IRB/EC must review and 
approve this protocol and the ICF prior to initiation of the study.  
12.3 
Ethics and Regulatory Review 
An IRB/EC should approve the final study protocol, including the final version of the ICF, assent 
forms and any other written information and/or materials to be provided to the subjects. The 
Investigator will ensure the distribution of these documents to the applicable IRB/EC, and to the 
study center staff. 
The opinion of the IRB/EC should be given in writing. The Investigator should submit the 
written approval to Sponsor before enrollment of any subject into the study.  
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.  

 
 
 
 
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The Investigator and the Sponsor will ensure that all clinical trial information shall be recorded, 
processed, handled, and stored, in such a way that it can be accurately reported, interpreted and 
verified while the confidentiality, integrity and availability of records and the personal data of 
the subjects remain protected in accordance with the applicable (local) laws on personal data 
protection. Measures taken to ensure all of the above include, but are not limited to, encryption, 
anonymization, multifactor authentication, Intrusion Protection, segregation of authentication. 
In compliance with applicable regulations, it is required that the Investigator and institution 
permit authorized representatives of the Sponsor, the United States (US) Food and Drug 
Administration (FDA), other regulatory authorities (eg, European Union/European Economic 
Area Member State inspector), and the IRB/EC direct access to review the subject’s original 
medical records for verification of study-related procedures and data. Direct access includes 
examining, analyzing, verifying, and reproducing any or all records and reports that are 
important to the evaluation of this study. The Investigator is obligated to inform and obtain the 
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 trial subjects without 
prior IRB/IEC approval/favorable opinion. In this case, as soon as possible, the implemented 

 
 
 
 
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deviation or change, the reasons for it, and, if appropriate, the proposed protocol amendment(s) 
should be submitted to the sponsor, IRB/EC and if applicable the regulatory authority. 
13.3 
Study Termination 
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. 

 
 
 
 
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No study document is to be destroyed without prior written agreement between Sponsor and the 
Investigator. Should the Investigator wish to assign the study records to another party or move 
them to another location, he/she must notify the Sponsor in writing of the new responsible person 
and/or the new location. 
13.5 
Use of Information 
All personal data pertaining to the subjects in this study and in any subsequent reports will be 
kept confidential. Subjects will be identified only by their month and year of birth and a subject 
number. It is the responsibility of the Investigator to keep a subject listing for cross-referencing.  
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 
The end of the study is defined as the date of the last visit of the last subject in the study globally. 
The Investigator or delegate must notify the IRB/EC upon study completion or termination in 
compliance with local regulations.  
The Sponsor or its designee will provide a final report and/or synopsis to the Investigators, the 
IRB/EC and Regulatory Authorities in accordance with local requirements.  

 
 
 
 
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13.7 
Financing and Insurance 
Financing and Insurance are addressed separately in the Clinical Study Agreement. 
13.8 
Publication Policy 
Publication policy is addressed separately in the Clinical Study Agreement. 

 
 
 
 
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14.0 
REFERENCES 
American Academy of Ophthalmology. Clinical Statement. Intravitreal Injections. AAO Hoskins 
Center for Quality Eye Care. March 2015. Available at: https://www.aao.org/clinical-
statement/intravitreal-injections-statement. 
Avery RL, Bakri SJ, Blumenkranz MS, Brucker AJ; Cunningham ET; DʼAmico DJ, et al. 
Intravitreal injection technique and monitoring: updated guidelines of an expert panel. Retina. 
2014; 34:S1–S18.  
Brunner, E., and Munzel, U. (2000), “The Nonparametric Behrens-Fisher Problem: Asymptotic 
Theory and a Small-Sample Approximation,” Biometrical Journal, 42, 17–25. 
EC Directive 2001/20/EC. Ethical Considerations for clinical trials on medicinal products with 
the paediatric population. Recommendations of the Ad hoc group for the development of 
implementing guidelines for Directive 2001/20/EC. 2008. Available at 
http://ec.europa.eu/health//sites/health/files/files/eudralex/vol-10/ethical_considerations_en.pdf. 
EC Clinical Trial Directive 2005/28/EC. Commission directive 2005/28/EC of 8 April 2005 
2005. Available at http://ec.europa.eu/health//sites/health/files/files/eudralex/vol-
1/dir_2005_28/dir_2005_28_en.pdf. 
EC Communication from the Commission — Detailed guidance on the collection, verification 
and presentation of adverse event/reaction reports arising from clinical trials on medicinal 
products for human use (‘CT-3’) (2011/C 172/01) 2011. Available at 
http://ec.europa.eu/health//sites/health/files/files/eudralex/vol-
10/2011_c172_01/2011_c172_01_en.pdf. 
Fledelius HC, Christensen AS, Fledelius C. Juvenile eye growth, when completed? An 
evaluation based on IOL-Master axial length data, cross-sectional and longitudinal. Acta 
Ophthalmol. 2014 May;92(3):259-64. doi: 10.1111/aos.12107.  
General Data Protection Regulation (EU) 2016/679 of the European Parliament and of the 
Council of 27 April 2016 on the protection of natural persons with regard to the processing of 
personal data and on the free movement of such data. Available at: https://eur-
lex.europa.eu/eli/reg/2016/679/oj. 
Glassman AR, Stockdale CR, Beck RW, Baker C, Bressler NM. Evaluation of study participant 
masking of intravitreal injections in a randomized clinical trial. Arch Ophthalmol. 2012 Feb; 
130(2):190–94. 
Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. Lancet 2006; 368(9549):1795-809.  

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

 
 
 
 
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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 TestsI 
 
Chemistry 
Hematology 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Blood urea nitrogen (BUN)  
Creatinine 
Glucose 
Calcium 
Phosphorus 
Albumin 
Total protein 
Alkaline phosphatase (ALP) 
Aspartate aminotransferase (AST)  
Alanine aminotransferase (ALT) 
Gamma-glutamyl transferase (ɣGT) 
Total and direct bilirubin 
Lactic dehydrogenase (LDH) 
Creatinine clearance (eGFR by 
CKD-EPI)* 
C-reactive protein (CRP) 
Hematocrit 
Hemoglobin 
Red blood cells 
White blood cells (WBCs) 
Neutrophils  
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Platelets 
 
Other Tests 
Coagulation 
Pregnancy testing 
INR 
Prothrombin time 
* Estimated eGFR is to be calculated using the CKD-EPI Creatinine Equation 2009 calculation 
 
 
 

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