Clinical trial NCT03913130
Conditions: Leber Congenital Amaurosis 10 Blindness Leber Congenital Amaurosis Vision Disorders Sensation Disorders Neurologic Manifestations Eye Diseases Eye Diseases, Hereditary Eye Disorders Congenital Retinal Disease
Keywords: LCA10 CEP290 p.Cys998X c.2991+1655A>G Leber's Congenital Amaurosis Antisense oligonucleotide RNA therapy
Sponsor: Laboratoires Thea
Start date: 2019-05-13; Completion date: 2022-10-03
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Subjects completing participation in study PQ-110-001 (EudraCT 2017-000813-22 / NCT03140969) will be given the opportunity to enroll into the extension study for continued dosing if available data support current and/or future benefits for the subject. Study PQ-110-002 will provide long-term safety, tolerability, pharmacokinetic (PK), and efficacy data of QR-110.

Detailed description:
Subjects completing participation in study PQ-110-001 (EudraCT 2017-000813-22 / NCT03140969) will be given the opportunity to enroll into the extension study for continued dosing if available data support current and/or future benefits for the subject.

Subjects will be given the opportunity to enroll into this extension study for continued dosing if available data support current and/or future benefits for the subject. The Investigator, in consultation and agreement with the Medical Monitor, will decide on enrollment of each individual subject, as well as on dosing of the first treated eye and treatment initiation of the contralateral eye. Continued subject treatment in this study is desirable, but cannot be guaranteed, since it will depend on the risks and benefit of further treatment on a case-by-case basis, as discussed and agreed upon with the Medical Monitor.

The contralateral eye and the first treated eye will be injected 3 months apart. The injection interval of 3 months between both eyes will limit burden for the subjects, with a 3 month-visit frequency during the course of the study. This between-eye interval could be adapted if safety data are supportive, and for logistic reasons, and in agreement with the Medical Monitor.

The same safety monitoring protocol and efficacy assessments will apply to both eyes.

QR-110 will be administered via intravitreal (IVT) injection.

Arms: arm 1: First treated eye: maintenance dose every 6 months, intravitreal administration Contralateral eye: loading dose followed by maintenance dose, every 6 months, intravitreal administration
Interventions: intervention 1: QR-110
Intervention descriptions: intervention 1: First treated eye: maintenance dose every 6 months, intravitreal administration Contralateral eye: loading dose followed by maintenance dose, every 6 months, intravitreal administration

Protocol documents:
Prot_000.pdf: 
 
 
 
CLINICAL STUDY PROTOCOL 
 
An Open-Label Extension Study to Evaluate the Safety, Tolerability,  
Efficacy, and Pharmacokinetics of QR-110 in Subjects with 
Leber Congenital Amaurosis (LCA) due to the  
c.2991+1655A>G Mutation (p.Cys998x) in the CEP290 Gene 
 
Protocol No. PQ-110-002 
Protocol/Amendment Date: 17-Mar-2022 
Protocol/Amendment No.: 03 
Protocol Version: 4.0 
Supersedes: Protocol version 3.0 
EudraCT/IND Number 2018-003500-40/130557 
Sponsor: ProQR Therapeutics  
Zernikedreef 9 
2333 CK Leiden 
The Netherlands 
 
 
 


Investigational Product:  QR-110 
Protocol No. PQ-110-002 (Version 4.0) 
 
ProQR Therapeutics   
 
Page 2 of 66
 
 
17-Mar-2022 
INVESTIGATOR SIGNATURE PAGE 
 
PRINCIPAL INVESTIGATOR COMMITMENT: 
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. 
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. 
 
 
Signature of Principal Investigator 
 
Printed Name of Principal Investigator 
 
Date 
 


Investigational Product:  QR-110 
Protocol No. PQ-110-002 (Version 4.0) 
 
ProQR Therapeutics   
 
Page 3 of 66
 
 
17-Mar-2022 
PROTOCOL APPROVAL PAGE 
 
STUDY TITLE: An Open-Label Extension Study to Evaluate the Safety, Tolerability, 
Efficacy, and Pharmacokinetics of QR-110 in Subjects with Leber 
Congenital Amaurosis (LCA) due to the c.2991+1655A>G Mutation 
(p.Cys998x) in the CEP290 Gene 
 
I have read this protocol and agree that it contains all necessary information required to conduct 
the study. 
 
 
 
 
 
Date 
 


Investigational Product:  QR-110 
Protocol No. PQ-110-002 (Version 4.0) 
 
ProQR Therapeutics   
 
Page 4 of 66
 
 
17-Mar-2022 
1.0 
SYNOPSIS 
Name of the Sponsor: 
ProQR Therapeutics 
Name of Investigational 
Product: 
QR-110 Solution for Intravitreal Injection 
Name of Active Ingredient: QR-110 
Title of Study:  
An Open-Label, Extension Study to Evaluate the Safety, Tolerability, Efficacy 
and Pharmacokinetics of QR-110 in Subjects with Leber Congenital Amaurosis 
(LCA) due to the c.2991+1655A>G Mutation (p.Cys998X) in the CEP290 Gene 
Protocol number: 
PQ-110-002 
Study Centers:  
3 centers 
Phase of Development: 
Phase 1b/2 
Study Period:  
Until provision of continued treatment by other means is available.  
 
Duration of Subject 
Participation: 
 
Rationale:  
Leber congenital amaurosis (LCA) is a severe inherited retinal degenerative 
disease resulting in blindness, often in early childhood. In subjects with LCA due 
to the p.Cys998X mutation in Centrosomal Protein of 290 kDa (CEP290), visual 
symptoms are usually detectable before 1 year of age and further deterioration 
over time has also been reported (den Hollander 2008; Yzer 2012). 
Patients show severe vision disturbances from an early age and slow progressive 
loss of remaining vision (Cideciyan 2007; Cideciyan 2011, Jacobson, 2017). 
There are currently no approved therapies for the treatment of LCA due to the 
p.Cys998X mutation in CEP290 (subsequently referred to as the CEP290 
p.Cys998X mutation) and a large unmet medical need exists. 
The CEP290 p.Cys998X mutation results in aberrant splicing of CEP290 with 
mutant messenger ribonucleic acid (mRNA) and truncated protein production in 
affected individuals. Study drug QR-110 is a single-stranded, chemically 
modified, ribonucleic acid (RNA) oligonucleotide that is designed to correct 
aberrant splicing in CEP290 gene, enabling production of fully functional RNA 
and protein.  
 Subjects completing 
participation in study PQ-110-001 will be given the opportunity to enroll into the 
extension study for continued dosing if available data support current and/or 
future benefits for the subject. 
Study PQ-110-002 will provide long-term safety, tolerability, pharmacokinetic 
(PK), and efficacy data of QR-110. 


Investigational Product:  QR-110 
Protocol No. PQ-110-002 (Version 4.0) 
 
ProQR Therapeutics   
 
Page 5 of 66
 
 
17-Mar-2022 
Objectives 
Primary  
• 
To evaluate long-term safety and tolerability 
of QR-110 administered via intravitreal 
(IVT) injection 
Endpoints 
Primary endpoints 
• 
Frequency and severity of ocular adverse events (AEs) 
• 
Frequency and severity of non-ocular AEs 
Secondary  
• 
To evaluate long-term and sustained 
efficacy of QR-110 administered by IVT 
injection, as assessed by functional and 
structural outcome measures   
• 
To evaluate changes in Patient Reported 
Outcome (PROs) measures in subjects 
treated with QR-110 
• 
To evaluate long-term serum 
pharmacokinetics (PK) of QR-110 
administered by IVT injection   
 
Secondary endpoints 
• 
Change in Best Corrected Visual Acuity (BCVA) 
• 
Change in Mobility course score (unilateral and binocular) 
• 
Change in photoreceptor outer segment layer thickness by 
Optical Coherence Tomography (OCT) (if applicable) 
• 
Change in Oculomotor Instability (OCI) 
• 
Change in Full-Field Stimulus Testing (FST) (blue and red 
stimuli; white at Investigator discretion) (thresholds) 
• 
Change in PROs, as measured by: 
o 
Visual Function Questionnaire-25 (VFQ-25) score 
(adult subjects), or 
o 
Cardiff Visual Ability Questionnaire for Children 
(CVAQC) score (pediatric subjects)  
• 
Change in Pupillary Light Reflex (PLR) (latency and 
amplitude) 
• 
Change in Near Infrared AutoFluorescence (NIRAF) 
• 
Pharmacokinetics: Characterize the PK profile of QR-110 
in serum 
Exploratory 
 
 
Exploratory endpoints (at Investigator discretion) 
 
 
 
 
 
   
 
   
  
Study Design: 
PQ-110-002 study is an open-label, extension study to evaluate the safety, 
tolerability, efficacy, and pharmacokinetics of QR-110 in subjects with LCA due 
to p.Cys998X in the CEP290 gene. 
Subjects will be given the opportunity to enroll into this extension study for 
continued dosing if available data support current and/or future benefits for the 
subject. The Investigator, in consultation and agreement with the Medical 
Monitor, will decide on enrollment of each individual subject, as well as on 
dosing of the first treated eye and treatment initiation of the contralateral eye. 
Continued subject treatment in this study is desirable, but cannot be guaranteed, 
since it will depend on the risks and benefit of further treatment on a case-by-case 
basis, as discussed and agreed upon with the Medical Monitor. 
Dose modifications or modifications of the dosing interval will be considered on 
the basis of emerging safety and/or efficacy data and if it is anticipated to be in the 
best interest of the subject. 


Investigational Product:  QR-110 
Protocol No. PQ-110-002 (Version 4.0) 
 
ProQR Therapeutics   
 
Page 6 of 66
 
 
17-Mar-2022 
The contralateral eye and the first treated eye will be injected 3 months apart. The 
injection interval of 3 months between both eyes will limit burden for the subjects, 
with a 3 month-visit frequency during the course of the study. This between-eye 
interval could be adapted if safety data are supportive, and for logistic reasons, 
and in agreement with the Medical Monitor.  
The same safety monitoring protocol and efficacy assessments will apply to both 
eyes.  
QR-110 will be administered via IVT injection in accordance with the procedures 
outlined by the American Academy of Ophthalmology (Avery 2014). 
Baseline functional and structural measurements for the first treated eye will be 
those from study PQ-110-001. Baseline functional and structural measurements 
for the contralateral eye will be those from the Screening /Day 1 visit of the 
current study. 
Study Plan: 
The Screening/Day 1 visit for this study should be the last visit (EOS visit) of 
study PQ-110-001, ie, all Screening/Day 1 assessments should take place during 
the EOS visit of study PQ-110-001. If these visits do not occur at the same time, a 
separate Screening/Day 1 visit should be performed as part of PQ-110-002. 
During the Screening/Day 1 visit, subjects will be assessed according to the 
eligibility criteria.  
Measures of visual function (including BCVA, FST, OCI, and mobility course), 
and retinal anatomy (OCT) will be assessed a minimum of 1 time prior to the 
subject receiving study drug. Any pre-dose assessment may be repeated if the 
results are considered unreliable or of unacceptable quality by the Investigator or 
if the assessment could not be completed. Additional assessments may be 
performed at Investigator discretion. 
Assessments can be completed over multiple days. 
The Investigator, in consultation with the Medical Monitor, will decide on 
subject’s enrollment upon assessment of subject’s benefit/risk.  
 
 
 
 
 
 
 
 
  
 
Any AE considered to be related to the study drug should be considered. 
Subjects who do not meet stopping criteria prior to their next scheduled injection 
will receive their planned dose. Subjects who meet stopping criteria will be 
discontinued from dosing and will be followed for safety and efficacy. The 
Sponsor, in consultation with the Investigator, may decide to modify the dose, the 
dosing interval, for repeat injections in one eye or both eyes, hold the dose (delay 
or skip), or discontinue study drug for an individual subject, based on emerging 
safety and efficacy data and if it is anticipated to be in the best interest of the 
subject. Subjects who discontinue study drug will continue to be followed for 
safety and efficacy for at least 3 months. The Investigator and/or the Sponsor may 
decide to stop treatment for an individual subject due to an AE. Stopping criteria 
are described in Section 4.2.2. 


Investigational Product:  QR-110 
Protocol No. PQ-110-002 (Version 4.0) 
 
ProQR Therapeutics   
 
Page 7 of 66
 
 
17-Mar-2022 
Subjects will be monitored in clinic for increases in intraocular pressure (IOP) and 
signs of intra-ocular inflammation and endophthalmitis during the post-injection 
period, ie, the day of the injection and on the day after injection (1 day post dose). 
The Day 7 post-dose visit will be a phone call from the site to the subject.  
All assessments will be performed on both eyes, even if the contralateral eye is 
not treated. The frequency of assessments is presented in the Schedule of Events 
 
More frequent evaluation may be undertaken for an individual subject to monitor 
safety and efficacy at the discretion of the Investigator. Data for all unscheduled 
visits should be recorded in the electronic case report form (eCRF). The Sponsor 
will perform safety and efficacy reviews on an ongoing basis. 
Number of Subjects 
(planned): 
Maximum of 11 subjects who have completed Study PQ-110-001. 
Diagnosis and Main 
Criteria for Eligibility: 
Inclusion Criteria: 
1. Subjects who completed participation in the study PQ-110-001 and who 
may derive benefit from continued treatment with QR-110, as assessed 
by the Investigator, in consultation with the Medical Monitor 
(Section 4.2). 
2. Persistence of detectable outer nuclear layer (ONL) in the area of the 
macula in the opinion of the Investigator, as determined by OCT. 
3. Clear ocular media and adequate pupillary dilation to permit good quality 
retinal imaging, as assessed by the Investigator. 
4. An adult (≥ 18 years) willing and able to provide informed consent for 
participation  
OR 
a minor (6 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. 
5. 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, in the opinion of the Investigator 
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, in the 
opinion of the Investigator. 
6. Female subjects who have reached menarche and male subjects must 
either practice true abstinence in accordance with their preferred and 
usual lifestyle, or agree to use acceptable, highly effective methods of 
contraception for up to 6 months following their last dose QR-110. 
Acceptable methods of contraception are defined in the protocol. Women 
of non-childbearing potential may be included without the use of 
adequate birth control, provided they meet the criteria in the protocol 
(Section 6.2.3). 
7. Adequate verbal communication as to allow assessment via mobility 
course, in the opinion of the Investigator. 


Investigational Product:  QR-110 
Protocol No. PQ-110-002 (Version 4.0) 
 
ProQR Therapeutics   
 
Page 8 of 66
 
 
17-Mar-2022 
Exclusion Criteria: 
8. Any contraindication to IVT injection according to the Investigator’s 
clinical judgment and international guidelines (Avery 2014). 
9. Safety issue during study PQ-110-001 that may compromise subject 
safety when continued dosing, as determined by the Investigator, and in 
consultation with the Medical Monitor. 
• 
Subjects with existing safety events from study PQ-110-001 
may be included as determined by the Investigator and in 
consultation with the Medical Monitor. 
10. Any ocular or systemic disease or condition (including medications and 
laboratory test abnormalities) that could compromise subject safety or 
interfere with assessment of efficacy and safety, as determined by the 
Investigator and in consultation with the Medical Monitor. 
11. Pregnant or breast-feeding female. 
Study Drug, Dosage, and 
Mode of Administration: 
QR-110 Solution for IVT Injection, 
 
• 
First treated eye: maintenance dose of 80 µg every 6 months  
• 
Contralateral eye: 160 µg loading dose followed by 80 µg maintenance 
dose, every 6 months 
Both eyes will be injected 3 months apart. 
Duration of Treatment: 
 
  
Reference Therapy,  
Dosage, and Mode of 
Administration: 
Not applicable. 
Pharmacokinetics: 
Blood samples will be collected at predefined time points for the presence of 
QR-110
 
Statistical Methods: 
Analyses will generally be descriptive in nature and will focus on data collected 
during this study. Baseline functional and structural measurements for the first 
treated eye will be those from study PQ-110-001. Baseline functional and 
structural measurements for the contralateral eye will be collected during the 
Screening visit and will serve as a control. The incidence of AEs and changes in 
clinical laboratory assessments will be summarized for subjects by dose group, 
age category (pediatrics and adults), and for the study population. Ocular AEs will 
be summarized for all subjects using descriptive statistics for each eye. Efficacy 
endpoints will be summarized for all subjects using descriptive statistics for each 
eye. For all the relevant analyses, the data may be summarized for subjects by 
dose group, age category, genetic status, and severity of the disease (BCVA and 
other visual function and/or functional vision parameters). Summary statistics for 
other safety, efficacy, and PK endpoints will be presented. Further details will be 
provided in the Statistical Analysis Plan (SAP). 
 
 


Investigational Product:  QR-110 
Protocol No. PQ-110-002 (Version 4.0) 
 
ProQR Therapeutics   
 
Page 9 of 66
 
 
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TABLE OF CONTENTS 
 
 
CLINICAL STUDY PROTOCOL ...............................................................................................1 
INVESTIGATOR SIGNATURE PAGE......................................................................................2 
PROTOCOL APPROVAL PAGE ...............................................................................................3 
1.0 
SYNOPSIS ..........................................................................................................................4 
TABLE OF CONTENTS ..............................................................................................................9 
LIST OF FIGURES .....................................................................................................................12 
LIST OF APPENDICES .............................................................................................................12 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................13 
2.0 
INTRODUCTION............................................................................................................16 
2.1 
Leber Congenital Amaurosis .................................................................................16 
2.2 
QR-110 for the Treatment of Leber Congenital Amaurosis due to CEP290 
p.Cys998X Mutation ..............................................................................................17 
2.2.1 
Nonclinical Experience .........................................................................18 
2.2.2 
Clinical Experience ...............................................................................19 
2.3 
Study Rationale ......................................................................................................19 
2.3.1 
Dose Selection .......................................................................................19 
2.4 
Study Population ....................................................................................................20 
2.4.1 
Pediatric Considerations ........................................................................20 
3.0 
STUDY OBJECTIVES ....................................................................................................21 
3.1 
Primary Objective ..................................................................................................21 
3.2 
Secondary Objectives.............................................................................................21 
3.3 
Exploratory Objectives ..........................................................................................21 
4.0 
STUDY OVERVIEW ......................................................................................................22 
4.1 
Criteria for Evaluation ...........................................................................................22 
4.1.1 
Primary Endpoint ..................................................................................22 
4.1.2 
Secondary Endpoints .............................................................................22 
4.1.3 
Exploratory Endpoints (at Investigator Discretion) ..............................22 
4.2 
Study Design ..........................................................................................................23 
4.2.1 
Study Plan .............................................................................................23 
4.2.2 
Stopping Criteria ...................................................................................25 
4.2.3 
Subject Withdrawal ...............................................................................26 
4.2.4 
Discontinuation of the Study .................................................................26 
5.0 
SELECTION OF STUDY POPULATION ....................................................................27 


Investigational Product:  QR-110 
Protocol No. PQ-110-002 (Version 4.0) 
 
ProQR Therapeutics   
 
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5.1 
Study Population ....................................................................................................27 
5.2 
Selection of Subjects ..............................................................................................27 
5.3 
Eligibility Criteria ..................................................................................................27 
5.3.1 
Inclusion Criteria ...................................................................................27 
5.3.2 
Exclusion Criteria..................................................................................28 
6.0 
STUDY DRUG AND CONCOMITANT THERAPIES................................................29 
6.1 
Study Drug .............................................................................................................29 
6.1.1 
Study Drug Description and Supply ......................................................29 
6.1.2 
Placebo ..................................................................................................29 
6.1.3 
Study Drug Shipment and Storage ........................................................29 
6.1.4 
Study Drug Accountability and Reconciliation .....................................29 
6.1.5 
Dosage and Administration ...................................................................30 
6.2 
Concomitant Medications and Ancillary Therapy .................................................30 
6.2.1 
Permitted Concomitant Medications .....................................................30 
6.2.2 
Prohibited Concomitant Medications ....................................................30 
6.2.3 
Adequate Forms of Birth Control ..........................................................30 
7.0 
STUDY VISITS ................................................................................................................32 
7.1 
Visit and Assessment Windows .............................................................................32 
7.2 
Dosing and Follow-up Visits .................................................................................32 
7.3 
End of Study Visit ..................................................................................................33 
8.0 
STUDY ASSESSMENT PROCEDURES ......................................................................34 
8.1 
Adverse Events ......................................................................................................34 
8.2 
Vital Signs ..............................................................................................................34 
8.3 
Laboratory Evaluations ..........................................................................................34 
8.4 
Immunogenicity .....................................................................................................35 
 
 
8.7 
Pharmacokinetic Evaluations .................................................................................35 
8.8 
Electrocardiogram ..................................................................................................35 
8.9 
Physical Examination.............................................................................................36 
8.10 
Ophthalmic Exams .................................................................................................36 
8.11 
Optical Coherence Tomography ............................................................................36 
8.12 
Efficacy Assessments .............................................................................................36 
9.0 
ASSESSMENT OF SAFETY OR ADVERSE EVENTS AND SERIOUS 
ADVERSE EVENTS .......................................................................................................38 
9.1 
Review of Safety Data ...........................................................................................38 


Investigational Product:  QR-110 
Protocol No. PQ-110-002 (Version 4.0) 
 
ProQR Therapeutics   
 
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9.2 
Definitions of Adverse Event, Serious Adverse Event, and Suspected 
Unexpected Serious Adverse Event .......................................................................38 
9.2.1 
Adverse Events ......................................................................................38 
9.2.2 
Serious Adverse Events .........................................................................39 
9.2.3 
Suspected Unexpected Serious Adverse Reaction Definition ...............39 
9.2.4 
Adverse Events of Special Interest ........................................................40 
9.3 
Assessment of Adverse Events ..............................................................................41 
9.3.1 
Assessment of Severity (Intensity) of Adverse Events .........................41 
9.3.2 
Assessment of the Relationship of Adverse Events to Study Drug .......41 
9.3.3 
Assessment of the Outcome of Adverse Events ....................................42 
9.4 
Reporting of Adverse Events .................................................................................42 
9.4.1 
Adverse Event Reporting Period ...........................................................42 
9.4.2 
Eliciting Adverse Events .......................................................................43 
9.4.3 
Recording Adverse and Serious Adverse Events ..................................43 
9.5 
Serious Adverse Events Notification .....................................................................45 
9.6 
Expedited Reporting of Suspected Unexpected Serious Adverse Reactions .........46 
10.0 
STATISTICAL METHODOLOGY ...............................................................................47 
10.1 
General Considerations ..........................................................................................47 
10.2 
Determination of Sample Size ...............................................................................47 
10.2.1 
Randomization and Blinding .................................................................47 
10.2.2 
Replacement of Subjects .......................................................................47 
10.3 
Analysis of Populations .........................................................................................48 
10.4 
Subject Disposition, Demographics and Baseline Disease Characteristics ............48 
10.5 
Treatment Compliance ...........................................................................................48 
10.6 
Safety Analyses ......................................................................................................48 
10.6.1 
Treatment Emergent Adverse Events ....................................................48 
10.6.2 
Vital Signs .............................................................................................49 
10.6.3 
Laboratory Assessments........................................................................49 
10.6.4 
Other Safety Assessments .....................................................................49 
10.7 
Pharmacokinetics Analyses ....................................................................................49 
10.8 
Efficacy Analyses ..................................................................................................50 
10.9 
Exploratory Analyses .............................................................................................51 
10.10 Interim Analysis .....................................................................................................51 
10.11 Subgroup Analyses.................................................................................................51 
11.0 
QUALITY CONTROL AND QUALITY ASSURANCE .............................................52 
11.1 
Data Collection and Study Monitoring ..................................................................52 


Investigational Product:  QR-110 
Protocol No. PQ-110-002 (Version 4.0) 
 
ProQR Therapeutics   
 
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11.2 
Audits and Inspections ...........................................................................................53 
12.0 
ETHICAL AND REGULATORY OBLIGATIONS .....................................................54 
12.1 
Ethical Considerations ...........................................................................................54 
12.2 
Informed Consent ...................................................................................................54 
12.3 
Ethics and Regulatory Review ...............................................................................54 
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 .................................................................................................56 
13.4 
Study Documentation and Storage .........................................................................56 
13.5 
Use of Information .................................................................................................57 
13.6 
End of Study and Final Report ...............................................................................57 
13.7 
Financing and Insurance ........................................................................................58 
13.8 
Publication Policy ..................................................................................................58 
14.0 
REFERENCES .................................................................................................................59 
15.0 
APPENDICES ..................................................................................................................62 
 
APPENDIX 2: 
CLINICAL LABORATORY ANALYTES ......................................66 
 
 
 
 
LIST OF FIGURES 
 
 
 
LIST OF APPENDICES 
 
Appendix 2: Clinical Laboratory Analytes ..................................................................................66 


Investigational Product:  QR-110 
Protocol No. PQ-110-002 (Version 4.0) 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation  Definition 
λz 
 
elimination rate constant 
 
ɣGT 
 
gamma-glutamyl transferase 
AE 
 
adverse event 
ALP 
 
alkaline phosphatase 
ALT 
 
alanine aminotransferase 
AON 
 
antisense oligonucleotide  
AREDS 
 
age-related eye diseases study 
ARLNS 
 
age-related eye diseases study clinical lens grading system 
AST 
 
aspartate aminotransferase 
AUC0-∞ 
 
area under the curve 0 hour to infinity 
AUC0-tlast 
 
area under the curve 0 hour to time of the last measurable concentration  
BCVA 
 
Best Corrected Visual Acuity 
BRVT 
 
Berkeley Rudimentary Vision Test 
BUN 
 
blood urea nitrogen 
CBC 
 
complete blood count  
CEP290 
 
Centrosomal Protein of 290 kDa 
CF 
 
counting fingers 
CFR 
 
Code of Federal Regulations 
CKD-EPI 
 
Chronic Kidney Disease Epidemiology Collaboration  
CL 
 
clearance 
Clast 
 
last observed concentration 
Cmax 
 
maximum concentration 
C0 
 
trough value 
CSR 
 
clinical study report 
CVAQC 
 
Cardiff Visual Ability Questionnaire for Children 
EC 
 
Ethics Committee 
ECG 
 
electrocardiogram 
eCRF 
 
electronic case report form 
eGFR 
 
estimated glomerular filtration rate 
EOS 
 
end of study 
 


Investigational Product:  QR-110 
Protocol No. PQ-110-002 (Version 4.0) 
 
ProQR Therapeutics   
 
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Abbreviation  Definition 
ESE 
 
exonic splicing enhancer 
ETDRS 
 
Early Treatment Diabetic Retinopathy Study 
FDA 
 
Food and Drug Administration 
FST 
 
Full-field Stimulus Testing (also, Full-field Stimulus Threshold Testing or Full-
field Scotopic Threshold Testing) 
GCP 
 
Good Clinical Practice 
GLP 
 
Good Laboratory Practice 
HM 
 
hand motion 
IB 
 
Investigator’s Brochure 
ICF 
ICH 
 
Informed Consent Form 
International Council on Harmonization 
INR 
 
international normalized ratio 
IOP 
 
intraocular pressure 
iPSC 
 
induced pluripotent stem cells 
IRB 
 
Institutional Review Board 
 
IVT 
 
intravitreal 
LCA 
 
Leber congenital amaurosis 
LDH 
 
lactic dehydrogenase 
LLOQ 
 
lower limit of quantification 
LogMAR 
 
Logarithm of the Minimum Angle of Resolution  
LP 
 
light perception 
MedDRA 
 
Medical Dictionary for Regulatory Activities  
mRNA 
 
messenger ribonucleic acid 
NEHD 
 
normalized equivalent human dose  
NIDDK 
 
National Institute of Diabetes and Digestive Kidney Disease 
NIH 
 
National Institute of Health 
NIRAF 
 
near infrared autofluorescence 
OCI 
 
oculomotor instability 
OCT 
 
optical coherence tomography 
ONL 
 
outer nuclear layer 
PBS 
 
Phosphate-buffered saline 


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Abbreviation  Definition 
p.Cys998X 
 
C.2991+1655A>G mutation in the CEP290 gene 
PD 
 
pharmacodynamic 
PK 
 
pharmacokinetic 
PLR 
 
pupillary light reflex 
PRO 
 
patient reported outcome 
ProQR 
 
ProQR Therapeutics 
PT 
 
preferred term 
RNA 
 
ribonucleic acid 
SAE 
 
serious adverse event 
SEM 
 
standard error of mean 
SAP 
 
statistical analysis plan 
SOC 
 
system organ class 
SOE 
 
schedule of events 
SOP 
 
standard operating procedure 
SUN 
 
Standardization of Uveitis Nomenclature 
SUSAR 
 
suspected unexpected serious adverse reaction 
TEAE 
 
treatment-emergent adverse event 
TLF 
 
table, listing, and figure 
T1/2 
 
terminal half-life 
Tmax 
 
time of maximum concentration 
ULN 
 
upper limit of normal 
US 
 
United States 
Vd 
 
volume of distribution 
 
VF 
 
visual field 
VFQ-25 
 
Visual Function Questionnaire-25  
WOCBP 
 
women of childbearing potential 
 


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2.0 
INTRODUCTION 
ProQR Therapeutics (ProQR) is developing an antisense oligonucleotide (AON) product, 
QR-110, for the treatment of patients with Leber congenital amaurosis (LCA) due to the 
c.2991  +1655A>G mutation (p.Cys998X or IVS26+1655A>G) in the Centrosomal Protein of 
290kDa (CEP290) gene. Leber congenital amaurosis is a severe inherited retinal degenerative 
disease resulting in blindness, often in early childhood. In patients with LCA due to the 
p.Cys998X mutation in the CEP290 gene (subsequently referred to as CEP290 p.Cys998X 
mutation), visual symptoms are usually detectable before 1 year of age and further deterioration 
over time has also been reported (den Hollander 2008, Yzer 2012). Patients show severe vision 
disturbances from an early age and slow progressive loss of remaining vision (Cideciyan 2007, 
Cideciyan 2011, McAnany 2013, Jacobson 2017). There are currently no approved therapies for 
the treatment of LCA due to the CEP290 p.Cys998X mutation and a large unmet medical need 
exists. The primary goal of the development plan for QR-110 is to provide a treatment to 
overcome the genetic defect in patients with at least one CEP290 allele containing the CEP290 
p.Cys998X mutation, resulting in functional vision restoration or preservation. The intended 
route of administration is intravitreal (IVT) injection. 
2.1 
Leber Congenital Amaurosis 
Leber congenital amaurosis is a non-syndromic retinopathy that affects both cone and rod 
photoreceptor cells of the retina. It is a rare autosomal recessive disorder, reported to be the most 
severe and one of the earliest onset forms of vision loss in children, with detection of disease 
symptoms as early as the first year of life. The symptoms and signs include severe and early 
vision loss, sensory nystagmus (involuntary eye movements), abnormalities of pupil reactions, 
oculo-digital sign, and nondetectable photoreceptor electrical signals on electroretinogram 
(ERG). There are approximately 20 genes identified to date in which mutations are causative for 
LCA (den Hollander 2008, Estrada-Cuzcano 2011, Kmoch 2015), and the LCA classification is 
based on the disease causing gene. The most frequently mutated LCA gene is CEP290, with 
mutations accounting for about 15% to 30% of LCA cases (Coppieters 2010, den Hollander 
2008, den Hollander 2006, Perrault 2007, Stone 2007). 
The CEP290 gene is located on the long (Q) arm of chromosome 12 and codes for CEP290 
protein, which has an important role in centrosome and cilia development. The most frequently 
occurring CEP290 mutation associated with retinal dystrophy in Caucasians, especially in 
European countries and the United States (US), is a change in intron 26 of the CEP290 gene 
(p.Cys998X) (Stone 2007, den Hollander 2006, Perrault 2007, Littink 2010). This mutation 
creates a cryptic splice donor site in intron 26, which results in the inclusion of an aberrant exon 
(exon-X) of 128 bases in the mutant CEP290 messenger ribonucleic acid (mRNA). This cryptic 
exon introduces a premature stop codon, predicted to render CEP290 a truncated protein. The 
mutation has been found in homozygosity or compound heterozygosity in patients with CEP290 
LCA (Cideciyan 2007, den Hollander 2006, Perrault 2007). Both the homozygous and 
heterozygous genotypes result in a similar clinical presentation. The CEP290 p.Cys998X 


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mutation appears to be hypomorphic in nature, with wild-type transcripts present in peripheral 
tissues, explaining the non-syndromic nature of the CEP290 p.Cys998X mutation (Parfitt 2016). 
2.2 
QR-110 for the Treatment of Leber Congenital Amaurosis due to CEP290 
p.Cys998X Mutation 
The primary goal of the development plan for study drug QR-110 is to provide a treatment to 
overcome the genetic defect in patients with at least 1 CEP290 allele containing the p.Cys998X 
mutation. 


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2.2.1 
Nonclinical Experience 


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These studies are summarized in the QR-110 Investigator’s Brochure (IB), Nonclinical Studies. 
2.2.2 
Clinical Experience 
The clinical development program started in the second half of 2017 with the first-in-human 
(FIH) clinical study (PQ-110-001), a Phase 1b/2, open-label, multiple-dose, dose-escalation to 
evaluate the safety and tolerability of QR-110. Following individual reports of efficacy an 
interim analysis was performed in August 2018. Available safety and efficacy data from Study 
PQ-110-001 support the therapeutic potential observed in the nonclinical studies. Reference is 
made to the IB for further details. 
2.3 
Study Rationale 
This extension study allows subjects completing study PQ-110-001, who derive benefit from 
QR-110 treatment, to continue to receive treatment and to observe the long-term safety, 
tolerability, PK, and efficacy of treatment with QR-110. Additionally, this extension study 
allows for the treatment of the previously untreated contralateral eye. 
2.3.1 
Dose Selection  
Each subject will receive a maintenance dose of 80 µg at 6-monthly intervals in the first treated 
eye. Treatment of the contralateral eye will begin with a loading dose of 160 µg and is followed 
by a maintenance dose of 80 µg at 6-monthly intervals. The contralateral eye and the first treated 
eye will be injected 3 months apart. Dose modifications or modifications of the dosing interval 
will be considered on the basis of emerging safety and/or efficacy data and if it is anticipated to 
be in the best interest of the subject. 
Details on the dose selection are provided in the QR-110 IB. 


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Minimizing the number of injections is important for safety reasons and to decrease subject 
burden. Based on observed durability of responses between injections in Study PQ-110-001, 
longer dosing intervals of up to 6 months will be explored in this study. 
2.4 
Study Population 
Subjects who completed study PQ-110-001, met eligibility requirements, and for whom the 
assessment of benefit/risk is positive may participate in the study. 
2.4.1 
Pediatric Considerations 
In accordance with best practices, the parent or legal representative of a participating pediatric 
subject must be informed as to procedures that are part of usual care and those specific to 
participation in this clinical study. Age-appropriate explanations of procedures should be given 
to all pediatric subjects. Investigators, staff, and facilities should be experienced in the care of 
pediatric subjects, in order to minimize pain, distress and fear. Separation of the pediatric subject 
from their parent or legal representative should be minimized and when necessary, the pediatric 
subject should be accompanied by a study staff member. Pain should be minimized (eg, use of 
indwelling catheters for blood draws or use of topical anesthetic agents), in accordance with 
local institutional practices (Directive 2001/20/EC, Regulation 536/2014). 


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3.0 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of the study is to evaluate long-term safety and tolerability of QR-110 
administered via IVT injection. 
3.2 
Secondary Objectives 
The secondary objectives of the study are to: 
• Evaluate long-term and sustained efficacy of QR-110 administered by IVT injection, as 
assessed by functional and structural outcome measures 
• Evaluate changes in Patient Reported Outcome (PROs) measures in subjects treated with 
QR-110 
• Evaluate long-term serum PK of QR-110 administered by IVT injection 
 
3.3 
Exploratory Objectives 
 


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4.0 
STUDY OVERVIEW 
4.1 
Criteria for Evaluation 
4.1.1 
Primary Endpoint 
• Frequency and severity of ocular adverse events (AEs) 
• Frequency and severity of non-ocular AEs 
 
4.1.2 
Secondary Endpoints 
• Change in BCVA 
• Change in Mobility course score (unilateral and binocular) 
• Change in photoreceptor outer segment layer thickness by optical coherence tomography 
(OCT) (if applicable) 
• Change in OCI 
• Change in Full-FST (blue and red stimuli; white at Investigator discretion) (thresholds) 
• Change  in PROs, as measured by:  
o Visual Function Questionnaire-25 (VFQ-25) score (adult subjects), or  
o Cardiff Visual Ability Questionnaire for Children (CVAQC) score (pediatric 
subjects) 
• Change in Pupillary Light Reflex (PLR) (latency and amplitude) 
• Change in Near Infrared AutoFluorescence (NIRAF)  
• Pharmacokinetics: Characterize the PK profile of QR-110 in serum 
 
4.1.3 
Exploratory Endpoints (at Investigator Discretion) 


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4.2 
Study Design 
PQ-110-002 study is an open-label extension study to evaluate the safety, tolerability, efficacy, 
and pharmacokinetics of QR-110 in subjects with LCA due to c.2991+1655A>G mutation 
(p.Cys998X) in the CEP290 gene. 
Subjects will be given the opportunity to enroll into the extension phase study PQ-110-002 for 
continued dosing if available data support current and/or future benefits for the subject from 
QR-110 treatment. The decision will be based on the assessment of individual subject’s 
benefit/risk based on individual data and data from QR-110 clinical studies. The Investigator, in 
consultation with the Medical Monitor, will decide on enrollment of each individual subject, as 
well as on dosing of the first treated eye and treatment initiation of the contralateral eye. 
Continued subject treatment in this study is desirable, but cannot be guaranteed, since it will 
depend on the risks and benefit of further treatment on a case-by-case basis, as discussed and 
agreed upon with the Medical Monitor.  
Dose modifications or modifications of the dosing interval will be considered on the basis of 
emerging safety and/or efficacy data and if it is anticipated to be in the best interest of the 
subject. 
The contralateral eye and the first treated eye will be injected 3 months apart. The injection 
interval of 3 months between both eyes allows thorough safety evaluation and will decrease 
subject burden, with a 3 month-visit frequency during the course of the study. This between-eye 
interval could be adapted if safety data are supportive, and for logistic reasons, and in agreement 
with the Medical Monitor. The same safety monitoring protocol and efficacy assessments will 
apply to both eyes.  
QR-110 will be administered via IVT injection in accordance with the procedures outlined by the 
American Academy of Ophthalmology (Avery 2014). 
A program-specific review of safety, which may include independent experts, will be in place to 
assess emerging data from clinical studies on an ongoing basis.  
Baseline functional and structural measurements for the first treated eye will be those from study 
PQ-110-001. Baseline functional and structural measurements for the contralateral eye will be 
those from the Screening/Day 1 visit of the current study which is the last visit of study 
PQ-110-001 (see Section 4.2.1.1).   
4.2.1 
Study Plan 
4.2.1.1 
Screening/ Day 1 
The Screening/Day 1 visit for this study should be the last visit (EOS visit) of study PQ-110-001, 
ie, all Screening/Day 1 assessments should take place during the EOS visit of study PQ-110-001.  
If these visits do not occur at the same time, a separate Screening/Day 1 visit should be 


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performed as part of PQ-110-002 (Appendix 1). During the Screening/Day 1 visit, subjects will 
be assessed according to the eligibility criteria.  
Measures of visual function (including BCVA, FST, OCI, and mobility course), and retinal 
anatomy (OCT) will be assessed a minimum of 1 time prior to the subject receiving study drug. 
Any pre-dose assessment may be repeated if the results are considered unreliable or of 
unacceptable quality by the Investigator or if the assessment could not be completed. Additional 
assessments may be performed at Investigator discretion.  
Assessments can be completed over multiple days instead of 1 full day, at the discretion of the 
Investigator. 
The Investigator, in consultation with the Medical Monitor, will decide on subject’s enrollment 
upon assessment of subject’s benefit/risk and the subject’s meeting of eligibility criteria. 
Continued subject treatment in this study is desirable, but cannot be guaranteed, since it will 
depend on the risks and benefit of further treatment on a case-by-case basis, as discussed and 
agreed upon with the Medical Monitor. 
Adverse events considered to be related to the study drug should be taken into account in the 
benefit/risk assessment. 
See Section 7.0 for more details on the screening process. 
4.2.1.2 
Study Drug Administration 
Subjects will receive study drug via unilateral IVT injection in accordance with the procedures 
outlined by the current international guidelines (Avery 2014) in their first treated eye and in the 
contralateral (previously untreated) eye and will be assessed for safety and tolerability at 
follow-up visits.  


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Subjects who do not meet stopping criteria prior to their next scheduled injection will receive 
their planned dose. Subjects who meet stopping criteria will be discontinued from dosing and 
will be followed for safety and efficacy. The Sponsor, in consultation with the Investigator, may 
decide to modify the dose, the dosing interval, hold a specific dose (delay or skip), or discontinue 
study drug for an individual subject, based on emerging safety and efficacy data and if it is 
anticipated to be in the best interest of the subject. Subjects who discontinue study drug will 
continue to be followed for safety and efficacy for at least 3 months. The Investigator and/or the 
Sponsor may decide to stop treatment for an individual subject due to an AE. Stopping criteria 
are described in Section 4.2.2. 
Specific study drug administration procedures can be found in the Study Reference Manual. 
4.2.1.3 
Assessment and Follow-up 
Subjects will be monitored in clinic for increases in intraocular pressure (IOP) and signs of intra-
ocular inflammation and endophthalmitis during the post-injection period, ie, the day of the 
injection, and on the day after injection (1-day post-dose). The Day 7 post-dose visit will be a 
phone call from the site to the subject.  If no dosing occurs at a visit; the +1D post dose visit and 
the +7D post dose phone call may be skipped; at the discretion of the Investigator. 
All assessments will be performed on both eyes, even if the contralateral eye is not treated. The 
frequency of 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 and 
efficacy at the discretion of the Investigator. Data for all unscheduled visits should be recorded in 
the electronic case report form (eCRF). The Sponsor will perform safety and efficacy reviews on 
an ongoing basis. 
Efficacy assessments will be performed according to the SOE 
 
4.2.2 
Stopping Criteria 
The Investigator or the Medical Monitor may stop treatment for an individual subject due to an 
AE (Section 9.0). The severity of the event(s), as well as the temporal relationship to study drug 
administration, potential for worsening of the event(s) with continued QR-110 treatment and 
association with other safety signals or laboratory values should be considered in the decision to 
stop treatment. The Medical Monitor must be notified of any subject who stops treatment due to 
an AE. Adverse events considered to be related to the study drug should be taken into account in 
the benefit/risk assessment. 
The Medical Monitor, in consultation with the Investigator, may decide to modify the dose, the 
dosing interval, hold a specific dose (delay or skip), or discontinue study drug for an individual 


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subject, based on emerging safety and efficacy data and if it is anticipated to be in the best 
interest of the subject. 
Subjects who discontinue study drug will be encouraged to remain in the study for observation 
for at least 3 months post last dose.  
The Medical Monitor will perform ongoing safety reviews of systemic and ophthalmic safety 
data and AEs to identify any safety signal.
 
The Investigator and/or the Sponsor may decide to stop treatment for an individual subject due to 
an AE.  
4.2.3 
Subject Withdrawal 
Subjects are free to withdraw from the study at any time (ie, discontinue study drug and 
assessments), without prejudice to further treatment. A subject who withdraws consent will 
always be asked about the reason(s) and the presence of any AEs.  The Investigator should 
follow-up on AEs outside of the clinical study to ensure subject safety; however, no data on such 
events will be collected for study purposes. 
4.2.4 
Discontinuation of the Study 
The Medical Monitor will evaluate the safety and tolerability data as described in Section 4.2.2 
and thereafter on an ongoing basis to recommend if the study should continue or cease, or if any 
modifications should be made as to how subjects are treated or managed. 


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5.0 
SELECTION OF STUDY POPULATION 
5.1 
Study Population 
A maximum of 11 subjects who have completed Study PQ-110-001, meet all eligibility 
requirements, and for whom the assessment of benefit/risk is positive are eligible to participate in 
this extension study. 
5.2 
Selection of Subjects 
Subjects will be evaluated against all assessments of eligibility criteria as presented in the SOE 
Results of assessments for all eligibility criteria must be available and reviewed 
prior to the subject’s first dose of study drug in this extension study. 
5.3 
Eligibility Criteria 
5.3.1 
Inclusion Criteria 
The subject is eligible for the study if all the following inclusion criteria apply at Screening: 
1. Subjects who completed participation in study PQ-110-001 and who may derive benefit 
from continued treatment with QR-110, as assessed by the Investigator, in consultation 
with the Medical Monitor (Section 4.2). 
2. Persistence of detectable ONL in the area of the macula in the opinion of the Investigator, 
as determined by OCT. 
3. Clear ocular media and adequate pupillary dilation to permit good quality retinal 
imaging, as assessed by the Investigator. 
4. An adult (≥ 18 years) willing and able to provide informed consent for participation  
-OR-  
a minor (6 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. 
5. 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, in the opinion of 
the Investigator  
-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, in the opinion of the Investigator. 


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6. Female subjects who have reached menarche and male subjects must either practice true 
abstinence in accordance with their preferred and usual lifestyle, or agree to use 
acceptable, highly effective methods of contraception for up to 6 months following their 
last dose of QR-110. Acceptable methods of contraception are defined in the protocol. 
Women of non-childbearing potential may be included without the use of adequate birth 
control, provided they meet the criteria in the protocol (Section 6.2.3). 
7. Adequate verbal communication as to allow assessment via mobility course, in the 
opinion of the Investigator. 
No waivers to the inclusion criteria are permitted. 
5.3.2 
Exclusion Criteria 
The subject is ineligible for the study if any of the following criteria apply at Screening: 
1. Any contraindication to IVT injection according to the Investigator’s clinical judgment 
and international guidelines (Avery 2014) 
2. Safety issue during study PQ-110-001 that may compromise subject safety when 
continued dosing, as assessed by the Investigator, in consultation with the Medical 
Monitor. 
3. Any ocular or systemic disease or condition (including medications and laboratory test 
abnormalities) that could compromise subject safety or interfere with assessment of 
efficacy and safety, as determined by the Investigator and in consultation with the 
Medical Monitor. 
• Subjects with existing safety events from study PQ-110-001 may be included as 
determined by the Investigator and in consultation with the Medical Monitor. 
4. Pregnant or breast-feeding female. 
 
 


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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-110 study drug is a solution for IVT injection.
 
The QR-110 study drug is supplied in glass vials with rubber stoppers, aluminum seal, and white 
flip-off cap. Vials are individually packed in cartons. Vials and cartons are labelled in 
compliance with local regulatory requirements. 
All vials are sterile and for single use. 
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, and preparation. 
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. Used vials should be retained for drug 
accountability by the Sponsor representative (monitor), unless prohibited by local procedures, in 
which case an alternative drug accountability process will be agreed upon with the Sponsor. 
Additional details on study drug handling 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 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 on site. 
6.1.5 
Dosage and Administration 
Subjects will receive study drug with a 6-month dosing interval. Dose level or interval 
modifications may be considered on the basis of emerging safety and efficacy data from any 
QR-110 studies if this is anticipated to be in the best interest of the subject. 
QR 110 will be administered via IVT injection in accordance with the procedures outlined by the 
American Academy of Ophthalmology (Avery 2014). The pharmacist (or other personnel 
qualified to prepare study drug for administration) at each study center will receive study drug 
and will prepare and/or dilute the study drug according to the Pharmacy Manual for each 
administration. 
Subjects will receive study drug by IVT injection. Administration of study drug will only be 
performed by qualified ophthalmologists in an in-clinic setting. No other medications should be 
mixed with study drug. 
6.2 
Concomitant Medications and Ancillary Therapy 
6.2.1 
Permitted Concomitant Medications 
The medications usually used in ophthalmology care are permitted, including but not limited to: 
topical anesthetic agents, carbonic anhydrase inhibitors (intravenous, oral, topical), beta blocker 
ophthalmic solutions, prostaglandin analog ophthalmic solutions, ophthalmic solutions/gels of 
corticosteroids, antibiotics and antiseptics, topical agents for pupillary dilatation, and anti-
allergic ophthalmic solutions, in accordance with the approved label or Summary of Product 
Characteristics of the products. 
The concomitant medications recommended for IVT injection in the most recent guidelines 
(Avery 2014) are detailed in the Study Reference Manual. 
6.2.2 
Prohibited Concomitant Medications 
The use of any investigational drug (other than QR-110) or device within 90 days or 5 half-lives 
of the drug at Day 1, whichever is longer, or plans to participate in another investigational study 
during the PQ-110-002 study period is prohibited. During the study, use of any new medication 
or change in the dose of a medication that may have side effects on vision will need to be 
reviewed and approved by the Medical Monitor. 
6.2.3 
Adequate Forms of Birth Control 
Female subjects who have reached menarche and male subjects must either practice true 
abstinence in accordance with their preferred and usual lifestyle, or agree to use acceptable, 


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highly effective methods of contraception 
 Women of non-childbearing potential may be included without the use of adequate 
birth control, provided they meet the criteria in the protocol.  
Double barrier methods (a combination of condom with cap, diaphragm, or sponge with 
spermicide) are not considered highly effective. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy and bilateral oophorectomy. Highly effective methods of 
birth control include: 
• Combined (estrogen and progesterone containing) hormonal contraception associated 
with inhibition of ovulation (oral, intravaginal, transdermal) 
• Progesterone-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 
Birth control measures must be employed during the time of participation (beginning at the 
Screening/Day 1 visit) in this study. 
 
A man is considered fertile unless permanently sterile by bilateral orchidectomy or has 
undergone vasectomy and received medical assessment of surgical success. 
 


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7.0 
STUDY VISITS 
All study visits, assessments and procedures should be completed as indicated per the SOE 
 
7.1 
Visit and Assessment Windows 
The timing of assessments, procedures, and sample collections are indicated in the SOE 
  
Study center phone calls to the subjects will occur 7 days post-IVT injection, ±3 days. Study 
visits will occur every 3 months.  If no dosing occurs, the phone call visits may be skipped at the 
discretion of the Investigator. 
The Screening/ Day 1 visit should be the last visit of study PQ-110-00, ie, all Screening/Day 1 
assessments should take place during the EOS visit of study PQ-110-001. If these visits do not 
occur at the same time, a separate Screening/Day 1 visit should be performed as part of 
PQ-110-002.    
At the Screening/Day 1 visit, subjects will be assessed according to the eligibility criteria and 
specified assessments conducted, as presented in the SOE 
. For all subjects, 
assessments should be conducted in a stepwise manner so that eligibility is confirmed first with 
less intensive assessments. More intensive assessments or any assessments requiring sedation or 
anesthesia for a specific subject are to be conducted once eligibility by other criteria have been 
confirmed to minimize risk. 
Assessments can be completed over multiple days.  
7.2 
Dosing and Follow-up Visits 
Dosing visits occur on Day 1 for the contralateral eye and then every 6 months. Dosing visits for 
the previously (first) treated eye will occur 3 months after the dosing visit for the contralateral 
eye and then every 6 months.  
This between-eye interval could be adapted in agreement with the Medical Monitor if safety data 
are supportive, and for logistic reasons. 
Study drug will be administered by qualified ophthalmologists via IVT injection. If sedation or 
anesthesia is performed during the administration of the IVT injection, general health monitoring 
should be provided by the study anesthesiologist pre and post sedation/anesthesia, according to 
local institutional guidelines. Subjects should be monitored for increases in IOP and signs of 
inflammation and endophthalmitis during the post-injection period. 
Study center phone calls to the subjects will occur 7 days post-IVT injection, ±3 days. 


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All follow-up study visits, assessments and procedures should be completed as indicated in the 
SOE 
  However, if no dosing occurs at a visit; the +1D post dose visit and the +7D 
post dose phone call may be skipped at the discretion of the Investigator. 
7.3 
End of Study Visit 
The End of Study (EOS) visit occurs 3 months after the last dose of study drug for a subject.  
Subjects who discontinue study treatment but do not withdraw consent will be encouraged to 
remain in the study for observation for at least 3 months post last dose.  
 


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8.0 
STUDY ASSESSMENT PROCEDURES 
Safety parameters will be assessed by monitoring AEs, vital signs, physical examinations, 
ophthalmic exams, OCTs, infrared imaging, electrocardiograms (ECGs), and laboratory data 
(serum chemistry, hematology, and inflammatory markers). Assessments will be conducted as 
indicated on the SOE 
 
8.1 
Adverse Events 
Information regarding occurrence of AEs will be captured throughout the study. Duration (start 
and stop dates), severity/grade, outcome, treatment and relationship to study drug will be 
recorded. Refer to Section 9.0, Assessment of Safety or Adverse Events and Serious Adverse 
Events. 
8.2 
Vital Signs 
Blood pressure, heart rate and oral temperature will be measured after the subject has been 
resting in a seated position for a minimum of 5 minutes. 
8.3 
Laboratory Evaluations 
All laboratory evaluations will be conducted at a central laboratory. Reference ranges for all 
laboratory parameters are provided in the Laboratory Manual. 
A list of all clinical laboratory evaluations is presented in Appendix 2. 
Serum chemistries will include sodium, potassium, chloride, bicarbonate, uremia or blood urea 
nitrogen (BUN), creatinine, glucose, calcium, phosphorus, albumin, total protein, ALP, AST, 
ALT, gamma-glutamyl transferase (ɣGT), total and direct bilirubin, uric acid, lactic 
dehydrogenase (LDH), creatinine clearance (estimated glomerular filtration rate [eGFR]), and 
international normalized ratio (INR). Estimated GFR will be calculated using the Chronic 
Kidney Disease Epidemiology Collaboration (CKD-EPI) Creatinine Equation 2009 calculation 
for adult subjects and the Schwartz equation, according to the recommendation from National 
Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases 
(NIH/NIDDK), for pediatric subjects. 
Hematology will include a complete blood count (CBC) with absolute differential (hematocrit, 
hemoglobin, red blood cell count, white blood count, neutrophils, granulocytes, lymphocytes, 
monocytes, eosinophils, basophils, platelet count).  
For female subjects of childbearing potential, a urine pregnancy test is recommended at any visit 
that may warrant a pregnancy test. 
Eligibility of the subject to participate in the extension study is based in part on safety signals 
that may be indicated by laboratory values.  


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Repeat laboratory tests are permitted to confirm potentially spurious values or false positive 
results, at the discretion of the Investigator. Repeat analysis results for any laboratory 
assessments that indicate safety concerns should be discussed with the Medical Monitor prior to 
subject inclusion. 
8.4 
Immunogenicity  
Blood samples will be obtained to monitor for possible development of antibodies to QR-110, as 
indicated per the SOE 
  
8.7 
Pharmacokinetic Evaluations 
Blood samples will be obtained from all subjects to assess QR-110 PK parameters (area under 
the curve from 0 hour to infinity [AUC0-∞], area under the curve from 0 hour to time of the last 
measurable concentration BCVA [AUC0-tlast], maximum concentration (Cmax), trough value [C0], 
time to maximum concentration [Tmax], terminal half-life [T1/2], clearance [CL], volume of 
distribution [Vd]) as indicated per the SOE
 PK parameters will only be evaluated 
if measurable serum levels are obtained. 
8.8 
Electrocardiogram 
Twelve-lead ECG will be obtained as indicated per the SOE
 
Electrocardiograms should be done in triplicate after the subject has been resting comfortably in 
a supine position for a minimum of 8 minutes. The mean of triplicate results will be captured in 
the eCRF. 


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A repeat of ECGs (in triplicate) is permitted to confirm potentially spurious results, at the 
discretion of the Investigator. Repeat analysis results should be discussed with the Medical 
Monitor. Details on the conduct of ECGs is provided in the Study Reference Manual. 
8.9 
Physical Examination 
Complete and symptom-directed physical examinations (urogenital exams not required) will be 
performed as indicated per the SOE 
 
8.10 
Ophthalmic Exams 
Ophthalmic examinations will be performed per the SOE 
 The ophthalmic exam is 
comprised of: anterior segment examination, including grading of anterior chamber 
inflammation according to the Standardization of Uveitis Nomenclature (SUN) Working Group 
Grading Scheme for Anterior Chamber Flare; OCI; FST; IOP; clinical lens grading using the 
Age-Related Eye Diseases Study (AREDS) Clinical Lens Grading System (ARLNS); posterior 
segment/fundus examination including grading inflammation in the vitreous using the NIH 
Grading Scale for Vitreous Haze.  
Best Corrected Visual Acuity will also be assessed at specified time points as indicated per the 
SOE 
 The BCVA will be assessed using the BRVT and the ETDRS acuity test. The 
procedures for ophthalmic exams are outlined in the Study Reference Manual. 
8.11 
Optical Coherence Tomography 
Changes in OCT findings are of relevance to the safety profile of QR-110. Optical Coherence 
Tomography images will be evaluated for changes in the remaining volume of ONL and foveal 
thickness as safety parameters. All OCT scans should be performed in accordance with the 
procedures outlined in the Image Acquisition and Submission Protocol. 
The Medical Monitor should review all OCT scans, with particular attention to identifying 
changes including, remaining volume of ONL, foveal thickness, appearance of cystoid macular 
edema, or macular edema as compared to baseline. 
8.12 
Efficacy Assessments 
Efficacy assessments include BCVA, mobility course, FST, OCI, PROs, PLR, and NIRAF. 
 
   
If possible, photoreceptor outer segment layer thickness will be calculated from OCT images as a 
secondary efficacy parameter. This assessment will be conducted for those subjects for whom 
high quality imaging to evaluate this parameter can be obtained, as determined by the 
Investigator. 


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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 for adult subjects by 
the VFQ-25 and for pediatric subjects by the CVAQC. 
Secondary efficacy response criteria will be obtained as indicated per the SOE
 


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9.0 
ASSESSMENT OF SAFETY OR ADVERSE EVENTS AND SERIOUS ADVERSE 
EVENTS 
All subjects who receive study drug will be assessed for safety. 
Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting the Sponsor regarding any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the subject. The Investigator is responsible for appropriate 
medical care of subjects during the study. 
9.1 
Review of Safety Data 
A program-specific review of safety data, which may include independent experts, will be in 
place to assess emerging data from clinical studies on an ongoing basis. 
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 physical examination, 
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 (eg, invasive 
procedures such as IVT injections) 
• Adverse events that occur prior to study treatment that are related to a protocol-mandated 
intervention (eg, invasive procedures such as blood draws, anesthesia prior to IVT 
injection) 


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9.2.2 
Serious Adverse Events 
A serious adverse event (SAE) is any AE that suggests a significant hazard, contraindication, 
side effect, or precaution regardless of the relationship to study drug. An SAE is any AE that 
results in any of the following outcomes: 
• Death 
• Life-threatening AE. This definition implies that the subject, in the view of 
the Investigator, is at immediate risk of death from the event as it occurred. 
It does not include an event that, had it occurred in a more severe form, 
might have caused death 
• Inpatient hospitalization or prolongs existing hospitalization, except for 
hospitalization for planned post dose sample collections 
• 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. 
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) (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 SAEs on the 
AE eCRF and SAE form. 
9.2.3 
Suspected Unexpected Serious Adverse Reaction Definition 
A suspected unexpected serious adverse reaction (SUSAR) is a suspected unexpected serious 
adverse reaction. In order to be qualified as a 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 


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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. 
9.2.4 
Adverse Events of Special Interest 
The following are considered AEs of special interest, based on the route of administration and 
safety profile for QR-110. 


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9.3 
Assessment of Adverse Events 
The Investigator is responsible for assessing the severity and causality of AEs. 
9.3.1 
Assessment of Severity (Intensity) of Adverse Events 
On the AE eCRF, the Investigator will use the adjectives MILD, MODERATE, or SEVERE to 
describe the maximum intensity of the AE. For purposes of consistency, these intensity grades 
are defined as follows: 
• MILD: Does not interfere with subject's usual function. 
• MODERATE: Interferes to some extent with subject's usual function. 
• SEVERE: Interferes significantly with subject's usual function. 
As described previously in Section 9.2.2, note the distinction between the severity and the 
seriousness of AE. A severe event is not necessarily a serious event. For example, a headache 
may be severe (interferes significantly with subject's usual function) but would not be classified 
as serious unless it met one of the criteria for SAEs, listed above in Section 9.2.2. 
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. 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 first dose of study drug). 
Possibly Related: An AE that follows a reasonable temporal sequence from administration of 
the study drug, follows a known or expected response pattern to the study drug, but that could 
readily have been produced by a number of other factors. 
Probably Related: An AE that is clearly 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 is confirmed by 
improvement on stopping and reappearance of the event on repeated exposure and that could not 
be reasonably explained by the known characteristics of the subject’s clinical state). 
Definitely Related: The AE is clearly related to the study drug; a re-challenge confirms the 
association (not required or desirable in some circumstances but provides strong evidence when 
it happens). 


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For all AEs and SAEs, Investigators will make separate assessments of causality about the 
relationship of the event to study drug and to drug administration (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. 
• 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. 
9.4.1 
Adverse Event Reporting Period 
Any event/condition noted once the subject receives their first dose of study drug in the 
contralateral eye will be captured as an AE.  
In the first treated eye all events/conditions will be captured as an AE as treatment continues 
from study PQ-110-001.  
All AEs and SAEs regardless of attribution will be collected until at least 3 months 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. 


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Adverse events and SAEs related to study drug that persist > 3 months after the last study drug 
dose should be followed until resolution or until they return to baseline, stabilize, the subject is 
lost to follow-up, or it has been determined that the study drug or participation is not the cause of 
the AE/SAE.  
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). 
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?” 
Age-appropriate non-directive questions should be employed for eliciting AEs from pediatric 
subjects. Non-directive questions may also be used to elicit AEs from parents/caregivers of 
pediatric subjects, at the discretion of the Investigator. 
9.4.3 
Recording Adverse and Serious Adverse Events 
Investigators should use correct medical terminology/concepts when recording AEs or SAEs on 
the eCRF and/or SAE form. Colloquialisms and abbreviations should be avoided. Serious AEs 
must also be recorded on the AE eCRF. Only one medical concept should be recorded in the 
event field on the AE eCRF and SAE form (if applicable). 
9.4.3.1 
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, on the SAE form. 
9.4.3.2 
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 


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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. 
9.4.3.3 
Abnormal Laboratory Values 
Only clinically significant laboratory abnormalities will be recorded as AEs on the eCRF and 
SAE form (if applicable). 
If the laboratory abnormality can be characterized by a precise clinical term, the clinical term 
should be recorded as the AE or SAE. For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as “hyperkalemia”. 
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs on the eCRF and SAE form (if applicable), unless their 
severity, seriousness, or etiology changes. 
9.4.3.4 
Deaths 
All deaths that occur during the protocol-specified AE reporting period (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. 
9.4.3.5 
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 and Surgical 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”). 


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9.4.3.6 
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. 
9.4.3.7 
Pregnancy 
If a female subject or a female partner of a male subject becomes pregnant while the female 
subject or the male partner is receiving study drug 
 a Pregnancy Report form should be completed and faxed to the Drug Safety designee 
within 24 hours of learning of the pregnancy, using the fax numbers listed in the Study 
Reference Manual. 
Abortion, whether therapeutic or spontaneous, will be reported on a Pregnancy Report form and 
faxed to the Sponsor according to the instructions in the Study Reference Manual. If the abortion 
meets seriousness criteria (Section 9.2.2, Serious Adverse Event Definition), this information 
will be captured on the AE eCRF and SAE form. 
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. 
9.4.3.8 
Overdose Reporting 
Overdoses must be reported to the Sponsor on an AE eCRF and an SAE form for tracking 
purposes and will be considered a protocol deviation. Overdose is defined as any study drug dose 
administered above the intended dose. Additional instructions for reporting overdose information 
will be provided by the Sponsor at the time of notification. 
9.5 
Serious Adverse Events Notification 
For all SAEs, regardless of suspected causality, an SAE form must be completed (or faxed if 
using paper form) within 24 hours of discovery of the event to: 
DRUG SAFETY 
Fax toll-free: See Study Reference Manual for Fax Number 
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 toll-free: See Study Reference Manual for Phone Number 
followed by submission of written case details on an SAE form within 24 hours. 


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Serious AEs occurring any time after study participation that are considered by the Investigator 
to be possibly related to study drug must also be reported. The following are important points to 
remember when completing the SAE form: 
• If complete information is not available, at a minimum, subject identifier, suspect drug, 
study center identifier, event or outcome, and Investigator assessment of causal 
relationship to study drug should be provided. 
• A rationale for the causality assessment of an SAE should always be included, so that a 
better understanding of the event can be compiled. 
• Follow-up information, such as laboratory reports, discharge summaries, autopsy reports, 
and information concerning outcome of the event should be submitted by revising the 
SAE form as soon as the information becomes available. Copies of source documents, 
with subject identifiers redacted, should be submitted only when they are written in 
English. If source documents are not in English, the Investigator must summarize the 
source documents, providing a complete English narrative that includes a description of 
the events as it evolved, the results of all diagnostic procedures performed, treatments 
administered, and outcome of the event. A query regarding a follow-up report should be 
answered within 5 working days from receipt of the query. 
• Appropriate diagnostic tests and therapeutic measures are to be performed as necessary 
and reported on the SAE form. 
• All SAEs must be reported to the IRB/EC, if applicable. See the International Council for 
Harmonization (ICH) Good Clinical Practice (GCP) E6, Section 4.11.1 (ICH GCP 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 (ie, 7/15 Day SUSARs) 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 local requirements. All SUSARs will be 
reported to the Regulatory Authorities as per local requirements. 
• 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, 
the Detailed Guidance CT-3 (2011/C 172/01), and Regulation 536/2014.  


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10.0 
STATISTICAL METHODOLOGY 
10.1 
General Considerations 
Analyses will generally be descriptive in nature and will focus on data collected during this 
study. Baseline functional and structural measurements for the first treated eye will be those 
from study PQ-110-001. Baseline functional and structural measurements for the contralateral 
eye will be collected during the Screening visit. The incidence of AEs and changes in clinical 
laboratory assessments will be summarized for subjects by dose group, age category (pediatrics 
and adults), and for the study population. Efficacy endpoints will be summarized for all subjects 
using descriptive statistics for each eye. For all the relevant analyses, the data may be 
summarized for subjects by dose group, age category, genetic status, and severity of disease 
(BCVA and other visual function and/or functional vision parameters). An analysis by 3- or 
6-month intervals may also be performed. Summary statistics for other safety, efficacy, and PK 
endpoints will be presented. Further details will be provided in the Statistical Analysis Plan 
(SAP). 
A comprehensive SAP will specify 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-110 unless obviously 
unrelated. As an open-label extension study, exploratory analyses not necessarily identified in 
the SAP may be performed to support the clinical development program. Any p values that will 
be calculated according to the analysis plan will be interpreted in view of the exploratory nature 
of the study. Additionally, no adjustment for multiplicity will be done due to the exploratory 
nature of the study. Any post-hoc, or unplanned, analyses not identified in the SAP will be 
clearly identified in the CSR, in accordance with applicable Standard Operating Procedures 
(SOPs) of the Sponsor. 
10.2 
Determination of Sample Size 
The sample size is determined by the number of subjects completing study PQ-110-001 who 
meet the inclusion and exclusion criteria and provide informed consent. 
10.2.1 
Randomization and Blinding 
This is an open-label study; randomization and blinding are not required. 
10.2.2 
Replacement of Subjects 
Not applicable as this is an extension study. 


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10.3 
Analysis of Populations 
Safety Population: the population for safety analysis will consist of all subjects who receive any 
QR-110 or pre-medications required for the study. 
Efficacy Evaluable Population: the population for efficacy (clinical activity) analysis will consist 
of all subjects who receive any QR-110 with at least one baseline and one post baseline efficacy 
observation or measurement. 
Per Protocol Efficacy Population: this population will consist of all eyes in the Efficacy 
Evaluable Population with the exception of eyes with major protocol deviations who will be 
excluded. The list of major protocol deviations for exclusion from this population will be 
completed prior to database lock. 
Pharmacokinetics Population: the population for PK analyses will consist of all subjects who 
receive QR-110 and who have measurable drug concentrations in blood samples. 
10.4 
Subject Disposition, Demographics and Baseline Disease Characteristics 
Subject disposition will be summarized for the safety population by dose group and age. The 
number and percentage of subjects enrolled in each study center will be presented by geographic 
region (North America and Europe). 
The number and percentage of subjects who receive QR-110 will be tabulated by the number of 
doses and the QR-110 dose group. 
Subject demographics and baseline characteristics will be summarized for each dose group, age, 
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.  Baseline data is defined as the data most recently collected and/or 
the measure reflecting the highest level of visual function (eg, for ophthalmic assessments 
performed two or more times) prior to the first dose of study drug in this or study PQ-110-001. 
10.5 
Treatment Compliance 
All doses are observed and administered by study staff. Treatment compliance will be 
determined by source records documenting treatment observations and summarized. 
10.6 
Safety Analyses 
10.6.1 
Treatment Emergent Adverse Events 
A treatment emergent adverse event (TEAE) is defined as an event that was not present prior to 
administration of the first dose of study drug and present after the first dose or if it represents the 
exacerbation of an event that was present prior to the first dose. 


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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 dose group and classified by 
SOC and PT. Deaths, AE severity, seriousness, relationship to study drug and study 
discontinuation due to AE will also be tabulated by dose group. An AE will be considered drug- 
related 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 listing 
and summarized by numbers and percentages of subjects by dose for each portion of the study 
separately. If a subject reports the occurrence of a particular event more than once, the most 
severe of those events will be included in the summary tables of TEAEs, and the most severe of 
the treatment-related events will be included in the summary tables of TEAEs. 
10.6.2 
Vital Signs 
Vital signs measurements will consist of heart rate, blood pressure and temperature. Descriptive 
summaries (number of subjects, mean, standard deviation, median, minimum, and maximum) of 
actual values and changes from baseline will be presented for each time point. These summaries 
will be presented for the safety population and by dose group. 
10.6.3 
Laboratory Assessments 
Laboratory measurements (hematology, chemistry and urinalysis) obtained at baseline and each 
study visit will be summarized by dose group and age by: 
• Descriptive statistics of actual results (number of subjects, mean, standard deviation, 
median, minimum, and maximum) for the continuous data and frequencies and 
percentages for the categorical data, for each time point. 
• Descriptive statistics (number of subjects, mean, standard deviation, median, minimum, 
and maximum) of change from baseline to each time point. 
• Shift tables summarizing the frequencies of subjects below, within and above the normal 
ranges at baseline and at each time point. 
10.6.4 
Other Safety Assessments 
Other safety assessments, such as ophthalmic exams, OCT, infrared imaging, ECGs and physical 
examinations will be summarized and listed as specified in the SAP. 
10.7 
Pharmacokinetics Analyses 
To determine the PK profile of IVT injections at the different dose levels of QR-110, the 
following PK parameters will be calculated if sufficient data are available for each dose: 


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• AUC0-∞: Area under the curve to infinity will be calculated based on the last observed 
concentration (Clast [obs]) using formula: AUC0-∞=AUClast+Clast(obs)/elimination rate 
constant (λz), if feasible. 
• AUC0-tlast: Area under the curve to the final sample with a concentration greater than 
lower limit of quantification (LLOQ) will be calculated based on the last observed 
concentration using the linear trapezoidal method. 
• Cmax, C0: The maximum and minimum serum concentrations will be taken directly from 
the data. 
• Tmax: Time to Cmax will be taken directly from the data. 
• T1/2 (if measurable serum levels are obtained): The terminal elimination half-life will be 
estimated by non-linear regression analysis of the terminal elimination slope, if feasible. 
• CL: Serum clearance will be estimated using the formula: CL = Dose/AUC0-∞. 
• Vd (if measurable serum levels are obtained and a λz is estimable): Apparent volume of 
distribution at steady state of the drug will be determined from trough levels. 
Serum concentration below lower limit of quantification (LLOQ) prior to dose for the assay will 
be set to zero for the PK analysis. For other cases concentrations below LLOQ will be set for 
non-informative missing. Exact procedure for imputation of data will be described in the SAP. 
All samples obtained from all cohorts will be analyzed to avoid bias in data presentation. 
Sparse sampling analysis may be used to mitigate the risk of insufficient data to create individual 
profiles. 
Drug concentrations will be summarized by nominal time point if 3 or more values are available. 
Descriptive statistics for PK parameters will be performed if ≥ 50% of subjects have evaluable 
data and number of values to summarize is ≥ 3. 
Geometric means and coefficients of variation will be tabulated for Cmax, C0, AUC0-tlast, AUC0-∞, 
CL, and Vd for each dose group if possible. Tmax will be summarized by median, minimum and 
maximum. Mean, standard deviation, minimum and maximum will be provided for T1/2. Exact 
details for statistical analysis of PK concentrations and derived PK parameters will be presented 
in the Pharmacokinetic Analysis Plan. 
10.8 
Efficacy Analyses 
The secondary efficacy evaluations will include changes from baseline in: 
• BCVA 
• Mobility course score 
• FST 


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• OCI 
• OCT (Change in photoreceptor outer segment layer thickness) 
• PLR 
• NIRAF 
• VFQ-25 (adult subjects) 
• CVAQC (pediatric subjects) 
Descriptive statistics of clinical efficacy will be tabulated by dose group, age, and genetic status, 
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. Continuous efficacy endpoints will be summarized and may 
be analyzed using appropriate parametric or nonparametric inference tests. 
Categorical endpoints will be summarized using: 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. 
Details of the statistical analyses can be reviewed in the SAP. 
10.9 
Exploratory Analyses 
 
10.10 Interim Analysis 
Ongoing review of safety and efficacy data will be conducted to inform the program. Interim 
analyses may be performed, eg, yearly, or at key time points during clinical development.   
10.11 Subgroup Analyses 
Exploratory analyses may be carried out for subgroups based on age, baseline visual acuity, and 
other factors identified in the SAP. 


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11.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 
Data Collection and Study Monitoring 
An eCRF will be used for this study. Study center personnel will be trained and authorized to use 
the system in compliance with the Code of Federal Regulations (CFR) 21CFR Part 11, 
International Council on Harmonization 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. All subjects screened for the study who sign an Informed 
Consent Form or assent document will be assigned a subject screening number that will be 
entered in the Screening and Enrollment Log. The subject screening number will be a unique 
4-digit subject identifier: a 2-digit site number and a consecutive 2-digit subject screening 
number. 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 screen 
fail. At the study’s conclusion, a Portable Document Format file will be created for each study 
center containing their subjects’ data submitted on eCRFs. In the event of an audit or regulatory 
authority inspection, copies of the eCRFs will be printed. 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. 
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. 
The Investigator will electronically sign and date the indicated places on the eCRF. These 
signatures will indicate that the Investigator inspected or reviewed the data on the eCRF and 
agrees with the content. 
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 


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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.  No other personal information will be disclosed to the 
monitor. 
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. 
11.2 
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. 


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12.0 
ETHICAL AND REGULATORY OBLIGATIONS 
12.1 
Ethical Considerations 
The Investigator agrees to conduct this study in accordance with ethical principles that have their 
origin in the Declaration of Helsinki and are consistent with ICH GCP. The Investigator will 
conduct all aspects of this study in compliance with the protocol, ICH GCP and applicable 
regulatory requirements. 
12.2 
Informed Consent 
Before the start of required study procedures, the Investigator or his/her associate must obtain 
informed consent from each study participant (or the subject’s legal representative) in 
accordance with ICH GCP, and country authority requirements. Age appropriate assent and 
permission from a minor subject’s parent or legal guardian is required for pediatric subjects. The 
subject or his/her legal representative must sign the current version of the written, IRB/EC- 
approved Informed Consent Form in the presence of a witness and be given a copy. The 
Investigator will ensure that a copy of the signed consent is kept with the subject’s records. 
Subjects may be asked to sign separate Informed Consent Forms for gene sequencing, lens tissue 
and aqueous humor collection, and travel assistance.  Consent for travel assistance may also be 
obtained prior to the Screening Visit. Consent for gene sequencing and/or lens tissue and 
aqueous humor collection may be obtained at any time during the study.  
In accordance with ICH GCP and country authority requirements, an IRB/EC must review and 
approve this protocol and the Informed Consent Form 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 Informed 
Consent Form, assent forms, parental permission 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 Informed Consent Form that are needed to 
meet local requirements. 
If required by local regulations, the protocol should be re-approved by the IRB/EC annually. 


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Before enrollment of any subject into the study, the final study protocol, including the final 
version of the Informed Consent Form, 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 must ensure that the subject’s confidentiality is maintained. On the eCRFs or 
other documents submitted to the Sponsor, subjects should be identified by their date of birth 
(month and year) and subject number only. Documents that are not for submission to the Sponsor 
(eg, signed Informed Consent Forms), should be kept in strict confidence by the Investigator. 
In compliance with applicable regulations, it is required that the Investigator and institution 
permit authorized representatives of the Sponsor, the US FDA, other regulatory authorities, 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. 


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13.0 
STUDY ADMINISTRATION 
13.1 
Investigator’s Brochure 
Before the study begins, the Investigator will receive the QR-110 IB describing all known 
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, then these changes will be documented 
in a protocol amendment and in a new version of the protocol. Protocol amendments must be 
made only with the prior approval of the Sponsor. The Sponsor will inform the Investigator in 
writing of any amendment to the protocol. The Investigator must submit the protocol 
modifications and any Informed Consent Form 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. 
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, 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 or administrative reasons. 
If the clinical development of QR-110 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 (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: 


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• Subject files containing informed consents 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 subject dairies and source documents. 
This information will be treated as confidential. 
No study document is to be destroyed without prior written agreement between Sponsor and the 
Investigator. Should the Investigator wish to assign the study records to another party or move 
them to another location, he/she must notify the Sponsor in writing of the new responsible person 
and/or the new location. 
13.5 
Use of Information 
All personal information 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 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. 
13.6 
End of Study and Final Report 
In North America, the Investigator or associate must notify the IRB/EC when the study is closed. 
If not initially provided by the Sponsor, a copy of the final study report must also be provided to 
Sponsor or its representative. 
In the European Union, the Sponsor or its designee must notify the Competent Authorities and 
ECs within 90 days of completion of the study in the concerned country and/or worldwide in 
accordance with local requirements. In case of early termination, the deadline is 15 days. The 
Sponsor or its designee must provide a final report and/or synopsis to the European Competent 
Authorities and ECs at the latest 1 year after the study termination worldwide, in accordance 
with local requirements. A copy of this final report and associated synopsis must also be 
provided to the Investigator. 


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End of Study will be defined as the last study visit for the last subject. 
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 
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. 
Cideciyan AV, Aleman TS, Jacobson SG, Khanna H, Sumaroka A, Aguirre GK, et al. 
Centrosomal-ciliary gene CEP290/-NPHP6 mutations result in blindness with unexpected 
sparing of photoreceptors and visual brain: implications for therapy of Leber congenital 
amaurosis. Hum Mutat. 2007 Nov; 28(11):1074-83. 
Cideciyan AV, Rachel RA, Aleman TS, Swider M, Schwartz SB, Sumaroka A, et al. Cone 
photoreceptors are the main targets for gene therapy of NPHP5 (IQCB1) or NPHP6 (CEP290) 
blindness: generation of an all-cone Nphp6 hypomorph mouse that mimics the human retinal 
ciliopathy. Hum Mol Genet. 2011. 20(7):1411-23. 
Coppieters F, Casteels I, Meire F, De Jaegere S, Hooghe S, van Regemorter N, et al. Genetic 
screening of LCA in Belgium: predominance of CEP290 and identification of potential modifier 
alleles in AHI1 of CEP290-related phenotypes. Hum Mutat. 2010 Oct; 31(10): E1709-66. 
den Hollander Al, Koenekoop RK, Yzer S, Lopez I, Arends ML, Voesenek KE, et al. Mutations 
in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis. Am J Hum 
Genet. 2006 Sep; 79(3):556-61. 
den Hollander AI, Roepman R, Koenekoop RK, Cremers FP. Leber congenital amaurosis- genes, 
proteins and disease mechanisms. Prog Retin Eye Res. 2008 Jul; 27(4):391-419. 
doi:10.1016/j.preteyeres.2008.05.003 
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. 


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Estrada-Cuzcano A, Koenekoop RK, Coppieters F, Kohl S, Lopez I, Collin RW, et al. IQCB1 
mutations in patients with Leber congenital amaurosis. Invest Ophthalmol Vis Sci. 2011 Feb 11; 
52(2):834-9. 
European Union Delegated Regulation No. 536/2014 for Clinical Trials. Available at: 
https://ec.europa.eu/health/human-use/clinical-trials/regulation_en 
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 
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 
Jacobson SG, Cideciyan AV, Sumaroka A, Roman AJ, Charng J, Lu M, et al. Outcome Measures 
for Clinical Trials of Leber Congenital Amaurosis Caused by the Intronic Mutation in the 
CEP290 Gene. Invest Ophthalmol Vis Sci. 2017 May 1;58(5):2609-2622. doi: 10.1167/iovs.17-
21560. 
Kmoch S, Majewski J, Ramamurthy V, Cao S, Fahiminiya S, Ren H, et al. Mutations in 
PNPLA6 are linked to photoreceptor degeneration and various forms of childhood blindness. Nat 
Commun. 2015 Jan 9; 6:5614. doi:10.1038/ncomms.56614 
Littink KW, Pott JWR, Collin RWJ, Kroes HY, Verheij JBGM, Blokland EAW, et al. A novel 
nonsense mutation in CEP290 induces exon skipping and leads to a relatively mild retinal 
phenotype. Invest Ophthal Vis Sci. 2010 July; 51(7):3646-52. 
McAnany JJ, Genead MA, Walia S, Drack AV, Stone EM, Koenekoop RK, et al. Visual acuity 
changes in patients with Leber congenital amaurosis and mutations in CEP290. JAMA 
Ophthalmol. 2013. 131(2):178-82. 
National Institute of Diabetes and Digestive and Kidney Diseases. Laboratory Evaluation. 
Glomerular Filtration Rate (GFR) Calculators. https://www.niddk.nih.gov/health- 
information/communication-programs/nkdep/laboratory-evaluation/glomerular-filtration-rate- 
calculators. Accessed 05 November 2017. 
Parfitt DA, Lane A, Ramsden CM, Carr A-J F, Munro PM, et al. Identification and correction of 
mechanisms underlying inherited blindness in human iPSC-derived optic cups. Cell Stem Cell. 
2016 Apr 12. pii: S1934-5909(16)30010-8. doi: 10.1016/j.stem.2016.03.021. 


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Perrault L, Delphin N, Hanein S, Gerber S, Dufier JL, Roche O, et al. Spectrum of NPHP6/- 
CEP290 mutations in Leber congenital amaurosis and delineation of the associated phenotype. 
Hum Mutat. 2007 Apr; 28(4):416. doi:10.1002/humu.9485 
Stone EM. Leber congenital amaurosis- a model for efficient genetic testing of heterogeneous 
disorders: LXIV Edward Jackson memorial lecture. Am J Ophthalmol. 2007 Dec; 144(6):791- 
811. doi:10.1016/j.ajo.2007.08.022 
Yzer S, Hollander AI, Lopez I, Pott JW, de Faber JT, Cremers FP, et al. Ocular and extra-ocular 
features of patients with Leber congenital amaurosis and mutations in CEP290. Mol Vis. 2012; 
18:412-25. 
 


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15.0 
APPENDICES 


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APPENDIX 2: 
CLINICAL LABORATORY ANALYTES 
Serum Chemistry Panel 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase  
Bicarbonate 
Calcium 
Chloride 
Creatinine 
Creatinine clearance (eGFR) [1] 
Gamma-glutamyl transferase 
Glucose 
INR 
Potassium 
Lactic dehydrogenase 
Sodium 
Phosphorus 
Total and direct bilirubin 
Total protein 
Uremia or blood urea nitrogen 
Uric acid 
1. Estimated glomerular filtration rate by CKD-EPI for adults and eGFR by Schwartz for pediatrics (Section 8.3). 
 
 
Hematology 
A complete blood count will include: 
Hematocrit 
Hemoglobin 
Red blood cell count 
White blood cell count and differential [1] 
Neutrophils 
Granulocytes 
Lymphocytes 
Platelets 
Eosinophils 
Basophils 
Monocytes 
 
1.  Manual microscopic review is performed only if white blood cell count and/or differential values are out of reference 
range. 
 
 
Pregnancy Testing 
For female subjects of childbearing potential, a urine pregnancy test is acceptable at any visit that 
warrants a pregnancy test. 
 
 
 

SAP_001.pdf: 
     Statistical Analysis Plan 
Sponsor:  
ProQR Therapeutics 
Protocol: 
PQ-110-002 
Document Version No.: 
1.0 
Document Date: 
04 JAN 2022 
 
 
 CRS-BS-TP-000005 V 1.0  
 
Page 1 of 75 
 
TABLE OF CONTENTS  
 
1. 
INTRODUCTION AND OBJECTIVES OF ANALYSIS .................................................................. 11 
1.1. 
INTRODUCTION ............................................................................................................................. 11 
1.2. 
OBJECTIVES OF STATISTICAL ANALYSIS ......................................................................................... 11 
2. 
STUDY DESIGN ................................................................................................................... 13 
2.1. 
SYNOPSIS OF STUDY DESIGN......................................................................................................... 13 
2.2. 
RANDOMIZATION METHODOLOGY .............................................................................................. 13 
2.3. 
STOPPING RULES AND .................................................................................................................. 13 
2.4. 
STUDY PROCEDURES ..................................................................................................................... 15 
2.5. 
SAFETY, EFFICACY AND PHARMACOKINETIC ENDPOINTS ............................................................. 20 
2.5.1. 
SAFETY ENDPOINTS ..................................................................................................... 20 
2.5.2. 
EFFICACY ENDPOINTS ................................................................................................. 20 
2.5.3. 
PHARMACOKINETIC ENDPOINTS ................................................................................ 21 
3. 
SUBJECT POPULATIONS ...................................................................................................... 22 
3.1. 
POPULATION DEFINITIONS ........................................................................................................... 22 
3.2. 
PROTOCOL DEVIATIONS ................................................................................................................ 23 
4. 
STATISTICAL METHODS ...................................................................................................... 24 
4.1. 
SAMPLE SIZE JUSTIFICATION ......................................................................................................... 24 
4.2. 
GENERAL STATISTICAL METHODS AND DATA HANDLING ............................................................ 24 
4.2.1. 
GENERAL METHODS .................................................................................................... 24 
4.2.2. 
TREATMENT GROUPS FOR ANALYSIS .......................................................................... 24 
4.2.3. 
COMPUTING ENVIRONMENT ...................................................................................... 25 
4.2.4. 
DEFINITION OF BASELINE ............................................................................................ 25 
4.2.5. 
ADJUSTMENTS FOR COVARIATES ............................................................................... 26 


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4.2.6. 
MULTIPLE COMPARISONS/MULTIPLICITY ................................................................... 26 
4.2.7. 
SUBPOPULATIONS....................................................................................................... 26 
4.2.8. 
DISCONTINUATIONS FROM STUDY DRUG AND DISCONTINUATIONS 
FROM THE TRIAL ......................................................................................................... 27 
4.2.9. 
MISSING, UNUSED, AND SPURIOUS DATA .................................................................. 27 
4.2.10. 
VISIT WINDOWS .......................................................................................................... 31 
4.3. 
INTERIM ANALYSES ....................................................................................................................... 32 
4.4. 
SUBJECT DISPOSITION ................................................................................................................... 32 
4.5. 
DRUG EXPOSURE ........................................................................................................................... 33 
4.6. 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ....................................................................... 34 
4.7. 
SAFETY ANALYSES ......................................................................................................................... 35 
4.7.1. 
ADVERSE EVENTS ........................................................................................................ 35 
4.7.2. 
LABORATORY DATA..................................................................................................... 38 
4.7.3. 
VITAL SIGNS AND PHYSICAL EXAMINATIONS .............................................................. 38 
4.7.4. 
ELECTROCARDIOGRAM ............................................................................................... 39 
4.7.5. 
OPHTHALMIC EXAMINATION ...................................................................................... 39 
4.7.6. 
OPTICAL COHERENCE TOMOGRAPH (OCT) ................................................................. 40 
4.7.7. 
PRIOR AND / OR CONCOMITANT MEDICATIONS ........................................................ 43 
4.8. 
EFFICACY EVALUATION ................................................................................................................. 44 
4.8.1. 
BCVA ........................................................................................................................... 44 
4.8.2. 
MOBILITY COURSE ...................................................................................................... 51 
4.8.3. 
FULL-FIELD STIMULUS THRESHOLD TESTING (FST) ..................................................... 55 
4.8.4. 
OPTICAL COHERENCE TESTING ................................................................................... 57 
4.8.5. 
NIRAF .......................................................................................................................... 58 
4.8.6. 
OCULOMOTOR INSTABILITY ........................................................................................ 58 
4.8.7. 
PUPILLARY LIGHT REFLEX ............................................................................................ 59 
4.8.8. 
VFQ-25/CVAQC ........................................................................................................... 60 
4.8.9. 
EXPLORATORY ENDPOINTS ......................................................................................... 64 
4.9. 
PHARMACOKINETIC EVALUATIONS .............................................................................................. 65 
5. 
CHANGES TO PLANNED ANALYSES ...................................................................................... 66 


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6. 
REFERENCES ...................................................................................................................... 67 
7. 
APPENDIX A ....................................................................................................................... 70 
 
 
 
 


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Protocol PQ-110-002 
AN OPEN-LABEL EXTENTION STUDY TO EVALUATE THE SAFETY, TOLERABILITY, EFFICACY, AND 
PHARMACOKINETICS OF QR-110 IN SUBJECTS WITH LEBER’S CONGENITAL AMAUROSIS (LCA) DUE TO 
THE c.2991+1655A>G MUTATION (p.Cys998X) IN THE CEP290 GENE 
Protocol Number: 
(Version Date) 
Version 3.0 
14 January 2019 
Name of Test Drug: 
QR-110 Solution for Intravitreal Injection 
Phase: 
1b/2 
Methodology: 
Open-label, extension study 
Sponsor: 
ProQR Therapeutics 
Zernikedreef 9 
2333 CK Leiden 
The Netherlands 
Sponsor Representative: 
Document Date: 
04 JAN 2022 
Document Version: 
1.0 
 
 
 


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SIGNATURE PAGE 
Protocol Title: 
An Open-Label, Extension Study to Evaluate the Safety, 
Tolerability, Efficacy and Pharmacokinetics of QR-110 in 
Subjects with Leber’s Congenital Amaurosis (LCA) due to 
the c.2991+1655A>G Mutation (p.Cys998X) in the CEP290 
Gene  
 
Sponsor: 
ProQR Therapeutics 
Zernikedreef 9 
2333 CK Leiden 
The Netherlands 
Protocol Number: 
PQ-110-002 
Document Date/Version: 
16 Jun 2021, version 0.2 
 
Signature:____________________________________ 
Date:________________________________________ 
 
Signature:____________________________________ 
Date:________________________________________ 
 
 
 


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Sponsor Approval 
By signing this document, I acknowledge that I have read the document and approve of the planned 
statistical analyses described herein.  I agree that the planned statistical analyses are appropriate for 
this study, are in accordance with the study objectives, and are consistent with the statistical 
methodology described in the protocol, clinical development plan, and all applicable regulatory 
guidance’s and guidelines. 
I have discussed any questions I have regarding the contents of this document with the biostatistical 
author. 
I also understand that any subsequent changes to the planned statistical analyses, as described herein, 
may have a regulatory impact and/or result in timeline adjustments.  All changes to the planned 
analyses will be described in the clinical study report (CSR). 
Sponsor Signatory: 
 
Signature:____________________________________ 
Date:________________________________________ 
 
 


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LIST OF IN-TEXT TABLES 
Table 
Page 
Table 6 
Scoring Key: Recoding of Items ....................................................................................... 58 
Table 7 
Averaging of Items to Generate VFQ-25 Sub-Scales ....................................................... 59 
Table 8 
CVAQC-25: Item Mesaure ............................................................................................... 60 
Table 9 
CVAQC-25: Category Mesaure ........................................................................................ 60 
 
 
 


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ABBREVIATIONS 
Abbreviation 
Definition 
λz 
elimination rate constant 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AON 
antisense oligonucleotide 
AREDS 
age-related eye diseases study 
ARLNS 
age-related eye diseases study clinical lens grading system 
AST 
aspartate aminotransferase 
AUC0-∞ 
area under the curve 0 hour to infinity 
AUC0-tlast 
area under the curve 0 hour to time of the last measurable concentration 
BCVA 
Best Corrected Visual Acuity 
BRVT 
Berkeley Rudimentary Vision Test 
BUN 
blood urea nitrogen 
CEP290 
Centrosomal Protein of 290 kDa 
CEP290 
CEP290 gene 
CF 
counting fingers 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CL 
clearance 
Clast 
last observed concentration 
Cmax 
maximum concentration 
C0 
trough value 
CSR 
clinical study report 
CVAQC 
Cardiff Visual Ability Questionnaire for Children 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
ERG 
electroretinogram 


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Abbreviation 
Definition 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FST 
Full-field Stimulus Testing (also, Full-field Stimulus Threshold Testing 
or Full- field Scotopic Threshold Testing) 
HM 
hand motion 
ICH 
International Council on Harmonisation 
INR 
international normalized ratio 
IOP 
intraocular pressure 
 
IVT 
intravitreal 
LCA 
Leber’s congenital amaurosis 
LDH 
lactic dehydrogenase 
LLOQ 
lower limit of quantification 
LogMAR 
Logarithm of the Minimum Angle of Resolution 
LP 
light perception 
MedDRA 
Medical Dictionary for Regulatory Activities 
NIH 
National Institute of Health 
NIRAF 
near infrared autofluorescence 
OCI 
oculomotor instability 
OCT 
optical coherence tomography 
ONL 
outer nuclear layer 
p.Cys998X 
Protein product from the c.2991+1655A>G mutation in the CEP290 
gene  
PK 
pharmacokinetic 
PLR 
pupillary light reflex 
PRO 
patient reported outcome 
PT 
preferred term 
SAE 
serious adverse event 
SEM 
standard error of mean 
SAP 
statistical analysis plan 
SOC 
system organ class 
SOE 
schedule of events 
SUN 
Standardization of Uveitis Nomenclature 


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Abbreviation 
Definition 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
T1/2 
terminal half-life 
Tmax 
time of maximum concentration 
ULN 
upper limit of normal 
US 
United States 
Vd
volume of distribution 
VF 
visual field 
VFQ-25 
Visual Function Questionnaire-25 
WOCBP 
women of childbearing potential 


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1. 
INTRODUCTION AND OBJECTIVES OF ANALYSIS 
1.1. 
Introduction 
ProQR Therapeutics (ProQR) is developing an antisense oligonucleotide (AON) product, sepofarsen, for 
the treatment of patients with Leber congenital amaurosis (LCA) due to the c.2991+1655A>G 
(p.Cys998X) mutation in the Centrosomal Protein of 290kDa (CEP290) gene.  Leber congenital 
amaurosis caused by mutations in the CEP290 gene (ie, LCA type 10 [LCA10]) is a severe inherited 
retinal degenerative disease resulting in blindness, often in early childhood. There are currently no 
approved therapies for the treatment of LCA10 due to the c.2991 +1655A>G mutation and an 
important unmet medical need exists. The primary goal of the development plan for sepofarsen is to 
provide a treatment to overcome the genetic defect in patients with at least 1 CEP290 allele containing 
the CEP290 mutation, resulting in functional vision restoration or preservation. The intended route of 
administration is intravitreal (IVT) injection. 
PQ-110-002 study is an open-label, extension study from study PQ-110-001, to evaluate the safety, 
tolerability, efficacy, and pharmacokinetics of sepofarsen in subjects with LCA due to c.2991+1655A>G  
mutation in the CEP290 gene. PQ-110-001 was a 1b/2 phase, open-label, multiple dose, dose escalation 
study to evaluate the safety and tolerability of sepofarsen in  subjects with LCA due to the above 
mentioned mutation.  
1.2. 
Objectives of Statistical Analysis 
This statistical analysis plan (SAP) describes the populations for analysis, data handling rules, statistical 
methods, and formats for data presentation that will be required for the analysis of data from trial PQ-
110-002. The statistical analyses and summary tabulations that will be produced for the analysis as 
described in this SAP will provide the basis for the results sections of the interim and final clinical study 


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reports (CSRs) for this trial.  The SAP will also outline any differences between the currently planned 
analyses and those specified in the clinical study protocol. 


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2. 
STUDY DESIGN 
2.1. 
Synopsis of Study Design 
This study is an open-label, extension study to evaluate the safety, tolerability, efficacy, and 
pharmacokinetics of sepofarsen in subjects with LCA due to c.2991 +1655A>G  mutation in the CEP290 
gene.  
Subjects will be given the opportunity to enroll into this extension study for continued dosing if 
available data support current and/or future benefits for the subject. The Investigator, in consultation 
and agreement with the Medical Monitor, will decide on enrollment of each individual subject, as well 
as on dosing of the first treated eye and treatment initiation of the contralateral eye. Continued subject 
treatment in this study is desirable, but cannot be guaranteed, since it will depend on the risks and 
benefit of further treatment on a case-by-case basis, as discussed and agreed upon with the Medical 
Monitor. 
Dose modifications or modifications of the dosing interval will be considered on the basis of emerging 
safety and/or efficacy data and if it is anticipated to be in the best interest of the subject.  
The contralateral eye and the first treated eye will be injected 3 months apart. The injection interval of 
3 months between both eyes will limit burden for the subjects. This between-eye interval could be 
adapted if safety data are supportive, and for logistic reasons, and in agreement with the Medical 
Monitor. The same safety monitoring protocol and efficacy assessments will apply to both eyes. 
2.2. 
Randomization Methodology 
This is an open-label study; randomization is not required as the study is not randomized. 
2.3. 
Stopping Rules and  
The Investigator or the Medical Monitor may stop treatment for an individual subject due to an 


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AE. The severity of the event(s), as well as the temporal relationship to study drug administration, 
potential for worsening of the event(s) with continued sepofarsen  and association with other safety 
signals or laboratory values should be considered in the decision to stop treatment. The Medical 
Monitor must be notified of any subject who stops treatment due to an AE. Adverse events considered 
to be related to the study drug should be taken into account in the benefit/risk assessment.  
Subjects who discontinue study drug will be encouraged to remain in the study for observation for at 
least 3 months post last dose. 
 The Investigator and/or the Sponsor may decide to stop treatment for an 
individual subject due to an AE. 
This is an open-label study; masking is not required. 


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2.4. 
Study Procedures 
The schedule of assessments, as outlined in the study protocol, is provided in 
 
 


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2.5. 
Safety, Efficacy and Pharmacokinetic Endpoints 
2.5.1. 
Safety Endpoints 
2.5.1.1. 
Primary Endpoint 
The primary endpoints are: 
• 
Frequency and severity of ocular AEs   
• 
Frequency and severity of non-ocular AEs 
2.5.2. 
Efficacy Endpoints 
2.5.2.1. 
Secondary Endpoints 
Secondary endpoints include: 
• 
Change from baseline in BCVA 
• 
Change from baseline in Mobility course score (unilateral and binocular) 
• 
Change from baseline in photoreceptor outer segment layer thickness by optical coherence 
tomography (OCT) (if applicable) 
• 
Change from baseline in OCI 
• 
Change from baseline in Full-FST (blue and red stimuli; white at Investigator discretion) (thresholds) 
• 
Change from baseline in PROs as measured by: 
o Visual Function Questionnaire-25 (VFQ-25) score (adult subjects), or 
o Cardiff Visual Ability Questionnaire for Children (CVAQC) score (pediatric subjects) 
• 
Change from baseline in Pupillary Light Reflex (PLR) (latency and amplitude) 


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• 
Change from baseline in Near Infrared AutoFluorescence (NIRAF) 
• 
Pharmacokinetics: Characterize the PK profile of sepofarsen in serum 
2.5.2.2. 
Exploratory Endpoints (at Investigator Discretion) 
2.5.3. 
Pharmacokinetic Endpoints 
It is expected that the vast majority of measured PK concentrations is below limit of quantification (BLQ). 
Thus, no pharmacokinetic parameters (Cmax, Tmax, AUC0-24, AUClast and AUC0-inf) will be derived. All individual 
measurement results above limit of quantification will be shown in a individual level table, and  all 
measurements – above or below limit of quantification will be presented in the listings. 
 
 


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3. 
SUBJECT POPULATIONS 
3.1. 
Population Definitions 
The following subject populations will be evaluated and used for presentation and analysis of the data: 
• 
All Screened Subjects: All subjects who provided informed consent or assent document to 
participate in the study. 
• 
Safety Population: All subjects who received any sepofarsen during study PQ-110-001 and were 
enrolled in this study.- 
• 
Efficacy Evaluable Population: All subjects who received any sepofarsen with at least one baseline 
002 and post-baseline 002 BCVA measurement.  
• 
Per Protocol Analysis Set: All subjects in the Efficacy Evaluable Population, with the exception of 
subjects and/or data points with major protocol deviations affecting subjects and/or specific 
assessments within a subject (see Section 3.2).  The list of major protocol deviations selected for 
exclusion from this analysis set will be completed prior to database lock. 
The Safety Population is the primary population for the summaries of demographics, baseline disease 
characteristics, medical history, concomitant medications, major protocol deviations and all safety 
endpoints. The Efficacy Evaluable Population is the primary population for the analyses of all efficacy 
endpoints, where missing values will be reported for subjects that have missing values in their baseline 
measurements of that specific secondary endpoint. A subset of efficacy endpoints may be evaluated 
for the Per Protocol Population.  
Unless otherwise stated, data presentations will be listed and summarized by treatment group. 


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3.2. 
Protocol Deviations 
Departures from the protocol will be classified as major or minor protocol deviations. The list of major 
protocol deviations, including those to be excluded from the per protocol analysis set, will be completed 
prior to database lock.  The details of the protocol deviations will be described in a separate Protocol 
Deviation Plan. 
 


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4. 
STATISTICAL METHODS 
4.1. 
Sample Size Justification 
The sample size is determined by the number of subjects completing study PQ-110-001 who meet the 
inclusion and exclusion criteria and provide informed consent or assent document. 
4.2. 
General Statistical Methods and Data Handling 
4.2.1. 
General Methods 
All outputs will be incorporated into bookmarked PDFs and /or Microsoft Excel or Word files, sorted and 
labeled according to the International Conference on Harmonisation (ICH) recommendations, and 
formatted to the appropriate page size(s).  
Tabulations will be produced for appropriate demographic, baseline,  safety and efficacy parameters. For 
continuous efficacy variables, the data will be summarized using the number of subjects, mean, standard 
deviation, standard error, median, minimum, maximum and 95% confidence intervals for the mean. For all 
other continuous variables, the data will be summarized using the mean, standard deviation, median, 
minimum and maximum. All categorical variables will be summarized by the number of subjects and 
percentage within each category (with a category for missing data, if any) of the parameter.  For any 
categorical variable for an efficacy endpoint, summary tabulations of the variable will also include 95% 
confidence intervals for the percentage. 
4.2.2. 
Treatment Groups for Analysis 
Safety and efficacy data will be summarized by treatment group. The first treated eyes data will be 
summarized based on the treatment group allocation in study PQ-110-001. The subjects who started 
with 320/160 µg in study PQ-110-001 will be moved to 160/80 ug group in study PQ-110-002; other 
subjects who started with 160/80 µg  in study PQ-110-001 will continue the same dose in study PQ-110-
002. The contralateral eyes data will be summarized for treated and non-treated for the overall study 


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population in study PQ-110-002.  
4.2.3. 
Computing Environment 
All descriptive statistical analyses will be performed using SAS statistical software (Version 9.4), unless 
otherwise noted.  Medical History and adverse events will be coded using MedDRA Version 20.0.  
Concomitant medications will be coded using World Health Organization (WHO) Drug Global B3/C3-format 
March 1, 2021.  
4.2.4. 
Definition of Baseline 
For the endpoints collected on the subject level, the screening visit value in study PQ-110-002 will be 
defined as Baseline 002 values. For the endpoints collected on the eye level, there are three types of 
baseline values used for study PQ-110-002: 
• 
Baseline 001:  for BCVA, it is defined as
 for mobility course and FST, the average of measurements at pre-dose in 
study PQ-110-001 is considered as baseline 001. 
• 
Baseline 002:  for BCVA, it is defined as 
; for mobility course and FST, 
it’s defined as the average of last two measurements only if the interval between them is up to 1 
month before entering study PQ-110-002. Otherwise the most recent value will be taken as 
baseline 002. For the other endpoints, the screening value in study PQ-110-002 is used as 
baseline 002 value. 
• 
Pre-dose Baseline: the efficacy endpoints collected on the eye level except BCVA, mobility course 
and FST, the baseline 002 will be used. For BCVA, mobility course and FST , Baseline 001 values 
are used for the first treated eye, non-treated contralateral eye as well as both eyes. For treated 
contralateral eye,  
➢ For BCVA, the baseline result corresponds to the best of the two most recent BCVA 
values available before the first dose of treatment with sepofarsen in that respective eye 


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in study PQ-110-002 (in a maximum time-window of 1 month before dosing). If only one 
observation is available on or prior to the subject’s first dose, that observation will be 
used as the pre-dose baseline value. For mobility course, FST and OCT, the data most 
recently collected prior to the subject’s first dose of study treatment in study PQ-110-002 
will be used as the pre-dose baseline value.  
➢ For other efficacy endpoints collected on the eye level, the baseline 002 will be used. 
4.2.5. 
Adjustments for Covariates 
Adjustment for baseline BCVA will be applied for any inferential statistical analysis performed. If inferential 
statistical analysis will be requested at some point, this will be described in an addendum to this SAP. 
4.2.6. 
Multiple Comparisons/Multiplicity 
Adjustment for baseline BCVA will be applied for any inferential statistical analysis performed. If inferential 
statistical analysis will be requested at some point, this will be described in an addendum to this SAP. 
4.2.7. 
Subpopulations 
Subject-level summary tables will be generated featuring the following subpopulations: 
• 
On-chart versus off-chart subjects. On-chart subjects are defined as subjects who can read letters 
on the ETDRS chart and for whom a logMAR value is available based on ETDRS in the logMAR 
category of < +1.7 logMAR. Off-chart subjects are defined as subjects who cannot read letters on 
the ETDRS chart and for whom a logMAR value is available based on BRVT in the logMAR category 
of ≥ +1.7 logMAR. 
• 
 Adult (≥ 18 years of age) versus pediatric (<18 years of age) subjects 
• 
Blue minus red FST response > 2 log cd/m2 versus blue minus red FST ≤2 log cd/m2  


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4.2.8. 
Discontinuations from Study Drug and Discontinuations from the Trial 
If the subject stops treatment for any reason, in general, the subject will be encouraged to remain in the 
study for observation for at least 3 months post last dose (see Protocol Section 4.2.2).  
Subjects who discontinued from the trial will not be replaced as this is an extension study. 
4.2.9. 
Missing, Unused, and Spurious Data 
Missing data are defined as values that are not available and that would be meaningful for analysis if they 
were observed.  Information that explains why data is missing data, including the relationship to COVID-19, 
will be captured in the electronic case report form and summarized in the clinical study report. 
Missing data handling for mobility course composite score, BCVA and FST data is described in Section 
4.2.9.1, 4.2.9.2. No imputation methods are planned for missing data for other efficacy endpoints or for 
safety data, except for partial or missing dates for the start and end of adverse events and for the use of 
concomitant medications, as described in Sections 4.2.9.3 and 4.2.9.4. The planned approach to handle 
partial and missing start dates for AEs and concomitant medications is conservative, in that the imputation 
is designed to impute a start date to occur within the period following the first dose of study treatment, 
rather than in the screening period.  The planned approach to impute partial and missing end dates for AEs 
and concomitant medications is also conservative, as the imputed dates are fixed at the latest plausible 
date given the available information for that data record and the timing of the individual subject’s visits. 
4.2.9.1 Missing data in Central Reading Center Mobility Course Composite Score 
Missing course composite scores from the central reading center will be imputed as follows for the mobility 
course analyses: 
• 
The reading center may not receive a video of the subject navigation attempt, or the video of the 
navigation attempt may be marginalized due to technical error, resulting in an inability to grade the 
navigation attempt. Marginalization of a video can occur due to lack of infra-red (IR) used on one or 
both cameras, truncated recording on one or both cameras, or one or both cameras recording out 


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of focus.  In these instances, the reading center graders cannot grade the video with maximum 
accuracy, resulting in missing data, and the site score will be used to impute the central reading 
center score. 
• 
An error in site level grading results in the early termination of the mobility test, before a pass 
occurs: The site technicians may grade the navigation attempt a “pass” and conclude the test 
prematurely (no video available), whereas the review from the reading center may identify the 
final navigation attempt as a “fail”.  Therefore, a passing light level would not be identified by the 
reading center, resulting in missing data.  In this case the following imputations will be used: 
o Last observation carried forward within the given eye (OD, OS, or OU) from prior visit. 
o In the event that imputing the last observation carried forward would result in the 
imputation of a pre-treatment score to a post-treatment time point, the following 
imputation will be used: the site level course composite score minus 1.  This is the next 
easiest course / light level score.  The next easiest score is defined as the score associated 
with passing the subsequent light level that would have been tested had the site correctly 
graded the navigation test as a fail and continued testing at the next light level.  If, after the 
above imputations are applied, the composite score is still missing (e.g., for other reasons 
such as a visit not having been conducted), then the composite score will be treated as 
missing for analysis. 
4.2.9.2  Missing BCVA and FST Data  
If a subject stops treatment of study drug for any reason before end of trial, in general, the subject will 
remain in the trial and BCVA and FST data will be available and used as is in the calculations. 
If a subject has no measurement within the defined visit window the value measured closest to the window 
will be taken. 
Data will be imputed if the subject has missing BCVA and FST  for any of the following reasons: 


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• 
a subject withdraws consent for unknown reasons or related to the medical procedure.  
• 
a subject withdraws consent for reasons unrelated to the medical procedure as elicited at the end of 
study/early termination visit, or the subject dies from an unrelated event.  
The following imputation methods will be used: 
• 
All-last observation carry-forward (ALL-LOCF): All missing data of the endpoint is imputed by the 
respective last observation carry forward method. 
• 
All-baseline carry-forward (ALL-BOCF): All missing data of the endpoint is imputed by the respective 
baseline value of the subject. 
For the handling of missing values for the Month 12 BCVA data, two analysis will be performed as below:  
• 
No imputation method will be used and analyze all available BCVA data.  
• 
For the subjects with at least one ongoing AE of cataract or retinal (CME) adverse events, Month 12 
assessment BCVA data will be considered as missing data and imputed using All-LOCF. 
4.2.9.3    Partial and Missing Data for Adverse Events  
4.2.9.3.1  Partial and Missing AE Start Dates 
If an AE start date is completely missing, and either the available (complete, partial) AE end date/time 
information indicates that the AE ended before the date/time of first dosing of study treatment on Day 1 or 
the subject did not receive study treatment, impute the AE start date as the date of informed consent and 
consider the adverse event as non-treatment-emergent. 
If an AE start date is completely missing, the subject received study treatment, and either the AE end date 
information is completely missing or the available AE end date/time information indicates that the AE did 
not end before the date/time of first dosing of study treatment on Day 1, impute the AE start date to Day 
1.  The adverse event will be assumed to be treatment-emergent following the first dose of study 
treatment. 


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If a partial AE start date is consistent with the actual start date being on Day 1, and either the AE end date 
information is completely missing, or the complete or imputed AE end date/time information indicates that 
the AE did not end before Day 1, the imputed AE start date will be Day 1 in the following scenarios: 
• 
The AE start time is missing (the adverse event will be flagged as treatment-emergent following the 
first dose of study treatment) 
• 
The AE start time is after the date/time of first dosing of study treatment on Day 1 (the adverse 
event will be flagged as treatment-emergent following the first dose of study treatment) 
• 
The AE start time is before the time of first dosing of study treatment on Day 1, and imputing the 
AE start date as Day 2 instead of Day 1 would be inconsistent with the partially recorded AE start 
date (e.g., the calendar month for Day 2 is not the same as for Day 1), or with the complete or 
imputed AE end date/time (in this case, the adverse event will not be flagged as treatment-
emergent following the first dose of study treatment). 
Otherwise, if the start date for an AE is partially recorded, the AE start date will be imputed  
as the date of first dose of study treatment, and the adverse event will be considered treatment emergent. 
4.2.9.3.2. 
Partial and Missing AE End Dates 
If the end date for an AE is completely missing, the Adverse event will be assumed to be ongoing on the 
date of the subject’s last visit. If the end date for an AE is partially recorded, then the AE end date will be 
re-imputed as the date of the subject’s last visit. 
4.2.9.4  Partial and Missing Dates for Concomitant Medications  
4.2.9.4.1    Partial and Missing Start Dates for Concomitant Medications 
If a medication start date is completely missing, the medication start date will be imputed as the date of 
informed consent. 


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If a partial medication start date is consistent with occurring on Day 1, the subject received study 
treatment, and the available medication end date information indicates that the medication did not end 
before Day 1, the imputed medication start date will be Day 1. 
Otherwise, if the medication start date is partially recorded, the medication start date will be imputed as 
follows: 
• 
The first day of the month if day is missing 
• 
January if month is missing 
• 
If only year is recorded, 1 January 
If medication start date imputed in this way is before the date of the subject’s informed consent, the 
medication start date will be re-imputed as the date of the informed consent. 
4.2.9.4.2. 
Partial and Missing End Dates for Concomitant Medications 
If the end date for a medication is completely missing, the end date will be imputed as the date of the 
subject’s last visit.  If the end date for a medication is partially recorded, the medication end date will be 
imputed as follows: 
• 
The last day of the month if day is missing 
• 
December if month is missing 
• 
If only year is recorded, 31 December 
If a medication end date imputed in this way is after the date of the subject’s last visit, the medication end 
date will be re-imputed as the date of the subject’s last visit.  
4.2.10. 
Visit Windows 
All visits should occur at the scheduled visits according to the schedule of events 
 Section 2.4), but 
unscheduled visits may be necessary and visits to be performed at scheduled time points may be 


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performed later or earlier than planned in the protocol.  All data to be summarized over time will be 
tabulated by visit, based on the schedule of events.  
The Screening/ Day 1 visit should be the last visit of study PQ-110-001, ie, all Screening/Day 1 
assessments should take place during the EOS visit of study PQ-110-001. If these visits do not occur at 
the same time, a separate Screening/Day 1 visit should be performed as part of PQ-110-002. Dosing visits 
occur on Day 1 for the contralateral eye and then every 6 months. Dosing visits for the previously (first) 
treated eye will occur 3 months after the dosing visit for the contralateral eye and then every 6 months. 
Study center phone calls to the subjects will occur 7 days post-IVT injection, ±3 days. The End of Study 
(EOS) visit occurs 3 months after the last dose of study drug for a subject. 
For each visit, a visit window will establish a time interval around which data from the scheduled visit and 
any unscheduled visits will be considered to determine which data within the visit window should be 
summarized.  In general, the visit window is the scheduled visit day +/-30 days. 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 schedule 
of event 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 the protocol. 
Actual dates and times will be used for pharmacokinetic analyses rather than nominal days and times. 
4.3. 
Interim Analyses 
Ongoing review of safety and efficacy data will be conducted to inform the program. Interim analyses may 
be performed, eg, yearly, or at key time points during clinical development. 
4.4. 
Subject Disposition 
A tabulation of subject disposition will be presented by treatment group, age category and all subjects 
combined. Subject disposition will be summarized for All Screened Subjects,  including the number 


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screened, the number screened failure, the number who received study drug in the first treated eye and 
contralateral eye,  the number in each subject population for analysis, the number that discontinued 
study drug, and the number that discontinued the study, and the reasons for study discontinuation.  
The same disposition summary described above will be also provided for the Safety Population.  
A by-subject listing of study completion information, including the reason for premature study 
discontinuation, will be presented. 
4.5. 
Drug Exposure  
The summary of exposure to study drug will be presented by treatment group for the Safety Population.  
The exposure summary will summarize administration of study treatment to the first treatment eye, and 
the contralateral eye. The summary will include the number of doses received, the duration of treatment, 
the duration of follow up post first dose, the duration of follow-up post last dose, the cumulative dose, and 
the average daily dose, which will be calculated as follows: 
• 
Duration of Treatment = date of last dose-date of first dose+1 
• 
Total Duration of Follow Up Post First Dose = date of last assessment - date of first dose+1 
• 
Duration of Follow Up Post Last Dose = date of last assessment – date of last dose+1 
• 
Cumulative Dose = sum of all doses received 
• 
Average Daily Dose = cumulative dose ÷ duration of follow up post first dose 
The number of doses received will be summarized as a categorical variable, with the following categories, 
and the categires may be changed as per the available data:  
• 
1, 2, 3, 4, 5, 6 or 7 doses for summaries of exposure in the treatment eye 
• 
1, 2, 3, 4, 5, 6 or 7 doses for summaries of exposure in the contralateral eye 
Listings of study drug exposure and compliance will be provided based on the Safety Population. 


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4.6. 
Demographic and Baseline Characteristics 
Subject demographics and baseline 001 and 002 characteristics information for the Safety Population will 
be summarized by treatment group, age category and all subjects combined using descriptive statistics. No 
formal statistical comparisons will be performed. 
Subject characteristics at baseline include age (as recorded on the eCRF), age category (<18 years, ≥18 
years older), gender, race, ethnicity, body weight, height and Body Mass Index (BMI) as well as genotype 
for CEP290 c. 2991+1655A>G (homozygous, compound heterozygous).  The following formulae will be used 
to calculate BMI: 
Body Mass Index (BMI)= kg/m2 (where kg is a person’s weight in kilograms and m2 is height in 
meters squared) 
Baseline 001 and 002 disease characteristics include ophthalmic examinations, measurements and tests 
and BCVA (logMAR) (with separate categories for BCVA based on the Holladay and on the Lange 
equivalency table, in case of subjects for whom BCVA values could only be obtained via the clinical practice 
assessment).  
Demographic and baseline characteristics data will also be provided in a by subject data listing.  
A summary of non-ocular medical history and ocular medical history will be provided for the Safety 
Population. Non-ocular and ocular medical history will be coded to system organ class (SOC) and preferred 
term (PT) using the Medical Dictionary for Regulatory Activities (MedDRA) Version 20.0.  Non-ocular and 
ocular medical will be summarized separately, by treatment group and for all subjects combined, SOC and 
PT.  If a subject has multiple non-ocular or ocular history records which are coded to the same PT within 
the same SOC, that PT  for that subject will only be reported once. The same applies if a subject has 
multiple non-ocular or ocular history records which are coded to the different PTs within the same SOC, 
that SOC will only be reported once for that subject.  


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Ocular and non-ocular medical history will also be listed separately using by-subject listings which will 
include medical and surgical history, date of onset and the date of resolution or ongoing status. 
4.7. 
Safety Analyses 
All reporting of safety data will be based on the Safety Population.  Listings will include all available data.  
4.7.1. 
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 20.0 
and displayed in tables and listings using System/Organ/Class (SOC) and Preferred Term. 
Adverse events are summarized by subject frequencies, therefore, in any tabulation, a subject contributes 
only once to the count for a given adverse event (SOC or preferred term). 
A treatment emergent adverse event (TEAE) is defined as an event that was not present prior to 
administration of the first dose of study drug and present after the first dose or if it represents the 
exacerbation of an event that was present prior to the first dose. 
The number and percentage of subjects with any TEAE, with any TEAEs assessed by the Investigator as 
related to study drug and those related to drug administration (definite, probable, or possible 
relationship), and with any serious adverse event will be summarized by treatment group and overall.  
Deaths, TEAE severity, seriousness, outcomes (resolved, resolved with sequelae, not resolved, resolving, 
fatal and unknown) and study discontinuation due to TEAE will also be tabulated by treatment group. In 
these tabulations, each subject will contribute only once (i.e., the most related occurrence or the most 
severe occurrence) to each of the counts in the descriptive analysis, regardless of the number of episodes.  
No formal hypothesis-testing analysis of adverse events will be performed.   
Missing or partial start and end dates will be imputed as described in Section 4.2.9.3 before determining 
whether an AE is treatment emergent.  For subjects with an actual or imputed AE start date on Day 1, the 


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AE is treatment-emergent if the AE start time was not recorded or was after the time of the first dosing of 
study treatment on Day 1. 
An ocular TEAE following the first dose of study treatment is an ocular adverse event that was not present 
prior to administration of the first dose of study treatment but was present after the first dose, or an 
event with onset prior to the first dose with an exacerbation of the event after the first dose.  
A non-ocular TEAE is a non-ocular adverse event with onset after the first dose of study treatment, or an 
event that was present prior to the first dose which had an exacerbation (worsening) occurring after the 
first dose. 
If an ocular TEAE affects both eyes, it will be listed and summarized as two ocular TEAEs, affecting the first 
treated and contralateral eye.  If a subject has multiple TEAEs which are coded to the same PT within the 
same SOC, that PT will only be reported once for that subject. Similarly, if a subject has multiple TEAEs 
which are coded to different PTs within the same SOC, that SOC will only be reported once for that subject.  
In summaries of TEAEs by relationship, if there is more than one occurrence of a particular event for a 
subject, the event of most related will be included in the summary tables of TEAEs. In addition to 
presenting TEAEs by each relationship category (possibly related, probably related, and definitely related ), 
as indicated for the event by the Investigator, TEAEs will be summarized by the categories as being either 
related or not related,  where an TEAE will be considered related to study treatment if the event is at least 
‘possibly’ related (i.e., to include ‘possibly related’, ‘probably related’ and ‘definitely related’) or if the 
relationship is missing.  
In summaries of TEAEs by severity, if there is more than one occurrence of a particular event for a subject, 
the event of greatest severity will be included in the summary tables of TEAEs. In summaries of TEAEs by 
both severity and relationship, the most severe of the TEAEs will be included in the summary tables of 
TEAEs. 


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Unless otherwise stated, the following summaries of TEAEs will be presented for all non-ocular TEAEs, and 
separately for ocular TEAEs in the first treated eye , in the treated contralateral eye before the first dose in 
the study , in the treated contralaertal eye after the first dose in the study and in the non-treated 
contralateral eye. Unless otherwise stated, any summary of any type of TEAEs or serious adverse events 
(SAEs) which includes the SOC and PT of the events, will order the SOC and the PTs within the SOC in 
alphabetical order.   
The tables that provide an overview of TEAEs will be presented by treatment group, to include the number 
(and percentage) of subjects who had any TEAE, SAE, TEAE leading to discontinuation from study 
treatment, TEAE leading to discontinuation from the trial, deaths and will summarize the number of 
subjects who had a TEAE by severity, by relationship to study treatment and by relationship to study 
treatment administration. 
The adverse events that were identified by the Investigator as meeting the definition of an adverse event 
of special interest (AESI), as defined in Section 9.2.4 of the clinical study protocol will be supplemented by 
events for which and AESI has been defined but for which are not meeting the criterion for an AESI.  
The following summary tables will be produced: 
• 
Overview of Non-ocular TEAEs 
• 
Overview of Ocular TEAEs 
• 
Non-ocular TEAEs by, SOC and PT  
• 
Treatment-emergent AESIs  
• 
Non-ocular TEAEs by Severity  
• 
Ocular TEAEs by Severity  
• 
Non-ocular TEAEs by Relationship to Study Treatment  
• 
Ocular TEAEs by Relationship to Study Treatment  
• 
Non-Ocular TEAEs by Severity and Relationship to Study Treatment 
• 
Ocular TEAEs by Severity and Relationship to Study Treatment 


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• 
Non-ocular TEAEs by Relationship to Study Treatment Administration  
• 
Ocular TEAEs by Relationship to study Treatment Administration  
• 
Non-ocular TEAEs by Severity and Relationship to Study Treatment Administration  
• 
Ocular TEAEs by Severity and Relationship to study Treatment Administration  
• 
Non-ocular Treatment-emergent SAEs   
• 
Ocular Treatment-emergent SAEs  
• 
Non-OcularTEAEs Leading to Discontinuation from Study Treatment  
• 
Ocular TEAEs Leading to Discontinuation from Study Treatment 
• 
Non-Ocular TEAEs Leading to Discontinuation from the Study  
• 
Ocular TEAEs Leading to Discontinuation from the Study 
Listings for AEs, and SAEs will be generated separately for ocular and non-ocular events. A listing of AESIs 
will be provided, as well as a listing of AESIs as defined in the protocol for events that do not meet the 
criteria for an AESI . Additionally, listings of AEs leading to death will be generated. 
4.7.2. 
Laboratory Data 
Observed values and change from baseline in each hematology and clinical chemistry parameter will be 
summarized by treatment group, age category and scheduled study visit by using descriptive statistics 
(number of subjects, mean, standard deviation, median, minimum, and maximum) for the continuous data 
and frequencies and percentages for the categorical data.  
Hematology, clinical chemistry and urinalysis data, and changes from baseline, will be presented in subject 
listings. 
4.7.3. 
Vital Signs and Physical Examinations 
Vital signs measurements will consist of height, weight, heart rate, blood pressure and oral temperature. 
Descriptive summaries (number of subjects, mean, standard deviation, median, minimum, and maximum) 
of actual values and changes from baseline will be presented for each time point. These summaries will 


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be presented for the Safety Population and by treatment group. 
By-subject listings of vital signs data and complete and symptom-directed physical examinations (urogenital 
exams not required) findings will be presented in a data listing. 
4.7.4. 
Electrocardiogram 
12-lead electrocardiogram (ECG) data will be presented in a listing. 
4.7.5. 
Ophthalmic Examination 
A single summary and listing will be generated to summarize the slit-lamp bio-microscopy examination, 
lens opacity grading, intraocular pressure (IOP) monitoring and dilated fundus examinations.  Data will be 
summarized by treatment group (see Section 4.2.2), eye (first treated eye contralateral eye and non- 
contralateral eye) and visit using continuous and categorical summary statistics.  
4.7.5.1. 
Slit-Lamp Bio-microscopy Examinations  
Slit-lamp bio-microscopy examinations of the eyelid/lashes, conjunctiva palpebral, conjunctiva bulbar, 
cornea, iris, anterior chamber, anterior chamber cells, anterior chamber flare, and lens examination will be 
summarized by treatment group, eye (first treated eye and contralateral eye) and visit.  With the exception 
of presence of hypopyon (recorded as Yes, No), anterior chamber cells, and anterior chamber flare, the 
results will be graded as normal, abnormal not clinically significant or abnormal clinically significant.  
Results for assessments of anterior chamber cells will be recorded as 0 (no cells / <1), 0.5+ or trace (1 5 
cells), 1+ (6 15 cells), 2+ (16 25 cells), 3+ (26 50 cells), or 4+ (>50 cells), and anterior chamber flare recorded 
using the Standardization of Uveitis Nomenclature (SUN) Working Group Grading Scheme: 0 (none), 1+ 
(faint), 2+ (moderate / iris and lens details clear), 3+ (marked / iris and lens details hazy), or 4+ (intense/ 
fibrin or plastic aqueous).  
 


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4.7.5.2. 
Cataract (Lens Opacity) – Grading  
Nuclear opacity, cortical opacity and posterior subcapsular opacity will be graded using the Age-Related 
Eye Disease Study (AREDS) lens grading system on a 7-unit scale (<1, 1, 1.5, 2, 2.5, 3, >3). 
4.7.5.3. 
Dilated Fundus Examinations  
A dilated fundus examination of the vitreous, vitreous cells, vitreous flare/haze, macula, optic nerve, 
peripheral retina, choroid and cup-to-disc ratio will be performed at each visit.  Except for vitreous 
flare/haze, vitreous cells and cup-to-disc ratio, the results will be graded as normal, abnormal not clinically 
significant or abnormal clinically significant.  Grading of vitreous flare/haze and vitreous cells will follow the 
National Eye Institute Grading System.  For vitreous flare/haze, the results will be recorded as 0 (clear, no 
inflammation present), 0.5+ (trace inflammation present), 1+ (few opacities, mild blurring, clear optic disc 
and vessels), 2+ (significant blurring, hazy optic disc and vessels), 3+ (optic disc visible, no vessels seen), 4+ 
(dense opacity obscures optic disc, optic disc not visible).  For vitreous cells, the results will be recorded as 
0 (0-cells), 0.5+ (1-10cells), 1+ (11-20cells), 2+ (20-30cells), 3+ (30-100cells), or 4+ (>100 cells).  Cup-to-disc 
ratio will be assessed in the dilated fundus examination on a 0.1 to 1.0 scale in increments of 0.1.  
 
4.7.5.4. 
Intraocular Pressure  
Intraocular pressure (IOP) will be measured in each eye by the examiner (different equipments might be 
used between visits) and the results will be recorded in mmHg at screening, dosing and follow -up visits. 
4.7.6. 
Optical Coherence Tomograph (OCT) 
Optical coherence tomography (OCT) will measure full retinal thickness (FRT), outer nuclear layer (ONL) 
thickness, presence of macular edema, and photoreceptor outer segment layer thickness (PROST) 
performed by an independent reading center according to the schedule of events (Section 2.4 
 
The OCT values will be summarized by treatment group, eye and visit for the Safety Population using 
continuous descriptive statistics or categorical descriptive statistics. OCT data and any comments that may 
be relevant to the OCT grading will be listed for each subject in the Safety Population.  The measures listed 


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below, regardless of confidence score (high confidence, adequate confidence, inadequate confidence) will 
be used for summaries and listings. 
The following categorical data are collected as part of the OCT assessments: 
• 
Confidence Score 
• 
Confidence Score Reason 
• 
Presence of Cystoid Macular Edema  
• 
Additional Retina Morphology on Any Scan: 
• 
Vitreous Debris/Cells 
• 
Epiretinal Membrane 
• 
Normal Retina/Fovea Contour 
• 
Retinal Striae 
• 
Foveal Distortion 
• 
Adverse event of special interest (AESI) parameters 
• 
Final AESI determination 
• 
AESI comments OCT related comments 
The following continuous data are collected as part of the OCT assessments, and are measured in mm: 


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Descriptive statistics will be provided in summary tables, along with counts of missing values, characterized 
as either ‘cannot grade’ or ‘not applicable’.  A listing of all available data (quantitative values and 
qualitative replies of ‘cannot grade’ or ‘not applicable’ will also be provided. 
4.7.7. 
Prior and / or Concomitant Medications 
Medications administered to subjects during the study will be categorized as prior and/or concomitant 
medication.  If usage of a medication stopped before the administration of the first dose of study 
treatment, it will be counted as a prior medication. 
Two definitions of concomitant medications are required for this study: 
A concomitant medication for the first treated eye will either have started prior to first dosing in the first 
treated eye and is defined as a ‘prior and concomitant medication for the first treated eye’, or will have 
started after first dosing in the first treated eye and is defined as a ‘concomitant medication for the first 
treated eye’. 
A concomitant medication for the treated and non-treated contralateral eye will either have started prior 
to first dosing in the contralateral eye and is defined as a ‘prior and concomitant medication for the 
contralateral eye’, or will have started after first dosing in the contralateral eye and is defined as a 
‘concomitant medication for the contralateral eye’. 
Missing or partial start and end dates will be imputed as described in Section 4.2.9.4 before identifying 
whether to classify medication usage as prior or the two categories of concomitant medication. 
Medications will be coded using the WHO Drug Global B3/C3-format March 1, 2021.  Prior and concomitant 
medication usage by subjects in the Safety Population will be summarized. The summaries will be tabulated 
by treatment group, Anatomic Therapeutic Class (ATC) and preferred term, and will be presented 
separately for ocular and non-ocular concomitant medication usage. 


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The listing of prior and concomitant medication usage will identify whether the medication was ocular or 
non-ocular and, for ocular medication, whether the medication was a prior medication, a concomitant 
medication for the first treated eye starting prior to or after first dose of study treatment, or a concomitant 
medication for the contralateral eye starting prior to or after first dose of study treatment in the 
contralateral eye. 
4.8. 
Efficacy Evaluation 
Descriptive statistics of efficacy endpoints (Section 2.5.2) will be tabulated by treatment group, age 
category, and if appropriate, for treatment groups combined. The efficacy analysis will be conducted using 
the Efficacy Evaluable Population and Per Protocol Analysis Set. If Per Protocol Analysis Set is identical to 
the Efficacy Evaluable Analysis Population, the analysis results are only reported for Efficacy Evaluable 
Analysis Population. 
4.8.1. 
BCVA 
The BCVA will be assessed using the BRVT and the ETDRS acuity test. The best BCVA reading (ie, smallest 
numerical value in logMAR) for the first treated eye (based on ETDRS/BRVT) at Screening is considered the 
baseline BCVA (see also Section 4.2.4).  
BCVA is assessed using an ETDRS chart, or the BRVT (Bailey et al, 2012).  ETDRS provides logMAR values 
using on-chart assessments (i.e., logMAR values < +1.7).  BRVT provides logMAR values based on off-chart 
assessments (i.e., logMAR values ≥ +1.7), which is meant for subjects who cannot read letters.  
For subjects whose vision cannot be assessed with BRVT Single Tumbling E or Grating Acuity charts yielding 
logMAR values, the following BCVA measures can be provided based on BRVT: white field projection (WFP) 
and black and white discrimination (BWD). The measures of WFP and BWD represent more qualitative 
levels of vision as described by Bailey et al. 2012. For this study, imputed logMAR values will be used for 
WFP and BWD, as outlined in Table 2. For subjects with vision equal or worse than light perception (LP) 
data can be collected through the clinical practice assessment 


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When a BCVA assessment is performed, the assessment by ETDRS is completed first and, for ‘off-chart’ 
subjects (for whom ETDRS yields no results), will be followed by assessment of counting fingers (CF), hand 
movement (HM) and light perception (LP), performed as per clinical practice (not BRVT) and, subsequently, 
by BRVT assessment.  Data based on ETDRS or BRVT will be the primary data used for analysis. If a logMAR 
value is available from both ETDRS and BRVT, only the ETDRS result will be used for analysis.  


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4.8.1.1. 
Descriptive Statistics and  Listings  
The mean observed value and change from baseline in logMAR values for BCVA based on ETDRS and BRVT 
will be summarized by treatment group, eye (first treated eye, treated contralateral eye, non-treated 
contralateral eye) and visit using continuous descriptive statistics on the logMAR scale for BCVA, using the 
Efficacy Evaluable Population. A second table with individual observed values and change from baseline 
over time will also be produced. In case subjects  have individual BCVA responses based only on the clinical 
practice assessment, the corresponding logMAR values to be presented in the table will be based on both 
the Holladay equivalency table and the Lange equivalency table as described in Section 4.8.1. 


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Descriptive summaries of BCVA for the subpopulations of subjects defined in Section 4.2.7 will also be 
provided.  
 
A subject listing of visual acuity (BCVA), including all available data will be produced for the Efficacy 
Evaluable Population, including both the actual value and change from baseline at post-baseline time 
points. 
4.8.1.2. 
Responder Analysis for Treated Contralateral Eye 
A responder analysis will be summarized on overall group and performed on all contralateral eyes treated 
in PQ-110-002 with the following definitions of responders: 
− BCVA change from baseline for on-chart subjects (ie, BCVA < 1.7 logMAR based on ETDRS): 
• 
Equal or better than -0.2 logMAR, smaller values are better 
• 
Equal or better than -0.3 logMAR, smaller values are better 
− BCVA change from baseline for off-chart subjects (ie, BCVA ≥ 1.7 logMAR based on BRVT/clinical 
practice assessment): 
• 
leading to a categorical change in VA category according to Holladay VA reference scale (Section 8): 
o From LP to HM or better, ie, 
▪ 
from logMAR 4 (clinical assessment) or logMAR 3.5 (BWD result from BRVT) to 
logMAR 3 (clinical assessment) or better (BRVT) 
▪ 
from logMAR 3.2 (WFP result from BRVT) to logMAR 2.9 or better (BRVT) 
o From HM to CF or better, ie,: 
▪ 
from logMAR 3 (if only clinical assessment result available) to logMAR 2 (if only 
clinical assessment result is available) or better (BRVT), OR: 


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▪ 
from logMAR 3 (if only clinical assessment result available) to logMAR 1.7 - 2 or 
better (BRVT), OR: 
▪ 
from logMAR >2 – 2.9 (based on BRVT) to logMAR 1.7 - 2 or better (based on 
BRVT), AND the BCVA change from baseline is equal or better than -0.3 logMAR (ie, 
≤ -0.3 logMAR)  
o From CF to on-chart, ie,: 
▪ 
from logMAR 2 (if only clinical assessment result available) to a logMAR value of < 
1.7 based on ETDRS 
▪ 
from logMAR 1.7 - 2 (based on BRVT) to a logMAR value of < 1.7 based on ETDRS 
AND the BCVA change from baseline is equal or better than -0.3 logMAR (ie, ≤ -0.3 
logMAR)  
• 
leading to a change in VA category according to Lange VA reference scale (Section 9)  
o From LP to HM or better, ie: 
▪ 
from logMAR >2.5 - 2.7 (based on BRVT/clinical assessment) to >2 - 2.5 (based on 
BRVT/clinical assessment) AND the BCVA change from baseline is equal or better 
than -0.3 logMAR (ie, ≤ -0.3 logMAR)  
o From HM to CF, ie,: 
▪ 
from logMAR 2.3 (if only clinical assessment result available) to logMAR 1.7 - 2 or 
better (based on BRVT), OR: 
▪ 
from logMAR >2 - 2.5 (based on BRVT) to logMAR 1.7 - 2 or better (based on BRVT), 
AND the BCVA change from baseline is equal or better than 
-0.3 logMAR (ie, ≤ -0.3 logMAR)  
o From CF to on-chart, ie,: 


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▪ 
from logMAR 2 (if only clinical assessment result available) to a logMAR value of < 
1.7 based on ETDRS 
▪ 
from logMAR 1.7-2 (based on BRVT) to a logMAR value of < 1.7 based on ETDRS 
AND the BCVA change from baseline is equal or better than -0.3 logMAR (ie, ≤ -0.3 
logMAR) 
4.8.1.3. 
Vision Preservation Analysis for the First Treated Eyes 
A vision preservation analysis will be summarized on overall group and performed on the first treated eyes 
which were treated in PQ-110-001 and continue to be treated in PQ-110-002 with the following definitions 
of achieving the vision preservation: 
− BCVA change from baseline for on-chart subjects (ie, BCVA < 1.7 logMAR based on ETDRS): 
• 
Among the subjects that are responders at month 12 to the -0.3 criterion 
➢ Remain responsders at -0.3 logMAR  
➢ Remain responsders at -0.2 logMAR (allowing a worsening of + 0.1 log MAR) 
➢ Have a worsening of equal or more than + 0.2 log MAR 
➢ Have a worsening of equal or more than + 0.3 log MAR 
• 
Among the subjects that are responders at month 12 to the -0.2 criterion 
➢ Remain responsders at -0.2 logMAR 
➢ Have a worsening of equal or more than + 0.1 log MAR 
➢ Have a worsening of equal or more than + 0.2 log MAR 
➢ Have a worsening of equal or more than + 0.3 log MAR 


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− BCVA change from baseline for off-chart subjects (ie, BCVA ≥ 1.7 logMAR based on BRVT/clinical 
practice assessment): leading to a categorical change in VA category according to Holladay VA 
reference scale (Section 8) or Lange VA reference scale (Section 9) 
• 
Among the subjects that are responders at month 12 to the responder criterion defined in the 
section 4.8.1.2, the same rule used for on-chart subjects will be performed. 
4.8.2. 
Mobility Course 


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4.8.3. 
Full-Field Stimulus Threshold Testing (FST) 
Full field stimulus testing captures threshold measurements for each stimulus (blue and red light).  
Measurements with a Fail value of “0” are successful, and any measurements with a Fail value of “1” are 
unsuccessful.  If the threshold value fails, the next successful value will be captured.  FST thresholds will be 
measured by an independent reading center according to the schedule of events in section 2.4 and the 
Imaging Charter. 
The mean FST values (i.e., light sensitivity) for each eye (first treated eye, treated and non-treated 
contralateral eye) will be summarized using continuous descriptive statistics by treatment group, eye and 
visit for each stimulus color, for all subjects in the Efficacy Evaluable Population.  The FST values are the 
average of all FST stimulus sizes (in log cd/m2) for the given eye at a given visit and stimulus color.  
Descriptive statistics will be based on only successful thresholds (‘acceptable data’).  
A responder analysis will be performed on the contralateral eyes treated in PQ-110-002 with the following 
definitions of responders: 
− Blue FST change from baseline: 
• 
Equal or better than -0.7 log (cd/ m2), smaller values are better 
• 
Equal or better than -0.5 log (cd/ m2), smaller values are better 
− Red FST change from baseline: 


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• 
Equal or better than -0.7 log (cd/ m2), smaller values are better 
• 
Equal or better than -0.5 log (cd/ m2), smaller values are better 
A vision preservation analysis for FST will be performed the first treated eyes which were treated in PQ-
110-001 and continue to be treated in PQ-110-002 with the following definitions of achieving the vision 
preservation: 
− Blue FST change from baseline: 
• 
Among the subjects that are responders at month 12 to the -0.7 criterion 
➢ Remain responsders at -0.7 log (cd/ m2) 
➢ Remain responsders at -0.6 log (cd/ m2)  (allowing a worsening of + 0.1 log (cd/ m2) ) 
➢ Remain responsders at -0.5 log (cd/ m2)  (allowing a worsening of + 0.2 log (cd/ m2) ) 
➢ Have a worsening of equal or more than + 0.3 log (cd/ m2) 
• 
Among the subjects that are responders at month 12 to the -0.5 criterion 
➢ Remain responsders at -0. 5 log (cd/ m2) 
➢ Have a worsening of equal or more than + 0.1 log (cd/ m2) 
➢ Have a worsening of equal or more than + 0.2 log (cd/ m2) 
➢ Have a worsening of equal or more than + 0.3 log (cd/ m2) 
− Red FST change from baseline: 
• 
Among the subjects that are responders at month 12 to the -0.7 criterion 
➢ Remain responsders at -0.7 log (cd/ m2) 
➢ Remain responsders at -0.6 log (cd/ m2)  (allowing a worsening of + 0.1 log (cd/ m2) ) 
➢ Remain responsders at -0.5 log (cd/ m2)  (allowing a worsening of + 0.2 log (cd/ m2) ) 


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➢ Have a worsening of equal or more than + 0.3 log (cd/ m2) 
• 
Among the subjects that are responders at month 12 to the -0.5 criterion 
➢ Remain responsders at -0. 5 log (cd/ m2) 
➢ Have a worsening of equal or more than + 0.1 log (cd/ m2) 
➢ Have a worsening of equal or more than + 0.2 log (cd/ m2) 
➢ Have a worsening of equal or more than + 0.3 log (cd/ m2) 
In addition, tables with individual values over time will also be produced, for both original and change from 
baseline values.  A subject listing of all failed and successful threshold FST, including FST related comments 
will be produced for the Efficacy Evaluable Population. 
4.8.4. 
Optical Coherence Testing 
OCT parameters related to EZ line/width are considered efficacy parameters and are presented in the 
current section.  These OCT values will be summarized by treatment group, eye and visit for the Efficacy 
Evaluable Population using continuous descriptive statistics. OCT data and any comments that may be 
relevant to the OCT grading will be listed for each subject in the Efficacy Evaluable Population.  The 
measures listed below, regardless of confidence score (high confidence, adequate confidence, inadequate 
confidence) will be used for summaries and listings. 
The following continuous data are considered efficacy endpoints collected as part of the OCT assessments, 
and are measured in mm: 


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 A second table with individual observed values and 
change from baseline over time will also be produced. Subject level listings will also be produced for OCT.  
4.8.5. 
NIRAF 
The following categorical data are collected as part of the NIRAF assessments performed by an 
independent reading center according to the schedule of events in Section 2.4 and the Imaging Charter: 
• 
Confidence Score 
• 
Confidence Score Reason 
The following continuous data are collected as part of the NIRAF assessments, and summarized using 
continuous descriptive statistics by treatment group, eye and visit for the Efficacy Evaluable Population: 
• 
Horizontal Diameter of Retained Central Hyperautofluorescent Island (mm) 
• 
Vertical Diameter of Retained Central Hyperautofluorescent Island (mm) 
• 
Area of Retained Central Hyperautofluorescent Island (mm) 
Confidence score will be listed and summarized using descriptive statistics for categorical data by 
treatment group, eye and visit, and confidence score reason will be listed only. 
Tables with individual values over time will be produced, for both original and change from baseline values. 
Subject level listings will also be produced for NIRAF. 
4.8.6. 
Oculomotor Instability 
A confidence score is collected for each eye as part of the oculomotor instability assessments (with and 
without fixation) performed by an independent reading center according to the Schedule of Events of 


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Section 2.4 and the Imaging Charter.  For oculomotor instability assessments with and without fixation, 
confidence score will be listed and summarized using descriptive statistics for categorical data, and 
comments that may be relevant to the grading will be listed. 
The following continuous data are collected as part of the oculomotor instability assessments (with and 
without fixation), and summarized using continuous descriptive statistics for the Efficacy Evaluable 
Population: 
• 
Mean Gaze Shift 
• 
Oculomotor Instability 
• 
Overall Oculomotor Instability Measurement 
• 
Excluded Frames Count 
• 
Calculated Frames Count 
All measures, regardless of confidence score (high confidence, adequate confidence, inadequate 
confidence) will be summarized by treatment group, fixation (with or without), eye and visit, and listed.  In 
addition, tables with individual values over time will also be produced, for both original and change from 
baseline values. 
4.8.7. 
Pupillary Light Reflex 
PLR imaging measures pupil size with various candela per square meter stimuli (ie, at 4, 40, 400 and 4000 
cd/m2); it is used to test integrity of the sensory and motor functions of the eye. For PLR amplitude 
parameters, higher values are indicative of better status. For PLR latency parameters, lower values are 
indicative of better status. 
The mean observed value and change from baseline values for the following parameters will be 
summarized for the different stimuli (ie, at 4, 40, 400 and 4000 cd/m2) by treatment group, eye and visit for 
the Efficacy Evaluable Population using descriptive statistics: 
• 
pre-stimulus (mm) 


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• 
maximum amplitude (mm) 
• 
0.9 seconds amplitude (mm)  
• 
Latency (s)  
In addition, the following derived parameter will be summarized as well: maximum amplitude minus pre-
stimulus at 4000 cd/m2  
Subject level listings will also be produced for PLR. 
4.8.8. 
VFQ-25/CVAQC 
The observed value and change from baseline values over time for overall VFQ-25 composite scores for 
adult subjects and CVAQC scores for pediatric subjects will be summarized  by treatment group and visit for 
the Efficacy Evaluable Population and Per Protocol Analysis Set using descriptive statistics. Descriptive 
summaries of VFQ-25/CVAQC for the subpopulations of subjects defined in Section 4.2.7 will also be 
provided. Subject level listings will be produced. 
• 
VFQ-25  Scoring VFQ-25 is a two-step process: 
Step 1: original numeric values from the survey are re-coded following the scoring rules outlined in Table 6. 
All items are scored so that a high score represents better functioning. Each item is then converted to a 0 
to 100 scale so that the lowest and highest possible scores are set at 0 and 100 points, respectively. In this 
format scores represent the achieved percentage of the total possible score, e.g. a score of 50 represents 
50% of the highest possible score. 
Step 2: items within each sub-scale are averaged together to create the 12 subscale scores. Table 7 
indicates which items contribute to each specific sub-scale. Items that are left blank (missing data) are not 
taken into account when calculating the scale scores. Sub-scales with at least one item answered can be 
used to generate a sub-scale score. Hence, scores represent the average for all items in the subscale that 
the respondent answered.  


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Composite Score Calculation  
To calculate an overall composite score for the VFQ-25, simply average the visiontargeted subscale scores, 
excluding the general health rating question. By averaging the sub-scale scores rather than the individual 
items we have given equal weight to each sub-scale, whereas averaging the items would give more weight 
to scales with more items. 
Table 6.  Scoring Key: Recoding of Items 
Item Numbers 
Change original response 
category(a) 
To recoded value of: 
1,3,4,15c(b) 
1 
2 
3 
4 
5 
100 
75 
50 
25 
0 
2 
1 
2 
3 
4 
5 
100 
80 
60 
40 
20 
0 
5,6,7,8,9,10,11,12,13,14,16,16a 
A3,A4,A5,A6,A7,A8,A9(c) 
1 
2 
3 
4 
5 
6 
100 
75 
50 
25 
0 
* 
17,18,19,20,21,22,23,24,25, 
A11a,A11b,A12,A13 
1 
2 
3 
4 
5 
0 
25 
50 
75 
100 
A1,A2 
0 
To 
10 
0 
To 
100 
(a) Precoded response choices as printed in the questionnaire. 


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(b) Item 15c has four-response levels, but is expanded to a five-levels using item 15b. 
Note: If 15b=1, then 15c should be recoded to "0" 
           If 15b=2, then 15c should be recoded to missing. 
           If 15b=3, then 15c should be recoded to missing. 
(c) "A" before the item number indicates that this item is an optional item from the Appendix. If optional 
items are used, the NEI-VFQ developers encourage users to use all items for a given subscale. 
This will greatly enhance the comparability of sub-scale scores across studies. 
* Response choice "6" indicates that the person does not perform the activity because of non-vision related 
problems. If this choice is selected, the item is coded as "missing." 
Table 7.  Averaging of Items to Generate VFQ-25 Sub-Scales 
Scale 
Number of Items 
Items to be averaged 
(after recoding per previous Table) 
General Health  
1 
1 
General Vision  
1 
2 
Ocular Pain  
2 
4, 19 
Near Activities  
3 
5, 6, 7 
Distance Activities  
3 
8, 9, 14 
Vision Specific: 
 
 
      Social Functioning 
2 
11, 13 
      Mental Health 
4 
3, 21, 22, 25 
      Role Difficulties 
2 
17, 18 
      Dependency 
3 
20, 23, 24 
Driving 
3 
15c, 16, 16a 
Color Vision 
1 
12 
Peripheral Vision 
1 
10 
• 
Cardiff Visual Ability Questionnaire for Children (CVAQC)-25 


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CVAQC-25 is a visual impairment ability questionnaire for children with 25 items. The response to each 
item has 5 categories. In this study, the CVAQC-25 total score will be calculated using “Rasch” scoring 
algorithm. Based on this method, each item has a base measure which calls Item Measure (Table 8), and 
each category of response has a measure  which calls Category Measure (Table 9). To calculate the total 
score following steps will be taken: 
1- For each item, Item Score will be calculated as sum of Item Measure and its Category Measure  
2- CVAQC-25 total score will be calculated as average of none missing item scores 
Table 8  
CVAQC-25: Item Mesaure 
 
 
 
Table 9  CVAQC-25: 
Category Measure 
Item No.  Item  
Item measure 
Category measures 
1 Maths Lessons 
0.33 
1 
-2.96 
2 Science Lessons  
-0.25 
2 
-0.85 
3 Geography 
-0.86 
3 
0.95 
4 Language  
0.06 
4 
2.8 
5 Text books/Work sheet 
-0.19 
5 
Missing data 
6 Smallest print 
-2.18 
 
 
7 Drawing/colouring/ Painting  
0.77 
 
 
8 Mobile phone 
0.10 
 
 
9 Restaurant menus 
-0.79 
 
 
10 Board in your classroom 
-0.76 
 
 
11 Television 
1.30 
 
 
12 Film at the cinema 
1.45 
 
 


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13 Day light  
0.42 
 
 
14 Crowded place 
-0.78 
 
 
15 Public transport 
-0.02 
 
 
16 Bus/Train Time table 
-1.90 
 
 
17 Chat with your friends 
1.69 
 
 
18 Recognising faces 
0.70 
 
 
19 Seeing friend in the Playground 
-1.06 
 
 
20 Use playstation 
1.04 
 
 
21 Computer games 
0.49 
 
 
22 Listening to Music  
0.65 
 
 
23 Swimming 
0.76 
 
 
24 Athletics  
-0.15 
 
 
25 Ball games 
-0.81 
 
 
 
 
 
 
 
4.8.9. 
Exploratory Endpoints  


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4.9. 
Pharmacokinetic Evaluations 
It is expected that the vast majority of measured PK concentrations is below limit of quantification (BLQ). 
Thus, no pharmacokinetic parameters (Cmax, Tmax, AUC0-24, AUClast and AUC0-inf) will be derived. All individual 
measurement results above limit of quantification will be shown in a individual level table, and  all 
measurements – above or below limit of quantification will be presented in the listings on the safety 
population. 
 
 
 
 


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5. 
CHANGES TO PLANNED ANALYSES 
The definition of baseline relevant to PQ-110-001 specified in the protocol has been changed and described 
in Section 4.2.4 of this SAP. 
More precise description with respect to the secondary endpoints are described in Section 2.5.1.2 of this 
SAP. 
The exploratory endpoint “Change in Ellipsoid Zone line by OCT” listed in the protocol which is refer to the 
same as the secondary endpoint related to OCT has been removed in this SAP. The more detail is described 
in Section 4.8.4. 
The definition of the Efficacy Evaluable Population has been changed from that in specified in the protocol 
by removing the requirement for at least one post-baseline assessment. 
The Pharmacokinetics (PK) Population has been removed since we will not derived pharmacokinetic 
parameters as it is expected that the vast majority of measured PK concentrations is below limit of 
quantitation (BLQ). 
 


     Statistical Analysis Plan Template 
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6. 
REFERENCES 
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. 
 
Cideciyan AV, Aleman TS, Jacobson SG, Khanna H, Sumaroka A, Aguirre GK, et al. Centrosomal-
ciliary gene CEP290/-NPHP6 mutations result in blindness with unexpected sparing of 
photoreceptors and visual brain: implications for therapy of Leber congenital amaurosis. Hum 
Mutat. 2007 Nov; 28(11):1074-83. 
 
Cideciyan AV, Rachel RA, Aleman TS, Swider M, Schwartz SB, Sumaroka A, et al. Cone photoreceptors 
are the main targets for gene therapy of NPHP5 (IQCB1) or NPHP6 (CEP290) blindness: generation of an 
all-cone Nphp6 hypomorph mouse that mimics the human retinal ciliopathy. Hum Mol Genet. 2011. 
20(7):1411-23. 
 
Coppieters F, Casteels I, Meire F, De Jaegere S, Hooghe S, van Regemorter N, et al. Genetic screening of 
LCA in Belgium: predominance of CEP290 and identification of potential modifier alleles in AHI1 of 
CEP290-related phenotypes. Hum Mutat. 2010 Oct; 31(10): E1709-66. 
 
Den Hollander Al, Koenekoop RK, Yzer S, Lopez I, Arends ML, Voesenek KE, et al. Mutations in the CEP290 
(NPHP6) gene are a frequent cause of Leber congenital amaurosis. Am J Hum Genet. 2006 Sep; 
79(3):556-61. 
 
Den Hollander AI, Roepman R, Koenekoop RK, Cremers FP. Leber congenital amaurosis- genes, proteins 
and disease mechanisms. Prog Retin Eye Res. 2008 Jul; 27(4):391-419. 
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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- 


     Statistical Analysis Plan Template 
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Protocol: 
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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. 
 
Estrada-Cuzcano A, Koenekoop RK, Coppieters F, Kohl S, Lopez I, Collin RW, et al. IQCB1 mutations in 
patients with Leber congenital amaurosis. Invest Ophthalmol Vis Sci. 2011 Feb 11; 52(2):834-9. 
 
European Union Delegated Regulation No. 536/2014 for Clinical Trials. Available at: 
https://ec.europa.eu/health/human-use/clinical-trials/regulation_en 
 
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 
 
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 
 
Jacobson SG, Cideciyan AV, Sumaroka A, Roman AJ, Charng J, Lu M, et al. Outcome Measures for Clinical 
Trials of Leber Congenital Amaurosis Caused by the Intronic Mutation in the CEP290 Gene. Invest 
Ophthalmol Vis Sci. 2017 May 1;58(5):2609-2622. doi: 10.1167/iovs.17- 21560. 
 
Kmoch S, Majewski J, Ramamurthy V, Cao S, Fahiminiya S, Ren H, et al. Mutations in PNPLA6 are linked to 
photoreceptor degeneration and various forms of childhood blindness. Nat Commun. 2015 Jan 9; 6:5614. 
doi:10.1038/ncomms.56614 
 
Littink KW, Pott JWR, Collin RWJ, Kroes HY, Verheij JBGM, Blokland EAW, et al. A novel nonsense 
mutation in CEP290 induces exon skipping and leads to a relatively mild retinal phenotype. Invest 


     Statistical Analysis Plan Template 
Sponsor:  
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Protocol: 
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Document Version No.: 
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Document Date: 
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Ophthal Vis Sci. 2010 July; 51(7):3646-52. 
 
McAnany JJ, Genead MA, Walia S, Drack AV, Stone EM, Koenekoop RK, et al. Visual acuity changes in 
patients with Leber congenital amaurosis and mutations in CEP290. JAMA Ophthalmol. 2013. 
131(2):178-82. 
 
National Institute of Diabetes and Digestive and Kidney Diseases. Laboratory Evaluation. Glomerular 
Filtration Rate (GFR) Calculators. https://www.niddk.nih.gov/health- information/communication-
programs/nkdep/laboratory-evaluation/glomerular-filtration-rate- calculators. Accessed 05 November 
2017. 
 
Parfitt DA, Lane A, Ramsden CM, Carr A-J F, Munro PM, et al. Identification and correction of mechanisms 
underlying inherited blindness in human iPSC-derived optic cups. Cell Stem Cell. 2016 Apr 12. pii: S1934-
5909(16)30010-8. doi: 10.1016/j.stem.2016.03.021. 
 
Perrault L, Delphin N, Hanein S, Gerber S, Dufier JL, Roche O, et al. Spectrum of NPHP6/- CEP290 
mutations in Leber congenital amaurosis and delineation of the associated phenotype. Hum Mutat. 
2007 Apr; 28(4):416. doi:10.1002/humu.9485 
 
Stone EM. Leber congenital amaurosis- a model for efficient genetic testing of heterogeneous disorders: 
LXIV Edward Jackson memorial lecture. Am J Ophthalmol. 2007 Dec; 144(6):791- 811. 
doi:10.1016/j.ajo.2007.08.022 
 
Yzer S, Hollander AI, Lopez I, Pott JW, de Faber JT, Cremers FP, et al. Ocular and extra-ocular features of 
patients with Leber congenital amaurosis and mutations in CEP290. Mol Vis. 2012; 18:412-25.


     Statistical Analysis Plan Template 
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Document Date: 
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7. 
APPENDIX A 
This SAP refers to the following documents: 
 
 
 
 
 
 
 
 
 
 


     Statistical Analysis Plan Template 
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Document Version No.: 
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Document Date: 
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     Statistical Analysis Plan Template 
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Protocol: 
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Document Date: 
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     Statistical Analysis Plan Template 
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ProQR Therapeutics 
Protocol: 
PQ-110-002 
Document Version No.: 
1.0 
Document Date: 
04 JAN 2022 
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     Statistical Analysis Plan Template 
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ProQR Therapeutics 
Protocol: 
PQ-110-002 
Document Version No.: 
1.0 
Document Date: 
04 JAN 2022 
 
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     Statistical Analysis Plan Template 
Sponsor:  
ProQR Therapeutics 
Protocol: 
PQ-110-002 
Document Version No.: 
1.0 
Document Date: 
04 JAN 2022 
 
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