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
Phase: PHASE1
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
Sponsor: Laboratoires Thea

 
 
 
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) 
 
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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) 
 
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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 

Investigational Product:  QR-110 
Protocol No. PQ-110-002 (Version 4.0) 
 
ProQR Therapeutics   
 
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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 
 

Investigational Product:  QR-110 
Protocol No. PQ-110-002 (Version 4.0) 
 
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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.