Conditions: Leber's Congenital Amaurosis
Keywords: CEP290 p.Cys998X c.2991+1655A>G RNA therapy Antisense oligonucleotide Leber's congenital amaurosis
Allocation: NA | Intervention model: SEQUENTIAL
Enrollment: 11
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety and tolerability of QR-110 administered via intravitreal injection in subjects with LCA due to the CEP290 p.Cys998X mutation.

Detailed description:
The purpose of this study is to evaluate the safety and tolerability of QR-110 administered via intravitreal injection in subjects with LCA due to the CEP290 p.Cys998X mutation. Subjects will receive QR-110 in one eye every 3 months, for a maximum of 4 doses. Up to 3 dose levels of QR-110 will be evaluated.

Arms:
arm 1: Administered every 3 months

Interventions: intervention 1: QR-110
Intervention descriptions: intervention 1: RNA antisense oligonucleotide for intravitreal injection

Protocol document:
Prot_000.pdf: 
Investigational Product: QR-110 
Protocol No. PQ-110-001 (Version 6.0) 
 
ProQR Therapeutics 
 
Page 1 of 80 
 
 
02-Aug-2018 
 
CLINICAL STUDY PROTOCOL 
AN OPEN-LABEL, MULTIPLE DOSE, DOSE ESCALATION STUDY TO EVALUATE 
THE SAFETY AND TOLERABILITY OF QR-110 IN SUBJECTS WITH LEBER’S 
CONGENITAL AMAUROSIS (LCA) DUE TO c.2991+1655A>G MUTATION 
(p.Cys998X) IN THE CEP290 GENE 
 
Protocol No. PQ-110-001 
Protocol/Amendment Date: 02-Aug-2018 
Protocol/Amendment No.: 05 
Protocol Version: 6.0 
Supersedes: Protocol version 3.0, 4.0 and 5.0 
EudraCT/IND Number 2017-000813-22/130557 
Sponsor: ProQR Therapeutics  
Zernikedreef 9 
2333 CK Leiden 
The Netherlands 
CRO Medical Monitor 
 
 
 
 
Sponsor Medical Monitor: 
Telephone Number: 
 
 
 


Investigational Product: QR-110 
Protocol No. PQ-110-001 (Version 6.0) 
 
ProQR Therapeutics 
 
Page 2 of 80 
 
 
 
02-Aug-2018 
 
INVESTIGATOR SIGNATURE PAGE 
 
PRINCIPAL INVESTIGATOR COMMITMENT: 
I will provide copies of the protocol, any subsequent protocol amendments and access to all 
information provided by the Sponsor to the study personnel under my supervision. I will discuss 
this material with them to ensure that they are fully informed about the study drug and the study 
protocol. 
I agree to conduct this clinical study according to the attached protocol, except when mutually 
agreed to in writing. I also agree to conduct this study in compliance with all applicable local 
regulations, Good Clinical Practices (GCP), as well as with the requirements of the appropriate 
Institutional Review Board(s) (IRB)/Ethics Committee(s) (EC) and any other Institutional 
requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Principal Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Institution 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Address of Institution 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phone Number of Investigator 
 
 


Investigational Product: QR-110 
Protocol No. PQ-110-001 (Version 6.0) 
 
ProQR Therapeutics 
 
Page 3 of 80 
 
 
 
02-Aug-2018 
 
PROTOCOL APPROVAL PAGE 
An Open-Label, Multiple Dose, Dose Escalation Study to Evaluate the Safety and Tolerability of 
QR-110 in Subjects with Leber’s Congenital Amaurosis (LCA) due to c.2991+1655A>G 
Mutation (p.Cys998X) in the CEP290 Gene 
Protocol No. PQ-110-001 
Protocol/Amendment Date: 02-Aug-2018 
Protocol/Amendment No.: 05 
Protocol Version: 6.0 
 
SPONSOR:  
ProQR Therapeutics 
Zernikedreef 9 
2333 CK Leiden 
The Netherlands 
 
 
 
 
 
 
 
 
 
Date 
 
Date 


Investigational Product: QR-110 
Protocol No. PQ-110-001 (Version 6.0) 
 
ProQR Therapeutics 
 
Page 4 of 80 
 
 
 
02-Aug-2018 
 
NATIONAL COORDINATING INVESTIGATORS 
 
Name 
Institution 
Street Address 
City, Country, Postal 
Code 
 
Name 
Institution 
Street Address 
City, Country, Postal 
Code 
 
 
 


Investigational Product: QR-110 
Protocol No. PQ-110-001 (Version 6.0) 
 
ProQR Therapeutics 
 
Page 5 of 80 
 
 
 
02-Aug-2018 
 
1.0 
SYNOPSIS 
Name of the Sponsor: 
ProQR Therapeutics 
Individual Study Table Referring to 
Part of the Dossier: 
Volume: NA 
Page: NA 
For National Authority Use Only 
 
Name of Study Drug: 
QR-110 Solution for Intravitreal Injection 
Name of Active Ingredient: 
QR-110 
Title of Study:  
An Open-Label, Multiple Dose, Dose Escalation Study to Evaluate the Safety and 
Tolerability of QR-110 in Subjects with Leber’s Congenital Amaurosis (LCA) due to 
c.2991+1655A>G Mutation (p.Cys998X) in the CEP290 Gene 
Study Centers:  
Participation of approximately 3 study centers planned 
Phase of Development: 
Phase 1b/2 
Study Period:  
Anticipated to be approximately 18 months 
Duration of Subject Participation: 
13 months (Screening 28 days; study period 12 months) 
Rationale:  
Leber’s 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). 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. QR-110 is a single stranded, chemically modified, RNA oligonucleotide 
that is designed to correct aberrant splicing in CEP290 gene, enabling production of 
fully functional RNA and protein. 
Objectives: 
Primary: To evaluate the safety and tolerability of QR-110 administered via intravitreal 
(IVT) injection in subjects with LCA due to the CEP290 p.Cys998X mutation  
Secondary: To evaluate the serum pharmacokinetics of QR-110 administered by IVT 
injection in subjects with LCA due to the CEP290 p.Cys998X mutation 
To evaluate the efficacy of QR-110 administered by IVT injection in subjects with LCA 
due to the CEP290 p.Cys998X mutation  
 
Number of Subjects (planned): 
12   
The final number of subjects is dependent on whether any dose levels are expanded by 
the Data Monitoring Committee (DMC) and Sponsor Medical Monitor. 
Study Design 
The first-in-human study of QR-110 will be an open-label, multiple dose, dose 
escalation study to evaluate the safety and tolerability of QR-110 administered via IVT 
injection in subjects with LCA due to the CEP290 p.Cys998X mutation. Subjects will 


Investigational Product: QR-110 
Protocol No. PQ-110-001 (Version 6.0) 
 
ProQR Therapeutics 
 
Page 6 of 80 
 
 
 
02-Aug-2018 
 
be assigned to receive a specified dose level of QR-110 (loading dose and maintenance 
dose) and will receive that dose throughout their participation, while they are monitored 
for safety. No intrasubject dose escalation is planned. Up to 3 dose levels of QR-110 
will be evaluated. Dose escalation decisions and initiation of dosing in pediatric 
subjects (6 to <18 years of age) will be determined by the DMC and Sponsor Medical 
Monitor review of safety and tolerability data. The DMC and Sponsor Medical Monitor 
will also review all available safety data at key study time points (eg, prior to the first 
subject in the first adult cohort (Cohort A1) receiving each subsequent dose of study 
drug).  
QR-110 will be administered by unilateral IVT injection. Each subject will receive up 
to 4 doses of QR-110 in their worse eye (as defined by visual acuity at Screening, 
subsequently referred to as treatment eye) every 3 months and will be assessed for 
safety and tolerability at follow up visits. If both eyes have the same visual acuity, the 
Investigator should determine the eye with the worse visual function as the treatment 
eye, according to other measures of ophthalmic function (Full-field Stimulus Testing 
[FST] or mobility course score). If the visual function is the same per the Investigator’s 
assessment, then the treatment eye will be determined at Investigator discretion. No 
placebo nor sham injections will be administered in the contralateral eye.  
The contralateral eye and the subject’s own baseline measurements will serve as 
controls.   
Subjects who do not meet stopping criteria prior to their next scheduled injection will 
receive their planned dose (Section 4.2.2). Subjects who meet stopping criteria will be 
discontinued from dosing and will be followed for safety and efficacy.  
The DMC and/or Sponsor Medical Monitor may decide to de-escalate the dose, hold the 
dose (delay or skip), or discontinue study drug for an individual subject, in consultation 
with the Investigator. Subjects who discontinue study drug will continue to be followed 
for safety and efficacy. 
An extension study, which would permit continued dosing of eligible subjects who 
complete PQ-110-001, is planned.  
Dose Escalation 
Specifics of the dose escalation plan are described in detail in Section 4.2.1.5. It is 
planned to dose at least 2 adults and, subsequently, at least 2 pediatric subjects at each 
dose level of QR-110. Up to 3 dose levels are planned across 3 dose cohorts. No 
intrasubject dose escalation will occur. Dosing will be staggered such that:  
• 
The first 2 subjects at any dose level will be dosed at least 2 weeks apart 
• 
At least 4 weeks of post dose safety and tolerability data on the previous 
cohort will be reviewed by the DMC and Sponsor Medical Monitor prior to 
dose escalation in subsequent subjects  
• 
Dosing and dose escalation of pediatric cohorts will be initiated following 
DMC and Sponsor Medical Monitor review and will follow that of the 
corresponding adult cohort by at least 4 weeks 
Following DMC and Sponsor Medical Monitor review and decision on dose escalation, 
the first subject at the next dose level may be dosed and the second subject at that dose 
level may be dosed 2 weeks later. Safety and tolerability data, including follow-up for 
at least 4 weeks post dose, will be reviewed by the DMC and Sponsor Medical Monitor. 
A complete discussion of the rules regarding timing of doses for individual subjects is 
presented in Section 4.2.1.5. 
Pediatric subjects will only receive a given dose level of QR-110 following DMC and 
Sponsor Medical Monitor acceptance of at least 4 weeks of post dose safety and 


Investigational Product: QR-110 
Protocol No. PQ-110-001 (Version 6.0) 
 
ProQR Therapeutics 
 
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tolerability data in the 2 adults at that same dose level. Therefore, dosing of pediatric 
subjects will remain a minimum of 4 weeks behind dosing of the corresponding adult 
cohort at the same dose level. The safety measures around the timing of dosing and 
dose escalation of adult subjects also apply to pediatric subjects. The first 2 pediatric 
subjects at each dose level will be dosed at least 2 weeks apart. At least 4 weeks of 
safety and tolerability data for the first 2 pediatric subjects at each dose level will be 
reviewed by the DMC and Sponsor Medical Monitor prior to enrollment and dose 
escalation of subsequent pediatric subjects.  
Safety review will be conducted by the DMC and Sponsor Medical Monitor before each 
cohort initiation and on an ad hoc basis as needed. The Sponsor will also perform safety 
review on an ongoing basis. 
Study Plan  
The study includes a 28-day screening period.  
During the screening period, subjects will be assessed according to the eligibility 
criteria. Historic genotyping results from a certified genetic laboratory are acceptable 
with Sponsor approval. For subjects without a historic genotyping result, genotyping 
and gene sequencing analysis to determine the presence of the CEP290 p.Cys998X 
mutation will be performed. It is recommended that screening be conducted in a 
stepwise manner, so that eligibility is confirmed first with less intensive assessments 
and more intensive assessments are conducted after eligibility by all other criteria have 
been confirmed.   
Most measures of visual function (Best-corrected Visual Acuity [BCVA], FST mobility 
course, oculomotor instability and Pupillary Light Reflex [PLR]) will be measured a 
minimum of 2 times prior to the subject’s first dose of study drug to evaluate 
intrasubject variability (Screening and predose on Day 1). Measures of retinal anatomy 
(infrared imaging, and Optical Coherence Tomography [OCT]) and electroretinogram 
(ERG) will be measured a minimum of 1 time prior to the subject’s first dose of study 
drug. Any predose 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. In the case of repeat assessments, the measure reflecting the average of the 
measures will be considered the Baseline value. 
Subjects who meet all eligibility criteria will be enrolled into the study and will receive 
their first dose of study drug on Day 1. QR-110 will be administered via IVT injection 
into the subject’s treatment eye in accordance with the procedures outlined by the 
American Academy of Ophthalmology (Avery 2014). 
Subjects will be monitored clinically for increases in intraocular pressure (IOP) and 
signs of inflammation and endophthalmitis during the post-injection period. 
Subjects will be evaluated the day after each administration of study drug for safety 
monitoring (all doses) and to enable collection of serum samples for pharmacokinetic 
(PK) analysis 
  
Subjects will return to the study center to complete safety assessments at 7 days, and 1 
month, 2 months (doses 1 and 2 only) and 3 months post dose. In addition, subjects will 
be evaluated by telephone interview at 14 days post dose for the first dose only. 
Efficacy assessments, including retinal imaging, functional assessments of vision, 
 
 All assessments will be performed on both the 
treatment and contralateral eyes.  


Investigational Product: QR-110 
Protocol No. PQ-110-001 (Version 6.0) 
 
ProQR Therapeutics 
 
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The Investigator, Sponsor Medical Monitor and/or the DMC may decide to stop 
treatment for an individual subject due to an adverse event (AE). Stopping criteria are 
described in Section 4.2.2. 
Diagnosis and Main Criteria for 
Eligibility: 
Inclusion Criteria: 
1. Male or female, ≥ 6 years of age at Screening with a clinical diagnosis of LCA 
and a molecular diagnosis of homozygosity or compound heterozygosity for 
the CEP290 p.Cys998X mutation, based on genotyping analysis at Screening. 
Historic genotyping results from a certified laboratory are acceptable with 
Sponsor approval.  
2. Best-corrected visual acuity greater than or equal to light perception in both 
eyes and equal to or worse than Logarithm of the Minimum Angle of 
Resolution (LogMAR) + 0.6 (Snellen notation 20/80) in the worse eye and 
equal to or worse than LogMAR + 0.4 (Snellen notation 20/50) in the 
contralateral eye. 
3. Detectable outer nuclear layer (ONL) in the area of the macula in the opinion 
of the Investigator, as determined by OCT  
4. An ERG result consistent with LCA, as determined by the Investigator and the 
Reading Center. A historic ERG result is acceptable for eligibility. 
5. Clear ocular media and adequate pupillary dilation to permit good quality 
retinal imaging, as assessed by the Investigator 
6. 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 
7. 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 
8. Female subjects of childbearing potential, who have reached menarche, and 
male subjects must be sexually inactive by abstinence, which is consistent with 
the preferred and usual lifestyle of the subject, or agree to use adequate birth 
control, as defined in Section 6.2.3. Women of non-childbearing potential may 
be included without the use of adequate birth control, provided they meet the 
criteria in Section 6.2.3. 
9. Adequate verbal communication as to allow assessment via mobility course, in 
the opinion of the Investigator 
 
No waivers to the inclusion criteria are permitted.  
 
Exclusion Criteria: 
1. Diagnosed with an inherited retinal degenerative disease other than LCA or 
diagnosed with LCA due to a mutation in CEP290 which does not include at 
least one copy of p.Cys998X, either in homozygosity or compound 
heterozygosity. Note: The confirmed presence of known disease causing 
mutations in other genes involved in retinal dystrophy is exclusionary. 
2. Syndromic disease such as Alstrӧm syndrome, Batten disease, Joubert 
syndrome, peroxisomal diseases and Senior-Løken syndrome or other disease 
with similar presentation  


Investigational Product: QR-110 
Protocol No. PQ-110-001 (Version 6.0) 
 
ProQR Therapeutics 
 
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3. Any contraindication to IVT injection according to the Investigator’s clinical 
judgment and international guidelines (Avery 2014) 
4. Pregnant or breast-feeding female 
5. Any clinically significant cardiac disease or defect, in the opinion of the 
Investigator  
6. Personal or family history of prolonged QT syndrome or QTcF ≥ 450 ms 
(adult subjects and pediatric subjects >10 years old) or QTcB ≥ 450 ms 
(pediatric subjects ≤10 years old) by electrocardiogram (ECG) at Screening 
NOTE: Exclusion criteria 7 through 9 are related to acceptable laboratory values at 
Screening. Subjects with a screening laboratory value outside of the specified range 
may be permitted if the value is not clinically significant in the opinion of the 
Investigator, with concurrence from the Sponsor’s Medical Monitor. 
7. Estimated Glomerular Filtration Rate (eGFR) less than the lower limit of 
normal  
8. Aspartase Aminotransferase (AST) or Alanine Aminotransferase (ALT) 
greater than 1.2x the upper limit of normal 
9. One or more coagulation parameters (platelet count, International Normalized 
Ratio [INR]) outside of the normal range 
10. Any ocular disease or condition that could compromise treatment safety, visual 
acuity or interfere with assessment of efficacy and safety, as determined by the 
Investigator 
11. Prior receipt of intraocular surgery or IVT injection within 3 months prior to 
study start or planned intraocular surgery or procedure during the course of the 
study 
12. Use of any investigational drug or device within 90 days or 5 half-lives of 
Day 1, whichever is longer, or plans to participate in another study of a drug or 
device during the PQ-110-001 study period 
13. Any prior receipt of genetic therapy for LCA 
14. Any severe, acute or chronic medical or psychiatric condition, including 
substance abuse, laboratory abnormality or other condition that, in the 
judgment of the Investigator, would place the subject at undue risk, interfere 
with the results of the study, or make the subject otherwise unsuitable 
15. History of malignancy within 5 years prior to Screening, except adequately 
treated cutaneous squamous or basal cell carcinoma 
 
No waivers to the exclusion criteria are permitted. 
 


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Protocol No. PQ-110-001 (Version 6.0) 
 
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Endpoints: 
Primary 
• Frequency and severity of ocular AEs in the treatment and contralateral eyes 
Secondary 
• Frequency and severity of non-ocular AEs 
• Changes in ophthalmic examination findings  
• Change in BCVA  
• Changes in infrared imaging  
• Changes in OCT findings 
• Changes in safety parameters, including vital sign measurements, physical 
examination findings, ECG and laboratory parameters 
• Characterize the PK profile of QR-110 in serum 
• Change in light sensitivity to red FST  
• Change in light sensitivity to blue FST 
• Change in amplitude to white PLR 
• Change in latency to white PLR 
Exploratory 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
Study Drug, Dosage and Mode of 
Administration: 
QR-110 Solution for IVT Injection, 
 
Up to 3 dose levels will be tested (loading dose/maintenance dose): 160 µg/80 µg, 
320 µg/160 µg, and 500 µg/270 µg.  
QR-110 will be administered every 3 months for a total of 4 doses per subject. 
Duration of Treatment: 
12 months 
Reference Therapy, Dosage and Mode of 
Administration: 
Not applicable 


Investigational Product: QR-110 
Protocol No. PQ-110-001 (Version 6.0) 
 
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Criteria for Evaluation: 
Safety and Tolerability: 
 
 
 
 
 
• Frequency and severity of ocular and non-ocular AEs 
• Ophthalmic examination findings 
• BCVA 
• Infrared imaging 
• OCT 
• Vital sign measurements 
• Physical examination findings 
• ECG 
• Laboratory parameters 
PK: 
• Subjects will provide blood samples for presence of QR-110 at multiple time points 
Efficacy: 
• BCVA 
• White PLR 
• Red FST 
• Blue FST 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Investigational Product: QR-110 
Protocol No. PQ-110-001 (Version 6.0) 
 
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Statistical Methods: 
Baseline demographics and disease characteristics, safety and efficacy endpoints will be 
summarized descriptively by dose group and for all subjects combined. Continuous 
efficacy endpoints will be summarized and may be analyzed using appropriate 
parametric or nonparametric inference tests. Serum concentrations of QR-110 will be 
summarized by dose level and time point. 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: 
• 
AUC0-∞: Area under the curve to infinity will be calculated based on the last 
observed concentration Clast (obs) using formula: 
AUC0-∞=AUClast+Clast(obs)/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 an elimination rate constant 
(λz) is estimable): Apparent volume of distribution at steady state of the drug 
will be determined from trough levels. 
Any p values that will be calculated according to the analysis plan will be interpreted in 
view of the exploratory nature of the study. Details on statistical analyses will be 
included in the Statistical Analysis Plan. 
 
 
 


Investigational Product: QR-110 
Protocol No. PQ-110-001 (Version 6.0) 
 
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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ...............................................................................................1 
INVESTIGATOR SIGNATURE PAGE......................................................................................2 
PROTOCOL APPROVAL PAGE ...............................................................................................3 
NATIONAL COORDINATING INVESTIGATORS ................................................................4 
1.0 
SYNOPSIS ..........................................................................................................................5 
TABLE OF CONTENTS ............................................................................................................13 
LIST OF TABLES .......................................................................................................................16 
LIST OF FIGURES .....................................................................................................................16 
LIST OF APPENDICES .............................................................................................................17 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................18 
2.0 
INTRODUCTION............................................................................................................22 
2.1 
Leber’s Congenital Amaurosis ..............................................................................22 
2.2 
QR-110 for the Treatment of Leber’s Congenital Amaurosis due to CEP290 
p.Cys998X Mutation ..............................................................................................23 
2.2.1 
Nonclinical Experience .........................................................................24 
2.2.2 
Clinical Experience ...............................................................................26 
2.3 
Study Rationale ......................................................................................................26 
2.3.1 
Rationale for Open-label Design in Patients .........................................27 
2.4 
Route of Administration, Dosage, Dosage Regimen and Treatment Period .........28 
2.4.1 
Dose Selection Rationale ......................................................................28 
2.5 
Study Population ....................................................................................................30 
2.5.1 
Inclusion of Pediatric Subjects ..............................................................30 
2.5.2 
Pediatric Considerations........................................................................31 
3.0 
STUDY OBJECTIVES ....................................................................................................32 
3.1 
Primary Objective ..................................................................................................32 
3.2 
Secondary Objectives.............................................................................................32 
3.3 
Exploratory Objective ............................................................................................32 
4.0 
STUDY OVERVIEW ......................................................................................................32 
4.1 
Criteria for Evaluation ...........................................................................................32 
4.1.1 
Primary Endpoint ..................................................................................32 
4.1.2 
Secondary Endpoints .............................................................................32 
4.1.3 
Exploratory Endpoints ..........................................................................33 
4.2 
Study Design ..........................................................................................................34 
4.2.1 
Study Plan .............................................................................................34 
4.2.2 
Stopping Criteria ...................................................................................37 


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4.2.3 
Subject Withdrawal ...............................................................................40 
4.2.4 
Discontinuation of the Study .................................................................40 
5.0 
SELECTION OF STUDY POPULATION ...................................................................40 
5.1 
Study Population ....................................................................................................40 
5.2 
Selection of Subjects ..............................................................................................41 
5.3 
Eligibility Criteria ..................................................................................................41 
5.3.1 
Inclusion Criteria ...................................................................................41 
5.3.2 
Exclusion Criteria..................................................................................42 
6.0 
STUDY DRUG AND CONCOMITANT THERAPIES ...............................................43 
6.1 
Study Drug .............................................................................................................43 
6.1.1 
Study Drug Description and Supply .....................................................43 
6.1.2 
Placebo ..................................................................................................43 
6.1.3 
Study Drug Shipment and Storage ........................................................43 
6.1.4 
Study Drug Accountability and Reconciliation ....................................43 
6.1.5 
Dosage and Administration ...................................................................44 
6.2 
Concomitant Medications and Ancillary Therapy .................................................44 
6.2.1 
Permitted Concomitant Medications .....................................................44 
6.2.2 
Prohibited Concomitant Medications ....................................................45 
6.2.3 
Adequate Forms of Birth Control .........................................................45 
7.0 
STUDY VISITS ................................................................................................................46 
7.1 
Visit and Assessment Windows .............................................................................46 
7.2 
Screening................................................................................................................46 
7.3 
Dosing and Follow-up Visits .................................................................................46 
7.4 
End of Study Visit ..................................................................................................47 
7.5 
Follow-up Extension Study....................................................................................47 
8.0 
STUDY ASSESSMENT PROCEDURES ......................................................................47 
8.1 
Adverse Events ......................................................................................................47 
8.2 
Vital Signs ..............................................................................................................47 
8.3 
Laboratory Evaluations ..........................................................................................48 
8.4 
Pharmacokinetic Evaluations .................................................................................48 
8.5 
Electrocardiogram ..................................................................................................49 
8.6 
Physical Examination.............................................................................................49 
8.7 
Height and Weight .................................................................................................49 
8.8 
Ophthalmic Exams .................................................................................................49 
8.9 
Optical Coherence Tomography ............................................................................49 


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8.10 
Leber’s Congenital Amaurosis Genetic Analysis ..................................................50 
8.11 
Biomarkers .............................................................................................................50 
8.12 
Efficacy Assessments.............................................................................................50 
9.0 
ASSESSMENT OF SAFETY OR ADVERSE EVENTS AND SERIOUS 
ADVERSE EVENTS .......................................................................................................51 
9.1 
Data Monitoring Committee ..................................................................................51 
9.2 
Definitions of Adverse Event, Serious Adverse Event, and Suspected 
Unexpected Serious Adverse Event .......................................................................52 
9.2.1 
Adverse Events......................................................................................52 
9.2.2 
Serious Adverse Events.........................................................................52 
9.2.3 
Suspected Unexpected Serious Adverse Reaction Definition ..............53 
9.2.4 
Adverse Events of Special Interest .......................................................53 
9.3 
Assessment of Adverse Events ..............................................................................54 
9.3.1 
Assessment of Severity (Intensity) of Adverse Events .........................54 
9.3.2 
Assessment of the Relationship of Adverse Events to Study Drug ......55 
9.3.3 
Assessment of the Outcome of Adverse Events ...................................55 
9.4 
Reporting of Adverse Events .................................................................................56 
9.4.1 
Adverse Event Reporting Period ...........................................................56 
9.4.2 
Eliciting Adverse Events .......................................................................56 
9.4.3 
Recording Adverse and Serious Adverse Events ..................................57 
9.5 
Serious Adverse Events Notification .....................................................................59 
9.6 
Expedited Reporting of Suspected Unexpected Serious Adverse Reactions .........60 
10.0 
STATISTICAL METHODOLOGY...............................................................................60 
10.1 
General Considerations ..........................................................................................60 
10.2 
Determination of Sample Size ...............................................................................61 
10.2.1 
Randomization and Blinding ................................................................61 
10.2.2 
Replacement of Subjects .......................................................................61 
10.3 
Analysis of Populations .........................................................................................61 
10.4 
Subject Disposition, Demographics and Baseline Disease Characteristics ...........62 
10.5 
Treatment Compliance ...........................................................................................62 
10.6 
Safety Analyses ......................................................................................................62 
10.6.1 
Treatment Emergent Adverse Events....................................................62 
10.6.2 
Vital Signs .............................................................................................63 
10.6.3 
Laboratory Assessments........................................................................63 
10.6.4 
Other Safety Assessments .....................................................................63 
10.7 
Pharmacokinetics Analyses ...................................................................................63 


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10.8 
Efficacy Analyses ..................................................................................................64 
10.9 
Interim Analysis .....................................................................................................65 
10.10 Multiplicity Considerations ...................................................................................65 
10.11 Subgroup Analyses ................................................................................................66 
11.0 
QUALITY CONTROL AND QUALITY ASSURANCE .............................................66 
11.1 
Data Collection and Study Monitoring ..................................................................66 
11.2 
Audits and Inspections ...........................................................................................67 
12.0 
ETHICAL AND REGULATORY OBLIGATIONS ....................................................67 
12.1 
Ethical Considerations ...........................................................................................67 
12.2 
Informed Consent...................................................................................................67 
12.3 
Ethics and Regulatory Review ...............................................................................68 
12.4 
Subject Confidentiality ..........................................................................................68 
13.0 
STUDY ADMINISTRATION ........................................................................................69 
13.1 
Investigator’s Brochure ..........................................................................................69 
13.2 
Protocol Amendments ............................................................................................69 
13.3 
Study Termination .................................................................................................69 
13.4 
Study Documentation and Storage .........................................................................70 
13.5 
Use of Information .................................................................................................70 
13.6 
End of Study and Final Report...............................................................................71 
13.7 
Financing and Insurance ........................................................................................71 
13.8 
Publication Policy ..................................................................................................71 
14.0 
REFERENCES .................................................................................................................72 
15.0 
APPENDICES ..................................................................................................................76 
 
LIST OF TABLES  
LIST OF FIGURES 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
A 
Adenine 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AON 
Antisense Oligonucleotide 
AREDS 
Age-Related Eye Diseases Study 
ARLNS 
Clinical Lens Grading System 
AST 
Aspartate Aminotransferase 
AUCo-∞ 
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 
BUN 
Blood Urea Nitrogen 
C 
Cytosine 
CBC 
Complete Blood Count 
CEP290 
Centrosomal Protein 290 kDa 
CEP290 
CEP290 gene 
CF 
Counting Fingers 
CFR 
Code of Federal Regulations 
CH50 
C4, Hemolytic complement 50 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CL 
Clearance 
CRP 
C Reactive Protein 
Cmax 
Maximum Concentration 
C0 
Trough Value 
CSR 
Clinical Study Report 


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DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
EOS 
End of Study 
ERG 
Electroretinogram 
ESE 
Exonic Splicing Enhancer 
ESR 
Erythrocyte Sedimentation Rate 
FDA 
Food and Drug Administration 
FST 
Full-field Stimulus Testing (also, Full-field Stimulus Threshold Testing or 
Full-field Scotopic Threshold Testing) 
G 
Guanine 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase 
GLP 
Good Laboratory Practice 
HM 
Hand Motion 
IB 
Investigator’s Brochure 
ICH 
The International Council on Harmonisation  
INR 
International Normalized Ratio 
IOP 
Intraocular Pressure 
iPSC 
Induced Pluripotent Stem Cells 
IRB 
Institutional Review Board 
 
IVT 
Intravitreal 
LCA 
Leber’s Congenital Amaurosis 
LDH 
Lactic Dehydrogenase 


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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 
NIH 
National Institute of Health 
OCI 
Oculomotor Instability 
OCT 
Optical Coherence Tomography 
ONL 
Outer Nuclear Layer 
PBS 
Phosphate Buffered Saline 
p.Cys998X 
c.2991+1655A>G mutation in the CEP290 gene 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PLR 
Pupillary Light Reflex 
ProQR 
ProQR Therapeutics 
PT 
Preferred Term 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
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 


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T1/2 
Terminal half-life 
Tmax 
Time of maximum concentration 
Tmin 
Time of minimum concentration 
ULN 
Upper Limit of Normal 
US 
United States 
Vd 
Volume of Distribution 
 
 
WOCBP 
Women of Childbearing Potential 
 
 
 
 


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2.0 
INTRODUCTION 
ProQR Therapeutics (ProQR) is developing an antisense oligonucleotide (AON) product, 
QR-110, for the treatment of patients with Leber’s 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’s 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). 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’s Congenital Amaurosis 
Leber’s 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’s Congenital Amaurosis due to CEP290 
p.Cys998X Mutation 
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 p.Cys998X mutation. 
QR-110 is an AON designed as a disease modifying therapy for LCA due to the CEP290 
p.Cys998X mutation. QR-110 targets the splicing mutation of the CEP290 protein through a 
mechanism of RNA modulation that skips the inclusion of the cryptic exon-X. The exclusion of 
this cryptic exon results in restoration of the open reading frame of CEP290 and excludes the 
premature stop codon present in exon-X.  


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2.2.2 
Clinical Experience 
No clinical studies have been conducted with QR-110 Solution for IVT Injection. 
2.3 
Study Rationale 
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. QR-110 is designed to target the 
splicing mutation in the CEP290 protein. The hybridization of the QR-110 oligonucleotide 
modulates the RNA splicing process, blocking access to the active cryptic splice site and 
restoring preference for the wild-type splice sites, skipping the inclusion of the cryptic exon-X in 
CEP290, and resulting in a functional CEP290 protein. 
This first-in-human study of QR-110 is an open-label, multiple dose, dose escalation study to 
evaluate the safety and tolerability of QR-110 administered via IVT injection in subjects with 
LCA due to the CEP290 p.Cys998X mutation. It is anticipated that repair of the splicing defect 
may be possible in patients with preservation of at least detectable ONL. Patients with LCA due 
to the CEP290 p.Cys998X mutation exhibit progressive retinal degeneration and substantial loss 
of rod photoreceptors in the peripheral retina; however, sparing of foveal/macular cone 
photoreceptors has been observed. Such cone photoreceptor sparing is noted in some patients by 
the presence of an almost normal retinal ONL thickness at the foveal region and retained cone-
specific retinal function. Importantly, age does not seem to be strictly associated with disease 
severity (Cideciyan 2007, Cideciyan 2011, Pasadhika 2010).  
The phenotype of LCA due to mutations in CEP290 is severe. However, in a cohort of Dutch 
patients, Yzer et al (2012) concluded that patients usually have a relatively normal optic disc, 
mild or moderate attenuation of vessels and a relatively preserved posterior pole, suggesting that 
anatomy is preserved. There is evidence of sparing of some photoreceptors in the macula of 
individuals with LCA carrying CEP290 mutations, which may allow for therapeutic intervention. 


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Restoration of protein expression to wild-type levels has the potential to delay, cease, or possibly 
to reverse disease progression (Chacon-Camacho 2015). 
2.3.1 
Rationale for Open-label Design in Patients 
Intravitreal injection is a well-established route of administration within ophthalmic indications; 
however, rare but potentially serious complications to IVT injections exist, including acute onset 
endophthalmitis, pseudo-endophthalmitis, cataract and retinal detachment. Although the risk of 
serious complications is small, it is well-documented (Artunay 2009, Fagan 2013, Falavarjani 
2013). Therefore, placebo injections will not be administered in this study to preserve subject 
safety. 
Use of sham injections to mask subjects to treatment assignment in studies of products 
administered via IVT injection eliminates the risk of complications due to injection in the 
contralateral eye. Sham injections that closely mimic the active injection can effectively mask 
participants to treatment assignment; however, the masking effect is less pronounced in the case 
where a single subject would receive both the real and sham injections, one in each of their eyes 
(Glassman 2012), as would be required in LCA due to the CEP290 p.Cys998X mutation.  
This study will be an open-label study and sham injections will not be used. Masking of 
participating subjects is of particular importance when subject effort or perception could bias 
evaluation of study endpoints; this is true for the assessment of subjective endpoints such as 
visual acuity (Glassman 2012). However, many assessments are objective tests (Pupillary Light 
Reflex [PLR], OCT, oculomotor instability [OCI], ERG, and infrared imaging) which are not 
related to subject responses. A central reading center will be used for several of the 
ophthalmologic assessments, including PLR, OCI, Full Field Stimulus Testing (FST), ERG, 
OCT and infrared imaging, which will be reviewed and interpreted by an independent masked 
evaluator. Mobility course scoring will also be reviewed and calculated by a masked evaluator. 
Furthermore, this study will evaluate safety and tolerability as the primary endpoint. Measures of 
safety will be monitored and severity and causality determined by the Investigator. Taken 
together, the risk of the introduction of bias to the determination of safety from the participant is 
low and sham injections will not reduce bias introduced by Investigators. 
Subjects will receive QR-110 as a unilateral IVT injection in their worse eye (see  
Section 4.2.1.2). Treatment of the worse eye is common practice in the development of 
ophthalmic products (Bainbridge 2008, Ghazi 2016, Jacobson 2012, Maguire 2009). Unilateral 
injection serves as an additional means to ensure safety, as visual function is driven by a 
subject´s better eye.  Unless otherwise specified, both safety and efficacy evaluations 
 will be based on the assessment of the treatment eye 
in comparison to baseline measures and to the untreated eye (referred to hereafter as the 
contralateral eye). As there is no approved therapy for the treatment of LCA due to the CEP290 
p.Cys998X mutation, no suitable comparator currently exists. The contralateral eye, therefore, 
serves as a control and removes the biases due to the absence of a relevant comparator, or the 


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administration of placebo by IVT injection, which is considered unethical in this population. 
Assessments based on both the comparison of the treatment eye to the contralateral eye, and 
changes from baseline in the treatment eye will provide the strongest comparisons from which to 
evaluate safety and efficacy data. 
2.4 
Route of Administration, Dosage, Dosage Regimen and Treatment Period 
Intravitreal injection is a well-established route of administration within ophthalmic indications. 
Systemic exposure to drugs administered via IVT injection is generally low and the technique 
enables targeting of the product to the intraocular tissues of the eye (AAO 2015). Intravitreal 
injection is used in several products for the chronic treatment of ophthalmic diseases (eg, 
Lucentis®, Eylea™, Macugen®) and the risk of complications is low when injections are 
performed by trained ophthalmologists (AAO 2015). 
Since IVT injections themselves carry a low risk of serious complications, independent of the 
product administered, dose levels to be investigated in the study are calculated to be 
pharmacologically efficacious doses. Evaluation of up to 3 dose levels of QR-110 is planned. 
Inclusion of up to 3 dose levels enables investigation of a potential dose response relationship for 
QR-110. Based on the chemistry of the molecule, PK data from toxicology studies, and what is 
known of other oligonucleotides approved for IVT injection (Macugen®, Vitravene®), systemic 
absorption is anticipated to be low.  
Each subject will receive up to 4 doses of QR-110 at 3 month intervals and will be monitored for 
3 months following their last dose of study drug. The dosing interval of 3 months and the 
12-month duration of dosing is expected to be in the efficacious range for QR-110. 
Administration of 4 doses has been selected to enable evaluation of the safety of repeat dosing of 
QR-110 and to evaluate potential efficacy parameters. The multiple dose design provides 
subjects with the potential opportunity for efficacy. A single dose design is not considered 
acceptable in this population because subjects would be exposed to the risks associated with IVT 
injection without the possibility of being able to derive any (sustained) benefit. To ensure subject 
safety in this multiple dose design, an independent Data Monitoring Committee (DMC) will 
review all available safety data prior to each dose escalation, prior to inclusion of pediatric 
subjects, and prior to the first subject receiving each subsequent dose of QR-110 (doses 2, 3, and 
4). Therefore, the study consists of a single initial dose, with DMC review of cumulative study 
data and a positive DMC recommendation prior to continuing to each subsequent dose. 
2.4.1 
Dose Selection Rationale 
 


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The proposed starting dose and 
escalation scheme for PQ-110-001 is considered conservative.  
The proposed dosing regimens to be studied are as follows:  
• Low dose: 
160 µg loading dose, followed by up to three 80 µg maintenance doses   
• Middle dose: 320 µg loading dose, followed by up to three 160 µg maintenance doses 
• High dose: 
500 µg loading dose, followed by up to three 270 µg maintenance doses 


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Details on the dose selection are provided in the QR-110 IB. 
2.5 
Study Population 
The study drug will be administered by IVT injection which carries a risk of serious 
complications, making the inclusion of healthy volunteers unethical. Furthermore, QR-110 is 
designed to exert the specific effect of masking the cryptic splice site in patients with the 
CEP290 p.Cys998X mutation, which is not present in healthy volunteers. It is, therefore, 
unknown if safety data obtained from healthy volunteers, would be similar to that of patients 
with the target mutation. Evaluation of patients with LCA due to the CEP290 p.Cys998X 
mutation is therefore necessary to evaluate the safety of QR-110.  
Eligible subjects will have LCA due to homozygosity or compound heterozygosity for the 
CEP290 p.Cys998X mutation, residual vision and detectable ONL in the area of the macula as 
determined by OCT. Preservation of at least some retained photoreceptor ONL is a prerequisite 
for restoration of the splicing defect and consequent impact on disease. Due to severe nystagmus 
in many subjects with LCA due to the CEP290 p.Cys998X mutation, it is anticipated that 
consistent, quantitative calculation of the volume of retained ONL across subjects may be a 
challenge in this population; therefore, eligibility will be determined by the existence of any 
detectable ONL on OCT, in the opinion of the Investigator.  
Since disease severity does not seem to clearly correlate with age, inclusion of subjects in the 
first-in-human trial should be guided by disease status and potential for obtaining a therapeutic 
benefit. The high unmet medical need warrants early therapeutic intervention in those patients 
with sufficient preserved vision and retinal anatomy in which a major clinical benefit (restoration 
or improvement of vision or delay in visual loss) could potentially be expected. Therefore, 
treatment with QR-110 is justified in those patients with LCA due to the CEP290 p.Cys998X 
mutation who present detectable ONL, irrespective of age.  
2.5.1 
Inclusion of Pediatric Subjects 
Symptoms of LCA due to the CEP290 p.Cys998X mutation occur in young pediatric patients; 
symptoms are usually detected before 1 year of age and patients show severe vision disturbances. 
Pediatric patients could benefit from treatment with a therapy for LCA due to the CEP290 
p.Cys998X mutation beginning at a very young age. Given the timing of symptom onset and 
substantial vision loss in young children, it is possible that early initiation of treatment may result 
in improved clinical outcomes for patients. While the potential to at least cease progression can 


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be assumed to be most beneficial to younger patients, the target patient population for the 
first-in-human study of QR-110 will only include pediatric patients at least 6 years of age to 
ensure subject safety and due to the complexity of study assessments. A staggered approach has 
been selected such that pediatric subjects (pediatric patients include those 6 to less than 18 years 
of age) will only start treatment following review of safety and tolerability data from adult 
subjects (adult subjects include those ≥18 years of age). 
In pediatric subjects at least 6 years of age, the average volume of vitreous is similar to that of 
adult subjects, as referred in Bhardwaj et al (2013) and Zadnik et al (2004). Intravitreal 
administration of anti-Vascular Endothelial Growth Factor A agents is used to treat newborns in 
cases of Retinopathy of Prematurity and no issues specific to the pediatric population have been 
identified in connection to the IVT injection (Mintz-Hittner 2008, Nazari 2010). For a product 
given via IVT injection, there is no evidence to suggest that the safety profile would differ in 
adult patients as compared to pediatric patients at least 6 years of age. Toxicity studies in 
juvenile animals are summarized in the QR-110 IB, Nonclinical Studies. 
For the purposes of an early phase clinical study such as PQ-110-001, it is essential that 
participating subjects be able to complete all necessary safety and efficacy assessments; 
therefore, specifying a minimum age for subject eligibility is appropriate. The psychophysical 
tests used in low vision populations are difficult for children younger than 6 years of age to 
complete due to complexity and the level of focus required. In practice, the ability to complete 
these tests, based on the individual child and the suitability of patients of any age to complete all 
required assessments, will be determined by the Investigator. Furthermore, the visit frequency 
for this first-in-human trial will be high and visit duration lengthy due to the large number of 
measures required to assess safety. Therefore, the target patient population for the PQ-110-001 
study will be patients at least 6 years of age who are able to complete all study assessments, in 
the opinion of the Investigator.  
2.5.2 
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).  


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3.0 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of the study is to evaluate the safety and tolerability of QR-110 
administered via IVT injection in subjects with LCA due to the CEP290 p.Cys998X mutation.  
3.2 
Secondary Objectives 
The secondary objectives of the study are: 
• to evaluate the serum pharmacokinetics of QR-110 administered by IVT injection in 
subjects with LCA due to the CEP290 p.Cys998X mutation 
• to evaluate the efficacy of QR-110 administered by IVT injection in subjects with LCA 
due to the CEP290 p.Cys998X mutation 
3.3 
Exploratory Objective 
4.0 
STUDY OVERVIEW 
4.1 
Criteria for Evaluation 
4.1.1 
Primary Endpoint 
• Frequency and severity of ocular AEs in the treatment and contralateral eyes 
4.1.2 
Secondary Endpoints 
• Frequency and severity of non-ocular AEs 
• Changes in ophthalmic examination findings 
• Change in BCVA 
• Changes in infrared imaging  
• Changes in OCT findings 
• Changes in safety parameters, including vital sign measurements, physical examination 
findings, electrocardiogram (ECG) and laboratory parameters 


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• Characterize the PK profile of QR-110 in serum 
• Change in light sensitivity to red FST  
• Change in light sensitivity to blue FST 
• Change in amplitude to white PLR 
• Change in latency to white PLR 
4.1.3 
Exploratory Endpoints 


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The study is not designed to have sufficient statistical power to assess efficacy of QR-110 in the 
treatment of LCA due to the CEP290 p.Cys998X mutation. However, changes in clinical 
outcome measures associated with LCA due to the CEP290 p.Cys998X mutation will be 
monitored over the course of the study. 
4.2 
Study Design 
The first-in-human study of QR-110 will be an open-label, multiple dose, dose escalation study 
to evaluate the safety and tolerability of QR-110 administered via IVT injection in subjects with 
LCA due to the CEP290 p.Cys998X mutation. Subjects will be assigned to receive a specified 
dose level (loading dose and maintenance dose) of QR-110. No intrasubject dose escalation is 
planned. Up to 3 dose levels of QR-110 will be evaluated. Dose escalation decisions and 
initiation of dosing in pediatric subjects will be determined by the DMC and Sponsor Medical 
Monitor review of safety and tolerability data. 
4.2.1 
Study Plan  
4.2.1.1 
Screening 
During the screening period, subjects will be assessed according to the eligibility criteria.  
Subjects who meet all eligibility criteria will be enrolled into the study. On Day 1, subjects will 
undergo a second set of predose baseline measures as specified in the SOE 
 and will 
subsequently receive their first dose of study drug. The data obtained from these two predose 
measures will serve to inform the level of intrasubject variability in study assessments (see 
Section 7.2 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 worse eye as defined by 
visual acuity (subsequently referred to as treatment eye) and will be assessed for safety and 
tolerability at follow up visits. If both eyes have the same visual acuity, the Investigator should 
determine the eye with the worse visual function, according to other measures of ophthalmic 
function at Screening (FST or mobility course score), as the treatment eye. If the visual function 
is the same per the Investigator’s assessment, then the treatment eye will be determined at 
Investigator discretion. 


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Specific study drug administration procedures can be found in the Study Reference Manual. 
4.2.1.3 
Assessment and Follow-up  
To closely monitor subject safety, subjects will be evaluated by the Investigator following each 
IVT injection and the following day, as well as 7 days, 14 days (first dose only, visit to be done 
via phone call), 1 month, 2 months (doses 1 and 2 only) and 3 months post dose. These frequent 
in-clinic visits are designed to ensure any untoward events in study subjects are quickly 
identified under the oversight of the Investigator and can be treated promptly.  
Efficacy assessments will be performed according to the SOE. (See Section 7.3 for details on 
dosing and follow-up visit procedures.)  
All study assessments will be performed for both the treatment and contralateral eyes.  
4.2.1.4 
Study Cohorts 
QR-110 will be administered at up to 3 escalating dose levels. The study will include up to 6 
cohorts (up to 3 adult cohorts and up to 3 pediatric cohorts). Each cohort will have at least 2 
subjects and each dose level will be tested in 1 adult cohort and 1 pediatric cohort (Table 2). 
Dose escalation will proceed as described in Section 4.2.1.5. QR-110 will be administered via 
unilateral IVT injection in the subject’s worse eye (Section 4.2.1.2) every 3 months and each 
subject will receive up to 4 doses of study drug. 
 
Table 2: 
Dose Cohorts 
Dose Level 
Adult Cohort  
(at least 2 Subjects) 
Pediatric Cohort  
(at least 2 Subjects) 
Low 
Cohort A1 
Cohort P1 
Mid 
Cohort A2 
Cohort P2 
High 
Cohort A3 
Cohort P3 
Details and instructions to Investigators regarding cohort enrollment and management are 
provided in the Study Reference Manual. 
4.2.1.5 
Dose Escalation 
The study will test loading and maintenance doses of QR-110 from an initial dose of 
160 µg/80 µg (loading dose/maintenance dose) to a maximum dose of 500 µg/270 µg (loading 
dose/maintenance dose) given by IVT injection every 3 months for a total of 12 months 
(4 doses). At each dose level, safety and tolerability data for at least 4 weeks post dose for the 
current cohort will be reviewed by the DMC and Sponsor Medical Monitor. 


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4.2.2 
Stopping Criteria  
4.2.2.1 
Stopping Criteria for Individual Subjects 
The Investigator, the DMC or the Sponsor Medical Monitor may stop treatment for an individual 
subject due to an AE (see 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 Sponsor Medical Monitor and DMC must be 
notified of any subject who stops treatment due to an AE. 
The DMC and Sponsor Medical Monitor may decide to de-escalate the dose, hold the dose 
(delay or skip), or discontinue study drug for an individual subject, in consultation with the 
Investigator.  


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Subjects who discontinue study drug will be encouraged to remain in the study for observation. 
Subjects who discontinue study drug, but do not withdraw consent will continue to be followed 
for safety through the End of Study (EOS) visit at Month 12. These subjects should complete: 1) 
all study visits until the time of their next scheduled dose, and 2) the remaining of Visits 8 
(Month 3), 13 (Month 6), 17 (Month 9) and 21 (Month 12/EOS).  
The DMC and the Sponsor Medical Monitor will perform ongoing safety reviews of systemic 
and ophthalmic safety data and AEs for safety signal.
  
 
 
Subjects who do not meet stopping criteria prior to their next scheduled injection will receive 
their planned dose of study drug. If in the interim a subject meets stopping criteria as identified 
by the Investigator, the Investigator will notify the DMC and an ad hoc meeting will be 
convened.  
4.2.2.2 
Stopping Criteria for Cohort 
The DMC and Sponsor Medical Monitor should evaluate the totality of safety data from all 
subjects receiving the same dose level of QR-110 and cumulative data of previous cohort(s), to 
evaluate whether a safety signal may be present. 
 
  
 


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Dose escalation may be stopped if it is determined that the limits of safety and/or tolerability 
have been reached. This decision will be made after a discussion between the Sponsor Medical 
Monitor and the DMC. 
In all cases, the decision to proceed to the next dose level will be made jointly by the DMC and 
Sponsor Medical Monitor, based on a review and consideration of all available safety and 
tolerability information for the study subjects.  
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. 
If a subject withdraws from participation in the study, then his/her subject number cannot be 
reused. Withdrawn subjects may be replaced (see Section 10.2.2). 
4.2.4 
Discontinuation of the Study 
The DMC and Sponsor Medical Monitor will evaluate the safety and tolerability data as 
described in Section 4.2.2 and Table 3 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.  
In the case of overwhelming efficacy as determined by ongoing analysis of efficacy (see 
Section 10.9), the DMC and Sponsor Medical Monitor may make a recommendation to 
discontinue the study. 
5.0 
SELECTION OF STUDY POPULATION  
5.1 
Study Population 
Subjects with a diagnosis of LCA due to the CEP290 p.Cys998X mutation who meet all 
eligibility criteria will be eligible for participation in this study. 


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5.2 
Selection of Subjects 
Screening of subjects will be performed within 28 days prior to dosing. Medical and ocular 
history, concomitant medications, physical examination findings and vital signs will be recorded. 
Subjects will be evaluated against all 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. 
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. Male or female, ≥ 6 years of age at Screening with a clinical diagnosis of LCA and a 
molecular diagnosis of homozygosity or compound heterozygosity for the CEP290 
p.Cys998X mutation, based on genotyping analysis at Screening. Historic genotyping results 
from a certified laboratory are acceptable with Sponsor approval. 
2. Best-corrected visual acuity greater than or equal to light perception in both eyes and equal to 
or worse than Logarithm of the Minimum Angle of Resolution (LogMAR) + 0.6 (Snellen 
notation 20/80) in the worse eye and equal to or worse than LogMAR + 0.4 (Snellen notation 
20/50) in the contralateral eye 
3. Detectable ONL in the area of the macula in the opinion of the Investigator, as determined by 
OCT 
4. An ERG result consistent with LCA, as determined by the Investigator and the Reading 
Center. A historic ERG result is acceptable for eligibility  
5. Clear ocular media and adequate pupillary dilation to permit good quality retinal imaging, as 
assessed by the Investigator 
6. 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 
7. An adult willing to comply with the protocol, follow study instructions, and 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, comply 
with the protocol and attend study visits with the subject as required, in the opinion of the 
Investigator 
8. Female subjects of childbearing potential, who have reached menarche, and male subjects 
must be sexually inactive by abstinence, which is consistent with the preferred and usual 
lifestyle of the subject, or agree to use adequate birth control as defined in Section 6.2.3. 


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Women of non-childbearing potential may be included without the use of adequate birth 
control, provided they meet the criteria in Section 6.2.3. 
9.  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. Diagnosed with an inherited retinal degenerative disease other than LCA or diagnosed with 
LCA due to a mutation in CEP290 which does not include at least one copy of p.Cys998X, 
either in homozygosity or compound heterozygosity. Note: The confirmed presence of 
known disease causing mutations in other genes involved in retinal dystrophy is 
exclusionary. 
2. Syndromic disease such as Alstrӧm syndrome, Batten disease, Joubert syndrome, 
peroxisomal diseases and Senior-Løken syndrome or other disease with similar presentation  
3. Any contraindication to IVT injection, according to the Investigator’s clinical judgment and 
international guidelines (Avery 2014) 
4. Pregnant or breast-feeding female 
5. Any clinically significant cardiac disease or defect, in the opinion of the Investigator 
6. Personal or family history of prolonged QT syndrome or QTcF ≥ 450 ms (adult subjects and 
pediatric subjects >10 years old) or QTcB ≥ 450 ms (pediatric subjects ≤ 10 years old) by 
ECG at Screening 
NOTE: Exclusion criteria 7 through 9 are related to acceptable laboratory values at Screening. 
Subjects with a screening laboratory value outside the specified range may be permitted if the 
value is not clinically significant in the opinion of the Investigator, with concurrence from the 
Sponsor’s Medical Monitor. 
7. Estimated Glomerular Filtration Rate (eGFR) less than the lower limit of normal. 
8. AST or ALT greater than 1.2x the ULN 
9. One or more coagulation parameters (platelet count, International Normalized Ratio [INR]) 
outside of the normal range 
10. Any ocular disease or condition that could compromise treatment safety, visual acuity or 
interfere with assessment of efficacy and safety, as determined by the Investigator 
11. Prior receipt of intraocular surgery or IVT injection within 3 months prior to study start or 
planned intraocular surgery or procedure during the course of the study 
12. Use of any investigational drug or device within 90 days or 5 half-lives of Day 1, whichever 
is longer, or plans to participate in another study of a drug or device during the PQ-110-001 
study period 
13. Any prior receipt of genetic therapy for LCA 


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14. Any severe, acute or chronic medical or psychiatric condition, including substance abuse, 
laboratory abnormality or other condition that, in the judgment of the Investigator, would 
place the subject at undue risk, interfere with the results of the study, or make the subject 
otherwise unsuitable 
15. History of malignancy within 5 years prior to Screening, except adequately treated cutaneous 
squamous or basal cell carcinoma 
 
No waivers to the exclusion criteria are permitted. 
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.
 
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 


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which case an alternative drug accountability process will be agreed upon with the Sponsor. 
Used mixing vials containing residual study drug should be stored at 2º to 8º C for accountability 
by a Sponsor representative (monitor). In case of serious adverse events (SAEs), used vials may 
be collected by the Sponsor for endotoxin testing and/or testing for bacterial contamination may 
be arranged locally by 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). 
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 
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), betablocker 
ophthalmic solutions, prostaglandin analog ophthalmic solutions, ophthalmic solutions/gels of 
corticosteroids, antibiotics and antiseptics, topical agents for pupillary dilatation, and antiallergic 
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.  


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6.2.2 
Prohibited Concomitant Medications 
The use of any investigational drug or device within 90 days or 5 half-lives of the drug at Day 1, 
whichever is longer, or plans to participate in another investigational study during the PQ-110-
001 study period is prohibited. 
6.2.3 
Adequate Forms of Birth Control 
Women of child bearing potential (WOCBP) must agree to use a highly effective method of birth 
control from the list below (defined as those, alone or in combination, that result in a failure rate 
of less than 1% per year when used consistently and correctly). Double barrier methods (a 
combination of condom with cap, diaphragm, or sponge with spermicide) are not considered 
highly effective. Childbearing potential is defined as menarche and until post-menopausal for ≥ 1 
year, unless permanently sterile. 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 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 outlined in the protocol. For 
those procedures for which a specific time point post dose is required (eg, PK blood draws), the 
protocol refers to nominal times. Actual times for such assessments are to be recorded in the 
source documentation and in the electronic Case Report Forms (eCRFs), and if any time points 
are missed, the reasons are also to be recorded. Recording of actual times is not required for 
assessments for which only a study visit and not a specific time is stated in the protocol. 
Each study visit may take up to 1 day, or may be conducted in multiple consecutive days instead 
of 1 full day, at the discretion of the Investigator. 
Visits 7 days post injections have a visit window of +/- 3 days. Visits 1 month and 2 months post 
injections have a visit window of +/- 7 days, and dosing visits have a visit window of +/- 10 
days. The visit 14 days post-dose 1 is conducted by telephone and has a visit window of +/- 3 
days. 
7.2 
Screening 
Subject screening should be conducted ≤ 28 days prior to study drug dosing (Day 1). A screening 
log of all consented subjects will be kept at each study center.  
During the screening period, subjects will be assessed according to the eligibility criteria and 
specified assessments conducted, as presented in the SOE 
. At the discretion of the 
Investigator, the feasibility of performing an IVT injection on the subject may be assessed using 
noninvasive methods, as outlined in the Study Reference Manual. Historic genotyping results 
from a certified laboratory are acceptable with Sponsor approval. For subjects without a historic 
genotyping result, genotyping and gene sequencing analysis to determine the presence of the 
CEP290 p.Cys998X mutation will be performed. For all subjects, screening 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.  
7.3 
Dosing and Follow-up Visits 
Dosing visits occur on Day 1 (Visit 2), Month 3 (Visit 8), Month 6 (Visit 13), and Month 9 
(Visit 17). 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 
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according to local institutional guidelines. 
 
All follow-up study visits, assessments and procedures should be completed as indicated per the 
SOE
 
7.4 
End of Study Visit  
The EOS visit occurs 3 months after the 4th dose of study drug, Month 12 (Visit 21) for subjects 
who have not discontinued study drug. Subjects who discontinue study drug but do not withdraw 
study consent will continue to be followed for safety through the EOS visit (see Section 4.2.2.1). 
Subjects who discontinue study drug should complete: 1) study visits until the time of their next 
scheduled dose, and 2) the remaining visits of 3, 6, 9 and 12 months. All EOS assessments and 
procedures should be completed as indicated per the SOE 
 
Subjects who discontinue the study (eg, withdraw consent) should have all assessments 
conducted at the EOS visit at the time of withdrawal, for safety monitoring purposes.  
7.5 
Follow-up Extension Study 
An extension study, which would permit continued dosing of eligible subjects who complete 
PQ-110-001, do not meet stopping criteria in PQ-110-001 and derive therapeutic benefit, is 
planned. The sponsor will base the decision to open an extension study on the safety and efficacy 
data obtained during PQ-110-001 and the risk/benefit analysis for subjects.  
8.0 
STUDY ASSESSMENT PROCEDURES 
Safety parameters will be assessed by monitoring AEs, vital signs, physical examinations, 
ophthalmic exams, OCTs, infrared imaging, ECGs and laboratory data (serum chemistry 
hematology, and inflammatory markers). Assessments will be conducted as indicated by the SOE 
. 
8.1 
Adverse Events 
Information regarding occurrence of AEs will be captured throughout the study. Duration (start 
and stop dates), severity/grade, outcome, treatment and relationship to study drug will be 
recorded. Refer to Section 9.0, Assessment of Safety or Adverse Events and Serious Adverse 
Events. 
8.2 
Vital Signs 
Blood pressure, heart rate and temperature will be measured after the subject has been at rest in a 
sitting position for a minimum of 5 minutes. 


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8.3 
Laboratory Evaluations 
All laboratory evaluations will be conducted at a central laboratory, except Erythrocyte 
Sedimentation Rate (ESR), which will be conducted locally. Reference ranges for all laboratory 
parameters are provided in the Laboratory Manual. 
Serum chemistries will include sodium, potassium, chloride, bicarbonate (or serum carbon 
dioxide), blood urea nitrogen (BUN), creatinine, glucose, calcium, phosphorus, ALT, AST, 
gamma-glutamyl transferase (GGT), alkaline phosphatase, total bilirubin, uric acid, lactic 
dehydrogenase (LDH), albumin, total protein, triglycerides, and cholesterol. Estimated 
Glomerular Filtration Rate (eGFR) is to be calculated using the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) Creatinine Equation 2009 calculation for adult subjects 
and Schwartz equation, according to the recommendation from National Institutes of 
Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK), for 
pediatric subjects.  
Hematology will include a complete blood count (CBC): CBC with absolute differential 
(hematocrit, hemoglobin, white blood count, red blood cell count, neutrophils, granulocytes, 
lymphocytes, monocytes, eosinophils, basophils, platelet count). Urinalysis (by visual inspection 
and dipstick) will include color and appearance, specific gravity, pH, protein, glucose, blood, 
ketones, bilirubin, leukocyte, nitrite, and urobilinogen. In addition, microscopic analyses will be 
performed on samples with abnormal dipstick results.  
C4, Hemolytic complement 50 (CH50), INR, ESR and C Reactive Protein (CRP) will also be 
assessed.  
For female subjects of child bearing potential, a serum pregnancy test is required at Screening. 
Urine pregnancy tests are acceptable for subsequent time points. 
Subject eligibility is determined based on Screening laboratory values. If any relevant changes in 
the subject’s medical history occur between Screening and Day 1, the Investigator should repeat 
laboratory assessments prior to the subject’s first dose of study drug to confirm eligibility. 
Repeat laboratory tests are permitted to confirm potentially spurious values or false positive 
results, at the discretion of the Investigator. Repeat analysis results for any laboratory 
assessments that are eligibility criteria should be discussed with the Sponsor Medical Monitor 
prior to subject inclusion. 
8.4 
Pharmacokinetic Evaluations 
Samples for PK analysis will be collected as indicated per the SOE 
 


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Blood samples will be obtained from all subjects to assess PK parameters of QR-110 (AUC0-∞, 
AUC0-tlast, Cmax, C0, Tmax, T1/2, CL, Vd) pre- and post-dosing as indicated per the SOE  
(Appendix 1). T1/2  and Vd will only be evaluated if measurable serum levels are obtained.  
8.5 
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.  
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 Sponsor 
Medical Monitor. Details on the conduct of ECGs is provided in the Study Reference Manual. 
8.6 
Physical Examination 
Complete and symptom-directed physical examinations (urogenital exams not required) will be 
performed as indicated per the SOE 
  
8.7 
Height and Weight 
Height will be measured using a calibrated, wall-mounted stadiometer and will be documented as 
indicated per the SOE. Body weight will be measured using a calibrated scale as indicated per 
the SOE 
  
8.8 
Ophthalmic Exams 
Ophthalmic examinations will be performed at all study visits. BCVA will also be assessed at 
specified time points as indicated per the SOE 
. The ophthalmic exam is comprised 
of: BCVA; 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; 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 National Institute of Health 
(NIH) Grading Scale for Vitreous Haze.  
The procedures for ophthalmic exams are outlined in the Study Reference Manual.  
8.9 
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.  


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The DMC and Sponsor 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. 
8.10 
Leber’s Congenital Amaurosis Genetic Analysis 
Genotyping results (either historic or at screening) are required for eligibility. For subjects 
without an acceptable historic genotyping result, genotyping and sequencing of genes associated 
with inherited retinal dystrophies will be performed at Screening. Separate informed consent 
may need to be obtained per local requirements. A blood sample for genotyping and gene 
sequencing should be obtained at the Screening Visit.  
8.11 
Biomarkers 
 
 
 and stored for later quantification. In addition, blood 
samples for biomarkers may be collected at any study visit at which inflammation, pain or 
redness of the eye is present, including any unscheduled visits.  
8.12 
Efficacy Assessments  
Subjects must perform all Screening examinations. If a subject is unable to perform a specific 
assessment at a subsequent visit, this should be recorded in the eCRF and the subject’s ability 
reassessed at the next specified visit. All attempts at performing assessments should be recorded 
in the eCRF. 
Most measures of visual function (BCVA, FST, mobility course, oculomotor instability, PLR) 
will be measured a minimum of 2 times prior to the subject’s first dose of study drug to evaluate 
intrasubject variability (Screening and predose on Day 1). Measures of retinal anatomy (infrared 
imaging and OCT) and ERG will be measured a minimum of 1 time prior to the subject’s first 
dose of study drug. Any predose 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. In the case of repeat assessments, the measure reflecting the average of the measures 
will be considered the Baseline value. 
If possible, photoreceptor outer segment layer thickness will be calculated from OCT images as 
an exploratory 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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Narratives will be written for all participating subjects on an ongoing basis. 
Exploratory efficacy response criteria will be obtained as indicated per the SOE 
   
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 
Data Monitoring Committee 
An independent DMC will provide safety oversight for the study. A DMC operational charter 
will be finalized and an initial organizational meeting held prior to screening of the first subject.  
Once the first 2 adult subjects have been dosed and safety and tolerability data for at least 
4 weeks post dose are available, the DMC will review safety and tolerability data, and provide 
their recommendation for proceeding to the next dosing cohort, as described in Section 4.2.2 and 
the DMC Charter.   


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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) 
9.2.2 
Serious Adverse Events 
An 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  


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• 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) (See Section 9.3.1). “Serious” is a regulatory definition 
and is based on subject or event outcome or action criteria usually associated with events that 
pose a threat to a subject’s life or vital functions. Seriousness (not severity) serves as the guide 
for defining regulatory reporting obligations. 
Severity and seriousness should be independently assessed when recording AEs and SAEs on the 
AE eCRF and SAE form. 
9.2.3 
Suspected Unexpected Serious Adverse Reaction Definition 
An 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 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 
 
 
 
 


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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. 


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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). 
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. 


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• 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 
All significant medical conditions including signs/symptoms of the underlying diagnosis found 
during the screening period and up to initiation of dosing (Visit 2) will be captured as medical 
history. Any event/condition related to participation in the study or study procedures but not 
related to underlying or concomitant disease that is noted after Screening up to the date of first 
dose will be captured as a non-treatment emergent AE. 
Any event/condition noted once the subject receives their first dose of study drug will be 
captured as an AE. All AEs and SAEs regardless of attribution will be collected until at least 
90 days following the last administration of study drug or the subject’s EOS visit, whichever is 
later. At the last scheduled visit, the Investigator should instruct each subject to report to the 
Investigator any subsequent AEs/SAEs that the subject’s personal physician believes could be 
related to prior study treatment.  
Adverse events and SAEs related to study drug that persist > 90 days 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: 


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“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 
adverse events 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). 
a. 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (eg, cascade events or clinical sequelae) 
should also be entered as separate AEs. For example, if severe diarrhea is known to have resulted 
in dehydration, both diarrhea and dehydration should be entered as AEs on the eCRF, and if also 
serious, on the SAE form.  
b. 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution between subject evaluation 
time points. Such events should only be recorded once in the eCRF unless their severity 
increases. If a persistent AE becomes more severe or occurs more frequently, it should be 
recorded again on the AE eCRF with the increased severity grading.  
A recurrent AE is one that occurs and resolves between subject evaluation time points and 
subsequently recurs. All recurrent AEs should be recorded individually on the AE eCRF. 
c. 
Abnormal Laboratory Values 
Only clinically significant laboratory abnormalities will be recorded as AEs on the eCRF and 
SAE form (if applicable).  
If the laboratory abnormality can be characterized by a precise clinical term, the clinical term 
should be recorded as the AE or SAE. For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as “hyperkalemia”. 
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs on the eCRF and SAE form (if applicable), unless their 
severity, seriousness, or etiology changes.  


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d. 
Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section 9.4.1), 
regardless of attribution, will be recorded on the AE eCRF and SAE form and reported to the 
Sponsor within 24 hours of event knowledge.  
When recording a death, the event or condition that caused or contributed to the fatal outcome 
should be recorded as a single medical concept. For example, if death resulted from respiratory 
failure, the AE recorded should be “Respiratory Failure”, and the outcome of the AE would be 
“Death”. If the cause of death is unknown and cannot be ascertained at the time of reporting, 
record “unexplained death” on the AE eCRF and SAE form. 
e. 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. Such conditions 
should be recorded on the Medical 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”). 
f. 
Hospitalization, Prolonged Hospitalization or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE unless specifically instructed otherwise in this protocol.  
g. 
Pregnancy 
If a female subject or a female partner of a male subject becomes pregnant while the female 
subject or the male partner is receiving study drug or within 6 months after the last dose of 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 (see 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. 


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h. 
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 for the cohort assignment. 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. 
Serious adverse events 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 


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administered, and outcome of the event. A query regarding a follow-up report should be 
answered within 5 working days from receipt of the query. 
• Appropriate diagnostic tests and therapeutic measures are to be performed as necessary 
and reported on the SAE form. 
• All SAEs must be reported to the IRB/EC, if applicable. See the International Council for 
Harmonisation (ICH) GCP E6, Section 4.11.1 (ICH 1996). 
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 country requirements. All SUSARs will be 
reported as required to the Competent Authorities of all involved European member 
states. 
• The Investigator will notify local IRB/EC of SUSARs or significant risks to subjects, per 
local country requirements. The Investigator must keep copies of all AE information, 
including correspondence with the Sponsor or local IRB/EC on file.  
• All studies that are conducted within any European country will comply with the 
European Clinical Trial Directive 2005/28/EC, the Clinical Trial Directive 2001/20/EC 
and the Detailed Guidance CT-3 (2011/C 172/01). 
10.0 
STATISTICAL METHODOLOGY 
10.1 
General Considerations 
A comprehensive Statistical Analysis Plan (SAP) specifies the statistical methodology, and table, 
listing and figure (TLF) formats for all aspects of the planned analyses. The SAP supports the 
completion of the Clinical Study Report (CSR) for this protocol. As the risk profile of QR-110 in 
humans is unknown and this is a first-in-human trial, all AEs will be considered in determining 
the safety profile of QR-110 unless obviously unrelated. As an early phase clinical study, 
exploratory analyses not necessarily identified in the SAP may be performed to support the 
clinical development program. Any p values that will be calculated according to the analysis plan 
will be interpreted in view of the exploratory nature of the study. Any post-hoc, or unplanned, 
analyses not identified in the SAP will be clearly identified in the CSR, in accordance with 
applicable Standard Operating Procedures (SOPs) of the sponsor.  


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10.2 
Determination of Sample Size 
This is a Phase 1b/2 safety study designed to evaluate the safety, tolerability and PK of QR-110. 
The sample size is not based on power calculations. It is chosen based on clinical experience and 
considered to be adequate to fulfill the objectives of the study. 
Twelve subjects are planned to be enrolled in the study. However, depending upon observed 
results, the DMC and Sponsor Medical Monitor may add subjects as indicated in Table 3  
(Section 4.2.2.2), for a maximum number of subjects up to a total of N=18. The decision to add 
subjects is based on DMC and Sponsor Medical Monitor review of safety and tolerability and not 
based on efficacy; hence, exploratory efficacy analyses will not impact the DMC and Sponsor 
Medical Monitor review of accumulating safety data and the potential for additional subjects 
above 12. 
10.2.1 
Randomization and Blinding 
No randomization or blinding is required for this study. 
10.2.2 
Replacement of Subjects 
Subjects who discontinue from the study without receiving any study drug will be replaced. 
Subjects discontinuing the study before the full course of study drug may be replaced by a 
subject who will be assigned the same dose as the subject being replaced. The decision for 
replacement will be made by the Sponsor based on available data and perceived need for 
additional data.  
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 subjects in the Efficacy 
Evaluable Population with the exception of subjects 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 (PK) Population: the population for PK analyses will consist of all subjects 
who receive QR-110 and who have measurable drug concentrations in blood samples. 


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10.4 
Subject Disposition, Demographics and Baseline Disease Characteristics 
Subject disposition will be summarized for the safety population by dose group. 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 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.  The baseline data is defined as the data most recently collected 
and/or the average of the measures (eg, for ophthalmic assessments performed two or more 
times) prior to the first dose. 
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 AE (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. 
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. 


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10.6.2 
Vital Signs 
Vital sign 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 in the following ways: 
• 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: 
• AUC0-∞: Area under the curve to infinity will be calculated based on the last observed 
concentration (Clast (obs)) using formula: AUC0-∞=AUClast+Clast(obs)/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. 


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• 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 an elimination rate constant (λz) is 
estimable): Apparent volume of distribution at steady state of the drug will be 
determined from trough levels. 
Serum concentration below 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 T½. 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 efficacy evaluations will include: 
• Secondary efficacy evaluations 
o BCVA 
o FST 
o PLR 
• Exploratory efficacy evaluations 
 


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Descriptive statistics of clinical efficacy will be tabulated by dose group, and if appropriate, for 
dose groups combined.  
All continuous endpoints will be summarized using the following descriptive statistics: number 
of subjects, mean, standard deviation, standard error, median, minimum, maximum and 95% 
confidence intervals for the mean. Categorical endpoints will be summarized using: number of 
subjects, frequency, percentages and 95% confidence intervals. If data appear highly skewed, 
natural log or other transformation may be used to compute summary statistics. 
Continuous efficacy endpoints will be summarized and may be analyzed using appropriate 
parametric or nonparametric inference tests.  
Details of the statistical analyses can be reviewed in the SAP. 
10.9 
Interim Analysis 
Safety will be assessed prior to each dose escalation and prior to the enrollment of pediatric 
subjects by the DMC and Sponsor Medical Monitor. Efficacy exploratory reviews will be 
planned on a continuous basis.  
10.10 Multiplicity Considerations 
No multiplicity adjustments are planned in this exploratory Phase 1b/2 study. 


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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. 
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 Harmonisation (ICH) Good Clinical Practice (GCP) and local 
regulations, before recording data on eCRFs. All corrections to eCRFs will be made by 
authorized users, and the changes will be automatically logged in the audit trail of the system 
(time and date stamps and the user entering or updating data). Electronic CRFs should be 
completed for every subject screened or enrolled in the study. 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. 


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A Sponsor representative (monitor) will contact the Investigator(s) at periodic intervals by 
telephone or on-site visit for the purpose of monitoring the facilities and assessing the progress 
of the study. Electronic CRFs and subject records will be reviewed at on-site visits at regular 
intervals throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical research. 
The monitor should have access to subject medical records and other study-related records 
needed to verify the entries on the eCRF. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected 
during these monitoring visits, including delays in completing eCRFs, are resolved. 
Monitoring of study center facilities (eg, pharmacy, drug storage areas, laboratories) and review 
of study-related records will occur to evaluate the study conduct and compliance with the 
protocol, ICH GCP, and applicable regulatory requirements. Study drug dispensing and 
accountability will also be assessed. 
11.2 
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. 
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. Separate Informed Consent 
Forms may be required for gene sequencing, and/or biomarker testing. Age appropriate assent 
and permission from a minor subject’s parent or legal guardian is required for pediatric subjects. 
The subject or his/her legal representative must sign the current version of the written, IRB/EC-


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approved Informed Consent Form in the presence of a witness and be given a copy. The 
Investigator will ensure that a copy of the signed consent is kept with the subject’s records. 
In accordance with ICH GCP and country authority requirements, an IRB/EC must review and 
approve this protocol and the 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. 
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.  


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In compliance with applicable regulations, it is required that the Investigator and institution 
permit authorized representatives of the Sponsor, the United States Food and Drug 
Administration (USFDA), 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. 
13.0 
STUDY ADMINISTRATION 
A coordinating Investigator for the PQ-110-001 study will be selected from the participating 
sites by the Sponsor. 
13.1 
Investigator’s Brochure 
Before the study begins, the Investigator will receive the QR-110 Investigator’s Brochure (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, DMC, 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 


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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 GCP 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: 
• 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. 


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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 European Competent 
Authorities and ECs when the study is terminated, within 90 days of the last subject’s 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.   
End of Study will be defined as the last visit for the last subject (LVLS) in the PQ-110-001 
clinical study (Visit 21 or the End of Study Visit). 
13.7 
Financing and Insurance 
Financing and Insurance are addressed separately in the Clinical Study Agreement. 
13.8 
Publication Policy 
Publication policy is addressed separately in the Clinical Study Agreement. 
 
 


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14.0 
REFERENCES 
American Academy of Ophthalmology. Clinical Statement. Intravitreal Injections. AAO Hoskins 
Center for Quality Eye Care. March 2015. Available at: https://www.aao.org/clinical-
statement/intravitreal-injections-statement. 
Artunay O, Yuzbasioglu E, Rasier R, Sengül A, Bahcecioglu H. Incidence and management of 
acute endophthalmitis after intravitreal bevacizumab (Avastin) injection. Eye. 2009; Dec; 
23(12):2187-93. doi: 10.1038/eye.2009.7. 
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.  
Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K, et al. Effect of gene 
therapy on visual function in Leber's congenital amaurosis. N Engl J Med. 2008 May 22; 
358(21):2231-9. doi: 10.1056/NEJMoa0802268. 
Bhardwaj V, Rajeshbhai GP. Axial length, anterior chamber depth-a study in different age 
groups and refractive errors. J Clin Diagn Res. 2013 Oct; 7(10):2211-2. doi: 
10.7860/JCDR/2013/7015.3473. Epub 2013 Oct 5. 
Chacon-Camacho OF, Zenteno JC. Review and update on the molecular basis of Leber 
congenital amaurosis. World J of Clin Cases. 2015 Feb; 3(2):112-124.  
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. 


Investigational Product: QR-110 
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02-Aug-2018 
 
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. 
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. 
Fagan XJ1, Al-Qureshi S. Intravitreal injections: a review of the evidence for best practice. Clin 
Exp Ophthalmol. 2013 Jul; 41(5):500-7. doi: 10.1111/ceo.12026. 
Falavarjani KG, Nguyen QD. Adverse events and complications associated with intravitreal 
injection of anti-VEGF agents: a review of literature. Eye. 2013 Jul; 27(7):787-94. doi: 
10.1038/eye.2013.107. 
Ghazi NG, Abboud EB, Nowilaty SR, Alkuraya H, Alhommadi A, Cai H. Treatment of retinitis 
pigmentosa due to MERTK mutations by ocular subretinal injection of adeno-associated virus 
gene vector: results of a phase I trial. Hum Genet. 2016 Mar; 135(3):327-43. doi: 
10.1007/s00439-016-1637-y. 
Glassman AR, Stockdale CR, Beck RW, Baker C, Bressler NM. Evaluation of study participant 
masking of intravitreal injections in a randomized clinical trial.  Arch Ophthalmol. 2012 
February; 130(2): 190–94. 
Hellström A, Svensson E, Strömland K. Eye size in healthy Swedish children and in children 
with fetal alcohol syndrome. Acta Ophthalmol Scand. 1997 Aug; 75(4):423-8. 


Investigational Product: QR-110 
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ICH Harmonized Tripartite Guideline: guideline for good clinical practice E6(R1) 1996. 
Available at 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_G
uideline.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, Ratnakaram R, Heon E, Schwartz SB, Roman AJ, et al. Gene 
therapy for Leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 
children and adults followed up to 3 years. Arch Ophthalmol. 2012. 130(1): 9-24. 
Kmoch S, Majewski J, Ramamurthy V, Cao S, Fahiminiya S, Ren H, MacDonald IM.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. 
Maguire AM1, High KA, Auricchio A, Wright JF, Pierce EA, Testa F, et al. Age-dependent 
effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial. 
Lancet. 2009 Nov 7; 374(9701):1597-605. doi: 10.1016/S0140-6736(09)61836-5. 
McAnany JJ, Genead MA, Walia S, Drack AV, Stone EM, Koenekoop RK, et al. Visual acuity 
changes in patients with Leber congential amaurosis and mutations in CEP290. JAMA 
Ophthalmol. 2013. 131(2):178-82. 
Mintz-Hittner HA, Kuffel, RR. Intravitreal injection of bevacizumab (Avastin) for treatment of 
stage 3 retinopathy of prematurity in zone I or posterior zone II. Retina. 2008; 28:831–8. 
Nazari H, Modarres M, Parvaresh MM, Falavarjani KG. Intravitreal bevacizumab in 
combination with laser therapy for the treatment of severe retinopathy of prematurity (ROP) 
associated with vitreous or retinal hemorrhage. Graefes Arch Clin Exp Ophthalmol. 2010; 
248(12):1713–8. 
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. 


Investigational Product: QR-110 
Protocol No. PQ-110-001 (Version 6.0) 
 
ProQR Therapeutics 
 
Page 75 of 80 
 
 
 
02-Aug-2018 
 
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. 
Pasadhika S, Fishman GA, Stone EM, Lindeman M, Zelkha R, Lopez I, et al. Differential 
macular morphology in patients with RPE65-, CEP290-, GUCY2D-, and AIPL1-related Leber 
congenital amaurosis. Invest Ophthalmol Vis Sci. 2010 May; 51(5):2608-14. 
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. 
Zadnik K, Mutti DO, Mitchell GL, Jones LA, Burr D, Moeschberger ML. Normal eye growth in 
emmetropic schoolchildren. Optom Vis Sci. 2004 Nov; 81(11):819-28.  
 


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15.0 
APPENDICES 
 


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SAP_001.pdf: 
 
FORM.152.03 Updated 30-Aug-2016 
 
STATISTICAL ANALYSIS PLAN  
AN OPEN-LABEL, MULTIPLE DOSE, DOSE ESCALATION STUDY TO 
EVALUATE THE SAFETY AND TOLERABILITY OF QR-110 IN 
SUBJECTS WITH LEBER’S CONGENITAL AMAUROSIS (LCA) DUE 
TO c.2991+1655A>G MUTATION (p.Cys998X) IN THE CEP290 GENE 
 
 
 
Sponsor:   
 
ProQR Therapeutics 
Zernikedreef 9 
2333 CK Leiden 
The Netherlands 
 
Protocol Number: 
PQ-110-001, Version 6.0 
 
Date:    
 
09-Aug-2019 
Version:  
 
Version 2.0


 
 
 
Page 2 of 56 
AN OPEN-LABEL, MULTIPLE DOSE, DOSE ESCALATION STUDY TO EVALUATE THE SAFETY 
AND TOLERABILITY OF QR-110 IN SUBJECTS WITH LEBER’S CONGENITAL AMAUROSIS (LCA) 
DUE TO c.2991+1655A>G MUTATION (p.Cys998X) IN THE CEP290 GENE 
 
Protocol Number: 
PQ-110-001, Version 6.0 
Version:  
 
Version 2.0  
Date:    
 
09-Aug-2019 
 
Statistical Analysis Plan Approval 
 
Prepared by: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reviewed by:  
 
 
 
 
          
___________ 
 
 
 
 
 
Approved by:  
 
 
 
 
 
 
 
 
 
 
 
  
 
 


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Table of Contents 
1. 
Introduction ............................................................................................................................ 8 
1.1 Primary Objective ..................................................................................................................... 8 
1.2 Secondary Objectives .............................................................................................................. 8 
1.3 Exploratory Objectives ............................................................................................................. 8 
1.4 Primary Endpoint ..................................................................................................................... 9 
1.5 Secondary Endpoints ............................................................................................................... 9 
1.6 Exploratory Endpoints .............................................................................................................. 9 
2. 
Study Design and Procedures ............................................................................................ 11 
2.1 General Study Design ............................................................................................................ 11 
2.2 Dose Escalation and DMC Review ........................................................................................ 11 
2.3 Study Cohorts and DMC Review Schedules ......................................................................... 12 
2.4 Study Visits ............................................................................................................................ 13 
2.5 Schedule of Visits and Assessments ..................................................................................... 15 
3. 
Study Treatments ................................................................................................................. 20 
4. 
Sample Size and Power Considerations ........................................................................... 20 
4.1 Randomization and Masking .................................................................................................. 20 
4.2 Replacement of Subjects ....................................................................................................... 20 
5. 
Data Preparation .................................................................................................................. 20 
6. 
Analysis Populations ........................................................................................................... 21 
6.1 All Enrolled Subjects Population ............................................................................................ 21 
6.2 Safety Population ................................................................................................................... 21 
6.3 Efficacy Evaluable Population................................................................................................ 21 
6.4 Pharmacokinetic (PK) Population .......................................................................................... 21 
7. 
General Statistical Considerations .................................................................................... 21 
7.1 Study/Treatment Eye Definition and Unit of Analysis ............................................................ 21 
7.2 Missing or Inconclusive Data Handling .................................................................................. 22 
 
 
7.3 Definition of Baseline ............................................................................................................. 23 
7.4 Data Analysis Conventions .................................................................................................... 24 
7.5 Data Monitoring Committee (DMC)........................................................................................ 24 
7.6 Interim Analyses .................................................................................................................... 25 
7.7 Adjustments for Multiplicity .................................................................................................... 25 
8. 
Disposition of Subjects ....................................................................................................... 25 
9. 
Demographics ...................................................................................................................... 26 


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9.1 Genotyping ............................................................................................................................. 27 
9.2 Baseline Characteristics ........................................................................................................ 27 
10. 
Medical History and Concomitant Medications ................................................................ 27 
10.1 Medical History ...................................................................................................................... 27 
10.2 Concomitant Medications ....................................................................................................... 27 
11. 
Treatment Exposure ............................................................................................................ 28 
12. 
Safety and Tolerability Analyses ........................................................................................ 28 
12.1 Adverse Events ...................................................................................................................... 28 
12.2 Slit-Lamp Biomicroscopy Examination .................................................................................. 32 
 
 
12.3 Posterior Segment/Fundus Examination ............................................................................... 33 
12.4 Intraocular Pressure (IOP) ..................................................................................................... 33 
12.5 Physical Examination ............................................................................................................. 34 
12.6 Vital Signs .............................................................................................................................. 34 
12.7 Electrocardiogram (ECG) ....................................................................................................... 34 
12.8 Clinical Laboratory Data ......................................................................................................... 34 
13. 
Pharmacokinetic Analyses ................................................................................................. 34 
14. 
Efficacy Analyses ................................................................................................................ 35 
14.1 Visual Acuity (BCVA) with ETDRS and BVRT ....................................................................... 36 
14.2 Red, Blue and White Full-Field Stimulus Testing (FST) ........................................................ 37 
14.3 Pupillary Light Reflex (PLR) ................................................................................................... 37 
14.4 Oculomotor Instability (OCI) ................................................................................................... 38 
14.5 Electroretinogram (ERG) in Scotopic and Photopic Conditions ............................................ 38 
14.6 Spectral Domain Ocular Coherence Tomography (SD-OCT) ............................................... 38 
14.7 Near-Infrared Auto Fluorescence (NIRAF) ............................................................................ 39 
 
 
 
 
15. 
Changes from Protocol-Stated Analyses .......................................................................... 47 
15.1 Analysis Populations .............................................................................................................. 47 
15.2 Data Analysis Conventions - Baseline ................................................................................... 47 
16. 
References ............................................................................................................................ 47 
17. 
Revision History ................................................................................................................... 47 


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17.1 Revision 01 ............................................................................................................................ 47 
 
 
 
21. 
Appendices ........................................................................................................................... 55 
21.1 Appendix 1: Table of Equivalency – Visual Acuity ................................................................. 55 
 
 


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List of Abbreviations 
A 
Adult Subject Cohort 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ARLNS 
Age-Related Eye Disease Study (AREDS) Clinical Lens Grading System  
ATC 
Anatomical Therapeutic Chemical Classification 
AUC 
Area Under the Curve 
BCVA 
Best-Corrected Visual Acuity 
BRE 
Backlit Room Exit® 
BRVT 
Berkeley Rudimentary Vision Test 
C 
Concentration 
CF 
Count Fingers 
CL 
Serum Clearance or Serum Clearance Level 
CME 
Cystoid Macular Edema 
CRF 
Case Report Form 
CRP 
C-Reactive Protein 
CSR 
Clinical Study Report 
CVAQC 
Cardiff Visual Ability Questionnaire for Children (25-items) 
CS 
Clinically Significant 
D 
Day 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EOS 
End of Study 
ERG 
Electroretinogram 
ESR 
Erythrocyte Sedimentation Rate 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FST 
Full-field Stimulus Testing 
HCRE 
High-Contrast Room Exit® 
HCVNC 
High-Contrast Visual Navigation Challenge® 
HIPAA 
Health Information Portability and Accountability Act 
HM 
Hand Movement 
ICH 
International Council for Harmonisation 
IOP 
Intraocular Pressure 
ISCEV 
International Society for Clinical Electrophysiology of Vision 
IVT 
Intravitreal 
LCA 
Leber’s Congenital Amaurosis 
LCVNC 
Low-Contrast Visual Navigation Challenge® 
LLOQ 
Lower Limit of Quantitation  
logMAR 
Logarithm of the Minimum Angle of Resolution 
LP 
Light Perception 
M 
Month 


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MedDRA 
Medical Dictionary for Regulatory Activities 
µg 
Microgram 
N 
Number of Subjects 
n 
Number of Observations 
N/A 
Not Applicable 
NCS 
Not Clinically Significant 
NIRAF 
Near-Infrared Autofluorescence 
OCI 
Oculomotor Instability 
SD-OCT 
Spectral Domain Optical Coherence Tomography 
ONL 
Outer Nuclear Layer 
P 
Pediatric Subject Cohort 
p 
p-value or probability value 
PSC 
Posterior Subcapsular Cataract 
PDF 
Portable Document Format 
PK 
Pharmacokinetics 
PLR 
Pupillary Light Reflex 
PP 
Per Protocol 
PT 
Preferred Term 
RTF 
Rich Text Format 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDC 
Statistics and Data Corporation, Incorporated 
SOC 
System Organ Class 
T1/2 
Half-Life 
TEAE 
Treatment-Emergent Adverse Event 
VA 
Visual Acuity 
Vd 
Apparent Volume of Distribution 
VEP 
Visual Evoked Potential 
VFQ-25 
25-Item Visual Functioning Questionnaire 
WHO DDE 
World Health Organization Drug Dictionary Enhanced 
WOCBP 
Women of Childbearing Potential 
 
 
 
 


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1. Introduction 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and reporting 
l in support of protocol PQ-110-001, version 
6.0 dated 02-Aug-2018. 
This SAP is being written with due consideration of the recommendations outlined in the most recent 
International Council for Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials and the most recent ICH E3 Guideline, entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports. 
This SAP describes the data that will be analyzed and the subject characteristics, efficacy, and safety 
assessments that will be evaluated. This SAP provides details of the specific descriptive statistical 
methods that will be used. 
In addition to this SAP, inferential analyses will be generated by 
 which will also be used to 
support the CSR. The descriptions of methods and statistical analyses used for these inferential 
analyses are described separately within the scope of the Cytel SAP of which a copy has been included 
in whole in 
 and which should be read in conjunction with this SAP. 
The statistical analysis methods presented in this document will supersede the statistical analysis 
methods described in the clinical protocol. If additional analyses are required to supplement the planned 
analyses described in this SAP they may be completed and will be identified in the Clinical Study Report 
(CSR).Study Objectives 
1.1 
Primary Objective 
The primary objective of the study is to evaluate the safety and tolerability of QR-110 administered via 
intravitreal (IVT) injection in subjects with Leber’s Congenital Amaurosis (LCA) due to the CEP290 
p.Cys998X mutation.  
1.2 
Secondary Objectives 
The secondary objectives of the study are: 
• 
to evaluate the serum pharmacokinetics (PK) of QR-110 administered by IVT injection in 
subjects with LCA due to the CEP290 p.Cys998X mutation 
• 
to evaluate the efficacy of QR-110 administered by IVT injection in subjects with LCA due 
to the CEP290 p.Cys998X mutation 
1.3 
Exploratory Objectives 
 
 


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1.4 
Primary Endpoint 
• 
Frequency and severity of ocular AEs in the treated and contralateral eyes 
1.5 
Secondary Endpoints 
• 
Frequency and severity of non-ocular Adverse Events (AEs) 
• 
Changes in ophthalmic examination findings 
• 
Change from baseline in Best-Corrected Visual Acuity (BCVA) in treated eye and 
contralateral eye 
• 
Change from baseline in near-infrared autofluorescence (NIRAF) data in treated eye and 
contralateral eye:  
• 
Horizontal diameter 
• 
Vertical diameter 
• 
Area 
• 
Changes in SD-OCT findings in treated eye and contralateral eye with horizontal and 
vertical scan for: 
• 
Change from baseline in full retinal thickness (FRT) at foveal pit 
• 
Change from baseline in mean FRT (line scan) 
• 
Change from baseline in outer nuclear layer (ONL) thickness at foveal pit 
• 
Change from baseline in extent of ONL region 
• 
Change from baseline in photoreceptor outer segment thickness (OST) at foveal pit 
• 
Change from baseline in mean photoreceptor OST (line scan) 
• 
Changes in safety parameters, including vital sign measurements, physical examination 
findings, electrocardiogram (ECG) and laboratory parameters 
• 
 Systemic exposure of QR-110 in serum 
• 
Change from baseline in light sensitivity to red Full-field Stimulus Testing (FST) in treated 
eye and contralateral eye 
• 
Change from baseline in light sensitivity to blue FST in treated and contralateral eye 
• 
Change from baseline in white Pupillary Light Reflex (PLR) at 4 levels of illumination (ie, 
4, 40, 400, and 4000 cd/m2) in treated eye and contralateral eye: 
• 
Pre-stimulus 
• 
Maximum amplitude 
• 
0.9 seconds amplitude 
• 
Overall latency (time to react) 
1.6 
Exploratory Endpoints 
 
 


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The study is not designed to have sufficient statistical power to assess efficacy of QR-110 in the 
treatment of LCA due to the CEP290 p.Cys998X mutation. However, changes in clinical outcome 
measures associated with LCA due to the CEP290 p.Cys998X mutation will be monitored over the 
course of the study. 
2. Study Design and Procedures 
2.1 
General Study Design 
The first-in-human study of QR-110 will be an open-label, multiple arm, multiple dose, dose escalation 
study to evaluate the safety and tolerability of QR-110 administered via IVT injection in subjects with 
LCA due to the CEP290 p.Cys998X mutation. Subjects will be assigned to receive a specified dose level 
(loading dose and maintenance dose) of QR-110. No intrasubject dose escalation is planned. Up to 3 
dose levels of QR-110 will be evaluated. Dose escalation decisions and initiation of dosing in pediatric 
subjects (6 to < 18 years of age) will be determined by the Data Monitoring Committee (DMC) and 
Sponsor Medical Monitor review of safety and tolerability data. The DMC and Sponsor Medical Monitor 
will also review all available safety data at key study time points (e.g., prior to the first subject in the first 
adult cohort (Cohort A1) receiving each subsequent dose of study drug).  
QR-110 will be administered by unilateral IVT injection. Each subject will receive up to 4 doses of QR-
110 in their worse eye (as defined by visual acuity at the Screening Visit, subsequently referred to as 
treatment eye) every 3 months and will be assessed for safety and tolerability at follow-up visits. The 
worst eye or treatment eye is defined in Section 8.1 of the SAP.  
No placebo nor sham injections will be administered in the contralateral eye. The contralateral eye and 
the subject’s own baseline measurements will serve as controls.  
The DMC and/or Sponsor Medical Monitor may decide to de-escalate the dose, hold the dose (delay or 
skip), or discontinue study drug for an individual subject, in consultation with the Investigator. Subjects 
who discontinue study drug will continue to be followed for safety and efficacy.  
An extension study is planned but is not within the scope of this SAP. 
2.2 
Dose Escalation and DMC Review 
Specifics of the dose escalation plan are described in detail in Section 4.2.1.5 of the protocol. 
 
 


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Safety review, DMC review and stopping criteria are further detailed in protocol Section 4.2.2 and 
Section 4.2.4, and the DMC Charter. Otherwise, safety reviews will be conducted by the DMC and 
Sponsor Medical Monitor before each cohort initiation and on an ad hoc basis as needed. The Sponsor 
will also perform safety review on an ongoing basis. 
2.3 
Study Cohorts and DMC Review Schedules 
QR-110 will be administered at up to 3 escalating dose levels and the study will include up to 6 cohorts 
(up to 3 adult cohorts and up to 3 pediatric cohorts). Each cohort will have at least 2 subjects and each 
dose level will be tested in 1 adult cohort and 1 pediatric cohort (Table 1). Dose escalation will proceed 
as described in Section 4.2.1.5 of the protocol. QR-110 will be administered via unilateral IVT injection 


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in the subject’s worse eye (defined in Section 8.1 of the SAP) every 3 months and each subject will 
receive up to 4 doses of study drug. 
While the protocol allows testing of up to 3 dose levels, no dose escalation to the highest dose was 
performed based on interim study results.
 
 
2.4 
Study Visits 
Study visits will be referred to in all tables and listings as the planned study day corresponding to the 
visit to enable reviewers to understand the assessment timing without referring to the protocol visit 
schedule shown in Table 1. Screening assessments may be repeated at a Re-Screening visit to 
reevaluate eligibility or safety parameters at the Investigator’s discretion. In listings the re-screening visit 
will be “Unscheduled (Day -28 to -1)” and will only be used for further analyses if an average of all pre-
dose measures is used for baseline. Dosing visits can occur over multiple days due to time constraints 
on subjects’ schedules and visit procedures. Note that there is no Day 0 and that Day 1 corresponds to 
the day of first treatment. Any unscheduled visits outside of 
 will be noted as “Unscheduled” on 
tables and listings. The following table shows the scheduled visits, their planned study day and the 
acceptable visit windows for each scheduled visit. Scheduled visits that occur outside of the visit window 
will not be considered unscheduled visits, but will be presented and summarized as the scheduled visit. 


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2.5 
Schedule of Visits and Assessments 


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3. Study Treatments 
In this multiple arm multiple dose escalation study QR-110 will be administered by unilateral IVT 
injection. Each subject will receive up to 4 doses of QR-110 in their worse eye (defined in Section 8.1 
of the SAP) at least 3 months apart and will be assessed for safety and tolerability at follow-up visits. 
Up to 3 dose levels will be tested (loading dose/maintenance dose):  
• 
Low Dose: One 160 µg loading dose, followed by up to three 80 µg maintenance doses 
• 
Mid Dose: One 320 µg loading dose, followed by up to three 160 µg maintenance doses 
• 
High Dose: One 500 µg loading dose, followed by up to three 270 µg maintenance doses 
QR-110 Solution for IVT Injection, 10 mg/mL and diluent, will hereby be referred to as IVT injection. 
As noted previously in Section 2.3, no subjects were treated at the high dose, therefore only the low 
dose and mid dose will be considered within the statistical TLFs for this study. 
4. Sample Size and Power Considerations 
This is a phase 1b/2 safety study designed to evaluate the safety, tolerability and PK of QR-110. The 
sample size is not based on power calculations. It is chosen based on clinical experience and considered 
to be adequate to fulfill the objectives of the study. 
Twelve subjects are planned to be enrolled in the study. However, depending upon observed results, 
the DMC and Sponsor Medical Monitor may add subjects as indicated in Section 4.2.2.2 of the protocol, 
for a maximum number of subjects up to a total of n = 18.  
4.1 
Randomization and Masking 
No randomization or masking is used for this phase 1b/2 open label safety study. 
Evaluators responsible for grading mobility course videos and reviewing and interpreting ophthalmologic 
imaging (FST, SD-OCT, PLR, OCI, ERG, NIRAF) will be masked to which eye is the treated eye for the 
entire course of the study to ensure that grading videos and ophthalmologic assessments are unbiased. 
4.2 
Replacement of Subjects 
Subjects who discontinue from the study without receiving any study drug will be replaced. Subjects 
discontinuing the study before the full course of study drug may be replaced by a subject who will be 
assigned the same dose as the subject being replaced. The decision for replacement will be made by 
the Sponsor based on available data and perceived need for additional data. 
5. Data Preparation 
All reported study data will be recorded on the electronic case report forms (eCRFs) 
 
 Only the 


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Principal Investigator and authorized study staff according to the Delegation of Responsibilities log are 
entitled to make entries in the eCRF. 
After data are entered into the clinical study database, electronic edit checks and data review will be 
performed. All data validation specifications and procedures are detailed in the Data Validation Manual 
as a separate document. When the database has been declared to be complete and accurate, the 
database will be locked. Any changes to the database after data have been locked can only be made 
with the approval of the Sponsor in consultation with SDC.  
All analyses outlined in this document will be carried out after the following have occurred: 
• 
All data management requirements are met according to SDC standard operating procedures, 
including data entry, performance of edit and validation checks, documentation and resolution 
of data queries, and database lock with written authorization provided by appropriate SDC and 
Sponsor personnel; 
• 
Protocol deviations have been identified and status defined (major/minor deviations);  
• 
Analysis populations have been determined. 
6. Analysis Populations 
The analysis population definitions in the SAP will supersede the analysis definitions in the protocol. 
6.1 
All Enrolled Subjects Population 
The All Enrolled Subjects population will consist of all subjects who have provided informed consent, 
including screen failures as well as subjects who received any QR-110 IVT injection.  
6.2 
Safety Population 
The population for safety analysis will consist of all subjects who received any QR-110 IVT injection. 
6.3 
Efficacy Evaluable Population 
The population for efficacy (clinical activity) analysis will consist of all subjects who received any QR-
110 with at least one baseline and one post-baseline efficacy observation or measurement.  
6.4 
Pharmacokinetic (PK) Population 
The population for PK analyses will consist of all subjects who received QR-110 and who have 
measurable drug concentrations (ie, above the lower limit of quantification) in blood samples. 
7. General Statistical Considerations 
7.1 
Study/Treatment Eye Definition and Unit of Analysis 
The study eye will be the treated eye for all efficacy and safety summaries. The study eye will always 
be referred to as the treated eye on TLFs and is defined as the eye with the worse visual acuity at 


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Screening. If both eyes have the same visual acuity, the Investigator should determine the eye with the 
worse visual function, according to other measures of ophthalmic function (FST or mobility course 
score). If the visual function is the same per the Investigator’s assessment, then the treated eye will be 
determined at Investigator discretion. 
The unit of analysis for all ocular endpoints will be the eye level. All ocular endpoints will be summarized 
by eye and by dose group and cohort (ie, adult versus pediatric) for the treated eye and contralateral 
eye where appropriate. Subject level information, non-ocular AEs, medical history, 
 
 
7.2 
Missing or Inconclusive Data Handling 
Other than the imputations described within Section 7.2.1, no special handling of missing data will be 
made and analyses will be conducted using observed values only. 
7.2.1 
MISSING MOBILITY COURSE COMPOSITE SCORE IMPUTATIONS FOR CENTRAL READING CENTER 
GRADING 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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7.3 
Definition of Baseline 
Baseline is defined as the last measurement prior to the first dose of study drug in the treated eye for 
 IOP, laboratory parameters, and the safety endpoints slit lamp biomicroscopy, 
posterior segment/fundus exam, vital signs, and ECG . For ophthalmic parameters BCVA, FST, mobility 
course, OCI and PLR measured at Screening and Visit 2 (Day 1) the average will be defined as baseline. 
For other ophthalmic parameters, NIRAF, SD-OCT, and ERG, planned to be done once at baseline, the 
average will be defined as baseline if the exam is repeated. Change from baseline will be calculated as 
follow-up visit/time point minus baseline visit/time point.  


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7.4 
Data Analysis Conventions 
All data analysis, data summaries, and formal listing preparation will be performed by Statistics & Data 
Corporation (SDC) for DMC meetings, Interim Analyses and upon the completion of the study. Analyses 
after the study is completed will be done with a locked database. Statistical programming and analyses 
will be performed using SAS® version 9.4 or higher. Output will be provided in Rich Text Format (RTF) 
for tables and Portable Document Format (PDF) for tables, listings, and figures using landscape 
orientation. All study data will be listed by subject, sorted by cohort/dose level (in the order of adult 
cohort 1 [low dose, 160 µg loading dose, followed by up to three 80 µg maintenance doses), pediatric 
cohort 1 [low dose], adult cohort 2 [middle dose, 320 µg loading dose, followed by up to three 160 µg 
maintenance doses], and pediatrics cohort 2 [middle dose]), and by eye (OD, OS and OU where 
applicable) and visit unless otherwise specified. Listings may also include time point, age, and sex where 
appropriate. 
Summaries for continuous and ordinal variables will include the number of observations (n), arithmetic 
mean, standard deviation (SD), median, minimum, and maximum. Minima and maxima will be reported 
with the same precision as the raw values; means and medians will be presented to one additional 
decimal place than reported in the raw values. Standard deviations will be presented to two additional 
decimal places than reported in the raw values. Imaging data will be rounded to 3 decimal places then 
follow the previously mentioned conventions. Summaries for discrete variables will include frequency 
counts and percentages. All percentages will be rounded to one decimal place (i.e., XX.X%). Change 
from baseline will be calculated as follow-up minus baseline. 
All continuous efficacy endpoints will be summarized using the following descriptive statistics: number 
of subjects (N), mean, standard deviation, standard error, median, minimum, maximum and 95% 
confidence intervals (CI) for the mean. Categorical endpoints will be summarized using: number of 
subjects, frequency, percentages and 95% asymptotic confidence intervals. If data appear highly 
skewed, natural log or other transformation may be used to compute summary statistics.  
Inferential testing is not planned as part of this SAP, summarization will be based on descriptive 
statistics. Inferential analysis is foreseen within the analyses described within the 
 SAP, further 
details may be found in the 
 
Unless otherwise specified, summaries will be presented by cohort/dose level for, Adult, and Pediatric 
separately and for adult and pediatric combined groups of subjects. 
7.5 
Data Monitoring Committee (DMC) 
Safety will be evaluated by the DMC prior to each dose escalation, prior to the first maintenance dose 
of each cohort, and prior to the enrollment of pediatric subjects by the DMC and Sponsor Medical 
Monitor. The DMC and Sponsor Medical Monitor will review data on an as needed basis as determined 


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by the Sponsor and in accordance with the protocol and DMC Charter. As such, a select number of 
Safety listings are produced for DMC meetings and Sponsor Medical Monitor reviews. The study’s 
reviewing biostatistician will assist the committee members during the open sessions of the meetings in 
accordance with the DMC Charter.  
7.6 
Interim Analyses 
An interim analysis of all outputs was conducted after the eighth subject in the study had at least 3 
months of data in accordance with SAP version 1.0. The interim analysis included all available study 
data (all monitored and cleaned) at the time of the data snapshot, .  
An additional interim analysis (interim analysis 2) of all outputs was performed using all available data 
(all monitored and cleaned) from all 11 subjects at the time of the data snapshot (ie, after mid-August 
2018). SAP Version 1.0 was in effect at the time of this interim analysis. 
A third interim analysis, consisting of all outputs produced for interim analysis #2, will be performed once 
the last subject has completed Visit 15 (end of study visit) and there is a soft lock. This  
third interim 
analysis (planned for August 2019) will consist of all outputs for interim analysis 2 and will include all 
available study data (all monitored and cleaned) at the time of the data snapshot. 
No alpha or family-wise error rate adjustments are made for interim analyses at the data for this early 
phase 1b/2 trial as all analyses are exploratory. 
7.7 
Adjustments for Multiplicity 
No adjustments for multiplicity will be made in this phase 1b/2 study. 
8. Disposition of Subjects 
Subject disposition will be summarized for the All Enrolled Subjects population. The number and 
percentage of subjects enrolled will be presented along with the number of subjects who screen fail. 
The number and percentage of subjects who receive QR-110 will be tabulated by the number of dosed 
subjects in each QR-110 cohort and dose group. 
The number of subjects in each of the analysis populations (Safety and Efficacy) will be displayed by 
dose group and cohort and percentages will be calculated using all treated subjects as the denominator. 
Any change from planned study dosing and maintenance dosing will be displayed on treatment listings 
by dose group. The subjects who prematurely discontinued from study drug will be summarized by dose 
group for all treated subjects. An AE listing of subjects who discontinue from study drug will also be 
presented. Treatment compliance will be displayed in listings and summarized on tables. 
The number and percentage of subjects prematurely discontinued from the study and the reasons for 
study discontinuation will be summarized among treated subjects by dose group and cohort for all 


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subjects. The reasons for study discontinuation that will be summarized include: completed study, 
withdrawn prior to study drug, administrative reasons, sponsor termination of study, adverse event(s), 
protocol deviation(s), and other. A subject listing will be provided that includes the date of and reason 
for study discontinuation. 
The number and percentage of subjects with major protocol deviations will be summarized among 
treated subjects by dose group. Major protocol deviations will be further summarized by category (e.g., 
visit conducted out of window) for all categories with one or more major protocol deviation. The protocol 
deviation categories include: informed consent, inclusion/exclusion, enrollment, subject was NOT 
treated with assigned treatment, assessment / procedure NOT conducted per protocol requirements, 
missed visit, visit conducted out of window, assessment not done, site failure to report AE/SAE, subject 
non-compliance and other. Protocol deviations related to inclusion/exclusion violations will have the 
specific criterion number indicated within the subject data listing. A subject listing will be provided that 
includes the date of the deviation, the deviation description and the classification of whether the 
deviation was judged to be major or minor. 
In addition, subject listings will be provided that include informed consent date and inclusion and 
exclusion criteria violations. 
9. Demographics 
The demographic variables collected in this study include age, sex, childbearing potential, acceptable 
method of birth control, race and ethnicity. Subjects who record more than one race will be grouped into 
a single category denoted as multi-racial. Demographic variables will be summarized for the Safety 
Population, separately by dose group and cohort (Adult, Pediatric, and Combined). 
Collection of date of birth depends on local regulations at study sites. In cases where only the year of 
birth is allowed to be collected, the month and day will be recorded in the eCRF as July 1 with the 
appropriate year. 
Age (years) will be summarized, overall and by treatment, using continuous descriptive statistics. Age 
will also be categorized as follows: 6 years to <18 years, 18 years to <65 years and ≥65 years. Age will 
be reported in years and calculated using the following formula:  
Age = (informed consent date – date of birth) / 365.25 truncated as an integer 
The number and percentage of subjects will be presented, overall and by treatment, for age category, 
gender, race and ethnicity. 
A subject listing that includes all demographic variables will be provided for each dose group. 


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9.1 
Genotyping 
Genotyping will be assessed by any historical records of the disease or new genetic testing for inclusion 
in the study. Date of the test, and any genetic mutation will appear on subject level listings.  
9.2 
Baseline Characteristics 
A summary listing of baseline characteristics will be produced showing select demographic, ocular 
history, disease history (including date of diagnosis and age at diagnosis), visual acuity, and other ocular 
information. 
10. Medical History and Concomitant Medications 
10.1 
Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) version 20.0. 
Non-ocular medical history will be summarized using discrete summary statistics and presented by dose 
group at the subject (i.e., counts and percentages based on incidence of subjects with an event) and 
event level by System Organ Class (SOC) and Preferred Term (PT) using the Safety population. Ocular 
medical history will be similarly summarized at the subject level (i.e., incidence of subjects with an event) 
and event level, separately for the treated eye and contralateral eye. If a subject reports the same PT 
multiple times within the same SOC, that PT will only be reported once within that SOC. As with the PT, 
if a subject reports multiple conditions within the same SOC, that SOC will only be reported once. 
Listings of medical history will be generated separately for ocular and non-ocular data. 
10.2 
Concomitant Medications 
Concomitant medications will be coded using WHO Drug Dictionary (Enhanced B2, March 2017) and 
summarized to the therapeutic drug class (Anatomical Therapeutic Chemical [ATC] 4 classification) and 
preferred name. If the ATC 4 classification is not provided, the next lowest classification that is provided 
in the coding dictionary will be used. The preferred name will be defined as the active ingredient; if the 
active ingredient is not provided or includes more than two ingredients (e.g., multivitamins) then the drug 
name will be summarized as the preferred name. Any un-coded terms will be summarized under the 
ATC classification and preferred name of “Encoded.” 
Concomitant medications are defined as those medications listed as having been taken 1) prior to 
initiation of study drug administration and continuing for any period following the first administration of 
study drug or 2) at any time following the first administration of study drug or 3) any pre-medication taken 
in conjunction with the normal conduct of the study (e.g., and medications for pupil dilation and/or 
general sedation/anesthesia for the IVT injection of the study drug). 


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Non-ocular and ocular concomitant medications will be summarized separately using the Safety 
population. Medications will be tabulated for each dose group using frequencies and percentages, ocular 
medications will be further summarized separately for treated eye and contralateral eye. Subjects may 
have more than 1 medication per ATC text. At each level of subject summarization, a subject will be 
counted once if he/she reports 1 or more medications. Percentages will be based on the number of 
subjects in each dose group. Listings of concomitant medications will be generated separately for ocular 
and non-ocular data. 
11. Treatment Exposure 
All doses are observed and administered by study staff. Therefore, treatment compliance will not be 
calculated. Treatment exposure will be assessed by calculating the number of doses expected, number 
of actual doses received, cumulative dosage (µg), and the duration of exposure. Number of doses 
expected will be determined by the highest visit completed, as follows: 
• 
Study discontinuation after Visit 2 but before Visit 9 (Month 3) implies 1 dose was expected. 
• 
Study discontinuation after Visit 9 but before Visit 13 (Month 6) implies 2 doses were expected. 
• 
Study discontinuation after Visit 13 but before Visit 18 (Month 9) implies 3 doses were expected. 
• 
Study discontinuation after Visit 18, or completion of study, implies 4 doses were expected. 
Number of actual doses received will be summarized as both continuous and categorical outcome (i.e., 
1, 2, 3, or 4 doses received). Duration of exposure will be calculated in days as the date of last dose – 
the date of first dose + 1. Treatment exposure parameters will be summarized descriptively by dose 
group and cohort. 
12. Safety and Tolerability Analyses 
12.1 
Adverse Events 
An Adverse Event (AE) is defined as any untoward medical occurrence associated with the use of a 
drug in humans, whether or not the event is considered drug-related. An AE can therefore be any 
unfavorable, noxious and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease 
temporally associated with use of a study drug or other protocol-imposed intervention, regardless of 
attribution. Any pre-existing medical condition that worsens after first administration of the study drug 
will also be considered a new AE. The AE reporting period ends 90 days following the last administration 
of study drug or the subject’s EOS visit, whichever is later. Adverse events and SAEs related to study 
drug that persist >90 days 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. All AEs will be coded using the MedDRA 20.0. 
Treatment-emergent adverse events (TEAEs) are defined as any event that occurs or worsens on or 
after the day that study treatment is initiated. Adverse events recorded in the eCRF which began prior 
to treatment will not be included in the summary tables but will be included in the AE data listings. 


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All significant medical conditions including signs/symptoms of the underlying diagnosis found during the 
screening period and up to initiation of dosing (Visit 2) will be captured as medical history. Any 
event/condition related to participation in the study or study procedures but not related to underlying or 
concomitant disease that is noted after Screening up to the date of first dose will be captured as a non-
treatment emergent AE (non-TEAE). 
An overall summary will be presented that includes the number of TEAEs and the number and 
percentage of subjects who experienced at least one TEAE, by dose group. This summary will also 
include breakdowns of TEAEs further categorized as ocular (treated eye and contralateral eye 
separately) or non-ocular, serious TEAEs (SAEs), TEAEs by maximum severity, TEAEs by maximum 
relationship, and TEAEs leading to subject withdrawal. 
Additional summaries of TEAEs will be provided showing the number and percentage of subjects who 
experienced at least one TEAE. These summaries will be presented by system organ class (SOC) and 
preferred term (PT). Non-ocular TEAEs will be summarized using discrete summary statistics and 
presented by dose group at the subject and event level by SOC and PT. Ocular TEAEs will be similarly 
summarized at the subject level for study and contralateral eyes separately. If the same PT is reported 
for a subject multiple times within the same SOC, that PT will only be reported once within that SOC. As 
with the PT, if multiple conditions within the same SOC are reported, that SOC will only be reported 
once. In the summary, SOC will be listed in ascending alphabetical order; PTs will be listed in order of 
descending frequency for all subjects within each SOC. The occurrence of non-ocular and ocular TEAEs 
will also be tabulated by SOC and PT for the following: maximal severity and suspected relationship to 
study drug. 
Separate summaries will be provided for the following categories of AEs:  
• 
All AEs 
• 
Ocular TEAEs in the treated eye and contralateral eye (includes treatment-related events) 
• 
Non-ocular TEAEs (includes treatment-related events) 
• 
TEAEs leading to treatment discontinuation 
• 
TEAEs leading to subject withdrawal or treatment discontinuation 
• 
Serious TEAEs (SAEs) 
• 
TEAEs by maximum severity 
• 
TEAEs by maximum relationship 
• 
TEAEs of special Interest 
Severity of an AE is defined as a qualitative assessment of the degree of intensity of an AE as 
determined by the Investigator or reported to him/her by the subject. The assessment of severity is made 


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irrespective of relationship to study drug or seriousness of the event and should be evaluated according 
to the following scale: 
• 
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. 
Summaries of TEAEs by maximal severity will be presented for ocular AEs and non-ocular AEs 
separately. The number of subjects with any TEAEs (along with percentages) will be tabulated by SOC 
and PT within each SOC by dose group. To count the number of subjects with any TEAEs, if a subject 
has multiple TEAEs coded to the same PT within the same SOC, the subject will be counted once under 
the maximal severity.  
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, the Investigators were instructed to apply 
the following general guideline: 
• 
Not Related: The AE has an etiology other than the study drug (e.g., preexisting medical 
condition, underlying disease, intercurrent illness, or concomitant medication); and/or the AE 
has no plausible temporal relationship to administration of the study drug (e.g., cancer 
diagnosed 2 days after 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 (i.e., an 
event that follows a reasonable temporal sequence from administration of the study 
intervention, follows a known or expected response pattern to the suspected intervention, that 
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). 
For all AEs and SAEs, Investigators will make separate assessments of causality about the relationship 
of the event to study drug. 
All TEAEs will be presented in a subject listing. The TEAEs leading to study treatment discontinuation 
will be listed separately. In addition, all serious AEs will be presented in a separate listing. 


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12.1.1 Adverse Events of Special Interest (AESI) 
 
 
  
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 


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12.2 
Slit-Lamp Biomicroscopy Examination 
A slit-lamp biomicroscopy examination of the cornea, conjunctiva (palpebral and bulbar), anterior 
chamber including flare, iris, lens including nuclear, cortical and posterior subcapsular cataract opacity 
scores, and eyelid/lashes will be performed according to the ocular exam detailed in Section 3.5 of the 
SAP. The results will be graded as normal, abnormal not clinically significant (NCS) or abnormal 
clinically significant (CS) with flare scores ranging from 0 to 4+ in whole number increments and lens 
opacity scores ranging from <1 to >3 in half-point increments. 
The results will be summarized using counts and percentages for each dose group and for all subjects 
for each eye (treated eye and contralateral eye). Tables with percentages will be based on the number 
of subjects in each dose group with responses. A subject listing of the slit-lamp biomicroscopy 
parameters will also be produced including the AESIs related to anterior chamber flare and lens 
opacities.  
12.2.1 Anterior Chamber Flare 
Anterior chamber flare will be graded according to the SUN Working Group Grading Scheme using a 5-
unit scale where 0 = None, 1+ = Faint, 2+ = Moderate (iris and lens details clear), 3+ = Marked (iris and 
lens details hazy) and 4+ = Intense (fibrin or plastic aqueous). Anterior chamber flare grade at each visit 
and change from baseline will be tabulated using continuous and discrete summary statistics. 
AESI related to anterior chamber flare will include those TEAEs with MedDRA PT of ‘Flare’, as described 
in . The onset date of each reported AESI will be compared to dates of slit lamp biomicroscopy results, 
and exams with dates between the onset date and resolution of the corresponding AESI will be flagged 
as having led to an AESI report. The incidence of AESI related to lens opacities will be included in the 
aforementioned discrete summary by visit. 
AESIs related to anterior chamber flare will also be summarized with counts and percentages for each 
dose group and cohort with the definition of the anterior chamber flare related AESI according to Section 
13.1.1 of the SAP. AESI related to anterior chamber flare will include those TEAEs with MedDRA PT of 
‘flare’. In order to establish if results at individual visits resulted in an AESI report or not, the onset date 
of each reported AESI related to anterior chamber flare will be compared to dates of slit lamp 
biomicroscopy results, and exams with dates between the onset date and resolution of the 
corresponding AESI will be flagged as having led to an AESI report.  
12.2.2 Lens Opacity Examination 
Clinical lens opacities will be graded using the Age-Related Eye Diseases Study (AREDS) protocol and 
the Clinical Lens Grading System (ARLNS) on a 7-unit scale from <1 to >3 with half unit increments. . 
Lens nuclear opacity, cortical opacity and PSC opacity and changes from baseline summarized using 
continuous and discrete descriptive statistics. 


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AESIs related to lens opacities will also be summarized with counts and percentages for each dose 
group and cohort with the definition of the lens opacity related AESI according to Section 13.1.1 of the 
SAP. AESI related to lens opacities will include those TEAEs with MedDRA PT of ‘eye opacity’. In order 
to establish if results at individual visits resulted in an AESI report or not, the onset date of each reported 
AESI related to lens opacities will be compared to dates of slit lamp biomicroscopy results, and exams 
with dates between the onset date and resolution of the corresponding AESI will be flagged as having 
led to an AESI report.  
12.3 
Posterior Segment/Fundus Examination 
A posterior segment/fundus examination of the vitreous, macula, optic nerve, peripheral retina and 
choroid will be performed at each visit. The results will be graded as normal, abnormal NCS or abnormal 
CS. Vitreous haze is also assessed with possible scores of 0, 0.5+, 1+, 2+, 3+, or 4+. Cup-to-Disc ratio 
is also assessed in the Posterior Segment/Fundus Examination on a 0.1 to 1.0 scale in increasing 
increments of 0.1. 
The results will be summarized using counts and percentages for each dose group and for all subjects 
at each visit for each eye (treated eye and contralateral eye). Percentages will be based on the number 
of subjects in each dose group with responses. AESI will also be summarized with counts and 
percentages for each dose group and cohort with the definition of the vitreous haze related AESIs 
according to Section 12.1.1 of the SAP. A subject listing of the posterior segment/fundus examination 
parameters will also be produced. Vitreous haze related AESI will include those TEAEs with MedDRA 
PT of ‘vitreous haze’. In order to establish if results at individual visits resulted in an AESI report or not, 
the onset date of each reported AESI related to lens opacities will be compared to dates of fundus exam 
results, and exams with dates between the onset date and resolution of the corresponding AESI will be 
flagged as having led to an AESI report. 
12.4 
Intraocular Pressure (IOP) 
Intraocular pressure (IOP) will be assessed by tonometry (Goldmann Applanation Tonometer, Tono-
pen, Noncontact Tonometer [puff tonometry], or Icare Tonometer [rebound tonometry]) according to the 
optical exam schedule of Section 3.5 of the SAP. Results will be taken from a single measurement per 
eye and will be recorded in mmHg.  
The IOP values and changes from baseline for each eye (treated eye and contralateral eye) will be 
summarized using continuous descriptive statistics by visit and eye for each dose group and for all 
subjects. Baseline IOP is the last measurement prior to the first dose of study drug in the treated eye 
and may occur on a different date than dosing. The first measure taken immediately post-dose will be 
included in a change from baseline analysis. A subject listing of IOP will also be produced include IOP 
related AESIs. Tables will also include AESI for each visit with counts and percentages for each dose 


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group and cohort with the definition for the IOP related AESI according to Section 13.1.1 of the SAP. 
IOP related AESI will include those TEAEs with MedDRA PT of ‘intraocular pressure increased’. In order 
to establish if results at individual visits resulted in an AESI report or not, the onset date of each reported 
AESI related to IOP will be compared to dates of IOP assessments, and assessments with dates 
between the onset date and resolution of the corresponding AESI will be flagged as having led to an 
AESI report. 
12.5 
Physical Examination 
The physical examination results, graded as normal or abnormal NCS or abnormal CS, will be 
summarized by dose group and for all subjects using counts and percentages (including a summary of 
baseline values). A subject listing of the physical examination results will also be produced. 
12.6 
Vital Signs 
Vital signs, including pulse, blood pressure, height, weight and temperature, will be summarized with 
continuous descriptive statistics at each day (including a summary of baseline values) by dose group 
and for all subjects. Change from baseline will also be summarized to each post-baseline visit. A subject 
listing of the vital signs results will also be produced. 
12.7 
Electrocardiogram (ECG) 
Heart rate (HR), PR, QRS, QT, and QTc with correction specified as either Bazett or Fridericia, intervals 
will be summarized using descriptive statistics by dose group and for all subjects at each visit the 
assessment is taken. Change from baseline to each post-baseline visit and time point will be also 
summarized. A subject listing of the ECG results will also be produced. 
12.8 
Clinical Laboratory Data 
Clinical laboratory data including hematology, coagulation, serum chemistry and urinalysis are collected 
at specified visits. Other lab tests which are collected and will be summarized include Complement C4 
NEPH, C-reactive protein (CRP), complement total, and erythrocyte sedimentation rate. The quantitative 
variables will be summarized by dose group and for all subjects with continuous descriptive statistics at 
each visit and time point where appropriate. The qualitative variables (counts and percentages) will be 
summarized by dose group and for all subjects at each visit and time point where appropriate. Change 
from baseline will also be summarized by dose group and for all subjects.  
13. Pharmacokinetic Analyses 
Pharmacokinetic (PK) analyses will be primarily performed on the PK population with observed data 
only. 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)/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 level will be estimated using the formula: CL = Dose/AUC0-∞. 
• 
Vd (if measurable serum levels are obtained and an elimination rate constant (λz) is estimable): 
Apparent volume of distribution at steady state of the drug will be determined from trough levels. 
Serum concentration below 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 to one half of LLOQ. 
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.  
14. Efficacy Analyses 
The Efficacy Evaluable population will be used for the efficacy analyses including mobility course, BCVA, 
FST, OCI, PLR and VFQ-25/CVAQC. Ocular imaging endpoints will also be summarized with the 
Efficacy population for all imaging endpoints including ERG imaging, SD-OCT (Photoreceptor Outer 
Segment Thickness, Full Retinal Thickness, ONL Thickness, Macular Edema), and NIRAF imaging. 
Selected efficacy endpoints which also constitute a safety outcome may be rerun using the Safety 
Population if the Efficacy Evaluable and Safety Populations differ. Tables will summarize endpoints 
using continuous or categorical descriptive statistics by visit and time point where appropriate. Change 
from baseline visit will be calculated as follow-up visit minus baseline visit. Tables will include sections 
for adults, pediatrics and combined cohorts according to dose groups. 
Subject listings by visit, time point (when applicable) and eye will also be produced. 


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14.1 
Visual Acuity (BCVA) with ETDRS and BVRT 
The logarithm of the minimum angle of resolution (logMAR) visual acuity is assessed using an EDTRS 
chart according to Section 3.5 of this SAP. Light perception (LP), detection of hand movement (HM) and 
ability to count fingers (CF) are also acceptable measures of visual acuity for this study. The Berkeley 
Rudimentary Vision Test (BRVT) will also be used to assess subjects’ visual acuity. Since BCVA is an 
efficacy endpoint but also a safety output, this analysis will be produced primarily for the Efficacy 
Evaluable Population, and only repeated for the Safety Population if the Safety Population is different 
than the Efficacy Evaluable Population.  
The observed value and change from baseline visual acuity will be summarized for each eye (treated 
eye and contralateral eye) for BCVA using continuous descriptive statistics on the logMAR scale by visit 
for each dose group and for all subjects. If there is no logMAR evaluation available from the EDTRS 
chart or BRVT assessment, visual acuity measures of LP, HM, and CF will be summarized using the 
following logMAR equivalents (refer to Section 21 Appendix 1 for full table): 
• 
Light Perception = 4.0 logMAR 
• 
Hand Movement = 3.0 logMAR 
• 
Count Fingers = 2.0 logMAR 
BRVT will be summarized in a similar manner as described for BCVA via ETDRS, with discrete summary 
statistics for frequency of Light Perception, Black White Discrimination, White Field Projection, and Cord 
Pair. The BRVT logMAR value will be summarized with continuous descriptive statistics. For BRVT, if 
the Light Perception question is not answered on the eCRF, then values will be imputed from the 
corresponding Best Corrected Visual Acuity (BCVA) Light Perception answer. 


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BCVA related AEs of special interest (AESI) will also be summarized with counts and percentages for 
each dose group and cohort with the definition of the BCVA related AESI according to Section 13.1.1 of 
the SAP. BCVA related AESI will include those TEAEs with MedDRA PTs of ‘visual acuity reduced’ or 
‘blindness’. In order to establish if results at individual visits resulted in an AESI report or not, the onset 
date of each reported AESI related to BCVA will be compared to dates of BCVA assessments, and 
assessments with dates between the onset date and resolution of the corresponding AESI will be 
flagged as having led to an AESI report. 
A subject listing of visual acuity will also be produced. This BCVA listing will include a variable that 
indicates if a subject had a visual acuity change from baseline of ≥0.3 (15-letters or more) on the logMAR 
scale. 
Shifts from baseline to post-BL in vision category will be summarized for BCVA using categories of LP, 
HM, CF and logMAR BCVA (i.e. visual acuity reported as better than CF), and for BRVT using categories 
of light perception, black white field discrimination, white field projection and logMAR BRVT (i.e. visual 
acuity better than light perception). 
14.2 
Red, Blue and White Full-Field Stimulus Testing (FST) 
The Full-Field Stimulus Testing (FST) captures threshold measurements for each stimulus (red, blue 
and white light) that will be evaluated. Measurements with a Fail value of “0” are successful. A 
measurement with a Fail value of “1” is unsuccessful. If the threshold value fails, the next successful 
value will be captured. FST thresholds will be measured according to the imaging schedule of Section 
3.5 of the SAP and Imaging Charter. 
The FST values (ie, light sensitivity) and changes from baseline for each eye (treated eye and 
contralateral eye) will be summarized using continuous descriptive statistics and 95% CIs by visit and 
eye for each dose group and stimuli color for all subjects. Baseline FST is the average of all pre-dose 
FST assessments for that stimuli. Post-Baseline FST values are the average of all FST values for the 
given eye at a given time point and light color. An analysis of all failed and successful thresholds will be 
produced as well as an analysis of only successful thresholds. A subject listing of all failed and 
successful threshold FST will also be produced. 
14.3 
Pupillary Light Reflex (PLR) 
Pupillary Light Reflex (PLR) imaging will measure the pupil size in various candela per square meter 
stimulus (ie, at 4, 40, 400 and 4000 cd/m2). Maximum amplitude, delayed amplitude at 0.9 sec and 
overall latency (time to react) will be measured according to the imaging schedule of Section 3.5 of the 
SAP and Imaging Charter.  


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The PLR values and changes from baseline for each eye (treated eye and contralateral eye) will be 
summarized using continuous descriptive statistics and 95% CIs by visit and eye for each dose group 
and for all subjects. Baseline PLR is the average of all pre-dose PLR assessments. A subject listing of 
PLR will also be produced.  
14.4 
Oculomotor Instability (OCI) 
Oculomotor Instability (OCI) will be measured with fixation and without fixation according to the imaging 
schedule of Section 3.5 of the SAP and Imaging Charter. The OCI values and changes from baseline 
for each eye (treated eye and contralateral eye) will be summarized using continuous descriptive 
statistics and 95% CIs by visit and eye for each dose group for all subjects. Baseline OCI is the average 
of all pre-dose OCI assessments. A subject listing of OCI will also be produced. 
14.5 
Electroretinogram (ERG) in Scotopic and Photopic Conditions 
Electroretinogram (ERG) will measure a-wave (initial corneal-negative deflection) and b-wave (corneal-
positive deflection) under scotopic (low light conditions or dark adaptive measures) and photopic (normal 
light conditions or light adaptive measures) conditions. Dark adaptive oscillatory potentials, light adaptive 
flicker response, overall rod and cone waves and overall rod and cone functioning will also be assessed. 
ERG measurements will be taken in accordance to the imaging schedule of Section 3.5 of the SAP and 
the Imaging Charter.  
The ERG values and changes from baseline for each eye (treated eye and contralateral eye) will be 
summarized using continuous descriptive statistics and 95% CIs by light/dark adaptive condition, visit 
and eye for each dose group for all subjects. Baseline ERG is the average of all pre-dose ERG 
assessments for that light/dark adaptive condition. A subject listing of ERG will also be produced. 
14.6 
Spectral Domain Ocular Coherence Tomography (SD-OCT) 
Spectral Domain Ocular Coherence Tomography (SD-OCT) will measure Full Retinal Thickness (FRT), 
Outer Nuclear Layer (ONL) Thickness, presence of Macular Edema, and Photoreceptor Outer Segment 
Layer Thickness (PROST) according to the imaging schedule of Section 3.5 of the SAP and the Imaging 
Charter. 
Since SD-OCT is an efficacy endpoint but also a safety endpoint, this analysis will be produced primarily 
for the Efficacy Evaluable Population, and repeated for the Safety Population only if the Safety 
Population is different than the Efficacy Evaluable Population. 
The SD-OCT values and changes from baseline for each eye (treated eye and contralateral eye) will be 
summarized using continuous descriptive statistics and 95% CIs by visit and eye for each dose group 
for all subjects. All measures, regardless of confidence score will be used for analyses. Baseline SD-
OCT is the average of all pre-dose SD-OCT assessments if the exam was repeated. Tables will include 


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AESI for each visit with counts and percentages for each dose group and cohort with SD-OCT AESI 
according to Section 13.1.1 of the SAP. Post-BL values for individual SD-OCT parameters which are 
considered to have met AESI criteria will be based on determinations provided by the imaging reader. 
A subject listing of SD-OCT will also be produced including an overview of SD-OCT related AESIs if 
reported.  
14.7 
Near-Infrared Auto Fluorescence (NIRAF) 
Near-Infrared Auto Fluorescence (NIRAF) will measure the retained central hyper-autofluorescent island 
in subjects’ eyes with the horizontal and vertical diameters and the overall area according to the imaging 
schedule of Section 3.5 of the SAP and Imaging Charter. 
Since NIRAF parameters are an efficacy outcome but also represent a safety outcome, this analysis will 
be produced primarily for the Efficacy Evaluable Population, and repeated for the Safety Population only 
if the Safety Population is different than the Efficacy Evaluable Population. 
The NIRAF values and changes from baseline for each eye (treated eye and contralateral eye) will be 
summarized using continuous descriptive statistics and 95% CIs by visit and eye for each dose group 
for all subjects. Baseline NIRAF is the average of all pre-dose NIRAF assessments if the exam was 
repeated. All measures, regardless of confidence score will be used for analyses. Tables will include 
NIRAF related AESIs for each visit with counts and percentages for each dose group and cohort with 
definition of the NIRAF related AESI according to Section 13.1.1 of the SAP. Post-BL values for 
individual NIRAF parameters (e.g, horizontal diameter decreased, vertical diameter increased) which 
are considered to have met AESI criteria will be based on determinations provided by the imaging 
reader. 
A subject listing of NIRAF will also be produced including footnotes and superscript markers for each 
AESI.  


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15. Changes from Protocol-Stated Analyses 
15.1 
Analysis Populations 
Safety Population 
The safety population in Protocol Section 10.3 is defined as all subjects who receive any QR-110 or pre-
medications required for the study. “Or pre-medications” is removed from the safety population so 
analyses will only contain subjects who receive the active study IVT injection.  
Per Protocol Efficacy Population 
The per protocol efficacy population is defined in Protocol Section 10.3, however due to the limited 
number of potential subjects for such a population, additional analyses on a Per Protocol population will 
not be conducted.  
15.2 
Data Analysis Conventions - Baseline 
In Sections 8.12, 10.4 and in the Study Plan section of the synopsis in the protocol, baseline is referred 
to as the highest level of visual functioning in the case of repeat assessments, the measure reflecting 
the highest level of visual function will be used as baseline. Contrary to this, baseline will be 
measurement specific according to the current SAP Section 8.3. 
16. References 
17. Revision History 
17.1 
Revision 01 
. Changes were made throughout the SAP for the following reasons: 


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• 
To align to the information found within the current version (6.0) of the protocol. 
• 
To update the description of the analysis methods to incorporate decisions made during 
previous interim analysis as well as to better harmonize the SAP text to the actual outputs which 
have been produced. 
• 
To add details relevant to generation of new or revised tables and listings which will be produced 
for final analysis, following end of study database lock. 
The following table summarizes major revisions which implemented with this version.  
Summary of Changes in the Statistical Analysis Plan 
Section Number 
Description of Change 
Rationale 
1 
Added brief description of additional 
SAP prepared by Cytel, Inc. for 
analyses produced beyond scope of 
this SAP. 
Comprehensive accounting of 
planned analyses. 
2.5 
Additional details for protocol defined 
list of endpoints were added 
To enhance clarity 
3.3 
Update enrollment status, including no 
dosing at high dose 
Clarify dose groups for analysis 
7 
Added All Enrolled Subjects Population,  Needed for analysis. 
8.2 and 8.2.1 
 
 
 
 
 
8.3 
Added “and most safety endpoints.”  
Assumption was clarified. 
8.4 
The “combined” cohort is 1st. 
Re-organized cohort order to match 
with actual output. 
8.5 
Added “prior to the first maintenance 
dose of each cohort,”. 
Added information to rational for DMC 
meetings based on Sponsor’s 
rational. 
8.6 
Second and third interim analysis 
paragraph added. 
Added for additional interim analysis 
to explain rational. 
10.2 
Added section to explain baseline 
characteristics overview listing.  
Added for Sponsor request analyses. 
11 
Ocular summaries to be produced 
separately for TE and CE 
Sponsor requested analysis. 


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12 
Added variable “number of doses 
received” and added derivation of 
“number of doses expected” 
Sponsor requested analysis, and to 
provide clarification of how expected 
doses is derived.  
13.1.1 
Updated description of identification of 
AESI events 
Updated description to match current 
process. 
13.2-13,4 
Updated description identification of 
specific AESI and for linking of AESI 
within AE data to individual examination 
Updated description to match current 
process. 
15 
Updated description of analysis 
populations to be used for efficacy 
analyses. 
Added “responder analysis” section and 
tables. 
 
Safety Population to be used only if 
differs from Efficacy Evaluable. 
Added for Sponsor request analyses. 
 
 
15.1 
Visual Acuity moved from Safety 
Section (formerly 13.2) to Efficacy 
Section (15.1) 
Updated description of AESI 
identification for BCVA. 
 
 
Added shift table for BCVA and BRVT. 
BCVA is primary efficacy endpoint for 
analysis. 
 
To align to current process. 
 
Table was being produced, 
description had been omitted from 
SAP text. 
15.6, 15.7 
Added conditional rerun of results on 
Safety Population. 
Updated description identification of 
specific AESI and for linking of AESI 
within AE data to individual examination 
Sponsor requested analysis. 
 
Updated description to match current 
process. 
15.8.1 
Mobility course section updated to 
provide additional details of testing 
procedure, including courses used. 
To provide greater clarity of mobility 
course assessment. 
17 and 17.1 
Revision History section added 
Revision History section added 


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21. Appendices 
21.1 
Appendix 1: Table of Equivalency – Visual Acuity 
  


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