Clinical trial NCT02532764
Conditions: Cystic Fibrosis
Keywords: cystic fibrosis ΔF508 RNA therapies antisense oligonucleotide CFTR F508del CF RNA therapy
Sponsor: ProQR Therapeutics
Start date: 2015-06-01; Completion date: 2017-09-14
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
A randomized, double-blind, placebo-controlled study of single and multiple ascending doses of QR-010 in adults homozygous for ΔF508 Cystic Fibrosis.

Detailed description:
The purpose of this study is to evaluate the safety, tolerability, and to determine the pharmacokinetics of QR-010 administered via inhalation in adult homozygous for ΔF508 Cystic Fibrosis.

Arms: arm 1: QR-010 administered via inhalation either as a single dose or three times weekly for four weeks. arm 2: Placebo (normal saline) administered via inhalation either as a single dose or three times weekly for four weeks.
Interventions: intervention 1: QR-010 intervention 2: Placebo
Intervention descriptions: intervention 1: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton intervention 2: Normal Saline

Protocol documents:
Prot_000.pdf: 
Investigational Product: QR-010 
Protocol No. PQ-010-001 (Version 8.0) 
 
ProQR Therapeutics 
 
Page 1 of 103 
Proprietary and Confidential 
 
04 April 2017 
 
CLINICAL STUDY PROTOCOL 
PHASE 1B, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, DOSE 
ESCALATION STUDY TO EVALUATE THE SAFETY, TOLERABILITY AND 
PHARMACOKINETICS OF QR-010 IN SUBJECTS WITH HOMOZYGOUS ΔF508 
CYSTIC FIBROSIS 
 
Protocol No. PQ-010-001 
Protocol/Amendment Date: 04 April 2017 
Protocol/Amendment No.: 20 
Protocol Version: 8.0 
Supersedes: 7.0, 7.1, 7.2 
EudraCT/IND Number 2014-004352-57/120893 
Sponsor: ProQR Therapeutics  
Zernikedreef 9 
2333 CK Leiden 
The Netherlands 
Sponsor Chief Development Officer 
and Study Medical Monitor: 
Telephone Number: 
Noreen Roth Henig, MD 
 
+1-415-231-6429 
+31 6 29 72 45 76 
 
 
 
CONFIDENTIALITY STATEMENT 
This document contains proprietary and confidential information of ProQR Therapeutics. Acceptance of this 
document constitutes agreement by the recipient that no previously unpublished information contained herein will 
be published or disclosed without the prior written approval of ProQR Therapeutics with the exception that this 
document may be disclosed to study personnel under your supervision who need to know the contents for 
conducting the study and appropriate Institutional Review Boards (IRBs)/Ethics Committees (EC) under the 
condition that the personnel have agreed to keep this information confidential. The foregoing shall not apply to 
disclosure required by governmental regulations or laws, however, ProQR Therapeutics shall be promptly notified 
of any such disclosure. 
 
1. Title Page


Investigational Product: QR-010 
Protocol No. PQ-010-001 (Version 8.0) 
 
ProQR Therapeutics 
 
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INVESTIGATOR SIGNATURE PAGE 
ProQR Therapeutics  
Protocol No. PQ-010-001, Version No. 8.0 
04 April 2017 
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 investigational drug and 
the study protocol. 
I agree to conduct this clinical trial according to the attached protocol, except when mutually 
agreed to in writing. I also agree to conduct this study in compliance with all federal, state and 
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 


Investigational Product: QR-010 
Protocol No. PQ-010-001 (Version 8.0) 
 
ProQR Therapeutics 
 
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PROTOCOL APPROVAL PAGE 
Phase 1b, Randomized, Double-blind, Placebo-controlled, Dose Escalation Study to Evaluate the 
Safety, Tolerability and Pharmacokinetics of QR-010 in Subjects With Homozygous ΔF508 
Cystic Fibrosis 
Protocol No. PQ-010-001 
Protocol/Amendment Date: 04 April 2017 
Protocol/Amendment No.: 20 
Protocol Version: 8.0 
 
SPONSOR:  
ProQR Therapeutics  
Zernikedreef 9 
2333 CK Leiden 
The Netherlands 
 
 
 
 
04 April 2017 
Noreen Roth Henig, MD 
Chief Development Officer 
Study Medical Monitor 
ProQR Therapeutics  
 
Date 
 


Investigational Product: QR-010 
Protocol No. PQ-010-001 (Version 8.0) 
 
ProQR Therapeutics 
 
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NATIONAL COORDINATING INVESTIGATORS 
 
Name 
Institution 
Street Address 
City, Country, Postal 
Code 
 
Name 
Institution 
Street Address 
City, Country, Postal 
Code 
 
 
 


Investigational Product: QR-010 
Protocol No. PQ-010-001 (Version 8.0) 
 
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1.0 
SYNOPSIS 
Name of Sponsor/Company:  
ProQR Therapeutics  
Individual Study Table Referring 
to Part of the Dossier 
Volume: NA 
Page: NA 
(For National Authority Use only) 
Name of Investigational Product: 
QR-010 Solution for Nebulization 
Name of Active Ingredient: QR-010 
Title of Study: 
Phase 1b, Randomized, Double-blind, Placebo-controlled, Dose Escalation 
Study to Evaluate the Safety, Tolerability and Pharmacokinetics of QR-010 
in Subjects With Homozygous ΔF508 Cystic Fibrosis 
Investigators:  
To be determined 
Study Centers: 
Approximately 27 centers in North America and European Union (EU) 
Phase of Development: 
1b 
Study Period:  
24 months  
Duration of Subject Participation: 9 days (single ascending dose cohorts) 
8 weeks (multiple ascending dose cohorts) 
Objectives: 
Primary: To evaluate the safety and tolerability of QR-010 administered via 
inhalation and identify the maximum tolerated dose (MTD).  
Secondary: To evaluate the change from baseline analysis for laboratory 
parameters and vital signs as well as the pharmacokinetics (PK) of QR-010 
administered via inhalation.  
Exploratory: To explore the efficacy of QR-010 administered via inhalation. 
Study Design: 
Randomized, double-blind (investigator and subject), placebo-controlled, 
single ascending and multiple ascending dose-escalation study. This study 
includes two portions: four single ascending dose (SAD) cohorts (1-4) and 
four multiple ascending dose (MAD) cohorts (5-8). 
An independent Data Safety Monitoring Committee (DSMC) will be 
designated to review all safety data at the end of each cohort. Safety data 
will include 7 days of follow up after the dose administered for SAD cohort 
subjects, and 7 days after the last dose administered for MAD cohort 
subjects. Initiation of the first MAD dose cohort will be based on the 
determination of the DSMC that an adequate safety profile has been 
demonstrated in the first two SAD cohorts. Similarly, subsequent MAD 
dosing cohorts will be initiated based on the determination of the DSMC 
that an adequate safety profile is demonstrated in the corresponding 
supportive SAD and MAD cohorts. Lastly, the DSMC will review safety 
data on an ad hoc basis. The type of adverse event (AE) that would trigger 
such an ad hoc DSMC review would be documented in the data safety 
monitoring plan. 


Investigational Product: QR-010 
Protocol No. PQ-010-001 (Version 8.0) 
 
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Number of Subjects (planned):  
Approximately 32 subjects in each of the SAD and MAD portions will be 
enrolled in the study, with 8 subjects per cohort, randomized at a 3:1 ratio 
(6 active and 2 placebo), for a total of 64 subjects in the study. The exact 
number of subjects enrolled is dependent on whether any dose levels are to 
be expanded due to the occurrence of dose-limiting toxicities (DLTs).  
Diagnosis and Main Criteria for 
Eligibility:  
 
Inclusion Criteria: 
1. 
Able and willing to comply with the protocol and provide written 
informed consent prior to study-specific screening procedures 
2. 
Able and willing to adequately and consistently perform spirometry as 
required by the protocol 
3. 
Able and willing to participate in standardized airway clearance 
techniques 
4. 
Confirmed diagnosis of CF as defined by iontophoretic pilocarpine 
sweat chloride test (sweat chloride) of > 60 mmol/L   
5. 
Confirmation of cystic fibrosis transmembrane conductance regulator 
(CFTR) gene mutations homozygous for the ΔF508 mutation. Genetic 
testing performed prior to the year 2000 must be re-confirmed. 
6. 
Male or female 18 to 60 years of age 
7. 
Body mass index (BMI) of ≥ 17 kg/m2 
8. 
Non-smoking for a minimum of two years, including cigarettes, cigars, 
and e-cigarettes 
9. 
Stable pulmonary symptoms associated with CF 
10. Creatinine Clearance > 60 mL/min, as calculated by Cockcroft-Gault 
equation based on actual body weight 
11A. Women of childbearing potential must agree to use a highly effective 
method of birth control (defined as those, alone or in combination, that 
result in a low failure rate [ie, less than 1% per year]). See Section 
6.3.3 for a list of highly effective methods of birth control. 
11B. Men must agree to use barrier contraception (ie, condoms) except 
when infertility is documented (eg, bilateral orchidectomy or 
azospermia and/or infertility secondary to CF) 
12. FEV1 ≥ 70% of predicted normal for age, gender, and height (post-
bronchodilator value using NHANES III standards) at screening 
13. Stable lung function determined by the treating physician, provided 
FEV1 at Day -1 is within 10% of FEV1 at screening 
NOTE: Eligibility criteria 14 through 20 relate 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. 
14. Total WBC ≤ 12,000/L 


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15. Hemoglobin > 10 g/dL 
16. Hematocrit > 30% 
17. Platelet count between 150 and 450 x 103/µL 
18. Prothrombin time, international normalized ratio (INR) and partial 
thromboplastin time within normal limits 
19. Serum albumin > 2.5 g/dL at screening 
20. Liver function tests within 2X the upper limit of normal (SGPT/ALT, 
SGOT/AST, GGT, alkaline phosphatase, bilirubin [total and direct]) 
Exclusion Criteria:  
1. 
Personal or family history of prolonged QT syndrome; or a QTc 
interval > 430 msec (males) or > 450 msec (females) using Bazett’s 
formula (QTcB)  
2. 
Change in body weight within 90 days prior to Day 1 that is 
considered clinically significant by the Investigator 
3. 
Abnormal vital signs at screening: heart rate > 120 bpm at rest; systolic 
blood pressure > 140 or < 90 mmHg; respiration rate > 24 bpm; and 
SpO2 < 92% at rest 
4. 
History of alcohol abuse within the past 24 months or positive drug 
test at screening. Presence of drug(s) administered for known 
conditions are permitted with concurrence from the Sponsor’s Medical 
Monitor (eg, benzodiazepine, oral cannabis). 
5. 
Any infection including acute upper respiratory or lower respiratory 
infections, pulmonary exacerbation, changes in therapy for pulmonary 
disease, or any non CF-related illness which results in the initiation of 
any new therapy within 30 days prior to Day 1  
6. 
Clinically significant, abnormal screening laboratory value (as 
determined by the Investigator) or any abnormal screening laboratory 
value that would place the subject at undue risk while participating in 
the study (as determined by the Investigator with concurrence from the 
Sponsor’s Medical Monitor) 
7. 
Breast‐feeding or pregnant female 
8. 
Significant change in maintenance medications for CF within 30 days 
of Day 1 
9. 
Use of lumacaftor or ivacaftor within 45 days of Day 1 
10. Use of any investigational drug (other than QR-010) or device within 
30 days of Day 1 
11. Unable to or unwilling to perform key safety evaluations such as 
spirometry 
12. Unable to participate in standardized airway clearance techniques 
13. Presence or medical history of clinically significant disease which 
precludes study participation or prevents determination of outcome 
measures 
14. History of lung transplantation 
15. Hemoptysis of greater than 30 mLs within 90 days prior to Day 1, or 
hospitalization for hemoptysis within 6 months of Day 1 
16. Any severe, acute, or chronic medical or psychiatric condition, 
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 


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17. Any difficulty complying with protocol requirements that may increase 
the risk associated with study participation or study drug 
administration or may interfere with safety 
Test Product, Dosage and Mode of 
Administration: 
QR-010 Solution for Nebulization, 50 mg/mL (2 mL/vial) in isotonic 
sodium chloride solution, Inhalation via nebulizer. 
 
SAD cohorts: 6.25, 12.5, 25, or 50 mg, once per subject. 
MAD cohorts: 6.25, 12.5, 25, or 50 mg, thrice weekly for 4 weeks, for a 
total of 12 doses per subject. 
Duration of Treatment: 
Cohorts 1-4: 1 day  
Cohorts 5-8: 4 weeks 
Reference Therapy, Dosage and 
Mode of Administration:  
Placebo Solution for Nebulization, 0.9% sodium chloride solution, 
Inhalation via nebulizer. 
Placebo in the SAD will be administered once. 
Placebo in the MAD will be administered thrice weekly for 4 weeks, for a 
total of 12 doses per subject. 
Criteria for Evaluation: 
 
Safety and Tolerability: Safety will be assessed by monitoring AEs, vital signs, laboratory data 
(chemistries, hematology and urinalysis), immunogenicity evaluation, 
ECGs, pulmonary function, and physical examinations.  
 
Adverse events (AEs)  
 
Physical examination (PE) at screening, baseline and end of study 
 
Vital signs 
 
Electrocardiograms (ECGs) at screening, baseline and end of study 
 
Continuous cardiac monitoring (telemetry)  
 
Spirometry (FEV1) at baseline, 10, 30, and 60 minutes, and 2, 4, and 8 
hours post-dose following the first dose to evaluate for provoked 
bronchospasm  
 
Chest radiograph at screening and end of treatment (MAD only) 
 
Laboratory analysis for signs of toxicity: hepatic, renal, 
immunogenicity 
PK: Subjects will provide blood, urine and expectorated sputum samples for 
presence of QR-010 at multiple time points.  
Exploratory Safety and Efficacy: The following will be performed or collected for exploratory evaluation and 
analysis: 
 
Blood (serum and plasma) and expectorated sputum for inflammatory 
biomarkers 
 
Spirometry (FEV1) baseline, weekly during dosing, end of study, and at 
the follow-up visits (MAD Cohorts only) 
 
Cystic Fibrosis Questionnaire-Revised Respiratory Symptom Score 
(CFQ-R RSS) at baseline, prior to dose 7, and end of treatment (MAD 
Cohorts only) 
 
Sweat chloride determination by pilocarpine iontophoresis at screening 
(all cohorts), on the last dosing day, and at follow-up visits 7 and 8 days 
after last dose (MAD cohorts only) 


Investigational Product: QR-010 
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 
Body weight at baseline, and throughout the study 
 
Sputum microbiology at baseline and end of study for SAD cohorts, 
and at the End of Treatment Visit for MAD cohorts 
Statistical Methods: 
Baseline safety and exploratory endpoints will be summarized descriptively 
for SAD and MAD separately. No inferential testing will be performed. 
Serum concentrations of QR-010 will be summarised by dose level and time 
point. Individual concentration-time graphs will be presented. Graphs of 
mean concentration over time, for each dose, will also be presented. 
Summary statistics for AUC, Cmax, Tmax, t1/2, and dose-normalized AUC and 
Cmax will be presented by dose level. Graphs of AUC and Cmax versus dose 
will be displayed. Dose proportionality may be explored using analysis of 
variance (ANOVA) on log-transformed and dose normalized Cmax and AUC 
parameters, if there are sufficient data to support the analysis. Additionally, 
the power approach could be used to investigate for dose proportionality. 
Any p values that will be calculated according to the analysis plan will be 
interpreted in view of the exploratory nature of the study. 
 
 
 


Investigational Product: QR-010 
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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 ............................................................................................................10 
LIST OF TABLES .......................................................................................................................14 
LIST OF FIGURES .....................................................................................................................15 
LIST OF APPENDICES .............................................................................................................15 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................16 
2.0 
INTRODUCTION............................................................................................................20 
2.1 
Background ............................................................................................................23 
2.1.1 
Description of Drug Substance (Active Pharmaceutical Ingredient) ....23 
2.1.2 
Description of Drug Product .................................................................23 
2.1.3 
Nonclinical ............................................................................................24 
2.1.4 
Clinical Experience ...............................................................................24 
2.2 
Study Rationale ......................................................................................................25 
2.2.1 
Dose Selection Rationale ......................................................................26 
3.0 
STUDY OBJECTIVES ....................................................................................................26 
3.1 
Primary Objective ..................................................................................................26 
3.2 
Secondary Objective(s) ..........................................................................................26 
3.3 
Exploratory Objective(s) ........................................................................................27 
4.0 
STUDY OVERVIEW ......................................................................................................27 
4.1 
Criteria for Evaluation ...........................................................................................27 
4.1.1 
Primary Endpoint ..................................................................................27 
4.1.2 
Secondary Endpoint(s) ..........................................................................27 
4.1.3 
Exploratory Efficacy Endpoints ............................................................27 
4.2 
Study Design ..........................................................................................................27 
4.3 
Dose Escalation ......................................................................................................29 
4.4 
Definition of Dose-Limiting Toxicity (DLT) ........................................................31 
4.5 
Determination of Maximum Tolerated Dose (MTD) ............................................32 
5.0 
SELECTION OF STUDY POPULATION ...................................................................33 
5.1 
Study Population ....................................................................................................33 
5.2 
Selection of Subjects ..............................................................................................33 
5.3 
Inclusion Criteria ...................................................................................................33 


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5.4 
Exclusion Criteria ..................................................................................................34 
5.5 
Study Completion and Discontinuation Criteria ....................................................35 
5.5.1 
Study Completion/Withdrawal..............................................................35 
5.5.2 
Criteria for Study Drug Discontinuation ...............................................36 
5.5.3 
Stopping Rules ......................................................................................36 
6.0 
INVESTIGATIONAL PRODUCT(S)/STUDY MEDICATIONS ...............................37 
6.1 
Investigational Product ..........................................................................................37 
6.1.1 
QR-010 ..................................................................................................37 
6.1.2 
Diluent and Placebo ..............................................................................38 
6.1.3 
Packaging and Labeling ........................................................................38 
6.1.4 
Drug Shipment and Storage ..................................................................38 
6.1.5 
Drug Accountability and Reconciliation ...............................................38 
6.1.6 
Dosage and Administration ...................................................................39 
6.1.7 
Overdose ...............................................................................................39 
6.1.8 
Premedication ........................................................................................39 
6.2 
Nebulizer ................................................................................................................39 
6.2.1 
eFlow Nebulizer System .......................................................................39 
6.3 
Concomitant Medications and Ancillary Therapy .................................................40 
6.3.1 
Permitted Concomitant Medications .....................................................40 
6.3.2 
Prohibited Concomitant Medications ....................................................40 
6.3.3 
Adequate Forms of Birth Control .........................................................40 
6.4 
Adverse Reaction Management .............................................................................41 
7.0 
EVALUATIONS BY VISIT ............................................................................................42 
7.1 
Visit and Assessment Windows .............................................................................42 
7.2 
Screening Visit (All Cohorts) ................................................................................42 
7.3 
SAD Cohorts (Cohorts 1-4) ...................................................................................44 
7.3.1 
Day -1 (Start of In-Clinic Phase) ..........................................................44 
7.3.2 
Day 1 .....................................................................................................44 
7.3.3 
Day 2 .....................................................................................................45 
7.3.4 
Day 3 .....................................................................................................46 
7.3.5 
Day 4 (Day of Discharge) .....................................................................46 
7.3.6 
Day 8 End of Study Visit ......................................................................47 
7.4 
MAD Cohorts (Cohorts 5-8) ..................................................................................47 
7.4.1 
Dosing Schedule ...................................................................................47 
7.4.2 
Day -1 ....................................................................................................47 
7.4.3 
Week 1, Day 1 (Dose 1) ........................................................................48 


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7.4.4 
Week 1, Day 3 (Dose 2) ........................................................................49 
7.4.5 
Week 1, Day 4 .......................................................................................50 
7.4.6 
Week 1, Day 5 (Dose 3) ........................................................................51 
7.4.7 
Weeks 2, 3 and 4 (Doses 4, 7, and 10) ..................................................51 
7.4.8 
Weeks 2, 3, and 4 (Doses 5, 6, 8, 9 and 11) ..........................................52 
7.4.9 
Week 4 (Dose 12)..................................................................................53 
7.4.10 
Follow-up Visit for PK—24 hours +/- 12 hours After Last Dose ........53 
7.4.11 
Follow-up Visit for PK—96 hours +/- 48 hours After Last Dose ........53 
7.4.12 
Follow-up Visits—7 and 28 Days After Last Dose ..............................53 
8.0 
STUDY PROCEDURES .................................................................................................55 
8.1 
Adverse Events ......................................................................................................55 
8.2 
Vital Signs ..............................................................................................................55 
8.3 
Telemetry ...............................................................................................................55 
8.4 
Oximetry ................................................................................................................55 
8.5 
Laboratory Evaluations ..........................................................................................55 
8.6 
Pharmacokinetic Evaluations .................................................................................56 
8.7 
Chest Xray .............................................................................................................57 
8.8 
Biomarkers .............................................................................................................57 
8.9 
Electrocardiogram (ECG) ......................................................................................57 
8.10 
Pulmonary Function ...............................................................................................57 
8.11 
Physical Examination.............................................................................................58 
8.12 
Height and Weight .................................................................................................58 
8.13 
Sweat Chloride .......................................................................................................58 
8.14 
CFQ-R ....................................................................................................................58 
8.15 
CFTR Genotyping and Sequencing .......................................................................58 
9.0 
OTHER CONSIDERATIONS ........................................................................................59 
9.1 
Routine CF Pulmonary Medications ......................................................................59 
9.2 
Chest Physiotherapy...............................................................................................59 
10.0 
PHARMACOKINETIC AND EXPLORATORY EFFICACY 
MEASUREMENTS .........................................................................................................59 
10.1 
Pharmacokinetic Measurements ............................................................................59 
10.2 
Exploratory Efficacy Measurements......................................................................59 
11.0 
STUDY TERMINATION ...............................................................................................60 
12.0 
ASSESSMENT OF SAFETY OR ADVERSE EVENTS AND SERIOUS 
ADVERSE EVENTS .......................................................................................................60 
12.1 
Data Safety Monitoring Committee .......................................................................60 
12.2 
Definitions of Adverse Event.................................................................................60 


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12.2.1 
Adverse Event .......................................................................................60 
12.3 
Assessment of Adverse Events ..............................................................................61 
12.3.1 
Assessment of the Severity (Intensity) of Adverse Events ...................61 
12.3.2 
Assessment of the Relationship of Adverse Events to Study Drug ......62 
12.3.3 
Assessment of the Outcome of Adverse Events ...................................62 
12.4 
Reporting of Adverse Events .................................................................................63 
12.4.1 
Adverse Event Reporting Period ...........................................................63 
12.4.2 
Eliciting Adverse Events .......................................................................63 
12.4.3 
Recording Adverse and Serious Adverse Events ..................................63 
12.5 
Serious Adverse Event Definition .........................................................................66 
12.6 
Suspected Unexpected Serious Adverse Reaction Definition ...............................67 
12.7 
Serious Adverse Events Notification .....................................................................67 
12.8 
Expedited Reporting of SUSARs...........................................................................68 
12.9 
Emergency Unblinding Procedure .........................................................................68 
13.0 
STATISTICAL METHODOLOGY...............................................................................68 
13.1 
General Considerations ..........................................................................................68 
13.2 
Determination of Sample Size ...............................................................................69 
13.3 
Randomization and Blinding .................................................................................69 
13.3.1 
Randomization Procedures....................................................................69 
13.3.2 
Blinding Procedures ..............................................................................69 
13.3.3 
Replacement of Subjects .......................................................................70 
13.4 
Analysis of Populations .........................................................................................70 
13.5 
Subject Disposition, Demographics and Baseline Disease Characteristics ...........70 
13.6 
Treatment Compliance ...........................................................................................71 
13.7 
Safety Analyses ......................................................................................................71 
13.7.1 
Treatment Emergent Adverse Events....................................................71 
13.7.2 
Dose-Limiting Toxicities ......................................................................71 
13.7.3 
Vital Signs .............................................................................................71 
13.7.4 
Laboratory Assessments........................................................................71 
13.7.5 
Other Safety Assessments .....................................................................72 
13.8 
Pharmacokinetics Analyses ...................................................................................72 
13.9 
Immunogenicity .....................................................................................................73 
13.10 Exploratory Efficacy Analyses ..............................................................................73 
13.11 Interim Analysis .....................................................................................................73 
13.12 Subgroup Analyses ................................................................................................73 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .............................................74 


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14.1 
Changes to the Protocol .........................................................................................74 
14.2 
Data Collection and Study Monitoring ..................................................................74 
15.0 
ETHICAL AND REGULATORY OBLIGATIONS ....................................................75 
15.1 
Ethical Considerations ...........................................................................................75 
15.2 
Informed Consent...................................................................................................75 
15.3 
Pre-study Documentation Requirements ...............................................................76 
15.4 
Subject Confidentiality ..........................................................................................76 
16.0 
STUDY ADMINISTRATION ........................................................................................77 
16.1 
Good Clinical Practice and Regulatory Requirements ..........................................77 
16.2 
Investigator’s Brochure ..........................................................................................77 
16.3 
Protocol Amendments and Study Termination ......................................................77 
16.4 
Study Documentation and Storage .........................................................................78 
16.5 
Use of Information .................................................................................................78 
16.6 
End of Trial and Final Report ................................................................................78 
16.7 
Financing and Insurance ........................................................................................79 
16.8 
Publication Policy ..................................................................................................79 
17.0 
REFERENCES .................................................................................................................80 
18.0 
APPENDICES ..................................................................................................................82 
 
LIST OF TABLES  
Table 1: 
Dose Escalation ..........................................................................................30 
Table 2: 
Adverse Events of Interest .........................................................................31 
Table 3:  
Dose Escalation Rules................................................................................32 
Table 4: 
Adverse Event Intensity (Severity) Scale ..................................................61 
Table A.1-1: 
Single Ascending Dose Cohorts 1-4 ..........................................................83 
Table A.1-2: 
Multiple Ascending Dose Cohorts 5-8, WEEK 1 ......................................85 
Table A.1-3: 
Multiple Ascending Dose Cohorts 5-8, WEEK 2 ......................................87 
Table A.1-4: 
Multiple Ascending Dose Cohorts 5-8, WEEK 3 ......................................88 
Table A.1-5: 
Multiple Ascending Dose Cohorts 5-8, WEEK 4 ......................................89 
Table A.1-6: 
Multiple Ascending Dose Cohorts 5-8, Follow-Up Visits .........................90 
Table A.2-1: 
Single Ascending Dose Cohorts 1-4 ..........................................................91 
Table A.2-2: 
Multiple Ascending Dose Cohorts 5-8, WEEK 1 ......................................93 
Table A.2-3: 
Multiple Ascending Dose Cohorts 5-8, WEEK 2 ......................................95 
Table A.2-4: 
Multiple Ascending Dose Cohorts 5-8, WEEK 3 ......................................96 
Table A.2-5: 
Multiple Ascending Dose Cohorts 5-8, WEEK 4 ......................................97 
Table A.2-6: 
Multiple Ascending Dose Cohorts 5-8, Follow-up ....................................98 


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LIST OF FIGURES 
Figure 1: 
Classes of CFTR Mutations .......................................................................21 
Figure 2: 
Hybridization of QR-010 to the ΔF508-CFTR RNA.................................23 
Figure 3: 
PQ-010-001 Study Schematic ....................................................................28 
 
LIST OF APPENDICES 
Appendix 1: 
Schedule of Assessments ...........................................................................83 
Appendix 2: 
Schedule of Laboratory Tests ....................................................................91 
Appendix 3: 
Adult CFQ-R (English) ..............................................................................99 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Term 
Definition/Explanation 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
ALT (SGPT) 
Alanine aminotransferase (Serum Glutamic Pyruvic Transaminase) 
ANOVA 
Analysis of Variance 
AON 
Antisense Olignucleotide 
AST (SGOT) 
Aspartate aminotransferase (Serum Glutamic Oxaloacetic Transaminase) 
ATP 
Adenosine triphosphate 
ATS 
American Thoracic Society 
AUC 
Area Under the Curve 
AUC0- 
Area under the curve from time zero to infinity 
AUC0-t 
Area under the curve from time zero to the final time point 
bpm 
Beats per minute; Breaths per minute 
bps 
Base pairs 
BUN 
Blood Urea Nitrogen 
C 
Celsius 
CBC 
Complete Blood Count 
CF 
Cystic Fibrosis 
CFR 
Code of Federal Regulations 
CFQ-R 
Cystic Fibrosis Questionnaire-Revised 
CFQ-R RSS 
Cystic Fibrosis Questionnaire-Revised Respiratory Symptoms Score 
CFTR 
Cystic Fibrosis Transmembrane Conductance Regulator 
CH50 
Total Complement 
CL 
Serum Clearance 
Clinically significant 
An abnormal finding/laboratory value that indicates a new disease process, an 
exacerbation or worsening of an existing condition, or requires further action(s) to be 
taken (eg, initiation of new therapy). 
Cmax 
Maximum Concentration 
Cmin 
Minimum Concentration 
CRF, eCRF 
Case Report Form, Electronic Case Report Form 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 


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Abbreviation or Term 
Definition/Explanation 
CTCAE 
Common Terminology Criteria for Adverse Events 
CXR 
Chest Xray 
DAT 
Direct Antiglobulin Test 
dL 
Deciliter 
DLT 
Dose–Limiting Toxicity 
DP 
Drug Product 
DS 
Drug Substance 
DSMC 
Data Safety Monitoring Committee 
EC, IEC 
Ethics Committee, Independent Ethics Committee 
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
ENaC 
Epithelial Sodium Channel 
ERS 
European Respiratory Society 
ESR 
Erythrocyte Sedimentation Rate 
ET 
Early Termination 
EU 
European Union 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
FEF25-75 
Forced Expiratory Flow between 25 and 75% of the FVC 
FEV1 
Forced Expiratory Volume in 1 second 
FVC 
Forced Vital Capacity 
g 
Gram 
GCP 
Good Clinical Practice 
Hct 
Hematocrit 
HED 
Human Equivalent Dose 
Hgb 
Hemoglobin 
HHS 
Health and Human Services 
HIPAA 
Health Information Portability and Accountability Act of 1996 
HR 
Heart Rate  
ICH 
International Conference on Harmonisation 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 


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Abbreviation or Term 
Definition/Explanation 
IUD 
Intrauterine Device 
IUS 
Intrauterine hormone-releasing system 
IV 
Intravenous 
IWRS 
Interactive web response system 
kg 
Kilogram 
L 
Liter 
LABA 
Long-acting -agonist 
LDH 
Lactic Dehydrogenase 
LLQ 
Lower Limit of Quantitation 
MAD 
Multiple Ascending Dose 
MDD 
Maximum Deliverable Dose 
mRNA 
Messenger Ribonucleic Acid 
µg 
Microgram 
mg 
Milligram 
mL 
Milliliter 
mmHg 
Millimeters of Mercury 
MRSD 
Maximum Recommended Starting Dose 
MTD 
Maximum Tolerated Dose 
NCI CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
N 
Normal 
ng 
Nanogram 
NOAEL 
No Adverse Effect Level 
NPD 
Nasal Potential Difference 
OTC 
Over the Counter 
PCL 
Periciliary Layer 
PD 
Pharmacodynamics 
PDD 
Pulmonary Deposited Dose 
PE 
Physical examination 
pH 
Hydrogen ion concentration 
PK 
Pharmacokinetics 
POC 
Proof of Concept 
Post 
After 


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Abbreviation or Term 
Definition/Explanation 
Pre 
Before 
PS 
Phosphorothioate 
PT 
Prothrombin Time, Preferred Term 
PTT 
Partial Thromboplastin Time 
QTc 
QT Interval-Corrected 
RBC 
Red Blood Cell 
RNA 
Ribonucleic Acid 
SABA 
Short-acting -agonist 
SAD 
Single Ascending Dose 
SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SGOT (AST) 
Serum Glutamic Oxaloacetic Transaminase 
SGPT (ALT) 
Serum Glutamic Pyruvic Transaminase 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
Terminal elimination phase half-life 
TEAE 
Treatment-Emergent Adverse Event 
tiw 
Thrice Weekly (three times per week) 
TK 
Toxicokinetic 
TLF 
Tables, Listings and Figures 
tmax 
Time to maximum concentration 
ULN 
Upper Limit of Normal 
US 
United States 
WBC 
White Blood Cell 
WT 
Wild Type 
 
 


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2.0 
INTRODUCTION 
ProQR Therapeutics (ProQR, the Sponsor) is developing an antisense oligonucleotide (AON) 
product, QR-010, for the chronic treatment of patients with cystic fibrosis (CF) that is associated 
with either a compound hetero- or homozygous genotype for the absence of phenylalanine at 
position 508 (ΔF508/p.Phe508del) on cystic fibrosis transmembrane conductance regulator 
(CFTR)-encoded ribonucleic acid (RNA). QR-010 is a single-stranded RNA oligonucleotide that 
is complementary to the ∆F508 region on the RNA transcription product of the CFTR gene. 
Translation of the repaired CFTR encoded RNA should result in a wild-type (WT) or normal 
CFTR protein. The intended route of clinical administration is oral inhalation (inhalation) of 
nebulized QR-010 solution. 
Cystic Fibrosis Associated with ΔF508 CFTR Genotype 
Cystic fibrosis is an autosomal recessive disorder that is caused by a mutation in a gene that 
encodes CFTR, a membrane protein with pleiotropic functions. CFTR regulates the surface 
liquid layer and is found in the epithelial cells of the respiratory, gastrointestinal, and biliary 
systems; male reproductive tract; and exocrine sweat glands. This protein consists of 1480 amino 
acids that are divided into five domains, two of which cross the membrane to form a 
bidirectional, trans-membrane chloride channel (Riordan et al., 1989). Although CFTR functions 
primarily as a chloride channel, it has many other regulatory roles that affect the CF phenotype. 
These include inhibition of sodium transport through the epithelial sodium channel (ENaC), 
regulation of the outwardly rectifying chloride channel, regulation of adenosine triphosphate 
(ATP) channels, regulation of intracellular vesicle transport, acidification of intracellular 
organelles, and inhibition of endogenous calcium-activated chloride channels. The CFTR protein 
is also involved in bicarbonate–chloride exchange. A deficiency in bicarbonate secretion leads to 
poor solubility and aggregation of luminal mucins. Lack of CFTR function results in the multi-
organ system clinical syndromes described in patients with CF (Collawn et al., 2012; Mehta , 
2005; O’Sullivan & Freedman, 2009; Quinton , 1999; Reisin et al., 1994; Vankeerberghen et al., 
2002).  
The CFTR gene is encoded on chromosome 7 (Chr 7 117,120,017 through to 117,308,715). The 
transcription product of the CFTR gene (189 kb) is a messenger RNA (mRNA) (6.1 kb) that is 
translated into the CFTR protein. A patient with a CF phenotype has a CFTR gene mutation on 
both alleles and may be homozygous for a single mutation or compound heterozygous with a 
different mutation on each allele. There are nearly 2000 CFTR gene variants. However, only 159 
variants have an allele frequency ≥ 0.01% and 127 of those 159 variants meet both the clinical 
(pilocarpine iontophoresis sweat chloride test) and functional (affects RNA quality/quantity or 
CFTR protein) criteria to cause CF. Together, these 159 variants account for 96.4% of identified 
cystic fibrosis alleles. The ΔF508 mutation is the most common allelic mutation and accounts for 
about 66-70% of identified mutated alleles in northern European and North American 
populations. According to the Cystic Fibrosis Foundation National Patient Registry Annual Data 
Report (2012), a total of 23,053 CF patients (86.7% of the CF population in the US) in the US 


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had one or two copies of the ΔF508 mutation (O’Sullivan & Freedman, 2009; Sosnayet al.,  
2013). 
The various CFTR mutations are often classified into 5 specific functional classes, as shown in 
Figure 1. The ΔF508 mutation (hetero- or homozygous) is a Class II CFTR functional mutation 
that is characterized by defective CFTR processing; the gene is transcribed but the translated 
protein product is not trafficked through the endoplasmic reticulum and is degraded before 
reaching the cell surface. The ΔF508 mutation results in a CFTR protein that is mis-folded, 
which results in ubiquination and degradation. As a result, little, if any, CFTR reaches the 
plasma membrane. QR-010 has the potential to treat all CF patients with the ΔF508 mutation on 
at least one allele (O’Sullivan & Freedman, 2009; Pasyk & Foskett, 1995; Zamecnik et al.,  
2004).  
Figure 1: 
Classes of CFTR Mutations 
 
Classes of CFTR mutations. Categories of CFTR mutations with mutations resulting in no synthesis (Class I), 
defective processing (Class II), defective regulation (Class III), defective or deficient conductance (Class IV), 
and reduced amount of functional CFTR protein (Class V). 
Source: Gelfond & Borowitz, 2013 
The most common cause of death in patients with CF is respiratory failure due to progressive 
loss of lung function and/or pulmonary disease (Davies et al., 2007). There are several 
hypotheses regarding the mechanism by which the ΔF508 mutation leads to the multi-organ 
system CF phenotype and progressive loss of function, however the causal relationship between 
CFTR dysfunction and the CF phenotype is well established (Sosnay, 2013). In the simplest 
pathophysiological scenario, functional CFTR is either absent or substantially reduced at the 
apical membrane; the absence of functional CFTR at the apical membrane of ciliated airway 
epithelial cells of the respiratory tract results in a reduced capacity to secrete chloride ions to the 
airway surface and, indirectly, in an increased absorption of sodium ions from airway surfaces  
(Collawn et al., 2012; O’Sullivan & Freedman, 2009). This imbalance of active ion transport 
favors the net removal of salt and concomitant water from airway surfaces. Loss of water in the 
gel-like periciliary layer results in a loss of lubrication of the airway surface and increased 
concentrations of mucin in the mucus layer. Dehydrated periciliary layer (PCL) leads to thicker 
mucus and cilia collapse, which results in a reduced mucociliary clearance. The ‘stuck’ mucus 


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ultimately creates an adhesive plaque, or ‘mucus plug’. These plaques stimulate inflammation, 
obstruct the airway lumen, produce airflow obstruction, and serve as a nidus for persistent 
bacterial infections. It is the same loss of CFTR-mediated ion regulation that leads to dysfunction 
in other organ systems, including the gastrointestinal (eg, malabsorption), biliary, pancreatic and 
sweat exocrine, reproductive (congenital bilateral absence of the vas deferens in males) systems. 
QR-010 Product Description 
QR-010 is under development for the chronic treatment of patients with CF that is associated 
with either a compound hetero- or homozygous genotype for the absence of ΔF508 on CFTR-
encoded RNA. The goal of treatment with QR-010 is repair of the CFTR region of the RNA 
encoded with the ΔF508 mutation. Translation of the repaired CFTR encoded RNA should result 
in a WT or normal CFTR protein. The intended route of clinical administration is inhalation of 
nebulized QR-010 solution, which is anticipated to result in both local effects to the respiratory 
system and systemic absorption. Hence, QR-010 has the potential to treat both pulmonary and 
extra-pulmonary manifestations of CF. 
QR-010 was developed from a synthetic RNA oligonucleotide duplex that was described in a 
2004 paper by Dr. Paul Zamecnik, a pioneer of antisense therapeutics (Stephenson & Zamecnik, 
1978, Zamecnik & Stephenson, 1978, Zamecnik et al., 1986, Zamecnik et al., 2004). That 
duplex, CF4-CF6, was composed of a 33-mer oligonucleotide with 2’O-Me modifications and a 
complementary 11-mer oligonucleotide with phosphates at the 3’ and 5’ end. The Sponsor 
in-licensed the technology that was developed by Dr. Zamecnik from Massachusetts General 
Hospital in 2012. The Sponsor’s product development program explored various chemical 
modifications to the original molecule to optimize function (ability to restore CFTR activity to 
WT) in vitro and cellular uptake in vivo. The molecule selected for further development, 
QR-010, is a single-stranded, 33-mer RNA oligonucleotide with 2’O-Me base modifications and 
a full phosphorothioate (PS) backbone. QR-010 is highly specific for the CFTR RNA, with 14 
and 16 complementary base-pairs on either side of the ΔF508 deletion region, as confirmed 
using the basic local alignment search tool (BLAST) at the National Center for Biotechnology 
Information (search most-recently conducted 21 August 2014)1.  
As described above, QR-010 is a single-stranded 33-mer RNA oligonucleotide with 2’O-Me 
base modifications and a full PS backbone. QR-010 is highly specific for the CFTR RNA, with 
14 complementary base pairs (bps) on the 5’ side and 16 complementary bps on the 3’ side of the 
ΔF508 deletion region. To address the question of whether or not QR-010 was specific to this 
region of the CFTR RNA, a basic local alignment search tool (BLAST) at the National Center 
for Biotechnology Information was conducted and showed 100% specificity for this region. 
Repeated BLAST searches were completed, with the most recent conducted 21 August 2014.  
                                                 
1 
Available at http://blast.ncbi.nlm.nih.gov/Blast.cgi 


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Figure 2 illustrates the sequence that contains the ΔF508 mutation and the complementary 
hybridization of QR-010 to that region.  
Figure 2: 
Hybridization of QR-010 to the ΔF508-CFTR RNA 
 
Sequence with grey shading (C-U-U) on ΔF508 RNA represents the absence of phenylalanine at position 508 
(ΔF508 mutation). Because both A-U-C (wild-type) and A-U-U (ΔF508) code for isoleucine, position 507's 
amino acid is unchanged, and the net effect of the 3 nucleotides missing in the ΔF508 mutation is omission of a 
phenylalanine ("F") at position 508 in the translated protein. Vertical bars represent the QR-010 binding region. 
Bold text (G-A-A) on QR-010 represents the complement of the missing C-U-U sequence.  
 
2.1 
Background 
2.1.1 
Description of Drug Substance (Active Pharmaceutical Ingredient) 
QR-010 Drug Substance (DS) is a white to off-white lyophilized powder. It is an anhydrous 
sodium salt with molecular formula C347H420N122Na32O195P32S32 and molecular mass of 12172.66 
Daltons. QR-010 DS is stable at ambient temperature but undergoes some degradation when 
exposed to 80°C and significant degradation when exposed to oxidative stress (0.3% H2O2 
solution).  
2.1.2 
Description of Drug Product 
2.1.2.1 
Drug Product 
QR-010 Drug Product (DP) is a solution for nebulization presented in a Type I glass vial 
containing a clear, colorless solution available at a concentration of 50 mg/mL (2 mL/vial) in 
0.7% sodium chloride solution. The DP has a pH between 6.0 and 8.0, and osmolality equal to 
0.9% sodium chloride solution. QR-010 DP is labeled with the appropriate information as 
specified in the clinical protocol and as necessitated by local regulatory requirements. 
Throughout the document the name used for the DP is: QR-010 Solution for Nebulization.  
ΔF508 RNA 
 
QR-010 
 
  
503 504 505 506 507 508 509 510 511 512 513 (amino acid)  
                  C UU 
AAA GAA AAU AUC AU    U GGU GUU UCC UAU GAU (5’ to 3’) 
||| ||| ||| ||| ||    | ||| ||| ||| ||| |||  
UUU CUU UUA UAG UAG AAA CCA CAA AGG AUA CUA  


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The eFlow® Nebulizer System (PARI Pharma GmbH) will be used for study drug administration 
in the European Union (EU). The Investigational eFlow® Nebulizer System (PARI Respiratory 
Equipment) will be used for study drug administration in North America. These devices are 
identical and will be referred to as eFlow in this protocol.  
2.1.2.2 
Placebo 
Placebo, QR-010 Placebo Solution for Nebulization, is a solution of 0.9% sodium chloride. It is 
similar to QR-010 Solution for Nebulization except the active ingredient, QR-010, is excluded. 
The placebo is labeled with the appropriate information as specified in the clinical protocol and 
as necessitated by local regulatory requirements. 
2.1.3 
Nonclinical 
The nonclinical pharmacology program investigated QR-010 using both in vitro (human cell line 
and primary cells) and in vivo (mice, Cynomolgus monkeys) systems. The nonclinical 
pharmacodynamics data demonstrated the inhalation of QR-010 in mice and supported the 
proposed mechanism of action of treatment with QR-010 in facilitating the phenotypic reversion 
of ∆F508 CFTR activity to WT CFTR activity. These studies are summarized in QR-010 
Investigator’s Brochure, Section 5.2 - Nonclinical Pharmacology.  
Three preliminary studies contributed bio-distribution data for QR-010. These analyses were 
conducted in mouse variant C57BL/6J (considered wild-type [WT] for the purposes of these 
studies). One additional 28-day, repeat-dose GLP-compliant toxicity study in Cynomolgus 
monkeys provided toxicokinetic (TK) data. These studies are summarized in QR-010 
Investigator’s Brochure, Section 5.3 - Pharmacokinetics and Product Metabolism in Animals.  
The nonclinical toxicology program for QR-010 was conducted in accordance with the following 
guidelines: 
 ICH M3 (R2): Guidance on Nonclinical Safety Studies for the Conduct of Human 
Clinical Trials and Marketing Authorization for Pharmaceuticals 
 ICH S4 Guidance: Duration of Chronic Toxicity Testing in Animals (Rodent and Non 
Rodent Toxicity Testing) 
 ICH S3A Guidance: The Assessment of Systemic Exposure in Toxicity Studies  
A total of seven toxicity studies in mice and Cynomolgus monkeys contributed relevant data for 
the determination of safety and maximum recommended starting dose. These studies are 
summarized in QR-010 Investigator’s Brochure, Section 5.4 – Toxicology.  
2.1.4 
Clinical Experience 
No clinical studies have been conducted with QR-010 Solution for Nebulization. 


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2.2 
Study Rationale 
A patient with a CF phenotype has a CFTR gene mutation on both alleles and may be 
homozygous for a single mutation or compound heterozygous with a different mutation on each 
allele. There are nearly 2000 CFTR gene variants. However, only 159 variants have an allele 
frequency ≥ 0.01% and 127 of those 159 variants meet both the clinical (sweat chloride test) and 
functional (affects RNA quality/quantity or CFTR protein) criteria to cause CF. Together, these 
159 variants account for 96.4% of identified cystic fibrosis alleles. The ΔF508 mutation is the 
most common allelic mutation and accounts for about 66-70% of identified mutated alleles in 
northern European and North American populations. According to the Cystic Fibrosis 
Foundation National Patient Registry Annual Data Report (2012), a total of 23,053 CF patients 
(86.7% of the CF population in the US) in the US had one or two copies of the ΔF508 mutation  
(O’Sullivan & Freedman, 2009; Sosnay, et al., 2013). 
The ΔF508 mutation (hetero- or homozygous) is a Class II CFTR functional mutation that is 
characterized by defective CFTR processing; the gene is transcribed but the translated protein 
product is not trafficked through the endoplasmic reticulum and is degraded before reaching the 
cell surface. The ΔF508 mutation results in a CFTR protein that is mis-folded, which results in 
ubiquination and degradation. As a result, little, if any, CFTR reaches the plasma membrane. The 
absence of functional CFTR at the apical membrane of ciliated airway epithelial cells of the 
respiratory tract results in loss of CFTR-mediated ion regulation, which ultimately results in 
airway inflammation, obstruction, and persistant bacterial infections (Collawn et al., 2012; 
O’Sullivan & Freedman, 2009). It is the same loss of CFTR-mediated ion regulation that leads to 
dysfunction in other organ systems, including the gastrointestinal (eg, malabsorption), biliary, 
pancreatic and sweat exocrine, reproductive (congenital bilateral absence of the vas deferens in 
males) systems.  
Although many organ systems are affected in CF, the most common cause of death is respiratory 
failure due to progressive loss of lung function and/or pulmonary disease (Davies et al., 2007). 
Hence, patients with CF would greatly benefit from a therapy targeted to the respiratory system 
that facilitated the phenotypic reversion of ∆F508 CFTR activity to WT or normal CFTR 
activity. Worldwide, there is no marketed therapy that facilitates repair of the CFTR protein by 
targeting the RNA transcription product of the CFTR gene.  
QR-010 is a single-stranded RNA oligonucleotide that is complementary to the CFTR region on 
the RNA transcription product of the CFTR gene. Hence, QR-010 has the potential to treat all CF 
patients with the ΔF508 mutation on at least one allele. The QR-010 nonclinical program 
demonstrated that QR-010 facilitated the phenotypic reversion of ∆F508 CFTR activity to WT 
CFTR activity both in mice that were homozygous for the ∆F508 mutation and in cystic fibrosis 
human cell cultures with the ∆F508 mutation. The QR-010 nonclinical program also 
demonstrated the inhalation safety and toxicology of QR-010 in WT mice and WT Cynomolgus 
monkeys. The clinical development program will investigate the long-term safety and efficacy of 
QR-010 in treating in adult and pediatric patients who exhibit CF phenotypes with varying 
degrees of disease severity. 


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The initial clinical study, PQ-010-001, will be a single- and multiple-ascending dose (SAD and 
MAD, respectively) study that will evaluate safety, tolerability, and the maximum tolerated dose 
(MTD) of QR-010 Solution for Nebulization in CF patients who are homozygous for the ΔF508 
mutation. Exploratory efficacy endpoints are proposed but the study will not be sufficiently 
powered to test efficacy. Subjects will have baseline lung function defined as FEV1 ≥ 70% 
predicted for safety reasons. The Phase 1b study will be conducted in North America and select 
European countries. 
2.2.1 
Dose Selection Rationale 
Dose selection was based on the human equivalence dose (HED) and maximum recommended 
starting dose (MRSD) that were derived from 28-day toxicology studies in mouse and 
Cyanomolgus monkey studies, and further details can be found in the Investigator Brochure.  
The doses in the intended dose escalation scheme (6.25, 12.5, 25, and 50 mg) in Study 
PQ-010-001 correspond to the fill dose (mg loaded into the nebulizer) for the nebulizer. The 
maximum fill volume of the eFlow, the device that will be used to deliver study medication, is 
4 mL. In Study PQ-010-001, the fill volume will be 4 mL for all doses in the dose escalation 
scheme. The doses will be adjusted by diluting the 50 mg/mL solution. The actual delivered dose 
of QR-010 Solution for Nebulization using the eFlow with a 4 mL fill is < 80% of the fill dose. 
Hence, the maximum amount of drug delivered to patients will be approximately 5, 10, 20, and 
40 mg under the dose escalation scheme.  
The maximum loaded (50 mg) and estimated maximum delivered doses (40 mg) roughly 
correspond to one-half of the MRSD of 104 mg. In addition, the MRSD incorporated a safety 
factor of greater than 5 times the pulmonary deposited dose (PDD) (based on data from the 
28-day toxicity study that was conducted in Cynomolgus monkeys), and it is expected that there 
will be a lower bioavailability of QR-010 in the lungs of CF patients. In consideration of all the 
points above, the proposed dose escalation scheme for PQ-010-001 is considered highly 
conservative. 
3.0 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of the study is to evaluate the safety and tolerability of QR-010 
administered by inhalation to subjects with homozygous ∆F508 cystic fibrosis, and to identify 
the maximum tolerated dose (MTD) of QR-010.  
3.2 
Secondary Objective(s) 
The secondary objectives of the study are: 
 To evaluate the change from baseline analysis for laboratory and vital signs 
 To evaluate the pharmacokinetics (PK) of QR-010 administered by inhalation.  


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3.3 
Exploratory Objective(s) 
An additional objective of the study is to explore the clinical efficacy of QR-010 administered 
via inhalation by FEV1, Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Symptom 
Score (RSS), change in body weight, and iontophoretic pilocarpine sweat chloride. 
4.0 
STUDY OVERVIEW 
4.1 
Criteria for Evaluation 
4.1.1 
Primary Endpoint 
 Incidence and severity of adverse events (AEs) from baseline through end of study 
 Occurrence of dose-limiting toxicities (DLT) in each dose cohort from baseline through 
end of study  
4.1.2 
Secondary Endpoint(s) 
Safety: Changes from baseline to end of treatment or presence of abnormalities on frequent 
monitoring in laboratory parameters (chemistry, hematology, sputum microbiology, and 
urinalysis), vital signs, ECG, spirometry, and physical examinations. A chest radiograph will be 
obtained at screening and at end of treatment (MAD cohorts).  
Pharmacokinetics: The PK of QR-010 will be examined in all stages of the study, from first dose 
through end of study. Specifically, subjects will provide blood, urine and expectorated sputum 
samples for PK assessments.  
4.1.3 
Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints of clinical activity will include FEV1, the patient reported 
outcome measure CFQ-R Respiratory Symptom Score (CFQ-R RSS), body weight, and 
pilocarpine iontophoresis sweat chloride at the end of study compared to baseline, for MAD 
cohorts. 
The study will not be sufficiently powered to determine efficacy of QR-010 in the treatment of 
CF. However, changes in clinical outcome measures that are associated with CF will be 
monitored over the course of the study in all MAD cohorts. Observed changes in these 
well-established measures of CF health may inform design of future studies, and include FEV1, 
body weight, change in CFQ-R RSS, and pilocarpine iontophoresis sweat chloride. Data 
indicating potential immunogenicity of QR-010 and change from baseline in inflammatory 
biomarkers will also be captured. 
4.2 
Study Design 
The study is a multicenter, randomized, double-blind, and placebo-controlled Phase 1b SAD and 
MAD design. The subject, investigator, and site personnel (except pharmacist) will be blinded to 
treatment, while the sponsor will be unblinded. Sponsor personnel will be unblinded to subject 


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treatments in order to permit real-time interpretation of the safety, pharmacokinetic, and 
pharmacodynamic data. The site monitor will remain blinded to individual subject treatment 
allocation until all monitoring of study data has been completed. To minimize the potential for 
bias, individual subject treatment randomization information will not be released to the 
investigator or blinded study site personnel until the study database has been locked.  
Eligible subjects with homozygous ∆F508 CF will be randomized at a 3:1 ratio to receive either 
QR-010 or placebo vial oral inhalation (nebulization). This study will be conducted in North 
America and select European countries.  
The study includes 2 stages. The first stage is a single ascending dose-escalation (SAD) design to 
determine safety and tolerability of a single dose of QR-010. The second stage is a multiple 
ascending dose escalation (MAD) design to further assess the safety, tolerability, and exploratory 
efficacy of 12 doses of QR-010 over 4 weeks. All doses will be administered in a clinical setting.  
For the SAD cohorts, subjects will receive the dose in an inpatient observation unit and be 
observed for a total 4 days, and will be discharged on Day 4. Subjects will return for PK and 
safety follow-up as an outpatient on Day 8 (End of Study Visit).  
For the MAD cohorts, subjects will receive doses 1 through 12 in a clinic while under 
observation. On Day 1 and Day 3 subjects will be observed until 12 hours post dose. Following 
the last dose (dose 12), subjects will return twice for PK sampling, and will be evaluated 7 and 
28 days after the last visit for this additional safety monitoring and sampling for PK.  
A schematic of the study design is presented in Figure 3. 
Figure 3: 
PQ-010-001 Study Schematic 
 
 
Single Ascending Dose Escalation Cohorts: The first two subjects of each cohort may be dosed 
on the same day, at least 4 hours apart. If no significant AEs occur, the remainder of the cohort 
may be dosed at least 24 hours later, with at least 1 hour between subjects.  
After each single dose cohort, an independent Data Safety Monitoring Committee (DSMC) will 
review available safety data, including 7 days of follow up after administration of QR-010. Dose 
escalation may occur upon recommendation of the DSMC.  


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Multiple Ascending Dose Escalation Cohorts: The safety results from the single dose 
escalation portion of the study will support the initiation of the corresponding multiple dose 
escalation cohorts, as illustrated in Figure 3.  
After each multiple dose cohort, the DSMC will review available safety data, including 7 days of 
follow up after administration of the last dose of QR-010 (End of Treatment Visit). Dose 
escalation may occur upon recommendation of the DSMC.  
Both Stages: Subjects must sign informed consent before any study-related procedures are 
initiated. Subjects will receive QR-010 by inhalation via the eFlow device. 
Blood, urine and sputum samples will be obtained from all subjects to obtain PK data pre- and 
post-dosing. 
Subjects will undergo clinical and laboratory assessments for safety. Subjects will be withdrawn 
from the study when intolerable toxicity occurs, or when the subject withdraws consent.  
The schedule of assessments is summarized in Appendix 1 and 2. 
AE profiles by cohort and dose escalation decisions by the DSMC are communicated to all study 
sites after DSMC review of cumulative and cohort-specific safety data. 
4.3 
Dose Escalation  
The single dose escalation scheme will test fill doses of 6.25 mg to 50 mg over 4 dose levels, and 
the multiple dose escalation scheme will test fill doses of 6.25 mg to 50 mg given thrice weekly 
(tiw) for 4 weeks (Table 1). As described in Section 2.2.1, the dose delivered to subjects via the 
eFlow device is < 80% of the fill dose, hence the delivered doses that correspond to the dose 
escalation schemes are shown in Table 1.  


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Table 1: 
Dose Escalation 
Dose Cohort 
Fill Dose (mg) 
Estimated Exposure Dose 
< 80% of Fill Dose (mg) 
Single Dose Cohorts 
1 
6.25 
5 
2 
12.5 
10 
3 
25 
20 
4 
50 
40 
Multiple Dose Cohorts 
(administered tiw for 4 Weeks) 
5 
6.25 
5 
6 
12.5 
10 
7 
25 
20 
8 
50 
40 
tiw = thrice weekly (three times per week) 
 
Dose escalation will initially proceed in single subject cohorts from fill dose level 1 (6.25 mg) to 
fill dose level 4 (50 mg). 
Initiation of MAD Cohort 5 will be based on the safety profile of SAD Cohort 2. Initiation of 
Cohort 6 will be based on the safety profiles of Cohorts 3 and 5. Similarly, initiation of Cohort 7 
will be based on the safety profiles of Cohorts 4 and 6, and finally, the initiation of Cohort 8 will 
be based on the safety profile of Cohort 7. The first dose between subjects in each cohort must be 
separated by a minimum of 4 hours. 
For the single dose cohorts 1 to 4, dose escalation to the next cohort may occur upon 
recommendation of the DSMC after the subjects have been observed for at least 7 days and no 
DLTs have occurred or, if a DLT has occurred, per the dose escalation rules in Section 4.5. For 
the multiple dose cohorts 5 to 8, dose escalation to the next cohort may occur upon 
recommendation of the DSMC after the subjects have been observed for at least 7 days after the 
last dose (End of Treatment Visit). If a DLT occurs in any cohort, the AEs and DLTs will be 
reviewed by the Investigator and the DSMC before dosing can continue in that cohort. In 
addition, if ≥ 2 subjects experience a decrease in absolute FEV1 of ≥ 15% from baseline in any 
cohort, the data will be reviewed by the DSMC before dose escalation can continue. 
The AEs of Interest listed in Table 2 are AEs commonly seen with inhaled products. If AEs of 
interest occur at a Grade 2 level or higher in a single subject in a cohort, then an additional 4 
subjects will be added to the cohort. Any of the Grade ≥ 2 toxicities shown in Table 2, as well as 


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any other respiratory AEs reported, will be evaluated and considered when making dose 
escalation decisions. If no additional subjects experience any Grade ≥ 2 AEs of Interest, dose 
escalation may proceed (if recommended by the DSMC).  
The Investigator will base decisions to de-escalate to a lower dose, hold the dose (delay or skip), 
or discontinue study drug for an individual subject using the CTCAE (modified for CF) toxicity 
grades, in consultation and agreement with the Sponsor’s Medical Monitor. In addition to the 
CTCAE (modified for CF) toxicity grades, the Investigator should also review the stopping rules 
in Section 5.5.3 with regard to decreases in FEV1. 
For the multiple dose cohorts, subjects who experience a DLT (defined in Section 4.4) should be 
discontinued from study drug (whether or not the event resolves), and the End of Treatment Visit 
procedures should be conducted. An End of Study Visit should also be conducted 28 days after 
the last study drug dose.  
Table 2: 
Adverse Events of Interest 
Adverse Event of Interest 
Symptoms (Grade ≥ 2 per CTCAE or as Specified Below) 
Atelectasis 
Symptomatic (eg, dyspnea, cough); medical intervention indicated (eg, 
chest physiotherapy, suctioning); bronchoscopic suctioning 
Hypotension 
non-urgent medical intervention indicated 
Bronchospasm 
symptomatic, medical intervention indicated 
Liver Function Test Elevation 
alanine aminotransferase (ALT) > 3-5 x ULN or aspartate aminotransferase 
(AST) > 3-5 x ULN AND a doubling from the baseline value 
Pneumonitis 
Symptomatic; medical intervention indicated; limiting instrumental ADL 
Crackles 
Scattered or focal 
Dyspnoea 
Shortness of breath with minimal exertion; limiting instrumental ADL 
Hypoxia 
Decreased oxygen saturation with exercise (eg, pulse oximeter < 88%); 
intermittent supplemental oxygen 
ADL = Activities of Daily Living 
 
4.4 
Definition of Dose-Limiting Toxicity (DLT) 
A Dose-limiting Toxicity (DLT) is defined as follows: 
 Allergic reaction requiring medical intervention 
 Acute bronchospasm requiring medical intervention 
 Other acute AEs of interest requiring immediate medical intervention 
Allergic reactions and acute bronchospasm not requiring intervention (Grade 1) are usually 
considered subject-specific and are not included in the definition of DLT. In this protocol, 


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allergic reactions and acute bronchospasm not requiring medical intervention are not included in 
the DLT definition since such reactions may not be product and dose-specific with QR-010. 
4.5 
Determination of Maximum Tolerated Dose (MTD) 
The MTD is defined as one dose level below the dose level at which 2 subjects receiving 
QR-010 experience a dose limiting toxicity (DLT) for dose cohorts 1-4 or within the first 4 
weeks for dose cohorts 5-8. Dose escalation will occur based on the number of DLTs 
encountered according to the rules in Table 3, as assessed by the DSMC. Dose escalation will 
continue until the MTD is reached or the maximum dose included in the study, whichever is 
lower. With the highest planned fill dose of 50 mg, subject exposure will be approximately < 40 
mg (< 80% efficiency of the eFlow including residual volume). For the MTD determination, the 
fill dose will be used. 
Table 3:  
Dose Escalation Rules 
Number of Subjects Receiving 
QR-010 With a DLT at a  
Given Dose  
Dose-Escalation Decision Rule 
0 of 6 
Proceed to next dose level 
1 of 6 
If one serious AE (SAE) or Grade ≥ 2 AE occurs, four additional subjects will 
be enrolled at the same dose. If no additional subjects experience a similar 
SAE or Grade ≥ 2 AE in the same organ class, the dose escalation may 
continue pending review of safety by the DSMC. 
If  2 subjects experience similar SAE or Grade ≥ 2 AE of the same organ 
class, dose escalation is to be stopped, pending review by the DSMC. The 
preceding dose may be considered the MTD by the DSMC. 
  2 of 6 
Dose escalation will be stopped. 
The preceding dose will be considered the MTD. 
DLT = dose-limiting toxicity; MTD = maximum tolerated dose (one dose level lower than the dose level at which 2 
or more subjects experience a DLT of the same organ class)  
 
 
 


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5.0 
SELECTION OF STUDY POPULATION  
5.1 
Study Population 
Subjects with a diagnosis of CF, homozygous for the ΔF508 CFTR mutation who meet all 
inclusion and exclusion criteria will be eligible for participation in this study. 
5.2 
Selection of Subjects 
Screening of subjects will be performed within 14 days prior to dosing. Medical history, physical 
examination and vital signs will be recorded. Subjects will undergo electrocardiogram (ECG), 
chest Xray (CXR), spirometry, and clinical laboratory safety testing. During the study subjects 
will be permitted to continue on their chronic medications that are considered standard of care 
for CF. For subjects using inhaled anti-infective agents, preferably the same therapy and dose 
should be administered throughout the study period (Refer to Section 6.3.1). Subjects with signs 
of a pulmonary exacerbation or other acute illness will not be included. 
The exact number of subjects needed to complete the study depends on the number of cohorts 
required to reach the MTD and the number enrolled in each dose-escalation cohort. The number 
of subjects for each of the single dose and multiple dose escalation cohorts is 8 subjects, for a 
total of 64 subjects, but could theoretically expand to approximately 96 subjects if there are 
DLTs that require every dose cohort to be expanded. Subjects will be enrolled at approximately 
20 study sites in North America and select European countries. 
5.3 
Inclusion Criteria 
1. Able and willing to comply with the protocol and provide written informed consent prior 
to study-specific screening procedures 
2. Able and willing to adequately and consistently perform spirometry as required by the 
protocol 
3. Able and willing to participate in standardized airway clearance techniques 
4. Confirmed diagnosis of CF as defined by iontophoretic pilocarpine sweat chloride test 
(sweat chloride) of > 60 mmol/L   
5. Confirmation of cystic fibrosis transmembrane conductance regulator (CFTR) gene 
mutations homozygous for the ΔF508 mutation. Genetic testing performed prior to the 
year 2000 must be re-confirmed. 
6. Male or female 18 to 60 years of age 
7. Body mass index (BMI) of ≥ 17 kg/m2 
8. Non-smoking for a minimum of two years, including cigarettes, cigars, and e-cigarettes 
9. Stable pulmonary symptoms associated with CF 
10. Creatinine clearance > 60 mL/min, as calculated by Cockcroft-Gault equation based on 
actual body weight 


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11. A. Women of childbearing potential must agree to use a highly effective method of birth 
control (defined as those, alone or in combination, that result in a low failure rate [ie, less 
than 1% per year]). See Section 6.3.3 for a list of highly effective methods of birth 
control. 
11. B. Men must agree to use barrier contraception (ie, condoms) except when infertility is 
documented (eg, bilateral orchidectomy or azospermia and/or infertility secondary to CF) 
12. FEV1 ≥ 70% of predicted normal for age, gender, and height (post-bronchodilator value 
using NHANES III standards) at screening 
13. Stable lung function determined by the treating physicia, provided FEV1 at Day -1 is 
within 10% of FEV1 at screening. 
NOTE: Eligibility criteria 14 through 20 relate 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. 
14. Total WBC ≤ 12,000/L 
15. Hemoglobin > 10 g/dL 
16. Hematocrit > 30% 
17. Platelet count between 150 and 450 x 103/µL 
18. Prothrombin time, international normalized ratio (INR) and partial thromboplastin time 
within normal limits 
19. Serum albumin > 2.5 g/dL at screening 
20. Liver function tests within 2X the upper limit of normal (SGPT/ALT, SGOT/AST, GGT, 
alkaline phosphatase, bilirubin [total and direct]) 
5.4 
Exclusion Criteria 
1. Personal or family history of prolonged QT syndrome; or a QTc interval > 430 msec 
(males) or > 450 msec (females) using Bazett’s formula (QTcB) 
2. Change in body weight within 90 days prior to Day 1 that is considered clinically 
significant by the Investigator 
3. Abnormal vital signs at screening: heart rate > 120 bpm at rest; systolic blood pressure 
> 140 or < 90 mmHg; respiration rate > 24 bpm; and SpO2 < 92% at rest 
4. History of alcohol abuse within the past 24 months or positive drug test at screening. 
Presence of drug(s) administered for known conditions are permitted with concurrence 
from the Sponsor’s Medical Monitor (eg, benzodiazepine, oral cannabis). 
5. Any infection including acute upper respiratory or lower respiratory infections, 
pulmonary exacerbation, changes in therapy for pulmonary disease, or any non 


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CF-related illness which results in the initiation of any new therapy within 30 days prior 
to Day 1  
6. Clinically significant, abnormal screening laboratory value (as determined by the 
Investigator) or any abnormal screening laboratory value that would place the subject at 
undue risk while participating in the study (as determined by the Investigator with 
concurrence from the Sponsor’s Medical Monitor) 
7. Breast‐feeding or pregnant female 
8. Significant change in maintenance medications for CF within 30 days of Day 1 
9. Use of lumacaftor or ivacaftor within 45 days of Day 1 
10. Use of any investigational drug (other than QR-010) or device within 30 days of Day 1 
11. Unable to or unwilling to perform key safety evaluations such as spirometry 
12. Unable to participate in standardized airway clearance techniques 
13. Presence or medical history of clinically significant disease which precludes study 
participation or prevents determination of outcome measures 
14. History of lung transplantation 
15. Hemoptysis of greater than 30 mLs within 90 days prior to Day 1, or hospitalization for 
hemoptysis within 6 months of Day 1 
16. Any severe, acute, or chronic medical or psychiatric condition, 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 
17. Any difficulty complying with protocol requirements that may increase the risk 
associated with study participation or study drug administration or may interfere with 
safety 
5.5 
Study Completion and Discontinuation Criteria 
5.5.1 
Study Completion/Withdrawal 
A subject will have the right to withdraw from the study at any time for any reason. 
A subject will be discontinued from the study by the Investigator if unacceptable toxicity or 
withdrawal of consent occurs. 
Subjects participating in a MAD cohort that is determined to be greater than the MTD based on 
dose escalation rules can opt to continue in the study at the next lower dose cohort (ie, at the 
MTD). 
Subjects withdrawn from SAD cohorts should have all assessments conducted at the End of 
Study Visit at the time of withdrawal. Subjects withdrawn from MAD cohorts should have all 


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assessments conducted at the End of Treatment Visit as well as the End of Study Visit, for safety 
monitoring purposes.  
Subjects who have completed a SAD cohort are eligible to participate in a MAD cohort, 
provided there is at least 90 days between the dose in the SAD cohort and the first dose in the 
MAD cohort. 
Allergic reactions may include local dermatitis, angioedema, throat constriction, or anaphylaxis. 
Appropriate treatment may include administration of antihistamines, hydrocortisone, or 
epinephrine at the discretion of the assessing physician. Subjects diagnosed with a systemic 
allergic reaction requiring therapy will be withdrawn from the study. 
Given the proposed mechanism of action of QR-010, it could be anticipated that subjects could 
experience a change in baseline cough, change in sputum quality, or change in sputum volume. 
A pulmonary exacerbation should be considered if these symptoms are accompanied by fever, 
body weight loss, generalized malaise. If a pulmonary exacerbation is diagnosed, appropriate 
interventions including appropriate additional antibiotics should be prescribed by the Investigator 
or treating physician. Subjects diagnosed with a pulmonary exacerbation requiring the addition 
of antibiotics will be withdrawn from the study. 
5.5.2 
Criteria for Study Drug Discontinuation 
Subjects should be continued on study treatment unless an intolerable AE is experienced, or until 
an SAE and/or Grade ≥ 2 AE in the same system organ class is experienced by two or more 
subjects in the same cohort. Study treatment for that dose cohort should be stopped and subjects 
advised regarding available treatment options. 
When study treatment is discontinued in the MAD cohorts due to an intolerable AE, the 
Investigator should obtain all procedures specified for the End of Treatment Visit, followed by 
an End of Study Visit, conducted 28 days after the last study drug dose.   
5.5.3 
Stopping Rules  
5.5.3.1 
Stopping Rules for Study 
The DSMC will evaluate the safety data after each dose cohort and thereafter on an ongoing 
basis to recommend if the study should continue or cease, or if any modifications should be 
made as to how subjects are treated or managed. 
5.5.3.2 
Stopping Rules for Individual Subjects 
For individual subjects in the SAD cohorts, any of the criteria below will result in 
discontinuation of study drug administration in the SAD portion of the study, as well as 
exclusion from participation in the MAD portion. These subjects will continue to be followed for 
safety through the End of Study visit. 


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 Any SAE suspected of being related to study drug 
 Any Grade ≥ 2 AE suspected of being related to study drug 
 Decrease in absolute FEV1 volume of ≥ 15% from baseline value following study drug 
administration 
 Unacceptable toxicity considered by the Investigator to be related to study drug treatment 
 Further treatment is deemed to be unsafe in the Investigator’s clinical judgment. The 
decision to discontinue a subject may also result from any clinically significant alteration 
in any clinical or laboratory finding  
 If at any time the subject fails to follow the requirements of the protocol   
 The subject withdraws consent. Subjects may withdraw from the study at any time 
without repercussion to their treatment or affiliation with their healthcare providers.   
For individual subjects in the MAD cohorts, any of the following will result in permanent 
discontinuation of study drug: 
 Any SAE suspected of being related to study drug 
 Any Grade ≥2 AE suspected of being related to study drug 
 Cumulative decrease in absolute FEV1 volume of ≥ 15% from baseline value following 
study drug administration 
 Unacceptable toxicity considered by the Investigator to be related to study drug treatment 
 Further treatment is deemed to be unsafe in the Investigator’s clinical judgment. The 
decision to discontinue a subject may also result from any clinically significant alteration 
in any clinical or laboratory finding 
 If at any time the subject fails to follow the requirements of the protocol 
 The subject withdraws consent. Subjects may withdraw from the study at any time 
without repercussion to their treatment or affiliation with their healthcare providers.  
If study drug is discontinued for any of these stopping rules, administration will not be resumed, 
even after resolution of the event.  
6.0 
INVESTIGATIONAL PRODUCT(S)/STUDY MEDICATIONS 
6.1 
Investigational Product 
6.1.1 
QR-010  
The investigational drug product, QR-010 Solution for Nebulization, is available at a 
concentration of 50 mg/mL (2 mL/vial) in a sterile isotonic solution of sodium chloride in water 
for injection. QR-010 Solution for Nebulization is a clear, colorless solution. The pH is between 
6 and 8, and QR-010 Solution for Nebulization storage condition is 2-8°C. QR-010 Solution for 


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Nebulization will be administered to the subjects via oral inhalation, using the designated 
nebulizer. 
6.1.2 
Diluent and Placebo  
Placebo Solution for Nebulization will be the same as the diluent for QR-010 Solution for 
Nebulization. It is 10 mL 0.9% isotonic solution of sodium chloride in water for injection. It is a 
clear, colorless solution. Placebo Solution for Nebulization will be administered to the subjects 
via inhalation, using the nebulizer described in Section 6.2. 
6.1.3 
Packaging and Labeling 
QR-010 Solution for Nebulization is supplied in 2 mL Type 1 glass vials with a grey bromobutyl 
rubber stopper and a light blue tear off seal. Vials are packed into an outer carton, which is 
labeled per country-specific requirements. 
Placebo Solution for Nebulization is packaged in 10 mL individual, sterile plastic vial/ampules. 
Each vial/ampule and carton is labelled to comply with local guidelines. 
6.1.4 
Drug Shipment and Storage 
An initial supply of QR-010 Solution for Nebulization will be shipped refrigerated (2-8°C) to the 
site investigational pharmacy upon completion of site activation process. Re-supply will occur 
through the central inventory management system. The drug should be stored refrigerated in the 
site pharmacy or a designated locked area at 2-8°C until use.  
Please refer to the Study Manual for additional details on site activation, drug supply and the 
central inventory management system.  
6.1.5 
Drug Accountability and Reconciliation 
The Investigator must designate a research pharmacist or other staff member to be unblinded and 
maintain an inventory record of drugs received and dispensed. Used vials should be retained for 
drug accountability by the site monitor, unless prohibited by local procedures, in which case an 
alternative drug accountability process will be agreed upon with the Sponsor. It is acceptable to 
destroy used vials per site standard operating procedure (SOP) after drug accountability has been 
completed by the site monitor. Additional details on study drug handling will be provided in the 
Pharmacy Manual.  
Forms will be 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 Sponsor. The study drug must be dispensed only at the institution(s) specified on 
form FDA 1572 or Statement of Investigator (as applicable). 


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Upon completion or termination of the study and after inventory by a Sponsor-designated 
monitor, it will be determined if unopened drug is to be sent to the Sponsor in the original 
containers or is to be destroyed on site. Residual solutions must be discarded after use.  
6.1.6 
Dosage and Administration 
The pharmacist (or other personnel qualified to prepare study drug for administration) at each 
site will receive study drug and will prepare and/or dilute the study drug according to the 
Pharmacy Manual for each administration. Pharmacy staff will be unblinded to subject treatment 
assignment (as assigned by the designated randomization system for the study). All other study 
site staff, including the Investigator and subjects, will be blinded to study treatment assignment. 
Study drug doses will only be administered by a healthcare professional in an in-clinic setting. 
No at-home dose administration will be allowed. Subjects will receive study drug by inhalation 
via nebulizer. No other medications should be mixed with study drug in the nebulizer medication 
chamber. Appropriate study drug dilutions or placebo will be prepared by an Unblinded Study 
Pharmacist, as detailed in the Pharmacy Manual. The prepared doses will be loaded into the 
nebulizer medication chamber by study staff just prior to administration to the subject. 
6.1.7 
Overdose  
The effects of overdose of this product are not known. 
6.1.8 
Premedication  
For subjects whose standard CF medications include a short-acting -agonist (SABA), the 
SABA should be administered within 15 minutes to 2 hours prior to the first study drug dose. If 
no adverse reaction occurs with the first dose, subsequent doses need not be preceeded by a 
SABA, as determined by the Investigator.  
For those subjects whose standard CF medications include a long-acting -agonist (LABA), the 
LABA should be administered between 1 and 4 hours prior to each study drug dose. 
6.2 
Nebulizer 
6.2.1 
eFlow Nebulizer System 
The eFlow® Nebulizer System (PARI Pharma GmbH) will be used for study drug administration 
in the EU. The Investigational eFlow® Nebulizer System (PARI Respiratory Equipment) will be 
used for study drug administration in North America.  
Study drug dose dilutions prepared by the unblinded pharmacist will be provided to the study 
staff (who are blinded to the treatment assignment) who will load the medication chamber of the 
eFlow nebulizer with the study drug dose specified by randomization. The nebulizer Instructions 
for Use will be followed for all subjects for study drug administration. To minimize cross 
contamination between subjects, a new nebulizer handset will be provided for each dose. 


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Study drug will be administered in the clinic by qualified site personnel via the designated study 
nebulizer, until all study drug solution has been administered. Complete administration of study 
drug/placebo, if uninterrupted, should take approximately less than 20 minutes (a minimal 
amount of study drug solution will remain in the nebulizer medication chamber—this is normal). 
6.3 
Concomitant Medications and Ancillary Therapy 
6.3.1 
Permitted Concomitant Medications 
All concurrent CF therapies should be continued for the duration of the study. Prior to study drug 
dosing on a given day, the following order of concurrent treatment should be adhered to: Long- 
and/or Short acting bronchodilator, mucolytic therapy (eg, Pulmozyme), chest physiotherapy 
(airway clearance technique), inhaled corticosteroid, inhaled antibiotics.  
Subjects who are prescribed chronic, intermittent inhaled antibiotics should participate in the 
study when they are most stable and continue the inhaled antibiotic throughout the study. For 
most patients, this would mean that the subject initiates the inhaled antibiotic during the 
screening period and continues taking it as prescribed through the end of study, including some 
additional days or weeks. As the regimens of chronic inhaled antibiotics varies significantly from 
patients to patient, the Investigator is encouraged to discuss with the Sponsor’s Medical Monitor 
the appropriate regimen for the course of the study. 
Ancillary therapy regimens and airway clearance techniques should remain consistent throughout 
the study period. Other ancillary therapy may be administered at the discretion of the 
Investigator. Subjects should receive full supportive care, including antibiotics, antiemetics, 
bronchodilators, etc., as appropriate. The reason(s) for ancillary therapy, including dosage and 
date(s) of treatment, will be recorded in the source documents. 
6.3.2 
Prohibited Concomitant Medications 
Oral corticosteroid medications may not be used prophylactically with the first dose. Chronic 
administration of oral corticosteroids at a stable dosage for at least 30 days prior to enrollment 
are permitted. The reason(s) for ancillary therapy, including dosage and date(s) of treatment, will 
be recorded in the source documents. Use of ivacaftor (Kalydeco™) or lumacaftor are prohibited 
within 45 days of Day 1, through the End of Study visit. Use of any investigational drug (other 
than QR-010) or device are prohibited within 30 days of Day 1, through the End of Study visit. If 
the subject received therapy with ivacaftor or lumacaftor within 90 days prior to Day 1, the start 
and stop dates will be recorded in the source documents and CRF. 
6.3.3 
Adequate Forms of Birth Control 
Women of child bearing potential 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 low failure rate, ie, 
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 


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highly effective. Childbearing potential is defined as being fertile following menarche and until 
becoming post-menopausal, 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 (IUD) 
 Intrauterine hormone-releasing system (IUS) 
 Bilateral tubal occlusion 
 Vasectomized partner (provided that 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 trial, 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 trial. Protections against pregnancy must be continued for at least 3 
months after the last dose of study drug. 
A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. 
Male subjects with CF with medical confirmation of azospermia and/or infertility will be 
considered permanently sterile. A man who is fertile should use a condom during treatment and 
until 90 days after the last dose of study drug. 
6.4 
Adverse Reaction Management 
AEs in the study will be treated with appropriate therapies. Acute bronchospasm (defined as a ≥ 
15 % decrease in FEV1 % predicted) should be treated with treatment cessation and with β2 
agonists, IV hydrocortisone (100 mg), or other agents as appropriate. Additional supportive care 
should be provided as necessary by qualified staff with emergency resuscitation equipment.  
A Grade 4 (as defined by Common Terminology Criteria for Adverse Events [NCI CTCAE 
Version 4.03] Modified for CF) adverse reaction requires permanent discontinuation of study 
drug.  
If Grade 2-3 toxicity is noted during the dose administration, the administration should be halted 
and the subject assessed. If the adverse reaction symptoms resolve promptly, then study drug 


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administration may be re-initiated. Any Grade ≥ 2 adverse reaction suspected of being related to 
study drug will result in study drug discontinuation.  
7.0 
EVALUATIONS BY VISIT  
All tests and procedures are detailed in Appendix 1, Schedule of Assessments. All laboratory 
tests are detailed in Appendix 2, Schedule of Laboratory Assessments. Refer to these appendices 
for the required assessments for each study day. Throughout the protocol, the term “baseline” is 
used to refer to tests or procedures performed at screening, Day -1, or on Day 1 prior to dosing. 
7.1 
Visit and Assessment Windows 
The flexibility regarding scheduling of study days and corresponding procedures differ 
depending on the cohort and phase of the study. The timing of assessments, procedures and 
sample collections outlined in the protocol are nominal times. It is understood that in the phase 1 
setting, actual times will approximate rather than match the nominal times exactly. Actual times 
are to be recorded in the source documentation and in the case report forms (CRFs), and, if any 
time points are missed, the reasons are also recorded. 
For the SAD cohorts, there is no flexibility regarding the timing of the scheduled study days in 
relation to dose Day 1.  
For the MAD cohorts, there is some flexibility regarding the timing of the scheduled study days 
in relation to dose Day 1. The description of procedures assumes a Monday-Wednesday-Friday 
dosing schedule. An alternative dosing schedule can be used, provided that there is at a minimum 
2 days between doses, and a maximum of 4 days between doses. Missed doses are to be recorded 
as such, and the overall treatment period should remain at 4 weeks, and not be extended to 
accommodate the missed doses. Missed doses are to be recorded in the CRF. 
Details regarding acceptable windows for timing of study procedures for both the SAD and 
MAD cohorts can be found in the Laboratory Manual. 
7.2 
Screening Visit (All Cohorts) 
A screening log of all consented subjects will be kept at each site. Subject screening should be 
conducted ≤ 14 days prior to study drug dosing (Day 1). Screening evaluations may be 
completed over several days, if necessary.  
If the first administration of study drug does not occur within the initial 14 days of screening, the 
screening period may be extended up to an additional 14 days and subjects may be reassessed for 
eligibility with an interim medical history, focused physical examination, and repeat of 
laboratory studies (standard laboratory assessments). 
At the discretion of the Sponsor’s Medical Monitor, the screening period for an individual 
subject may be extended for an additional 7 days. In this case, the subject may be reassessed for 


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eligibility with an interim medical history and repetition of all screening assessments, with the 
exception of sweat chloride, 12-lead ECG, chest Xray and CFTR genotyping.  
If the screening period extends beyond 28 days (or up to 35 days with concurrence of the 
Sponsor’s Medical Monitor), the potential subject will be considered a screening failure, but may 
be re-screened at a later date. 
All screening evaluations must be reviewed by the Investigator to establish subject eligibility 
before dosing the subject for this study. Local laboratory results will determine subject eligibility 
for laboratory criteria. 
The following screening evaluations should be obtained for all subjects: 
1. Informed consent 
2. Review of inclusion/exclusion criteria (Selection of Subjects) 
3. Review of medical history 
4. Demographics 
5. Complete physical examination (including height and body weight) 
6. Vital signs: blood pressure, heart rate, respiratory rate, and temperature 
7. Oximetry 
8. Chest Xray 
9. Review of concomitant medication (record all medication within 30 days prior to screening), 
including prescription medications, over the counter (OTC) medications, herbal preparations, 
and use of lumacaftor or ivacaftor within 90 days prior to Day 1 
10. Twelve-lead ECG  
11. Spirometry (FEV1, FVC, and FEF25-75) 
12. Obtain urine sample for local laboratory assessments 
13. Obtain urine or blood sample for drug screen 
14. Obtain urine or blood sample for pregnancy test (for women of child-bearing potential) 
15. Obtain blood samples for local laboratory assessments 
16. Obtain blood and sputum for inflammatory biomarkers 
17. Obtain blood sample for CFTR genotyping (if adequate prior documentation is not available) 
18. Obtain sample for sweat chloride determination 


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7.3 
SAD Cohorts (Cohorts 1-4) 
7.3.1 
Day -1 (Start of In-Clinic Phase) 
1. Confirm study eligibility 
2. Complete physical examination (including body weight) 
3. Vital signs: blood pressure, heart rate, respiratory rate, and temperature measured  
4. Oximetry 
5. Concomitant medication review 
6. AE review 
7. Obtain blood and urine samples for local laboratory assessments (only assessments that were 
abnormal but not clinically significant at screening) 
8. Obtain urine or blood sample for pregnancy test (for women of child-bearing potential) 
9. Obtain sputum sample for the following local laboratory assessment: 
 Microbiology organism identification 
10. Obtain blood sample for CFTR sequencing (required, separate consent form may be 
required). Note: this blood sample may be collected on Day 1 pre-dose instead of Day -1. 
11. Obtain blood and sputum samples for inflammatory biomarkers. Note: these blood and 
sputum samples may be collected on Day 1 pre-dose instead of Day -1. 
12. Spirometry (FEV1, FVC, and FEF25-75) post administration of short-acting bronchodilator 
7.3.2 
Day 1 
Pre-dose: 
1. Symptom-directed physical examination (including body weight)  
2. Vital signs 
3. Oximetry 
4. Concomitant medications review 
5. AE review 
6. Administer any routine pulmonary medications and airway clearance techniques, including 
SABA and/or LABA, Pulmozyme, inhaled corticosteroids and/or antibiotics 
7. Initiate continuous cardiac and vital signs monitoring and continue for 24 hours post dose 
8. Spirometry (FEV1, FVC, and FEF25-75) 
9. Obtain blood samples for local laboratory assessments 
10. Obtain urine sample for urinalysis (Time 0, pre-dose) 


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11. Obtain blood and urine samples for PK (Time 0, pre-dose) 
Study Drug Administration: 
Study drug to be administered by qualified site personnel via the designated study nebulizer, 
until all study drug solution has been administered. Subjects are to be seated during the entire 
duration of study drug administration, inhaling the nebulized study drug using normal tidal 
breathing (no noseclips). Details regarding study drug preparation, device preparation and 
handling, as well as administration of study drug will be included in the Pharmacy Manual and 
Study Manual. 
Post-dose: 
1. Symptom-directed physical examination at 15, 60 minutes, 2, 3, 4, 6, 8, and 12 hours post 
dose 
2. Vital signs at 1, 10, 30, 60 minutes, 2, 4, 12 hours post dose 
3. Oximetry at 1, 10, 30, 60 minutes, 2, 4, 12 hours post dose 
4. Concomitant medications review 
5. AE review 
6. Spirometry at 10, 30, and 60 minutes, and 2, 4, and 8 hours post dose 
7. Obtain blood samples for local laboratory assessments at 30, 60 minutes, 2, 4, 8, and 12 
hours post dose 
 Complete blood count (CBC) with absolute differential  
 Serum chemistry 
8. Obtain the following samples for PK: 
 Blood at 0.5, 1, 2, 3, 4, 12 hours post dose 
 Pooled urine from 0 to 4 hours, 4 to 12 hours, and 12 to 24 hours post dose. Subjects 
should empty their bladders just prior to dosing and at the end of each time interval for 
the final urine collection of that interval. Urinalysis by dipstick will be performed on the 
pooled urine samples for each time interval. 
 Sputum at 3 times post dose, within the first 6 hours post dose. Suggest obtaining 
samples in conjunction with performing spirometry at 10, 60 minutes, and 4 hours post 
dose. 
7.3.3 
Day 2 
1. Symptom-directed physical examination  
2. Vital signs  
3. Oximetry  


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4. Review of concomitant medications 
5. AE review 
6. Spirometry  
7. Obtain blood and urine samples for local laboratory assessments 24 hours post dose 
8. Obtain the following samples for PK: 
 Blood at 24 hours post dose 
 Urine at 24 hours post dose 
 Sputum at 24 hours post dose 
9. Obtain blood and sputum samples for inflammatory biomarkers (24 hours post dose) 
7.3.4 
Day 3 
1. Vital signs  
2. Oximetry  
3. Concomitant medications review 
4. AE review  
5. Obtain blood and urine samples for local laboratory assessments 48 hours post dose 
6. Obtain the following samples for PK: 
 Blood at 48 hours post dose 
 Urine at 48 hours post dose 
7.3.5 
Day 4 (Day of Discharge) 
1. Symptom-directed physical examination  
2. Vital signs  
3. Oximetry  
4. Review of concomitant medications 
5. AE review 
6. Spirometry  
7. Obtain blood and urine samples for local laboratory assessments 
8. Obtain blood and sputum samples for inflammatory biomarkers 
9. Obtain the following samples for PK: 
 Blood at 54 and 72 hours post dose 
 Urine at 72 hours post dose 


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 Sputum at any time prior to discharge 
10. Discharge subject 
7.3.6 
Day 8 End of Study Visit 
If at any time during the study the subject discontinues the study early, the subject should return 
to the clinic to complete the End of Study Visit procedures below. 
1. Complete physical examination (including body weight) 
2. Vital signs  
3. Oximetry 
4. Concomitant medications review 
5. AE review 
6. Chest Xray for subjects who experience pulmonary AEs during the study 
7. 12-lead ECG 
8. Spirometry  
9. Obtain blood and urine samples for local laboratory assessments 
10. Obtain urine or blood sample for pregnancy test (for women of child-bearing potential) 
11. Obtain blood, urine, and sputum samples for PK 168 hours post dose. Sputum for PK may be 
obtained at any time during the visit. 
12. Obtain sputum sample for the following local laboratory assessment: 
 Microbiology organism identification  
13. Obtain blood and sputum samples for inflammatory biomarkers 
7.4 
MAD Cohorts (Cohorts 5-8) 
7.4.1 
Dosing Schedule 
Study drug will be administered in the clinic for all dosing days. The dosing schedule below 
assumes a Monday-Wednesday-Friday (thrice-weekly or tiw) dosing scheme. Subjects will be 
observed until 12 hours post dose on Day 1 and Day 3. The subject will return to the clinic for all 
subsequent doses and required assessments. 
7.4.2 
Day -1 
1. Confirm study eligibility 
2. Complete physical examination (including body weight) 
3. Vital signs:  blood pressure, heart rate, respiratory rate, and temperature measured  
4. Oximetry 


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5. Concomitant medication review 
6. AE review 
7. Obtain blood and urine for local laboratory assessments (only assessments that were 
abnormal but not clinically significant at screening) 
8. Obtain urine or blood for pregnancy test (for women of child-bearing potential) 
9. Obtain sputum sample for the following local laboratory assessment: 
 Microbiology organism identification 
10. Obtain blood samples for CFTR sequencing (required, separate consent form may be 
required). Note: this blood sample may be collected on Day 1 pre-dose instead of Day -1, and 
should not be collected if subject already participated in a SAD cohort. 
11. Obtain blood and sputum samples for inflammatory biomarkers. Note: these blood and 
sputum samples may be collected on Day 1 pre-dose instead of Day -1. 
12. Spirometry (FEV1, FVC, and FEF25-75) post administration of short-acting bronchodilator 
7.4.3 
Week 1, Day 1 (Dose 1) 
Pre-dose: 
1. Subject self-completes the CFQ-R prior to all other procedures and assessments 
2. Symptom directed physical examination (including body weight) 
3. Vital signs 
4. Oximetry 
5. Concomitant medications review 
6. AE review 
7. Administer any routine pulmonary medications and airway clearance techniques, including 
SABA and/or LABA, Pulmozyme, inhaled corticosteroids and/or antibiotics 
8. Initiate continuous cardiac and vital signs monitoring and continue for 12 hours post dose 
9. Spirometry (FEV1, FVC, and FEF25-75), post administration of short-acting bronchodilator 
10. Obtain blood samples for local laboratory assessments 
11. Obtain urine sample for urinalysis (Time 0/pre-dose) 
12. Obtain blood and urine samples for PK (Time 0/pre-dose) 
Study Drug Administration: 
Study drug to be administered by qualified site personnel via the designated study nebulizer, 
until all study drug solution has been administered. Subjects are to be seated during the entire 


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duration of study drug administration, inhaling the nebulized study drug using normal tidal 
breathing (no noseclips). Details regarding study drug preparation, device preparation and 
handling, as well as administration of study drug will be included in the Pharmacy Manual and 
Study Manual. 
Post-dose: 
1. Symptom-directed physical examination at 15, 60 minutes, 2, 4, 6, 8, and 12 hours post dose 
2. Vital signs at 1, 10, 30, 60 minutes, 2, 4, and 12 hours post dose 
3. Oximetry at 1, 10, 30, 60 minutes, 2, 4, and 12 hours post dose 
4. Concomitant medications review 
5. AE review 
6. Spirometry at 10, 30, and 60 minutes, and 2, 4, and 8 hours post dose 
7. Obtain blood samples for local laboratory assessments at 30, 60 minutes, 2, 4, 8, and 12 
hours post dose 
 Complete blood count (CBC) with absolute differential  
 Serum chemistry 
8. Obtain the following samples for PK: 
 Blood at 0.5, 1, 2, 3, 4, 12 hours post dose 
 Pooled urine from 0 to 4 hours and 4 to 12 hours post dose. Subjects should empty their 
bladders just prior to dosing and at the end of each time interval for the final urine 
collection of that interval. Urinalysis by dipstick will be performed on the pooled urine 
samples for each time interval. 
 Sputum at 3 times post dose, within the first 6 hours post dose. Suggest obtaining 
samples in conjunction with performing spirometry at 10, 60 minutes, and 4 hours post 
dose.  
9. Discharge subject 
7.4.4 
Week 1, Day 3 (Dose 2) 
Pre-dose: 
1. Symptom-directed physical examination  
2. Vital signs 
3. Oximetry 
4. Concomitant medications review 
5. AE review 


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6. Administer any routine pulmonary medications and airway clearance techniques, including 
SABA and/or LABA, Pulmozyme, inhaled corticosteroids and/or antibiotics 
7. Obtain blood for PK sample prior to dosing (approximately 48 hours post dose 1) 
8. Administer study drug 
Post-dose: 
1. Symptom-directed physical examination at 15, 60 minutes, 4, 8, and 12 hours post dose 
2. Vital signs at 1, 10, 30, 60 minutes, 2, 4 and 12 hours post dose 
3. Oximetry at 1, 10, 30, 60 minutes, 2, 4 and 12 hours post dose 
4. AE review 
5. Spirometry at 20, and 60 minutes, and 4 hours post dose 
6. Obtain blood samples for local laboratory assessments at 60 minutes and 4 hours post dose 
 Complete blood count (CBC) with absolute differential  
 Serum chemistry 
7. Obtain urine sample for local urinalysis at 60 minutes and 4 hours post dose 
8. Obtain blood sample for PK at 2 hours post dose 
9. Discharge subject 
7.4.5 
Week 1, Day 4 
1. Symptom-directed physical examination  
2. Vital signs  
3. Oximetry  
4. Concomitant medications review 
5. AE review 
6. Spirometry  
7. Obtain blood and urine samples for local laboratory assessments 
8. Obtain blood and sputum samples for inflammatory biomarkers 
9. Obtain the following samples for PK (approximately 72 hours post dose 1): 
 Blood, urine, and sputum 


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7.4.6 
Week 1, Day 5 (Dose 3) 
Pre-dose: 
1. Symptom-directed physical examination  
2. Vital signs 
3. Oximetry 
4. Concomitant medications review 
5. AE review 
6. Administer any routine pulmonary medications and airway clearance techniques, including 
SABA and/or LABA, Pulmozyme, inhaled corticosteroids and/or antibiotics 
7. Spirometry (FEV1, FVC, and FEF25-75) 
8. Obtain blood sample for PK (approximately 96 hours post dose 1) 
9. Administer study drug 
Post-dose: 
1. Symptom-directed physical examination at 15, 60 minutes, and 2 hours post dose 
2. Vital signs at 1, 10, 30, 60 minutes, and 2 hours post dose 
3. Oximetry at 1, 10, 30, 60 minutes, and 2 hours post dose 
4. AE review 
5. Spirometry at 20, and 60 minutes, and 4 hours post dose (if FEV1 at 60 minutes was 
decreased 15% from pre-dose value) 
7.4.7 
Weeks 2, 3 and 4 (Doses 4, 7, and 10) 
Pre-dose 
1. Subject self-completes the CFQ-R prior to all other procedures and assessments (Week 3 
dose 7 only) 
2. Complete physical examination (including body weight) 
3. Vital signs 
4. Oximetry 
5. Concomitant medications review 
6. AE review 
7. Administer any routine pulmonary medications and airway clearance techniques, including 
SABA and/or LABA, Pulmozyme, inhaled corticosteroids and/or antibiotics 


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8. Spirometry (FEV1, FVC, and FEF25-75) 
9. Obtain blood and urine samples for local laboratory assessments  
10. Obtain blood sample for PK  
11. Obtain pre-dose sputum sample for PK (prior to dose 4 only). Suggest obtaining sample in 
conjunction with performing spirometry prior to dosing  
12. Obtain blood and sputum samples for inflammatory biomarkers 
13. Administer study drug 
Post-dose: 
1. Symptom-directed physical examination at 15, 60 minutes, 2 hours post dose 
2. Vital signs at 1, 10, 30, 60 minutes, 2 hours post dose 
3. Oximetry at 1, 10, 30, 60 minutes, 2 hours post dose 
4. Concomitant medications review 
5. AE review 
6. Spirometry at 20, and 60 minutes post dose 
7. Obtain blood samples for local laboratory assessments at 15, 60 minutes, 2 hours post dose 
8. Obtain blood for PK at 1 hour post dose 7 only 
9. Obtain urine sample for urinalysis at 60 minutes and 2 hours post dose 
7.4.8 
Weeks 2, 3, and 4 (Doses 5, 6, 8, 9 and 11) 
1. Symptom-directed physical examination  
2. Vital signs  
3. Oximetry  
4. Concomitant medications review 
5. AE review 
6. Confirm administration of all routine pulmonary medications and airway clearance 
techniques prior to administration of study drug  
7. Obtain blood for PK prior to dosing 
8. Obtain pre-dose sputum for PK (prior to doses 5 and 6 only)  
9. Administer study drug 


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7.4.9 
Week 4 (Dose 12) 
Pre-dose: 
1. Complete physical examination (including body weight) 
2. Vital signs 
3. Oximetry 
4. Concomitant medications review 
5. AE review 
6. Obtain blood and urine samples for PK prior to dosing 
7. Administer any routine pulmonary medications and airway clearance techniques, including 
SABA and/or LABA, Pulmozyme, inhaled corticosteroids and/or antibiotics  
8. Spirometry (FEV1, FVC, and FEF25-75) 
9. Administer study drug 
Post-dose: 
1. Symptom-directed physical examination within 2 hours post dose 
2. Vital signs within 2 hours post dose 
3. Oximetry within 2 hours post dose 
4. Spirometry at 20, and 60 minutes, 4 hours post dose 
5. Obtain the following samples for PK: 
 Blood at 1, 2, 3, 4, and 8 hours post dose 
6. Obtain sample for sweat chloride determination 
7.4.10 
Follow-up Visit for PK—24 hours +/- 12 hours After Last Dose 
Subject to return to clinic to obtain serum and urine samples for PK. The samples can be 
collected any time within the time window specified. 
7.4.11 
Follow-up Visit for PK—96 hours +/- 48 hours After Last Dose 
Subject to return to clinic to obtain serum and urine samples for PK. The samples can be 
collected any time within the time window specified. 
7.4.12 
Follow-up Visits—7 and 28 Days After Last Dose 
Follow-up visits will occur 7 and 28 days after the last dose of study drug (dose 12).  


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If at any time during the study the subject discontinues the study early, the subject should return 
to the clinic to complete the End of Treatment Visit procedures below, and should also return to 
the clinic to complete the End of Study Visit procedures 28 days after the last study drug dose. 
7.4.12.1 
7 Days After Last Dose—End of Treatment Visit 
1. Subject self-completes the CFQ-R prior to all other procedures and assessments 
2. Complete physical examination (including body weight)  
3. Vital signs 
4. Oximetry 
5. Concomitant medication review 
6. AE review 
7. Chest Xray 
8. 12-lead ECG 
9. Spirometry  
10. Obtain blood and urine samples for local laboratory assessments  
11. Obtain urine or blood for pregnancy test (for women of child-bearing potential) 
12. Obtain blood samples for PK 
13. Obtain sputum sample for the following local laboratory assessment: 
 Microbiology organism identification  
14. Obtain blood and sputum samples for inflammatory biomarkers 
15. Obtain sample for sweat chloride determination 
7.4.12.2 
28 Days After Last Dose—End of Study Visit 
1. Subject self-completes the CFQ-R prior to all other procedures and assessments 
2. Complete physical examination (including body weight) 
3. Vital signs 
4. Oximetry 
5. Concomitant medication review 
6. AE review 
7. Spirometry  
8. Obtain blood and urine samples for local laboratory assessments 
9. Obtain urine or blood for pregnancy test (for women of child-bearing potential) 
10. Obtain blood and sputum samples for inflammatory biomarkers 


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11. Obtain serum samples for PK 
12. Obtain sample for sweat chloride determination 
8.0 
STUDY PROCEDURES 
Safety parameters will be assessed by monitoring AEs, vital signs, oximetry, laboratory data 
(chemistries, hematology and urinalysis), ECGs, pulmonary function (spirometry), and physical 
examinations. AEs and SAEs including laboratory tests (chemistries, hematology, and urinalysis) 
and ECGs will be graded according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events Modified for CF (CTCAE v4.03). 
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 12.0, Assessment of Safety or Adverse Events and Serious Adverse 
Events. 
8.2 
Vital Signs 
Blood pressure, heart rate, respiration rate, and temperature will be measured at rest in a sitting 
position. During the first 24 hours post first dose (SAD cohorts) or 12 hours post first dose 
(MAD cohorts), vital signs will be monitored via Holter and automated vital signs monitoring. 
8.3 
Telemetry 
On dosing Day 1, continuous cardiac and vital signs monitoring will be conducted. Recorded 
measurements (eg, via Holter monitoring) are acceptable (if observed monitoring is not 
available). 
8.4 
Oximetry 
Digital oximetry will be measured at rest in a sitting position. 
8.5 
Laboratory Evaluations 
Laboratory evaluations will be performed according to the study schedule. For screening 
purposes, should the screening period require longer than 14 days (eg, CFTR genotype testing 
required longer than 14 days), safety evaluations (serum chemistries, hematologies, urinalysis, 
physical exam, vital signs, spirometry) must be re-obtained for confirmation of eligibility and 
enrollment into the study. 
Serum chemistries will include sodium, potassium, chloride, bicarbonate, blood urea nitrogen 
(BUN), creatinine, glucose, calcium, phosphorus, SGPT/ALT, SGOT/AST, GGT, alkaline 
phosphatase, bilirubin (total and direct), uric acid, lactic dehydrogenase (LDH), albumin, 


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total protein, triglycerides, and cholesterol. Creatinine clearance is to be calculated using the 
Cockcroft-Gault equation adjusted for actual body weight. At screening, tocopherol (Vitamin E) 
levels will also be measured. 
Hematologies will include a complete blood count: Complete blood count (CBC) with absolute 
differential (hematocrit, hemoglobin, white blood count, segmented neutrophils, bands, 
lymphocytes, monocytes, eosinophils, basophils, platelet count).  
A Direct Antiglobulin Test (DAT) will also be performed at screening and 7 days after last dose. 
Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) will be measured at baseline, 
24 hours post dose, and End of Study Visit for SAD cohorts, and at baseline, prior to doses 4, 7 
and 10, and at the End of Treatment Visit for MAD cohorts. Two baseline measurements will be 
made; one on Day -1, and the other prior to dosing on Day 1. 
Urinalysis (by visual inspection and dipstick) will include color and appearance, specific gravity, 
pH, protein, glucose, occult blood, ketones, bilirubin, leukocyte esterase, nitrite, and 
urobilinogen. In addition, microscopic analyses will be performed on samples with abnormal 
dipstick results. Urine microalbumin will be measured at baseline for SAD and MAD cohorts; 
end of study for SAD cohorts; and prior to dose 10 and end of study for MAD cohorts. Time of 
void will be recorded for each urine sample collected. At screening, testing for drugs of abuse 
will also be performed, specifically for amphetamines, methamphetamines, 
methylenedioixymethamphetamine, cocaine, cannabinoids, phencyclidine, opiates, methadone, 
barbiturates, benzodiapines, ethyl alcohol. Urine or blood testing for drugs of abuse is permitted. 
Coagulation testing (INR, PT, PTT, fibrinogen) and total complement (CH50) will be performed 
at screening and the End of Study Visit for the SAD cohorts, and at screening, prior to dose 4, 
and at End of Treatment Visit for the MAD cohorts. Any abnormalities of coagulation will be 
followed with additional testing as determined by the Investigator and/or Medical Monitor to 
diagnose the coagulopathy.  
For female subjects, a pregnancy test (preferably serum, but urine tests are also accepted) will 
also be obtained as designated by the study schedule. 
Sputum for microbiology will be obtained as designated by the study schedule (for organism 
identification only). 
8.6 
Pharmacokinetic Evaluations 
Samples for PK analysis will be collected as detailed in Appendix 1 and Appendix 2. 
Expectorated sputum samples for PK assessment can be difficult to obtain at the specified time 
points. It is suggested that samples be collected in conjunction with spirometry, as often 
spirometry maneuvers can provoke coughing and sputum expectoration. Subjects should rinse 
their mouths with water or saline prior to collection of expectorated sputum samples. 


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Serum PK samples, when scheduled at time points when safety labs and/or biomarker samples 
are also to be collected, are to be collected first, followed by safety lab samples, and lastly 
biomarker samples.  
Urine PK samples will be obtained over the following time intervals (in hours post dose 
administration completion): Pooled samples collected from 0 to 4 hours, 4 to 12 hours, and 12 to 
24 hours post dose (SAD cohorts only), and at additional time points on subsequent study days 
(see Appendices 1 and 2 for specific timing of sample collection). Subjects should empty their 
bladders just prior to dosing and at the end of each time interval for the final urine collection of 
that interval. Urinalysis will be performed on each pooled sample prior to storage for PK 
analysis. Time and volume will be recorded for each void or urine collection interval at the 
designated time points. 
8.7 
Chest Xray 
A chest radiograph should be obtained at screening for the SAD cohorts, and at end of study for 
subjects exhibiting pulmonary AEs. A chest radiograph or CT scan obtained within 90 days of 
Screening Visit is acceptable if there was no occurrence of intercurrent pulmonary illness during 
the interim.   
A chest radiograph should be obtained at both screening and 7 days after last dose (end of 
treatment) for the MAD cohorts. A centralized reading of all chest radiographs may be 
performed at the end of the study. 
8.8 
Biomarkers 
Immune response monitoring will be performed per Appendices 1 and 2. Biomarkers of interest 
will be measured in both blood and sputum, and may include cytokines and proteases. The 
immune profile seen may prompt further exploratory immune response biomarker analysis. 
Blood (serum and plasma) and expectorated sputum samples will be collected per the study 
schedule, and stored for later quantification. 
8.9 
Electrocardiogram (ECG) 
12-lead ECG will be obtained at screening and end of study for the SAD cohorts, and at 
screening and 7 days post last dose for the MAD cohorts. 12-lead continuous telemetry will be 
obtained pre- and during the first 24 hours post first dose for SAD cohorts, and during the first 
12 hours post first dose for MAD cohorts. 
8.10 
Pulmonary Function 
Spirometry will be performed per American Thoracic Society (ATS)/European Respiratory 
Society (ERS) Standards. FEV1, FVC, and FEF25-75 will be collected. Actual liter values will be 
recorded. Prior to study drug dosing on a given day, the following order of concurrent treatment 
should be adhered to: Long- and/or Short acting bronchodilator, mucolytic therapy (eg, 


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Pulmozyme), chest physiotherapy (airway clearance technique), inhaled corticosteroid, inhaled 
antibiotics. Ancillary therapy regimens and airway clearance techniques should remain 
consistent throughout the study period, and the order of therapies and medications should also 
remain the same. 
8.11 
Physical Examination 
Complete physical examinations (urogenital exams not required) will be performed at screening, 
Day -1, prior to dosing for dose Days 4, 7, 10, and 12 (Cohorts 5-8), and at the End of Treatment 
and End of Study Visits. Symptom-directed physical exams will be performed at all other time 
points, as indicated by the study schedule. 
8.12 
Height and Weight 
Height will be measured using a calibrated, wall-mounted stadiometer and will be documented at 
the Screening Visit. Body weight will be measured using a calibrated scale per study schedule. 
8.13 
Sweat Chloride 
Documentation of pilocarpine iontophoresis sweat chloride of > 60 mmol/L is required for 
eligibility for all subjects. As sweat chloride is a measure of exploratory efficacy in the MAD 
cohorts, sweat chloride will be measured by pilocarpine iontopheresis at screening for all 
subjects, at the dose 12 Visit, and at the End of Treatment and End of Study follow-up visits for 
the MAD cohorts only. Determination of sweat chloride must be performed in an accredited 
laboratory using a method accepted by the Cystic Fibrosis Foundation and documented 
accordingly. 
The sweat chloride sample collection at the dose 12 Visit can be performed pre- or post-dose. 
8.14 
CFQ-R 
The CFQ-R subject health-related quality of life questionnaire will be administered using the 
self-administered format (Adult version) [Appendix 3], according to the study schedule for MAD 
cohorts only. The CFQ-R will be administered prior to any other test or procedure on each of the 
required study days. 
8.15 
CFTR Genotyping and Sequencing 
Confirmation of CFTR gene mutations homozygous for the ΔF508 mutation are required for all 
subjects for eligibility. Genetic testing performed prior to the year 2000 must be re-confirmed, 
and a blood sample for CFTR genotyping should obtained at the Screening Visit. Genotyping 
results must be received and confirmed as homozygous for the ΔF508 mutation prior to 
randomization. 


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Complete CFTR gene sequencing will be performed for all subjects randomized into the study. 
Blood samples will be collected at baseline (Day -1 or Day 1 pre-dose), and stored until the end 
of the study for analysis. 
Both CFTR genotyping and gene sequencing analysis are not optional for this study. Separate 
informed consent may be need to be obtained per local requirements. 
9.0 
OTHER CONSIDERATIONS 
9.1 
Routine CF Pulmonary Medications 
Administer any routine pulmonary medications, including SABA and/or LABA, Pulmozyme, 
and inhaled corticosteroids and/or antibiotics, in the same order each dosing day, prior to 
spirometry and study drug dosing, during the in-house phase of the study. 
9.2 
Chest Physiotherapy 
Any chest physiotherapy techniques utilized by an individual subject should remain consistent 
throughout the study. The order in which chest physiotherapy techniques are performed, in 
relation to other medications and administration of study drug should remain consistent 
throughout the study. 
10.0 
PHARMACOKINETIC AND EXPLORATORY EFFICACY MEASUREMENTS  
10.1 
Pharmacokinetic Measurements 
Blood samples will be obtained from all subjects to obtain PK data pre- and post-dosing.  
Samples for assessment of PK parameters of QR-010 (Cmax, Cmin, CL, Vd, AUC0-t and AUC0-∞, 
and t1/2) will be obtained only at the visits shown in Appendices 1 and 2.   
10.2 
Exploratory Efficacy Measurements 
Exploratory efficacy response criteria will be evaluated per the schedule.  
Efficacy Assessment 1 
FEV1 
Efficacy Assessment 2 
Sweat chloride measurement (MAD cohorts only) 
Efficacy Assessment 3 
CFQ-R Respiratory Symptoms Scale Score 


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Efficacy Assessment 4 
Body weight 
11.0 
STUDY TERMINATION 
If the Sponsor, DSMC, Sponsor’s Medical Monitor or designee, study 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 
site’s executed clinical trial agreement. ProQR Therapeutics reserves the right to discontinue the 
trial 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-010 is discontinued, the Sponsor shall immediately inform all 
trial Investigators/institutions and regulatory authorities. Study termination and follow-up will be 
performed in compliance with the conditions set forth in the ICH E6 on Good Clinical Practice 
guidelines and local regulatory requirements. 
12.0 
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. 
12.1 
Data Safety Monitoring Committee 
An independent DSMC from the Cystic Fibrosis Foundation Therapeutics Development Network 
Data and Safety Monitoring Board will provide safety oversight for the study. All DSMC 
members have significant experience with oversight of cystic fibrosis clinical trials. A DSMC 
operational charter will be finalized prior to randomization of the first subject. The DSMC will 
review unblinded safety data from each cohort, and provide their recommendation for 
proceeding to the next dosing cohort, as described in Section 4.2.   
12.2 
Definitions of Adverse Event  
12.2.1 
Adverse Event  
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related. AEs can include any unfavorable, noxious, unintended sign, 
symptom, or disease temporally associated with use of an investigational medicinal product or 
other protocol-imposed intervention, regardless of attribution. AEs may be spontaneously 


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reported by the subject, discovered by Investigator questioning, or detected through physical 
examination, laboratory test, or other means. 
AEs 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 
 AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period (as specified in Section 12.4.1)  
 Complications that occur as a result of protocol-mandated interventions (eg, invasive 
procedures such as blood draws) 
 AEs that occur prior to assignment of study treatment that are related to a 
protocol-mandated intervention (eg, invasive procedures such as blood draws, medication 
washout, or no treatment run-in) 
12.3 
Assessment of Adverse Events  
The Investigator is responsible for assessing the severity and causality of AEs. 
12.3.1 
Assessment of the Severity (Intensity) of Adverse Events 
Maximum intensity is to be graded using the NCI CTCAE (V 4.0) Modified for CF (National 
Cancer Institute, 2011). If grading table does not have grading criteria for the event, the criteria 
in Table 4 will be used. 
Table 4: 
Adverse Event Intensity (Severity) Scale  
Grade 
Severity 
Alternative Description of the Adverse Eventa 
1 
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
2 
Moderate 
Minimal, local, or noninvasive intervention indicated; discomfort sufficient to 
reduce or interfere with daily activities.  
3 
Severe 
Medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization may be indicated; disabling; limits self-care with 
significant interference with daily activities; incapacitating with inability to perform 
self care activities of daily living.  
4 
Life-threatening Urgent intervention indicated; immediate risk of death.  
5 
Death 
 
Note: Regardless of severity, some events may also meet regulatory serious criteria. Refer to definitions of an SAE. 
a. 
Use these alternative definitions for Grade 1, 2, 3, and 4 events when the observed or reported AE is not in the 
NCI CTCAE Modified for CF listing. 


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Any AE that meets the seriousness criteria (see Section 12.5, Serious Adverse Event Definition) 
will be considered an SAE, including all life-threatening AEs. In addition, AEs with Grade 4 
intensity may be considered serious if the event is determined to be clinically significant. 
12.3.2 
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. Treatment-related conditions must be distinguished from disease-related conditions. 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).  
Related: There is a plausible (possible, probable, or definite) temporal relationship between the 
onset of the AE and administration of the investigational product, and the AE cannot be readily 
explained by the subject’s clinical state, intercurrent illness, or concomitant therapies; and/or the 
AE follows a known pattern of response to the investigational product; and/or the AE abates or 
resolves upon discontinuation of the investigational product or dose reduction and, if applicable, 
reappears upon rechallenge. 
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 CRF, and SAE 
form if applicable. AEs recorded without the Investigator’s assessment of the relationship to 
study drug will be followed up until causality is assigned. 
12.3.3 
Assessment of the Outcome of Adverse Events 
Recovered/resolved: The subject has fully recovered from the event, with no residual effects 
observable. 
Recovered/resolved with sequelae: The subject has recovered from the event, but with residual 
sequelae effects observable. 
Not recovered/resolved: Effects of the event are still present. 
Recovering/resolving: The subject has improved, but has not fully recovered from the event. 
Fatal: The death is related to the event. 
Unknown: The outcome of the event is unknown to the reporter (eg, subject was lost to 
follow-up). 


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12.4 
Reporting of Adverse Events 
The Investigator is responsible for ensuring that all AEs and SAEs are recorded in the source 
document, AE CRF, and/or SAE form, and reported to the Sponsor in accordance with protocol 
instructions.  
12.4.1 
Adverse Event Reporting Period 
All significant medical conditions including signs/symptoms of the underlying diagnosis found 
during the screening period and up to randomization will be captured as medical history. Any 
event/condition related to participation in the trial but not related to underlying or concomitant 
disease that is noted after screening up to the randomization date will be captured as a 
non-treatment emergent AE. 
Any event/condition noted once the subject is randomized will be captured as an AE. All AEs 
and SAEs regardless of attribution will be collected until at least 30 days following the last 
administration of study treatment or initiation of new therapy, whichever is earlier. At the last 
scheduled visit, the Investigator should instruct each subject to report to the Investigator any 
subsequent SAEs that the subject’s personal physician believes could be related to prior study 
treatment. Any related non-serious AE occurring after the reporting period may be reported at 
the discretion of the Investigator. 
AEs and SAEs related to study drug that persist >30 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 treatment or participation is not the cause of the 
AE/SAE. Resolution of AEs and SAEs (with dates) should be documented on the AE CRF 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).  
12.4.2 
Eliciting Adverse Events 
A consistent methodology of non-directive questioning for eliciting AEs at all subject evaluation 
time points should be adopted. Examples of non-directive questions include: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last here?” 
12.4.3 
Recording Adverse and Serious Adverse Events  
Investigators should use correct medical terminology/concepts when recording AEs or SAEs on 
the CRF and/or SAE form. Colloquialisms and abbreviations should be avoided. SAEs must also 


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be recorded on the AE CRF. Only one medical concept should be recorded in the event field on 
the AE CRF and SAE form (if applicable). 
a. 
Signs and Symptoms versus Diagnosis 
Signs and symptoms should be recorded on the AE CRF rather than the unifying diagnosis. The 
unifying event term or diagnosis should be recorded as the “etiology” in the CRF (if known), and 
the SAE form, if applicable. For example, jaundice, asterixis, and elevated transaminases should 
be recorded on the CRF, and “liver failure” should be recorded as the etiology. As another 
example, cough, rhinitis, and sneezing should be recorded as AEs on the CRF, and record “upper 
respiratory tract infection” as the etiology. Vague, nonspecific AE terms such as “erythema,” 
“rash,” or “lump on head” should be avoided and more specific information should be provided, 
such as “erythematous macule on right leg,” “allergic dermatitis,” and “scalp cyst.” 
b. 
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 CRF, and if also 
serious, on the SAE form.  
c. 
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 CRF unless their severity increases. 
If a persistent AE becomes more severe or occurs more frequently, it should be recorded again 
on the AE CRF 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 CRF. 
d. 
Abnormal Laboratory Values 
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs on the CRF and SAE form (if applicable). For example, abnormalities that 
require study drug dose modification, discontinuation of study treatment, more frequent follow-
up assessments, further diagnostic investigation, etc.  
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 CRF and SAE form (if applicable), unless their 
severity, seriousness, or etiology changes.  


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e.  
Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section 12.4.1), 
regardless of attribution, will be recorded on the AE CRF 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 CRF and SAE form. 
f. 
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 CRF. 
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 CRF 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”). 
g. 
Pulmonary Exacerbation  
Given the proposed mechanism of action of QR-010, it could be anticipated that subjects will 
experience a change in baseline cough, change in sputum quality, or change in sputum volume. 
A diagnosis of pulmonary exacerbation should be considered if these symptoms are accompanied 
by fever, body weight loss, generalized malaise. If a pulmonary exacerbation is diagnosed, 
appropriate interventions including additional antibiotics should be prescribed by the PI or 
treating physician. Subjects diagnosed with a pulmonary exacerbation requiring the addition of 
antibiotics will be withdrawn from the study. 
h. 
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.  
i. 
Pregnancy 
If a female partner of a male subject in the study becomes pregnant while her partner is receiving 
investigational therapy or within 6 months after the last dose of study, a Pregnancy form should 
be completed and faxed to the Sponsor’s Drug Safety Department or its designee within 24 hours 
of learning of the pregnancy, using the fax numbers listed in the Study Manual. 


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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 Manual. If the abortion meets 
seriousness criteria (see Section 12.5, Serious Adverse Event Definition), this information will 
be captured on the AE CRF 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 investigational product should be recorded and reported as an SAE. 
j. 
Overdose Reporting 
Overdoses must be reported to the Sponsor on an AE CRF and an SAE form for tracking 
purposes and will be considered a protocol violation. 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. 
12.5 
Serious Adverse Event Definition 
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. 
 In-subject hospitalization or prolongs existing hospitalization, except for hospitalization 
for planned post-dose sample collections 
 Persistent or significant disability/incapacity (ie, the AE results in substantial disruption 
of the subject’s ability to conduct normal life functions) 
 Congenital anomaly or birth defect. This serious criterion applies if a congenital 
anomaly/birth defect is diagnosed in a child born to a female subject, or a female partner 
of a male subject exposed to the investigational product. 
 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. Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependence or abuse. 
All AEs that do not meet any of the criteria for serious should be regarded as non-serious AEs. 


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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). “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 
CRF and SAE form. 
12.6 
Suspected Unexpected Serious Adverse Reaction Definition 
A 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 medical product 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 of all involved European member states and to the Ethics Committee of the member 
states concerned. 
12.7 
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 Manual for Fax Number 
Any fatal or life-threatening (ie, imminent risk of death) event that is attributed by the 
Investigator to the investigational product must be telephoned to Drug Safety immediately, 
followed by submission of written case details on an SAE form within 24 hours. 
SAEs 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, 
site identifier, event or outcome, and Investigator assessment of causal relationship to 
study drug should be provided. 
 A rationale for the causality assessment of an SAE should always be included, so that a 
better understanding of the event can be compiled. 


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 Follow-up information, such as laboratory reports, discharge summaries, autopsy reports, 
and information concerning outcome of the event should be submitted by revising the 
SAE form as soon as the information becomes available. Copies of source documents 
with subject identifiers redacted should be submitted only when they are written in 
English. If source documents are not in English, the Investigator must summarize the 
source documents, providing a complete English narrative that includes a description of 
the events as it evolved, the results of all diagnostic procedures performed, treatments 
administered, and outcome of the event. A query regarding a follow-up report should be 
answered within 5 working days from receipt of the query. 
 Appropriate diagnostic tests and therapeutic measures are to be performed as necessary 
and reported on the SAE form. 
 All SAEs must be reported to the IRB/Independent Ethics Committee, if applicable. See 
ICH GCP E6, Section 4.11.1. 
12.8 
Expedited Reporting of SUSARs 
 The Sponsor or its designee is responsible for notifying the investigational sites of all 
expedited SAEs (ie, 7/15 Day SUSARs) that occur during any clinical studies that are using 
the investigative compound. The Sponsor or its designee shall also notify Central Ethics 
Committees 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 or Local Ethics Committees (LECs) 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 Ethics 
Committees 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). 
12.9 
Emergency Unblinding Procedure 
In the event of a medical emergency, when knowledge of treatment assignment is needed for 
immediate medical management of the subject’s health, Investigators can obtain unblinded 
treatment assignment through the centralized IWRS system at any time. Thorough 
documentation of the rationale for unblinding is required. Consultation of the study Medical 
Monitor is recommended for all unblinding requests. 
13.0 
STATISTICAL METHODOLOGY 
13.1 
General Considerations 
A comprehensive Statistical Analysis Plan (SAP) specifies the statistical methodology, and table, 
figure and listing (TLF) formats for all aspects of the planned analyses. The SAP supports the 


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completion of Clinical Study Report (CSR) for this protocol. As the risk profile of QR-010 in 
humans is unknown and this is a first in human trial, all AEs will be considered in determining 
the safety profile of QR-010 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 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.  
13.2 
Determination of Sample Size 
This is a Phase 1 safety study designed to evaluate the safety, tolerability and PK of QR-010. 
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. 
Approximately 64 subjects will be enrolled in the study, with 8 subjects per cohort (6 QR-010 
and 2 placebo), 32 each in the SAD and MAD portions of the study. The exact number of 
subjects enrolled is dependent on whether any dose level are to be expanded due to the 
occurrence of DLTs. 
13.3 
Randomization and Blinding 
13.3.1 
Randomization Procedures 
At screening, potential subjects will be randomized into the current enrolling cohort. In the event 
that there is both a SAD and MAD cohort enrolling in parallel, the subject may elect 
participation in either an open SAD or MAD cohort. All sites will be capable of and expected to 
enroll all cohorts of the study. Subjects who meet all of the inclusion criteria and none of the 
exclusion criteria will be eligible for randomization. Eligible subjects will be randomized on 
Day -1 by a centralized interactive web response system (IWRS), utilizing the randomization 
schedule generated by the designated unblinded statistician. The IWRS system will be used to 
assign dose level and treatment assignments to subjects, within the cohort type (SAD or MAD) 
selected by the subject at screening.   
Within each dosing cohort, subjects will be randomized 3:1, QR-010 to placebo. At least one of 
the first two subjects enrolled in the first cohort will be randomized to receive QR-010.  
13.3.2 
Blinding Procedures 
Study drug will be administered in a double-blind fashion. Study drug and placebo are both 
clear, colorless, and odorless aqueous solutions. Subjects, Investigators and study site staff will 
be blinded to treatment assignment. However, due to the requirement for study pharmacists to 
prepare the various study drug dilutions depending on the dosing cohort to which a given study 
subject is assigned, the study pharmacist(s) will be unblinded to treatment assignment. 


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13.3.3 
Replacement of Subjects 
Subjects who discontinue from the study after randomization without receiving any treatment 
will be replaced. Subjects discontinuing the trial before the full course of treatment may be 
replaced by a subject who will be assigned the same treatment/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.  
13.4 
Analysis of Populations 
Due to its exploratory nature, the analyses for this study will be mainly descriptive. If inferential 
statistics are provided they will be interpreated as hypothesis generation. Data analysis will be 
based on descriptive statistics for the dose groups, and when appropriate, pooled across dose 
groups. For continuous variables, the statistics include the following: geometric mean, mean, 
median, log-scale standard deviation, standard error of the mean, minimum and maximum. For 
categorical variables the statistics include frequency and proportions.  
Screened: All subjects with an informed consent date will be part of this population. 
Randomized: All subjects with a randomization date. 
Safety Population: the population for safety analysis will consist of all subjects who receive any 
QR-010 or placebo. Subjects will be considered in the actual treatment received. 
Exploratory Analysis Population: the population for efficacy (clinical activity) analysis will 
consist of all subjects randomized who receive at least one dose of QR-010 or placebo. Subjects 
will be considered in the actual treatment received. 
Pharmacokinetics (PK) Population: will consist of all subjects who receive QR-010 and who 
have sufficient drug concentration measurements in blood samples or urine or sputum. This 
population will be used for PK analysis. 
13.5 
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 site will be presented by geographic region (North 
America and Europe).  
The number and percentage of subjects who receive QR-010 will be tabulated by the number of 
doses and the QR-010 dose group.  
Subject demographics and baseline characteristics will be summarized for each dose group. 
Subject characteristics at baseline include age, race, body weight, and height. Baseline disease 
characteristics include pulmonary function (percent predicted), body weight, and CFQ-R 


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Respiratory Symptoms Score. The baseline data is defined as the data most recently collected 
prior to the first dose. 
13.6 
Treatment Compliance 
All doses are observed and administered by study staff. Treatment compliance will be 
determined by source records documenting treatment observations and summarized. 
13.7 
Safety Analyses 
13.7.1 
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. 
AEs noted during the study will be coded to system organ classes (SOCs) and preferred terms 
(PTs) using the 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. AEs 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 percents 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 treatment-related events. 
13.7.2 
Dose-Limiting Toxicities 
Potential DLTs are reviewed and adjudicated by the DSMC. DLTs will be summarized by dose 
groups. Individual subject listings will be provided for each DLT including severity. Additional 
descriptive information such as associated laboratory values and action taken will be described in 
the clinical study report. 
13.7.3 
Vital Signs 
Vital sign measurements will consist of respiratory rate, pulse, blood pressure, temperature and 
oximetry. 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. 


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13.7.4 
Laboratory Assessments 
Laboratory measurements (hematology and chemistry) obtained at baseline and each study visit 
will be summarized by dose group, whenever possible, 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 to maximum and to minimum value during treatment and after 
treatment will be presented.  
 Site local laboratories were used; summaries will be provided as units/ranges permit. 
13.7.5 
Other Safety Assessments 
Other safety assessments, such as urinalysis, ECGs, and physical examinations will be 
summarized and listed as specified in the statistical analysis plan (SAP). 
13.8 
Pharmacokinetics Analyses 
To determine the PK profile of inhaled administrations at the different dose levels of QR-010, 
the following PK parameters will be calculated if sufficient data are available for each dose: 
 Cmax: The maximum serum concentration will be taken directly from the data. 
 Tmax: Time to Cmax will be taken directly from the data. 
 T½: The terminal elimination half-life will be estimated by non-linear regression analysis 
of the terminal elimination slope, if feasible. 
 AUC0-t: Area under the curve to the final sample with a concentration greater than lower 
limit of quantification (LLQ) will be calculated using the linear trapezoidal method. 
 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. 
 CL: Serum clearance will be estimated using the formula: CL = Dose/AUC0-∞. 
Achievement of steady state of the drug will be determined from trough levels. 
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. 


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Sparse sampling analysis may be used to mitigate the risk of insufficient data to create individual 
profiles. The same approach may be used for non-compartmental analysis of sputum 
concentrations. This option provides the opportunity to characterize drug PK in CF patients as 
thoroughly as possible while keeping blood draws to a reasonable minimum for ethical 
considerations. 
Correlation between concentrations in different matrices (serum, urine, sputum) may be 
explored. 
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, AUC0-t, AUC0-∞ and Cl 
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 SAP. 
13.9 
Immunogenicity  
For subjects with positive anti-QR-010 antibodies, the impact of the antibodies on the PK and 
safety of QR-010 will be evaluated. 
13.10 Exploratory Efficacy Analyses 
The exploratory clinical efficacy endpoints for the study will be evaluated for subjects enrolled 
in MAD cohorts. The exploratory efficacy evaluations will include: 
 Pulmonary function 
 Body weight 
 CFQ-R RSS 
 Sweat chloride 
Descriptive statistics of clinical efficacy will be tabulated by dose group.  
All continuous endpoints will be summarized using the following descriptive statistics: number 
of subjects, mean, standard deviation, standard error, median, minimum and maximum and 95% 
confidence intervals for the mean. Categorical endpoints will be summarized using: number of 
subjects, frequency, percentages and the 95% confidence intervals. 
13.11 Interim Analysis 
Safety will be assessed prior to each dose escalation by the DSMC.  


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For development purposes data analyses may be performed during the study.  
13.12 Subgroup Analyses 
No subgroup analyses are planned. 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Changes to the Protocol 
Protocol amendments must be made only with the prior approval of Sponsor. Sponsor will 
inform the Investigator in writing of any amendment to the protocol. The Investigator must 
submit the protocol modifications and any informed consent modifications to the IRB/IEC and 
applicable country authorities, and approval must be obtained before the modifications are 
implemented (unless a life threatening situation). The Investigator must send a copy of the 
approval letter from the IRB/IEC to the designated contract research organization (CRO) for 
Sponsor review. 
Both the Sponsor and the Investigator reserve the right to terminate the study according to the 
study contract. The Investigator should notify the IRB/IEC and applicable country authorities in 
writing of the trial’s completion or early termination and send a copy of the notification to the 
Sponsor. 
14.2 
Data Collection and Study Monitoring 
An electronic CRF (eCRF) will be used for this study. Study site personnel will be trained and 
authorized to use the system in compliance with the Code of Federal Regulations (CFR) 21CFR 
Part 11, ICH 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). 
eCRFs should be completed for every subject screened or enrolled in the study. Each subject will 
be identified by a unique subject identifier (site number and subject number). At the study’s 
conclusion, a PDF file will be created for each site 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 never obliterated or destroyed. 
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 sites, 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 


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adherence to the protocol and GCP. To resolve any questions arising from the clinical data 
management review process, data queries will be sent to the site. Corrections or updates to the 
data resulting from queries should be made on the eCRF. All changes will be automatically 
documented in the software’s audit trail, including the reason for change. 
The Investigator will electronically sign and date the indicated places on the eCRF. These 
signatures will indicate that the Investigator inspected or reviewed the data on the eCRF and 
agrees with the content. 
A Sponsor representative will contact the Investigator(s) at periodic intervals by telephone or 
visit for the purpose of inspecting the facilities and assessing the progress of the study. CRFs, 
eCRFs, 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 CRFs and eCRF. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits, including delays in completing CRFs/eCRF, are resolved. 
Inspection of site facilities (eg, pharmacy, drug storage areas, laboratories) and review of study-
related records will occur to evaluate the trial conduct and compliance with the protocol, ICH 
GCP, and applicable regulatory requirements. Study drug dispensing and accountability will also 
be assessed. 
15.0 
ETHICAL AND REGULATORY OBLIGATIONS 
15.1 
Ethical Considerations 
The Investigator agrees to conduct this study in accordance with the ICH principles of GCP and 
with the Declaration of Helsinki (October 2013). The Investigator will conduct all aspects of this 
study in accordance with all national, state and local laws of the applicable regulatory agencies. 
15.2 
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, the U.S. federal regulations (21 CFR Part 50) and corresponding 
country authority requirements. Separate informed consent may be required for CFTR 
genotyping, CFTR gene sequencing, and/or biomarker testing. The subject or his/her legal 
representative must sign the current version of the written, IRB/IEC-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. 


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In accordance with ICH GCP and federal regulations (21 CFR 312.66), an IRB/IEC that 
complies with regulations in 21 CFR Part 56 must review and approve this protocol and the 
informed consent form prior to initiation of the study. The Investigator will submit a list of the 
names, occupations, and affiliations of the members of the IRB/IEC and documentation that the 
IRB/IEC is duly constituted or a General Assurance Number. No supplies will be shipped until 
the IRB/IEC and applicable country authorities have given written approval of the protocol and 
informed consent and the Sponsor has received copies of these approvals.  
The Investigator must submit and, where necessary, obtain approval from the IRB/IEC and 
applicable country authorities for all subsequent protocol amendments and changes to the 
informed consent document. The Investigator should notify the IRB/IEC of deviations from the 
protocol or SAEs occurring at the site. SUSARs and other AE reports will be reported to the ECs 
and applicable country authorities by the Sponsor, in accordance with local procedures. 
The Investigator will be responsible for obtaining annual IRB/IEC renewal throughout the 
duration of the study. Copies of the Investigator’s reports and the IRB/IEC continuance of 
approval must be sent to the Sponsor. 
Each U.S. IRB or corresponding regulatory authority participating in this clinical study is 
required to be registered with the U.S. Department of Health and Human Services (HHS) or 
corresponding agency respectively.  
15.3 
Pre-study Documentation Requirements 
The Investigator is responsible for forwarding the following documents to the CRO for Sponsor 
review before the initial shipment of study drug to the site. 
 Signed and dated protocol signature page (Investigator’s Agreement) 
 Copy of the IRB/IEC –approved informed consent form 
 Copy of the IRB/IEC approval of the protocol 
 Copy of applicable country authority approvals of the protocol 
 Up-to-date curricula vitae of Investigator and all co/sub-investigators listed on Form 
FDA 1572 
 The IRB/EC composition and/or written statement that the IRB/IEC is in compliance 
with regulations 
 Laboratory normal ranges and documentation of laboratory certification (or equivalent) 
 Signed study contract 
 Completed FDA Form 1572 or Investigator Agreement 
 Financial Disclosure Form 


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15.4 
Subject Confidentiality 
The Investigator must ensure that the subject’s confidentiality is maintained. On the CRFs or 
other documents submitted to the Sponsor, subjects should be identified by their date of birth and 
subject number only. For countries where local regulatory guidelines prohibit capture of full date 
of birth, partial date will be recorded in line with local regulations. Documents that are not for 
submission to the Sponsor (eg, signed informed consent forms), should be kept in strict 
confidence by the Investigator.  
In compliance with federal and local regulations, it is required that the Investigator and 
institution permit authorized representatives of the Sponsor, the Food and Drug Administration, 
other regulatory authorities, and the IRB/IEC 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. 
16.0 
STUDY ADMINISTRATION 
16.1 
Good Clinical Practice and Regulatory Requirements 
This study will be conducted in accordance with good clinical practices as described in the ICH 
E6 GCP, adopted 1 May 1996, and in accordance with CFR Parts 50, 56, 312, and 314. The ICH 
guideline may be obtained at the ICH web site: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6_R1/Step4
/E6_R1__Guideline.pdf    
Where applicable, this study must also be conducted in accordance with Directive 2001/20/EC of 
the European Parliament and of the Council of April 4, 2001 on the approximation of the laws, 
regulations, and administrative provisions of the Member States relating to the implementation 
of GCP in the conduct of clinical trials on medicinal products for human use.  
16.2 
Investigator’s Brochure 
Before the study begins, the Investigator will receive the QR-010 Investigator’s Brochure 
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 brochure will be amended or revised and the Sponsor will provide the most current 
version to the Investigator. 
16.3 
Protocol Amendments and Study Termination 
Protocol amendments must be made only with the prior approval of Sponsor. Sponsor will 
inform the Investigator in writing of any amendment to the protocol. The Investigator must 


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submit the protocol modifications and any informed consent modifications to the IRB/IEC, and 
approval must be obtained before the modifications are implemented. The Investigator must send 
a copy of the approval letter from the IRB/IEC to the CRO for Sponsor to review. 
Both the Sponsor and the Investigator reserve the right to terminate the study according to the 
study contract. The Investigator should notify the IRB/IEC in writing of the trial’s completion or 
early termination and send a copy of the notification to the Sponsor. 
16.4 
Study Documentation and Storage 
The Sponsor will provide the Investigator with records of drug shipments, CRFs/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: 
 Subject files containing informed consents and supporting copies of source 
documentation. Any paper CRFs will also be contained in such a file. 
 Study files containing the protocol with all amendments, Investigator’s Brochure, copies 
of prestudy documentation, and all correspondence to and from the IRB/IEC, applicable 
country authorities, and the Sponsor 
 Records of drug disposition and all drug-related correspondence. 
In addition, all original source documents supporting entries in the CRFs/eCRFs must be 
maintained and be readily available.   
Upon the request of the Sponsor, designees, or the regulatory authorities, the Investigator will 
make any and 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. 
16.5 
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 date of birth and a subject 
number. It is the responsibility of the Investigator to keep a subject listing for cross-referencing. 
The Investigator understands that the information developed in the clinical study will be used by 
the Sponsor in connection with the development of the study drug. This information may be 


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disclosed to other clinical Investigators, to the U.S. Food and Drug Administration (FDA), and to 
other government agencies. 
16.6 
End of Trial and Final Report 
In North America, the Investigator or associate must notify the IRB/IEC when the study is closed 
and provide a final report to the IRB/IEC within 90 days of the last subject’s completion of the 
study. If not initially provided by the Sponsor, a copy of this final report must also be provided to 
Sponsor or its representative.   
In the EU, 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.   
16.7 
Financing and Insurance 
Financing and Insurance are addressed separately in the Clinical Study Agreement. 
16.8 
Publication Policy 
The publications policy is also provided in the Clinical Study Agreement. The data from this 
study will be available to the Investigators for publication upon the completion of the study. The 
Sponsor agrees to have the results published, whether positive or negative. A publication 
committee will be formed composed of the Investigators. The Sponsor will review any 
manuscripts to ensure that proprietary information has the appropriate patent protection prior to 
journal submission. 
 
 


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17.0 
REFERENCES 
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Davies JC, Alton EW and Bush A. Cystic fibrosis. BMJ 2007, Dec 15;335(7632):1255-9. 
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Sosnay PR, Siklosi KR, Van Goor F, et al. Defining the disease liability of variants in the 
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Stephenson ML and Zamecnik PC. Inhibition of rous sarcoma viral RNA translation by a 
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Vankeerberghen A, Cuppens H and Cassiman JJ. The cystic fibrosis transmembrane 
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Zamecnik PC and Stephenson ML. Inhibition of rous sarcoma virus replication and cell 
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15. 
Zamecnik PC, Goodchild J, Taguchi Y et al. Inhibition of replication and expression of 
human T-cell lymphotropic virus type III in cultured cells by exogenous synthetic 
oligonucleotides complementary to viral RNA. Proceedings of the National Academy of 
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Zamecnik PC, Raychowdhury MK, Tabatadze DR, et al. Reversal of cystic fibrosis 
phenotype in a cultured Δ508 cystic fibrosis transmembrane conductance regulator cell 
line by oligonucleotide insertion. Proc Natl Acad Sci U S A 2004;101(21):8150-5. 
 
 


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18.0 
APPENDICES 
Appendix 1 
Schedule of Assessments 
Appendix 2 
Schedule of Laboratory Assessments 
Appendix 3 
CFQ-R, Adult Version (English) 
 


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APPENDIX 1: 
SCHEDULE OF ASSESSMENTS 
Table A.1-1: Single Ascending Dose Cohorts 1-4 
Study Procedures 
Screening Check-In 
 
 
 
Discharge 
 
 
 
End of 
Study 
Study Day 
≤-14 daysa 
-1 
1b 
2 
3 
4 
5 
6 
7 
8 
In Hours 
 
-24 
0 
24 
48 
72 
96 
120 
144 
168 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Eligibility Review 
X 
X 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
 
 
 
X 
Physical Exam 
C 
C 
S 
S 
 
S 
 
 
 
C 
Height & Weight 
H/W 
W 
W 
 
 
 
 
 
 
W 
Vital Signsc & Oximetry 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Spirometryd 
X 
X 
X 
X 
 
X 
 
 
 
X 
Chest Xray  
Xe 
 
 
 
 
 
 
 
 
Xf 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
X 
24-Hour Telemetry 
 
 
X 
 
 
 
 
 
 
 
Blood for Safety Labsg 
X 
Xh 
X 
X 
X 
X 
 
 
 
X 
Urinalysisg 
U 
Uh 
U 
U 
U 
U 
 
 
 
U 
Drug Screeng 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Testg,i 
X 
X 
 
 
 
 
 
 
 
X 
Sputum for Microbiologyg 
 
X 
 
 
 
 
 
 
 
X 
Blood for CFTRg 
Genotyping Sequencing 
 
 
 
 
 
 
 
 
Biomarkersg 
X 
X 
 
X 
 
X 
 
 
 
X 
Sweat Chlorideg 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Study Drug Administrationj 
 
 
X 
 
 
 
 
 
 
 
Collect Samples for PKg 
 
 
X 
X 
X 
X 
 
 
 
X 


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Abbreviations: C = complete physical exam; H = height; S = symptom-directed physical exam; U = urinalysis (dipstick); W = 
weight 
a The screening period for an individual subject may be extended for an additional 7 days at the discretion of the Sponsor’s Medical 
Monitor. See Section 7.2 for details.  
b See Section 7.3.2 for details on timing of these assessments relative to study drug administration on Day 1. 
c Includes blood pressure, heart rate, respiratory rate, and temperature. 
d Includes FEV1, FVC, and FEF25-75. 
e A Chest Xray or CT scan obtained within 90 days of screening is acceptable if there was no intercurrent pulmonary illness during 
the interim. 
f Only subjects who experience pulmonary AEs during the study. 
g See Appendix 2 for a detailed schedule of these assessments, broken down by type of specimen and time relative to dose. 
h Only laboratory assessments that are abnormal (but not clinically significant) at screening should be repeated at Day-1. 
i Pregnancy test (preferably serum but urine is accepted) required for women of childbearing potential only. 
j Subjects who are taking concurrent CF therapy should receive this therapy prior to study drug dosing in the order specified in 
Section 6.3.1. 
 
 


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Table A.1-2: Multiple Ascending Dose Cohorts 5-8, WEEK 1 
Dosing Schedule assumes Monday-Wednesday-Friday dosing: 
Study Procedures 
Screening 
 
Dose 1 Dose 2 
 
Dose 3 
 
 
Study Day 
≤-14 
daysa 
-1 
1 
3 
4 
5 
6 
7 
In Hours Post Dose 1 
 
-24 
0 
48 
72 
96 
120 
144 
Informed consent 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Eligibility Review 
X 
X 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
 
 
Physical Exam 
C 
C 
S 
S 
S 
S 
 
 
Height & Weight 
H/W 
W 
W 
 
 
 
 
 
Vital Signsb & Oximetry 
X 
X 
X 
X 
X 
X 
 
 
Spirometryc 
X 
X 
X 
X 
X 
X 
 
 
Chest Xray 
Xd 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
Telemetry 
 
 
X 
 
 
 
 
 
CFQ-R RSSe 
 
 
X 
 
 
 
 
 
Blood for Safety Labsf 
X 
Xg 
X 
X 
X 
 
 
 
Urinalysisf 
U 
Ug 
U 
U 
U 
 
 
 
Drug Screenf 
X 
 
 
 
 
 
 
 
Pregnancy Testf,h 
X 
X 
 
 
 
 
 
 
Sputum for Microbiologyf 
 
X 
 
 
 
 
 
 
Blood for CFTRf 
Genotyping Sequencing 
 
 
 
 
 
 
Biomarkersf 
X 
X 
 
 
X 
 
 
 
Sweat Chloridef 
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Study Drug Administrationi 
 
 
X 
X 
 
X 
 
 


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Study Procedures 
Screening 
 
Dose 1 Dose 2 
 
Dose 3 
 
 
Collect Samples for PKf 
 
 
X 
X 
X 
X 
 
 
Abbreviations: C = complete physical exam; CFQ-R RSS = Cystic Fibrosis Questionnaire-Revised Respiratory Symptom Score; ECG = 
electrocardiogram; H = height; PK = pharmacokinetic; S = symptom-directed physical exam; U = urinalysis (dipstick); W = weight 
NOTE: See also Section 7.4 for details on timing of assessments relative to study drug administration. 
a The screening period for an individual subject may be extended for an additional 7 days at the discretion of the Sponsor’s Medical 
Monitor. See Section 7.2 for details. 
b Includes blood pressure, heart rate, respiratory rate, and temperature. 
c Includes FEV1, FVC, and FEF25-75. 
d A Chest Xray or CT scan obtained within 90 days of screening is acceptable if there was no intercurrent pulmonary illness during the 
interim. 
e Should be completed prior to any other procedures or assessments. 
f See Appendix 2 for a detailed schedule of these assessments, broken down by type of specimen and time relative to dose. 
g Only laboratory assessments that are abnormal (but not clinically significant) at screening should be repeated at Day-1. 
h Pregnancy test (preferably serum but urine is accepted) required for women of childbearing potential only. 
i Subjects who are taking concurrent CF therapy should receive this therapy prior to study drug dosing in the order specified in Section 
6.3.1. 


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Table A.1-3: Multiple Ascending Dose Cohorts 5-8, WEEK 2 
 
Study Procedures 
Dose 4 
 
Dose 5 
 
Dose 6 
 
 
Study Day 
8 
9 
10 
11 
12 
13 
14 
In Hours Post Dose 1 
168 
192 
216 
240 
264 
288 
312 
Concomitant Medications 
X 
 
X 
 
X 
 
 
Adverse Events 
X 
 
X 
 
X 
 
 
Physical Exam 
C/S 
 
S 
 
S 
 
 
Height & Weight 
W 
 
 
 
 
 
 
Vital Signsa & Oximetry 
X 
 
X 
 
X 
 
 
Spirometryb 
X 
 
 
 
 
 
 
Blood for Safety Labsc 
X 
 
 
 
 
 
 
Urinalysisc 
U 
 
 
 
 
 
 
Biomarkersc 
X 
 
 
 
 
 
 
Study Drug Administrationd 
X 
 
X 
 
X 
 
 
Collect Samples for PKc 
X 
 
X 
 
X 
 
 
Abbreviations: C = complete physical exam; PK = pharmacokinetic; S = symptom-directed physical exam; U = urinalysis 
(dipstick); W = weight 
NOTE: See also Section 7.4 for details on timing of assessments relative to study drug administration. 
a Includes blood pressure, heart rate, respiratory rate, and temperature. 
b Includes FEV1, FVC, and FEF25-75. 
c See Appendix 2 for a detailed schedule of these assessments, broken down by type of specimen and time relative to dose. 
d Subjects who are taking concurrent CF therapy should receive this therapy prior to study drug dosing in the order specified in 
Section 6.3.1. 
 
 


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Table A.1-4: Multiple Ascending Dose Cohorts 5-8, WEEK 3 
 
Study Procedures 
Dose 7 
 
Dose 8 
 
Dose 9 
 
 
Study Day 
15 
16 
17 
18 
19 
20 
21 
In Hours Post Dose 1 
336 
360 
384 
408 
432 
456 
480 
Concomitant Medications 
X 
 
X 
 
X 
 
 
Adverse Events 
X 
 
X 
 
X 
 
 
Physical Exam 
C/S 
 
S 
 
S 
 
 
Height & Weight 
W 
 
 
 
 
 
 
Vital Signsa & Oximetry 
X 
 
X 
 
X 
 
 
Spirometryb 
X 
 
 
 
 
 
 
CFQ-R RSSc 
X 
 
 
 
 
 
 
Blood for Safety Labsd 
X 
 
 
 
 
 
 
Urinalysisd 
U 
 
 
 
 
 
 
Biomarkersd 
X 
 
 
 
 
 
 
Study Drug Administratione 
X 
 
X 
 
X 
 
 
Collect Samples for PKd 
X 
 
X 
 
X 
 
 
Abbreviations: C = complete physical exam; CFQ-R RSS = Cystic Fibrosis Questionnaire-Revised Respiratory Symptom Score; 
PK = pharmacokinetic; S = symptom-directed physical exam; U = urinalysis (dipstick); W = weight 
NOTE: See also Section 7.4 for details on timing of assessments relative to study drug administration. 
a Includes blood pressure, heart rate, respiratory rate, and temperature. 
b Includes FEV1, FVC, and FEF25-75. 
c Should be completed prior to any other procedures or assessments. 
d See Appendix 2 for a detailed schedule of these assessments, broken down by type of specimen and time relative to dose. 
e Subjects who are taking concurrent CF therapy should receive this therapy prior to study drug dosing in the order specified in 
Section 6.3.1. 
 
 
 


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Table A.1-5: Multiple Ascending Dose Cohorts 5-8, WEEK 4 
 
Study Procedures 
Dose 10 
 
Dose 11 
 
Dose 12 
Study Day 
22 
23 
24 
25 
26 
In Hours Post Dose 1 
504 
528 
552 
576 
600 
Concomitant Medications 
X 
 
X 
 
X 
Adverse Events 
X 
 
X 
 
X 
Physical Exama 
C/S 
 
S 
 
C/S 
Height & Weight 
W 
 
 
 
W 
Vital Signsb & Oximetrya 
X 
 
X 
 
X 
Spirometrya,c 
X 
 
 
 
X 
Blood for Safety Labsd 
X 
 
 
 
 
Urinalysisd 
U 
 
 
 
 
Biomarkersd 
X 
 
 
 
 
Sweat Chlorided 
 
 
 
 
X 
Study Drug Administratione 
X 
 
X 
 
X 
Collect Samples for PKd 
X 
 
X 
 
X 
Abbreviations: C = complete physical exam; PK = pharmacokinetic;  
S = symptom-directed physical exam; U = urinalysis (dipstick); W = weight 
a See Section 7.4 for details on timing of these assessments relative to study drug administration. 
b Includes blood pressure, heart rate, respiratory rate, and temperature. 
c Includes FEV1, FVC, and FEF25-75. 
d See Appendix 2 for a detailed schedule of these assessments, broken down by type of specimen and 
time relative to dose. 
e Subjects who are taking concurrent CF therapy should receive this therapy prior to study drug dosing in 
the order specified in Section 6.3.1. 
 
 


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Table A.1-6: Multiple Ascending Dose Cohorts 5-8, Follow-Up Visits 
 
Study Procedures 
PK Follow-up 
24 Hours After 
Last Dose 
PK Follow-up 
96 Hours After 
Last Dose 
7 Days 
After Last Dose 
(End of 
Treatment) 
Follow-up 
28 Days after 
Last Dose 
(End of Study) 
Study Day 
27 ± 1 
30 ± 2 
33 
54 
In Hours Post Dose 1 
624 ± 12 
696 ± 48 
768 
1272 
Concomitant Medications 
 
 
X 
X 
Adverse Events 
 
 
X 
X 
Physical Exam 
 
 
C 
C 
Height & Weight 
 
 
W 
W 
Vital Signsa & Oximetry 
 
 
X 
X 
Spirometryb 
 
 
X 
X 
Chest Xray  
 
 
X 
 
12-lead ECG 
 
 
X 
 
CFQ-R RSSc 
 
 
X 
X 
Blood for Safety Labsd 
 
 
X 
X 
Urinalysisd 
 
 
U 
U 
Pregnancy testd,e 
 
 
X 
X 
Sputum for Microbiologyd 
 
 
X 
 
Biomarkersd 
 
 
X 
X 
Sweat Chlorided 
 
 
X 
X 
Collect Samples for PKd 
X 
X 
X 
X 
Abbreviations:  C = complete physical exam; CFQ-R RSS = Cystic Fibrosis Questionnaire-Revised Respiratory Symptom Score; 
PK = pharmacokinetic;U = urinalysis (dipstick); W = weight 
a Includes blood pressure, heart rate, respiratory rate, and temperature. 
b Includes FEV1, FVC, and FEF25-75. 
c Should be completed prior to any other procedures or assessments. 
d See Appendix 2 for a detailed schedule of these assessments, broken down by type of specimen and time relative to dose. 
e Pregnancy test (preferably serum but urine is accepted) required for women of child-bearing potential only. 
 
 


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APPENDIX 2: 
SCHEDULE OF LABORATORY TESTS 
Table A.2-1: Single Ascending Dose Cohorts 1-4 
Labs 
Screening Check-In Dose 
 
 
Discharge 
 
 
 
End of Studya 
Study Day 
≤-14 daysb 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
In Hours 
 
-24 
0 
24 
48 
72 
96 
120 
144 
168 
Hematology 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Serum Chemistry 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Hematology & Chemistry Day 1: Pre-dose, 30, 60 minutes, 2, 4, 8, 12 hours post dose 
C-Reactive Protein 
 
X 
X 
X 
 
 
 
 
 
X 
Erythrocyte Sedimentation Rate 
 
X 
X 
X 
 
 
 
 
 
X 
C-Reactive Protein & 
Erythrocyte Sedimentation Rate 
Day -1 
Day 1: Pre-dose, 24 hours post dose 
Coagulation and CH50 
X 
 
 
 
 
 
 
 
 
X 
Direct Antiglobulin Test 
X 
 
 
 
 
 
 
 
 
X 
Serum Tocopherol (Vit. E) 
X 
 
 
 
 
 
 
 
 
 
Urine microalbumin 
 
X 
 
 
 
 
 
 
 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Day 1: On pooled PK samples 
Day 2, 3, 4, 8: Random sample, preferably 1st morning void 
Drug Screen 
Xc 
 
 
 
 
 
 
 
 
 
Pregnancy testd 
X 
X 
 
 
 
 
 
 
 
X 
Sputum for Microbiology 
 
X 
 
 
 
 
 
 
 
X 
CFTR Genotypinge 
X 
 
 
 
 
 
 
 
 
 
CFTR Sequencing 
 
Xf 
 
 
 
 
 
 
 
 
Sweat Chloride 
X 
 
 
 
 
 
 
 
 
 
PK Sampling 
Serum: 0, 0.5, 1, 2, 3, 4, 12, 24, 48, 54, 72, 168 hours post dose 
Urine: Pre-dose; Pooled from 0 to 4, 4 to 12, and 12 to 24 hours post-dose; and 48, 72, and 
168 hours post dose (UA on each pooled sample).   
Sputum: 3 samples obtained within first 6 hours post dose; 24 hours post dose; Day 4 (72 
hours post dose); and Day 8 (168 hours post dose) 
Serum for PK 
 
 
X 
X 
X 
X 
 
 
 
X 
Urine for PK 
 
 
X 
X 
X 
X 
 
 
 
X 
Sputum for PK 
 
 
Xg 
X 
 
Xh 
 
 
 
Xg 


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Labs 
Screening Check-In Dose 
 
 
Discharge 
 
 
 
End of Studya 
Biomarker Sampling 
 
Blood (serum and plasma) for 
Biomarkers 
X 
Xg 
 
X 
 
X 
 
 
 
X 
Sputum for Biomarkers 
X 
Xg 
 
X 
 
X 
 
 
 
X 
a For subjects who withdraw prematurely from the study, this visit will occur whenever they leave the study. 
b  The screening period for an individual subject may be extended for an additional 7 days at the discretion of the Sponsor’s 
Medical Monitor. See Section 7.2 for details. 
c Drug screening may be performed on urine or blood sample. 
d  Women of child-bearing potential only 
e Required if original documentation for CF genotyping is not available or is earlier than the year 2000. 
f Samples may be collected on Day 1 pre-dose instead of Day -1. 
g Suggest obtaining samples in conjunction with performing spirometry at 10, 60 minutes, and 4 hours post dose. 
h Sample may be taken any time prior to discharge (Day 4) or during visit (End of Study). 
  
 
 


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Table A.2-2: Multiple Ascending Dose Cohorts 5-8, WEEK 1 
Dosing Schedule assumes Monday-Wednesday-Friday dosing: 
Study Procedures 
Screening 
 
Dose 1 
Dose 2 
 
Dose 3 
 
 
Study Day 
≤-14 daysa 
-1 
1 
3 
4 
5 
6 
7 
In Hours 
 
-24 
0 
48 
72 
96 
120 
144 
Hematology 
X 
X 
X 
X 
X 
 
 
 
Serum Chemistry 
X 
X 
X 
X 
X 
 
 
 
Hematology & Chemistry Dose 1: Pre-dose, 30, 60 minutes, 2, 4, 8, 12 hours post Dose 1 
Dose 2: 60 minutes and 4 hours post Dose 2 
C-Reactive Protein 
 
X 
X 
 
 
 
 
 
Erythrocyte Sedimentation Rate 
 
X 
X 
 
 
 
 
 
C-Reactive Protein & Erythrocyte 
Sedimentation Rate 
Day -1 
Day 1: Pre-dose 
Coagulation and CH50 
X 
 
 
 
 
 
 
 
Direct Antiglobulin Test 
X 
 
 
 
 
 
 
 
Serum Tocopherol (Vit. E) 
X 
 
 
 
 
 
 
 
Urine microalbumin 
 
X 
 
 
 
 
 
 
Urinalysis 
X 
X 
X 
X 
X 
 
 
 
Dose 1: Pre-dose, 0-4, 4-12 hours post dose (UA on each pooled sample) 
Dose 2: 60 minutes and 4 hours post dose 
Drug Screen 
Xb 
 
 
 
 
 
 
 
Pregnancy Testc 
X 
X 
 
 
 
 
 
 
Sputum for Microbiology 
 
X 
 
 
 
 
 
 
CFTR Genotypingd 
X 
 
 
 
 
 
 
 
CFTR Sequencing 
 
Xe 
 
 
 
 
 
 
Sweat Chloride 
X 
 
 
 
 
 
 
 
PK Sampling 
Serum: 0, 0.5, 1, 2, 3, 4, 12; pre-Dose 2; 2 hours post Dose 2; 72 hours post Dose 1; 96 
hours post Dose 1 (pre-Dose 3) 
Urine: Pre-dose; Pooled from 0 to 4 and 4 to 12 hours post Dose 1 (UA on each pooled 
sample).  A separate sample should be collected at 72 hours post Dose 1. 
Sputum: 3 samples obtained within first 6 hours post Dose 1 and Day 4 (72 hours) 
Serum for PK 
 
 
X 
X 
X 
X 
 
 
Urine for PK 
 
 
X 
 
X 
 
 
 
Sputum for PK 
 
 
Xf 
 
X 
 
 
 
Biomarker Sampling 
 
Blood (serum and plasma) for Biomarkers 
X 
Xe 
 
 
X 
 
 
 
Sputum for Biomarkers 
X 
Xe 
 
 
X 
 
 
 
 


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a The screening period for an individual subject may be extended for an additional 7 days at the discretion of the Sponsor’s Medical Monitor. 
See Section 7.2 for details. 
b Drug screening may be performed on urine or blood sample. 
c Women of child-bearing potential only. 
d Required if original documentation for CF genotyping is not available or is earlier than the year 2000. 
e Samples may be collected on Day 1 pre-dose instead of Day -1. Samples for CFTR sequencing should not be collected for subjects who 
participated in SAD cohort. 
f Suggest obtaining samples in conjunction with performing spirometry at 10, 60 minutes, and 4 hours post dose. 


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Table A.2-3: Multiple Ascending Dose Cohorts 5-8, WEEK 2 
 
Labs 
Dose  4 
 
Dose 5 
 
Dose 6 
 
 
Study Day 
8 
9 
10 
11 
12 
13 
14 
In Hours 
168 
192 
216 
240 
264 
288 
312 
Hematology 
X 
 
 
 
 
 
 
Serum Chemistry 
X 
 
 
 
 
 
 
Hematology & Chemistry Dose 4: Pre-dose, 15, 60 minutes, 2 hours post dose 
C-Reactive Protein 
X 
 
 
 
 
 
 
Erythrocyte Sedimentation Rate 
X 
 
 
 
 
 
 
C-Reactive Protein & 
Erythrocyte Sedimentation Rate Dose 4: Pre-dose 
Coagulation and CH50 
X 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
Dose 4: Pre-dose, 60 minutes and 2 hours post dose 
PK Sampling Serum: Prior to Dose 4, 5, and 6 
Sputum: Prior to Doses 4, 5, and 6 
Serum for PK 
X 
 
X 
 
X 
 
 
Sputum for PK 
X 
 
X 
 
X 
 
 
Biomarker Sampling Dose 4: Pre-dose 
Blood (serum and plasma) for 
Biomarkers 
X 
 
 
 
 
 
 
Sputum for Biomarkers 
X 
 
 
 
 
 
 
 
 
 
 
 
 


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Table A.2-4: Multiple Ascending Dose Cohorts 5-8, WEEK 3 
 
Study Procedures 
Dose 7 
 
Dose 8 
 
Dose 9 
 
 
Study Day 
15 
16 
17 
18 
19 
20 
21 
In Hours 
336 
360 
384 
408 
432 
456 
480 
Hematology 
X 
 
 
 
 
 
 
Serum Chemistry 
X 
 
 
 
 
 
 
Hematology & Chemistry Dose 7: Pre-dose, 15, 60 minutes, 2 hours post dose 
C-Reactive Protein 
X 
 
 
 
 
 
 
Erythrocyte Sedimentation Rate 
X 
 
 
 
 
 
 
C-Reactive Protein & Erythrocyte 
Sedimentation Rate Dose 7: Pre-dose 
Urinalysis 
X 
 
 
 
 
 
 
Dose 7: Pre-dose, 60 minutes and 2 hours post dose 
PK Sampling Serum: Prior to Dose 7, and 1 hours post Dose 7; Prior to Doses 8 and 
9 
Serum for PK 
X 
 
X 
 
X 
 
 
Biomarker Sampling Dose 7: Predose 
Blood (serum and plasma) for Biomarkers 
X 
 
 
 
 
 
 
Sputum for Biomarkers 
X 
 
 
 
 
 
 
 
 


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Table A.2-5: Multiple Ascending Dose Cohorts 5-8, WEEK 4 
 
Study Procedures 
Dose 10 
 
Dose 11 
 
Dose 12 
Study Day 
22 
23 
24 
25 
26 
In Hours 
504 
528 
552 
576 
600 
Hematology 
X 
 
 
 
 
Serum Chemistry 
X 
 
 
 
 
Hematology & Chemistry Dose 10: Pre-dose, 15, 60 minutes, 2 hours post dose 
C-Reactive Protein 
X 
 
 
 
 
Erythrocyte Sedimentation Rate 
X 
 
 
 
 
C-Reactive Protein & Erythrocyte 
Sedimentation Rate Dose 10: Pre-dose 
Urine microalbumin 
X 
 
 
 
 
Urinalysis 
X 
 
 
 
 
Dose 10: Urine microalbumin pre-dose  
Dose 10: Urinalysis pre-dose, 60 minutes and 2 hours post dose 
Sweat Chloride 
 
 
 
 
X 
PK Sampling 
Serum: Pre-Dose 10 and 11; Dose 12 (pre-dose; post dose at 1, 2, 3, 4, 8 
hours) 
Urine: Dose 12 pre-dose only 
Serum for PK 
X 
 
X 
 
X 
Urine for PK 
 
 
 
 
X 
Biomarker Sampling Dose 10: Pre-dose 
Blood (serum and plasma) for 
Biomarkers 
X 
 
 
 
 
Sputum for Biomarkers 
X 
 
 
 
 
 
 


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Table A.2-6: Multiple Ascending Dose Cohorts 5-8, Follow-up 
 
Study Procedures 
PK Follow-up 
24 hours After 
Last Dose 
PK Follow-up 
96 Hours After 
Last Dose 
7 Days 
After Last Dose 
(End of 
Treatment)a 
28 Days  
After Last Dose 
(End of Study)a 
Study Day 
27 
30 
33 
54 
In Hours Post Dose 1 
624 ± 12 
696 ± 96 
768 
1272 
Hematology 
 
 
X 
X 
Serum Chemistry 
 
 
X 
X 
C-Reactive Protein 
 
 
X 
 
Erythrocyte Sedimentation Rate 
 
 
X 
 
Coagulation and CH50 
 
 
X 
 
Direct Antibody Test 
 
 
X 
 
Urine microalbumin 
 
 
 
X 
Urinalysis 
 
 
X 
X 
Pregnancy testb 
 
 
X 
X 
Sputum for Microbiology 
 
 
X 
 
Sweat Chloride 
 
 
X 
X 
PK Sampling 
Serum post last dose: 24 ±12 hrs, 96 ± 48, hours post last dose, and at End of 
Treatment and End of Study Visit  
Urine post last dose: 24 ±12 hrs, 96 ± 48, hours post last dose 
Serum for PK 
X 
X 
X 
X 
Urine for PK 
X 
X 
 
 
Biomarker Sampling End of Treatment and End of Study Visits 
Blood (serum and plasma) for 
Biomarkers 
 
 
X 
X 
Sputum for Biomarkers 
 
 
X 
X 
a See Section 5.5.2 for details on these visits for subjects who withdraw prematurely from the study. 
b Women of child-bearing potential only 
 


 
 
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APPENDIX 3: 
ADULT CFQ-R (ENGLISH)  
 


 
 
Investigational Product: QR-010 
 
 
Protocol No. PQ-010-001 (Version 8.0) 
 
ProQR Therapeutics 
 
Page 100 of 103 
Proprietary and Confidential 
 
04 April 2017 
 


 
 
Investigational Product: QR-010 
 
 
Protocol No. PQ-010-001 (Version 8.0) 
 
ProQR Therapeutics 
 
Page 101 of 103 
Proprietary and Confidential 
 
04 April 2017 
 


 
 
Investigational Product: QR-010 
 
 
Protocol No. PQ-010-001 (Version 8.0) 
 
ProQR Therapeutics 
 
Page 102 of 103 
Proprietary and Confidential 
 
04 April 2017 
 
 


 
 
Investigational Product: QR-010 
 
 
Protocol No. PQ-010-001 (Version 8.0) 
 
ProQR Therapeutics 
 
Page 103 of 103 
Proprietary and Confidential 
 
04 April 2017 
 
 

SAP_001.pdf: 
 
 
 
Confidentiality 
This document is confidential and proprietary property of ProQR Therapeutics and to be used only as 
authorized by ProQR Therapeutics.  No part is to be reproduced, disclosed to others, or quoted without prior 
written authorization from ProQR Therapeutics 
STATISTICAL ANALYSIS PLAN 
Protocol PQ-010-001 
PHASE 1B, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, DOSE ESCALATION STUDY TO EVALUATE THE 
SAFETY, TOLERABILITY AND PHARMACOKINETICS OF QR-010 
IN SUBJECTS WITH HOMOZYGOUS ΔF508 CYSTIC FIBROSIS 
Protocol Number: 
(Version Date) 
PQ-010-001 
Version 8.0, 04 April 2017, Version 8.1, 5 April 2017, 
Version 8.2, 5 April 2017 
Name of Test Drug: 
QR-010 Solution for Nebulization 
Phase: 
1b 
Methodology: 
Randomized, double-blind, placebo-controlled, single 
ascending and multiple ascending dose-escalation study. 
This study includes two portions: four single ascending dose 
(SAD) cohorts (1-4) and four multiple ascending dose 
(MAD) cohorts (5-8) 
Sponsor: 
ProQR Therapeutics  
Zernikedreef 9 
2333 CK Leiden 
The Netherlands 
Sponsor Representative: 
Sonya Montgomery, ND 
VP Clinical Development and Study Medical Monitor 
 
 
Document Date: 
18 April 2017 
Document Version: 
Final V1.0 
 


 
SIGNATURE PAGE 
Protocol Title: 
Phase 1b, Randomized, Double-blind, Placebo-
controlled, Dose Escalation Study to Evaluate the 
Safety, Tolerability and Pharmacokinetics of QR-010 
in Subjects With Homozygous ΔF508 Cystic Fibrosis 
Sponsor: 
ProQR Therapeutics  
Zernikedreef 9 
2333 CK Leiden 
The Netherlands 
Protocol Number: 
PQ-010-001 
Document Date/Version: 
18 April 2017, V1.0 
Cytel, Inc. Author: 
Florilene Bouisset 
Director, Biostatistics 
Cytel, Inc. 
Route de Pré-Bois 20 
C.P. 1839 
1215 Geneva 15, Switzerland 
 
Signature:____________________________________ 
Date:________________________________________ 
Cytel, Inc. Author: 
Tina Checchio 
Associate Director, Quantitative 
Pharmacology & Pharmacometrics 
Cytel, Inc. 
460 Totten Pond Road, Suite 640, 
Waltham, MA 02541, USA 
 
Signature:____________________________________ 
Date:________________________________________ 
Sponsor Approval 
By signing this document, I acknowledge that I have read the document and approve of the 
planned statistical analyses described herein.  I agree that the planned statistical analyses are 
appropriate for this study, are in accordance with the study objectives, and are consistent with 
the statistical methodology described in the protocol, clinical development plan, and all 
applicable regulatory guidances and guidelines. 
I have discussed any questions I have regarding the contents of this document with the 
biostatistical author. 
I also understand that any subsequent changes to the planned statistical analyses, as described 
herein, may have a regulatory impact and/or result in timeline adjustments.  All changes to the 
planned analyses will be described in the clinical study report (CSR). 


ProQR Therapeutics 
SAP for Protocol PQ-010-001 
18 April 2017 
 
CONFIDENTIAL 
Sponsor Signatory: 
Jaakko Perquin 
Clinical Trial Manager 
ProQR Therapeutics 
Zernikedreef 9 
2333 CK Leiden 
The Netherlands 
 
 
Signature:____________________________________ 
Date:________________________________________ 
Sonya Montgomery, ND 
VP Clinical Development and Study 
Medical Monitor 
ProQR Therapeutics 
Zernikedreef 9 
2333 CK Leiden 
The Netherlands 
 
Signature:____________________________________ 
Date:________________________________________ 
Nicolas Lamontagne 
VP Program Development 
ProQR Therapeutics 
Zernikedreef 9 
2333 CK Leiden 
The Netherlands 
 
Signature:____________________________________ 
Date:________________________________________ 
 
 


ProQR Therapeutics 
SAP for Protocol PQ-010-001 
18 April 2017 
 
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4
TABLE OF CONTENTS 
Section 
Page 
1. 
INTRODUCTION AND OBJECTIVES OF ANALYSIS .......................................... 10 
1.1. 
Introduction ........................................................................................................ 10 
1.2. 
Objectives of Statistical Analysis ...................................................................... 10 
2. 
STUDY DESIGN ............................................................................................................ 11 
2.1. 
Synopsis of Study Design ................................................................................... 11 
2.2. 
Definition of Dose-Limiting Toxicity (DLT) .................................................... 12 
2.3. 
Determination of Maximum Tolerated Dose (MTD) ...................................... 12 
2.4. 
Randomization Methodology ............................................................................ 13 
2.5. 
Stopping Rules and Unblinding ........................................................................ 13 
2.5.1. 
Stopping Rules ...................................................................................... 13 
2.5.2. 
Unblinding ............................................................................................ 14 
2.6. 
Study Procedures ............................................................................................... 14 
2.7. 
Efficacy, Pharmacokinetic, and Safety Variables ........................................... 14 
2.7.1. 
Efficacy Variables................................................................................. 14 
2.7.2. 
Pharmacokinetic Variables ................................................................... 14 
2.7.3. 
Safety Variables .................................................................................... 14 
3. 
SUBJECT POPULATIONS .......................................................................................... 15 
3.1. 
Population Definitions ....................................................................................... 15 
3.1.1. 
SAD ...................................................................................................... 15 
3.1.2. 
MAD ..................................................................................................... 15 
3.2. 
Protocol Deviations ............................................................................................ 16 
4. 
STATISTICAL METHODS ......................................................................................... 17 
4.1. 
Sample Size Justification ................................................................................... 17 
4.2. 
General Statistical Methods and Data Handling ............................................ 17 
4.2.1. 
Baseline Values..................................................................................... 17 
4.2.2. 
Change (absolute) and % Change (relative change) ............................. 17 
4.2.3. 
Study Day ............................................................................................. 17 
4.2.4. 
End of Study Date ................................................................................. 17 
4.2.5. 
Table Shell ............................................................................................ 17 
4.2.6. 
Multiple Comparisons/Multiplicity ...................................................... 18 


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SAP for Protocol PQ-010-001 
18 April 2017 
 
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Section 
Page 
4.2.7. 
Visit Windows ...................................................................................... 18 
4.2.8. 
Descriptive Statistics............................................................................. 29 
4.2.9. 
Dictionaries ........................................................................................... 30 
4.2.10. 
Computing Environment....................................................................... 30 
4.3. 
Interim Analyses ................................................................................................ 30 
4.4. 
Subject Disposition............................................................................................. 30 
4.5. 
Demographic and Baseline Characteristics ..................................................... 30 
4.6. 
Medical History .................................................................................................. 31 
4.7. 
Treatment Compliance and Extent of Treatment Exposure ......................... 31 
4.8. 
Exploratory Efficacy Evaluation ...................................................................... 31 
4.8.1. 
SAD ...................................................................................................... 31 
4.8.2. 
MAD ..................................................................................................... 34 
4.9. 
Pharmacokinetic Evaluations ........................................................................... 37 
4.10. Safety Analyses ................................................................................................... 40 
4.10.1. 
Adverse Events ..................................................................................... 41 
4.10.2. 
Laboratory Data .................................................................................... 43 
4.10.3. 
Vital Signs and Oximetry ..................................................................... 46 
4.10.4. 
Physical Examinations .......................................................................... 47 
4.10.5. 
Electrocardiogram ................................................................................. 47 
4.10.6. 
Prior and Concomitant Medications ..................................................... 47 
5. 
CHANGES TO PLANNED ANALYSES .................................................................... 48 
6. 
REFERENCES ............................................................................................................... 49 
7. 
APPENDICES ................................................................................................................ 50 
Appendix 1: Schedule of Assessments ...................................................................................... 50 
Appendix 2: Schedule of Laboratory Tests ............................................................................. 58 
 
 
 
 


ProQR Therapeutics 
SAP for Protocol PQ-010-001 
18 April 2017 
 
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LIST OF IN-TEXT TABLES 
Table 
Page 
Table 1: Dose Escalation ........................................................................................................................... 12 
Table 2: Dose Escalation Rules ................................................................................................................. 13 
Table 3: Header for the SAD Cohort ......................................................................................................... 18 
Table 4: Header for the MAD Cohort ....................................................................................................... 18 
Table 5: Target Visit/Days for MAD ........................................................................................................ 19 
Table 6: Time Point for Spirometry SAD ................................................................................................. 20 
Table 7: Time point for Spirometry MAD ................................................................................................ 21 
Table 8: Time points for Hematology and Chemistry SAD ...................................................................... 22 
Table 9: Time points for Hematology and Chemistry MAD ..................................................................... 23 
Table 10: Time points for Urinalysis SAD ................................................................................................ 24 
Table 11: Time points for Urinalysis MAD .............................................................................................. 24 
Table 12: Time points for Coagulation, Direct Antiglobulin Test and Microbiology SAD ...................... 25 
Table 13: Time points for Coagulation MAD ........................................................................................... 25 
Table 14: Time points for Direct Antiglobulin Test and Microbiology MAD .......................................... 25 
Table 15: Time points for CRP and ESR SAD ......................................................................................... 25 
Table 16: Time points for CRP and ESR MAD ........................................................................................ 25 
Table 17: Time points for Sweat Chloride MAD ...................................................................................... 26 
Table 18: Time points for Vital Signs SAD .............................................................................................. 26 
Table 19: Time points for Weight SAD .................................................................................................... 26 
Table 20: Time points for Vital Signs MAD ............................................................................................. 27 
Table 21: Time points for Weight MAD ................................................................................................... 29 
Table 22: Time points for CFQ-R MAD ................................................................................................... 29 
Table 23: Time points for ECG SAD ........................................................................................................ 29 
Table 24: Time points for ECG MAD ....................................................................................................... 29 
Table 25: Set of Candidate Models for Dose-Response ............................................................................ 32 
Table 26: Planned Pharmacokinetic Parameters by Matrix and Study Day .............................................. 38 
Table 27: Microbiology Pathogen List ...................................................................................................... 44 
 
 
 
 


ProQR Therapeutics 
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18 April 2017 
 
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LIST OF IN-TEXT FIGURES 
 
Figure 
Page 
Figure 1: PQ-010-001 Study Schematic .................................................................................................... 11 
Figure 2: Candidate model for ppFEV1 dose response ............................................................................. 33 
 


ProQR Therapeutics 
SAP for Protocol PQ-010-001 
18 April 2017 
 
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ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
Ae 
Amount of QR-010 excreted unchanged in the urine 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase 
APTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Classification 
AUCinf 
Area under the concentration-time curve from time 0 extrapolated to 
infinite 
AUClast 
Area under the concentration-time curve from time 0 to the last 
quantifiable time point 
AUCtau 
Area under the concentration-time curve from time 0 to the end of the 
dosing interval tau. 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CF 
Cystic Fibrosis 
CFQ-R 
Cystic Fibrosis Questionnaire-Revised 
CFQ-R RSS 
CFQ-R Respiratory Symptoms Score 
CH50 
Total hemolytic complement 
Cl/F 
Apparent clearance 
Clr 
Renal Clearance 
Cmax 
Maximum concentration observed during a dosing interval 
CRF 
Case Report Form 
CRP 
C-Reactive Protein 
CSR 
Clinical Study Report 
Css 
Steady-State QR-010 concentration 
Ctrough 
Concentration of QR-010 observed just prior to administering a 
multiple dose 
DSMC 
Data Safety Monitoring Committee 
DLT 
Dose Limiting Toxicity 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ED50 
Median effective dose 
EOT 
End Of Treatment 
ESR 
Erythrocyte Sedimentation Rate 
FDA 
Food and Drug Administration 
fe% 
Fraction of QR-010 dose excreted unchanged in the urine 
FEF 
Forced Expiratory Flow 


ProQR Therapeutics 
SAP for Protocol PQ-010-001 
18 April 2017 
 
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Abbreviation 
Definition 
FEV1 
Forced Expiratory Volume in 1 second 
FVC 
Forced Vital Capacity 
GGT 
Gamma-Glutamyl Transferase 
HGB 
Hemoglobin 
hr 
hour 
ICH 
International Conference on Harmonisation 
INR 
International Normalized Ratio 
IWRS 
Interactive Web Response System 
Lambda z (z) 
Terminal elimination rate constant 
lb 
pound 
LDH 
Lactacte Dehydrogenase 
MAD 
Multiple Ascending Doses 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCPMOD 
Multiple Comparison Procedure Modelling 
mmol/L 
Millimole per Liter 
MTD 
Maximal Tolerated Dose 
PK 
Pharmacokinetic 
ppFEV1 
Percent Predicted Forced Expiratory Volume in 1 second 
PT 
Prothrombin Time / Preferred Term 
Ro 
Accumulation ratio based on total systemic exposure 
Ro,Cmax 
Accumulation ratio based on maximal systemic exposure 
SAD 
Single Ascending Dose 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
Tmax 
Time of maximum concentration observed during a dosing interval 
T1/2 
Elimination half-life 
V/F 
Apparent volume of distribution 
WHO 
World Health Organization  
 
 
 
 
 


ProQR Therapeutics 
SAP for Protocol PQ-010-001 
18 April 2017 
 
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1. 
INTRODUCTION AND OBJECTIVES OF ANALYSIS 
1.1. 
Introduction 
The study is a multicenter, randomized, double-blind, and placebo-controlled Phase 1b single 
ascending dose-escalation (SAD) followed by a multiple ascending dose-escalation (MAD). 
Eligible subjects with homozygous ΔF508 Cystic Fibrosis (CF) were to be randomized at a 3:1 
ratio to receive either QR-010 or placebo vial oral inhalation (nebulization).  
The study includes 2 parts. The first stage is a single ascending dose-escalation (SAD) design to 
determine safety and tolerability of a single dose of QR-010. The second stage is a multiple 
ascending dose escalation (MAD) design to further assess the safety, tolerability, and 
exploratory efficacy of 12 doses of QR-010 over 4 weeks.  
This study comprises intermediate analyses reviewed by an independent Data Safety Monitoring 
Committee (DSMC). The DSMC provides recommendation for dose escalation. 
This document refers to Protocol No. PQ-010-001 version 8.0, 04 April 2017, version 8.1, 5 
April 2017, version 8.2, 5 April 2017, to the DSMC Charter version 4.0, 2 August 2016, to the 
Data Management Plan version 2.0, 28 February 2017, to the Protocol Deviation Plan version 
1.0 dated 26 September 2016 and the eCRF dated 17 March 2017. 
1.2. 
Objectives of Statistical Analysis 
This statistical analysis plan (SAP) is designed to outline the methods to be used in the SAD and 
MAD final analysis of study data in order to answer the study objective(s) of the entire study. 
Populations for analysis, data handling rules, statistical methods, and formats for data 
presentation are provided. The statistical analyses and summary tabulations described in this 
SAP will provide the basis for the results sections of the clinical study report (CSR) for this 
trial. 
The SAP is prepared in compliance with ICH E9. 


ProQR Therapeutics 
SAP for Protocol PQ-010-001 
18 April 2017 
 
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2. 
STUDY DESIGN 
2.1. 
Synopsis of Study Design 
This is a randomized, double-blind (investigator and subject), placebo-controlled, single 
ascending and multiple ascending dose-escalation study to evaluate the safety, tolerability and 
pharmacokinetics and pharmacodynamics of QR-010 in subjects with CF who are homozygous 
for the ΔF508 mutation. Immunogenicity is to be evaluated amongst other safety considerations. 
Exploratory clinical efficacy measures are also included. There are two parts to the Phase 1b 
study: the study will start with four single ascending dose (SAD) cohorts and will move through 
four multiple ascending dose (MAD) cohorts. 
SAD (Cohorts 1-4): single dose inhaled administration. The doses for SAD cohorts are Placebo 
(0 mg), QR-010 6.25, 12.5, 25, or 50 mg. Subjects will receive the dose will be observed for a 
total 4 days, and will be discharged on Day 4. Subjects will return for PK and safety follow-up 
as an outpatient on Day 8. 
MAD (Cohorts 5-8): multiple dose inhaled administration. The doses for the MAD cohorts are 
Placebo (0 mg), QR-010 6.25, 12.5, 25, or 50 mg, thrice weekly for 4 weeks, for a total of 12 
doses per subject. Subjects are followed weekly with end of treatment (EoT) visit to be 
performed 7 days after last dose and a safety follow-up visit to be performed 28 days after last 
dose.  
An independent Data Safety Monitoring Committee (DSMC) was designated to review all 
safety data at the end of each cohort and to determine the maximum tolerated dose (MTD). 
A schematic of the study design is presented in Figure 1. 
Figure 1: PQ-010-001 Study Schematic 
 
The dose delivered to subjects via the eFlow device is < 80% of the fill dose, hence the 
delivered doses that correspond to the dose escalation schemes are shown in Table 1. 


ProQR Therapeutics 
SAP for Protocol PQ-010-001 
18 April 2017 
 
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Table 1: Dose Escalation 
Dose Cohort 
Fill Dose (mg) 
Estimated Exposure Dose 
< 80% of Fill Dose (mg) 
Single Dose Cohorts 
1 
6.25 
5 
2 
12.5 
10 
3 
25 
20 
4 
50 
40 
Multiple Dose Cohorts (administered tiw for 4 Weeks) 
5 
6.25 
5 
6 
12.5 
10 
7 
25 
20 
8 
50 
40 
tiw = thrice weekly (three times per week) 
 
2.2. Definition of Dose-Limiting Toxicity (DLT) 
A Dose-limiting Toxicity (DLT) is defined as follows: 
 Allergic reaction requiring medical intervention 
 Acute bronchospasm requiring medical intervention 
 Other acute AEs of interest requiring immediate medical intervention 
Allergic reactions and acute bronchospasm not requiring intervention (Grade 1) are usually 
considered subject-specific and are not included in the definition of DLT. In this protocol, 
allergic reactions and acute bronchospasm not requiring medical intervention are not included in 
the DLT definition since such reactions may not be product and dose-specific with QR-010. 
2.3. Determination of Maximum Tolerated Dose (MTD) 
The MTD is defined as one dose level below the dose level at which 2 or more subjects 
receiving QR-010 experience a dose limiting toxicity (DLT) in the same organ class for dose 
cohorts 1-4 or within the first 4 weeks for dose cohorts 5-8. Dose escalation will occur based on 
the number of DLTs encountered according to the rules in Table 3, as assessed by the DSMC. 
Dose escalation will continue until the MTD is reached or the maximum dose included in the 
study, whichever is lower. With the highest planned fill dose of 50 mg, subject exposure will be 
approximately < 40 mg (< 80% efficiency of the eFlow including residual volume). For the 
MTD determination, the fill dose will be used. 


ProQR Therapeutics 
SAP for Protocol PQ-010-001 
18 April 2017 
 
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13 
Table 2: Dose Escalation Rules 
Number of Subjects Receiving 
QR-010 With a DLT at a  
Given Dose  
Dose-Escalation Decision Rule 
0 of 6 
Proceed to next dose level 
1 of 6 
If one serious AE (SAE) or Grade ≥ 2 AE occurs, four additional subjects will 
be enrolled at the same dose. If no additional subjects experience a similar 
SAE or Grade ≥ 2 AE in the same organ class, the dose escalation may 
continue pending review of safety by the DSMC. 
If  2 subjects experience similar SAE or Grade ≥ 2 AE of the same organ 
class, dose escalation is to be stopped, pending review by the DSMC. The 
preceding dose may be considered the MTD by the DSMC. 
  2 of 6 
Dose escalation will be stopped. 
The preceding dose will be considered the MTD. 
DLT = dose-limiting toxicity; MTD = maximum tolerated dose (one dose level lower than the dose level at which 2 
or more subjects experience a DLT of the same organ class)  
 
2.4. 
Randomization Methodology 
Within each dosing cohort, subjects will be randomized 3:1, QR-010 to placebo.  
The randomization is performed using a centralized interactive web response system (IWRS).  
Study drug will be administered in a double-blind fashion. Study drug and placebo are both 
clear, colorless, and odorless aqueous solutions. Subjects, Investigators and study site staff will 
be blinded to treatment assignment. However, due to the requirement for study pharmacist(s) to 
prepare the various study drug dilutions depending on the dosing cohort to which a given study 
subject is assigned, the study pharmacist(s) will be unblinded to treatment assignment. 
2.5. 
Stopping Rules and Unblinding 
2.5.1. 
Stopping Rules 
At subject level: Subjects may withdraw from the study at any time without repercussion to their 
treatment or affiliation with their healthcare providers. Investigator can decide at any time 
during the study to discontinue treatment for an individual subject based on her/his own medical 
judgment. Reasons for stopping should be documented in the CRF (End of Treatment Visit), 
and subjects will be encouraged to participate to the follow-up period (End of Study Visit) for 
safety monitoring purposes.  
At study level: The DSMC will evaluate the safety data after each dose cohort 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. Refer to protocol and DSMC charter 
for description of the DLT/MTD criteria. 
Subjects participating in a MAD cohort that is determined to be greater than the MTD based on 
dose escalation rules can opt to continue in the study at the next lower dose cohort (i.e., at the 
MTD). 


ProQR Therapeutics 
SAP for Protocol PQ-010-001 
18 April 2017 
 
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14 
2.5.2. 
Unblinding 
The DSMC is unblinded to the Study Treatment. Safety data from each cohort will be provided 
unblinded and evaluated by the DSMC at the end of each cohort, prior to escalation to the next 
dosing level. Additionally if AEs of interest occur at a Grade 2 level or higher, as defined in the 
protocol, they will be provided to the DSMC for evaluation in a timely fashion (i.e., without 
waiting for completion of the cohort) to support dose escalation decisions and determination of 
dose limiting toxicity events.  
Sponsor personnel may be unblinded to subject treatments in order to permit interpretation of 
the safety, pharmacokinetic, and pharmacodynamic data. The site monitor will remain blinded 
to individual subject treatment allocation until all monitoring of study data has been completed. 
To minimize the potential for bias, individual subject treatment randomization information will 
not be released to the investigator or blinded study site personnel until the study database has 
been locked. 
In the event of a medical emergency, when knowledge of treatment assignment is needed for 
immediate medical management of the subject’s health, Investigators can obtain unblinded 
treatment assignment through the centralized IWRS system at any time. Thorough 
documentation of the rationale for unblinding is required. Consultation of the study Medical 
Monitor is recommended for all unblinding requests. 
2.6. 
Study Procedures 
All tests and procedures are detailed in Appendix 1, Schedule of Assessments. All laboratory 
tests are detailed in Appendix 2, Schedule of Laboratory Assessments. Refer to these appendices 
for the required assessments for each study day.  
2.7. 
Efficacy, Pharmacokinetic, and Safety Variables 
2.7.1. 
Efficacy Variables 
Please refer to section 4.6 
2.7.2. 
Pharmacokinetic Variables 
Please refer to section 4.7 
2.7.3. 
Safety Variables 
Please refer to section 4.8 


ProQR Therapeutics 
SAP for Protocol PQ-010-001 
18 April 2017 
 
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3. 
SUBJECT POPULATIONS 
3.1. 
Population Definitions 
The following subject populations will be evaluated and used for data presentation. Safety 
analyses will be conducted based on the safety population. Exploratory efficacy analyses will be 
conducted based on the Exploratory Analysis Population.  
3.1.1. 
SAD 
Screened: All subjects with an informed consent date will be part of this population. 
Safety Population: the population for safety analysis will consist of all subjects who receive any 
QR-010 or placebo. 
Subjects will be analysed according to the actual treatment received (this is checked versus kit 
numbers, which may be different to randomization received). 
Exploratory Analysis Population: the population for efficacy (clinical activity) analysis will 
consist of all subjects randomized who receive at least one dose of QR-010 or placebo. 
Subjects will be analysed according to the actual treatment received. Applying this criterion is 
consistent with the objective of exploratory of clinical efficacy in this relatively small sample 
size phase 1 safety and tolerability study. 
Pharmacokinetics (PK) Population: the population for PK analyses will consist of all subjects 
who receive at least one dose of QR-010 and who have sufficient drug concentrations to support 
analysis. 
3.1.2. 
MAD  
Screened: All subjects with an informed consent date will be part of this population. 
Randomized: All subjects with a randomization date. 
Safety Population: the population for safety analysis will consist of all subjects who receive any 
QR-010 or placebo. 
Subjects will be analysed according to the actual treatment received (this is checked versus kit 
numbers, which may be different to randomization received). 
Exploratory Analysis Population: the population for efficacy (clinical activity) analysis will 
consist of all subjects randomized who receive at least one dose of QR-010 or placebo. 
Subjects will be analysed according to the actual treatment received. Applying this criterion is 
consistent with the objective of exploratory of clinical efficacy in this relatively small sample 
size phase 1 safety and tolerability study. 
Pharmacokinetics (PK) Population: the population for PK analyses will consist of all subjects 
who receive at least one dose of QR-010 and who have sufficient drug concentrations to support 
analysis.  For subjects in whom dosing was discontinued early, pharmacokinetic parameters for 
week 4, dose 12 will not be generated, but all available PK concentrations in serum, urine and 
sputum will be listed regardless of time of last dose; however PK parameters will be generated 
on all other days where study dose was administered as per protocol. 
 


ProQR Therapeutics 
SAP for Protocol PQ-010-001 
18 April 2017 
 
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3.2. 
Protocol Deviations 
Protocol deviations are defined as a deviation from the approved protocol. 
Prior to database lock, ProQR’s Medical Monitor will review the study’s protocol deviation list 
and will define/document which subjects/deviations are considered minor/major protocol 
deviations. 
Protocol deviations will be summarized by characteristics (Minor/Major), category and reason.  
All protocol deviations will be presented in data listings. 
 


ProQR Therapeutics 
SAP for Protocol PQ-010-001 
18 April 2017 
 
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17 
4. 
STATISTICAL METHODS 
4.1. 
Sample Size Justification 
This is a Phase 1 safety study designed to evaluate the safety, tolerability and PK of QR-010. 
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. 
Approximately 64 subjects will be enrolled in the study, with 8 subjects per cohort (6 QR-010 
and 2 placebo), 32 each in the SAD and MAD portions of the study. The exact number of 
subjects enrolled is dependent on whether any dose levels are to be expanded due to the 
occurrence of AEs of interest. 
4.2. 
General Statistical Methods and Data Handling 
4.2.1. Baseline Values  
Unless otherwise specified, baseline data is defined as the data most recently collected prior to 
the first dose. 
For Sweat Chloride, baseline is the average of all assessments of the day the closest to first dose, 
first dose day after dose time excluded. 
4.2.2. Change (absolute) and % Change (relative change) 
Change and % change (relative) from baseline is calculated as: 
Change = Post baseline visit value – baseline value. 
% Change = 100*((Post baseline visit value – baseline value)/baseline value). 
If either the baseline or visit value is missing, the change from baseline/% change is set to 
“missing”. 
4.2.3. Study Day 
Study Day is the number of days since the administration of the first dose of study drug, which 
is counted as Study Day 1. If the assessment date is after the date of the first dose, the study day 
is calculated as (date of assessment - date of the first dose administration + 1). If the assessment 
date is prior to the date of the first dose, the study day is calculated as (date of assessment - date 
of the first dose administration). All assessments prior to Study Day 1, including the Screening 
and Check-In visits, will have negative study days. 
4.2.4. End of Study Date 
End of study date is defined as the date when a subject completes the study (all doses given and 
all visits completed) or withdraws from the study early, it is computed as the maximum date for 
a subject-visit taken from any database panel. 
4.2.5. Table Shell 
Separate outputs will be produced for the SAD cohorts and the MAD cohorts. In general, the 
total group will be presented for disposition, baseline information, and treatment exposure, 
unless otherwise specified. 
 


ProQR Therapeutics 
SAP for Protocol PQ-010-001 
18 April 2017 
 
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Table 3: Header for the SAD Cohort 
 
Placebo 
QR-010 
6.25 mg 
QR-010 
12.5 mg 
QR-010 
25 mg 
QR-010 
50 mg 
Total SAD 
(optional) 
Screened 
… 
… 
… 
… 
… 
… 
  Screen failure 
 
 
 
 
 
 
Treated 
 
 
 
 
 
 
Exploratory Analysis 
Population 
 
 
 
 
 
 
Safety Population 
 
 
 
 
 
 
Xxx 
 
Table 4: Header for the MAD Cohort 
 
Placebo 
QR-010 
6.25 mg 
QR-010 
12.5 mg 
QR-010 
25 mg 
QR-010 
50 mg 
Total MAD 
(optional) 
Screened 
… 
… 
… 
… 
… 
… 
  Screen failure 
 
 
 
 
 
 
Treated 
 
 
 
 
 
 
Exploratory Analysis 
Population 
 
 
 
 
 
 
Safety Population 
 
 
 
 
 
 
xxx 
 
4.2.6. Multiple Comparisons/Multiplicity 
Due to the exploratory nature of the study, all tests for exploratory efficacy are conducted at 
alpha level 5%, two-sided (or 2.5% one-sided), and there will be no adjustment for multiplicity. 
4.2.7. Visit Windows 
4.2.7.1. 
General Rules 
Definition of target visit dates for SAD: 
Day 1 is defined as the date of first (and unique) dose. Day 2,3,4,8 are defined relatively to Day 
1 (Ex: Day 4=Day 1+3). 
 
Definition of target dose visits dates for MAD: 
When possible, visits windows are defined with the doses dates. 
 If a subject receives all 12 doses: target dates/times are the doses dates/times 
 If a subject receives less than 12 doses: use the table below for definition of expected 
dates.  
o If there is a dose in the window EXPDATE +/-1 days then target visit date=this 
particular dose date.  
o If there is no dose in the window EXPDATE +/-1 days then the subject has 
missed the dose at the visit or missed the visit,  
o Then EXPDATE will be taken as the target visit date, with time 00:00.  


ProQR Therapeutics 
SAP for Protocol PQ-010-001 
18 April 2017 
 
CONFIDENTIAL 
19 
 
Table 5: Target Visit/Days for MAD 
Dose (Visit) 
Expected date EXPDATE 
(Dose n-1 date + expected number of days) 
Target Dose Visit Date 
Dose 1 (Day 1) 
Day 1 
Dose 1 date 
Dose 2 (Day 3) 
Dose 1 date + 2 days (i.e. 3-1), time 00:00 
 
If any dose within expected date 
+/-1 days then = this dose date,  
 
else = expected date (i.e. = Dose 
1 date + 2 days) 
Day 4  
Day 3 Target date+1 day 
Day 3 Target date+1 day 
Dose 3 (Day 5) 
Day 3 Target date + 2 days  (5-3), time 00:00 
 
If any dose within expected 
date+/-1 days then = this dose 
date,  
 
else = expected date (i.e. Day 3 
Target Date + 2 days) 
Dose 4 (Day 8) 
Day 5 Target date + 3 days  (8-5), time 00:00 
“ 
Dose 5 (Day 10) 
Day 8 Target date + 2 days, time 00:00 
“ 
Dose 6 (Day 12) 
Day 10 Target date + 2 days, time 00:00 
“ 
Dose 7 (Day 15) 
Day 12 Target date + 3 days, time 00:00 
“ 
Dose 8 (Day 17) 
Day 15 Target date + 2 days, time 00:00 
“ 
Dose 9 (Day 19) 
Day 17 Target date + 2 days, time 00:00 
“ 
Dose 10 (Day 22) 
Day 19 Target date + 3 days, time 00:00 
“ 
Dose 11 (Day 24) 
Day 22 Target date + 2 days, time 00:00 
“ 
Dose 12 (Day 26) 
Day 24 Target date + 2 days, time 00:00 
“ 
Day 33 
Day 26 Target date + 7 days 
Day 26 Target date + 7 
Day 54 
Day 26 Target date + 28 days 
Day 26 Target date + 28 
 
For time points with time precision relative to dose (i.e. “Dose time+ XX min”), the time is 
computed with respect to the end time of dosing (end of inhalation). 
 


ProQR Therapeutics 
SAP for Protocol PQ-010-001 
18 April 2017 
 
CONFIDENTIAL 
20 
4.2.7.2. 
Spirometry 
Table 6: Time Point for Spirometry SAD 
Time point 
Target 
Interval for Analysis 
Baseline 
Pre-dose Day 1 
Most recent value prior to first dose 
Day 1 10 min Post-dose 
Day 1 dose end time+10 
min 
]Day 1 dose end time, Day 1 dose end time+20 min] 
Day 1 30 min Post-dose 
Day 1 dose end time+30 
min 
]Day 1 dose end time+20min, Day 1 dose end 
time+45 min] 
Day 1 60 min Post-dose 
Day 1 dose end time+60 
min 
]Day 1 dose end time+45min, Day 1 dose end 
time+90 min] 
Day 1 2 hr Post-dose 
Day 1 dose end time+2 
hours 
]Day 1 dose end time+90min, Day 1 dose end 
time+3h] 
Day 1 4 hr Post-dose 
Day 1 dose end time+4 
hours 
]Day 1 dose end time+3h, Day 1 dose end time+6h] 
Day 1 8 hr Post-dose 
Day 1 dose end time+8 
hours 
]Day 1 dose end time+6h, Day 2[ 
Day 2 
Day 2 
[Day 2, Day 4[ 
Day 4 
Day 4 
[Day 4, Day 7[ 
Day 8 
Day 8 
[Day 7, End of Study] 
 
 
 
 


ProQR Therapeutics 
SAP for Protocol PQ-010-001 
18 April 2017 
 
CONFIDENTIAL 
21 
Table 7: Time point for Spirometry MAD 
Time point 
Target Date/Time  
Interval for Analysis 
Baseline 
Day 1 dose start time 
Most recent value prior to first dose 
Day 1 10 min Post-dose 
Day 1 dose end time+10 
min 
]Day 1 dose end time, Day 1 dose end time 
+20min] 
Day 1 30 min Post-dose 
Day 1 dose end time+30 
min 
]Day 1 dose end time+20min, Day 1 dose end time 
+45min] 
Day 1 60 min Post-dose 
Day 1 dose end time+60 
min 
]Day 1 dose end time+45min, Day 1 dose end time 
+90min] 
Day 1 2 hr Post-dose 
Day 1 dose end time+2 
hours 
]Day 1 dose end time+90min, Day 1 dose end time 
+3h] 
Day 1 4 hr Post-dose 
Day 1 dose end time+4 
hours 
]Day 1 dose end time+3h, Day 1 dose end time 
+6h] 
Day 1 8 hr Post-dose 
Day 1 dose end time+8 
hours 
]Day 1 Dose end time+6h, Day 2[ 
Day 3 Pre-dose 
Day 3 dose start time 
[Day 2, Day 3 dose start time[ 
Day 3 20 min Post-dose 
Day 3 dose end time +20 
min 
]Day 3 dose end time, Day 3 dose end time 
+40min] 
Day 3 60 min Post-dose 
Day 3 dose end time +60 
min 
]Day 3 dose end time+40min, Day 3 dose end time 
+2h] 
Day 3 4 hr Post-dose 
Day 3 dose end time+4 
hours 
]Day 3 dose end time+2h, Day 4[ 
Day 4  
Day 4 
]Day 3, Day 5[ 
Day 5 Pre-dose 
Day 5 dose start time 
[Day 5, Day 5 dose start time[ 
Day 5 20 min Post-dose 
Day 5 dose end time +20 
min 
]Day 5 dose end time, Day 5 dose end time 
+40min] 
Day 5 60 min Post-dose 
Day 5 dose end time +60 
min 
]Day 5 dose end time+40min, Day 6] 
Day 8 Pre-dose 
Day 8 dose end time 
[Day 7, Day 8 dose end time[ 
Day 8 20 min Post-dose 
Day 8 dose end time +20 
min 
]Day 8 dose end time, Day 8 dose end time 
+40min] 
Day 8 60 min Post-dose 
Day 8 dose end time +60 
min 
]Day 8 dose end time+40min, Day 10] 
Day 15 Pre-dose 
Day 15 dose start time 
]Day 10, Day 15 dose start time[ 
Day 15 20 min Post-dose 
Day 15 dose end time +20 
min 
]Day 15 dose end time, Day 15 dose end time 
+40min] 
Day 15 60 min Post-dose 
Day 15 dose end time +60 
min 
]Day 15 dose end time+40min, Day 17] 
Day 22 Pre-dose 
Day 22 dose start time 
]Day 17, Day 22 dose start time[ 
Day 22 20 min Post-dose 
Day 22 dose end time +20 
min 
]Day 22 dose end time, Day 22 dose end time 
+40min] 
Day 22 60 min Post-dose 
Day 22 dose end time +60 
min 
]Day 22 dose end time+40min, Day 24 ] 
Day 26 Pre-dose 
Day 26 dose start time 
]Day 24, Day 26 dose start time[ 
Day 26 20 min Post-dose 
Day 26 dose end time +20 
min 
]Day 26 dose end time, Day 26 dose end time 
+40min] 
Day 26 60 min Post-dose 
Day 26 dose end time +60 
min 
]Day 26 dose end time+40min, Day 26 +3 days ] 


ProQR Therapeutics 
SAP for Protocol PQ-010-001 
18 April 2017 
 
CONFIDENTIAL 
22 
Day 33  
Day 33  
[Day 26+4 ; Day 33+7] 
Day 54 
Day 54 
[Day 33+8 ; End of Study] 
 
 
4.2.7.3. 
Laboratory Tests 
Table 8: Time points for Hematology and Chemistry SAD 
Time point 
Target 
Interval for Analysis 
Baseline 
Day 1 dose start time 
Most recent value prior to first dose 
Day 1 30 min Post-dose 
Day 1 dose end time+30 min 
]Day 1 dose end time, Day 1 dose end time +45 
min] 
Day 1 60 min Post-dose 
Day 1 dose end time+60 min 
]Day 1 dose end time+45min, Day 1 dose end 
time+90min] 
Day 1 2 hr Post-dose 
Day 1 dose end time+2 hours 
]Day 1 dose end time+90min,Day 1 dose end 
time+3h] 
Day 1 4 hr Post-dose 
Day 1 dose end time+4 hours 
]Day 1 dose end time+3h, Day 1 dose end time+6h] 
Day 1 8 hr Post-dose 
Day 1 dose end time+8 hours 
]Day 1 dose end time+6h,Day 1 dose end time+10h] 
Day 1 12 hr Post-dose 
Day 1 dose end time+12 
hours 
]Day 1 dose end time+10h, Day 2[ 
Day 2 
Day 2 
[Day 2, Day 3[ 
Day 3 
Day 3 
[Day 3, Day 4[ 
Day 4 
Day 4 
[Day 4, Day 7[ 
Day 8  
Day 8 
[Day 7, End of study] 
 
 
 


ProQR Therapeutics 
SAP for Protocol PQ-010-001 
18 April 2017 
 
CONFIDENTIAL 
23 
Table 9: Time points for Hematology and Chemistry MAD 
Time point 
Target 
Interval for Analysis 
Baseline 
Day 1 dose start time 
Most recent value prior to first dose 
Day 1 30 min Post-dose 
Day 1 dose end time+30 min 
]Day 1 dose end time, Day 1 dose end time +45 
min] 
Day 1 60 min Post-dose 
Day 1 dose end time+60 min 
]Day 1 dose end time+45min, Day 1 dose end 
time+90min] 
Day 1 2h Post-dose 
Day 1 dose end time+2 hours 
]Day 1 dose end time+90min,Day 1 dose end 
time+3h] 
Day 1 4h Post-dose 
Day 1 dose end time+4 hours 
]Day 1 dose end time+3h, Day 1 dose end 
time+6h] 
Day 1 8h Post-dose 
Day 1 dose end time+8 hours 
]Day 1 dose end time+6h, Day 1 dose end 
time+10h] 
Day 1 12h Post-dose 
Day 1 dose end time+12 hours 
]Day 1 dose end time+10h, Day 3 dose end time] 
Day 3 60min Post-dose 
Day 3 dose end time+60min 
]Day 3 dose end time, Day 3 dose end 
time+180min] 
Day 3 4h Post-dose 
Day 3 dose end time+4hours 
]Day 3 dose end time+180min, Day 4[ 
Day 4 
Day 4 
[Day 4, Day 6] 
Day 8  Pre-dose 
Day 8 dose start time 
[Day 7, Day 8 dose start time[ 
Day 8  15min Post-dose 
Day 8 dose end time+15min 
]Day 8 dose end time, Day 8 dose end time+30 
min] 
Day 8  60min Post-dose 
Day 8 dose end time+60min 
]Day 8 dose end time+30min, Day 8 dose end 
time+90min]  
Day 8  2h Post-dose 
Day 8 dose end time+2h 
]Day 8 dose end time+90min, Day 10] 
Day 15  Pre-dose 
Day 15 dose start time 
]Day 10, Day 15 dose start time[ 
Day 15  15min Post-dose 
Day 15 dose end time+15min 
]Day 15 dose end time, Day 15 dose end time+30 
min] 
Day 15  60min Post-dose 
Day 15 dose end time+60min 
]Day 15 dose end time+30min, Day 15 dose end 
time+90min]  
Day 15  2h Post-dose 
Day 15 dose end time+2h 
]Day 15 dose end time+90min, Day 17] 
Day 22  Pre-dose 
Day 22 dose start time 
]Day 17, Day 22 dose start time[ 
Day 22 15min Post-dose 
Day 22 dose end time+15min 
]Day 22 dose end time, Day 22 dose end time+30 
min] 
Day 22  60min Post-dose 
Day 22 dose end time+60min 
]Day 22 dose end time+30min, Day 22 dose end 
time+90min]  
Day 22 2h Post-dose 
Day 22 dose end time+2h 
]Day 22 dose end time+90min, Day 26] 
Day 33 
Day 33 
]Day 26 ; Day 33+7] 
Day 54 
Day 54 
]Day 33+7 ; End of Study] 
 
 
 


ProQR Therapeutics 
SAP for Protocol PQ-010-001 
18 April 2017 
 
CONFIDENTIAL 
24 
Table 10: Time points for Urinalysis SAD 
Time point 
Target 
Interval for Analysis 
Baseline 
Day 1 dose start time 
Most recent value prior to first dose 
Day 2 
Day 2 
]Day 1 dose time, Day 3[ 
Day 3 
Day 3 
[Day 3, Day 4[ 
Day 4 
Day 4 
[Day 4, Day 7[ 
Day 8  
Day 8 
[Day 7, End of study] 
 
Table 11: Time points for Urinalysis MAD 
Time point 
Target 
Interval for Analysis 
Baseline 
Day 1 dose start time 
Most recent value prior to first dose 
Day 3 60min Post-dose 
Day 3 dose end time+60min 
]Day 1 dose end time, Day 3 dose end 
time+180min] 
Day 3 4h Post-dose 
Day 3 dose end time+4hours 
]Day 3 dose end time+180min, Day 4[ 
Day 4 
Day 4 
[Day 4, Day 6] 
Day 8  Pre-dose 
Day 8 dose start time 
[Day 7, Day 8 dose start time[ 
Day 8  60min Post-dose 
Day 8 dose end time+60min 
]Day 8 dose end time, Day 8 dose end 
time+90min]  
Day 8  2h Post-dose 
Day 8 dose end time+2h 
]Day 8 dose end time+90min, Day 10] 
Day 15  Pre-dose 
Day 15 dose start time 
]Day 10, Day 15 dose start time[ 
Day 15  60min Post-dose 
Day 15 dose end time+60min 
]Day 15 dose end time, Day 15 dose end 
time+90min]  
Day 15  2h Post-dose 
Day 15 dose end time+2h 
]Day 15 dose end time+90min, Day 17] 
Day 22 Pre-dose 
Day 22 dose start time 
]Day 17, Day 22 dose start time[ 
Day 22 60min Post-dose 
Day 22 dose end time+60min 
]Day 22 dose end time, Day 22 dose end 
time+90min]  
Day 22 2h Post-dose 
Day 22 dose end time+2h 
]Day 22 dose end time+90min, Day 26] 
Day 33 
Day 33 
]Day 26 ; Day 33+7] 
Day 54 
Day 54 
]Day 33+7 ; End of Study] 
 
 


ProQR Therapeutics 
SAP for Protocol PQ-010-001 
18 April 2017 
 
CONFIDENTIAL 
25 
Table 12: Time points for Coagulation, Direct Antiglobulin Test and Microbiology SAD 
Time point 
Target 
Interval for Analysis 
Baseline 
Day 1 dose start time 
Most recent value prior to first dose 
Day 8  
Day 8 
]Day 1 dose end time, End of study] 
 
Table 13: Time points for Coagulation MAD 
Time point 
Target 
Interval for Analysis 
Baseline 
Day 1 dose start time 
Most recent value prior to first dose 
Day 8 Pre-dose 
Day 8 dose start time 
]Day 1 dose end time, Day 8 dose start time[ 
Day 33 
Day 33 
[Day 8 dose end time, End of Study] 
 
Table 14: Time points for Direct Antiglobulin Test and Microbiology MAD 
Time point 
Target 
Interval for Analysis 
Baseline 
Day 1 dose start time 
Most recent value prior to first dose 
Day 33 
Day 33 
]Day 1 dose end time, End of Study] 
 
Table 15: Time points for CRP and ESR SAD 
Time point 
Target 
Interval for Analysis 
Baseline 
Day 1 dose start time 
Most recent value prior to first dose 
Day 2 
Day 2 
[Day 2, Day 3[ 
Day 8 
Day 8 
[Day 3, End of Study] 
 
Table 16: Time points for CRP and ESR MAD 
Time point 
Target 
Interval for Analysis 
Baseline 
Day 1 dose start time 
Most recent value prior to first dose 
Day 15 Pre-dose 
Day 15 dose start time 
[Day 1 dose end time, Day 15 dose start time[ 
Day 22 Pre-dose 
Day 22 dose start time 
[Day 15 dose end time, Day 22 dose start time[ 
Day 33 
 
[Day 22 dose end time, End of Study] 
 
 
 


ProQR Therapeutics 
SAP for Protocol PQ-010-001 
18 April 2017 
 
CONFIDENTIAL 
26 
4.2.7.4. 
Sweat Chloride 
Table 17: Time points for Sweat Chloride MAD 
Time point 
Target 
Interval for Analysis 
Baseline 
Day 1 dose start time 
Most recent value prior to first dose 
Day 26  
Day 26 
[Day 1 dose end time, Day 26+3 days] 
Day 33  
Day 33 
[Day 26+4 days ; Day 33+ 7 days] 
Day 54 
Day 54 
[Day 33+8 days ; End of Study] 
If several assessments are done on the same day, the average of these assessments will be used. 
4.2.7.5. 
Vital Signs and Weight 
Table 18: Time points for Vital Signs SAD 
Time point 
Target 
Interval for Analysis 
Baseline 
Day 1 dose start time 
Most recent value prior to first dose 
Day 1 1min Post-dose 
Day 1 dose end time+1min 
]Day 1 dose end time, Day 1 dose end 
time+5min] 
Day 1 10 min Post-dose 
Day 1 dose end time+10min 
]Day 1 dose end time+5min, Day 1 dose end 
time+20min] 
Day 1 30min Post-dose 
Day 1 dose end time+30min 
]Day 1 dose end time+20min, Day 1 dose end 
time+45min] 
Day 1 60min Post-dose 
Day 1 dose end time+60min 
]Day 1 dose end time+45min, Day 1 dose end 
time+90min] 
Day 1 2hrs Post-dose 
Day 1 dose end time+2h 
]Day 1 dose end time+90min, Day 1 dose end 
time+3h] 
Day 1 4hrs Post-dose 
Day 1 dose end time+4h 
]Day 1 dose end time+3h, Day 1 dose end 
time+8h] 
Day 1 12hrs Post-dose 
Day 1 dose end time+12h 
]Day 1 dose end time+8h, Day 2[ 
Day 2 
Day 2 
[Day 2, Day 3[ 
Day 3 
Day 3 
[Day 3, Day 4[ 
Day 4 
Day 4 
[Day 4, Day 7[ 
Day 8 
Day 8 
[Day 7, End of Study] 
 
Table 19: Time points for Weight SAD 
Time point 
Target 
Interval for Analysis 
Baseline 
Day 1 dose start time 
Most recent value prior to first dose 
Day 8  
Day 8 
]Day 1 dose end time, End of study] 
 
 
 


ProQR Therapeutics 
SAP for Protocol PQ-010-001 
18 April 2017 
 
CONFIDENTIAL 
27 
Table 20: Time points for Vital Signs MAD 
Time point 
Target 
Interval for Analysis 
Baseline 
Day 1 dose start time 
Most recent value prior to first dose 
Day 1 1min Post-dose 
Day 1 dose end 
time+1min 
]Day 1 dose end time, Day 1 dose end time+5min] 
Day 1 10 min Post-dose 
Day 1 dose end 
time+10min 
]Day 1 dose end time+5min, Day 1 dose end 
time+20min] 
Day 1 30min Post-dose 
Day 1 dose end 
time+30min 
]Day 1 dose end time+20min, Day 1 dose end 
time+45min] 
Day 1 60min Post-dose 
Day 1 dose end 
time+60min 
]Day 1 dose end time+45min, Day 1 dose end 
time+90min] 
Day 1 2hrs Post-dose 
Day 1 dose end time+2h 
]Day 1 dose end time+90min, Day 1 dose end time+3h] 
Day 1 4hrs Post-dose 
Day 1 dose end time+4h 
]Day 1 dose end time+3h, Day 1 dose end time+8h] 
Day 1 12hrs Post-dose 
Day 1 dose end time+12h 
]Day 1 dose end time+8h, Day 3[ 
Day 3 Pre-dose 
Day 3 dose start time 
[Day 3, Day 3 dose start time[ 
Day 3 1min Post-dose 
Day 3 dose end 
time+1min 
]Day 3 dose end time, Day 3 dose end time+5min] 
Day 3 10 min Post-dose 
Day 3 dose end 
time+10min 
]Day 3 dose end time+5min, Day 3 dose end 
time+20min] 
Day 3 30min Post-dose 
Day 3 dose end 
time+30min 
]Day 3 dose end time+20min, Day 3 dose end 
time+45min] 
Day 3 60min Post-dose 
Day 3 dose end 
time+60min 
]Day 3 dose end time+45min, Day 3 dose end 
time+90min] 
Day 3 2hrs Post-dose 
Day 3 dose end time+2h 
]Day 3 dose end time+90min, Day 3 dose end time+3h] 
Day 3 4hrs Post-dose 
Day 3 dose end time+4h 
]Day 3 dose end time+3h, Day 3 dose end time+8h] 
Day 3 12hrs Post-dose 
Day 3 dose end time+12h 
]Day 3 dose end time+8h, Day 4[ 
Day 4 
Day 4 
[Day 4, Day 5[ 
Day 5 Pre-dose 
Day 5 dose start time 
[Day 5, Day 5 dose start time[ 
Day 5 1min Post-dose 
Day 5 dose end 
time+1min 
]Day 5 dose end time, Day 5 dose end time+5min] 
Day 5 10 min Post-dose 
Day 5 dose end 
time+10min 
]Day 5 dose end time+5min, Day 5 dose end 
time+20min] 
Day 5 30min Post-dose 
Day 5 dose end 
time+30min 
]Day 5 dose end time+20min, Day 5 dose end 
time+45min] 
Day 5 60min Post-dose 
Day 5 dose end 
time+60min 
]Day 5 dose end time+45min, Day 5 dose end 
time+90min] 
Day 5 2hrs Post-dose 
Day 5 dose end time+2h 
]Day 5 dose end time+90min, Day 7[ 
Day 8 Pre-dose 
Day 8 dose start time 
[Day 7, Day 8 dose start time[ 
Day 8 1min Post-dose 
Day 8 dose end 
time+1min 
]Day 8 dose end time, Day 8 dose end time+5min] 
Day 8 10 min Post-dose 
Day 8 dose end 
time+10min 
]Day 8 dose end time+5min, Day 8 dose end 
time+20min] 
Day 8 30min Post-dose 
Day 8 dose end 
time+30min 
]Day 8 dose end time+20min, Day 8 dose end 
time+45min] 
Day 8 60min Post-dose 
Day 8 dose end 
time+60min 
]Day 8 dose end time+45min, Day 8 dose end 
time+90min] 
Day 8 2hrs Post-dose 
Day 8 dose end time+2h 
]Day 8 dose end time+90min, Day 9[ 
Day 10 Pre-dose 
Day 10 dose start time 
[Day 9, Day 10 dose start time[ 


ProQR Therapeutics 
SAP for Protocol PQ-010-001 
18 April 2017 
 
CONFIDENTIAL 
28 
Day 12 Pre-dose 
Day 12 dose start time 
]Day 10 dose end time, Day 12 dose start time[ 
Day 15 Pre-dose 
Day 15 dose start time 
]Day 12 dose end time, Day 15 dose start time[ 
Day 15 1min Post-dose 
Day 15 dose end 
time+1min 
]Day 15 dose end time, Day 15 dose end time+5min] 
Day 15 10 min Post-dose 
Day 15 dose end 
time+10min 
]Day 15 dose end time+5min, Day 15 dose end 
time+20min] 
Day 15 30min Post-dose 
Day 15 dose end 
time+30min 
]Day 15 dose end time+20min, Day 15 dose end 
time+45min] 
Day 15 60min Post-dose 
Day 15 dose end 
time+60min 
]Day 15 dose end time+45min, Day 15 dose end 
time+90min] 
Day 15 2hrs Post-dose 
Day 15 dose end time+2h 
]Day 15 dose end time+90min, Day 16[ 
Day 17 Pre-dose 
Day 17 dose start time 
[Day 16, Day 17 dose start time[ 
Day 19 Pre-dose 
Day 19 dose start time 
]Day 17 dose end time, Day 19 dose start time[ 
Day 22 Pre-dose 
Day 22 dose start time 
]Day 19 dose end time, Day 22 dose start time[ 
Day 22 1min Post-dose 
Day 22 dose end 
time+1min 
]Day 22 dose end time, Day 22 dose end time+5min] 
Day 22 10 min Post-dose 
Day 22 dose end 
time+10min 
]Day 22 dose end time+5min, Day 22 dose end 
time+20min] 
Day 22 30min Post-dose 
Day 22 dose end 
time+30min 
]Day 22 dose end time+20min, Day 22 dose end 
time+45min] 
Day 22 60min Post-dose 
Day 22 dose end 
time+60min 
]Day 22 dose end time+45min, Day 22 dose end 
time+90min] 
Day 22 2hrs Post-dose 
Day 22 dose end time+2h 
]Day 22 dose end time+90min, Day 23 [ 
Day 24 Pre-dose 
Day 24 dose start time 
[Day 23, Day 24 dose start time[ 
Day 26 Pre-dose 
Day 26 dose start time 
]Day 24 dose end time, Day 26 dose start time[ 
Day 26 1min Post-dose 
Day 26 dose end 
time+1min 
]Day 26 dose end time, Day 26 dose end time+5min] 
Day 26 10 min Post-dose 
Day 26 dose end 
time+10min 
]Day 26 dose end time+5min, Day 26 dose end 
time+20min] 
Day 26 30min Post-dose 
Day 26 dose end 
time+30min 
]Day 26 dose end time+20min, Day 26 dose end 
time+45min] 
Day 26 60min Post-dose 
Day 26 dose end 
time+60min 
]Day 26 dose end time+45min, Day 26 dose end 
time+90min] 
Day 26 2hrs Post-dose 
Day 26 dose end time+2h 
]Day 26 dose end time+90min, Day 26+3days ] 
Day 33 
Day 33 
[Day 26+4 days ; Day 33+ 7 days] 
Day 54 
Day 54 
[Day 33+8 days ; End of Study] 
 
 
 


ProQR Therapeutics 
SAP for Protocol PQ-010-001 
18 April 2017 
 
CONFIDENTIAL 
29 
Table 21: Time points for Weight MAD 
Time point 
Target 
Interval for Analysis 
Baseline 
Day 1 dose start time 
Most recent value prior to first dose 
Day 8 
Day 8 
]Day 1 dose end time, Day 8 + 3days] 
Day 15  
Day 15 
[Day 8 +4days, Day 15+3 days] 
Day 22 
Day 22 
[Day 15 +4days, Day 22+2 days] 
Day 26 
Day 26 
[Day 22 +3days, Day 26+3 days] 
Day 33 
Day 33 
[Day 26+4 days ; Day 33+ 7 days] 
Day 54 
Day 54 
[Day 33+8 days ; End of Study] 
 
4.2.7.6. 
Cystic Fibrosis Questionnaire Revised (CFQ-R) 
Table 22: Time points for CFQ-R MAD 
Time point 
Target 
Interval for Analysis 
Baseline 
Day 1 dose start time 
Most recent value prior to first dose 
Day 15  
Day 15 
[Day 1 dose end time, Day 15+9 days] 
Day 33 
Day 33 
[Day 15+10 days ; Day 33+ 7 days] 
Day 54 
Day 54 
[Day 33+8 days ; End of Study] 
 
4.2.7.7. 
Electrocardiogram (ECG) 
Table 23: Time points for ECG SAD 
Time point 
Target 
Interval for Analysis 
Baseline 
Day 1 dose start time 
Most recent value prior to first dose 
Day 8  
Day 8 
]Day 1 dose end time, End of study] 
 
Table 24: Time points for ECG MAD 
Time point 
Target 
Interval for Analysis 
Baseline 
Day 1 dose start time 
Most recent value prior to first dose 
Day 33 
Day 33 
]Day 1 dose end time, End of Study] 
 
4.2.8. 
Descriptive Statistics 
Tabulations will be produced for appropriate demographic, baseline, efficacy, pharmacokinetic 
and safety parameters.   
For categorical variables, summary tabulations of the number and percentage within each 
category (with a category for missing data) of the parameter will be presented.   
For continuous variables, the mean, standard deviation, median, first quartile (Q1), third quartile 
(Q3), minimum and maximum values will be presented.  


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For PK parameters percentage of coefficient of variation will be added. 
4.2.9. 
Dictionaries 
Adverse events and Medical history are to be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) using the latest version available at the time of the lock for the 
SAD. The same version for the SAD and the MAD should be used.  
Concomitant medications are to be coded using the WHODrug dictionary using the latest 
version available at the time of the lock.  
4.2.10. 
Computing Environment 
Statistical analyses will be performed using SAS statistical software (Version 9.2 or higher). 
R software version 3.3.2 or higher will be also used for modelling and some graphics.  
Cytel Proc MCPMod 1.1, East 6.3 PROCs for SAS will be used modelling 
PK parameters will be generated using validated software (Phoenix WinNonlin® Version 6.3, or 
higher). 
4.3. 
Interim Analyses 
Safety will be assessed prior to each dose escalation by the DSMC.  
For development purposes data analyses may be performed during the study.  
4.4. 
Subject Disposition 
The number of subjects enrolled, number of screened failure will be tabulated. 
The number of subjects in each population will be presented. 
The number and percentage of subjects randomized, treated, completed treatment/discontinued 
from treatment (reasons), completed study and discontinued from the study and reasons will be 
presented for the safety population. The enrollment by geographic region (North America and 
Europe) region and by site will be tabulated. 
Display will be presented by dose and total. Display may be repeated with the exploratory 
analysis population if exploratory analysis and safety populations differ. 
A by-subject listing of study disposition (informed consent date, first dose, completion status, 
last treatment date, and last study date, including the reason for premature treatment/study 
withdrawal, if applicable) will be presented. 
4.5. 
Demographic and Baseline Characteristics 
Subject demographics including gender, ethnicity, race, age (years), baseline weight (kg), height 
(cm), and body mass index (BMI) (kg/m2) will be tabulated. The baseline disease characteristics 
including pulmonary function (Forced Expiratory Volume in 1 second in Liters (FEV1 (L)), 
percent predicted FEV1 (ppFEV1) (%), Sweat Chloride (mmol/L), and CFQ-RSS (only 
applicable in MAD cohort) will be summarized.  
Data will be summarized by dose group and overall for subjects in the safety population. 
Display may be repeated with the exploratory analysis population if the exploratory analysis and 
safety populations differ. 


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Height (in cm) = height (in inches) * 2.54 
Weight (in kg) = weight (in lbs) * 0.4536 
BMI (kg/m2) = Weight (kg) / [Height (m2)]. BMI at each visit will be calculated using 
weight at the visit and height from the screening visit 
  
ppFEV1 (%) = percent predicted FEV1 (with a unit of percentage points) is the ratio of 
FEV1 (L) to the predicted FEV1 (L), expressed as a percentage. The predicted FEV1 (L) is 
computed using the NHANES III normal value (REFERENCES 
Hankinson et al., Spirometric Reference Values from a Sample of the General U.S. Population, 
(1999), AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 
VOL 159 179-187 ) according to gender, race, age & height. 
Demographic and Baseline data will be provided in data listings. 
4.6. 
Medical History 
Medical History will be summarized by dose group and overall for the safety population. 
Outputs may be repeated for the exploratory analysis population if exploratory analysis and 
safety populations differ. 
4.7. 
Treatment Compliance and Extent of Treatment Exposure 
Study drug will be administered in the clinic by qualified site personnel, by inhalation via the 
designated study nebulizer, until all study drug solution has been administered. Complete 
administration of study drug/placebo, if uninterrupted, should take approximately less than 20 
minutes. 
Treatment compliance and extent of exposure will be summarized by treatment group and 
overall, including time on study, number of study doses completed, number of subjects that 
completed dose at each dose visit, number of device pauses, status of full dose delivery, and 
nebulization duration at each dose visit. A listing of treatment exposure will be provided. 
Treatment compliance will be presented for the safety population. 
Outputs may be repeated for the exploratory analysis population if exploratory analysis and 
safety populations differ. 
Time on study is defined as end of study date – first dose date +1. See section 4.2.4 for 
definition of end of study date. 
For dose-visit dates, please refer to Section 4.2.7. 
4.8. 
Exploratory Efficacy Evaluation 
Efficacy analyses will be conducted using the exploratory analysis population.   
4.8.1. 
SAD 
The exploratory efficacy evaluations will include the following endpoints. 
4.8.1.1. 
ppFEV1 (%)  
The ppFEV1 value, absolute change from baseline and % change from baseline (relative change) 
will be presented descriptively over time (considering all time points from the visit windows for 
this parameter), per treatment group.  


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Graphical representation may be provided (mean change+ 95% CI overtime). Particularly a 
zoom on the data for the first 24 hours following first dose will be given). 
In order to assess differences versus placebo a mixed model with repeated time measures on the 
change from baseline ppFEV1 as outcome variable and including treatment, baseline ppFEV1 
value, time and interaction between time and treatment as covariates. By default, an 
unstructured covariance matrix will be used, unless convergence issue, in which case other 
covariance matrix will be explored. Adjusted means and corresponding confidence interval will 
be presented.  
For Day 1, several spirometry assessments (pre and post dose) are planned. Subjects usually 
suffer from fatigue due to the multiple assessments, resulting in low post-dose values of FEV1. 
Additionally, inhalation of the IMP may transiently impact the spirometry results. Thus the 
following time points will be included in the repeated measures analysis: Baseline, Day 2, Day 4 
and Day 8, using the time windows. 
Analyses to explore the dose response using the MCPMod methodology will be followed. A set 
of dose-response models will be tested including change from baseline ppFEV1 at Day 4 as 
dependent variable, the treatment as factor (0, 6.25, 12.5, 25, 50 mg) and ppFEV1 value at 
baseline (see Table 25 and Figure 2). The presence of a dose-response signal will be 
demonstrated if at least one of the candidate models is significant, adjusting for the different 
models (overall alpha=5% two-sided). Due to the small sample size, overall alpha for this 
exploratory dose-response analysis may be adapted. If a model is selected, an estimate of the 
minimum effective dose will be performed. Thresholds of 3%, 5% and 7% will be tested as 
sizes of interest of treatment effect (differences versus placebo). 
Table 25: Set of Candidate Models for Dose-Response 
 
Model 
 
Parameters 
ED 50 
Scale δ 
Linear 
- 
- 
Loglinear 
- 
- 
Emax 
25 
- 
Exponential 
- 
12.5 
Logistic  
25 
3 


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4.8.1.2. 
FEV1 (L)  
FEV1 value, change from baseline and % change from baseline will be presented descriptively 
over time, per treatment group. Graphical representation may be provided. 
4.8.1.3. 
FVC (L)  
FVC value, change from baseline and % change from baseline will be presented descriptively 
over time, per treatment group. 
4.8.1.4. 
FEF25/75 (L)  
FEF25/75 value, change from baseline and % change from baseline will be presented 
descriptively over time, per treatment group. 
4.8.1.5. 
C-Reactive Protein (CRP) (mg/L) 
CRP value and change from baseline will be presented descriptively over time, per treatment 
group. Graphical representation may be provided (mean +95% CI overtime). 
4.8.1.6. 
Erythrocyte Sedimentation Rate (ESR) (mg/L) 
ESR value and change from baseline will be presented descriptively over time, per treatment 
group. Graphical representation may be provided (mean +95% CI overtime). 
 
Figure 2: Candidate model for ppFEV1 dose response 


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4.8.2. 
MAD 
4.8.2.1. 
ppFEV1 (%)  
The ppFEV1 value, absolute change from baseline and % change from baseline (relative change) 
will be presented descriptively over time (considering all time points from the visit windows for 
this parameter), per treatment group.  
Graphical representation may be provided (mean change+ 95% CI overtime). Particularly a 
zoom on the data for the first 24 hours following first dose will be given).  
In addition, the SAD and MAD ppFEV1 for the first 24 hours will be pooled in order to provide 
more robust data to the first day evolution. 
The mixed-model analysis will be performed with repeated time measures on the change from 
baseline ppFEV1 as outcome variable and including treatment, baseline ppFEV1 value, time and 
interaction between time and treatment as covariates. By default, an unstructured covariance 
matrix will be used, unless convergence issue, in which case other covariance matrix will be 
explored. Adjusted means and corresponding confidence interval will be presented.  
For visits with a dose, several spirometry assessments (pre and post dose) are planned. Subjects 
usually suffer from fatigue due to the multiple assessments, resulting in low post-dose values of 
FEV1. Thus the following time points, concentrating on the pre-dose evaluations during 
treatment, and the post-treatment time points will be considered: Baseline, Day 3 pre-dose, Day 
4, Day 5 pre-dose, Day 8 pre-dose, Day 15 pre-dose, Day 22 pre-dose, Day 26 pre-dose, Day 26 
4 hours post-dose, Day 33 and Day 54. Differences versus Placebo will be estimated at Day 26 
pre-dose, Day 26 4 hours post-dose, Day 33 and Day 54. 
A sensitivity analysis including presence/absence of Pseudomonas aeruginosa at Baseline as a 
covariate will be performed. 
Analyses to explore the dose response using the MCPMOD methodology as described in the 
SAD section will be followed. The change from baseline in ppFEV1 at Day 26 pre-dose, Day 26 
4 hours post-dose and Day 33 will be assessed.  
4.8.2.2. 
FEV1 (L) 
FEV1 value, change from baseline and % change from baseline will be presented descriptively 
over time, per treatment group. 
4.8.2.3. 
FVC (L)  
FVC value, change from baseline and % change from baseline will be presented descriptively 
over time, per treatment group. 
4.8.2.4. 
FEF25/75 (L)  
FEF25/75 value, change from baseline and % change from baseline will be presented 
descriptively over time, per treatment group. 
4.8.2.5. 
Sweat Chloride (mmol/L) 
Sweat chloride value and change from baseline will be presented descriptively over time, per 
treatment group. Graphical representation may be provided (mean change+ 95% CI overtime). 


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If several assessments are done on the same day, the average of these assessments will be used. 
See Section 4.2.1 for definition of baseline. 
4.8.2.6. 
C-Reactive Protein (CRP) (mg/L) 
CRP value and change from baseline will be presented descriptively over time, per treatment 
group. 
Graphical representation will be provided (mean change from baseline +95% CI overtime). 
4.8.2.7. 
Erythrocyte Sedimentation Rate (ESR) (mg/L) 
ESR value and change from baseline will be presented descriptively over time, per treatment 
group. 
Graphical representation will be provided (mean change from baseline+95% CI overtime). 
4.8.2.8. 
Glucose 
Glucose value and change from baseline will be presented descriptively over time, per treatment 
group. 
A mixed model with repeated time measures on the change from baseline of glucose (mmol/L) 
as outcome variable and including treatment, baseline glucose value, time and interaction 
between time and treatment as covariates. By default, an unstructured covariance matrix will be 
used, unless convergence issue, in which case other covariance matrix will be explored. 
Adjusted means and corresponding confidence interval will be presented.  
For some visits with a dose, several glucose assessments pre and/or post-dose are planned. We 
expect glucose values to differ post dose through the same day as meals are consumed; for 
stability of the data only the first glucose assessment performed at the selected visit days will be 
used.  
Thus the following time points will be included in the repeated measures analysis: Baseline 
(baseline, Day 7 pre-dose, Day 15 pre-dose, Day 22 pre-dose, Day 33 and Day 54. Differences 
versus placebo will be estimated at Day 22, Day 33 and Day 54. 
A sensitivity analysis including presence/absence of Cystic Fibrosis Related Diabetes with or 
without glucose intolerance at Baseline as a covariate will be performed. 
Cystic Fibrosis related Diabetes at Baseline is defined as medical history term containing 
‘diabetes’ ‘cystic fibrosis related diabetes’, ‘diabetes mellitus’.  Glucose tolerance will be 
defined as medical history term containing ‘glucose tolerance impaired'. Descriptive statistics 
will be provided as appropriate. 
The MCPMOD methodology will be applied to evaluate the dose-response, with change from 
baseline of glucose at Day 22 pre-dose as dependent variable. Thresholds of -0.5, -1, -2 will be 
tested as sizes of interest of treatment effect. 
Graphical representation will be provided (mean change +95% CI overtime). 
4.8.2.9. 
CFQ-R (Cystic Fibrosis Questionnaire – Revised) 
The CFQ-R subject health-related quality of life questionnaire will be administered using the 
self-administered format (Adolescent and Adult version in the protocol Appendix 3), according 


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to the study schedule for MAD cohorts only. The CFQ-R is administered prior to any other test 
or procedure on each of the required study days (Baseline, Day 15, Day 33 and Day 54). 
Cystic Fibrosis Questionnaire- Revised Respiratory Symptoms Score (CFQ-R RSS) 
The CFQ-R RSS is calculated based on mean score of Questions 40 to 46 excluding question 43 
as below if <=3 item scores are missing: 
Assuming a coding of 1 to 4 with categories such as 
1=A great deal / Always 
2=Somewhat / Often 
3=A little / Sometimes 
4=Not at all / Never, 
 
CFQ-R RSS = mean [(resp40, resp41, resp42, resp44, resp45, resp46)-1]/3*100; 
The score will be missing if more than three of the six scores are missing. 
Descriptive summary overtime will be provided for the values and change from baseline at each 
time point following the time windows, by treatment group. 
A mixed model analysis with repeated time measures on the change from baseline of CFQ-R 
RSS as outcome variable, including treatment, baseline CFQ-R RSS value, time and interaction 
between time and treatment as covariates will be performed. By default, an unstructured 
covariance matrix will be used, unless convergence issue occurs, in which case other covariance 
matrix will be explored. Adjusted means and corresponding confidence interval will be 
presented. The following time points will be included in the repeated measures analysis: 
Baseline, Day 15, Day 33 and Day 54. Differences versus placebo will be estimated at Day 33 
and Day 54. 
A dose-response analysis using MCPMOD methodology will be performed with change from 
baseline of CFQ-R RSS at Day 33 as dependent variable, the treatment (0, 6.25, 12.5, 25, 50 
mg) and CFQ-R RSS at baseline as factors. Thresholds of +4, +5, +8 and +10 will be tested as 
sizes of interest of treatment effect. 
CFQ-R Other Domains: 
Descriptive summary over time will be provided for the values and change from baseline at each 
time point following the time windows, by treatment group. 
Details for re-coding are provided in http://www.psy.miami.edu/cfq_QLab/scoring.html . 
All CFQ-R domain scores will be reported in listings. 
4.8.2.10. 
Weight (kg) 
Weight value and change from baseline will be presented descriptively over time at each time 
point (Baseline, Day 4, Day 15, Day 22, Day 26, Day 33, Day 54) per treatment group. 
A mixed model with repeated time measures on the change from baseline of Weight as outcome 
variable, including treatment, baseline weight value, time and interaction between time and 
treatment as covariates will be performed. By default, an unstructured covariance matrix will be 


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used, unless convergence issue, in which case other covariance matrix will be explored. 
Adjusted means and corresponding confidence interval will be presented. The following time 
points will be included in the repeated measures analysis: Baseline, Day 15, Day 33 and Day 54. 
Differences versus placebo will be estimated at Day 33 and Day 54. 
A dose-response analysis using MCPMOD methodology will be performed with change from 
baseline of weight at Day 33 as dependent variable, the treatment (0, 6.25, 12.5, 25, 50 mg) and 
weight at baseline as factors. Thresholds of 0.5, 1 , 2 and 3 (kg) will be tested as sizes of interest 
of treatment effect. 
4.9. 
Pharmacokinetic Evaluations 
In the SAD portion of the study, sample collections for support of PK analysis are planned as 
follows: 
 Blood (i.e. serum):  pre-dose (time 0), 0.5, 1, 2, 3, 4, 12, 24, 48, 54, 72, 168 hours post-
dose. 
 Urine:  Pre-dose (time 0); Pooled from 0 to 4, 4 to 12, and 12 to 24 hours post-dose; and 
48, 72, and 168 hours post dose. 
 Sputum: 3 samples obtained within first 6 hours post dose; 24 hours post dose; Day 4 
(72 hours post dose); and Day 8 (168 hours post dose) 
 
In the MAD portion of the study, sample collections for support of PK analysis are planned as 
follows: 
Week 1, Dose 1 
 Serum: 0, 0.5, 1, 2, 3, 4, 12; pre-Dose 2 (48 hours post-dose 1) 
 Urine: Pre-dose; Pooled from 0 to 4 and 4 to 12 hours post Dose 1.   
 Sputum: pre-dose, 3 samples obtained within first 6 hours post Dose 1. 
Week 4, Dose 12 
 Serum: pre-dose (0), 1, 2, 3, 4, 8, 24, 96, 144 (7 days post-last dose) and 648 hours (28 
days post-last dose). 
 Urine: Pre-dose; 24 and 96 hours, post-dose. 
 
Additional sample collections are planned on interim study days during the MAD portion of the 
study.  The measured concentrations will be presented in listings and used to confirm adequate 
QR-010 exposure; however, they will not be used to support generation of PK parameters.  
Additionally, urine concentrations that did not come from pooled collections or for which 
sample volumes were not collected will only be displayed in listings and will not be used to 
support generation of renal PK parameters. 
The planned PK parameters for each portion of the study may be found in Table 26 below. Area 
under the serum concentration curve (AUC) will be generated using the linear-log trapezoidal 
rule.   


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Table 26: Planned Pharmacokinetic Parameters by Matrix and Study Day 
Parameter 
Definition 
Calculation 
SAD, Study Day 1, Serum PK Parameters 
Cmax 
Maximum serum 
concentration 
Observed 
Tmax 
Time of maximum 
serum 
concentration 
Observed 
AUClast 
Area under the 
concentration-time 
curve from 0 to the 
last quantifiable 
serum 
concentration 
Linear-Log trapezoidal method 
AUCinf 
Area under the 
concentration-time 
curve from 0 
extrapolated to 
infinite 
Calculated as AUC0-last + Cest,last/λz, where Cest,last is 
the estimated last measurable concentration 
T1/2 
Apparent terminal 
elimination half-
life 
ln(2)/λz, where λz is the apparent first-order terminal 
elimination rate constant. 
λz 
Terminal 
elimination rate 
constant 
Log-linear regression of the concentration-time curve 
during terminal elimination 
Cl/F 
Apparent 
Clearance 
Dose/AUCinf 
Vd/F 
Apparent volume 
of distribution 
Dose/AUCinf* λz 
SAD, Study Day 1, Urine PK Parameters 
Ae 
Amount excreted 
unchanged in the 
urine 
Cumulative: Sum of concentration* volume per collection 
interval 
Fe% 
Fraction of Dose 
excreted 
Calculated as Ae/Dose, where Ae is the amount of 
unchanged drug excreted in urine during a collection 


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unchanged in the 
urine 
interval and D is the Dose  
Clr 
Renal Clearance 
Calculated as Ae24/AUC24 where Ae is the amount of 
unchanged drug excreted in urine during the first 24 hours 
post-dose and AUC24 is the Area under the concentration 
versus time curve from 0 to 24 hr. 
MAD, Week 1, Dose 1, Serum 
Cmax 
Maximum serum 
concentration 
Observed 
Tmax 
Time of maximum 
serum 
concentration 
Observed 
AUCtau 
Area under the 
concentration-time 
curve from 0 to the 
end of the dosing 
interval (tau, where 
tau will equal 48 
hours). 
Linear-log trapezoid 
MAD, Week 4, Dose 12, Serum 
Ctrough 
Trough serum 
concentration 
Observed 
Cmax 
Maximum serum 
concentration 
Observed 
Tmax 
Time of maximum 
serum 
concentration 
Observed 
AUCtau* 
Area under the 
concentration-time 
curve from 0 to the 
end of the dosing 
interval (tau, where 
tau will equal 48 
hours). 
Linear-log trapezoid 
Css 
Steady-state 
concentration 
AUCtau/tau, where tau will equal 48 hours 


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Ro 
Accumulation 
ratio 
AUCtau (week 4, dose 12)/ AUCtau (week 1, dose 1) 
Ro,Cmax 
Cmax, 
accumulation ratio 
Cmax(week 4, dose 12)/ Cmax (week 1, dose 1) 
Accumulation 
Index 
Estimated 
accumulation 
index 
1/(1 – e –*tau) 
CL/F 
Apparent 
clearance 
Dose/AUCtau 
V/F 
Apparent volume 
Dose/AUCtau* λz 
*Sampling collection scheme during week 4, dose 12 allows for sample collection windows.  The 96-hr sample time 
collection may occur between 48 and 144 hours post dose.  For samples in which C48 was collected, AUCtau will 
be generated using observed data.  For samples in which C48 was not collected, C48 will be estimated using each 
subject’s individually estimated from week 4, dose 12, provided there is sufficient data to estimate the 
elimination rate constant.  Data will be considered sufficient if there are no less than 3 time points included in the 
estimation, R-squared values are at least 0.9, and the percent of data extrapolated is less than 20%.   
Concentrations below the limit of quantification (BQL) will be considered to be 0 concentration.  
With the possible exception of C48 (week 4, dose 12), missing values will not be imputed.  If 
sufficient data are missing for a given subject, that subject may be considered non-evaluable for 
pharmacokinetic analysis and will not be included in the PK Population. 
All serum, urine and sputum concentration data and the per-subject pharmacokinetic parameters 
will be displayed in listings. Summary statistics will be generated for each pharmacokinetic 
parameter unless there are less than three subjects will evaluable data.  Summary statistics will 
include mean, median, geometric mean, standard deviation, minimum, maximum, and 
percentage of coefficient of variation.  Concentration-time profiles will be plotted by individual 
and mean concentration-time profiles will be plotted by dose and study day on both the log and 
linear scales (if applicable).  Dose-normalized parameters will be plotted for dose-ranging 
studies.  Because there may be a relationship between pseudomonas and QR-010 systemic 
exposure, summary statistics and descriptive figures may also be generated by day, dose and 
pseudomona at the discretion of the team, but no formal statistical analysis will be performed 
and these additional tables and figures will be excluded from the top line report. 
4.10. 
Safety Analyses 
Safety analyses will be conducted using the safety population.   
There will be separate reporting for SAD and MAD, with all treatment groups. No total column 
will be provided. In general, SOC and PT will be presented alphabetically.  


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4.10.1. 
Adverse Events 
4.10.1.1. 
General Adverse Event Reporting 
Adverse events will be summarized with MedDRA System Organ Class (SOC) and Preferred 
Term, by subject incidence rates, therefore, in any tabulation, a subject contributes only once to 
the count for a given adverse event (SOC or preferred term or AESI). 
A treatment emergent Adverse Event (TEAE) is defined as an event with start date at/or after 
first dose. 
An overall summary of TEAEs will include the number of 
 
Subjects with at least one TEAE,  
 
Number of TEAE, 
 
Subjects with study drug-related TEAEs,  
 
Subjects with device-related TEAEs, 
 
Subjects with TEAEs by maximum severity grade,  
 
Subjects with serious AEs,  
 
Subjects with TEAEs Leading to Treatment Discontinuation, 
 
Subjects with TEAEs Leading to Study Discontinuation, 
 
Deaths 
 
The overall incidence of TEAEs will be summarized by treatment group and classified by SOC 
and PT. Reporting will include reports for Serious AEs, AEs leading to treatment 
discontinuation, deaths, AEs related to study drug, AEs related to device. AEs by SOC and PT 
will be presented by maximum severity. 
An AE will be considered drug-related if the Investigator or Sponsor indicated that the event is 
coded “possibly” or "definitely" related to study drug or if the relationship is missing. The same 
definition applies for relationship to device. 
AE intensity is graded on a 5 level category (Mild/Grade 1, Moderate/Grade 2, Severe/Grade 3, 
Life threatening/Grade 4, Death/Grade 5). Maximum intensity per PT is reported.  
TEAEs will be listed in subject listings. Listings of Serious TEAEs, Death, Grade 2 or higher 
TEAEs will also be presented. 
A listing for the non-treatment emergent events (with start date and time prior to first dose) will 
be provided, the listing will be provided only if events are collected. 
4.10.1.2. 
AESI 
AESI definition are based on MedDRA Coding version 17.1. 
An overall summary of AESI and DLT will be presented. AESI will be summarized by SOC 
and PT and for AESI4, a summary of liver function test elevation will be presented. AESI will 
be reported in listings. 
4.10.1.2.1. AESI1: Atelectasis 
Atelectasis is defined as the AEs of at least Grade 2 with the preferred term that contains 
"atelectasis". 


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4.10.1.2.2. AESI2: Hypotension 
Hypotension is defined as the AEs of at least Grade 2 with the preferred term that contains any 
of terms below: 
 Blood pressure ambulatory decreased 
 Blood pressure decreased 
 Blood pressure diastolic decreased 
 Blood pressure orthostatic decreased 
 Blood pressure systolic decreased 
 Diastolic hypotension 
 Hypotension 
 Mean arterial pressure decreased 
 Orthostatic hypotension 
 Procedural hypotension 
4.10.1.2.3. AESI3: Bronchospasm 
Bronchospasm is defined as the AEs of at least Grade 2 with the preferred term that contains 
“Bronchospasm" or "asthma" or "wheezing" or "bronchial obstruction" 
4.10.1.2.4. AESI4: Liver Function Test Elevation 
Liver Function Test Elevation is defined from laboratory data as: Alanine Aminotransferase 
(ALT) >3 x ULN  or Aspartate Aminotransferase (AST) >3 x ULN and doubling from baseline 
value. 
4.10.1.2.5. AESI5: Pneumonitis 
Pneumonitis is defined as the AEs of at least Grade 2 with the preferred term that contains 
"pneumonitis ". 
4.10.1.2.6. AESI6: Crackles 
Crackles is defined as the AEs of at least Grade 2 with the preferred term that contains 
"crepitation" or "rales". 
4.10.1.2.7. AESI7: Dypnoea 
Dyspnoea is defined as the AEs of at least Grade 2 with the preferred term that contains 
"dyspnoea" or "orthopnoea". 
4.10.1.2.8. AESI8: Hypoxia 
Hypoxia is defined as: Pulse Oximeter < 88% 


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4.10.1.2.9. AESI9: Allergic Reaction 
Allergic Reaction is defined as the AEs of at least Grade 2 with the preferred term that contains  
"Hypersensitivity" or "Alveolitis" or "vasculitis" or "urticaria" or "dermatitis allergic" or 
"anaphylactic" or "anaphylaxis". 
4.10.1.3. 
DLT definition  
Potential DLTs are reviewed and adjudicated by the DSMC. Adjudicated DLTs will be loaded 
from an excel file and summarized by treatment group. Individual subject listings will be 
provided for each DLT including severity. 
 
4.10.1.4. 
Change FEV<=-15% from baseline 
The number of subjects with a change from baseline of FEV1 (L) <=-15% at least once and 
overtime will be summarized by treatment group. FEV1 evolution will be graphically presented 
for those subjects. A listing will be provided. 
 
4.10.2. 
Laboratory Data 
Local laboratory measurements are performed for this study, thus different units and normal 
ranges may be collected. Summary statistics will be provided when relevant. 
4.10.2.1. 
General Display 
Laboratory measurements obtained will be summarized by treatment group overtime following 
analysis time points (time windows) that may differ according to parameter data collection. 
Descriptive statistics for the continuous data of actual results and change from baseline for each 
time point will be presented. Frequencies and percentages per time point will be presented for 
categorical data. 
Frequencies and percentages of subjects with values outside of the normal ranges overall (post-
baseline) and for each time point will be presented.   
Shift tables summarizing the count of subjects below, within and above the normal ranges at 
baseline and to maximum and to minimum value during treatment and after treatment for MAD 
and after treatment only for SAD will be presented. For shift tables all post-baseline assessments 
will be used (in particular unscheduled assessments). 
Listing of laboratory data will be presented. A listing presenting the data for clinically relevant 
abnormal values will be provided.  
 
4.10.2.2. 
Hematology 
Hematology includes: hematocrit, hemoglobin, erythrocyte mean corpuscular HGB 
concentration, erythrocyte mean corpuscular hemoglobin, erythrocyte mean corpuscular 
volume, erythrocytes, white blood count, segmented neutrophils, bands, total neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count).  
All analyses described in the general display section will be performed when possible. 


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4.10.2.3. 
Chemistry 
Serum chemistries will include sodium, potassium, chloride, bicarbonate, blood urea nitrogen 
(BUN), creatinine, glucose, calcium, phosphorus, SGPT/ALT, SGOT/AST, GGT, alkaline 
phosphatase, bilirubin (total and direct), uric acid, lactic dehydrogenase (LDH), albumin, 
total protein, triglycerides, and cholesterol. Creatinine clearance is to be calculated using the 
Cockcroft-Gault equation adjusted for actual body weight.  
All analyses described in the general display section will be performed when possible. 
4.10.2.4. 
Coagulation tests and Direct Antiglobulin Test 
Coagulation tests include INR, PT, APTT, fibrinogen and total complement (CH50). All 
analyses described in the general display section will be performed when possible. 
Direct Antiglobulin test results will be summarized over time and reported in listing. They will 
be included in Coagulation outputs. 
 
4.10.2.5. 
Urinalysis 
Urinalysis (by visual inspection and dipstick) will include color and appearance, microalbumin, 
casts, crystals, epithelial cells, erythrocytes, specific gravity, pH, protein, glucose, occult blood, 
ketones, bilirubin, leukocytes, leukocyte esterase, nitrite, and urobilinogen. 
Urinalysis data will be reported in listings only. 
 
4.10.2.6. 
Microbiology pathogen 
Sputum sample or oropharyngeal swab for microbiology organism identification are collected 
prior to and after treatment. Number and frequency of observed pathogens (included details for 
others) will be provided by time point. 
The following format will be displayed for (CRF defined categories and Others) 
Table 27: Microbiology Pathogen List 
Reported 
Formatted 
Flag for 
Pseudomonas 
Terms from the coded list 
 
 
Achromobacter xylosoxidans  
 
Aspergillus spp  
 
Burkholderia spp  
 
Candida spp  
 
Hemophilus influenzae  
 


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Inquilinus limosus  
 
Non-tuberculous mycobacterium - MAC  
 
Non-tuberculous mycobacterium - M.cheloni or 
M. abscessus 
 
 
Pandoraea apista  
 
Pseudomonas aeruginosa  
Y 
Ralstonia spp  
 
Staphylococcus aureus  
 
Stenotrophomonas maltophilia  
 
Terms from the Other category (free text) 
 
 
'commensal bacteria Normal Flora 
 
BURKHOLDERIA CENOCEPACIA, 
STAFYLOCOCCUS AEREUS, YEAST 
This is three different pathogens: 
Burkholderia spp, Staphylococcus 
aureus, Yeast spp 
* will be consider "Others", or in 
separate if the data changes. 
 
Escherichia coli Escherichia coli 
 
MRSA Staphylococcus aureus 
 
Methicillin Resistant Staph aureus Staphylococcus aureus 
 
Methicillin-Resistant Staphylococcus  Staphylococcus aureus 
 
Mucoid Pseudomonas Aeruginosa Pseudomonas aeruginosa 
Y 
Mycobacterium fortuitum Mycobacterium fortuitum 
 
Normal Flora Normal Flora 
 
PROTEUS MIRABILLIS Proteus mirabilis 
 
Pseudomonas positive Pseudomonas aeruginosa 
Y 
Yeast Yeast spp 
 


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enterobacter asburiae Enterobacter spp 
 
enterobacter cloacae Enterobacter spp 
 
fungi (non specific) Fungi spp 
 
haemophylus parainfluenzae Haemophilus parainfluenzae 
 
haemphilus influenza-candida 
albicans/dubliniencis 
This 
is 
multiple 
pathogens: 
Haemophilus 
influenza, 
and  
Candida spp,  
 
micro organism filamentous fungus evoking Fungi spp 
 
microbiota reasident Normal flora 
 
microbiota resident Normal flora 
 
mold Mold spp 
 
proteus mirabilis Proteus mirabilis 
 
staphylococcus aureus Staphylococcus aureus 
 
yeast Yeast spp 
 
yeasts Yeast spp 
 
 
The list may be updated based on latest database. 
 
4.10.2.7. 
Parameters collected at baseline only 
Descriptive summaries of actual values will be reported for the following parameters: 
Tocopherol Vitamin E (continuous reporting) and Drug screen (categorical Negative/Positive). 
4.10.2.8. 
Pregnancy test 
Pregnancy test results will be presented in a by subject data listing. 
4.10.3. 
Vital Signs and Oximetry 
Descriptive summaries of actual values and changes from baseline of vital signs will be reported 
for each time point, in the following parameters: Height (baseline only), Weight, BMI, Heart 
rate, Systolic and Diastolic Blood Pressure, Temperature, Pulse rate and Pulse Oximetry. 
By-subject listings of vital sign measurements will be presented including flag for abnormality 
(if exist). A special listing reporting vital signs measurements considered clinically relevant will 
be provided. 


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4.10.4. 
Physical Examinations 
Physical examination abnormal findings will be presented in a by subject data listing. 
4.10.5. 
Electrocardiogram 
12-Lead Standard electrocardiogram data are collected as Normal/Abnormal. Number and 
percentage of Normal/Abnormal Not Clinically Significant/Abnormal Clinically Significant 
values will be presented overall (number of subjects) and by visit (prior to treatment and post 
treatment (Day 8 for SAD, Day 33 for MAD). 
Clinically Significant Abnormal ECG results with comments will be reported in listings.  
4.10.6. 
Prior and Concomitant Medications 
Concomitant medications are to be coded using the WHO Drug dictionary. 
Prior and Concomitant Medications will be tabulated separately by ATC level 2 and Preferred 
Name (number and percent of subjects). Tables will be sorted by alphabetical order of ATC 
level 2 and Preferred Name. 
 


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5. 
CHANGES TO PLANNED ANALYSES 
As of this date, there have been no changes between the protocol-defined statistical analyses and 
pharmacokinetics analyses those presented in this statistical plan. 
 


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6. 
REFERENCES 
1. 
Hankinson et al., Spirometric Reference Values from a Sample of the General U.S. 
Population, (1999), AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL 
CARE MEDICINE, VOL 159 179-187 
2. 
User Manuel for Proc MCPMod 1.1, East 6.3 PROCs for SASR 
3. 
Bjoern Bornkamp, Jose Pinheiro and Frank Bretz (2016). DoseFinding: Planningand 
Analyzing Dose Finding Experiments. R package version 0.9-15. https://CRAN.R-
project.org/package=DoseFinding 
4. 
Zhao Yang. (2013). Dose-response and finding in phase II clinical studies - MCPMod 
Methodologies. 
5. 
Pinheiro, J. C., Bornkamp, B., Glimm, E. and Bretz, F. (2014) Model-based dose finding 
under model uncertainty using general parametric models, Statistics in Medicine, 33, 
1646-1661 
 
 


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7. 
APPENDICES 
APPENDIX 1: SCHEDULE OF ASSESSMENTS 
Table A.1-1: Single Ascending Dose Cohorts 1-4 
Study Procedures 
Screening Check-In 
 
 
 
Discharge 
 
 
 
End of 
Study 
Study Day 
≤-14 daysa 
-1 
1b 
2 
3 
4 
5 
6 
7 
8 
In Hours 
 
-24 
0 
24 
48 
72 
96 120 144 
168 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Eligibility Review 
X 
X 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
 
 
 
X 
Physical Exam 
C 
C 
S 
S 
 
S 
 
 
 
C 
Height & Weight 
H/W 
W 
W 
 
 
 
 
 
 
W 
Vital Signsc & Oximetry 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Spirometryd 
X 
X 
X 
X 
 
X 
 
 
 
X 
Chest Xray  
Xe 
 
 
 
 
 
 
 
 
Xf 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
X 
24-Hour Telemetry 
 
 
X 
 
 
 
 
 
 
 
Blood for Safety Labsg 
X 
Xh 
X 
X 
X 
X 
 
 
 
X 
Urinalysisg 
U 
Uh 
U 
U 
U 
U 
 
 
 
U 
Drug Screeng 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Testg,i 
X 
X 
 
 
 
 
 
 
 
X 
Sputum for Microbiologyg 
 
X 
 
 
 
 
 
 
 
X 
Blood for CFTRg 
Genotyping Sequencing 
 
 
 
 
 
 
 
 
Biomarkersg 
X 
X 
 
X 
 
X 
 
 
 
X 
Sweat Chlorideg 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 


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Study Procedures 
Screening Check-In 
 
 
 
Discharge 
 
 
 
End of 
Study 
Study Drug Administrationj 
 
 
X 
 
 
 
 
 
 
 
Collect Samples for PKg 
 
 
X 
X 
X 
X 
 
 
 
X 
Abbreviations: C = complete physical exam; H = height; S = symptom-directed physical exam; U = urinalysis (dipstick); W = 
weight 
a The screening period for an individual subject may be extended for an additional 7 days at the discretion of the Sponsor’s 
Medical Monitor. See Protocol Section 7.2 for details.  
b See Protocol Section Section 7.3.2 for details on timing of these assessments relative to study drug administration on Day 1. 
c Includes blood pressure, heart rate, respiratory rate, and temperature. 
d Includes FEV1, FVC, and FEF25-75. 
e A Chest Xray or CT scan obtained within 90 days of screening is acceptable if there was no intercurrent pulmonary illness 
during the interim. 
f Only subjects who experience pulmonary AEs during the study. 
g See Protocol Appendix 2 for a detailed schedule of these assessments, broken down by type of specimen and time relative to 
dose. 
h Only laboratory assessments that are abnormal (but not clinically significant) at screening should be repeated at Day-1. 
i Pregnancy test (preferably serum but urine is accepted) required for women of childbearing potential only. 
j Subjects who are taking concurrent CF therapy should receive this therapy prior to study drug dosing in the order specified in 
Protocol Section 6.3.1. 
 
 


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Table A.1-2: Multiple Ascending Dose Cohorts 5-8, WEEK 1 
Dosing Schedule assumes Monday-Wednesday-Friday dosing: 
Study Procedures 
Screening 
 
Dose 1 
Dose 2 
 
Dose 3 
 
 
Study Day 
≤-14 daysa 
-1 
1 
3 
4 
5 
6 
7 
In Hours Post Dose 1 
 
-24 
0 
48 
72 
96 
120 
144 
Informed consent 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Eligibility Review 
X 
X 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
 
 
Physical Exam 
C 
C 
S 
S 
S 
S 
 
 
Height & Weight 
H/W 
W 
W 
 
 
 
 
 
Vital Signsb & Oximetry 
X 
X 
X 
X 
X 
X 
 
 
Spirometryc 
X 
X 
X 
X 
X 
X 
 
 
Chest Xray 
Xd 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
Telemetry 
 
 
X 
 
 
 
 
 
CFQ-R RSSe 
 
 
X 
 
 
 
 
 
Blood for Safety Labsf 
X 
Xg 
X 
X 
X 
 
 
 
Urinalysisf 
U 
Ug 
U 
U 
U 
 
 
 
Drug Screenf 
X 
 
 
 
 
 
 
 
Pregnancy Testf,h 
X 
X 
 
 
 
 
 
 
Sputum for Microbiologyf 
 
X 
 
 
 
 
 
 
Blood for CFTRf 
Genotyping 
Sequencing 
 
 
 
 
 
 
Biomarkersf 
X 
X 
 
 
X 
 
 
 
Sweat Chloridef 
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Study Drug Administrationi 
 
 
X 
X 
 
X 
 
 


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Study Procedures 
Screening 
 
Dose 1 
Dose 2 
 
Dose 3 
 
 
Collect Samples for PKf 
 
 
X 
X 
X 
X 
 
 
Abbreviations: C = complete physical exam; CFQ-R RSS = Cystic Fibrosis Questionnaire-Revised Respiratory Symptom Score; 
ECG = electrocardiogram; H = height; PK = pharmacokinetic; S = symptom-directed physical exam; U = urinalysis (dipstick); 
W = weight 
NOTE: See also Protocol Section 7.4 for details on timing of assessments relative to study drug administration. 
a The screening period for an individual subject may be extended for an additional 7 days at the discretion of the Sponsor’s 
Medical Monitor. See Protocol Section 7.2 for details. 
b Includes blood pressure, heart rate, respiratory rate, and temperature. 
c Includes FEV1, FVC, and FEF25-75. 
d A Chest Xray or CT scan obtained within 90 days of screening is acceptable if there was no intercurrent pulmonary illness 
during the interim. 
e Should be completed prior to any other procedures or assessments. 
f See Protocol Appendix 2 for a detailed schedule of these assessments, broken down by type of specimen and time relative to 
dose. 
g Only laboratory assessments that are abnormal (but not clinically significant) at screening should be repeated at Day-1. 
h Pregnancy test (preferably serum but urine is accepted) required for women of childbearing potential only. 
i Subjects who are taking concurrent CF therapy should receive this therapy prior to study drug dosing in the order specified in 
Protocol Section 6.3.1. 


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Table A.1-3: Multiple Ascending Dose Cohorts 5-8, WEEK 2 
 
Study Procedures 
Dose 4 
 
Dose 5 
 
Dose 6 
 
 
Study Day 
8 
9 
10 
11 
12 
13 
14 
In Hours Post Dose 1 
168 
192 
216 
240 
264 
288 
312 
Concomitant Medications 
X 
 
X 
 
X 
 
 
Adverse Events 
X 
 
X 
 
X 
 
 
Physical Exam 
C/S 
 
S 
 
S 
 
 
Height & Weight 
W 
 
 
 
 
 
 
Vital Signsa & Oximetry 
X 
 
X 
 
X 
 
 
Spirometryb 
X 
 
 
 
 
 
 
Blood for Safety Labsc 
X 
 
 
 
 
 
 
Urinalysisc 
U 
 
 
 
 
 
 
Biomarkersc 
X 
 
 
 
 
 
 
Study Drug Administrationd 
X 
 
X 
 
X 
 
 
Collect Samples for PKc 
X 
 
X 
 
X 
 
 
Abbreviations: C = complete physical exam; PK = pharmacokinetic; S = symptom-directed physical exam; U = urinalysis 
(dipstick); W = weight 
NOTE: See also Protocol Section 7.4 for details on timing of assessments relative to study drug administration. 
a Includes blood pressure, heart rate, respiratory rate, and temperature. 
b Includes FEV1, FVC, and FEF25-75. 
c See Protocol Appendix 2 for a detailed schedule of these assessments, broken down by type of specimen and time relative to 
dose. 
d Subjects who are taking concurrent CF therapy should receive this therapy prior to study drug dosing in the order specified in 
Protocol Section 6.3.1. 
 
 


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Table A.1-4: Multiple Ascending Dose Cohorts 5-8, WEEK 3 
 
Study Procedures 
Dose 7 
 
Dose 8 
 
Dose 9 
 
 
Study Day 
15 
16 
17 
18 
19 
20 
21 
In Hours Post Dose 1 
336 
360 
384 
408 
432 
456 
480 
Concomitant Medications 
X 
 
X 
 
X 
 
 
Adverse Events 
X 
 
X 
 
X 
 
 
Physical Exam 
C/S 
 
S 
 
S 
 
 
Height & Weight 
W 
 
 
 
 
 
 
Vital Signsa & Oximetry 
X 
 
X 
 
X 
 
 
Spirometryb 
X 
 
 
 
 
 
 
CFQ-R RSSc 
X 
 
 
 
 
 
 
Blood for Safety Labsd 
X 
 
 
 
 
 
 
Urinalysisd 
U 
 
 
 
 
 
 
Biomarkersd 
X 
 
 
 
 
 
 
Study Drug Administratione 
X 
 
X 
 
X 
 
 
Collect Samples for PKd 
X 
 
X 
 
X 
 
 
Abbreviations: C = complete physical exam; CFQ-R RSS = Cystic Fibrosis Questionnaire-Revised Respiratory Symptom Score; 
PK = pharmacokinetic; S = symptom-directed physical exam; U = urinalysis (dipstick); W = weight 
NOTE: See also Protocol Section 7.4 for details on timing of assessments relative to study drug administration. 
a Includes blood pressure, heart rate, respiratory rate, and temperature. 
b Includes FEV1, FVC, and FEF25-75. 
c Should be completed prior to any other procedures or assessments. 
d See Appendix 2 for a detailed schedule of these assessments, broken down by type of specimen and time relative to dose. 
e Subjects who are taking concurrent CF therapy should receive this therapy prior to study drug dosing in the order specified in 
Protocol Section 6.3.1. 
 
 


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Table A.1-5: Multiple Ascending Dose Cohorts 5-8, WEEK 4 
 
Study Procedures 
Dose 10 
 
Dose 11 
 
Dose 12 
Study Day 
22 
23 
24 
25 
26 
In Hours Post Dose 1 
504 
528 
552 
576 
600 
Concomitant Medications 
X 
 
X 
 
X 
Adverse Events 
X 
 
X 
 
X 
Physical Exama 
C/S 
 
S 
 
C/S 
Height & Weight 
W 
 
 
 
W 
Vital Signsb & Oximetrya 
X 
 
X 
 
X 
Spirometrya,c 
X 
 
 
 
X 
Blood for Safety Labsd 
X 
 
 
 
 
Urinalysisd 
U 
 
 
 
 
Biomarkersd 
X 
 
 
 
 
Sweat Chlorided 
 
 
 
 
X 
Study Drug Administratione 
X 
 
X 
 
X 
Collect Samples for PKd 
X 
 
X 
 
X 
Abbreviations: C = complete physical exam; PK = pharmacokinetic;  
S = symptom-directed physical exam; U = urinalysis (dipstick); W = weight 
a See Protocol Section 7.4 for details on timing of these assessments relative to study drug administration. 
b Includes blood pressure, heart rate, respiratory rate, and temperature. 
c Includes FEV1, FVC, and FEF25-75. 
d See Protocol Appendix 2 for a detailed schedule of these assessments, broken down by type of specimen and time relative to 
dose. 
e Subjects who are taking concurrent CF therapy should receive this therapy prior to study drug dosing in the order specified in 
Protocol Section 6.3.1 
 
 


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Table A.1-6: Multiple Ascending Dose Cohorts 5-8, Follow-Up Visits 
Study Procedures 
PK Follow-up 
24 Hours After Last Dose 
PK Follow-up 
96 Hours After Last Dose 
7 Days 
After Last 
Dose 
(End of 
Treatment) 
Follow-up 
28 Days 
after Last 
Dose 
(End of 
Study) 
Study Day 
27 ± 1 
30 ± 2 
33 
54 
In Hours Post Dose 1 
624 ± 12 
696 ± 48 
768 
1272 
Concomitant Medications 
 
 
X 
X 
Adverse Events 
 
 
X 
X 
Physical Exam 
 
 
C 
C 
Height & Weight 
 
 
W 
W 
Vital Signsa & Oximetry 
 
 
X 
X 
Spirometryb 
 
 
X 
X 
Chest Xray  
 
 
X 
 
12-lead ECG 
 
 
X 
 
CFQ-R RSSc 
 
 
X 
X 
Blood for Safety Labsd 
 
 
X 
X 
Urinalysisd 
 
 
U 
U 
Pregnancy testd,e 
 
 
X 
X 
Sputum for Microbiologyd 
 
 
X 
 
Biomarkersd 
 
 
X 
X 
Sweat Chlorided 
 
 
X 
X 
Collect Samples for PKd 
X 
X 
X 
X 
Abbreviations:  C = complete physical exam; CFQ-R RSS = Cystic Fibrosis Questionnaire-Revised Respiratory Symptom 
Score; PK = pharmacokinetic; U = urinalysis (dipstick); W = weight 
a Includes blood pressure, heart rate, respiratory rate, and temperature. 
b Includes FEV1, FVC, and FEF25-75. 
c Should be completed prior to any other procedures or assessments. 
d See Protocol Appendix 2 for a detailed schedule of these assessments, broken down by type of specimen and time relative to 
dose. 
e Pregnancy test (preferably serum but urine is accepted) required for women of child-bearing potential only. 
 
 


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APPENDIX 2: SCHEDULE OF LABORATORY TESTS 
Table A.2-1: Single Ascending Dose Cohorts 1-4 
Labs 
Screening 
Check-
In 
Dose 
 
 
Discharge 
 
 
 
End of 
Studya 
Study Day 
≤-14 daysb 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
In Hours 
 
-24 
0 
24 
48 
72 
96 
120 
144 
168 
Hematology 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Serum Chemistry 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Hematology & Chemistry Day 1: Pre-dose, 30, 60 minutes, 2, 4, 8, 12 hours post dose 
C-Reactive Protein 
 
X 
X 
X 
 
 
 
 
 
X 
Erythrocyte Sedimentation 
Rate 
 
X 
X 
X 
 
 
 
 
 
X 
C-Reactive Protein & 
Erythrocyte Sedimentation 
Rate 
Day -1 
Day 1: Pre-dose, 24 hours post dose 
Coagulation and CH50 
X 
 
 
 
 
 
 
 
 
X 
Direct Antiglobulin Test 
X 
 
 
 
 
 
 
 
 
X 
Serum Tocopherol (Vit. E) 
X 
 
 
 
 
 
 
 
 
 
Urine microalbumin 
 
X 
 
 
 
 
 
 
 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Day 1: On pooled PK samples 
Day 2, 3, 4, 8: Random sample, preferably 1st morning void 
Drug Screen 
Xc 
 
 
 
 
 
 
 
 
 
Pregnancy testd 
X 
X 
 
 
 
 
 
 
 
X 
Sputum for Microbiology 
 
X 
 
 
 
 
 
 
 
X 
CFTR Genotypinge 
X 
 
 
 
 
 
 
 
 
 
CFTR Sequencing 
 
Xf 
 
 
 
 
 
 
 
 
Sweat Chloride 
X 
 
 
 
 
 
 
 
 
 
PK Sampling 
Serum: 0, 0.5, 1, 2, 3, 4, 12, 24, 48, 54, 72, 168 hours post dose 
Urine: Pre-dose; Pooled from 0 to 4, 4 to 12, and 12 to 24 hours post-dose; and 48, 
72, and 168 hours post dose (UA on each pooled sample).   
Sputum: 3 samples obtained within first 6 hours post dose; 24 hours post dose; Day 
4 (72 hours post dose); and Day 8 (168 hours post dose) 
Serum for PK 
 
 
X 
X 
X 
X 
 
 
 
X 
Urine for PK 
 
 
X 
X 
X 
X 
 
 
 
X 
Sputum for PK 
 
 
Xg 
X 
 
Xh 
 
 
 
Xg 


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Labs 
Screening 
Check-
In 
Dose 
 
 
Discharge 
 
 
 
End of 
Studya 
Biomarker Sampling 
 
Blood (serum and plasma) for 
Biomarkers 
X 
Xg 
 
X 
 
X 
 
 
 
X 
Sputum for Biomarkers 
X 
Xg 
 
X 
 
X 
 
 
 
X 
a For subjects who withdraw prematurely from the study, this visit will occur whenever they leave the study. 
b  The screening period for an individual subject may be extended for an additional 7 days at the discretion of the Sponsor’s 
Medical Monitor. See Protocol Section 7.2 for details. 
c Drug screening may be performed on urine or blood sample. 
d  Women of child-bearing potential only 
e Required if original documentation for CF genotyping is not available or is earlier than the year 2000. 
f Samples may be collected on Day 1 pre-dose instead of Day -1. 
g Suggest obtaining samples in conjunction with performing spirometry at 10, 60 minutes, and 4 hours post dose. 
h Sample may be taken any time prior to discharge (Day 4) or during visit (End of Study). 
 
 
 


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Table A.2-2: Multiple Ascending Dose Cohorts 5-8, WEEK 1 
Dosing Schedule assumes Monday-Wednesday-Friday dosing: 
Study Procedures 
Screening 
 
Dose 1 
Dose 2 
 
Dose 3 
 
 
Study Day 
≤-14 daysa 
-1 
1 
3 
4 
5 
6 
7 
In Hours 
 
-24 
0 
48 
72 
96 
120 
144 
Hematology 
X 
X 
X 
X 
X 
 
 
 
Serum Chemistry 
X 
X 
X 
X 
X 
 
 
 
Hematology & Chemistry Dose 1: Pre-dose, 30, 60 minutes, 2, 4, 8, 12 hours post Dose 1 
Dose 2: 60 minutes and 4 hours post Dose 2 
C-Reactive Protein 
 
X 
X 
 
 
 
 
 
Erythrocyte Sedimentation 
Rate 
 
X 
X 
 
 
 
 
 
C-Reactive Protein & 
Erythrocyte Sedimentation 
Rate 
Day -1 
Day 1: Pre-dose 
Coagulation and CH50 
X 
 
 
 
 
 
 
 
Direct Antiglobulin Test 
X 
 
 
 
 
 
 
 
Serum Tocopherol (Vit. E) 
X 
 
 
 
 
 
 
 
Urine microalbumin 
 
X 
 
 
 
 
 
 
Urinalysis 
X 
X 
X 
X 
X 
 
 
 
Dose 1: Pre-dose, 0-4, 4-12 hours post dose (UA on each pooled sample) 
Dose 2: 60 minutes and 4 hours post dose 
Drug Screen 
Xb 
 
 
 
 
 
 
 
Pregnancy Testc 
X 
X 
 
 
 
 
 
 
Sputum for Microbiology 
 
X 
 
 
 
 
 
 
CFTR Genotypingd 
X 
 
 
 
 
 
 
 
CFTR Sequencing 
 
Xe 
 
 
 
 
 
 
Sweat Chloride 
X 
 
 
 
 
 
 
 
PK Sampling 
Serum: 0, 0.5, 1, 2, 3, 4, 12; pre-Dose 2; 2 hours post Dose 2; 72 hours post Dose 1; 96 
hours post Dose 1 (pre-Dose 3) 
Urine: Pre-dose; Pooled from 0 to 4 and 4 to 12 hours post Dose 1 (UA on each pooled 
sample).  A separate sample should be collected at 24 and 72 hours post Dose 1. 
Sputum: 3 samples obtained within first 6 hours post Dose 1 and Day 4 (72 hours) 
Serum for PK 
 
 
X 
X 
X 
X 
 
 
Urine for PK 
 
 
X 
 
X 
 
 
 
Sputum for PK 
 
 
Xf 
 
X 
 
 
 
Biomarker Sampling 
 
Blood (serum and plasma) 
for Biomarkers 
X 
Xe 
 
 
X 
 
 
 
Sputum for Biomarkers 
X 
Xe 
 
 
X 
 
 
 


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a The screening period for an individual subject may be extended for an additional 7 days at the discretion of the Sponsor’s 
Medical Monitor. See Protocol Section 7.2 for details. 
b Drug screening may be performed on urine or blood sample. 
c Women of child-bearing potential only. 
d Required if original documentation for CF genotyping is not available or is earlier than the year 2000. 
e Samples may be collected on Day 1 pre-dose instead of Day -1. Samples for CFTR sequencing should not be collected for 
subjects who participated in SAD cohort. 
f Suggest obtaining samples in conjunction with performing spirometry at 10, 60 minutes, and 4 hours post dose. 


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18 April 2017 
 
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Table A.2-3: Multiple Ascending Dose Cohorts 5-8, WEEK 2 
 
Labs 
Dose  4 
 
Dose 5 
 
Dose 6 
 
 
Study Day 
8 
9 
10 
11 
12 
13 
14 
In Hours 
168 
192 
216 
240 
264 
288 
312 
Hematology 
X 
 
 
 
 
 
 
Serum Chemistry 
X 
 
 
 
 
 
 
Hematology & Chemistry Dose 4: Pre-dose, 15, 60 minutes, 2 hours post dose 
C-Reactive Protein 
X 
 
 
 
 
 
 
Erythrocyte Sedimentation Rate 
X 
 
 
 
 
 
 
C-Reactive Protein & Erythrocyte Sedimentation Rate Dose 4: Pre-dose 
Coagulation and CH50 
X 
 
 
 
 
 
 
Urine microalbumin 
 
 
X 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
Dose 4: Pre-dose, 60 minutes and 2 hours post dose 
Dose 10: Urine microalbumin pre-dose 
PK Sampling Serum: Prior to Dose 4, 5, and 6 
Sputum: Prior to Doses 4, 5, and 6 
Serum for PK 
X 
 
X 
 
X 
 
 
Sputum for PK 
X 
 
X 
 
X 
 
 
Biomarker Sampling Dose 4: Pre-dose 
Blood (serum and plasma) for Biomarkers 
X 
 
 
 
 
 
 
Sputum for Biomarkers 
X 
 
 
 
 
 
 
 
 
 
 
 
 


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18 April 2017 
 
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Table A.2-4: Multiple Ascending Dose Cohorts 5-8, WEEK 3 
 
Study Procedures 
Dose 7 
 
Dose 8 
 
Dose 9 
 
 
Study Day 
15 
16 
17 
18 
19 
20 
21 
In Hours 
336 
360 
384 
408 
432 
456 
480 
Hematology 
X 
 
 
 
 
 
 
Serum Chemistry 
X 
 
 
 
 
 
 
Hematology & Chemistry Dose 7: Pre-dose, 15, 60 minutes, 2 hours post dose 
C-Reactive Protein 
X 
 
 
 
 
 
 
Erythrocyte Sedimentation Rate 
X 
 
 
 
 
 
 
C-Reactive Protein & Erythrocyte 
Sedimentation Rate Dose 7: Pre-dose 
Urinalysis 
X 
 
 
 
 
 
 
Dose 7: Pre-dose, 60 minutes and 2 hours post dose 
PK Sampling Serum: Prior to Dose 7, and 1 hours post Dose 7; Prior to Doses 
8 and 9 
Serum for PK 
X 
 
X 
 
X 
 
 
Biomarker Sampling Dose 7: Predose 
Blood (serum and plasma) for Biomarkers 
X 
 
 
 
 
 
 
Sputum for Biomarkers 
X 
 
 
 
 
 
 
 
 


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18 April 2017 
 
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Table A.2-5: Multiple Ascending Dose Cohorts 5-8, WEEK 4 
 
Study Procedures 
Dose 10 
 
Dose 11 
 
Dose 12 
Study Day 
22 
23 
24 
25 
26 
In Hours 
504 
528 
552 
576 
600 
Hematology 
X 
 
 
 
 
Serum Chemistry 
X 
 
 
 
 
Hematology & Chemistry Dose 10: Pre-dose, 15, 60 minutes, 2 hours post dose 
C-Reactive Protein 
X 
 
 
 
 
Erythrocyte Sedimentation Rate 
X 
 
 
 
 
C-Reactive Protein & Erythrocyte 
Sedimentation Rate Dose 10: Pre-dose 
Urinalysis 
X 
 
 
 
 
Dose 10: Pre-dose, 60 minutes and 2 hours post dose 
Sweat Chloride 
 
 
 
 
X 
PK Sampling 
Serum: Pre-Dose 10 and 11; Dose 12 (pre-dose; post dose at 1, 2, 
3, 4, 8 hours) 
Urine: Dose 12 pre-dose only 
Serum for PK 
X 
 
X 
 
X 
Urine for PK 
 
 
 
 
X 
Biomarker Sampling Dose 10: Pre-dose 
Blood (serum and plasma) for Biomarkers 
X 
 
 
 
 
Sputum for Biomarkers 
X 
 
 
 
 
 
 


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18 April 2017 
 
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Table A.2-6: Multiple Ascending Dose Cohorts 5-8, Follow-up 
 
Study Procedures 
PK Follow-up 
24 hours After 
Last Dose 
PK Follow-up 
96 Hours After 
Last Dose 
7 Days 
After Last Dose (End of 
Treatment)a 
28 Days  
After Last Dose 
(End of Study)a 
Study Day 
27 
30 
33 
54 
In Hours Post Dose 1 
624 ± 12 
696 ± 96 
768 
1272 
Hematology 
 
 
X 
X 
Serum Chemistry 
 
 
X 
X 
C-Reactive Protein 
 
 
X 
 
Erythrocyte Sedimentation 
Rate 
 
 
X 
 
Coagulation and CH50 
 
 
X 
 
Direct Antibody Test 
 
 
X 
 
Urine microalbumin 
 
 
 
X 
Urinalysis 
 
 
X 
X 
Pregnancy testb 
 
 
X 
X 
Sputum for Microbiology 
 
 
X 
 
Sweat Chloride 
 
 
X 
X 
PK Sampling 
Serum post last dose: 24 ±12 hrs, 96 ± 48, hours post last dose, and at End of 
Treatment and End of Study Visit  
Urine post last dose: 24 ±12 hrs, 96 ± 48, hours post last dose 
Serum for PK 
X 
X 
X 
X 
Urine for PK 
X 
X 
 
 
Biomarker Sampling End of Treatment and End of Study Visits 
Blood (serum and plasma) 
for Biomarkers 
 
 
X 
X 
Sputum for Biomarkers 
 
 
X 
X 
a See Protocol Section 5.5.2 for details on these visits for subjects who withdraw prematurely from the study. 
b Women of child-bearing potential only