Clinical trial NCT02971839
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2016-12-01; Completion date: 2017-08-01
Enrollment: 11 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the efficacy and safety of CTP-656 in patients with cystic fibrosis (CF) who have a cystic fibrosis transmembrane conductance regulator (CFTR) gating mutation.

Detailed description:
This is a randomized, parallel-group, double-blind, placebo controlled multicenter study to evaluate the safety and efficacy of CTP-656 in CF patients with CFTR gating mutations, compared to Kalydeco, for a total of 28 days. Subjects will be randomized to receive either double-blind CTP-656 or placebo, or open-label Kalydeco.

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None
Interventions: intervention 1: VX-561 intervention 2: Placebo intervention 3: IVA
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_000.pdf: 
CTP-656 
 
Amendment #1 October 24, 2016 
Protocol CP656.2001 
 
Concert Pharmaceuticals, Inc. 
 
 
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                 A PHASE 2, RANDOMIZED, PARALLEL-GROUP, DOUBLE-
BLIND, PLACEBO CONTROLLED STUDY TO EVALUATE THE SAFETY 
AND EFFICACY OF CTP-656 WITH AN OPEN-LABEL ACTIVE 
COMPARATOR IN PATIENTS WITH CYSTIC FIBROSIS WITH CFTR 
GATING MUTATIONS 
  
INVESTIGATIONAL PRODUCT (IP):  
CTP-656 
PROTOCOL NUMBER: 
 
CP656.2001 
DATE FINAL: 
 
July 15, 2016 
AMENDMENT #1 DATE: 
 
October 24, 2016 
SPONSOR NAME / ADDRESS: 
 
 
 
Concert Pharmaceuticals, Inc. 
99 Hayden Avenue, Suite 500 
Lexington, MA  02421 
 
CONFIDENTIAL 
This protocol is provided to you as an Investigator, potential Investigator, or consultant for review by 
you, your staff, and ethics committee/institutional review board.  The information contained in this 
document is regarded as confidential and, except to the extent necessary to obtain informed consent, 
may not be disclosed to another party unless such disclosure is required by law or regulations.  
Persons to whom the information is disclosed must be informed that the information is confidential 
and may not be further disclosed by them. 
 
 




CTP-656 
 
Amendment #1 October 24, 2016 
Protocol CP656.2001 
 
Concert Pharmaceuticals, Inc. 
 
 
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SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
Protocol Number:  CP656.2001 
 
 
 
 
 
Signature of Principal Investigator 
 
dd mmm yyyy 
 
 
Printed Name of Principal Investigator 
Institution Name:   
 
By my signature, I agree to personally supervise the conduct of this study at my study 
site and to ensure its conduct is in compliance with the protocol, informed consent, 
Human Research Ethics Committees (IRBs or ECs) procedures, instructions from 
Concert representatives, the Declaration of Helsinki, ICH Good Clinical Practices 
Guidelines, and local regulations governing the conduct of clinical studies. 
 
 


CTP-656 
 
Amendment #1 October 24, 2016 
Protocol CP656.2001 
 
Concert Pharmaceuticals, Inc. 
 
 
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SYNOPSIS 
Name of Sponsor/Company: 
Concert Pharmaceuticals 
Name of Investigational Product: 
CTP-656 
Name of Active Ingredients: 
CTP-656  
Title of Study:  
A Phase 2, Randomized, Parallel-Group, Double-Blind, Placebo Controlled Study to 
Evaluate the Safety and Efficacy of CTP-656 with an Open-Label Active Comparator in 
Patients with Cystic Fibrosis with CFTR Gating Mutations 
Study center(s): Multicenter study; approximately 15-20 sites 
Studied period (years):  
The estimated duration of the study is 15 
months. 
Phase of development: 2 
 
Objective: The objectives of this study are to evaluate the efficacy and safety of CTP-656 in 
patients with cystic fibrosis (CF) who have one of the following cystic fibrosis 
transmembrane conductance regulator (CFTR) gating mutations: G551D, G1244E, G1349D, 
G178R, G551S, S1251N, S1255P, S549N, or S549R, and have been stable for at least 3 
months on Kalydeco® therapy prior to screening. 
Methodology:  
This is a randomized, parallel-group, double-blind, placebo controlled multicenter study to 
evaluate the safety and efficacy of CTP-656 in patients with CF with CFTR gating 
mutations.  The study will include an open-label active comparator, i.e., Kalydeco.  Patients 
will be ≥ 18 years old, have been stable on Kalydeco therapy for at least 3 months prior to 
screening, and have a percent predicted forced expiratory volume in 1 second (FEV
1) ≥ 60% 
predicted for age, sex, and height, at screening and baseline (Day 1 of study treatment).  
There will be an opportunity for including patients with a percent predicted FEV1 ≥ 50% 
predicted for age, sex, and height, at screening, if interim data reviewed by an independent 
Data Monitoring Committee (DMC) supports this.  Following screening, patients meeting 
all inclusion and no exclusion criteria will be randomized (1:1:1:1:1), utilizing an Interactive 
Response System (IXRS), to one of the 5 treatment groups shown below:  
• Double-blinded CTP-656 20 mg for 28 days  
• Double-blinded CTP-656 100 mg for 28 days 
• Double-blinded CTP-656 150 mg for 28 days 
• Double-blinded Placebo for 28 days 
• Remain on (open-label) Kalydeco for 28 days 


CTP-656 
 
Amendment #1 October 24, 2016 
Protocol CP656.2001 
 
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Methodology (continued): 
 
Patients will return to the clinic on Day 1 (start of study treatment) for baseline assessments, 
including spirometry, sweat chloride, physical examination, and laboratory assessments 
including a baseline blood sample collection for pharmacokinetic (PK) evaluation 
(excluding open-label Kalydeco group).  
Patients who continue to have percent predicted FEV1 ≥ 60% at the baseline (Day 1) 
assessment will be randomized to one of the five treatment groups.     
Patients randomized to the double-blind CTP-656 or Placebo groups will be administered 
their dose in the clinic on Day 1 after consuming a small meal.  Patients randomized to the 
open-label Kalydeco group will be instructed to take their dose in the clinic on Day 1 with 
fat-containing food as prescribed.  All patients will remain in the clinic for safety/tolerability 
assessments.  All patients (excluding open-label Kalydeco group) will be available for 2 
separate blood collections for PK assessments; the first will be anytime between 30 minutes 
and 2 hours post-dose and the second collection will be anytime between 4 and 6 hours post-
dose.  The actual time collected will be recorded in each case. Patients will be instructed to 
continue to take their assigned study treatment each day after consuming a small meal for 
those on CTP-656 or Placebo, or fat-containing food for those on Kalydeco, for a total of 28 
days.  On Day 3, each patient will receive a phone call to discuss any adverse events (AEs) 
or other medical changes that may have occurred since Day 1. 
Patients will return to the clinic on Day 7, Day 14, and Day 28 to complete assessments 
outlined in the Schedule of Events (Table 5.   
Twenty-four hours after the administration of the last dose of CTP-656 or Placebo, all 
patients will resume taking Kalydeco as prescribed by the Investigator. Patients in the open-
label Kalydeco group will continue taking Kalydeco as prescribed after the end of study 
treatment period (Day 28)  One week after the last dose of study treatment (Day 35), 
patients will have a follow-up visit.   
The safety of the subjects will be monitored throughout the study by the investigator and as 
spontaneously reported by the subject, in addition to the independent DMC.  An interim 
analysis will be performed which will be described in the DMC Charter and the Statistical 
Analysis Plan (SAP).  At any time during the study, patients who experience  
≥ 10 percentage point decrease in percent predicted FEV1 and/or have signs and symptoms 


CTP-656 
 
Amendment #1 October 24, 2016 
Protocol CP656.2001 
 
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of pulmonary exacerbations as defined by the Fuchs criteria1 may resume Kalydeco at the 
instruction and discretion of the Investigator.  These patients will have Visit 5 safety, 
spirometry and CFQ-R assessments performed prior to resuming Kalydeco, if possible, and 
will be followed until the end of the study, as applicable.  
Number of Subjects (planned):  
Approximately 30-40 patients are planned to be enrolled, with approximately 6-8 patients 
randomized to each treatment group. 
Main Criteria for Inclusion and Exclusion:   
Patients eligible for enrollment in the study must meet all of the following inclusion criteria 
and none of the exclusion criteria:   
Inclusion Criteria: 
1. Is capable of giving written informed consent, ensuring that the patient will be 
compliant with the requirements and restrictions listed in the consent form and the 
protocol 
2. Has a confirmed diagnosis of CF
2, 3, as determined by prior genotyping, with at least 
one allele of the following CFTR gating mutations: G551D, G1244E, G1349D, 
G178R, G551S, S1251N, S1255P, S549N, and S549R.  The CF mutations must be 
appropriately documented in the medical record 
3. Has been stable on Kalydeco therapy for at least 3 months prior to screening 
4. Is willing to remain off Kalydeco for 28 days if not assigned to the open label 
Kalydeco treatment arm 
5. Is willing to remain on stable CF background therapy regimen as directed by 
physician/investigator for the duration of study participation   
6. Has FEV1 ≥ 60% of predicted normal for age, sex, and height
4 at screening and 
baseline (Day 1) assessments 
7. Is 18 years of age or older 
8. Weighs at least 40 kg at screening 
9. Patients of either gender and women of childbearing potential must be willing to use 
a medically highly effective form of birth control during the treatment period and 30 
days after the last dose of study treatment.  Examples of medically highly effective 
forms of birth control are: 
o Surgically sterile (via hysterectomy or bilateral ligation) 
o Has a male sexual partner who is sterile 
o Use of implants of levonorgestrel 
o Use of oral contraceptive (combined or progesterone only) 
o Use of double-barrier method (any combination of physical and chemical 
methods) 
o Use of any intrauterine device or other method with published data showing 
that the lowest expected failure rate is less than 1% per year (not all 
intrauterine devices meet this criterion) 
10. If needed, has access to a care provider to provide assistance in completing study 
activities 
Note: (a) Patients who do not meet the percent predicted FEV1 ≥ 60% criterion at the 
screening assessment may return for a reassessment of FEV1 within 5 days.  Patients 
who do not meet the FEV1 ≥ 60% criterion at the baseline assessment will not be eligible 
for enrollment. 


CTP-656 
 
Amendment #1 October 24, 2016 
Protocol CP656.2001 
 
Concert Pharmaceuticals, Inc. 
 
 
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Exclusion Criteria: 
1. Acute upper respiratory infection within 14 days of the first dose of study treatment 
2. Lower respiratory infection, pulmonary exacerbation, or changes in therapy 
(excluding inhaled antibiotics) for pulmonary disease within 4 weeks before the first 
dose of study treatment  
3. Uncontrolled type 2 diabetes, or uncontrolled CF-related diabetes 
4. History of  hepatitis C or chronic active hepatitis B infection 
5. History of pulmonary tuberculosis, non-tuberculosis mycobacterial infections or 
allergic bronchopulmonary aspergillosis (ABPA) treated during screening or within 
2 years prior to screening 
6. Colonization with B. cenocepacia, B. dolosa, B. multivorans, and/or M. abcessus 
within 2 years prior to Screening  
7. Abnormal liver function at Screening, defined as ≥ 3 × upper limit of normal (ULN), 
of any 3 or more of the following: serum alanine transaminase (ALT), serum 
aspartate transaminase (AST), gamma-glutamyl transpeptidase (GGT), serum 
alkaline phosphatase (ALP), total bilirubin at screening 
8. Are current smokers, or previous smokers with cessation less than 6 months before 
screening 
9. History of abnormal renal function (creatinine clearance < 50 mL/min using the 
Cockgroft-Gault equation) 
10. History of prolonged QT/QTc interval with Fridericia’s correction (QTcF) > 450 
msec for males or QTcF > 470 msec for females at screening 
11. History of solid organ or hematological transplantation 
12. History of alcohol, medication, or illicit drug abuse within 1 year before screening 
13. Currently participating in another therapeutic clinical study or previously 
participated in an investigational drug study within 30 days before screening  
14. Using any inhibitor or inducer of cytochrome P450 3A during the study or within 30 
days of screening 
15. Women who are pregnant or lactating, or have plans to become pregnant during the 
study or within 1 month following the last dose 
16. Unable or unwilling to comply with study requirements 
17. History of any illness or condition that, in the opinion of the investigator might 
confound the results of the study or pose an additional risk in administering  
CTP-656 to the patient 
Investigational Product, Dosage and Mode of Administration:  
CTP-656:  20 mg, 100 mg or 150 mg, taken orally, once daily, with a small meal.   
Reference Therapy, Dosage and Mode of Administration:  
Kalydeco: 150 mg, taken orally, once every 12 hours with fat-containing food 
Placebo: Taken orally, once daily, with a small meal. 
Duration of Study Participation:  
Patients will be screened within 14 days of administration of first dose of study treatment 
(Day 1) and if eligible will be randomized to 1 of the 5 treatment groups.  Patients will be 


CTP-656 
 
Amendment #1 October 24, 2016 
Protocol CP656.2001 
 
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treated double-blind with 1 of 3 doses of CTP-656, or Placebo, or will remain on open-label 
Kalydeco for 28 days; 1 week after the last dose of study treatment, patients will have a 
follow-up visit.  Therefore, each patient’s study participation (including the screening 
period) will be up to approximately 49 days or 7 weeks in duration. 
Criteria for Evaluation: 
Efficacy will be primarily assessed by changes in sweat chloride. Changes in percent 
predicted FEV1, and quality of life using the Cystic Fibrosis Questionnaire-Revised  
(CFQ-R) will also be assessed.  Safety and tolerability will be evaluated by monitoring AEs, 
and by results of physical examinations, vital signs, electrocardiograms, and clinical 
laboratory tests.   
 
Efficacy Measures 
 
Primary Endpoint 
• Change from baseline in sweat chloride at Day 28 
 
Secondary Endpoints 
• Change from baseline in percent predicted FEV1 at Day 28 
• Change from baseline in CFQ-R Respiratory Domain at Day 28   
 
Where: 
baseline is the measurement prior and closest to the administration of the first of treatment 
on Day 1, and change = value at scheduled day – value at baseline  
 
Safety Measures 
Safety and tolerability of study treatment will be evaluated by monitoring AEs, and by 
results of physical examinations, vital signs, electrocardiograms (ECGs), and clinical 
laboratory tests.  Adverse events will be coded by Medical Dictionary for Regulatory 
Activities system organ class and preferred term.  Concomitant medications will be coded 
by World Health Organization Drug Dictionary Anatomical-Therapeutic-Chemical 
classification and preferred drug name.   
 
Statistical Methods: 
Analysis Populations: 
The Safety Population is defined as all randomized patients who receive at least one dose of 




CTP-656 
 
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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................15
 
2. 
INTRODUCTION 
......................................................................................................17
 
 
 
 
 
 
 
3. 
STUDY OBJECTIVES ..............................................................................................22
 
4. 
OVERALL STUDY DESIGN 
....................................................................................23
 
4.1. 
Study Design 
...............................................................................................................23
 
 
 
4.3. 
Study Duration 
............................................................................................................25
 
4.4. 
End of Trial 
.................................................................................................................25 
5. 
STUDY PROCEDURES 
............................................................................................26
 
5.1. 
Schedule of Events .....................................................................................................26 
5.2. 
Study Procedures 
........................................................................................................28
 
5.2.1. 
Visit 1, Day -14 to Day -1 (Screening Visit) 
..............................................................28
 
5.2.2. 
Treatment Period ........................................................................................................29
 
5.2.2.1. 
Visit 2, Day 1 (Start of treatment) 
..............................................................................29
 
5.2.2.2. 
Telephone Call, Day 3 
................................................................................................30 
5.2.2.3. 
Visit 3, Day 7 and Visit 4, Day 14 
..............................................................................30 
5.2.2.4. 
Telephone Call, Day 21 
..............................................................................................31 
5.2.2.5. 
Visit 5, Day 28 (End of Treatment Visit), or Early Termination ...............................31
 
5.2.2.6. 
Visit 6, Day 35 (Follow-Up) 
.......................................................................................32
 
6. 
STUDY POPULATION 
.............................................................................................34
 
6.1. 
Number of Patients and Sites 
......................................................................................34 
6.2. 
Inclusion Criteria 
........................................................................................................34
 
6.3. 
Exclusion Criteria 
.......................................................................................................35
 
7. 
DESCRIPTION OF STUDY TREATMENTS ..........................................................37
 
7.1. 
Description of Study Treatments 
................................................................................37
 
7.2. 
Study Treatment Administration and Schedule 
..........................................................37 
7.3. 
Method of Study Treatment Assignment 
....................................................................37 
7.4. 
Packaging and Labeling 
..............................................................................................38
 


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7.5. 
Investigational Product Accountability and Disposal 
.................................................38 
7.6. 
Study Treatment Compliance 
.....................................................................................38
 
8. 
CONCOMITANT MEDICATIONS AND PROCEDURES 
......................................39
 
9. 
EFFICACY PROCEDURES 
......................................................................................40
 
9.1. 
Pulmonary Function 
....................................................................................................40
 
9.2. 
Sweat Chloride Analysis 
.............................................................................................41
 
9.3. 
Health-Related Quality of Life 
...................................................................................41
 
10. 
SAFETY PROCEDURES 
..........................................................................................42
 
10.1. 
Physical Examination 
.................................................................................................42
 
10.2. 
Vital Signs ..................................................................................................................42
 
10.3. 
Electrocardiograms 
.....................................................................................................42
 
10.4. 
Clinical Laboratory Assessments ...............................................................................42
 
11. 
PHARMACOKINETIC ASSESSMENTS 
.................................................................44
 
11.1. 
PK Blood Sample Collection 
......................................................................................44
 
11.2. 
Plasma Sample Storage and Shipping 
........................................................................44 
11.3. 
Bioanalytical Methodology for Determination of Plasma Concentrations 
.................44 
12. 
STATISTICAL ANALYSES 
.....................................................................................45
 
12.1. 
Overview 
.....................................................................................................................45
 
12.2. 
Interim Analysis 
..........................................................................................................45
 
12.3. 
Determination of Sample Size 
....................................................................................45
 
12.4. 
Analysis Populations ..................................................................................................45 
12.5. 
Background and Demographic Characteristics ..........................................................45
 
12.6. 
Patient Disposition 
......................................................................................................46
 
12.7. 
Efficacy Analysis 
........................................................................................................46
 
12.8. 
Pharmacokinetic Analysis ..........................................................................................47
 
12.9. 
Safety Analysis 
...........................................................................................................47
 
12.9.1. 
Adverse Events 
...........................................................................................................47
 
12.9.2. 
Concomitant Medications 
...........................................................................................47 
12.9.3. 
Physical Examination 
.................................................................................................47
 
12.9.4. 
Vital Signs ..................................................................................................................47
 
12.9.5. 
Electrocardiogram 
.......................................................................................................47
 
12.9.6. 
Clinical Laboratory Assessments ...............................................................................48
 


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12.9.7. 
Study Treatment Compliance 
.....................................................................................48
 
13. 
ADVERSE EVENTS..................................................................................................49
 
13.1. 
Monitoring, Recording, and Reporting of Adverse Events 
........................................49 
13.2. 
Evaluation of Adverse Events ....................................................................................49 
13.2.1. 
Seriousness .................................................................................................................49 
13.2.2. 
Severity/Intensity 
........................................................................................................51
 
13.2.3. 
Causality 
.....................................................................................................................51
 
13.2.4. 
Duration 
......................................................................................................................52 
13.2.5. 
Action Taken ..............................................................................................................52
 
13.2.6. 
Outcome 
......................................................................................................................52 
13.2.7. 
Assessment of Expectedness 
......................................................................................52
 
13.3. 
Abnormal Laboratory Values 
.....................................................................................52 
13.4. 
Pregnancy ...................................................................................................................53
 
13.5. 
Adverse Event Documentation 
...................................................................................53
 
13.5.1. 
Adverse Event Recording and Reporting 
...................................................................53 
13.5.2. 
Follow-up of Adverse Events and Serious Adverse Events 
.......................................53 
13.6. 
Reporting of Serious Adverse Events 
.........................................................................53 
13.6.1. 
Urgent Safety Measures 
..............................................................................................54
 
13.6.2. 
Reporting 
....................................................................................................................54 
13.6.3. 
Safety Queries 
.............................................................................................................55
 
13.7. 
Expedited Reporting of Adverse Events 
.....................................................................56 
13.7.1. 
Immediately Reportable Experiences 
.........................................................................56
 
14. 
DISCONTINUATIONS 
.............................................................................................58
 
14.1. 
Handling of Early Terminations 
.................................................................................59 
14.2. 
Sponsor’s Termination of Study 
.................................................................................60 
15. 
EMERGENCY PROCEDURES ................................................................................61
 
15.1. 
Emergency Contact 
.....................................................................................................61
 
15.2. 
Emergency Unblinding of Treatment Assignment 
.....................................................61 
16. 
REGULATORY CONSIDERATIONS......................................................................62
 
16.1. 
Good Clinical Practice 
................................................................................................62
 
16.2. 
Sponsor’s Responsibility 
............................................................................................62 
16.3. 
Audits and Inspections 
................................................................................................62 


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16.4. 
Investigator Responsibilities 
.......................................................................................63
 
17. 
ETHICS 
......................................................................................................................64
 
17.1. 
Ethics Review 
.............................................................................................................64
 
17.2. 
Ethical Conduct of the Study 
......................................................................................65 
17.3. 
Patient Information and Informed Consent 
................................................................65 
17.4. 
Confidentiality 
............................................................................................................66
 
17.5. 
Patient Data Protection 
...............................................................................................66
 
17.6. 
Protocol Amendments ................................................................................................67 
17.7. 
Ongoing Information for Institutional Review Board / Ethics Committee ................67
 
17.8. 
Closure of the Study 
...................................................................................................67 
18. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................69
 
19. 
DATA HANDLING AND RECORDKEEPING 
.......................................................70
 
19.1. 
Data Collection 
...........................................................................................................70
 
19.2. 
Case Report Form Completion 
...................................................................................70
 
19.3. 
Database Management, Data Clarification, and Quality Assurance 
...........................70
 
19.4. 
Inspection of Records/Source Documents 
..................................................................71 
19.5. 
Retention of Records 
..................................................................................................72 
 
 
21. 
REFERENCES 
...........................................................................................................74
 
22. 
APPENDICES 
............................................................................................................76
 
APPENDIX A. LABORATORY ASSESSMENTS 
...................................................................77
 
APPENDIX B. CYTOCHROME P450 DRUG INTERACTIONS 
............................................78
 
 
 




CTP-656 
 
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1. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 1: 
Abbreviations and Specialist Terms 
Abbreviation or special term Explanation 
ABPA 
allergic bronchopulmonary aspergillosis 
AE  
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
Anatomical-Therapeutic-Chemical 
AUC 
area under the plasma concentration-time curve 
AUC0-24hr 
area under the plasma concentration-time curve from time 0 to 24 
hours post-dose 
AUC0-inf 
area under the plasma concentration-time curve from time 0 to 
infinity 
C24hr 
concentration 24 hours following a single dose 
CF 
cystic fibrosis 
CFQ-R 
Cystic Fibrosis Questionnaire-Revised 
CFR 
Code of Federal Regulations 
CFTR 
cystic fibrosis transmembrane conductance regulator 
Cmax 
maximum plasma concentration  
CRF/eCRF 
case report form/electronic case report form 
CRO 
clinical research organization  
CTCAE 
Common Terminology Criteria for Adverse Events 
CTP-656 
D9-ivacaftor 
CYP 
cytochrome P450 
DMC 
Data Monitoring Committee 
DMP 
data management plan 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
electronic data capture 
EENT 
eyes/ears/nose/throat 
FAS 
Full Analysis Set 


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Abbreviation or special term Explanation 
FEV1 
forced expiratory volume in 1 second 
FVC 
forced vital capacity 
FEF25-75 
forced expiratory flow over the middle half of the forced vital 
capacity 
G551D 
a missense mutation that results in the replacement of a glycine 
residue at position 551 of the CFTR with an aspartic acid residue 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Probability and Accountability Act 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IP 
investigational medicinal product 
IRB 
Institutional Review Board 
IXRS 
Interactive Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
PHI 
protected health information 
PK 
pharmacokinetic(s) 
QoL 
quality of life 
QTcF 
Fridericia-corrected QT interval 
SAE 
serious adverse event 
SDV 
source document verification 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
T1/2 
apparent terminal half-life 
Tmax 
Time to reach maximum plasma concentration 
ULN 
upper limit of normal 
WHO 
World Health Organization 
 


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2. 
INTRODUCTION  
Cystic fibrosis (CF) is an autosomal recessive disease with serious, chronically debilitating 
morbidities and high premature mortality.  Cystic fibrosis is caused by mutations in the cystic 
fibrosis transmembrane conductance regulator (CFTR) gene that results in absent or deficient 
function of the CFTR protein at the cell surface.  The CFTR protein is an epithelial chloride 
channel responsible for aiding in the regulation of salt and water absorption and secretion in 
various tissues.  Gating mutations result in a CFTR protein with a primary defect of low channel 
open probability compared to normal CFTR.  The G551D mutation is the most common gating 
mutation worldwide, and when paired with another mutation associated with minimal CFTR 
function (e.g. F508del), will most often result in a severe CF clinical phenotype.  
Kalydeco® (ivacaftor), is the first targeted therapeutic agent for the treatment of CF in patients 
with the G551D CFTR mutation.  Ivacaftor potentiates the function of the mutant CFTR chloride 
channel present on the apical surface of bronchial epithelial cells.  Ivacaftor is extensively 
metabolized in humans and is dosed twice-daily.   
Kalydeco was first approved by the U.S. Food and Drug Administration (FDA) in January 2012 
for use in people with CF ages 6 and older who have at least one copy of the G551D mutation.  
Kalydeco was subsequently approved by the European Medicines Agency (EMA) in July 2012, 
Health Canada in November 2012, and by the Australian Therapeutic Goods Administration 
(TGA) in July 2013 for the same indication.  In February 2014, Kalydeco was approved by the 
FDA for use in people with CF ages 6 and older who have the following additional CFTR 
mutations: G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P and G1349D.  In 
December 2014, Kalydeco was approved for use in patients suffering from CF aged six years and 
above with an R117H mutation. In March 2015, Kalydeco was approved by the U.S. FDA for 
use in CF patients aged two to less than six years who have one of the following mutations in the 
CFTR gene: G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, G1349D and 
R117H. 
CTP-656 is a deuterated isotopolog of ivacaftor that has demonstrated an improved PKprofile in 
non-clinical studies as well as Phase 1 studies in healthy volunteers, enabling once daily dosing 
in the clinical setting.  
The CTP-656 Investigator’s Brochure (IB) can be consulted for more detailed technical 
information, discussion of nonclinical evaluations, and relevant information regarding the known 
and theoretical safety profile. 










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3. 
STUDY OBJECTIVES 
The objectives of this study are to evaluate the efficacy and safety of CTP-656 in patients with 
cystic fibrosis (CF) who have one of the following cystic fibrosis transmembrane conductance 
regulator (CFTR) gating mutations: G551D, G1244E, G1349D, G178R, G551S, S1251N, 
S1255P, S549N, or S549R, and have been stable for at least 3 months on Kalydeco therapy prior 
to screening. 


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4. 
OVERALL STUDY DESIGN  
4.1. 
Study Design 
This is a randomized, parallel-group, double-blind, placebo controlled multicenter study in 
approximately 30-40 patients with CF who have a CFTR gating mutation (G1244E, G1349D, 
G178R, G551S, S1251N, S1255P, S549N, or S549R).  The study will include an open-label 
active comparator, i.e., Kalydeco.  Patients will be ≥ 18 years old, have been stable for 3 months 
on Kalydeco therapy prior to the screening, and have percent predicted FEV1 ≥ 60% predicted 
for age, sex and height.  Following screening, patients meeting all inclusion and no exclusion 
criteria will be randomized (1:1:1:1:1), utilizing an Interactive Response System (IXRS), to one 
of the 5 treatment groups shown below:  
• Double-blinded CTP-656 20 mg for 28 days  
• Double-blinded CTP-656 100 mg for 28 days 
• Double-blinded CTP-656 150 mg for 28 days 
• Double-blinded Placebo for 28 days 
• Remain on (open-label) Kalydeco for 28 days 
 
Figure 4: 
Study Design   
 
 
Patients will return to the clinic on Day 1 (start of study treatment) for a review of eligibility 
criteria and for baseline assessments, including spirometry, sweat chloride, physical examination, 
and laboratory assessments including a baseline blood sample collection for PK evaluation 
(excluding open-label Kalydeco group).  


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Patients who have percent predicted FEV
1 ≥ 60% at the baseline (Day 1) assessment will be 
randomized to one of the five treatment groups.  Patients who do not meet the percent predicted 
FEV1 ≥ 60% criterion at the baseline assessment will not be enrolled. 
Patients who are randomized to the double-blind CTP-656 or Placebo groups will be dispensed 
appropriate study treatment and will take the first dose in the clinic on Day 1 after consuming a 
small meal.  Patients who are randomized to the open-label Kalydeco group will take their dose 
of Kalydeco in the clinic on Day 1 after consuming fat-containing food as prescribed.  Each 
patient will remain in the clinic for safety and tolerability assessments.  Patients (excluding open-
label Kalydeco group) will be available for blood collection for PK assessments at 1 time point 
each within of the following 2 time windows post-dose (1) between 30 minutes and 2 hours post-
dose and (2) between 4 and 6 hours post-dose.  Patients will be instructed to continue taking 
CTP-656 or Placebo each day (once a day) after a small meal for a total of 28 days.  Patients in 
the open-label Kalydeco group will be instructed to continue taking Kalydeco after consuming 
fat-containing food as prescribed for 28 days.   
On Day 3, each patient will receive a phone call to discuss any adverse events (AEs) or other 
medical changes that may have occurred since Day 1. 
Patients will return to the clinic on Day 7, Day 14, and Day 28 to complete assessments outlined 
in the Schedule of Events (Table 5).  On Day 21 patients will receive a phone-call to discuss any 
adverse events (AEs) or other medical changes that may have occurred between study visit days. 
Twenty-four hours after the last dose of CTP-656 or Placebo, patients will resume taking 
Kalydeco as prescribed by the Investigator.  Patients in the open-label Kalydeco group will 
continue taking Kalydeco as prescribed after the end of study treatment period (Day 28).  One 
week after the administration of the last dose of study treatment (Day 35), each patient will have 
a follow-up visit.   
The safety of the subjects will be monitored throughout the study by the DMC. An interim 
analysis will be performed which will be described in the DMC Charter and the Statistical 
Analysis Plan (SAP).     
 
Patients who experience ≥ 10 percentage point decrease in percent predicted FEV1 and/or signs 
and symptoms of pulmonary exacerbations as defined by the Fuchs criteria1 at anytime during 
the study may resume Kalydeco at the instruction and discretion of the Investigator.  These 
patients will have Visit 5 safety, spirometry and CFQ-R assessments performed prior to 
resuming Kalydeco, if possible, and will be followed until the end of the study, as applicable.       
Patients who withdraw consent from the study prior to Day 28 will be asked if they are willing  
to return to the clinic for an early-termination evaluation. 
Efficacy will be assessed by changes in sweat chloride and percent predicted FEV1, and quality 
of life will be assessed using the CFQ-R.  Safety and tolerability will be evaluated by monitoring 
AEs, and by results of physical examinations, vital signs, electrocardiograms, and clinical  
laboratory tests.  Blood/plasma concentrations of CTP-656 and its metabolites may also be 
assessed. 


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4.3. 
Study Duration  
Patients will be screened within 14 days of administration of first dose of study treatment  
(Day 1) and if eligible will be randomized (1:1:1:1:1) to one of the 5 treatment groups: (1) 
Double-blind CTP-656 20 mg for 28 days (2) Double-blind CTP-656 100 mg for 28 days (3) 
Double-blind CTP-656 150 mg for 28 days (4) Double-blind Placebo for 28 days (5) Open-label 
Kalydeco for 28 days.  One week after the last dose of study treatment, each patient will have a 
follow-up visit.  Therefore, each patient’s study participation (including the screening period) 
will be up to approximately 49 days or 7 weeks in duration.  
4.4. 
End of Trial 
The End of Trial is defined as the date of the last visit of the last patient required for primary 
and/or secondary analysis, as specified in the protocol and/or the Statistical Analysis Plan. 


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5. 
STUDY PROCEDURES 
5.1. 
Schedule of Events 
The schedule of events is provided in Table 5. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 5: 
Schedule of Events 
Event 
Screening 
Study Treatment 
Follow-
up 
Visit 1 
Day - 14 to Day -1 
Visit 2 
Day 1 
Day 3±1 
Visit 3 
Day 7±1 
Visit 4 
Day 14±1 
Day 21±1 
Visit 5 (or ET) 
Day 2810 
Visit 6 
Day 35±1 
Informed consent 
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Eligibility assessment1 
X 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history2 
X 
X 
 
 
 
 
 
 
Physical examination3 
X 
X 
 
X 
X 
 
X (full physical for ET) 
X 
Height (cm) 
X 
 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
X 
 
X 
X 
Pregnancy test4 
X 
X 
 
 
 
 
 
X 
Clinical laboratories5 
X 
X 
 
 
 
 
X 
X 
LFTs 
X 
X 
 
 
X 
 
X 
 
HbsAg, and HCV antibodies 
X 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
X 
 
12-lead ECG 
X 
X 
 
X 
X 
 
X 
X 
Vital signs 
X 
X 
 
X 
X 
 
X 
X 
Sweat chloride assessment 
 
X 
 
X 
X 
 
X (not for ET) 
 
Spirometry (FEV1 assessment) 
X 
X 
 
X 
X 
 
X 
 
CFQ-R 
 
X 
 
 
 
 
X 
 
Dispense study treatment6  
(CTP-656 or Placebo) 
 
X 
 
X 
X 
 
 
 
Study treatment accountability  
(for CTP-656 and Placebo) 
 
 
 
X 
X 
 
X 
 
Blood/plasma collection for PK7 
(excluding open-label Kalydeco) 
 
X 
 
 
X 
 
X (not for ET) 
 
Phone-call 
 
 
X8 
 
 
X8 
 
 
Adverse events 
Ongoing (including screening visit) 
Prior and concomitant medications  
X9 
CFQ-R = Cystic Fibrosis Questionnaire-Revised; LFTs = liver function tests; ECG = electrocardiogram; ET = early termination; FEV1 = Forced expiratory volume in 1 second; HbsAg = hepatitis 
B surface antigen; HCV = hepatitis C virus; PK = pharmacokinetics 
1 Eligibility assessment will include CF mutation genotype confirmation via medical record; FEV
I assessment will be the only eligibility assessment conducted on Day 1 
2 Medical history will 
include history of alcohol and illicit drug use and HIV infection
3 Full physical examination will be performed at screening,Visit 2, Visit 5 (if ET), and Visit 6; symptom-directed physical 
examinations will be performed at other visits 
4 Pregnancy tests are required for women of childbearing potential 
5 Clinical chemistry, hematology, and coagulation: to be conducted prior to 
administration of dose on Day 1 and after the last dose on Day 27 or Day 28 6 Applicable only to patients randomized to the double-blind CTP-656 or Placebo groups 7 Blood samples will be 
collected pre-dose and 1 time point each within the following 2 time windows postdose: (1) between 30 minutes and 2 hours postdose and (2) between 4 and 6 hours post-dose 
on Visit 2, Visit  4 
and Visit 5; At Visit 5, the predose sample should be taken at 24±4 hours from the previous/last dose 
8 On Day 3 and Day 21, the patient will receive a phone call or text message to discuss any 
adverse events or other medical changes 
9 Patients who are prescribed inhaled cycling antibiotics should start Day 1 of the 28-day cycle on Day 1 of CTP-656 or Placebo  treatment 
10 Day 28 visit 
can occur on Day 27 or Day 28 


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5.2. 
Study Procedures  
5.2.1. 
Visit 1, Day -14 to Day -1 (Screening Visit) 
Patients will undergo a screening examination between Day -14 and Day -1. 
Prior to performing any study-related activities or evaluations, the patient must be thoroughly 
informed about all aspects of the study, including scheduled visits and activities.  Patients will 
sign the study-specific consent form(s) prior to any screening procedure.  Patients will be 
instructed to report all AEs that occur during the study from the time of informed consent 
forward.   
Patients should continue to perform airway clearance procedures and take their stable CF therapy 
regimen per their regular schedule during the screening period. 
The following information and procedures will be performed and documented as part of the 
screening assessment: 
• Informed consent and, where applicable, Health Insurance Probability and 
Accountability Act (HIPAA) authorization 
• Assessment of eligibility according to inclusion/exclusion criteria.  The CF mutation 
genotype should be appropriately documented in the medical record. 
• Demographics, including sex, ethnic origin, and date of birth, if permitted, according 
to local regulations. 
• Medical history, including query for baseline signs/symptoms (ie, an AE with onset 
prior to dosing is to be recorded as a pretreatment AE) 
• Review of concomitant medications (taken 30 days prior to screening) including  
stable CF background therapy regimen 
− Patients who are on prescribed inhaled cycling antibiotics should start Day 1 of 
the 28-day cycle on Day 1 of CTP-656 or Placebo treatment  
• Complete physical examination plus height and weight 
• Vital signs measured including blood pressure, pulse rate, respiratory rate, and 
temperature 
• Standard 12-lead ECG  
• Blood samples for clinical chemistry, hematology, coagulation, and hepatitis B and C 
evaluations 
• Serum Pregnancy tests for women of childbearing potential  
• Urinalysis (see Appendix A) 
• Spirometry assessment (preferably pre-bronchodilator, see Section 9.1) 
− Patients who do not meet the percent predicted FEV1 ≥ 60% criterion may return 
for a reassessment of percent predicted FEV
1 within 5 days 


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Compliance with inclusion criteria (listed in Section 6.2) and exclusion criteria (listed in    
Section 6.3) will be verified against information collected and documented in the source 
documents and the electronic case report form (eCRF).  Local laboratory results obtained at 
screening will be used to verify eligibility. 
5.2.2. 
Treatment Period 
Patients should continue to perform airway clearance procedures prior to visits and take their 
stable CF background therapy regimen per their regular schedule during the treatment period 
with the exception of Kalydeco if randomized to a CTP-656 or Placebo treatment group.  
Patients who are on prescribed inhaled cycling antibiotics should start Day 1 of the 28-day cycle 
on Day 1 of study treatment if randomized to a CTP-656 or Placebo treatment group.  Patients 
who are randomized to the open-label Kalydeco group should continue their inhaled cycling 
antibiotic treatment regimen as scheduled. 
5.2.2.1. Visit 2, Day 1 (Start of treatment) 
The following baseline assessments will be performed and documented: 
• Cystic Fibrosis Questionnaire-Revised (CFQ-R; should be the first assessment at 
visit) 
• Spirometry assessment prior to dose of CTP-656, Placebo or Kalydeco (preferably 
pre-bronchodilator, see Section 9.1)  
− Patients are required to meet the FEV1 ≥ 60% criterion prior to randomization  
− Patients who do not meet the percent predicted FEV1 ≥ 60% criterion will not be 
enrolled 
• Following confirmation of eligibility, consenting patients will be randomized to 1 of 
the 5 study treatment groups 
• Update of medical history including query for baseline signs/symptoms.  Reports of 
AEs that occur before or on Day 1 prior to dosing will be noted as “pretreatment” on 
the eCRF; otherwise, all reported AEs will be post-treatment 
• Review of concomitant medications including stable CF background therapy regimen 
• Abbreviated physical examination, including weight 
• Vital signs measured including blood pressure, pulse rate, respiratory rate, and 
temperature 
• Standard 12-lead ECG  
• Blood samples for safety laboratory testing (hematology, clinical chemistry, and 
coagulation)  
• Urine pregnancy test for women of childbearing potential  
• Sweat chloride assessment prior to dose of CTP-656, Placebo or Kalydeco 


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• Dispensation of CTP-656 or Placebo tablets 
• Patients should bring their Kaldyeco supply to the clinic 
• Administration of first dose of CTP-656 or Placebo in the clinic after consumption of 
a small meal 
• Patients who are randomized to the open-label Kalydeco group will take their dose in 
the clinic after consumption of fat-containing food 
• Blood sample for PK assessments (excluding open-label Kalydeco group); predose, 
and at 2 post-dose time points  
− Time window 1: anytime between 30 minutes and 2 hours post-dose, and  
− Time window 2: anytime between 4 and 6 hours post-dose 
− Note: Actual collection times will be recorded 
• Patients randomized to CTP-656 or placebo should be instructed to take their dose 
each day after consuming a small meal while patients remaining on Kalydeco should 
be instructed to take their dose each day with fat-containing food as prescribed. 
Instructions to bring all used and unused CTP-656, Placebo tablets to all study visits; 
reminder for the open label Kalydeco arm subjects to bring Kalydeco tablets to study 
visits   
• Instructions that dose of CTP-656, Placebo or Kalydeco should be taken in the clinic 
on visit days  
• Reminder that the patient will receive a phone call on Day 3 to discuss any AEs or 
other medical changes that may have occurred since Day 1 
• Instructions to return to clinic for Visit 3 (Day 7) 
5.2.2.2. Telephone Call, Day 3  
On Day 3, each patient will receive a phone call to discuss any possible AEs or other medical 
changes that may have occurred since the Day 1 visit.   
5.2.2.3. Visit 3, Day 7 and Visit 4, Day 14  
The following assessments will be performed and documented: 
• Monitoring of AEs (ie, query of any AEs that have occurred since prior visit and 
follow up on ongoing AEs) 
• Review of concomitant medications including stable CF therapy regimen 
• Abbreviated physical examination depending on patient symptoms, including weight 
• Vital signs measured including blood pressure, pulse rate, respiratory rate, and 
temperature 
• Standard 12-lead ECG  


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• Blood samples for safety laboratory testing of LFTs (ALT, AST, total and direct 
bilirubin, alkaline phosphatase, albumin, total serum protein and GGT; Visit 4 only)  
• Administration of dose of CTP-656 or Placebo in the clinic (Visit 3 and 4) after 
consumption of a small meal 
• Patients who are randomized to the open-label Kalydeco group will take their dose in 
clinic after consumption of fat-containing food 
• Sweat chloride assessment within 4 hours post CTP-656, Placebo or Kalydeco dose  
• Spirometry assessment within 4 hours post CTP-656, Placebo or Kalydeco dose 
(preferably pre-bronchodilator, see Section 9.1)  
• Blood sample for PK assessments (Visit 4 only; excluding open-label Kalydeco 
group): predose, and at 2 post-dose time points 
− Time window 1: anytime between 30 minutes and 2 hours post-dose, and  
− Time window 2: anytime between 4 and 6 hours post-dose 
− Note: Actual collection times will be recorded 
• Patients randomized to CTP-656 or placebo should be instructed to take their dose 
each day after consuming a small meal while patients on Kalydeco should be 
instructed to take their dose each day with fat-containing food as prescribed. 
Assessment of CTP-656 or Placebo compliance via tablet count  
• Instructions to bring all used and unused CTP-656 or Placebo tablets to all study 
visits; reminder for the open label Kalydeco arm subjects to bring Kalydeco tablets to 
study visits 
• Instructions to return to the clinic for Visits 4 (Day 14) and 5 (Day 28) 
5.2.2.4. Telephone Call, Day 21 
On Day 21, each patient will receive a phone call to discuss any possible AEs or other medical 
changes that may have occurred since the Day 14 visit.   
5.2.2.5. Visit 5, Day 28 (End of Treatment Visit), or Early Termination 
The following assessments will be performed and documented at the final treatment visit; 
patients who prematurely discontinue the study will be encouraged to complete the Visit 5 
safety, spirometry and CFQ-R assessments prior to stopping study treatment, if not 
contraindicated: 
• CFQ-R (should be the first clinical assessment at visit) 
• Monitoring of AEs (ie, query of any AEs that have occurred since prior visit and 
follow up on ongoing AEs) 
• Review of concomitant medications including stable CF background therapy regimen 


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• Abbreviated physical examination depending on patient symptoms, including weight 
(full physical examination including height and weight for Early Termination) 
• Vital signs measured including blood pressure, pulse rate, respiratory rate, and 
temperature 
• Standard 12-lead ECG 
• Blood samples for safety laboratory testing (hematology, clinical chemistry, and 
coagulation).   
• Urinalysis 
• Urine pregnancy test for women of childbearing potential (serum pregnanacy test for 
Early Termination) 
• Administration of dose of CTP-656 or Placebo in the clinic after consumption of a 
small meal (not for Early Termination) 
• Patients who are randomized to the open-label Kalydeco group will take their dose in 
clinic after consumption of fat-containing food (not for Early Termination) 
• Sweat chloride assessment within 4 hours post CTP-656, Placebo or Kalydeco dose 
(not for Early Termination)  
• Spirometry assessment within 4 hours post CTP-656, Placebo or Kalydeco dose 
(preferably pre-bronchodilator, see Section 9.1)  
• Blood sample for PK assessments (excluding open-label Kalydeco group; not for 
Early Termination): predose, and at 2 post-dose time points 
− Time window 1: anytime between 30 minutes and 2 hours post-dose, and  
− Time window 2: anytime between 4 and 6 hours post-dose 
− Note: Actual collection times will be recorded 
• Assessment of CTP-656 or Placebo compliance via tablet count  
• Collection of all used and unused CTP-656 or Placebo tablets  
Following completion of all Visit 5 procedures, patients will have completed the treatment 
period.  As prescribed by the Investigator, patients on the CTP-656 or Placebo groups will 
resume Kalydeco 24 hours after the administration of the last dose of CTP-656 or Placebo.  
Patients in the open-label Kalydeco group will continue taking Kalydeco per their prescription.  
5.2.2.6. Visit 6, Day 35 (Follow-Up) 
One week after the administration of the last dose of study treatment the patients will have a 
follow-up visit.  The following asssessments will be performed and documented.   
• Monitoring of AEs (ie, query of any AEs that have occurred since prior visit and 
follow up on ongoing AEs) 


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• Review of concomitant medications including resumption of Kalydeco and any other 
new medications since prior visit 
• Full physical examination including height and weight 
• Vital signs measured including blood pressure, pulse rate, respiratory rate, and 
temperature 
• Standard 12-lead ECG  
• Blood samples for safety laboratory testing (hematology, clinical chemistry, and 
coagulation).   
• Serum pregnancy test for women of child bearing potential 
All attempts will be made that patients with unresolved AEs at the time of Visit 6 will be 
contacted regularly until AE is resolved (see Section 13). 


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6. 
STUDY POPULATION 
6.1. 
Number of Patients and Sites 
This is a multicenter study; approximately 15-20 study sites are planned.   
Approximately 30-40 patients with CF who have a CFTR gating mutation (G1244E, 
G1349D,G178R, G551S, S1251N, S1255P, S549N, or S549R), are ≥ 18 years old, have been 
stable for 3 months on Kalydeco therapy prior to the screening, and have FEV1 ≥ 60%  predicted 
for age, sex and height at screening will be enrolled in this study.  There will be an opportunity 
for including patients with a percent predicted FEV1 ≥ 50% predicted for age, sex, and height, at 
screening, if interim data reviewed by the Data Monitoring Committee (DMC) supports this.   
6.2. 
Inclusion Criteria 
Patients must satisfy the following criteria to be enrolled in the study: 
1. Is capable of giving written informed consent ensuring that patient will be compliant with 
the requirements and restrictions listed in the consent form and the protocol 
2. Has a confirmed diagnosis of CF
2,3, as determined by prior genotyping, with at least one 
allele of the following CFTR gating mutations: G551D, G1244E, G1349D, G178R, 
G551S, S1251N, S1255P, S549N, and S549R.  The CF mutations must be appropriately 
documented in the medical record 
3. Has been stable on Kalydeco for at least 3 months 
4. Is willing to remain off Kalydeco for 28 days if randomized to the CTP-656 or Placebo 
groups 
5. Is willing to remain on stable CF background therapy regimen for the duration of study 
participation 
6. Has FEV1 ≥ 60%  of the predicted for age, sex, and height (Hankinson) at screening and 
baseline (Day 1) assessments 
7. Is 18 years of age or older 
8. Weighs at least 40 kg at screening 
9. Patients of either gender and women of childbearing potential must be willing to use a 
medically highly effective form of birth control during the treatment period and 30 days 
after the last dose of study treatment.   
Examples of medically highly effective forms of birth control are as follows: 
o Surgically sterile (via hysterectomy or bilateral ligation) 
o Has a male sexual partner who is surgically sterilized 
o Use of implants of levonorgestrel 
o Use of oral contraceptive (combined or progesterone only)  
o Use of double-barrier method (any combination of physical and chemical 
methods) 
o Use of any intrauterine device or other method with published data showing that 
the lowest expected failure rate is less than 1% per year (not all intrauterine 
devices meet this this criterion) 


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10. If needed, has access to a caretaker to provide assistance in completing study activities. 
Note: (a) Patients who do not meet the FEV
1 ≥ 60% criterion at the screening assessment 
may return for a reassessment within 5 days.  Patients who do not meet the FEV
1 ≥ 60% 
criterion  at the baseline assessment will not be eligible for enrollment. 
6.3. 
Exclusion Criteria 
The presence of any of the following will exclude a patient from enrollment: 
1. Acute upper respiratory infection within 14 days of the first dose of study treatment 
2. Lower respiratory infection, pulmonary exacerbation, or changes in therapy (excluding    
inhaled antibiotics) for pulmonary disease within 4 weeks before first dose of study 
treatment 
3. Uncontrolled type 2 diabetes, or uncontrolled CF-related diabetes 
4. History of  hepatitis C or chronic active hepatitis B infection 
5. History of pulmonary tuberculosis, non-tuberculosis mycobacterial infections or allergic 
bronchopulmonary aspergillosis (ABPA), treated during screening or within 2 years prior 
to screening 
6. Colonization with B. cenocepacia, B. dolosa, B. multivorans, and/or M. abcessus  within 
the last 2 years prior to Screening 
7. Abnormal liver function at Screening, defined as ≥ 3 × upper limit of normal (ULN), of 
any 3 or more of the following: serum alanine transaminase (ALT), serum aspartate 
transaminase (AST), gamma-glutamyl transpeptidase (GGT), serum alkaline phosphatase 
(ALP), total bilirubin  
8. Are current smokers, or previous smokers with cessation less than 6 months before 
screening 
9. History of abnormal renal function (creatinine clearance < 50 mL/min using the 
Cockgroft-Gault equation) 
10. History of prolonged QT/QTc interval with Fridericia’s correction (QTcF) > 450 msec 
for males or QTcF>470 msec for females at screening 
11. History of solid organ or hematological transplantation 
12. History of alcohol, medication, or illicit drug abuse within 1 year before screening 
13. Currently participating in another therapeutic clinical study or previously participated in 
an investigational drug study within 30 days before randomization  
14. Using any inhibitor or inducer of cytochrome P450 3A during the study or within 30 days 
of screening 
15. Women who are pregnant or lactating, or have plans to become pregnant during the study 
or within 1 month following the last dose 
16. Unable or unwilling to comply with study requirements 


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17. History of any illness or condition that, in the opinion of the investigator might confound 
the results of the study or pose an additional risk in administering CTP-656 to the patient 


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7. 
DESCRIPTION OF STUDY TREATMENTS 
7.1. 
Description of Study Treatments 
CTP-656 will be formulated as a white, film-coated oval tablet containing 20, 75, or 100 mg of 
CTP-656. CTP-656 will be processed to a stabilized amorphous state which is then incorporated 
into the tableting process.  Each CTP-656 tablet will contain the following inactive ingredients:  
colloidal silicon dioxide, croscarmellose sodium, hydroxypropylmethylcellulose acetate 
succinate, lactose monohydrate, magnesium stearate, microcrystalline cellulose, PEG 3350, 
polyvinyl alcohol, sodium lauryl sulfate, talc, and titanium dioxide.  The matching placebo for 
CTP-656 tablets will contain the same inactive ingredients as the CTP-656 tablet, with the 
exception of hydroxypropylmethylcellulose acetate succinate. 
The active comparator product, Kalydeco tablet, 150 mg, will be the marketed dosage form. 
7.2. 
Study Treatment Administration and Schedule 
CTP-656 (20 mg, 100 mg or 150 mg) or Placebo will be administered orally once-daily after 
consumption of a small meal.  Patients in the open-label Kalydeco group will be instructed to 
continue taking Kalydeco after consumption of fat-containing food as prescribed.    
 
Table 6: CTP-656  and Placebo Administration Schedule 
Treatment Group 
Dose Unit 
Dose  
CTP-656 20 mg 
20 mg  
1 x CTP-656 tablet (20 mg) + 1 x Placebo tablet  
CTP-656 100 mg 
100 mg  
1 x CTP-656 tablet (100 mg) + 1 x Placebo tablet 
CTP-656 150 mg 
75 mg 
2 x CTP-656 tablets (75 mg)  
Placebo 
Not applicable 2 x Placebo tablets  
 
7.3. 
Method of Study Treatment Assignment 
Following screening, patients meeting all inclusion and no exclusion criteria will be randomized 
(1:1:1:1:1), utilizing an Interactive Response System (IXRS), to one of the 5 treatment groups 
shown below:  
• Double-blinded CTP-656 20 mg for 28 days  
• Double-blinded CTP-656 100 mg for 28 days 
• Double-blinded CTP-656 150 mg for 28 days 
• Double-blinded Placebo for 28 days 


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• Remain on (open-label) Kalydeco for 28 days 
Once a randomization number has been assigned to a patient, it will not be reassigned to any 
other patient. 
7.4. 
Packaging and Labeling 
CTP-656 tablets (20 mg, 75 mg, 100 mg), and Placebo tablets, will be packaged in PVC/Aclar 
blister packs.  All products should be stored at room temperature in the original packaging.  A 
stability study will run concurrent with the clinical study to support continued use of the clinical 
trial material. 
The labels for the study treatments will include sponsor name, address, and telephone number, 
the protocol number, study treatment name, dosage form and strength (where applicable), 
amount of study treatment per container, lot number, expiration/retest date as applicable, 
medication identification /kit number, storage conditions, and required caution statements and/or 
regulatory statements, as applicable.  Additional information may be included on the label, as 
applicable, per local regulations. 
7.5. 
Investigational Product Accountability and Disposal  
All study treatments should be stored in a secure, locked area, under the responsibility of the 
Investigator or other authorized individual until dispensed to the patients.   
Study treatment must be stored in the original package at room temperature as stated on the 
package label.  No special handling procedures are required. 
The Investigator or designee must maintain accurate records of the receipt of all study treatment, 
including date received, lot number, expiration/retest date as applicable, amount received, 
condition of the package, and the disposition of all study treatment. 
Current dispensing records will also be maintained, including the date and amount of medication 
dispensed to each individual patient.  Returned study treatment records will be maintained and 
final study treatment  reconciliation will also be recorded for each patient. 
Concert (or designee) will review with the Investigator and relevant site personnel the process 
for study treatment return, disposal, and/or destruction, including responsibilities for the site 
versus Concert (or designee). 
7.6. 
Study Treatment Compliance 
Compliance will be monitored for study treatment accountability (CTP-656 and Placebo) 
throughout the study firstly by the investigative site and secondly by Concert or its designee.  All 
patients should strive for 100% compliance with the dosing schedule and documentated 
retraining should occur in cases of non-compliance.  The Medical Monitor should be consulted if 
compliance drops below 80% at any visit.  All study treatment not used in the study must be 
destroyed by the study site or returned to Concert or its designee after the study is completed.   


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8. 
CONCOMITANT MEDICATIONS AND PROCEDURES 
All medications, including over-the-counter therapies (eg, vitamins, herbal and nutritional 
supplements), taken in the 30 days prior to screening will be recorded in the patient’s source 
documentation and documented in the eCRF.   
The medications permitted during the study will be those that the patients have been taking as 
part of their stable CF background therapy regimen and those that may be necessary for the 
treatment of an AE, in the opinion of the Investigator.  The use of concomitant medication must 
be documented in the patient’s eCRF and in the source documents.  Prohibited concomitant 
medications are the substances known to be substrates that induce or inhibit CYP3A 
(Appendix B).  These compounds must not have been taken within 30 days of Day 1 and may 
not be administered as a concomitant medication.  Use of oral, injectable, or implant 
contraceptives is permitted for female patients.   


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9. 
EFFICACY PROCEDURES 
9.1. 
Pulmonary Function 
Spirometry will be performed according to American Thoracic Society guidelines10.  During the 
study, including the Screening Period, FEV
1 measurements should be performed pre-
bronchodilator administration, and on Day 1 (baseline assessment), prior to administration of 
study treatment. Thereafter spirometry assessments should be performed within 4 hours after 
administration of study treatment and preferably at the same time of day at each visit including 
the baseline (Day 1) visit.   
Pre-bronchodilator spirometry is defined as spirometry testing performed for a patient who has: 
• Witheld their short-acting β-agonist (e.g., albuterol) or anticholinergic (e.g., 
Atrovent®) for more than 4 hours before the spirometry assessment; AND 
• Witheld their long-acting bronchodilator (e.g., salmeterol) for more than 12 hours 
before the spirometry assessment; AND 
• Witheld their once-daily, long-acting bronchodilator (e.g., tiotropium bromide 
[Spiriva
®]) for more than 24 hours before the spirometry assessment 
The time and date of all pre-spirometry doses of bronchodilators taken within the previous 24 
hours will be recorded for each spirometry assessment. 
In the event that a patient forgets to withhold bronchodilators, spirometry should be performed 
according to the following: 
• During the Screening Period, if a patient forgets to withhold their dose of 
bronchodilator, spirometry should be performed post-bronchodilator and all 
subsequent spirometric measurements (Days 1, 7, 14 and 28) should be performed 
pre-bronchodilator 
• If a patients’s Day 1 spirometry is pre-bronchodilator, but on a subsequent the patient 
forgets to withhold the bronchodilator, a post-bronchodilator spirometry will be 
obtained for that visit only and the visit will not be rescheduled 
• If on Day 1 the patient forgets to withhold their dose of bronchodilator, spirometry 
should be performed post-bronchodilator and all subsequent spirometric 
measurements (Days 7, 14 and 28) should be performed post-bronchodilator 
• Each spirometry assessment will be recorded in the source documents as pre-
bronchodilator or post-bronchodilator 
The following parameters will be recorded as part of the spirometry assessment (according to 
Hankinson standards):  
• FEV1: liter and percent predicted for age, gender and height  
• Forced vital capacity (FVC): liter and percent predicted for age, gender and height 


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• Forced expiratory flow over the middle half of the FVC (FEF
25-75): liter/second and 
percent predicted for age, gender, and height  
9.2. 
Sweat Chloride Analysis 
The sweat test, the major diagnostic tool of cystic fibrosis, measures sweat electrolyte levels, 
including chloride, using quantitative pilocarpine iontophoresis.  The sweat chloride 
concentration of an untreated patient with cystic fibrosis is typically ≥ 60 mmol/L.  Intermediate 
concentrations of 40-59 mmol/L may be observed in patients with CF but are considered 
diagnostically indeterminate.  Sweat chloride concentrations ≤ 39 mmol/L are generally 
considered normal, although CF patients have been observed with these low concentrations, 
particularly at very young ages.  
To ensure consistency and reproducibility in this multicenter study, sweat secretions will be 
collected at each site according to the standardized procedure of the Macroduct
® Model 3700 
Collection System (Wescor, Inc. Logan, Utah), with standardized solutions provided to each site. 
Two sweat collections, 1 from each arm, will be obtained from each patient at each time point.  
Sweat samples will be analyzed and interpreted at a central laboratory.  Specific instructions for 
collection, handling, and processing of sweat chloride samples to the central analysis and reading 
center will be provided in a separate manual.   
The sweat chloride test will be conducted within 4 hours of CTP-656, Placebo or Kalydeco dose 
except at the Day 1 visit when the sweat chloride test should be performed prior to 
administration of CTP-656, Placebo or Kalydeco dose.  Analyses will be performed using the 
chloride value obtained from the collection with the greater amount of sweat at each time point.  
If only one of the collections is available, this value will be used.  
9.3. 
Health-Related Quality of Life  
Patients will complete the adult version of the CFQ-R, a validated disease-specific instrument 
that measures health-related quality of life (QoL) for persons with CF
11, in their native language.  
  Validated translations of the 
CFQ-R will be provided for participating sites in non-English-speaking countries, if applicable  
The CFQ-R consists of 50 items across 12 domains, i.e., 9 QoL dimensions (physical 
functioning, role, vitality, emotional functioning, social, body image, eating disturbances, 
treatment burden, and health perceptions) and 3 symptom scales (weight, respiratory symptoms, 
and digestive symptoms).  Responses are provided on a 4-point Likert scale and rescaled within 
each domain to a score range from zero to 100 points, with higher scores representing better 
health.  For the CFQ-R, a minimal clinically important difference of at least 4 points has been 
established for the respiratory domain
12.  The CFQ-R will be administered on Day 1 (Baseline) 
and Day 28 (End of study treatment administration or Early Termination) and must be completed 
prior to the start of any assessments scheduled at the visit and prior to the dose of CTP-656, 
Placebo or Kalydeco on each of those days.   


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10. 
SAFETY PROCEDURES 
10.1. 
Physical Examination 
A complete physical examination, including assessment of the following body systems: 
head/neck/thyroid, eyes/ears/nose/throat (EENT), chest, lungs, heart, lymph nodes, abdomen, 
skin, musculoskeletal, and neurological systems will be performed by qualified personnel at the 
screening visit, Visit 2 (Day 1) and Visit 5 (Day 28 or early termination).  A symptom-directed 
examination will be performed on Visit 3 (Day 7), Visit 4 (Day 14), and Visit 5 (Day 28).  
Weight (kilograms) will be measured as part of all physical examinations.  Height (centimeters) 
will be measured only at the screening visit. 
10.2. 
Vital Signs 
Vital signs, including blood pressure, pulse rate, respiratory rate, and temperature, will be 
measured at each study visit, after the patient has rested for approximately 5 minutes.   
10.3. 
Electrocardiograms 
Twelve-lead ECGs will be performed (see Section 12.9.5) at screening and each treatment visit.  
All scheduled ECGs will be performed after the patient has rested for approximately 5 minutes.  
ECGs must be evaluated for safety by the Investigator or his/her designee.  If clinically 
significant abnormalities are recorded, ECGs will be repeated at the discretion of the 
Investigator. 
10.4. 
Clinical Laboratory Assessments 
The list of clinical laboratory assessments is included in Appendix A.   
Virus serology (hepatitis B surface antigen, and hepatitis C virus antibodies) will be assessed at 
the screening visit. 
Clinical laboratory tests (clinical chemistry, hematology, coagulation, and urinalysis) will be 
performed according to the schedule of assessments and analyzed at the site’s local laboratory.  
The results of clinical laboratory tests conducted during screening must be assessed by the 
Investigator to determine each patient’s eligibility for participation in the study.  The Investigator 
should indicate review of the laboratory reports by signing and dating the report.  Any significant 
abnormalities should be fully investigated.  Whenever possible, the etiology of the abnormal 
findings will be documented on the eCRF.  Laboratory results with significantly abnormal values 
should be repeated for verification.  Additional tests or other evaluations required to establish the 
significance or etiology of an abnormal result or to monitor the course of an AE should be 
obtained when clinically indicated.  In particular, if a clinically significant abnormal result is 
observed that is not resolved by the final study visit, repeat tests will be performed if possible 
and resolution or stability of the abnormality will be recorded in the source documentation. 
Any significant laboratory abnormalities that are either serious or unexpected will be promptly 
reported to Concert Pharmaceuticals’ representative.  Any additional relevant laboratory results 


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obtained by the Investigator during the course of this study will be reported to Concert 
Pharmaceuticals or its representative. 


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11. 
PHARMACOKINETIC ASSESSMENTS 
11.1. 
PK Blood Sample Collection 
Blood samples for PK analysis will be collected from all study groups except the open-label 
Kalydeco group at 3 times per visit on Day 1, Day 14 and Day 28 (Visits 2, 4 and 5). The time of 
last dose of CTP-656 or Placebo prior to the blood collection and the exact time of the blood 
collection must be recorded for each sample. The PK schedule requires 1 predose, and 2 post-
dose draws, each within a distinct post-dose window.  The following schedule for PK draws 
should be observed: 
• Predose (a blood collection before in-clinic dosing for all patients enrolled in the study 
• Window 1: between 30 minutes and 2 hours post-dose (1 draw at any time within the 
specified window) 
• Window 2: between 4 and 6 hours post-dose (1 draw at any time within the specified 
window) 
A total of 9 PK samples should be taken for a patient in the CTP-656 or Placebo group that 
completes the study. All attempts to adhere to the PK schedule should be made.  However, the 
inability to follow the schedule or to obtain/process a sample will not be considered a protocol 
deviation. 
Details for PK blood sample processing will be detailed in a separate laboratory manual. 
11.2. 
Plasma Sample Storage and Shipping 
Details will be provided in a separate laboratory manual. 
11.3. 
Bioanalytical Methodology for Determination of Plasma 
Concentrations 
Plasma concentrations of CTP-656 and its metabolites, D-M1 and D-M6 will be measured using 
validated bioanalytical methods using LC/MS/MS techniques and according to the bioanalytical 
laboratory’s standard operating procedures (SOP).   




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12.6. 
Patient Disposition 
Patient disposition (analysis population allocation, randomized, discontinued, along with primary 
reason for discontinuation, completed) will be summarized using frequency and percentage.  
Protocol deviations will be summarized using frequency tabulations. 
12.7. 
Efficacy Analysis 
The efficiacy endpoints that will be measured are: 
Primary Endpoint 
• Change from baseline in sweat chloride at Day 28 
Secondary Endpoints 
• Change from baseline in percent predicted FEV1 at Day28 
• Change from baseline in CFQ-R Respiratory Domain at Day 28   
Where: 
baseline is the measurement prior and closest to the administration of the first of treatment on 
Day 1, and change = value at scheduled day – value at baseline 
 
Efficacy endpoints will be summarized by treatment group and timepoint, and will be analyzed 
by timepoint using analysis of covariance (ANCOVA) with a fixed effect for treatment and with 
the corresponding baseline value as a covariate, with a test of the treatment effect at a two-sided 
significance level of 0.05, as follows: 
 
1. Each of CTP-656 20 mg, CTP-656 100 mg, CTP-656 150 mg vs. Placebo 
2. CTP-656 20 mg vs. CTP-656 150 mg, CTP-656 20 mg vs. 100 mg, CTP-656 100 mg vs. 
CTP-656 150 mg 
3. Each of CTP-656 20 mg, CTP-656 100 mg, CTP-656 150 mg vs. Kalydeco 
4. Kalydeco vs. Placebo 
 
All statistical tests will be 2 tailed with Type I error = 0.05.  Given that this is a Phase 2, dose-
ranging study, no adjustment for multiple comparisons will be performed. 
Handling of missing values and additional details on the methods of analyses will be specified in 
the SAP.  


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12.8. 
Pharmacokinetic Analysis  
PK analyses may be performed as appropriate.  
12.9. 
Safety Analysis 
Safety evaluations will be based on the incidence, intensity, and type of AEs including clinically 
significant changes in the patient’s physical examination findings, vital signs, ECGs, and clinical 
laboratory results.  Safety variables will be tabulated and presented for all patients in the Safety 
Population.  Data will be summarized by treatment group.  Exposure to study treatment, dosing 
compliance, and reasons for discontinuation of study treatment will be tabulated.   
12.9.1. Adverse Events 
Adverse events will be summarized by MedDRA system organ class and preferred term by 
treatment group.   
Separate summaries will be produced for all treatment-emergent AEs (AEs that occur post first 
study drug doseor AEs noted prior to the first study drug administration that wosen after 
Baseline), treatment-related AEs (those considered by the Investigator as suspected; see 
Section 13.2), SAEs, discontinuations due to AEs, and AEs ≥ Grade 3 severity, according to 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.  By-patient listings 
will be provided for any deaths, SAEs, and AEs leading to discontinuation of treatment.   
12.9.2.  Concomitant Medications 
Concomitant medications will be summarized by World Health Organization (WHO) Drug 
Dictionary Anatomical-Therapeutic-Chemical (ATC) classification and preferred drug name by 
treatment group.   
12.9.3. Physical Examination 
All abnormal physical examination findings will be documented in the eCRF.  Results of 
physical examinations will be listed by patient.  
12.9.4. Vital Signs 
Vital signs will be summarized at each time point for each treatment group, using descriptive 
statistics.  Change from baseline in vital signs values will also be summarized.  Mean (SD) 
temporal profiles for vital signs (systolic and diastolic blood pressure and pulse rate) may be 
presented graphically. 
12.9.5. Electrocardiogram 
From the 12-lead ECG data, heart rate, PR, QRS, QT, and Fridericia-corrected QT interval 
(QTcF) will be reported for each time point and summarized using descriptive statistics.  Mean 
(SD) temporal profiles for 12-lead ECG (QT and QTcF) may be presented graphically.  The 
frequency (number) of clinically significant findings may be reported and summarized by 
treatment group. 


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12.9.6. Clinical Laboratory Assessments 
Subjects with clinically significant abnormal laboratory values will be identified. Clinically 
significant laboratory values (i.e., meets ≥ Grade 3, according to CTCAE, version 4.0 ) will be 
summarized by treatment group.  Laboratory values will also be evaluated for any potential 
trends within/across treatments groups. 
12.9.7. Study Treatment Compliance 
Dosing compliance (CTP-656 and placebo) will be assessed by comparing the number of doses 
scheduled and those taken by each patient.  If a patient only takes a partial dose at an occasion, 
he/she will not be counted as taking all of his/her study treatment.  Descriptive statistics will be 
used to summarize the dosing compliance percentage within each treatment group.  
The number of patients exposed to each study treatment will be summarized using descriptive 
statistics.  
 


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13. 
ADVERSE EVENTS 
13.1. 
Monitoring, Recording, and Reporting of Adverse Events 
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen 
in a patient during the course of a study.  It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the patient’s health, including 
laboratory test values, regardless of etiology.  Any worsening (ie, any clinically significant 
adverse change in the frequency or intensity of a pre-existing condition) should be considered an 
AE.  A diagnosis or syndrome should be recorded on the AE page of the eCRF rather than the 
individual signs or symptoms of the diagnosis or syndrome.   
An overdose, accidental or intentional, whether or not it is associated with an AE, or abuse, 
withdrawal, sensitivity or toxicity to an investigational product should be reported as an AE.  If 
an overdose is associated with an AE, the overdose and AE should be reported as separate terms.   
All patients will be monitored for AEs during the study.  Assessments may include monitoring of 
any or all of the following parameters: the patient’s clinical symptoms including pulmonary 
exacerbations (as defined by Fuch’s criteria), cutaneous reactions/rash, laboratory, pathological, 
radiological or surgical findings, physical examination findings, or findings from other tests 
and/or procedures. 
An adverse event reported after consent but before the day of the first dose of study treatment, ie, 
Day 1, is to be documented by the Investigator as a pretreatment AE.  An adverse event recorded 
on the first day of dosing but before any study treatment dose is taken will also be recorded as a 
pretreatment AE.  Adverse events will be considered treatment emergent if the onset date and 
time is after the first dose of study treatment.   
All AEs will be recorded by the Investigator until end of study or resolution of AE.  AEs and 
SAEs will be recorded on the AE page of the eCRF and in the patient’s source documents.  All 
SAEs must be reported to Concert’s designated Drug Safety Unit and Medical Monitor within 24 
hours of the Investigator’s knowledge of the event by facsimile or other appropriate method 
using the SAE Report Form or approved equivalent form.   
13.2. 
Evaluation of Adverse Events 
A
 qualified Investigator at the site will evaluate all AEs as to seriousness, severity/intensity
, 
causality
, duration, action taken, and outcome.  The Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.013 will be used for grading the severity of Adverse Events.  A
 copy 
of the CTCAE will be provided in the Safety Manual. 
13.2.1. Seriousness  
An SAE is any AE occurring at any dose that fulfills the following criteria, as per Title 21 Code 
of Federal Regulations (CFR) 312.32 and International Conference on Harmonisation (ICH) 
E2A.II.B.   
• Is fatal (results in death) 


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• Is life-threatening (Note: the term “life-threatening” refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event that 
could hypothetically have caused death had it been more severe) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay) 
• Results in persistent or significant disability/incapacity (a substantial disruption of the 
patient’s ability to conduct normal life functions) 
• Is a congenital anomaly/birth defect or 
• Constitutes an important medical event that may jeopardize the patient or may require 
medical or surgical intervention to prevent one of the other outcomes listed above. 
Important medical events are defined as those occurrences that may not be immediately life 
threatening or result in death, hospitalization, or disability, but may jeopardize the patient or 
require medical or surgical intervention to prevent one of the other outcomes listed above.  
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious. 
Events not considered to be SAEs are hospitalizations for: 
• A standard procedure for protocol therapy administration.  However, hospitalization 
or prolonged hospitalization for a complication of therapy administration will be 
reported as an SAE.   
• A procedure for protocol/disease-related investigations (eg, surgery, scans, 
endoscopy, sampling for laboratory tests, bone marrow sampling).  However, 
hospitalization or prolonged hospitalization for a complication of such procedures 
remains a reportable SAE. 
• Hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE. 
• A procedure that is planned (ie, planned prior to starting of treatment on study); must 
be documented in the source document and the eCRF.  Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE. 
• An elective treatment of or an elective procedure for a pre-existing condition 
unrelated to the studied indication.   
• Emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above. 
If an AE is considered serious, both the AE page/screen of the eCRF and the SAE Report Form 
must be completed. 
For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to study treatment, action taken regarding study treatment, and outcome. 


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13.2.2. Severity/Intensity 
For both AEs and SAEs, the Investigator must assess the severity/intensity of the event.   
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This criterion is not the same as “serious” which is 
based on patient/event outcome or action criteria associated with events that pose a threat to a 
patient’s life or functioning.   
Seriousness, not severity, serves as a guide for defining regulatory obligations. 
13.2.3. Causality  
The Investigator must determine the relationship between the administration of study treatment 
and the occurrence of an AE/SAE as reasonable possibility of relatedness and no reasonable 
possibility of relatedness, as defined below: 
Definitely Related: There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out.  The event, including an abnormal laboratory test result, 
occurs in a plausible time relationship to study drug administration and cannot be explained by 
concurrent disease or other drugs or chemicals.  The event resolves or improves upon withdrawal 
of study drug (de-challenge).  The event would be considered as definitely related to the study 
drug upon results of a positive re-challenge procedure. 
Probably Related: There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely.  The clinical event, including an abnormal laboratory test result, occurs within 
a reasonable time sequence to administration of the drug, is unlikely to be attributed to 
concurrent disease or other concomitant treatments, and follows a clinically reasonable response 
on withdrawal (dechallenge), if dechallenge was done.  
Possibly Related: There is evidence to suggest a causal relationship (e.g., the event occurred 
within a reasonable time after administration of the study drug).  However, the influence of other 
factors may have contributed to the event (e.g., the patient’s clinical condition, other concurrent 
disease, concomitant medications or events).   
Unlikely Related: An event, including an abnormal laboratory test result, whose temporal 
relationship to drug administration makes a causal relationship improbable (eg, the event did not 
occur within a reasonable time after administration of the study drug) and in which other drugs 
or concurrent or underlying disease provide plausible explanations (eg, the patient’s clinical 
condition, other concomitant treatments). 
Not related: The event is completely independent of study drug administration, and/or evidence 
exists that the event is definitely related to another etiology.  There must be an alternative, 
definitive etiology documented by the clinician. 
 
  
 
 


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Causality should be assessed and provided for every AE/SAE based on currently available 
information.  Causality is to be reassessed and provided as additional information becomes 
available. 
13.2.4. Duration 
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event. 
13.2.5. Action Taken 
The Investigator will record the action taken with the study treatment as a result of an AE or 
SAE on the case report form, as applicable (eg, discontinuation, interruption, or reduction of 
CTP-656 dose, as appropriate) and record if concomitant and/or additional treatments were given 
for the event.   
13.2.6. Outcome 
All AEs that have not resolved upon discontinuation of the patient’s participation in the study 
must be followed in accordance with the Principal Investigator’s and Medical Monitor’s  
judgment until resolution, but non-related AEs will be followed in accordance with the Principal 
Investigator’s and Medical Monitor’s judgment.   
13.2.7. Assessment of Expectedness 
Each SAE that is Suspected to be related to the study treatment must be assessed for 
expectedness by the Sponsor to determine whether it is reportable as a SUSAR (Suspected 
Unexpected Serious Adverse Reaction).  The Reference Safety Information (RSI) for this study, 
against which expectedness assessments are made, can be found in the IB.  Determination of the 
expectedness of an event is the responsibility of the Sponsor. 
13.3. 
Abnormal Laboratory Values 
An abnormal laboratory value is considered to be an AE if the abnormality: 
• results in discontinuation from the study; 
• requires treatment, modification/ interruption of study treatment, or any other 
therapeutic intervention; or 
• is judged to be of significant clinical importance. 
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as an SAE.   
If a laboratory abnormality is 1 component of a diagnosis or syndrome, only the diagnosis or 
syndrome should be recorded on the AE page/screen of the eCRF.  If the abnormality was not a 
part of a diagnosis or syndrome, the laboratory abnormality should be recorded as the AE.  If 
possible, the laboratory abnormality should be recorded as a medical term and not simply as an 
abnormal laboratory result (eg, record thrombocytopenia rather than decreased platelets). 


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13.4. 
Pregnancy 
If a patient or male patient’s partner becomes pregnant any time during the treatment period the 
appropriate form should be used to report the pregnancy to Investigator, Sponsor or its designee.  
Patient pregnancies (or pregnancy of a male patient’s partner) must be followed until termination 
of pregnancy or for a minimum of 6 months following the birth of the child.    
13.5. 
Adverse Event Documentation 
13.5.1. Adverse Event Recording and Reporting 
Each individual AE is to be listed as a separate entry on the AE eCRF.  The Investigator will 
provide information about dates of onset and resolution, seriousness, severity, frequency, 
action(s) taken, outcome, and relationship to CTP-656.   
Documentation of immediately reportable events will follow procedures described in 
Section 13.6. 
The Investigator must report to Sponsor or its designee all AEs that occur during the study from 
the time written informed consent is given until the final study visit or early termination, 
regardless of their relationship to CTP-656. 
If an Investigator becomes aware of an SAE within 30 days after the last dose of study treatment 
is administered, the event must be documented and reported, as described in Section 13.6.   
13.5.2. Follow-up of Adverse Events and Serious Adverse Events 
All AEs assessed as not related to CTP-656 or procedure, including clinically significant 
laboratory tests, ECGs, or physical examination findings, must be followed until the event 
resolves, the condition stabilizes, the event is otherwise explained, or the final study visit occurs, 
whichever comes first.  Adverse events assessed as related to CTP-656 or procedure will be 
followed for as long as necessary to adequately evaluate the patient’s safety, until the event 
stabilizes, or the patient is lost to follow up.  If resolved, a resolution date should be provided.  
The Investigator is responsible for ensuring that follow-up includes any supplemental 
investigations indicated to elucidate the nature and/or causality of the AE.  This may include 
additional clinical laboratory testing or investigations, examinations, or consultation with other 
health care professionals as is practical. 
Any SAE brought to the attention of the Investigator within 30 days after cessation of CTP-656 
or study procedure and considered by him/her to be caused by CTP-656 with a reasonable 
possibility, should be reported through the SAE reporting process. 
13.6. 
Reporting of Serious Adverse Events 
Suspected unexpected serious adverse reactions (SUSARs) are AEs that are believed to be 
related to an Investigational Product (IP) and are both unexpected (ie, the nature or severity is 
not expected from the information provided in the IB) and serious.  SUSARs are subject to 
expedited reporting to the Sponsor, Sponsor’s designee, regulatory authorities, and the 
Institutional Review Board (IRB) or Ethics Committee (EC) (see Section 13.6.2 for reporting 
details on reporting SUSARs). 


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In addition to SUSARs, other safety issues may qualify for expedited reporting if they might 
materially alter the current benefit-risk assessment of study treament or would be sufficient to 
consider changes in the administration of the study treatment or in the overall conduct of the 
study, for instance: 
• An increase in the rate of occurrence or a qualitative change of an expected SAE, 
which is judged by the Principal Investigator in consultation with the Sponsor and the 
Medical Monitor to be clinically important 
• SAEs that occur after the patient has completed the clinical study and the Sponsor 
considers them to be a SUSAR 
• New events related to the conduct of the study or the development of the study 
treatment and likely to affect the safety of the patients, such as: 
− an SAE that could be associated with the study procedures and that could modify 
the conduct of the study 
− a significant hazard to the patient population such as lack of efficacy of study 
treatment used for the treatment of a life-threatening disease 
− a major safety finding from a newly completed animal study (such as 
carcinogenicity) 
− any anticipated end or temporary halt of a study for safety reasons and conducted 
with the same study treatment in another country by the same Sponsor. 
13.6.1. Urgent Safety Measures 
If the study site staff becomes aware of an actual or potential urgent safety issue, then the 
Sponsor and Sponsor’s designee (Medical Monitor) must be immediately contacted so that 
appropriate urgent safety measures can be agreed upon.  An urgent safety issue is defined as:  
• An immediate hazard to the health or safety of patients participating in a clinical trial 
• A serious risk to human health or potentially a serious risk to human health 
An urgent safety issue may include: (i) issues with an investigational drug or comparators, 
(ii) study procedures, (iii) inter-current illness (including pandemic infections), (iv) concomitant 
medications, (v) concurrent medical conditions, or (vi) any other issues related to the safe 
conduct of the study or that pose a risk to study patients. 
In exceptional circumstances of imminent hazard and in order to safeguard the health or safety of 
individuals, the Investigators may take urgent safety measures before informing the Sponsor, but 
the Sponsor must be informed immediately after the hazard has resolved.   
13.6.2. Reporting 
• Reporting SAEs - The Investigator is responsible and required to report all SAEs 
within 24 hours after becoming aware of the occurrence of an SAE or serious adverse 
reaction.  All SAE reporting will be done electronically via electronic data capture 
(EDC).  This will be done on the AE eCRF by ticking the box, “Is the event Serious” 


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as “yes”.  The investigator will then be prompted to complete additional fields to 
capture the event.  The EDC will electronically notify the study Sponsor and the 
Sponsor’s designated Pharmacovigilance Department. Reporting of SUSARs - It is 
the responsibility of the Sponsor to determine whether a reported SAE fits the 
classification of a SUSAR and to notify the Investigator of its decision as soon as 
possible. 
• Expedited Reporting of Events - It is the responsibility of the Sponsor to determine 
whether an event requires expedited reporting and to notify the Investigator of its 
decision as soon as possible.  When expedited reporting is required, the following 
procedures should be followed. 
− Fatal or life-threatening SUSARs - It is the responsibility of Sponsor or its 
designee to report fatal or life-threatening SUSARs to regulatory authorities as 
soon as possible, but no later than 7 calendar days after Sponsor first becomes 
aware of the reaction.  All SAE reporting will be done electronically via EDC. 
The Investigator is required to notify the IRB or EC of any SUSAR as soon as 
possible, but no later than 7 calendar days after first becoming aware of the 
reaction.  Any additional relevant information should be updated in EDC system 
within 8 days after the date of submission of the initial the report. 
− Other SUSARs - It is the responsibility of Sponsor or its designee to report other 
SUSARs to regulatory authorities as soon as possible, but no later than 
15 calendar days after the date the Sponsor first becomes aware of the reaction. 
− The Investigator is required to notify the IRB or EC of any other SUSAR as soon 
as possible, but no later than 15 calendar days after first becoming aware of the 
reaction. 
• Reporting of Urgent Safety Issues - The Sponsor or its designee is required to 
inform the appropriate competent authorities, Investigators, and IRB or EC within 
3 calendar days after it becomes aware of the urgent safety issue. 
• Serious Breaches - It is the responsibility of the clinical site and staff to notify the 
Sponsor and Sponsor’s designee immediately upon becoming aware of a serious 
breach of GCP or of the study protocol.  It is the responsibility of the Sponsor or its 
designee to notify regulatory authorities of any serious breach which is likely to 
effect, to a significant degree, the safety or mental integrity of the patients of the 
study or the scientific value of the study.  The Sponsor or its designee will notify the 
regulatory authorities within 7 days after becoming aware of a serious breach.   
13.6.3. Safety Queries 
Queries pertaining to SAEs will be communicated via the EDC system.  The response time is 
expected to be no more than 5 business days.  Urgent queries (eg, missing causality assessment 
must be answered at the time of reporting/entering the data into the EDC system. 


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13.7. 
Expedited Reporting of Adverse Events 
13.7.1. Immediately Reportable Experiences 
The following events may occur during participation in this clinical study and must be reported 
to the Sponsor immediately: 
• Death or other SAE  
• Pregnancy of a patient or patient’s partner (during the treatment period) 
The events listed above must be reported within 24 hours after first knowledge of the event by 
study personnel to the appropriate Sponsor contacts provided below, or other designated Sponsor 
designee.  For immediately reportable experiences, the appropriate form (eg, SAE Report Form, 
Pregnancy Form, Drug Discrepancy Form) should be completed as thoroughly as possible and 
signed by the Investigator or his/her designee before transmittal to Sponsor or its designee.  For 
SAEs, it is important that the Investigator provide his/her assessment of causality to study 
treatment or procedure at the time of the initial report.  If the Investigator’s assessment of 
causality changes then a follow-up SAE form must be submitted. 
 
 


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Contact Person (USA): 
, MD 
 
 
 (office) 
 (mobile) 
 (after hours answering service) 


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14. 
DISCONTINUATIONS 
All patients are free to withdraw from participation in the study at any time, for any reason, and 
without prejudice.  The Investigator must withdraw any patient from the study if the patient 
requests to stop participating in the study.  The Investigator, Sponsor, or its designee may 
remove a patient from the study at any time and for any reason.  The specific reason for the 
withdrawal should be carefully documented on the eCRF.   
Patients who withdraw consent from the study prior to Day 28 will be asked if they are willing  
to return to the clinic for an early-termination evaluation. 
A patient who prematurely discontinues study treatment should have early termination safety, 
spirometry and CFQ-R assessments performed (Refer to Table 5) and will be followed, as 
applicable.       
 
Patients who withdraw or are withdrawn from the study may not be replaced.   
Patients who are in the double-blind CTP-656 or Placebo groups may resume Kalydeco at the 
instruction and discretion of the Investigator if they experience ≥ 10 percentage point decrease in 
absolute percent predicted FEV
1 and/or have signs and symptoms of pulmonary exacerbations as 
defined by the Fuchs criteria
1:   
• Clinical need for  new or change in antibiotics (oral, intravenous or inhaled) as 
indicated by presence of at least 4 or 12 possible signs or symptoms: 
− Change in sputum volume or color 
− New or increased haemoptysis 
− Increased cough 
− Increased dyspnea 
− Increased malaise, fatigue or lethargy 
− Temperature over 38oC 
− Anorexia or weight loss 
− Sinus pain or tenderness 
− Change in sinus discharge 
− Change in physical findings on examination of the chest 
− Decrease in pulmonary function by 10% or more 
− Radiographic changes 
Patients who resume Kalydeco due to the reasons outlined above will have Visit 5 safety, 
spirometry and CFQ-R assessments prior to resuming Kalyedco, if possible, and will be followed 
until the end of the study, as applicable.   


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Patients in the open-label Kalydeco group who experience ≥ 10 percentage point decrease in 
absolute percent predicted FEV
1 and/or have signs and symptoms of pulmonary exacerbations
1 
should be referred to their primary CF physcican. 
It is strongly recommended that all patients with ALT or AST elevations of ≥ 3 × ULN and 
clinical symptoms be followed closely, including repeat confirmatory testing within 48 to 72 
hours of the initial finding and subsequent close monitoring of ALT and AST level, as clinically 
indicated.  Study treatment must be interrupted immediately and the Medical Monitor must be 
notified if any of the following criteria are met: 
• ALT or AST > 5 × ULN 
• ALT or AST > 3 × ULN for more than 2 weeks   
• Total bilirubin > 2 × ULN and/or clinical jaundice, in association with elevation of 
ALT or AST > 3 × ULN 
A thorough investigation of potential causes should be conducted and the subject should be 
followed closely for clinical progression.  Patients discontinued for elevated transaminases 
should be followed until their transaminases normalize or return to baseline. 
In addition, patients should be withdrawn if they: 
• Experience a serious, intolerable or life-threatening AE 
• Develop a clinically significant laboratory or ECG abnormality 
• Require a medication that is prohibited by the protocol 
• Do not follow guidelines specified in the protocol (ie, is noncompliant with protocol 
procedures or study treatment administration) 
• Are lost to follow-up 
• Do not continue to meet certain entry criteria or meets certain exclusion criteria 
during the course of the study   
Adverse events resulting in termination will be followed to the satisfactory resolution and 
determination of outcome, as ascertained by the Investigator (and/or Sponsor, or its designee).  
The data will be recorded on the appropriate eCRF. 
14.1. 
Handling of Early Terminations 
If a patient terminates early from the study, either at his or her request or at the Investigator’s 
discretion, the Investigator will record the reason(s) for early termination on the relevant eCRF 
page and notify the Sponsor immediately.  The specific reason for the withdrawal should be 
carefully documented on the eCRF.   
All attempts should be made to obtain follow-up data on any patient who is terminated because 
of an AE including pulmonary excaerbations, abnormal laboratory test, or ECG finding.. Sites 
should document attempts to follow patients including evidence of a registered letter in cases 
where patients are lost to follow-up.   


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14.2. 
Sponsor’s Termination of Study 
The Sponsor reserves the right to discontinue the study at any time for clinical or administrative 
reasons. 
Such a termination must be implemented by the Investigator, if instructed to do so by the 
Sponsor, in a time frame that is compatible with the patient’s well-being. 


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15. 
EMERGENCY PROCEDURES 
15.1. 
Emergency Contact 
In emergency situations, the Investigator should contact the responsible Concert Clinical 
Research personnel or designee by telephone at the number(s) listed in the Study Reference 
Manual. 
15.2. 
Emergency Unblinding of Treatment Assignment 
In the case of an adverse event for which it is medically required to break the blind in order to 
determine appropriate treatment, unblinding can be achieved by using the IXRS. A study subject 
for whom the blind is broken should stop the treatment of study drug prematurely.  The Medical 
Monitor must be notified immediately of the blind break. 
 


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16. 
REGULATORY CONSIDERATIONS 
16.1. 
Good Clinical Practice 
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that the Sponsor, its authorized 
representative, and Investigator abide by GCP, as described in ICH Guideline E6 and in 
accordance with the general ethical principles outlined in the Declaration of Helsinki.  The study 
will receive approval from IRB or EC prior to commencement.  The Investigator will conduct all 
aspects of this study in accordance with applicable national, state, and local laws of the pertinent 
regulatory authorities. 
16.2. 
Sponsor’s Responsibility 
The Sponsor or its designee is responsible for the following: 
1. Selecting qualified Investigators 
2. Providing Investigators with the information they need to properly conduct an 
investigation 
3. Ensuring proper monitoring of the investigation 
4. Ensuring that the applicable regulatory authorities, and all participating Investigators are 
properly informed of significant new information regarding AEs or risks associated with 
the medication being studied 
As the Sponsor, Concert Pharmaceuticals has delegated some responsibilities to a designee, or 
contract research organization (CRO). 
16.3. 
Audits and Inspections 
The Sponsor’s Quality Assurance Unit (or representative) may conduct audits at the study site(s).  
Audits will include, but are not limited to: drug supply, presence of required documents, the 
informed consent process, laboratory specimen processing, and comparison of CRFs/eCRFs with 
source documents.  The Investigator agrees to cooperate with audits conducted at a reasonable 
time and in a reasonable manner. 
Regulatory authorities worldwide may also audit the Investigator during or after the study.  The 
Investigator should contact the Sponsor immediately if this occurs, and must fully cooperate with 
the audits conducted at a reasonable time in a reasonable manner. 
The Investigator is required to make all study documentation promptly available for inspection, 
review or audit at the study site upon request by Sponsor, its representatives, or any appropriate 
regulatory agencies. 


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16.4. 
Investigator Responsibilities 
Investigator responsibilities are set out in the ICH Guideline for GCP and in the local 
regulations.  The Sponsor staff or an authorized representative will evaluate and approve all 
Investigators who in turn will select their staff. 
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, and study treatments, as well as study-related duties and 
functions.  The Investigator should maintain a list of Sub-Investigators and other appropriately 
qualified persons to whom he or she has delegated significant study-related duties. 
The Investigator is responsible for keeping a record of all patients who sign an informed consent 
document and are screened for entry into the study.  Patients who fail screening must have the 
reason(s) recorded in the patient’s source documents. 
The Investigator or a designated member of the Investigator’s staff must be available during 
monitoring visits to review data, resolve queries, and allow direct access to patient records (eg, 
medical records, office charts, hospital charts, and study-related charts) for source data 
verification.  The Investigator must ensure timely and accurate completion of eCRFs and queries. 


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17. 
ETHICS 
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that the Sponsor and the Investigator conduct 
the study in accordance with GCP, (as defined by ICH guidelines and directives, and applicable 
local regulatory requirements and laws, including Title 21 CFR Parts 50, 56, and 312).  
Compliance with these regulations and guidelines also constitutes compliance with the ethical 
principles described in the current revision of the Declaration of Helsinki, Tokyo 2013. 
Copies of these materials are available from the Sponsor and the Sponsor’s designee upon 
request.  The purpose of these regulations, legal obligations, and guidances is to define the 
standards and principles for the proper conduct of clinical trials that have been developed by the 
medical, scientific, and regulatory communities.  They are not intended to impede or restrict 
clinical research. 
The ethical standards defined within GCP are intended to ensure that: 
1. Human patients are provided with an adequate understanding of the possible risks of their 
participation in the study, and that they have a free choice to participate or not. 
2. The study is conducted with diligence and in conformance with the protocol in such a 
way as to protect patient safety and ensure the integrity of the findings. 
3. The potential benefits of the research justify the risks. 
The Investigator is responsible for protecting the rights, safety, and welfare of patients under 
his/her care, and for the control of the medications under investigation. 
The Principal Investigator will ensure that all persons assisting with the study are adequately 
informed about the protocol, any amendments to the protocol, CTP-656, and their study-related 
duties and functions.  The Investigator will maintain a list of sub-investigators and other 
appropriately qualified persons to whom he or she has delegated significant study-related duties.  
Individuals ineligible to conduct or work on clinical studies, including those ineligible as a result 
of debarment under the Generic Drug Enforcement Act of 1992, will not be allowed to conduct 
or work on studies sponsored by Concert Pharmaceuticals.  The Investigator is required to 
immediately disclose to the Sponsor in writing if any person involved in the conduct of the study 
is debarred pursuant to a hearing by the United States Food and Drug Administration under this 
anti-fraud law, or if any proceeding for debarment is pending, or is (to the best of the 
Investigator’s knowledge) threatened.   
The rest of this section of the protocol describes in more detail the specific GCP-defined 
responsibilities the Investigator assumes by agreeing to participate in this study. 
17.1. 
Ethics Review 
The Investigator (or designee) must submit this study protocol, the Sponsor’s approved Informed 
Consent Form (ICF), patient information sheets, patient recruitment materials, and other 
appropriate documents to IRB or EC, and following review of the submitted materials, is 


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required to forward to the Sponsor (or designee) a copy of the written and dated 
approval/favorable opinion signed by the appropriate IRB or EC designee. 
The approval/favorable opinion should clearly state the trial (study number, protocol title, and 
version number), the documents reviewed (eg, protocol, ICF, IB) and the date of the review. 
The study will not commence at the study site until the Sponsor has received a copy of this 
written and dated approval/favorable opinion. 
During the trial, any amendment to the protocol and the ICF (as appropriate) should be submitted 
to IRB or EC.  The IRB or EC should also be informed of any event likely to affect the safety of 
patients or the continued conduct of the trial, in particular any change in safety.  Additionally, all 
updates to the IB will be sent to IRB or EC.  A progress report will be sent to IRB or EC and the 
protocol will be reviewed annually (eg, re-approved) or more frequently, as required by IRB or 
EC or local regulations. 
The Investigator will notify the IRB or EC of the conclusion of the clinical study within 1 month 
of completion or termination of the study.  The final report sent to IRB or EC will also be sent to 
the Sponsor along with the completed eCRFs and all necessary regulatory documents, thereby 
fulfilling the Investigator’s regulatory responsibility. 
The Investigator will maintain a copy of all correspondence with the IRB or EC, including copies 
of approved documents.  The Investigator will also maintain a copy of the IRB or EC 
membership list with occupation and qualification (or a statement confirming compliance with 
GCP requirements for committee composition).  An IRB or EC General Assurance Number may 
be accepted in lieu of a membership roster. 
Any advertisements used to recruit patients for the study must be approved by the Sponsor and 
IRB or EC prior to use.   
17.2. 
Ethical Conduct of the Study 
 Before the first patient is enrolled in the study, all ethical, regulatory, and legal requirements 
must be met. 
An Investigator participating in this study is required to maintain complete and accurate study 
documentation in compliance with current GCP standards and all applicable local regulations 
related to the conduct of a clinical study. 
Participating Investigators, including members of the Committees and National Coordinators, 
will receive compensation for their time but will receive no financial profit from their activities 
related to the trial.   
17.3. 
Patient Information and Informed Consent 
Prior to performing any study-related activities under this protocol, including screening tests and 
assessments, written informed consent with the approved ICF must be obtained from the patient 
or patient’s legally authorized representative, as applicable, in accordance with local practice and 
regulations.  Written informed consent must be obtained from all patients participating in a 
clinical study conducted by the Sponsor. 


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The background of the proposed study, the procedures, the benefits and risks of the study, and 
that study participation is voluntary for the patient must be explained to the patient.  The patient 
must be given sufficient time to consider whether to participate in the study.   
A copy of the ICF, signed and dated by the patient, must be given to the patient.  Confirmation of 
a patient’s informed consent must also be documented in the patient’s source documentation 
prior to any testing under this protocol, including screening tests and assessments.   
Each consent form should contain an authorization allowing the Principal Investigator(s) and the 
Sponsor to use and disclose protected health information (PHI) in compliance with local law.   
The original signed consent form will be retained with the study records. 
17.4. 
Confidentiality 
All information disclosed or provided by the Sponsor (or designee) produced during the trial 
including, but not limited to, the protocol, the eCRFs, the IB, and the results obtained during the 
course of the trial (if applicable), are confidential.  The Investigator or any person under his/her 
authority agrees to undertake to keep confidential and not to disclose the information to any third 
party without the prior written approval of the Sponsor. 
However, submission of this protocol and any other necessary documentation to IRB or EC is 
expressly permitted, IRB or EC members having the same obligation of confidentiality. 
All information generated in this study must be considered highly confidential and must not be 
disclosed to any persons not directly concerned with the study without written prior permission 
from the Sponsor.  However, authorized regulatory officials and sponsor personnel (or designee) 
will be allowed full access to inspect and copy the records.  The copied and inspected records 
will remain at the site and will not be transmitted or removed from the site.  All CTP-656, patient 
bodily fluids, and/or other materials collected shall be used solely in accordance with this 
protocol, unless otherwise agreed to in writing by the Sponsor and responsible ethics 
committee(s) or regulatory authorities. 
Patients will be identified only by unique patient numbers in eCRFs.  Their full names may, 
however, be made known to a regulatory agency or other authorized officials in the event of 
inspections.  Documents containing the full name or other personally identifiable information of 
the patient are to remain at the site.  This information will not be transferred to the Sponsor or be 
contained in regulatory filings.  In the event of inspections by authorized agencies, this patient 
identification may be disclosed. 
17.5. 
Patient Data Protection 
Prior to any testing under this protocol, including screening tests and assessments, candidates 
must also provide all authorizations required by local law (eg, PHI authorization in North 
America).   
The patient will not be identified by name in the eCRF or in any study reports and these reports 
will be used for research purposes only.  The Sponsor, its partner(s) and designee(s), and various 
government health agencies may inspect the records of this study.  Every effort will be made to 
keep the patients’ personal medical data confidential.   


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The Sponsor will protect individual patient information to the fullest extent possible during this 
trial.  At no time will a patient become identified in any publication or presentation.  However, 
the patient may have to become identified in the event of a Regulatory Authority audit or 
inspection in order to verify the accuracy of the data.  Access to patient information is at the 
discretion of the Sponsor and cannot occur prior to database lock or other specified events, as 
determined solely by the discretion of the Sponsor. 
17.6. 
Protocol Amendments 
The Investigator will not make any changes to this protocol without prior written consent from 
the Sponsor and subsequent approval by IRB or EC.  Any permanent change to the protocol, 
whether an overall change or a change for specific study center(s), must be handled as a protocol 
amendment.  Any amendment to the protocol that appears necessary as the study progresses will 
be fully discussed by the Investigator(s) and the Sponsor.  If agreement is reached regarding the 
need for an amendment, it will be written by the Sponsor.  The written amendment must be 
submitted to the chairman of IRB or EC identified with this responsibility.  Except for 
administrative amendments, Investigators must await IRB or EC approval of protocol 
amendments before implementing the change(s).  Administrative amendments are defined as 
having no effect on the safety of the research patients, scope of the investigation, or quality of 
the trial.  However, a protocol change intended to eliminate an apparent immediate hazard to 
patients should be implemented immediately, and IRB or EC notified within 5 days.  The 
Sponsor will ensure submission of any protocol amendments to the appropriate regulatory 
agencies. 
When, in the judgment of the chairman of the local IRB or EC, the Investigators, and/or the 
Sponsor, the amendment to the protocol substantially alters the study design and/or increases the 
potential risk to the patient, the currently approved written ICF will require similar modification.  
In such cases, repeat informed consent will be obtained from patients enrolled in the study before 
expecting continued participation. 
17.7. 
Ongoing Information for Institutional Review Board / Ethics 
Committee 
If required by legislation or IRB or EC, the Investigator must submit to IRB or EC: 
• Information on serious or unexpected AEs as soon as possible;  
• Periodic reports on the progress of the study; 
• Deviations from the protocol or anything that may involve added risk to patients. 
17.8. 
Closure of the Study 
The Sponsor reserves the right to terminate this study at any time for reasonable medical or 
administrative reasons.  Any premature discontinuation will be appropriately documented 
according to local requirements (eg, IRB or EC, regulatory authorities). 
In addition, the Sponsor has the right to discontinue a single site at any time during the study for 
medical or administrative reasons such as: 


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• Unsatisfactory enrollment; 
• GCP noncompliance; 
• Inaccurate or incomplete data collection; 
• Falsification of records; 
• Failure to adhere to the study protocol. 
 


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18. 
QUALITY CONTROL AND QUALITY ASSURANCE 
All aspects of the study will be carefully monitored by the Sponsor or its authorized 
representative for compliance with applicable government regulations with respect to current 
GCP and standard operating procedures.   
A quality-control and quality-assurance plan addressing aspects of the trial that may impact data 
integrity or the protection of human patients may be instituted for this study.  All audit findings 
will be summarized and placed on file with appropriate documentation of response/resolution.   
 


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19. 
DATA HANDLING AND RECORDKEEPING 
19.1. 
Data Collection  
Data obtained for analysis in the clinical study described in this protocol will be documented in 
the eCRF. All primary data generated by central laboratories will become part of the final study 
dataset.  All non-eCRF datasets (eg, PK results) will be reconciled, as appropriate, against the 
eCRF, queried and cleaned, prior to Database Lock.  Data reported in the eCRFs should be 
consistent with and substantiated by the patient’s medical record and original source documents.  
Any discrepancies must be explained.  Unless explicitly allowed in the eCRF instructions, blank 
data fields are not acceptable.  If a field is blank because the item was not done, the field will be 
marked “Not Done.”  If the item is unknown, the field will be marked “Unknown.” 
Prior to the start of the study, the Principal Investigator will complete a Delegation of Authority 
form (Site Signature and Delegation Log), showing the signatures and handwritten initials of all 
individuals and the delegation of responsibilities, such as identifying those individuals who are 
authorized to make or change entries on eCRFs 
19.2. 
Case Report Form Completion 
Data within the eCRF will be monitored by the Clinical Research Associate according to the 
Monitoring Plan.  Queries will be generated based on discrepancies found while monitoring.  
Site personnel will review and respond to these queries appropriately.  Additionally, the 
Sponsor’s designee and the Sponsor may periodically perform aggregate data reviews, which 
could result in queries being generated for site personnel resolution.  The final, completed eCRF 
for each patient must be signed and dated by the Principal Investigator to signify that the 
Principal Investigator has reviewed the eCRF and certifies it to be complete and accurate. 
19.3. 
Database Management, Data Clarification, and Quality Assurance 
The Sponsor’s designee, ie, a designated CRO, will be responsible for data management.  Data 
Management will develop a data management plan (DMP) document, and provide it to the 
Sponsor for approval.  The DMP document will define all activities in the data collection and 
cleaning process.  The detailed DMP will be based on the protocol, work scope, contract, 
analysis plans, data flows, eCRFs, data cleaning procedures, other supporting documents, and 
data management standards and practices. 
The programmed data validations will be run to check for database completeness and 
consistency, and queries will be generated upon data entry or via review by a Clinical Data 
Manager after entry.  The sites will respond to the data queries in a timely manner. 
Concurrent medications entered into the database will be coded using a WHO dictionary.  
Coexistent diseases and AEs will be coded using MedDRA. 
Quality control procedures will be conducted prior to database lock according to the designated 
CRO SOPs. 


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When the database has been declared to be complete and accurate, it will be locked.  Any 
changes to the database after that time will only be made by joint written agreement between the 
Sponsor, the trial statistician, the data manager, and the quality assurance auditor, according to 
designated CRO SOPs. 
19.4. 
Inspection of Records/Source Documents 
According to the ICH guidelines for GCP, the Sponsor or designee must verify data entered in 
the eCRF entries against the source documents, except for the pre-identified source data directly 
documented in the eCRF (if applicable).  The ICF will include a statement by which the patient 
allows the sponsor’s duly authorized personnel, the IRB or EC, and the regulatory authorities to 
have direct access to source data that supports the data in the eCRF (eg, patient’s medical file, 
appointment books, and original laboratory records).  These personnel, bound by professional 
secrecy, must keep confidential all personal medical information. 
The objective of source document verification (SDV) is to comply with GCP and international 
regulatory requirements and to reduce the risks of fraud.  Source Document Verification means 
ensuring that the source documents are an accurate and verifiable reflection of the patient’s 
participation in the study and that all relevant information that is recorded in the source 
document is accurately entered into the eCRF. 
Where source documents serve as the basis for deriving data for the trial, SDV should ensure that 
these documents are correctly labeled and filed and that the data derived from them are correct. 
All data required for this study should be captured in source notes.  No data obtained by the 
Investigator or other study personnel should be captured directly in the eCRF.  All source 
documents pertaining to this study will be maintained by the Investigator and made available for 
inspection by authorized persons.  If electronic progress notes and other electronic source 
documents are not Title 21 CFR Part 11 compliant, they are not considered a valid source for this 
study.  All progress notes must be dated and signed by the Principal Investigator or Sub-
Investigator at the time of the visit.  The Sponsor reserves the right to terminate the study for 
refusal of the Investigator to supply original source documentation for this clinical study. 
The Investigator will note in a source independent from the eCRF the following information: 
1. Information to confirm that the patient exists (eg, initials, date of birth, sex) 
2. Confirmation that the patient satisfies the inclusion/exclusion criteria 
3. Confirmation that the patient is taking part in the clinical trial 
4. Confirmation of the informed consent process 
5. Visit dates and documentation of protocol assessments and procedures 
6. Information concerning all AEs 
7. Details of concomitant and investigational medications. 
Source Document Verification is not a substitute for clinical trial monitoring, the purpose of 
which is to ensure that the protocol has been followed correctly, the eCRF has been fully and 


CTP-656 
 
Amendment #1 October 24, 2016 
Protocol CP656.2001 
 
Concert Pharmaceuticals, Inc. 
 
 
72 
 
 
accurately completed, SDV has been carried out, and the study timelines and enrollment goals 
and requirements have been met. 
19.5. 
Retention of Records 
In the United States, the investigator shall retain records for a period of 2 years following the 
date a marketing application is approved for the drug for the indication for which it is being 
investigated; or, if no application is to be filed or if the application is not approved for such 
indication, until 2 years after the investigation is discontinued and FDA is notified. 
The Investigator must take measures to prevent accidental or premature destruction of these 
documents. 
The Investigator must notify the Sponsor prior to destroying any study essential documents. 
If the Investigator can no longer ensure archiving, he/she shall inform the Sponsor.  The relevant 
records shall be transferred to a mutually agreed-upon designee.   


CTP-656 
 
Amendment #1 October 24, 2016 
Protocol CP656.2001 
 
Concert Pharmaceuticals, Inc. 
 
 
73 
 
 
 


CTP-656 
 
Amendment #1 October 24, 2016 
Protocol CP656.2001 
 
Concert Pharmaceuticals, Inc. 
 
 
74 
 
 
21. 
REFERENCES 
1. Fuchs HJ, Borowtiz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, 
Rosenstein BJ, Smith AL, Wohl ME.  Effect of aerosolized recombinant human 
DNase on exacerbations of respiratory symptoms and on pulmonary function in 
patients with cystic fibrosis. NEJM, 1994; 331:637-42. 
2. Farrell PM, Rosenstein BJ, White TB, et al.  Guidelines for diagnosis of cystic 
fibrosis in newborns through older adults:  Cystic Fibrosis Foundation consensus 
report.  J Pediatr 2008;153:S4-S14. 
3. Sawicki GS, Sellers DE, Robinson WM.  High treatment burden in adults with cystic 
fibrosis: challenges to disease self-management.  J Cyst Fibrosis 2009;8:91-6. 
4. Hankinson JL, Odencrantz JR, Fedan KB.  Spirometric reference values from a 
sample of the general U.S. population.  Am J Respir Crit Care Med 1999;159:179-87. 
5. Vermeulen F, Camus CL, Davies JC, Bilton D, Milenkovic D, De Boeck K.  
Variability in sweat chloride concentration in subjects with cystic fibrosis and G551D 
mutations.  J Cyst Fibrosis 2016; in press. 
6. Mayer-Hamblatt N, Boyle D, VanDevanter D.  Advancing clinical development 
pathways for new CFTR modulators in cystic fibrosis.  Thorax 2016.  
7. LeGrys VA.  Assesing quality assurance for sweat chloride testing. J Am Soc for Med 
Tech1992;5:354-57. 
8. United States Package Insert for Kalydeco, March 2015. 
10. Standardization of Spirometry, 1994 Update.  American Thoracic Society.  Am J 
Respir Crit Care Med 1995;152:1107-36. 
11. Quittner AL, Buu A, Messer MA, Modi AC, Watrous M.  Development and 
validation of The Cystic Fibrosis Questionnaire in the United States:  a health-related 
quality-of-life measure for cystic fibrosis.  Chest 2005;128:2347-54. 


CTP-656 
 
Amendment #1 October 24, 2016 
Protocol CP656.2001 
 
Concert Pharmaceuticals, Inc. 
 
 
75 
 
 
12. Quittner AL, Modi AC, Wainwright C, Otto K, Kirihara J, Montgomery AB.  
Determination of the minimal clinically important difference scores for the Cystic 
Fibrosis Questionnaire-Revised respiratory symptom scale in two populations of 
patients with cystic fibrosis and chronic Pseudomonas aeruginosa airway infection.  
Chest 2009; 135:1610-8. 
13. The Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Cancer 
Therapy Evaluation Program Web site. Available at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev4.pdf. 
Accessed 05 August 2009. 
 


CTP-656 
 
Amendment #1 October 24, 2016 
Protocol CP656.2001 
 
Concert Pharmaceuticals, Inc. 
 
 
76 
 
 
22. 
APPENDICES 


CTP-656 
 
Amendment #1 October 24, 2016 
Protocol CP656.2001 
 
Concert Pharmaceuticals, Inc. 
 
 
77 
 
 
APPENDIX A. LABORATORY ASSESSMENTS 
HEMATOLOGY 
CLINICAL CHEMISTRY 
URINALYSIS 
Complete blood count (CBC) 
Platelet count 
White blood cell (WBC) 
count with differential 
 
Alanine aminotransferase (ALT) 
Albumin (ALB) 
Alkaline phosphatase (ALK-P) 
Amylase  
Aspartate aminotransferase (AST) 
Total bilirubin 
Direct bilirubin 
Indirect bilirubin 
Blood urea nitrogen (BUN) 
Calcium (Ca) 
Carbon Dioxide (CO2) 
Chloride (Cl) 
Total cholesterol  
Creatinine 
Creatine kinase (CK) 
Gamma-glutamyl transferase (GGT) 
Glucose 
Lactic dehydrogenase (LDH) 
Lipase 
Total serum protein 
Phosphorus 
Potassium (K) 
Sodium (Na) 
Uric Acid 
Bilirubin 
Glucose 
Ketones 
Nitrates 
Occult Blood 
Protein 
Specific gravity 
Urobilinogen 
pH 
Leukocytes 
Microscopic urine analysis if 
dipstick positive 
LFTs 
Total bilirubin 
Direct bilirubin 
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate aminotransferase 
Albumin 
Gamma-glutamyl transferase 
Total serum protein  
SEROLOGY SCREEN 
COAGULATION  
PREGNANCY 
Hepatitis B surface 
antigen (HBsAg) 
Hepatitis C virus antibody 
(HCV-Ab) 
Prothrombin Time Test (PT) 
Partial Prothrombin Time Test 
(aPTT) 
International normalized ratio (INR) 
Human chorionic gonadotropin 
(hCG) 


CTP-656 
 
Amendment #1 October 24, 2016 
Protocol CP656.2001 
 
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78 
 
 
APPENDIX B. CYTOCHROME P450 DRUG INTERACTIONS  
CYP P450 3A4/3A5/3A7 Inhibitors: 
CYP P450 3A4/3A5Inducers: 
• Amiodarone 
• Aprepitant 
• Chloramphenicol 
• Cimetidine 
• Ciprofloxacin 
• Clarithromycin 
• Clotrimazole 
• Delaviridine 
• Diethyl-dithiocarbamate 
• Diltiazem 
• Erythromycin 
• Fluconazole 
• Fluvoxamine 
• Gestodene 
• Grapefruit juice 
• Imatinib 
• Indinavir 
• Itraconazole 
• Ketoconozole 
• Mifepristone 
• Nefazodone 
• Nelfinavir 
• Norfloxacin 
• Norfluoxetine 
• Ritonavir 
• Saquinavir 
• Star fruit 
• Telithromycin 
• Verapamil 
• Voriconazole 
• Barbiturates 
• Carbamazepine 
• Efavirenz 
• Glucocorticoids 
• Modafinil 
• Nevirapine 
• Oxcarbazepine 
• Phenobarbital 
• Phenytoin 
• Pioglitazone 
• Rifabutin 
• Rifampin 
• St. John’s Wort 
• Troglitazone 
 











SAP_001.pdf: 
Protocol: CP656.2001 
 
Vertex Pharmaceuticals Incorporated 
Version 2 Final 
       Page 1 of 36 
22SEP2017 
 
Statistical Analysis Plan 
 
Vertex Pharmaceuticals Incorporated 
 
 
Protocol: CP656.2001 
 
Treatment: CTP-656 
 
 
A Phase 2, Randomized, Parallel-Group, Double-Blind, Placebo Controlled 
Study to Evaluate the Safety and Efficacy of CTP-656 with an Open-Label 
Active Comparator in Patients with Cystic Fibrosis with CFTR Gating 
Mutations 
 
 
 
Document Status: 
Version 2 Final: 22SEP2017 
Version Dates: 
Version 1 Draft 1: 30NOV2016 
Version 1 Draft 2: 18JAN2017 
Version 1 Final: 21APR2017 
Version 2 Draft 1: 08SEP2017 
Version 2 Draft 2: 18SEP2017 
Pages: 
36 
 
 
 
CONFIDENTIAL   
This document contains confidential information. Any use, distribution, or disclosure without the prior written 
consent of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under 
applicable laws or regulations. Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 
 


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Vertex Pharmaceuticals Incorporated 
Version 2 Final 
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SIGNATURE PAGE 
 
 
 
 
Author: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
Reviewed by: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
Approved by: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
Vertex Pharmaceuticals Incorporated  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
, MD 
 
Date 
 
 
 
Vertex Pharmaceuticals Incorporated 
 
 
 
  


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Contents 
ABBREVIATIONS .................................................................................................................. 5 
1 
INTRODUCTION............................................................................................................ 6 
2 
STUDY OBJECTIVES .................................................................................................... 7 
2.1 EFFICACY ENDPOINTS ....................................................................................................... 7 
2.2 
SAFETY ENDPOINTS .................................................................................................... 7 
3 
STUDY DESIGN .............................................................................................................. 7 
3.1 
DISCUSSION OF STUDY DESIGN ................................................................................... 7 
3.2 
STUDY TREATMENT .................................................................................................... 8 
3.3 
STUDY SCHEDULE ....................................................................................................... 8 
3.4 
STUDY RESTRICTIONS AND PROHIBITIONS ................................................................ 10 
3.5 
ANALYSIS POPULATIONS .......................................................................................... 10 
3.5.1 All Randomized Patients ...................................................................................... 10 
3.5.2 Full Analysis Population Set (FAS) ..................................................................... 10 
3.5.3 Safety Population ................................................................................................. 10 
3.6 
PATIENT STUDY AND TREATMENT DISCONTINUATION ............................................. 10 
3.7 
RANDOMISATION ...................................................................................................... 11 
3.8 
BLINDING .................................................................................................................. 11 
3.9 
SAMPLE SIZE ............................................................................................................. 11 
4 
STATISTICAL METHODOLOGY............................................................................. 12 
4.1 
PLANNED ANALYSES ................................................................................................ 12 
4.2 
INTERIM ANALYSIS ................................................................................................... 12 
4.3 
TIME POINT ALGORITHMS......................................................................................... 12 
4.3.1 Relative Day ......................................................................................................... 12 
4.3.2 Windows ............................................................................................................... 12 
4.4 
PATIENT DISPOSITION ............................................................................................... 13 
4.5 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ..................................... 13 
4.6 
TREATMENT EXPOSURE AND COMPLIANCE ............................................................... 14 
4.7 
PRIOR AND CONCOMITANT MEDICATIONS ................................................................ 14 
4.8 
EFFICACY ANALYSIS ................................................................................................. 15 
4.8.1 Sweat Chloride ..................................................................................................... 15 
4.8.2 Percent Predicted FEV1 ....................................................................................... 15 
4.8.3 Cystic Fibrosis Questionnaire-Revised (CFQ-R) ................................................ 15 
4.9 
SAFETY ANALYSIS .................................................................................................... 16 
4.9.1 Adverse events ...................................................................................................... 16 
4.9.1.1 
Adverse Event Severity................................................................................ 16 
4.9.1.2 
Relationship of Adverse Events to Study Drug ........................................... 17 
4.9.1.3 
Serious Adverse Events ............................................................................... 17 
4.9.1.4 
Treatment-Emergent Adverse Events .......................................................... 17 
4.9.2 Clinical Laboratory Assessments ......................................................................... 18 
4.9.3 Vital Signs ............................................................................................................ 18 
4.9.4 12-Lead ECG ....................................................................................................... 18 
4.10 
PROTOCOL VIOLATIONS OR DEVIATIONS .................................................................. 18 
4.11 
 MISSING VALUES – MISSING VISITS ........................................................................ 18 
4.12 
DEVIATIONS FROM SAP ............................................................................................ 18 
4.13 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE PROTOCOL ................... 19 


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5 
TABLES AND LISTINGS ............................................................................................ 20 
5.1 
TABLE FORMAT ........................................................................................................ 20 
5.2 
CONVENTIONS .......................................................................................................... 20 
6 
LIST OF TABLES, FIGURES AND LISTINGS ........................................................ 22 
7 
REFERENCES ............................................................................................................... 24 
9 
APPENDICES ................................................................................................................ 25 
APPENDIX A. CYTOCHROME P450 DRUG INTERACTIONS...................................................... 25 
 
 
APPENDIX D. LABORATORY ASSESSMENTS .......................................................................... 31 
APPENDIX E. THRESHOLD ANALYSIS CRITERIA .................................................................... 32 
 
 
 


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Abbreviations 
 
Abbreviation or special term 
Explanation 
AE  
adverse event 
ATC 
Anatomical-Therapeutic-Chemical 
CF 
cystic fibrosis 
CFQ-R 
Cystic Fibrosis Questionnaire-Revised 
CFR 
Code of Federal Regulations 
CFTR 
cystic fibrosis transmembrane conductance regulator 
CRF/eCRF 
case report form/electronic case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTP-656 
D9-ivacaftor 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
FAS 
Full Analysis Set 
FEV1 
forced expiratory volume in 1 second 
FVC 
forced vital capacity 
FEF25-75 
forced expiratory flow over the middle half of the forced vital 
capacity 
G551D 
a missense mutation that results in the replacement of a glycine 
residue at position 551 of the CFTR with an aspartic acid residue 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
MedDRA 
Medical Dictionary for Regulatory Activities 
OC 
observed cases 
PK 
pharmacokinetic(s) 
PT 
preferred term 
QTcF 
Fridericia-corrected QT interval 
SAE 
serious adverse event 
SOC 
system organ class 
TEAE 
treatment emergent adverse event 
WHO 
World Health Organization 


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1 Introduction 
This document presents the statistical analysis plan (SAP) for Vertex Pharmaceuticals 
Incorporated Protocol CP656.2001: A Phase 2, Randomized, Parallel-Group, Double-Blind, 
Placebo Controlled Study to Evaluate the Safety and Efficacy of CTP-656 with an Open-
Label Active Comparator in Patients with Cystic Fibrosis with CFTR Gating Mutations. The 
study was terminated by Vertex Pharmaceuticals Incorporated on July 27, 2017 and a total of 
11 subjects were treated. 
Cystic fibrosis (CF) is an autosomal recessive disease with serious, chronically debilitating 
morbidities and high premature mortality.  Cystic fibrosis is caused by mutations in the cystic 
fibrosis transmembrane conductance regulator (CFTR) gene that results in absent or deficient 
function of the CFTR protein at the cell surface. 
Kalydeco® (ivacaftor), is the first targeted therapeutic agent for the treatment of CF in 
patients with the G551D CFTR mutation.  Ivacaftor potentiates the function of the mutant 
CFTR chloride channel present on the apical surface of bronchial epithelial cells.  Ivacaftor is 
extensively metabolized in humans and is dosed twice-daily. CTP-656 is a deuterated 
isotopolog of ivacaftor that has demonstrated a reduced rate of clearance, increased exposure, 
greater plasma levels at 24 hours, and longer half-life compared to Kalydeco in Phase 1 
studies in healthy volunteers, enabling once daily dosing in the clinical setting.  
This analysis plan is based on the protocol amendment #1 dated 24OCT2016. 
The SAP provides the description of the analysis for the final safety and efficacy analyses.  
 


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2 Study Objectives 
The objectives of this study are to evaluate the efficacy and safety of CTP-656 in patients 
with cystic fibrosis (CF) who have one of the following cystic fibrosis transmembrane 
conductance regulator (CFTR) gating mutations: G551D, G1244E, G1349D, G178R, G551S, 
S1251N, S1255P, S549N, or S549R, and have been stable for at least 3 months on Kalydeco 
therapy prior to screening.  
 
2.1 Efficacy Endpoints 
 
Primary Endpoint 
 Change from baseline in sweat chloride at Day 28 
Secondary Endpoints 
 Change from baseline in percent predicted FEV1 at Day 28 
 Change from baseline in CFQ-R Respiratory Domain at Day 28   
 
2.2 Safety Endpoints 
 Adverse Events 
 Prior and Concomitant Medications 
 Vital Signs 
 Electrocardiograms (ECGs) 
 Clinical Laboratory Tests 
 
3 Study Design 
3.1 Discussion of Study Design 
This is a randomized, parallel-group, double-blind, placebo controlled multicenter study in 
approximately 30-40 patients with CF who have a CFTR gating mutation (G1244E, G1349D, 
G178R, G551S, S1251N, S1255P, S549N, or S549R).  The study will include an open-label 
active comparator, i.e., Kalydeco.  Patients will be ≥ 18 years old, have been stable for 3 
months on Kalydeco therapy prior to the screening, and have percent predicted FEV1 ≥ 60% 
predicted for age, sex and height.  Following screening, patients meeting all inclusion and no 
exclusion criteria will be randomized (1:1:1:1:1), utilizing an Interactive Response System 
(IXRS), to one of the 5 treatment groups shown below:  
 Double-blinded CTP-656 20 mg for 28 days  


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 Double-blinded CTP-656 100 mg for 28 days 
 Double-blinded CTP-656 150 mg for 28 days 
 Double-blinded Placebo for 28 days 
 Remain on (open-label) Kalydeco for 28 days 
 
Figure 1 
 
 
3.2 Study Treatment 
CTP-656 (20 mg, 100 mg or 150 mg) or Placebo will be administered orally once-daily after 
consumption of a small meal.  Patients in the open-label Kalydeco group will be instructed to 
continue taking Kalydeco after consumption of fat-containing food as prescribed.    
 Table 1: 
CTP-656 and Placebo Administration Schedule 
Treatment Group 
Dose Unit 
Dose  
CTP-656 20 mg 
20 mg  
1 x CTP-656 tablet (20 mg) + 1 x Placebo tablet  
CTP-656 100 mg 
100 mg  
1 x CTP-656 tablet (100 mg) + 1 x Placebo tablet 
CTP-656 150 mg 
75 mg 
2 x CTP-656 tablets (75 mg)  
Placebo 
Not applicable 
2 x Placebo tablets  
 
3.3 Study Schedule 
Schedule of assessments are presented in Table 2 as follows. 


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Table 2: 
Schedule of Events 
Event 
Screening 
Study Treatment 
Follow-up 
Visit 1 
Day - 14 to Day -1 
Visit 2 
Day 1 
Day 3±1 
Visit 3 
Day 7±1 
Visit 4 
Day 14±1 
Day 21±1 
Visit 5 (or ET) 
Day 2810 
Visit 6 
Day 35±1 
Informed consent 
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Eligibility assessment1 
X 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history2 
X 
X 
 
 
 
 
 
 
Physical examination3 
X 
X 
 
X 
X 
 
X (full physical for ET) 
X 
Height (cm) 
X 
 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
X 
 
X 
X 
Pregnancy test4 
X 
X 
 
 
 
 
X 
X 
Clinical laboratories5 
X 
X 
 
 
 
 
X 
X 
LFTs 
X 
X 
 
 
X 
 
X 
 
HbsAg, and HCV antibodies 
X 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
X 
 
12-lead ECG 
X 
X 
 
X 
X 
 
X 
X 
Vital signs 
X 
X 
 
X 
X 
 
X 
X 
Sweat chloride assessment 
 
X 
 
X 
X 
 
X (not for ET) 
 
Spirometry (FEV1 assessment) 
X 
X 
 
X 
X 
 
X 
 
CFQ-R 
 
X 
 
 
 
 
X 
 
Dispense study treatment6  
(CTP-656 or Placebo) 
 
X 
 
X 
X 
 
 
 
Study treatment accountability  
(for CTP-656 and Placebo) 
 
 
 
X 
X 
 
X 
 
Blood/plasma collection for PK7 
(excluding open-label Kalydeco) 
 
X 
 
 
X 
 
X (not for ET) 
 
Phone-call 
 
 
X8 
 
 
X8 
 
 
Adverse events 
Ongoing (including screening visit) 
Prior and concomitant medications  
X9 
CFQ-R = Cystic Fibrosis Questionnaire-Revised; LFTs = liver function tests; ECG = electrocardiogram; ET = early termination; FEV1 = Forced expiratory volume in 1 second; HbsAg = hepatitis 
B surface antigen; HCV = hepatitis C virus; PK = pharmacokinetics 
1 Eligibility assessment will include CF mutation genotype confirmation via medical record; FEVI assessment will be the only eligibility assessment conducted on Day 1 2 Medical history will 
include history of alcohol and illicit drug use and HIV infection 3 Full physical examination will be performed at screening,  Visit 5 (if ET), and Visit 6; symptom-directed physical examinations 
will be performed at other visits 4 Pregnancy tests are required for women of childbearing potential 5 Clinical chemistry, hematology, and coagulation: to be conducted prior to administration of 
dose on Day 1 and after the last dose on Day 27 or Day 28 6 Applicable only to patients randomized to the double-blind CTP-656 or Placebo groups 7 Blood samples will be collected pre-dose and 
1 time point each within the following 2 time windows postdose: (1) between 30 minutes and 2 hours postdose and (2) between 4 and 6 hours post-dose on Visit 2, Visit  4 and Visit 5; At Visit 5, 
the predose sample should be taken at 24±4 hours from the previous/last dose 8 On Day 3 and Day 21, the patient will receive a phone call or text message to discuss any adverse events or other 
medical changes 9 Patients who are prescribed inhaled cycling antibiotics should start Day 1 of the 28-day cycle on Day 1 of CTP-656 or Placebo  treatment 10 Day 28 visit can occur on Day 27 or 
Day 28


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3.4 Study Restrictions and Prohibitions 
The medications permitted during the study will be those that the patients have been taking as 
part of their stable CF background therapy regimen, excluding specific prohibited 
concomitant medications, and those that may be necessary for the treatment of an AE, in the 
opinion of the Investigator.  The use of concomitant medication must be documented in the 
patient’s eCRF and in the source documents.  Prohibited concomitant medications are the 
substances known to be substrates that induce or inhibit CYP3A (Appendix A).  These 
compounds must not have been taken within 30 days of Day 1 and may not be administered 
as a concomitant medication. 
 
3.5 Analysis Populations 
 
3.5.1 All Randomized Patients  
All randomized patients includes all patients who are randomized into this study. Patients will 
be grouped by the treatment to which they are assigned at randomization. All listings except 
screen failure will use All Randomized Patients. 
 
3.5.2 Full Analysis Population Set (FAS) 
Patients who receive at least one dose of study treatment and have at least one post-baseline 
measurement of sweat chloride will be included in the Full Analysis Population Set (FAS). 
Patients will be grouped by the treatment to which they are assigned at randomization. 
Efficacy analyses will be based on the FAS population. 
 
3.5.3 Safety Population  
The Safety Population will include all randomized patients who receive at least one dose of 
study treatment.  In the unlikely event that errors may have occurred that the randomized 
treatment is different from the treatment received, analyses using the Safety Population will 
be based on treatment actually received. This population will be used for baseline 
characteristics and for safety data summaries. 
 
3.6  Patient Study and Treatment Discontinuation 
All patients are free to withdraw from participation in the study at any time, for any reason, 
and without prejudice.  The Investigator must withdraw any patient from the study if the 
patient requests to stop participating in the study.  The Investigator, Sponsor, or its designee 
may remove a patient from the study at any time and for any reason.  The specific reason for 
the withdrawal should be carefully documented on the eCRF.   
Patients who withdraw consent from the study prior to Day 28 will be asked if they are 
willing to return to the clinic for an early-termination evaluation. 
A patient who prematurely discontinues study treatment should have early termination safety, 
spirometry and CFQ-R assessments performed (Refer to Table 2) and will be followed, as 
applicable. 
Patients who withdraw or are withdrawn from the study may not be replaced. 
 


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3.7  Randomisation 
Patients will be randomized in (1:1:1:1:1) ratio to one of the 5 treatment groups: Double 
blinded CTP-656 20 mg, Double-blinded CTP-656 100 mg, Double-blinded CTP-656 150 
mg, Double-blinded Placebo, and continuing Open-label Kalydeco. 
 
3.8  Blinding 
Randomization schedule should be kept in blind status for the 4 double-blinded treatment 
groups during the entire study duration, to patients, investigator and all project team 
members, except if unblinding is needed due to an adverse event.  Only after database lock, 
randomization schedule could be unblinded based on Sponsor approval. 
 
3.9  Sample Size 
Estimates for the standard deviation of change from baseline in sweat chloride were obtained 
from 4 sources1,2,3,4.  Reported values ranged from 10 to 14 mmol/L, and a value of 15 
mmol/L was assumed for sample size calculations in order to reduce the likelihood of 
overestimating power.  
 
  A sample size of 6 subjects per 
group will provide 87% power for a 2-sided, unpaired t-test with 0.05 Type I error under 
these assumptions. 
 
 


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4 Statistical Methodology 
 
4.1  Planned Analyses 
  
 Efficacy assessments (sweat chloride, percent predicted FEV1, and CFQ-R domains) 
will be summarized by treatment group and visit in the FAS population according to 
the randomized treatment. 
 Demographic/baseline characteristic and safety data will be summarized by treatment 
group with descriptive statistics in the Safety population according to the actually 
received treatment.  
 All data will be reported in data listings. 
 
Unless otherwise specified, baseline is defined as the last assessment performed prior to 
or on the date of first dose of study treatment (Day 1).  
 
4.2  Interim Analysis 
An interim analysis for Data Monitoring Committee (DMC) review will be performed upon 
completion of 3 patients per treatment group through Day 14. A separate DMC SAP 
describing the DMC data analysis has been finalized. 
 
4.3  Time Point Algorithms 
 
4.3.1 Relative Day 
First study treatment dose will be administered on Day 1. The day of first dose of study 
treatment is considered as Day 1 and the day before the first dose of study treatment will be 
relative Day -1.  Relative days will be calculated as follows only when the full assessment 
date is known (i.e., partial dates will have missing relative days): 
 
Date of assessment – Date of start of study treatment 
for assessments before start of study treatment 
Relative day =             
Date of assessment – Date of start of study treatment + 1 
for assessments on or after start of study treatment 
 
4.3.2 Windows 
Data will be summarized, analyzed and reported as per the study visit as recorded on the 
electronic case report form (eCRF), even if the assessment is outside of the protocol-defined 
visit window. No windowing of visits will be performed for data tabulations. Data collected 
at unscheduled visits will be included in patient listings, but will not be assigned to a 
scheduled visit for data summaries.  
 


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4.4  Patient Disposition 
Disposition status (completed or discontinued the study and treatment), including reason for 
discontinuation, date of last dose, and date of study completion/discontinuation, will be 
presented. The following will be summarized for all randomized patients: 
 
 The number of patients randomized 
 The number of patients randomized but not dosed (if applicable)  
 The number and percentage of patients in the Safety population 
 The number and percentage of patients in the FAS population 
 The number and percentage of patients who completed study treatment 
 The number and percentage of patients who prematurely discontinued study treatment 
and the reason for discontinuation 
 The number and percentage of patients who completed study 
 The number and percentage of patients who prematurely discontinued study and the 
reason for discontinuation 
 
A listing including all disposition status data will be generated for all randomized patients. A 
separate listing will include the randomization number, date of randomization, randomized 
treatment and the population flags for all randomized patients. 
A listing of screen failures will also be produced. 
 
4.5  Demographics and Other Baseline Characteristics 
 
Demographics 
Age will be calculated as (Informed consent date – date of birth + 1)/365.25 and presented to 
1 decimal place. No rounding will be carried out prior to summarizing age. 
Body Mass Index (BMI) will be calculated as: Weight (kg) / [Height (m)]2. 
Sex, race, ethnicity, CF genotype, and categorized baseline percent predicted FEV1 (60%-
90%, and above 90%) will be summarized using counts and percentages.  Age, baseline 
percent predicted FEV1, baseline height (cm), baseline weight (kg), and baseline BMI 
(kg/m2) will be summarized with descriptive statistics (number of patients [n], mean, standard 
deviation [SD], median, minimum [min], and maximum [max]). Summaries will be generated 
for the Safety population. A corresponding listing will be generated. 
 
Medical History  
Medical history will be recorded at Screening. Medical history data will include any prior 
reaction to drugs, use of alcohol and tobacco, history and treatment (if any) of cardiovascular, 
pulmonary, gastrointestinal, hepatic, renal, immunologic, neurologic, or psychiatric diseases, 
and confirmation of relevant inclusion criteria. Medical history data will be coded with the 
Medical Dictionary for Regulatory Activities (MedDRA v19.1) and summarized using 
frequency tabulations by system organ class and preferred term. The incidence is only one 
occurrence of a system organ class/preferred term per subject. If a subject reports multiple 
medical histories under the same system organ class or preferred term, then the count of 
incidences for that system organ class or preferred term will only be incremented by one. 
Medical history information will be displayed in a patient listing. 
 


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4.6  Treatment Exposure and Compliance 
Exposure to study drug (i.e., duration of treatment) of the 4 blinded treatments will be 
summarized in terms of the duration of subject treatment (in days). Duration of treatment, 
defined as Date of last dose – Date of first dose + 1, will be summarized using descriptive 
statistics. Study drug exposure with the relevant information will be presented in an 
individual subject data listing for all randomized subjects. Exposure summaries will be based 
on the Safety Population. 
For the 4 blinded treatments, number of tablets dispensed, number of tablets returned, missed 
doses, and tablets unaccounted for (lost) will be recorded in the eCRF at study visits Day 1, 
Day 7, Day 14, and Day 28. Number of tablets taken for a patient is calculated as: 
𝑇𝑎𝑏𝑙𝑒𝑡𝑠 𝑑𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑 –  𝑇𝑎𝑏𝑙𝑒𝑡𝑠 𝑟𝑒𝑡𝑢𝑟𝑛𝑒𝑑 –  𝑇𝑎𝑏𝑙𝑒𝑡𝑠 𝑢𝑛𝑎𝑐𝑐𝑜𝑢𝑛𝑡𝑒𝑑 
As each patient would take 2 tablets once daily for 28 days per protocol, number of tables 
planned for a patient is expected to be 56.  
Patient treatment compliance (percentage) is calculated using number of tablets taken and 
number of tablets planned, compliance percentage = number of tablets taken / 56 × 100%.   
Compliance data will be presented in a listing for all randomized patients.  Treatment 
compliance will be summarized using descriptive statistics and presented in a table for the 
FAS population. 
 
4.7  Prior and Concomitant Medications 
All prior medications taken within 30 days prior to screening and concomitant medications 
taken during the study after the first study drug administration will be recorded.  The World 
Health Organization (WHO) Drug Dictionary March 2016 will be used to code prior and 
concomitant medications. The WHO Anatomical-Therapeutic-Chemical (ATC) classification 
and preferred drug name will be attached to the clinical database. 
Prior medications are defined as any medication given prior to and stopped before the subject 
receives the first dose of study medication. Concomitant medications are defined as any 
medication given to the subject starting on or after the day the subject received the first dose 
of study medication or given prior to the subject receiving the first dose of study medication 
and continuing to receive it during the study. 
If the start date of medication is unknown, then the medication will be considered: 
 Prior to study medication if the end date is prior to the subject receiving the first dose 
of study medication 
 Concomitant with study medication if the end date is either on or after the first dose of 
study medication, if the end date is unknown, or if the medication is ongoing. 
If both the start and end dates are unknown, then the medication will be considered 
concomitant. 
Prior and concomitant medications will be summarized by ATC classification and preferred 
name. 
A detailed listing will be produced for prior/concomitant medications with a yes/no flag for 
prior medications. 
 


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4.8  Efficacy Analysis 
 
Efficacy endpoints will be graphically displayed for each individual subject in a Swimmer’s 
plot. Subjects in different treatment group will use different symbol scheme to distinguish 
from each other.   
  
 
4.8.1 Sweat Chloride 
Sweat chloride is measured at Visit 2/Day 1, Visit 3/Day 7, Visit 4/Day 14, and Visit 5/Day 
28 Change from baseline at 
 Day 28 in sweat chloride will be graphically 
displayed in a Swimmer’s plot for each individual subject. 
Sweat chloride data will be presented in a listing. 
Given sweat chloride data would be potentially unblinding, dummy data will be generated for 
producing blinded statistical output before study unblinding. 
 
4.8.2 Percent Predicted FEV1  
FEV1 is assessed using spirometry at Visit 1/Screening, Visit 2/Day 1, Visit 3/Day 7, Visit 
4/Day 14, and Visit 5/Day 28. For percent predicted FEV1, recorded as “FEV1 Best (% 
predicted)” in eCRF, Change from baseline (Day 1) at 
 Day 28 in percent 
predicted FEV1 will be graphically displayed in a Swimmer’s plot for each individual subject.  
Spirometry data, including FEV1 Best (liter), FEV1 2nd Best (liter), FEV1 Best (% predicted), 
FVC Best (liter), FVC 2nd Best (liter), FVC Best (% predicted), FEF25-75 Best (liter/second), 
FEF25-75 2nd Best (liter/second), and FEF25-75 Best (% predicted), will be presented in a listing. 
 
4.8.3 Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
CFQ-R assessments are performed at Visit 2/Day 1 and Visit 5/Day 28. 
 
 The questionnaire consists of 12 domains: 
physical, vitality, emotion, eating, treatment burden, health perceptions, social, body image, 
role, weight, respiratory, and digestion. 
 
 Values for each question range from 1 to 4 
 For questions listed horizontally (left to right) the left response 
category should be assigned a value of 1, the second category should be assigned a 2, the 
third a 3, and the rightmost category should be assigned a 4. For questions that are listed 
vertically (top to bottom), the top category should be assigned a value of 1, the next a 2, the 
third a 3, and the bottom category a 4. Some of the questions
 
are phrased in a positive direction 
 and the score for each of these questions 
will be reversed as: 1 = 4, 2 = 3, 3 = 2, 4 = 1, 5 =5. 
The scaled score for each domain is calculated using the formula below: 
 
𝑆𝑐𝑎𝑙𝑒𝑑 𝑆𝑐𝑜𝑟𝑒= 
𝑆𝑢𝑚 𝑜𝑓 𝑟𝑒𝑠𝑝𝑜𝑛𝑠𝑒𝑠−𝑀𝑖𝑛𝑖𝑚𝑎𝑙 𝑝𝑜𝑠𝑠𝑖𝑏𝑙𝑒 𝑠𝑢𝑚 (𝑛× 1)
𝑀𝑎𝑥𝑖𝑚𝑢𝑚 𝑝𝑜𝑠𝑠𝑖𝑏𝑙𝑒 𝑠𝑢𝑚 (𝑛× 4) −𝑀𝑖𝑛𝑖𝑚𝑎𝑙 𝑝𝑜𝑠𝑠𝑖𝑏𝑙𝑒 𝑠𝑢𝑚 (𝑛× 1) × 100 
 
Where n is the number of items within the domain. 
If the respondent is missing more than half of the items within a domain, the domain scale 
will not be calculated. If the patient is missing half or less of the domain items at a specific 


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assessment, the missing values will be replaced by the mean of the other recorded responses 
in that domain. 
 
 
Change from baseline in CFQ-R respiratory scale at Day 28 will be graphically displayed in a 
plot for each individual subject. 
CFQ-R individual item scores and calculated scale scores for each of the 12 domains will be 
presented in a listing. 
 
 
4.9  Safety Analysis 
 
4.9.1 Adverse events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
coding system (using MedDRA v19.1).  
Adverse events will be classified as pretreatment AEs or treatment-emergent AEs (TEAEs). 
Pre-treatment AEs will be defined as AEs that are reported or worsened after signing the 
informed consent form and prior to date of first study drug dose. 
TEAEs will be defined as AEs that occur post first study drug dose or AEs noted prior to the 
first study drug administration that worsen after Baseline. Adverse events will be considered 
treatment emergent if the onset date is on or after the date of first dose study drug and on or prior 
to the date of last dose study drug + 28 days. Only TEAEs will be summarized in tables. 
Adverse event summary tables will include Overall summary of AEs (counts, percentage of 
patients, number of total events) for: (1) all Pre-treatment AEs (2) all TEAEs (3) treatment-
related TEAEs (4) treatment-emergent SAEs (5) TEAEs leading to study drug 
discontinuation (6) TEAEs of Grade 3 or higher severity (7) TEAEs by maximum severity 
Frequency tables will be presented by treatment group for TEAEs listed in the table of overall 
summary of AEs by system organ class and preferred term for number of events, number of 
patients, and percentage of patients. The patient level incidence is only one occurrence of a 
preferred term/system organ class per patient. That is, if a patient reports multiple AEs under 
the same preferred term, then the count of patient level incidences for that preferred term will 
only be incremented by one. If a patient reports multiple AEs under the same system organ 
class, then the count of patient level incidences for that system organ class will also only be 
incremented by one. 
In addition, a frequency table will be presented by treatment group for all TEAEs by system 
organ class and preferred term for number of events, number of patients, and percentage of 
patients by maximum severity and study drug relationship. 
 
4.9.1.1 
Adverse Event Severity 
Severity of AEs will be graded on a 5 point scale: mild = grade 1, moderate = grade 2, severe 
= grade 3, life-threatening = grade 4, and death = grade 5, according to Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0. The severity grade of events 
for which the investigator did not record severity will be categorized as “Missing” for tabular 
summaries and data listings, and will be considered the least severe for the purposes of 


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sorting for data presentation. For summaries by severity grade, if a subject has multiple 
events occurring in the same SOC or PT, then the most severe event will be presented. 
 
4.9.1.2 
Relationship of Adverse Events to Study Drug 
Causal relationship of AE with the study drug will be classified by the investigator as 
“definitely related”, “probably related”, “possibly related”, “unlikely related”, and “not 
related”. All AEs with relationship to study drug of “definitely related”, “probably related”, 
or “possibly related” will be defined as related to study drug. All AEs with relationship to 
study drug of “unlikely related” or “not related” will be defined as unrelated to study drug. 
Events for which the investigator did not record relationship to study drug will be considered 
related to study drug for tabular summaries. Data listings will show the relationship as 
missing for such events. 
 
4.9.1.3 
Serious Adverse Events 
A serious adverse event (SAE) is any AE during this study that results in one of the following 
outcomes: 
 
 Is fatal (results in death) 
 Is life-threatening (Note: the term “life-threatening” refers to an event in 
which the patient was at risk of death at the time of the event; it does not refer 
to an event that could hypothetically have caused death had it been more 
severe) 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of 
stay) 
 Results in persistent or significant disability/incapacity (a substantial 
disruption of the patient’s ability to conduct normal life functions) 
 Is a congenital anomaly/birth defect or 
 Constitutes an important medical event that may jeopardize the patient or may 
require medical or surgical intervention to prevent one of the other outcomes 
listed above. 
 
4.9.1.4 
Treatment-Emergent Adverse Events 
Treatment-emergent AEs (TEAEs) will be defined as AEs that occur post first study drug dose 
or AEs noted prior to the first study drug administration that worsen after Baseline. Adverse 
events will be considered treatment emergent if the onset date is on or after the date of first dose 
study drug and on or prior to the date of last dose study drug + 28 days. 
 
If the onset date of an AE is incomplete, then the event will be considered treatment-
emergent if the month and year (or year alone if month is not recorded) of the event is: 
 The same as or after the month and year (or year) of the first dose of study drug 
 
If the start date of an AE is unknown, then the following rules will apply: 
 If the AE onset is unknown and the end date is after the first dose of study drug or 
ongoing, then the AE will be considered treatment-emergent. 
 If the AE onset date is unknown and the end date is before the first dose of study 
drug, then the AE will not be considered treatment-emergent. 


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 If both the start and end dates are unknown (or end date is ongoing), then the AE will 
be considered treatment-emergent. 
For data presentation, SOC will be ordered alphabetically, with PT sorted by decreasing total 
frequency. The Safety Population will be used for all AE summaries. No inferential statistics 
will be provided for the AE data. 
By-patient listings will be provided for AEs, SAEs, and AEs leading to study drug 
discontinuation. 
 
4.9.2 Clinical Laboratory Assessments 
The list of clinical laboratory assessments is included in Appendix D.  
The number and percentage of subjects meeting at least 1 threshold analysis criterion event, 
during the TE period will be summarized by treatment group and overall.  The threshold 
analysis criteria are provided in Appendix E.  
All clinical laboratory data will be presented in listings. 
Pregnancy test results for women of childbearing potential will be presented in listings only. 
Results from serology screen Hepatitis B surface antigen (HBsAG) and Hepatitis C virus 
antibody (HCV-Ab) will also be listed. 
 
4.9.3 Vital Signs  
The number and percentage of subjects meeting at least 1 threshold analysis criterion during 
the TE will be summarized by treatment group and overall. The threshold analysis criteria are 
provided in Appendix E. 
All vital signs data will be presented in a listing. 
 
4.9.4 12-Lead ECG  
The number and percentage of subjects meeting at least 1 threshold analysis criterion during 
the TE period will be summarized by treatment group and overall. The threshold analysis 
criteria are provided in Appendix E. 
A listing of all ECG results, including normality assessment (including clinical significance), 
abnormality details and ECG measurements, will be generated. 
 
4.10  Protocol Violations or Deviations 
Any protocol deviations and violations will be identified by the study team and archived in 
the TMF. 
 
4.11  Missing Values – Missing Visits 
Missing values will not be imputed unless otherwise specified. 
 
4.12  Deviations from SAP 
Any deviations from the original statistical plan will be described and justified in the final 
clinical study report. 
 


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4.13  Changes in Conduct or Planned Analyses from the Protocol 
Due to the limited number of subjects being enrolled in the study, all model based analyses 
and summary statistics are no longer applicable and are therefore removed. For the same 
reason, lab, vital and ECG shift tables and summary statistics will not be created.  
 
 
 


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5 Tables and Listings 
 
5.1 Table Format 
All output will be produced using SAS version 9.2 or a later version. 
In the top left portion of each table/listing, a table/listing number followed by the title of the 
table/listing will be presented. After the title line, optional sub-title or population information 
can be presented. Horizontal lines will appear before and after the column heading of the 
table/listing. Footnotes will be put below a horizontal line under the main body of text at the 
bottom of the page.  
The sponsor name, protocol number, programmers User ID, status of the table/listing (i.e. 
draft or final) and SAS program name will appear bottom left in a string and the page number 
will appear on the bottom right corner of each table/listing. The date and time of creation of 
table/listing will appear bottom left under the sponsor name. The source listing number will 
appear bottom left.  
A landscape layout is proposed for both table and listing presentations. 
The left and right margins of all tables and listings will be a minimum of 2.1 cm from the left 
and 1.9 cm from the right. The top and bottom margins will be a minimum 2.92 cm. Header 
and footer will be both 1.27 cm. 
There is no special requirement of font type and size, but an 8-point font size for tables and 
7or 8-point for listings is proposed using Courier New font. A maximum SAS line size=141 
and page size=44 for 8-point font size, and line size=161 and page size=50 for 7-point will be 
used so as to fit on both UK and US paper sizes. 
In a listing, in the case that a subject’s record has been continued to the next page, an 
appropriate identification (e.g., the subject ID number) must be presented at the beginning of 
that page. 
 
5.2  Conventions 
Unless otherwise specified, in summary tables of continuous variables, the minimum and 
maximum values will be displayed to the same number of decimal places as the raw data, the 
mean and median will be presented to one extra decimal place compared to the raw data, and 
the standard deviation will be displayed to two extra decimal places compared to the raw 
data. Wherever possible data will be decimal aligned. 
 
Unless otherwise specified frequency tabulations will be presented by number and 
percentage, where the percentage is presented in brackets to 1 decimal place. 
 
Data analyses will be presented as follows: 
 
 For all serial assessments performed for adverse events, vital signs, ECG, efficacy 
endpoint, treatment exposure and compliance, and prior and concomitant medications 
data will be summarized by treatment.  
 Disposition data will be summarized by treatment and overall. 
 Demographics and baseline characteristics will be summarized by treatment and 
overall. 
 Laboratory data will be summarized by treatment and overall. 


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Patient listings of all data from the eCRFs as well as any derived variables will be presented. 
In all patient listings, the relative day (i.e., relative to date of first dose of study drug) of all 
the dates will be presented. 
Data collected at unscheduled visits will be included in the patient listings but will not be 
included in by-visit summary tables, unless otherwise specified. Data from unscheduled time 
points will be included in data summaries where indicated. 
 
 




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Listing 16.2.2.4 
Prior and Concomitant Medication (All Randomized Patients) 
Listing 16.2.3.1 
Sweat Chloride (All Randomized Patients) 
Listing 16.2.3.2 
Spirometry Measurements (All Randomized Patients) 
Listing 16.2.3.3.1 
Cystic Fibrosis Questionnaire-Revised Recorded Data (All 
Randomized Patients) 
Listing 16.2.3.3.2 
Cystic Fibrosis Questionnaire-Revised Domain Scale Scores (All 
Randomized Patients) 
Listing 16.2.4.1 
Adverse Events (All Randomized Patients) 
Listing 16.2.4.2 
Serious Adverse Events (All Randomized Patients) 
Listing 16.2.4.3 
Adverse Events Leading to Study Drug Discontinuation (All 
Randomized Patients) 
Listing 16.2.4.4 
Pulmonary Exacerbation Checklist (All Randomized Patients) 
Listing 16.2.5.1 
Laboratory Assessments: Hematology (All Randomized Patients) 
Listing 16.2.5.2 
Laboratory Assessments: Chemistry (All Randomized Patients) 
Listing 16.2.5.3 
Laboratory Assessments: Coagulation (All Randomized Patients) 
Listing 16.2.5.4 
Laboratory Assessments: Urinalysis (All Randomized Patients) 
Listing 16.2.5.5 
Serology Screen (All Randomized Patients) 
Listing 16.2.5.6 
Pregnancy Test (All Randomized Patients) 
Listing 16.2.6 
Vital Signs (All Randomized Patients) 
Listing 16.2.7 
12-Lead Electrocardiogram (All Randomized Patients) 
Listing 16.2.8 
12-Lead Electrocardiogram - Subjects with at Least 1 Abnormal (PCS) 
Findings (All Randomized Patients) 
 
 


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7 References  
 
1. Vermeulen F, Camus CL, Davies JC, Bilton D, Milenkovic D, De Boeck K.  Variability in 
sweat chloride concentration in subjects with cystic fibrosis and G551D mutations.  J Cyst 
Fibrosis 2016; in press. 
2. Mayer-Hamblatt N, Boyle D, VanDevanter D.  Advancing clinical development pathways 
for new CFTR modulators in cystic fibrosis.  Thorax 2016.  
3. LeGrys VA.  Assesing quality assurance for sweat chloride testing. J Am Soc for Med 
Tech1992;5:354-57. 
4. United States Package Insert for Kalydeco, March 2015. 
 


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9 Appendices 
 
Appendix A. Cytochrome P450 Drug Interactions 
 
CYP P450 3A4/3A5/3A7 Inhibitors: 
CYP P450 3A4/3A5 Inducers: 
 
Amiodarone 
 
Aprepitant 
 
Chloramphenicol 
 
Cimetidine 
 
Ciprofloxacin 
 
Clarithromycin 
 
Clotrimazole 
 
Delaviridine 
 
Diethyl-dithiocarbamate 
 
Diltiazem 
 
Erythromycin 
 
Fluconazole 
 
Fluvoxamine 
 
Gestodene 
 
Grapefruit juice 
 
Imatinib 
 
Indinavir 
 
Itraconazole 
 
Ketoconozole 
 
Mifepristone 
 
Nefazodone 
 
Nelfinavir 
 
Norfloxacin 
 
Norfluoxetine 
 
Ritonavir 
 
Saquinavir 
 
Star fruit 
 
Telithromycin 
 
Verapamil 
 
Voriconazole 
 Barbiturates 
 Carbamazepine 
 Efavirenz 
 Glucocorticoids 
 Modafinil 
 Nevirapine 
 Oxcarbazepine 
 Phenobarbital 
 Phenytoin 
 Pioglitazone 
 Rifabutin 
 Rifampin 
 St. John’s Wort 
 Troglitazone 
 
 
 
 
 












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Appendix D. Laboratory Assessments  
 
HEMATOLOGY 
CLINICAL CHEMISTRY 
URINALYSIS 
Complete blood count (CBC) 
Platelet count 
White blood cell (WBC) 
count with differential 
 
Alanine aminotransferase (ALT) 
Albumin (ALB) 
Alkaline phosphatase (ALK-P) 
Amylase  
Aspartate aminotransferase (AST) 
Total bilirubin 
Direct bilirubin 
Indirect bilirubin 
Blood urea nitrogen (BUN) 
Calcium (Ca) 
Carbon Dioxide (CO2) 
Chloride (Cl) 
Total cholesterol  
Creatinine 
Creatine kinase (CK) 
Gamma-glutamyl transferase (GGT) 
Glucose 
Lactic dehydrogenase (LDH) 
Lipase 
Total serum protein 
Phosphorus 
Potassium (K) 
Sodium (Na) 
Uric Acid 
Bilirubin 
Glucose 
Ketones 
Nitrates 
Occult Blood 
Protein 
Specific gravity 
Urobilinogen 
pH 
Leukocytes 
Microscopic urine analysis if 
dipstick positive 
LFTs 
Total bilirubin 
Direct bilirubin 
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate aminotransferase 
Albumin 
Gamma-glutamyl transferase 
Total serum protein  
SEROLOGY SCREEN 
COAGULATION  
PREGNANCY 
Hepatitis B surface 
antigen (HBsAg) 
Hepatitis C virus antibody 
(HCV-Ab) 
Prothrombin Time Test (PT) 
Partial Prothrombin Time Test 
(aPTT) 
International normalized ratio 
(INR) 
Human chorionic 
gonadotropin (hCG) 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix E. Threshold Analysis Criteria 
 
Table 11-8 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry (LFT) 
ALT 
>ULN - ≤3xULN 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>8x - ≤ 20.0xULN 
>20.0xULN 
FDA DILI Guidance Jul 2009.  
AST 
>ULN - ≤3xULN 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>8x - ≤ 20.0xULN 
>20.0xULN 
FDA DILI Guidance Jul 2009. 
ALT or AST 
 (ALT>ULN - ≤  3xULN) or 
(AST>ULN - ≤  3xULN) 
(ALT>3x - ≤  5xULN) or  (AST>3x 
- ≤  5xULN) 
(ALT>5x- ≤  8xULN) or  (AST>5x - 
≤    8xULN) 
(ALT>8x - ≤  20xULN) or (AST>8x 
- ≤ 20xULN) 
ALT>20xULN or AST> 20 xULN 
FDA DILI Guidance 
Alkaline Phosphatase 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2.5 xULN 
>2.5 – ≤ 5.0 x ULN 
>5.0 – ≤ 20.0 x ULN 
>20.0 x ULN 
FDA DILI Guidance Jul 2009.  
Total Bilirubin 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2xULN 
>2 – ≤ 3xULN  
>3 – ≤ 10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
Direct Bilirubin 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2xULN 
>2 – ≤ 3xULN  
>3 – ≤ 10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
ALT and Total Bilirubin 
ALT>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
 
AST and Total Bilirubin 
AST>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
 
(ALT or AST) and Total Bilirubin (ALT>3xULN or AST>3xULN) and 
TBILI>2×ULN 
FDA DILI Guidance Jul 2009. 
GGT 
>ULN - ≤ 2.5xULN 
>2.5 –  ≤ 5.0xULN 
>5.0 –  ≤ 20.0xULN  
>20.0xULN 
CTCAE grade 1-4 
Clinical Chemistry (NON-LFT) 
 


Protocol: CP656.2001 
 
Vertex Pharmaceuticals Incorporated 
Version 2 Final 
       Page 33 of 36 
22SEP2017 
Table 11-8 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Albumin 
<LLN - ≥ 30 g/L 
<30 – ≥ 20 g/L 
<20 g/L 
CTCAE grade 1-3 
Amylase 
>1x -  ≤  1.5xULN 
>1.5x -  ≤  2xULN 
>2x -  ≤  5xULN 
>5xULN 
Criteria based upon CTCAE 
Creatinine 
>ULN - ≤ 1.5xULN 
>1.5 - ≤ 3.0xULN 
>3.0 - ≤ 6.0xULN 
>6.0xULN 
CTCAE grades 1-4 
Lipase 
>ULN -  ≤  1.5xULN 
>1.5x -  ≤  2xULN 
>2x -  ≤  5xULN 
>5xULN 
Criteria based upon CTCAE 
Total protein 
 
<LLN  
>ULN 
No CTCAE 
Hematology 
Hemoglobin 
Hgb decreased (anemia) 
<LLN - ≥ 100 g/L 
<100 – ≥ 80 g/L  
< 80 g/L 
CTCAE grade 1-3 
 
Hgb increased 
>ULN - ≤ 20 g/L above ULN 
>20 g/L above ULN - ≤ 40 g/L 
above ULN 
>40 g/L above ULN 
CTCAE grade 1-3 
Platelets 
Platelet decreased 
<LLN - ≥ 75.0 x 10e9 /L 
<75.0 – ≥ 50.0 x 10e9 /L  
<50.0 – ≥ 25.0 x 10e9 /L  
<25.0 x 10e9 /L 
CTCAE grade 1-4 
 
Platelet increased   
>ULN 
No CTCAE available 
 
Reticulocytes/Erythrocytes (%)    <LLN 
>ULN 
No CTCAE 
 
 
 


Protocol: CP656.2001 
 
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Version 2 Final 
       Page 34 of 36 
22SEP2017 
 
Table 11-9 
Threshold Analysis Criteria for ECGs 
Parameter 
Threshold Analysis 
Comments 
HR 
Bradycardia 
 
<50 bpm        
<45 bpm        
Decrease from baseline ≥10 bpm 
Decrease from baseline ≥20 bpm 
<50 bpm and decrease from baseline ≥10 bpm 
<50 bpm and decrease from baseline ≥20 bpm 
 
Per HV grade 2, 3, plus shift change 
 
 
 
Tachycardia 
 
>100 bpm 
>115 bpm  
>130 bpm  
Increase from baseline ≥10 bpm 
Increase from baseline ≥20 bpm  
>100 bpm and increase from baseline ≥10 bpm 
>100 bpm and increase from baseline ≥20 bpm 
Per HV grade 1, 2, 3, plus shift change 
 
 
PR 
≥240 ms 
≥300 ms 
≥200 ms and increase from baseline ≥40 ms 
≥200 ms and increase from baseline ≥100 ms 
 
QRS 
>110 ms 
>160 ms 
Increase from baseline ≥20 ms 
Increase from baseline ≥40 ms 
 
QTc 
Borderline 
Prolonged* 
Additional 
 
 
>450 ms (Male) and <500ms; >470 ms and 
<500ms (Female) 
≥500 ms 
 
Increase from baseline 
Increase from baseline >10 ms 
Increase from baseline >20 ms 
Increase from baseline >40 ms 
Increase from baseline >60 ms 
 
To be applied to any kind of QT correction 
formula.  
 
 
 
 
Note: Based on CPMP 1997 guideline. 
 
 
 


Protocol: CP656.2001 
 
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Version 2 Final 
       Page 35 of 36 
22SEP2017 
 
Table 11-10 
Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
HR 
Same as above in ECG category 
 
 
SBP increased 
 
 
>140 mmHg 
>160 mmHg 
>10 mmHg increase from baseline 
>20 mmHg increase from baseline 
 
>140 mmHg & >10 mmHg increase from 
baseline 
>140 mmHg & >20 mmHg increase from 
baseline 
>160 mmHg & >10 mmHg increase from 
baseline 
>160 mmHg & >20 mmHg increase from 
baseline 
 
809/770 analyses 
SBP decrease 
 
 
<90 mmHg 
<80 mmHg 
>10 mmHg decrease from baseline 
>20 mmHg decrease from baseline 
 
<90 mmHg and >10 mmHg decrease from 
baseline 
<90 mmHg and >20 mmHg decrease from 
baseline 
<80 mmHg and >10 mmHg decrease from 
baseline 
<80 mmHg and >20 mmHg decrease from 
baseline 
 
Per HV grade 1, 3, plus shift change 


Protocol: CP656.2001 
 
Vertex Pharmaceuticals Incorporated 
Version 2 Final 
       Page 36 of 36 
22SEP2017 
Table 11-10 
Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
DBP increased 
 
>90 mmHg 
>100 mmHg 
>5 mmHg increase from baseline 
>10 mmHg increase from baseline 
 
>90 mmHg and >5 mmHg increase from 
baseline 
>90 mmHg and >10 mmHg increase from 
baseline 
>100 mmHg and >5 mmHg increase from 
baseline 
>100 mmHg and >10 mmHg increase from 
baseline 
 
 
DBP decreased 
 
 
<60 mmHg 
<45 mmHg 
>5 mmHg decrease from baseline 
>10 mmHg decrease from baseline 
 
<60 mmHg and >5 mmHg decrease from 
baseline 
<60 mmHg and >10 mmHg decrease from 
baseline 
<45 mmHg and >5 mmHg decrease from 
baseline 
<45 mmHg and >10 mmHg decrease from 
baseline 
 
 
Weight   
Weight gain  
≥5 % increase from baseline   
≥10 % increase from baseline  
≥ 20% increase from baseline  
 
CTCAE grade 1-3 
 
 
Weight loss  
≥5 % decrease from baseline   
≥10 % decrease from baseline  
≥ 20% decrease from baseline  
 
CTCAE grade 1-3