Clinical trial NCT02871778
Conditions: Primary Ciliary Dyskinesia
Sponsor: Parion Sciences
Start date: 2016-08-01; Completion date: 2018-11-20
Enrollment: 123 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
To evaluate the safety and efficacy of treatment with VX-371 with and without ivacaftor, and the effect of VX-371 with and without ivacaftor on quality of life (QOL) in subjects with primary ciliary dyskinesia (PCD).

Detailed description:

Arms: arm 1: Participants received 85 microgram (mcg) VX-371 diluted in 3 milliliter (mL) 4.2 percent (%) HS twice daily through oral nebulized inhalation from Day 1 through Day 29 in treatment period 1 followed by a 28 day washout period (from Day 29 through Day 56) and then received 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days (from Day 57 through Day 85) in treatment period 2. arm 2: Participants received 3 mL 4.2% HS through oral nebulized inhalation twice daily from Day 1 through Day 29 in treatment period 1 followed by a 28 day washout period (from Day 29 through Day 56) and then received 85 mcg VX-371 diluted in 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days (from Day 57 through Day 85) in treatment period 2. arm 3: Participants received 85 mcg VX-371 diluted in 3 mL 0.17% Saline (placebo) through oral nebulized inhalation twice daily from Day 1 through Day 29 in treatment period 1 followed by a 28 day washout period (from Day 29 through Day 56) and then received 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days (from Day 57 through Day 85) in treatment period 2. arm 4: Participants received 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily from Day 1 through Day 29 in treatment period 1 followed by a 28 day washout period (from Day 29 through Day 56) and then received 85 mcg VX-371 diluted in 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days (from Day 57 through Day 85) in treatment period 2. arm 5: Participants who were on 85 mcg VX-371 diluted in 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days (from Day 57 through Day 85) in treatment period 2 continued their inhaled study drug regimen from Treatment Period 2 and also received ivacaftor 150 mg tablet twice daily for 28 days (from Day 85 through Day 113) in treatment period 3. arm 6: Participants who were on 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days (from Day 57 through Day 85) in treatment period 2 continued their inhaled study drug regimen from Treatment Period 2 and also received ivacaftor 150 mg tablet twice daily for 28 days (from Day 85 through Day 113) in treatment period 3. arm 7: Participants who were on 85 mcg VX-371 diluted in 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days (from Day 57 through Day 85) in treatment period 2 continued their inhaled study drug regimen from Treatment Period 2 and also received ivacaftor 150 mg tablet twice daily for 28 days (from Day 85 through Day 113) in treatment period 3. arm 8: Participants who were on 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days (from Day 57 through Day 85) in treatment period 2 continued their inhaled study drug regimen from Treatment Period 2 and also received ivacaftor 150 mg tablet twice daily for 28 days (from Day 85 through Day 113) in treatment period 3.
Interventions: intervention 1: VX-371 intervention 2: Hypertonic Saline intervention 3: Placebo (0.17% saline) intervention 4: VX-371 + HS intervention 5: Ivacaftor
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None

Protocol documents:
Prot_000.pdf: 
Page 1 of 88 
 
 
TITLE PAGE 
 
PARION SCIENCES INCORPORATED 
Clinical Study Protocol 
 
A Phase 2a, 2-part, Randomized, Double-blind, 
Placebo-controlled, Incomplete Block Crossover 
Study to Evaluate the Safety and Efficacy of VX-371 
Solution for Inhalation With and Without  Oral 
Ivacaftor in Subjects With Primary Ciliary Dyskinesia 
Parion Sciences Study Number: PS-G202 
IND Number: 
 
EudraCT Number: 2015-004917-26 
 
Date of Protocol: 31 October 2016 (Version 6.0) 
 
Parion Sciences, Incorporated 
2800 Meridian Parkway, Suite 195 
Durham, NC USA 27713 
 
CONFIDENTIAL 
This document contains confidential information. Any use, distribution, or disclosure without the prior written consent 
of Parion Sciences 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. 
Report P155, Version 1.0 
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Protocol PS-G202, Version 6.0 
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Report P155, Version 1.0 
Study PS-G202 
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Protocol PS-G202, Version 6.0 
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Report P155, Version 1.0 
Study PS-G202 
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Protocol PS-G202, Version 6.0 
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Report P155, Version 1.0 
Study PS-G202 
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Parion Sciences, Inc. 


Protocol PS-G202, Version 6.0 
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Parion Sciences Incorporated 
 
Report P155, Version 1.0 
Study PS-G202 
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Vertex Pharmaceuticals Incorporated 
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Protocol PS-G202, Version 6.0 
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PROTOCOL SYNOPSIS 
Title A Phase 2a, 2-part, Randomized, Double-blind, Placebo-controlled, Incomplete 
Block Crossover Study to Evaluate the Safety and Efficacy of VX-371 Solution 
for Inhalation With and Without Oral Ivacaftor in Subjects With Primary Ciliary 
Dyskinesia 
 
Brief Title CLEAN-PCD: Clearing Lungs with ENaC Inhibition in Primary Ciliary 
Dyskinesia  
  
Clinical Phase and 
Clinical Study Type  
Phase 2a, safety and efficacy  
 
  
Objectives Part A Objectives 
Primary 
To evaluate the safety and efficacy of treatment with VX-371, administered with 
and without 4.2% hypertonic saline (HS) in subjects with primary ciliary 
dyskinesia (PCD) who are ≥12 years of age 
Secondary 
To evaluate the effect of VX-371, administered with and without 4.2% HS, on 
quality of life (QOL) in subjects with PCD who are ≥12 years of age 
Part B Objectives 
Primary 
To evaluate the safety and efficacy of treatment with ivacaftor and VX-371, 
administered with and without 4.2% HS in subjects with PCD who are ≥12 years 
of age 
Secondary 
To evaluate the effect of ivacaftor and VX-371, administered with and without 
4.2% HS on QOL in subjects with PCD who are ≥12 years of age 
Endpoints Part A Endpoints 
Primary 
 
Results of safety and tolerability assessments of adverse events (AEs), clinical 
laboratory values (urine, serum and plasma chemistry, and hematology), 
12-lead electrocardiograms (ECGs), spirometry, vital signs, and pulse 
oximetry 
 
Absolute change in percent predicted forced expiratory volume in 1 second 
(ppFEV1) from study baseline, after 28 days of treatment in Part A 
Secondary 
 
Change in QOL score as measured by the Quality of Life-PCD Questionnaire 
(QOL-PCD) and the St. George’s Respiratory Questionnaire (SGRQ) from 
study baseline, after 28 days of treatment in Part A 
Report P155, Version 1.0 
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Protocol PS-G202, Version 6.0 
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Part B Endpoints 
Primary 
 
Results of safety and tolerability assessments of AEs, clinical laboratory 
values (urine, serum and plasma chemistry, and hematology), 12-lead ECGs, 
spirometry, vital signs, and pulse oximetry 
 
Absolute change in ppFEV1 from study baseline and Part B baseline, after 28 
days of treatment in Part B 
Secondary 
 
Change in QOL score as measured by the QOL-PCD and SGRQ from study 
baseline and Part B baseline, after 28 days of treatment in Part B 
Number of Subjects Approximately 150 subjects will be randomized to 1 of 4 treatment sequences 
  
Study Population Male and female subjects ≥12 years of age with a confirmed diagnosis of PCD 
  
Investigational Drug Active substance: VX-371 
 Activity: Epithelial sodium channel (ENaC) inhibitor 
 Strength and Route of Administration: 85 µg VX-371 in 3 mL 0.17% saline, oral 
nebulized inhalation 
  
 Active substance: VX-371 in HS 
 Activity: ENaC inhibitor + osmolyte 
 Strength and Route of Administration: 85 µg VX-371 + 3 mL 4.2% HS, oral 
nebulized inhalation 
  
 Active substance: HS 
 Activity: Osmolyte 
 Strength and Route of Administration: 3 mL 4.2% HS, oral nebulized inhalation 
  
 Active substance: Not applicable 
 Activity: Placebo 
 Strength and Route of Administration: 3 mL 0.17% saline, oral nebulized 
inhalation 
  
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Protocol PS-G202, Version 6.0 
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 Active substance: ivacaftor 
 Activity: cystic fibrosis transmembrane regulator (CFTR) potentiator 
 Strength and Route of Administration: 150-mg tablet, oral  
  
Study Duration Part A Study Duration 
Excluding the Screening Period, the planned study duration is 113 days from 
Day 1 to Safety Follow-up Telephone Call, approximately 28 days after the last 
dose of study drug.  
Part A + Part B Study Duration 
Excluding the Screening Period, the planned study duration is 141 days from 
Day 1 to Safety Follow-up Telephone Call, approximately 28 days after the last 
dose of study drug.  
  
Study Design Phase 2a, 2-part, randomized, double-blind, placebo-controlled, incomplete block 
crossover, multicenter study in subjects ≥12 years of age with PCD.  
Subjects will be randomized to 1 of 4 treatment sequences as shown in Table 2-1. 
Table 2-1  
Study PS-G202 Treatment Sequences 
Sequence 
Part A 
Part B 
Treatment 
Period 1 
Treatment 
Period 2 
Treatment Period 3 
1 
VX-371 in 4.2% 
HS 
4.2% HS 
4.2% HS + ivacaftor 
2 
4.2% HS 
VX-371 in 
4.2% HS 
VX-371 in 4.2% HS + 
ivacaftor 
3 
VX-371 in 0.17% 
saline  
Placebo 
(0.17% saline) 
Placebo (0.17% saline) + 
ivacaftor 
4 
Placebo (0.17% 
saline) 
VX-371 in 
0.17% saline  
VX-371 in 0.17% saline + 
ivacaftor 
 
This study includes the following: 
 Screening Period: Day of Screening Visit until Day 1 (first dose of study 
drug). The Screening Visit can occur Day -38 to Day -5, relative to the first 
dose of study drug. 
 Treatment Periods: 
 
Part A:  
o Treatment Period 1: Day 1 (first dose of study drug) through Day 29  
(28 days of treatment) 
o Washout Period: Day 29  through Day 56 (28 days) 
o Treatment Period 2: Day 57 through Day 85 (28 days of treatment) 
 
Part B (Optional):  
o Treatment Period 3:  Day 85 (first dose of oral ivacaftor) through Day 
113 (28 days of treatment) 
Note: There is no Washout Period between the last dose of study drug 
in Part A and the first dose of study drug in Part B. 
 Safety Follow-up Period: 28 days (± 7 days) after the last dose of study drug 
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Protocol PS-G202, Version 6.0 
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If the subject prematurely discontinues study drug, an Early Termination of 
Treatment (ETT) Visit should be scheduled as soon as possible after the subject 
decides to terminate study drug treatment. Subjects who prematurely discontinue 
treatment will also be required to complete the Safety Follow-up Telephone Call 
approximately 28 days (± 7 days) after their last dose of study drug.  
  
Assessments Efficacy: spirometry, QOL-PCD, SGRQ 
Safety: AEs, spirometry, clinical laboratory values (urine, serum and plasma 
chemistry, and hematology), ECGs, vital signs, and pulse oximetry  
  
 
 
  
Statistical Analyses Statistical analysis details will be provided in the statistical analysis plan (SAP), 
which will be finalized before the clinical database lock for the study.   
Part A 
The primary efficacy objective of Part A is to evaluate the efficacy of VX-371 
with and without HS in subjects ≥12 years of age with PCD. For the Part A 
efficacy analysis, statistical inferences will be based on change from study 
baseline, and formal comparisons will be made between groups. The null 
hypotheses to be tested in Part A are that the absolute absolute change from study 
baseline in ppFEV1 after 28 days of treatment is the same for 1) VX-371 in HS 
versus placebo; 2) VX-371 versus placebo; and 3) VX-371 in HS versus HS alone.  
To have a feasible sample size and study duration, Part A of this study uses a 
crossover design. Assuming a standard deviation of 7 percentage points, 
50 subjects each for Treatment Sequence 1 and 2 are needed to have 
approximately 81% power to detect a 3-percentage point treatment difference in 
the mean absolute change in ppFEV1 from study baseline, after 28 days of 
treatment between VX-371 + HS and HS alone. Part A of the study will have 
approximately 87% power to detect a 4-percentage point change from baseline, 
after 28 days of treatment in ppFEV1 between VX-371 + HS and placebo. The 
power to detect a 3 percentage point difference between VX-371 and placebo is 
about 51%. The sample size estimate was based on 10000 simulation runs with an 
incomplete block design assuming no dropouts. In the simulation, the correlation 
between responses to the 2 treatments within a subject was assumed to be 0. 
Furthermore, a 2-sided significance level of 0.05 was used in the sample size 
determination with no multiplicity adjustment. The sample size also takes into 
consideration an assumed dropout rate of 10%. 
The primary efficacy endpoint is the absolute change in ppFEV1 from study 
baseline, after 28 days of treatment in each Treatment Period of Part A. The 
primary efficacy analysis is based on a mixed-effects model. This model will 
include the absolute change from study baseline in ppFEV1 after 28 days of 
treatment as the dependent variable, treatment and period as fixed effects, and 
subject as a random effect. The within-subject covariance will be assumed to have 
the compound symmetry (CS) structure. Denominator degrees of freedom for the 
F-test for fixed effects will be estimated using the Kenward-Roger approximation.  
The estimated mean of the dependent variable, a 95% confidence interval (CI), 
and a 2-sided P value will be provided for each treatment. There will be no 
adjustment for multiplicity. Similarly, the estimated between-treatment 
differences along with the corresponding 95% CI and 2-sided P values will be 
presented.  
Part B 
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For the Part B primary efficacy endpoints, absolute change in ppFEV1 from study 
baseline and Part B baseline, after 28 days of treatment, descriptive summary 
statistics (n, mean, SD, SE, median, minimum, and maximum), and within-group 
comparisons will be made. 
The within-group P value and the 95% CI based on normal approximation will be 
provided for absolute change in ppFEV1:  
 
From study baseline, after 28 days of treatment in Part B 
 
From Part B baseline, after 28 days of treatment in Part B 
IDMC Reviews The independent data monitoring committee (IDMC) will conduct regular planned 
safety reviews of study as described in the IDMC charter.  
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SCHEDULE OF ASSESSMENTS 
Schedules of Assessments are shown in Table 3-1, Table 3-2, and Table 3-3.  
Table 3-1 
Study PS-G202: Screening Period 
Event/Assessment 
Screening Period 
(Day -38 to Day -5) 
Clinic visit 
X 
Informed consent/assent  
X 
Inclusion/exclusion criteria reviewa 
X 
Demographics 
X 
Medical history 
X 
Medications review 
X 
Height and weightb 
X 
Pulse oximetry and vital signsc 
X 
Full physical examinationd 
X 
12-lead ECGe 
X 
Spirometryf 
X 
Single dose of HS to assess tolerability  
X 
Serum β-HCGg 
X 
Serum FSHh 
X 
Serum chemistry 
X 
Plasma chemistryi 
X 
Hematology 
X 
PCD genotypej 
X 
Urinalysis 
X 
Adverse events and serious adverse events 
Continuous from signing of ICF/assent (if 
applicable) and initiation of study procedures 
through the Safety Follow-Up Telephone Call 
 
a  
After obtaining informed consent/assent, inclusion criteria # 4A and # 4B (Section 9.1), as applicable, must be confirmed 
prior to initiating any other screening assessments during the Screening Period.  
b 
Height and weight will be measured with shoes off. BMI will be calculated. 
c 
Pulse oximetry and vital signs will be performed after the subject has been seated or supine for at least 5 minutes.  
d 
Physical examination of all body systems, excluding rectal and genitourinary examinations. 
e  
The ECG will be performed after the subject has been seated or supine for at least 5 minutes. Prior to placing ECG leads, the 
record will be reviewed for the presence of dextrocardia. Subjects with dextrocardia will have all ECG limb and chest (V) 
leads reversed. 
f      The spirometry assessment will be performed within 60 minutes before the test dose of HS and 60 minutes (± 5 minutes) 
after the test dose of HS. See Section 8.1.1 for more information.  
g 
 A serum pregnancy test will be performed for all female subjects of childbearing potential. 
h  
Follicle-stimulating hormone (FSH) will be measured for any suspected postmenopausal female with at least 12 months of 
continuous spontaneous amenorrhea. Serum FSH levels must be ≥40 mIU/mL to be considered postmenopausal. 
i 
 Plasma potassium. 
j   Unless a confirmed PCD genotype is an inclusion criterion for a particular subject (see Section 9.1), the genotype result is 
not required in order for randomization to occur.  
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Table 3-2  
Study PS-G202: Treatment Period  
Event/Assessment 
Part A 
Part B 
Treatment Period 1 
(Day 1 through Day 29) 
 
 
 
 
Washout 
Day 29 to 
Day 56 
(+3 Days) 
Treatment Period 2 
(Day 57 through Day 85) 
Treatment Period 3a 
(Day 85 through Day 113) 
Day 1 
Day 4 
Telephone 
Call 
(±1 Day) 
Day 15b 
Telephone 
Call 
(±1 Day) 
Day 
15b 
Visit 
(±3 
Days) 
Day 29 
Visit 
 (±3 
Days) 
Day  
57 
Visit 
Day 60 
Telephone 
Call 
(±1 Day) 
Day 71b 
Telephone 
Call 
(±1 Day) 
 
Day 
71b 
Visit 
(±3 
Days) 
Day 85c 
Visit 
(±3 
Days) 
Day 86 
Telephone 
Call 
 
Day 87 
Telephone 
Call 
 
Day 99b,d 
Telephone 
Call 
(-11 Days) 
 
Day 99b,d 
Visit 
(-11 Days) 
Day 113 
Visit 
(±3 Days) 
Pre-visit reminder 
contacte 
X  
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
Part B informed 
consent/assent 
 
 
 
 
 
 
Xf 
 
 
 
 
 
 
 
 
 
Clinic visit 
X 
 
 
X 
X 
 
X 
 
 
X 
X 
 
 
 
X 
X 
Safety telephone callg 
 
X 
X 
 
 
 
 
X 
X 
 
 
X 
X 
X 
 
 
Inclusion/exclusion 
criteria review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizationh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QOL-PCDi 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
SGRQi 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
 
a  
Subjects will sign a new ICF (or assent if applicable) before the Day 85 Visit in order to continue into Treatment Period 3. If the subject does not sign the new ICF, Treatment 
Period 2 will end at Day 85 and the subject will continue through to the Safety Follow-up Telephone Call. 
b  
Day 15, Day 71, and Day 99 clinic visit required for subjects randomized prior to IDMC approval to change visit to a telephone call.  
c  
At the Day 85 Visit, subjects will remain in clinic for a total of 2 to 4 hours after dosing with study drug. The duration of the extended time for each subject (2 to 4 hours) will 
be left up to the discretion of the investigator. Post-dose safety assessments will be done prior to discharge from the clinic.  
d      Day 99 Visit or telephone call may occur any time between Day 88 and Day 99. The clinic visit may be changed to a telephone call after approval from the IDMC. 
e  
Pre-visit reminder should be done 1 day before the visit, via telephone call, email, or text message, to remind subject to withhold short-acting bronchodilators for 4 hours prior 
to spirometry assessment performed at each visit, to withhold long-acting bronchodilators the night before the visit, and to administer study drug at least 4 hours before visits 
on Day 29, Day 85, and Day 113. 
f  
 Subjects who participate in Part B will sign a new ICF for Treatment Period 3. This should occur at least 2 weeks prior to Day 85 to allow for delivery of study drug for 
Treatment Period 3. 
g  
A safety telephone call will occur on Day 4, Day 15 (if no visit conducted), Day 60, Day 71 (if no visit conducted), Day 86, Day 87, and between Day 88 and Day 99 (if no 
Day 99 Visit conducted) for safety purposes (e.g., inquiry about adverse events). The telephone call on Day 86 and 87 will continue until the IDMC deems them unnecessary.  
h      Randomization will occur once it is confirmed that the subject meets all eligibility criteria, and approximately 5 to 10 days prior to Day 1, in order for study drug to be 
delivered to the site and in time for the first dosing. 
i  
The QOL-PCD assessment must be completed before the start of any other assessments scheduled at this visit. The SGRQ should be completed immediately following the 
QOL-PCD assessment and before the start of other assessments. 
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Table 3-2  
Study PS-G202: Treatment Period  
Event/Assessment 
Part A 
Part B 
Treatment Period 1 
(Day 1 through Day 29) 
 
 
 
 
Washout 
Day 29 to 
Day 56 
(+3 Days) 
Treatment Period 2 
(Day 57 through Day 85) 
Treatment Period 3a 
(Day 85 through Day 113) 
Day 1 
Day 4 
Telephone 
Call 
(±1 Day) 
Day 15b 
Telephone 
Call 
(±1 Day) 
Day 
15b 
Visit 
(±3 
Days) 
Day 29 
Visit 
 (±3 
Days) 
Day  
57 
Visit 
Day 60 
Telephone 
Call 
(±1 Day) 
Day 71b 
Telephone 
Call 
(±1 Day) 
 
Day 
71b 
Visit 
(±3 
Days) 
Day 85c 
Visit 
(±3 
Days) 
Day 86 
Telephone 
Call 
 
Day 87 
Telephone 
Call 
 
Day 99b,d 
Telephone 
Call 
(-11 Days) 
 
Day 99b,d 
Visit 
(-11 Days) 
Day 113 
Visit 
(±3 Days) 
Medications review 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
treatments and 
procedures 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetry, chest 
auscultation, and 
vital signsk 
Xl 
 
 
X 
X 
 
Xl 
 
 
X 
Xl 
 
 
 
X 
X 
Height and weightm 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
X 
Physical 
examinationn 
X 
 
 
X 
X 
 
X 
 
 
X 
X 
 
 
 
X 
X 
12-lead ECGo 
X 
 
 
X 
X 
 
X 
 
 
X 
X 
 
 
 
X 
X 
Spirometry 
  Xp 
 
 
X 
X 
 
Xp 
 
 
X 
Xp 
 
 
 
X 
X 
 
  
 
 
 
k  
Vital signs and pulse oximetry will be performed after the subject has been seated or supine for at least 5 minutes.  
l  
Vital signs, chest auscultation, and pulse oximetry will be performed pre-dose and 1 hour post-dose of study drug in clinic at the Day 1 Visit and Day 57 Visit. At the Day 85 
Visit, if the subject continues into Part B, vital signs, chest auscultation, and pulse oximetry will be performed pre-dose and post-dose prior to discharge from the clinic. If the 
subject does not continue into Part B, vital signs, chest auscultation, and pulse oximetry will only be performed once at the Day 85 Visit.  
m  
Height and weight will be measured with shoes off. BMI will be calculated.  
n  
Full physical examination of all body systems, excluding rectal and genitourinary examinations, on Day 1, Day 29, Day 57, Day 85, and Day 113. An abbreviated physical 
examination (HEENT, neck, chest auscultation, cardiovascular, and skin) at Day 15, Day 71, and Day 99, if the visits are planned.  
o  
The ECG will be performed after the subject has been seated or supine for at least 5 minutes. Prior to placing ECG leads, the record will be reviewed for the presence of 
dextrocardia. Subjects with dextrocardia will have all ECG limb and chest (V) leads reversed. 
p  
Spirometry will be performed prior to dosing with study drug and 1 hour post-dose at the Day 1 and Day 57 Visits. At the Day 85 Visit, if the subject continues into Part B, 
spirometry will be performed pre-dose and post-dose, prior to discharge from the clinic. If the subject does not continue into Part B, spirometry will only be performed once at 
the Day 85 Visit.  
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Table 3-2  
Study PS-G202: Treatment Period  
Event/Assessment 
Part A 
Part B 
Treatment Period 1 
(Day 1 through Day 29) 
 
 
 
 
Washout 
Day 29 to 
Day 56 
(+3 Days) 
Treatment Period 2 
(Day 57 through Day 85) 
Treatment Period 3a 
(Day 85 through Day 113) 
Day 1 
Day 4 
Telephone 
Call 
(±1 Day) 
Day 15b 
Telephone 
Call 
(±1 Day) 
Day 
15b 
Visit 
(±3 
Days) 
Day 29 
Visit 
 (±3 
Days) 
Day  
57 
Visit 
Day 60 
Telephone 
Call 
(±1 Day) 
Day 71b 
Telephone 
Call 
(±1 Day) 
 
Day 
71b 
Visit 
(±3 
Days) 
Day 85c 
Visit 
(±3 
Days) 
Day 86 
Telephone 
Call 
 
Day 87 
Telephone 
Call 
 
Day 99b,d 
Telephone 
Call 
(-11 Days) 
 
Day 99b,d 
Visit 
(-11 Days) 
Day 113 
Visit 
(±3 Days) 
Urine pregnancy test 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
Urine testsq  
X 
 
 
X 
X 
 
X 
 
 
X 
X 
 
 
 
X 
X 
Serum chemistry 
X 
 
 
X 
X 
 
X 
 
 
X 
X 
 
 
 
X 
X 
Plasma chemistryt 
X 
 
 
X 
X 
 
X 
 
 
X 
X 
 
 
 
X 
X 
Hematology 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
Inhaled study drug 
dose in clinic 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Meal or snack in 
clinic 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Ivacaftor dose in 
clinicu 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Dispense inhaled 
study drug 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Dispense ivacaftor 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
q  
Urinalysis at Day 1, Day 29, Day 57, Day 85, and Day 113. Urine sodium, potassium, and creatinine analysis at Day 1, Day 15 (if a visit is planned), Day 29, Day 57, Day 71 
(if a visit is planned), Day 85, Day 99 (if a visit is planned), and Day 113.  
  
 
  
 
  
 
u  
Ivacaftor should be administered every 12 hours (q12h) with fat-containing food.  The first dose of ivacaftor in Part B will be administered on the Day 85 Visit, after 
completion of the Day 85 pre-dose assessments.  
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Table 3-2  
Study PS-G202: Treatment Period  
Event/Assessment 
Part A 
Part B 
Treatment Period 1 
(Day 1 through Day 29) 
 
 
 
 
Washout 
Day 29 to 
Day 56 
(+3 Days) 
Treatment Period 2 
(Day 57 through Day 85) 
Treatment Period 3a 
(Day 85 through Day 113) 
Day 1 
Day 4 
Telephone 
Call 
(±1 Day) 
Day 15b 
Telephone 
Call 
(±1 Day) 
Day 
15b 
Visit 
(±3 
Days) 
Day 29 
Visit 
 (±3 
Days) 
Day  
57 
Visit 
Day 60 
Telephone 
Call 
(±1 Day) 
Day 71b 
Telephone 
Call 
(±1 Day) 
 
Day 
71b 
Visit 
(±3 
Days) 
Day 85c 
Visit 
(±3 
Days) 
Day 86 
Telephone 
Call 
 
Day 87 
Telephone 
Call 
 
Day 99b,d 
Telephone 
Call 
(-11 Days) 
 
Day 99b,d 
Visit 
(-11 Days) 
Day 113 
Visit 
(±3 Days) 
Instruct subject on 
Part B dietary and 
medication 
restrictions 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
Dispense nebulizer 
base 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense 2 handsets 
(aerosol heads) for 
nebulizer 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Instruct subject on 
proper use of 
nebulizerv 
X 
 
X 
X 
 
 
X 
 
X 
X 
X 
 
 
X 
X 
 
Collect unused study 
drug and perform 
study drug count 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
Collect subject diary 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
Adverse events and 
serious adverse 
events 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
v  
If inhaled study drug is administered in clinic, site staff should clean nebulizer before releasing to subject.  
  
  
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Table 3-3       Early Termination of Treatment Visit and Safety Follow-Up Telephone 
Call 
Event/Assessment 
Early Termination of  
Treatment Visit 
Safety Follow-up Telephone Call 
28 Days (± 7 Days) After Last Dose 
of Study Druga 
Clinic visit 
X 
 
QOL-PCDb 
X 
 
SGRQb 
X 
 
Height and weightc 
X 
 
Pulse oximetry and vital signs d 
X 
 
Full physical examinatione  
X 
 
12-lead ECGf 
X 
 
 
 
 
 
 
Spirometry  
X 
 
Urine pregnancy test 
X 
 
Hematology 
X 
 
Urine testsh  
X 
 
Serum chemistry 
X 
 
Plasma chemistryi 
X 
 
 
 
 
 
 
 
Collect unused study drug and 
perform study drug count 
X 
 
Collect subject diary 
X 
 
 
 
 
 
Medication review 
X 
X 
Concomitant treatments and 
procedures 
X 
X 
Adverse events and serious adverse 
events 
X 
X 
 
a  
If the subject prematurely discontinues study drug, an Early Termination of Treatment Visit should be scheduled as soon as 
possible after the subject decides to terminate study drug treatment. Subjects who prematurely discontinue treatment will 
also be required to complete the Safety Follow-up Telephone Call, approximately 28 days (± 7 days) after their last dose of 
study drug.  
b  
The QOL-PCD assessment must be completed before the start of any other assessments scheduled at this visit. The SGRQ 
should be completed immediately following the QOL-PCD. 
c  
Height and weight will be measured with shoes off. BMI will be calculated.  
d  
Vital signs and pulse oximetry will be performed after the subject has been seated or supine for at least 5 minutes. 
e  
Physical examination of all body systems, excluding rectal and genitourinary examinations.  
f  
The ECG will be performed after the subject has been seated or supine for at least 5 minutes. Prior to placing ECG leads, the 
record will be reviewed for the presence of dextrocardia. Subjects with dextrocardia will have all ECG limb and chest (V) 
leads reversed. 
  
 
 
  
h  
Urinalysis and urine sodium, potassium, and creatinine analysis. 
i  
Plasma potassium. 
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TABLE OF CONTENTS 
 
Title Page ................................................................................................................................ 1 
 
Protocol Synopsis ................................................................................................................... 6 
 
Schedule of Assessments...................................................................................................... 11 
 
Table of Contents ................................................................................................................. 17 
List of Tables............................................................................................................................ 21 
List of Figures .......................................................................................................................... 21 
Glossary of Terms .................................................................................................................... 22 
 
Introduction.......................................................................................................................... 25 
 
Background ..................................................................................................................... 25 
 
VX-371 Solution for Inhalation ...................................................................................... 29 
 
Ivacaftor .......................................................................................................................... 29 
 
Rationale for the Present Study ...................................................................................... 29 
 
Study Objectives .................................................................................................................. 30 
 
Part A Objectives ............................................................................................................ 30 
 
Part B Objectives ............................................................................................................ 30 
 
Study Endpoints ................................................................................................................... 30 
 
Part A Endpoints ............................................................................................................. 30 
7.1.1 
Primary Endpoints .................................................................................................. 30 
7.1.2 
Secondary Endpoint ................................................................................................ 31 
 
 31 
 
 31 
 
Part B Endpoints ............................................................................................................. 31 
7.2.1 
Primary Endpoints .................................................................................................. 31 
7.2.2 
Secondary Endpoint ................................................................................................ 31 
 
 
 
 
 
Study Design ......................................................................................................................... 31 
 
Overview of Study Design ............................................................................................. 31 
8.1.1 
Maintenance of Stable Medication Regimen for PCD ........................................... 33 
8.1.2 
Screening: Day -38 to Day -5 ................................................................................. 33 
8.1.2.1 
Repetition of Screening Assessment(s) ............................................................ 34 
8.1.2.2 
Rescreening ...................................................................................................... 34 
8.1.2.3 
Extension of Screening Period Window .......................................................... 35 
8.1.3 
Treatment Periods ................................................................................................... 35 
8.1.3.1 
Part A ............................................................................................................... 35 
8.1.3.1.1 Treatment Period 1 ...................................................................................... 35 
8.1.3.1.2 Washout Period ........................................................................................... 36 
8.1.3.1.3 Treatment Period 2 ...................................................................................... 36 
8.1.3.2 
Part B ................................................................................................................ 37 
8.1.3.2.1 Treatment Period 3 ...................................................................................... 37 
8.1.3.3 
Planned Pre-visit Subject Contacts .................................................................. 38 
8.1.4 
Follow-Up ............................................................................................................... 38 
8.1.5 
Early Termination of Treatment ............................................................................. 38 
8.1.6 
Unscheduled Visits ................................................................................................. 39 
8.1.7 
Independent Data Monitoring Committee .............................................................. 39 
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Rationale for Study Design and Study Drug Regimens ................................................. 39 
8.2.1 
Study Design........................................................................................................... 39 
8.2.2 
Study Drug Dose and Duration .............................................................................. 40 
8.2.3 
Rationale for Study Assessments ........................................................................... 40 
 
Study Population .................................................................................................................. 41 
 
Inclusion Criteria ............................................................................................................ 41 
 
Exclusion Criteria ........................................................................................................... 42 
9.2.1 
Additional Exclusion Criteria for Part B ................................................................ 44 
 
Study Restrictions ........................................................................................................... 44 
 
Prior and Concomitant Medications ............................................................................... 46 
9.4.1 
Prohibited Medications in Part B............................................................................ 47 
 
Removal of Subjects ....................................................................................................... 47 
 
Replacement of Subjects ................................................................................................ 48 
 Study Drug Administration and Management ................................................................. 48 
 Preparation and Dispensing ............................................................................................ 48 
 Administration ................................................................................................................ 48 
10.2.1 
Inhaled Study Drug Administration Via the Nebulizer .......................................... 48 
10.2.2 
Ivacaftor .................................................................................................................. 49 
10.2.3 
Dosing in Clinic ...................................................................................................... 49 
10.2.4 
Dosing at Home ...................................................................................................... 50 
10.2.5 
Missed Doses .......................................................................................................... 50 
 Method of Assigning Subjects to Treatment Groups ..................................................... 50 
 Dose Modification for Toxicity ...................................................................................... 51 
 Packaging and Labeling ................................................................................................. 51 
 Study Drug Supply, Storage, and Handling ................................................................... 51 
 Drug Accountability ....................................................................................................... 52 
 Disposal, Return, or Retention of Unused Drug ............................................................. 52 
 Compliance ..................................................................................................................... 52 
 Blinding and Unblinding ................................................................................................ 53 
10.10.1 Blinding .................................................................................................................. 53 
10.10.2 Unblinding .............................................................................................................. 53 
 Assessments .......................................................................................................................... 54 
 Timing of Assessments ................................................................................................... 54 
 Subject and Disease Characteristics ............................................................................... 54 
 Efficacy ........................................................................................................................... 56 
11.5.1 
Spirometry .............................................................................................................. 56 
11.5.2 
QOL-PCD ............................................................................................................... 57 
11.5.3 
SGRQ...................................................................................................................... 57 
 Safety .............................................................................................................................. 57 
11.6.1 
Adverse Events ....................................................................................................... 57 
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11.6.2 
Clinical Laboratory Assessments ........................................................................... 58 
11.6.2.1 Hyperkalemia ................................................................................................... 59 
11.6.2.2 Elevation of Liver Function Test Parameters................................................... 60 
11.6.3 
Physical Examinations and Vital Signs .................................................................. 60 
11.6.4 
Electrocardiograms ................................................................................................. 61 
11.6.5 
Contraception and Pregnancy ................................................................................. 61 
11.6.5.1 Contraception ................................................................................................... 61 
11.6.5.2 Pregnancy ......................................................................................................... 63 
 Statistical and Analytical Plans .......................................................................................... 63 
 Sample Size and Power .................................................................................................. 63 
 Analysis Sets .................................................................................................................. 64 
 Statistical Analysis ......................................................................................................... 65 
12.3.1 
General Considerations ........................................................................................... 65 
12.3.2 
Background Characteristics .................................................................................... 66 
12.3.2.1 Subject Disposition .......................................................................................... 66 
12.3.2.2 Demographics and Baseline Characteristics .................................................... 67 
12.3.2.3 Prior and Concomitant Medications................................................................. 67 
12.3.2.4 Study Drug Exposure and Compliance ............................................................ 67 
12.3.3 
Efficacy Analysis .................................................................................................... 68 
12.3.3.1 Analysis of Primary Efficacy Variables ........................................................... 68 
12.3.3.2 Analysis of Secondary Efficacy Variables ....................................................... 69 
 
 
12.3.4 
Safety Analysis ....................................................................................................... 70 
12.3.4.1 Adverse Events................................................................................................. 71 
12.3.4.2 Clinical Laboratory Assessments ..................................................................... 72 
12.3.4.3 Electrocardiogram ............................................................................................ 72 
12.3.4.4 Vital Signs ........................................................................................................ 72 
12.3.4.5 Physical Examination ....................................................................................... 73 
12.3.4.6 Spirometry ........................................................................................................ 73 
12.3.4.7 Other Safety Analysis ...................................................................................... 73 
12.3.4.7.1 Pulse Oximetry .......................................................................................... 73 
12.3.5 
Interim and IDMC Analyses ................................................................................... 73 
12.3.5.1 Interim Analysis ............................................................................................... 73 
12.3.5.2 IDMC Analysis ................................................................................................ 73 
 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 74 
 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 74 
13.1.1 
Adverse Events ....................................................................................................... 74 
13.1.1.1 Definition of an Adverse Event........................................................................ 74 
13.1.1.2 Clinically Significant Assessments .................................................................. 74 
13.1.1.3 Documentation of Adverse Events................................................................... 75 
13.1.1.4 Adverse Event Severity .................................................................................... 75 
13.1.1.5 Adverse Event Causality .................................................................................. 76 
13.1.1.6 Study Drug Action Taken ................................................................................ 76 
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13.1.1.7 Adverse Event Outcome .................................................................................. 77 
13.1.1.8 Treatment Given............................................................................................... 77 
13.1.2 
Serious Adverse Events .......................................................................................... 77 
13.1.2.1 Definition of a Serious Adverse Event............................................................. 77 
13.1.2.2 Documentation of Serious Adverse Events...................................................... 78 
13.1.2.3 Reporting Serious Adverse Events................................................................... 78 
13.1.2.4 Expedited Reporting and Investigator Safety Letters ...................................... 79 
13.1.3 
Adverse Device Effects .......................................................................................... 79 
13.1.3.1 Definition of an Adverse Device Effect ........................................................... 79 
13.1.3.2 Definition of Serious Adverse Device Effect................................................... 79 
13.1.3.3 Reporting Adverse Device Effects ................................................................... 79 
13.1.3.4 Expedited Reporting and Investigator Safety Letters ...................................... 80 
 Administrative Requirements ......................................................................................... 80 
13.2.1 
Ethical Considerations ............................................................................................ 80 
13.2.2 
Subject Information and Informed Consent ........................................................... 80 
13.2.3 
Investigator Compliance ......................................................................................... 81 
13.2.4 
Access to Records ................................................................................................... 81 
13.2.5 
Subject Privacy ....................................................................................................... 81 
13.2.6 
Record Retention .................................................................................................... 81 
13.2.7 
Study Termination .................................................................................................. 82 
 Data Quality Assurance .................................................................................................. 82 
 Monitoring ...................................................................................................................... 82 
 Electronic Data Capture ................................................................................................. 83 
 Publications and Clinical Study Report .......................................................................... 83 
 
 
13.6.2 
Clinical Study Report ............................................................................................. 83 
 References ............................................................................................................................. 84 
 Protocol Signature Pages .................................................................................................... 87 
 Parion Signature Page ..................................................................................................... 87 
 Investigator Signature Page ............................................................................................ 88 
 
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List of Tables 
Table 2-1  
Study PS-G202 Treatment Sequences .................................................................... 8 
Table 3-1 
Study PS-G202: Screening Period ........................................................................ 11 
Table 3-2  
Study PS-G202: Treatment Period........................................................................ 12 
Table 3-3        Early Termination of Treatment Visit and Safety Follow-Up Telephone Call ..... 16 
Table 8-1 
Study PS-G202 Treatment Sequences .................................................................. 32 
Table 9-1 
Prohibited Medications ......................................................................................... 45 
Table 9-2 
Antibiotic and Bronchodilator Restrictions .......................................................... 46 
Table 10-1 
Study Drug ............................................................................................................ 51 
Table 11-1 
Safety Laboratory Test Panels .............................................................................. 58 
Table 11-2 
Acceptable Methods of Contraception.................................................................. 62 
Table 13-1 
Grading of AE Severity ........................................................................................ 76 
Table 13-2 
Classifications for AE Causality ........................................................................... 76 
Table 13-3 
Classifications for Study Drug Action Taken with Regard to an AE ................... 76 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 77 
 
List of Figures 
Figure 5-1 
Proposed Feedback Model for PCL Hydration ..................................................... 26 
Figure 5-2 
Dependence of ASL Hydration on ATP Concentration ....................................... 27 
Figure 5-3 
PCD Cilia Model................................................................................................... 28 
Figure 8-1  
Schematic of Study Design PS-G202 ................................................................... 32 
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Glossary of Terms 
Abbreviation 
Term 
ACE 
angiotensin converting enzyme 
ADE 
adverse device effect 
AE 
adverse event 
ALT 
alanine aminotransferase 
ARB 
angiotensin receptor blocker 
ASL 
airway surface liquid 
AST 
aspartate aminotransferase 
ATP 
adenosine triphosphate 
ATS 
American Thoracic Society 
β-HCG 
beta-human chorionic gonadotropin 
bid 
twice per day 
BMI 
body mass index 
Ca++ 
calcium 
CF 
cystic fibrosis 
CFTR 
cystic fibrosis transmembrane receptor protein 
CFTR 
CF transmembrane conductance regulator gene 
CI 
confidence interval 
Cl- 
chloride ion 
CPAP 
continuous positive airway pressure 
CRO 
contract research organization 
CS 
compound symmetry 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
 
 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ENaC 
epithelial sodium channel 
ERS 
European Respiratory Society 
ETT 
Early Termination of Treatment 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FEF25%-75% 
forced midexpiratory flow, midexpiratory phase 
FEV1 
forced expiratory volume in 1 second 
FSH 
follicle-stimulating hormone 
FVC 
forced vital capacity 
G551D 
CFTR missense gene mutation that results in the replacement of a glycine residue 
at position 551 of CFTR with an aspartic acid residue  
GCP 
Good Clinical Practice 
GLI 
Global Lung Function Initiative 
GPS 
Global Patient Safety 
HEENT 
head, eyes, ears, nose, and throat 
HIPAA 
Health Insurance Portability and Accountability Act 
HS 
hypertonic saline 
ICF 
informed consent form 
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Abbreviation 
Term 
ICH 
International Council on Harmonization 
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
IND 
Investigational New Drug (application) (US) 
IRB 
institutional review board 
ISO 
isoflurane-treated 
IXRS 
interactive response system in which X represents voice or web 
K+ 
potassium 
LFT 
liver function test 
LMA 
low melting-point agarose 
max 
maximum 
MCC 
mucociliary clearance 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare Products Regulatory Agency (United Kingdom) 
min 
minimum 
N 
total sample size 
Na+ 
sodium 
NEP 
neural endopeptidase 
nNO 
nasal nitric oxide 
NPD 
nasal potential difference 
P 
probability 
pp 
percent predicted 
PBS 
phosphate buffered saline 
PCD 
primary ciliary dyskinesia 
PCL 
periciliary layer 
PK 
pharmacokinetic(s) 
PR 
PR interval, segment 
q12h 
every 12 hours 
QOL 
quality of life 
QOL-PCD 
PCD Quality of Life Questionnaire 
QRS 
the portion of an ECG comprising the Q, R, and S waves, together representing 
ventricular depolarization 
QTc 
QT interval corrected 
QTcF 
QT interval corrected by Fridericia’s formula 
R117H 
CFTR missense gene mutation that results in the replacement of an arginine 
residue at position 117 of CFTR with a histidine residue 
SADE 
serious adverse device effect 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error 
SGRQ 
St. George’s Respiratory Questionnaire 
SUSAR 
suspected, unexpected, serious adverse reaction 
TE 
treatment-emergent 
TEM 
transmission electron micrograph 
TEAE 
treatment-emergent adverse event 
UADE 
unanticipated adverse device effects 
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Abbreviation 
Term 
ULN 
upper limit of normal 
USA 
United States of America 
WHO-DDE 
World Health Organization-Drug Dictionary Enhanced 
 
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INTRODUCTION 
 
Background 
Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder characterized by various 
ciliary defects that result in loss of synchronous ciliary beating and ciliary propulsive function. In 
the ciliated airways of the lung, PCD is manifested by ineffective clearance of mucous secretions 
and inhaled particles, including bacteria. Clinical features of PCD include early onset of 
recurrent or persistent rhinitis, sinusitis, otitis media, bronchiectasis and bronchial infections.1 
About 50% of PCD patients have situs inversus or other laterality defects. Infertility occurs in 
nearly 100% of males due to immotile spermatozoa and females are often infertile due to 
impaired ciliary function in the fallopian tubes.2 In addition to the clinical presentation, PCD 
patients have very low nasal nitric oxide (nNO) concentrations, ranging from 1/10th to 1/50th that 
of healthy subjects.3,4 In addition, most patients have diagnostic ciliary defects on electron 
microscopic evaluations of ciliated airway cells.1,5 
PCD has been reported in many ethnic groups without apparent racial or gender preference and, 
consistent with being an autosomal recessive disorder, it has been observed with a higher 
incidence in consanguineous and isolated populations.6,7,8,9 The estimated incidence of PCD is 1 
in 16,000 to 1 in 20,000 births.10 To date, over 30 disease-causing genetic mutations have been 
identified that are associated with proteins that are critical for ciliary structure and function in 
PCD patients. The extent of ciliary dysfunction varies with the genetic defect in a particular 
patient, thus resulting in mutation-dependent rates and extent of loss of lung function.11 
Currently, there are no approved treatments for PCD and no completed, industry-sponsored, 
controlled clinical studies to evaluate treatments for PCD.12 Given the lack of demonstrated 
value of treatments, management of PCD patients is typically focused on clearance of airways 
along with prevention and treatment of airway infections. These therapies may include chest 
percussion, postural drainage, drugs to treat pulmonary symptoms and antibiotics (often oral). 
Given the importance of cough clearance in patients with PCD, the use of cough suppressants is 
avoided. 
It has been classically believed that mucus clearance is affected by cilia (i.e., mucociliary 
clearance; MCC) and cough (i.e., cough dependent clearance). Because of the absence of cilial 
activity in PCD, it has been concluded that PCD reflects a simple loss of mechanical transduction 
of cilial force into mucus transport. This scenario is consistent with the gravitational distribution 
of PCD bronchiectasis, i.e., it is more prevalent in lower lobes. 
However, it has been demonstrated that mucus clearance is more complicated than simply a 
combination of MCC and cough clearance and that mucus concentration is a major determinant 
of mucus transport. As a component of studies designed to explore how normal airways maintain 
mucus hydration (2% solids, 98% water) optimal for mucus transport, it was discovered that 
motile cilia sense the hydration status of mucus (see Figure 5-1).13  
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Figure 5-1 
Proposed Feedback Model for PCL Hydration 
  
Proposed feedback model of stimulation of adenosine triphosphate (ATP) release and subsequent fluid secretion 
by increased membrane stress during conditions of increased mucus concentration. Increased mucus 
concentration is sensed by beating cilia and leads to increased fluid secretion through ATP release. Once the 
mucus is rehydrated and has a lower viscoelasticity, the stress on the cilia is reduced, ATP release is decreased, 
and fluid homeostasis returns to the normal state (from Button 2013)13. 
The mechanism for the normal autoregulation of mucus hydration requires two elements: 1) 
strain on the cilial shaft, which is dependent on the interaction of a beating cilium and the 
concentration of mucus (i.e., a more concentrated mucus is more difficult to move) and which 
puts more strain on the cilial shaft/base; and 2) cilial strain-dependent release of ATP into the 
airway lumen, whereby ATP via interactions with purinoceptors inhibits epithelial sodium 
channel (ENaC)-dependent sodium (Na+) (and fluid) absorption and accelerates cystic fibrosis 
transmembrane receptor (CFTR)- and calcium (Ca++)-activated chloride (Cl-) channel-dependent 
fluid secretion. Thus, in PCD, the abnormally high rate of Na+ absorption and low rate of Cl- 
secretion that produces mucus hyperconcentration reflect the absence of normal regulation by 
extracellular ATP of ENaC and CFTR channels. Representative data showing the dependence of 
airway surface liquid (ASL) hydration on ATP concentrations and the dependence of ATP 
concentrations on motile cilia are shown in Figure 5-2. 
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Figure 5-2 
Dependence of ASL Hydration on ATP Concentration 
 
(A) Relationship between the magnitude of changes in luminal ATP concentrations and ASL height. Human 
airway cultures were subjected to varying degrees of oscillatory stress before measuring luminal [ATP] and 
steady-state ASL height. These data revealed a direct relationship between ATP and changes in ASL height. 
(B) Sample ZX confocal micrograph showing the distinct layering of fluorescently labeled low melting-point 
agarose (LMA; green layer at top) from the periciliary layer (PCL) (labeled with Texas Red dextran). Airway 
epithelial cells were labeled green using calcein AM. Scale bar, 7 μm. (C) Relationship between the 
concentration of luminal ATP and the concentration of LMA added to the airway surface. Means ± SE from 
6 to 8 cultures per point. *P <0.05 compared to vehicle (0% LMA). (D) Relationship between the change in 
ASL height and concentration of LMA for both poorly ciliated and well-ciliated cultures. Data are plotted as 
the difference in ASL height between the LMA relative and a vehicle control (PBS) at 30 min after exposure. 
Without LMA, (PBS control), the average ASL height at 30 min was 8.2 ± 0.3 μm for the well-ciliated and 
6.1 ± 0.4 μm for the poorly ciliated group. Mean ± SE from 3 cultures per point. *P <0.05 compared to the 
initial measurement (from Button 2013). 
As part of these studies, the question was asked whether the autoregulation of mucus/ASL 
hydration depended on motile cilia. Indeed, both an agent that acutely paralyzed cilial activity 
(isoflurane) and ciliated cultures from subjects with PCD revealed that motile cilia were required 
for this sensing mechanism (Figure 5-3). This observation led to the hypothesis that there may be 
a “second hit” in PCD mucus clearance, i.e., mucus hyperconcentration. Review of the literature 
revealed that PCD mucus was hyperconcentrated (dehydrated) to a degree similar to cystic 
fibrosis (CF).14 
 
 
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Figure 5-3 
PCD Cilia Model 
 
Data summarizing the role of cilia beating in control, isoflurane-treated (ISO), and primary ciliary dyskinesia 
(PCD) airway cultures exposed to 0.15% LMA and 0.3% LMA. Data are means ± SE from three cultures per 
group. *P <0.05 between groups (from Button 2013). 
The poor clearance of PCD mucus as a function of increased concentration may not appear to be 
relevant to PCD subjects who have no cilial activity (i.e., no MCC). However, recent analyses 
suggest that mucus hyperconcentration is a major factor in the clearance of mucus by cough and 
all the elements of that process. For example, simple measures of cough clearance suggest that 
cough clearance is decreased as a function of the mucus concentration cubed.16 Similarly, the 
disadhesion of mucus from the epithelial surface required for cough is heavily dependent on 
mucus concentration as is the “tearing” of mucus from adjacent mucus (i.e., mucus 
cohesion).17,18 Thus it is predicted that normalization of mucus concentration in PCD subjects 
will greatly improve the efficiency of cough clearance. 
Finally, there likely is a third mode of mucus clearance i.e., gas-liquid pumping. 19,20,21 Though 
described 30 years ago, little attention has been paid to this mode of transport. In essence, this 
transport reflects 3 variables: 1) there is hysteresis in shear on airway surfaces during normal 
respiration, so that shear is greatest on expiration; 2) entrainment of mucus flow by air; and 3) 
the friction generated by mucus flow over airway surfaces. Recent in vivo data support this 
mechanism in animals. Importantly, recent data have shown that the friction of mucus movement 
over airway surfaces is again highly dependent on mucus concentration, i.e., the higher the 
concentration, the higher the friction. Recent studies of mouse models of PCD suggest that gas-
liquid pumping contributes to basal mucus flow in PCD animals. Therefore, it predicted that 
agents that normalize mucus concentration in PCD subjects, i.e., hydrating agents, will reduce 
mucus-airways surface friction and accelerate gas-liquid dependent mucus clearance.  
In summary, it appears likely that the failure to clear mucus in PCD subjects reflects both the 
absence of cilial beat/force and the absence of normal regulation of mucus concentration. Mucus 
hyperconcentration is predicted to limit the effectiveness of the 2 “backup” mechanisms for 
mucus clearance in PCD subjects, i.e., cough and gas-liquid pumping. Consequently, restoring 
PCD mucus to its normal hydration status is predicted to be therapeutic in this population. 
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VX-371 Solution for Inhalation 
VX-371 (Parion Sciences P-1037) is a new chemical entity belonging to a family of amiloride 
derivatives referred to as pyrazinoylguanidines. VX-371 is a novel ENaC inhibitor that inhibits 
transport of sodium through direct exofacial block of the ENaC. ENaC is expressed in the apical 
membrane of epithelial cells lining the respiratory tract, distal nephron, colon, and other organs. 
Sodium ions enter cells through apical ENaC and are transported out by the Na+/ K+ ATPase 
located at the basolateral membrane. In the lungs, ENaC is one of the primary proteins that 
control the ASL volume and is therefore linked to airway hydration and mucus clearance. 
Optimal MCC requires that airway secretions be adequately hydrated. ENaC is activated by 
proteolytic cleavage, which can be due to constitutive proteases such as prostasin or by soluble 
inflammatory proteases such as neutrophil elastase. It is hypothesized that the inhibition of ENaC 
activity with VX-371 will increase hydration of airway secretions rendering them more 
susceptible to cough clearance and gas-liquid pumping in subjects with PCD. 
Additional information is available in the VX-371 Investigator’s Brochure. 
 
Ivacaftor 
Ivacaftor (Kalydeco®) is an orally administered CFTR potentiator that increases the 
channel-open probability of CFTR protein to enhance chloride transport, which yields clinical 
benefit in certain patients with CF.  
Kalydeco is indicated for the treatment of CF in patients as young as 2 years who have the 
G551D and certain other gating mutations as well the R117H mutation in the cystic fibrosis 
transmembrane conductance regulator gene (CFTR).  The indicated mutations and approved 
populations vary by country. 
Additional information about ivacaftor is available in the Ivacaftor Investigator’s Brochure. 
 
Rationale for the Present Study 
In PCD, the lack of ATP release into the lumen of the airways due to dysfunctional cilia leaves 
ENaC uninhibited, resulting in hyperconcentration of mucus. Inhibition of ENaC by VX-371 is 
expected to restore hydration of the mucus in PCD patients, resulting in improved cough 
clearance and gas-liquid pumping of mucus. 
 
 
 
 
The majority of PCD patients are expected to have intact CFTR function, although the regulation 
of CFTR activity by purinoceptors may be altered due to reduced airway luminal ATP. Ivacaftor 
improves chloride transport in vitro in normal human bronchial epithelial (HBE) cells that have 
intact CFTR, and in HBE cells from CF patients with various CFTR mutations, yielding 
increased ASL height.22 
 
 
 
 
  
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In Part A, the present study is designed to evaluate the safety and efficacy of VX-371 
administered with and without 4.2% HS for 28 days to subjects with PCD who are ≥12 years of 
age. In Part B, the study is designed to evaluate the safety and efficacy of VX-371 administered 
with and without 4.2% HS in subjects treated with orally-administered ivacaftor.  
Throughout this protocol, the term “inhaled study drug” is used to refer to VX-371 + placebo, 
VX-371 + HS, HS, and placebo administered by nebulizer. The term “study drug,” when it 
appears without a qualifier, is used to refer to both inhaled study drug and orally-administered 
ivacaftor.  
 
STUDY OBJECTIVES 
 
Part A Objectives 
Primary 
To evaluate the safety and efficacy of treatment with VX-371, administered with and without 
4.2% HS, in subjects with PCD who are ≥12 years of age 
Secondary 
To evaluate the effect of VX-371, administered with and without 4.2% HS, on quality of life 
(QOL) in subjects with PCD who are ≥12 years of age 
 
Part B Objectives 
Primary 
To evaluate the safety and efficacy of treatment with ivacaftor and VX-371, administered with 
and without 4.2% HS in subjects with PCD who are ≥12 years of age 
Secondary 
To evaluate the effect of ivacaftor and VX-371, administered with and without 4.2% HS on QOL 
in subjects with PCD who are ≥12 years of age 
 
STUDY ENDPOINTS 
 
Part A Endpoints 
7.1.1 
Primary Endpoints 
 Results of safety and tolerability assessments of adverse events (AEs), clinical laboratory 
values (urine, serum and plasma chemistry, and hematology), 12-lead electrocardiograms 
(ECGs), spirometry, vital signs, and pulse oximetry 
 Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from 
study baseline, after 28 days of treatment in Part A 
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7.1.2 
Secondary Endpoint 
 Change in QOL score as measured by the Quality of Life-PCD Questionnaire (QOL-PCD) 
and the St. George’s Respiratory Questionnaire (SGRQ) from study baseline, after 28 days of 
treatment in Part A 
 
Part B Endpoints 
7.2.1 
Primary Endpoints 
 Results of safety and tolerability assessments of AEs, clinical laboratory values (urine, serum 
and plasma chemistry, and hematology), 12-lead ECGs, spirometry, vital signs, and pulse 
oximetry 
 Absolute change in ppFEV1, from study baseline and Part B baseline after 28 days of 
treatment in Part B 
7.2.2 
Secondary Endpoint 
 Change in QOL score as measured by the QOL-PCD and SGRQ from study baseline and 
Part B baseline, after 28 days of treatment in Part B 
 
STUDY DESIGN 
 
Overview of Study Design 
This is a Phase 2a, 2-part, multicenter, randomized, double-blind, placebo-controlled, incomplete 
block crossover study in subjects ≥12 years of age with PCD.  
 
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Part A will consist of Treatment Period 1 and Treatment Period 2, separated by a Washout 
Period.  
Part B is optional and will consist of Treatment Period 3; subjects will complete Part A before 
beginning Part B. There will not be a Washout Period between Part A and Part B. 
 
Approximately 150 subjects will be randomized to 1 of 4 treatment sequences in Part A. Subjects 
who enroll in Part B will have oral ivacaftor added to the treatment they were receiving in 
Treatment Period 2 of Part A, as described in Table 8-1.  
A schematic of the study design is provided in Figure 8-1.  
Table 8-1 
Study PS-G202 Treatment Sequences 
 
Part A 
Part B 
Sequence 
Treatment Period 1 
Treatment Period 2 
Treatment Period 3 
N 
1 
VX-371 in 4.2% HS 
4.2% HS 
4.2% HS + ivacaftor 
50 
2 
4.2% HS 
VX-371 in 4.2% HS 
VX-371 in 4.2% HS + ivacaftor 
50 
3 
VX-371 in 0.17% saline  
Placebo (0.17% saline) 
Placebo (0.17% saline) + ivacaftor 
25 
4 
Placebo (0.17% saline) 
VX-371 in 0.17% saline  
VX-371 in 0.17% saline + ivacaftor 
25 
 
 
Figure 8-1  
Schematic of Study Design PS-G202 
 
This study includes the following: 
1. Screening Period: Day of Screening Visit until Day 1 (first dose of study drug). The 
Screening Visit can occur Day -38 to Day -5, relative to the first dose of study drug.  
2. Treatment Periods: 
Part A: 
 Treatment Period 1: Day 1 (first dose of study drug) through Day 29  
(28 days of treatment) 
 Washout Period: Day 29 through Day 56 (28 days) 
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 Treatment Period 2: Day 57 through Day 85 (28 days of treatment) 
Part B (Optional): 
 Treatment Period 3: Day 85 (first dose of oral ivacaftor) through Day 113  
(28 days of treatment) 
3. Safety Follow-up Period: 28 days (± 7 days) after the last dose of study drug.  
4. Early Termination of Treatment (ETT) Visit: The ETT Visit is to occur as soon as 
possible after the subject decides to terminate study drug treatment. 
8.1.1 
Maintenance of Stable Medication Regimen for PCD 
If the subject meets the criteria for study participation and is taking HS at the time of screening, 
the subject will be instructed to stop their usual regimen of inhaled HS for the duration of the 
study, beginning at least 28 days before the first dose of study drug in the study and continued 
through completion of the last study visit. If a subject is not taking HS as part of their ongoing 
PCD treatment, the Day 1 Visit may be scheduled to occur as soon as 5 days after the Screening 
Visit, provided that results of all screening procedures have been received. Each subject will be 
instructed to use an appropriate airway clearance technique throughout the study. 
All concomitant medications and airway clearance measures/techniques should be kept on a 
stable regimen for the duration of the study, other than the discontinuation of use of HS during 
the Screening Period. 
If taking daily chronic or chronic cycling antibiotics, the subject must have been on a consistent 
regimen for at least 4 months before the Screening Visit. The cycling regimen of antibiotics can 
be either intermittent monotherapy (e.g., 28 days on/28 days off) or continuous alternating 
therapy (e.g., 28-day cycles of 2 alternating antibiotics). For patients that take cycling antibiotics, 
with only 1 antibiotic, the first visit of Treatment Period 1 and Treatment Period 2 should be 
scheduled to occur on the same day of the subject’s antibiotic cycle (e.g., if Day 1 falls on the 4th 
day of a cycle, Day 57 should fall on the 4th day of the same antibiotic cycle). For patients that 
take cycling, alternating antibiotics, the first day of Treatment Period 1 and Treatment Period 2 
should be scheduled to occur on the same day of the subject’s antibiotic cycle with the same drug 
(e.g., if Day 1 falls on the 4th day of a cycle with antibiotic #1, Day 57 should also fall on the 4th 
day of the cycle with antibiotic #1). Subjects who are on a stable chronic antibiotic regimen 
should remain on this regimen through completion of the last study visit. 
8.1.2 
Screening: Day -38 to Day -5 
Screening Visit assessments are listed in Table 3-1.  
The Screening Visit will occur between Day -38 and Day -5 before administration of the first 
dose of inhaled study drug to confirm that the subject meets the inclusion and exclusion criteria 
for the study. The investigator (or an appropriate authorized designee at the study site) will 
obtain informed consent and assent (where applicable) from each subject. To prepare for study 
participation, subjects will be instructed on the study requirements for concomitant medications 
(Table 9-1 and Table 9-2). 
At the Screening Visit, each subject will receive a test dose of 4.2% HS via a PARI eFlow 
nebulizer to confirm tolerability of inhaled HS. Pre-dose spirometry will be performed within 60 
minutes before the test dose. Post-dose spirometry will be performed 60 (± 5) minutes after the 
test dose. If the subject’s post-HS test dose spirometry value shows a 15-percentage point or 
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greater absolute reduction in ppFEV1 compared to the subject’s pre-HS test dose ppFEV1 value, 
the investigator may either screen fail the subject or administer a short-acting bronchodilator to 
the subject.  
If the subject is treated with a short-acting bronchodilator, spirometry will be repeated at least 10 
minutes after administration of the short-acting bronchodilator. If the subject’s post-short-acting 
bronchodilator ppFEV1 value does not return to within 15 percentage points (absolute) of the 
subject’s pre-HS test dose ppFEV1 value, the investigator should screen fail the subject.  
If the subject’s ppFEV1 returns to within 15 percentage points (absolute) of the pre-HS test dose 
value, the investigator may provide a short-acting bronchodilator for use before all doses of 
inhaled study drug are administered.  
If the subject experiences a post-HS test dose absolute decline in ppFEV1 less than 15 percentage 
points, the investigator may choose to provide a short-acting bronchodilator for use before all 
doses of inhaled study drug are administered. 
While subjects can be screened based on evidence supportive of a PCD diagnosis, all subjects 
must meet the confirmatory diagnostic PCD criteria (including central review, as required) prior 
to randomization (Section 9.1). 
Screen failures and reason for failure will be documented within the eCRF. 
8.1.2.1 
Repetition of Screening Assessment(s) 
Repetition of individual screening assessment(s) that did not meet eligibility criteria is permitted 
1 time for the following reasons: 
 If there is clear evidence of a laboratory error (e.g., hemolyzed sample) or equipment 
malfunction.  
 Exclusionary liver function test (LFT) levels and/or serum or plasma potassium levels.  
 Collection of a repeat sample for a laboratory test or assessment, for any other reason, may 
be permitted only with prior approval of the Parion medical monitor. 
If screening spirometry measurements fail to meet acceptability and repeatability criteria as 
specified by American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines, 
repeat spirometry evaluation may be performed once. 
If repeat values of the individual assessment(s) are within the eligibility criteria and completed 
within the screening window, then the subject is eligible for the study. 
8.1.2.2 
Rescreening 
Subjects may be rescreened after investigator discussion with, and approval from, the Parion 
medical monitor. If a subject is rescreened, all Screening Visit assessments will be repeated 
except for PCD genotyping and follicle-stimulating hormone (FSH) level (if serum FSH level 
was ≥40 mIU/mL during prior screening). Subjects may only be rescreened once. If a subject is 
rescreened, the screening window will begin once the first rescreening assessment has been 
initiated. 
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8.1.2.3 
Extension of Screening Period Window 
A subject may have the Screening Period window extended by 2 weeks for the following 
reasons: 
 Repetition of the Screening Period assessments (Section 8.1.2.1), and/or 
 Unexpected operational or logistic delays, or to meet the eligibility criteria 
8.1.3 
Treatment Periods  
Treatment Period assessments are listed in Table 3-2. 
Subjects who prematurely discontinue study drug will complete an ETT Visit and will have a 
Safety Follow-up Telephone Call that is to occur 28 days (± 7 days) after the last dose of study 
drug, as described in Table 3-3, Section 8.1.4 and Section 8.1.5. 
All reasonable efforts should be made to schedule clinic visits at the same time of day.  
8.1.3.1 
Part A 
Part A comprises Treatment Period 1, the Washout Period, and Treatment Period 2.  
8.1.3.1.1 
Treatment Period 1 
At the Day 1 Visit, the subject is required to continue to meet all inclusion and exclusion criteria 
(Sections 9.1 and 9.2) and continue to have stable PCD disease, in the opinion of the 
investigator. The first dose of inhaled study drug will be administered after randomization on 
Treatment Period 1 Day 1.  Inhaled study drug should be taken according to instructions 
provided within the protocol. Study clinic visits will occur on Day 1 and Day 29 to allow for a 
full 28 days of treatment.  
If the first dose of inhaled study drug administered in the clinic on Day 1 is taken in the morning, 
the second dose will be taken that evening. The last dose of the twice daily study regimen will be 
taken on the evening of Day 28 and no dose will be taken before the morning visit on Day 29.   
If the first dose of inhaled study drug on Day 1 is taken in the clinic in the afternoon, a second 
dose will not be taken that evening. The last dose of the twice daily study regimen in Treatment 
Period 1 will be taken on the morning of Day 29, at least 4 hours before the Day 29 Visit. 
Subjects should only take the inhaled study drug at a maximum of twice daily.  
At Day 4 (± 1 day), subjects will have a telephone call from the study coordinator or authorized 
site designee for safety purposes to ascertain if there have been any AEs. If necessary to follow 
up on a new medical problem, the subject may be asked to return to clinic.   
Subjects randomized prior to Independent Data Monitoring Committed (IDMC) approval 
to convert Day 15 Visit to a telephone call:  
 If a subject reaches the Day 15 Visit prior to IDMC approval to convert the Day 15 Visit to a 
telephone call, the Day 15 Visit must be completed to assess safety parameters, including 
AEs, vital signs, pulse oximetry, ECG, physical exam, clinical laboratory values, and 
spirometry. No telephone call is required on this day if a visit is conducted.  
 If the IDMC does not approve to convert the Day 15 Visit to a telephone call, subjects will 
proceed as per the bullet above. 
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Subjects randomized after IDMC approval to convert Day 15 Visit to a Telephone Call:  
 The Day 15 Visit will be changed to a Day 15 Telephone Call to assess AEs. No visit is 
required on this day if a telephone call is conducted.  
8.1.3.1.2 
Washout Period 
Subjects will undergo a Washout Period of 28 days (+ 3 days) between Treatment Period 1 and 
Treatment Period 2. Subjects should continue to maintain a consistent medication and airway 
clearance regimen throughout the Washout Period. The Washout Period may be extended for an 
additional 28 days for acute upper or lower respiratory infections following discussion and 
approval of the Parion medical monitor. 
8.1.3.1.3 
Treatment Period 2 
In order to continue into Treatment Period 2, subjects must not have an acute upper or lower 
respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for 
pulmonary disease within 28 days before the Day 57 Visit. If the subject does not meet these 
criteria, then the continuation of the subject into Treatment Period 2 should be discussed with the 
Parion medical monitor.  
The first dose of inhaled study drug in Treatment Period 2 will be administered at the Day 57 
Visit.  
Study clinic visits will occur on Day 57 and Day 85 to allow for a full 28 days of treatment. If 
the dose of inhaled study drug administered in the clinic on Day 57 is taken in the morning, the 
second dose of inhaled study drug will be taken that evening. The last dose of the twice daily 
study regimen will be taken on the evening of Day 84 and no dose will be taken before the 
morning visit on Day 85.  
If the first dose of inhaled study drug on Day 57 is taken in the clinic in the afternoon, a second 
dose of inhaled study drug will not be taken that evening. The last dose of the twice daily study 
regimen in Treatment Period 2 will be taken on the morning of Day 85, at least 4 hours before 
the Day 85 Visit.  
Subjects should only take the inhaled study drug at a maximum of twice daily.  
On Day 60, subjects will have a telephone call for safety purposes (e.g., inquire about adverse 
events). If necessary to follow up on a new medical problem, the subject may be asked to return 
to clinic. 
Subjects randomized prior to IDMC approval to convert Day 71 Visit to telephone call:  
 If a subject reaches the Day 71 Visit prior to the IDMC approval to convert the Day 71 Visit 
to a telephone call, the Day 71 Visit must be completed to assess safety parameters, including 
AEs, vital signs, pulse oximetry, ECG, physical exam, clinical laboratory values, and 
spirometry. No telephone call is required on this day if a visit is conducted.  
 If the IDMC does not approve to convert the Day 71 Visit to a Telephone Call, subjects will 
proceed as per the bullet above. 
Subjects randomized after IDMC approval to convert Day 71 Visit to telephone call:  
 The Day 71 Visit will be changed to a Day 71 Telephone Call to assess AEs. No visit is 
required on this day if a telephone call is conducted.  
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8.1.3.2 
Part B 
Part B comprises Treatment Period 3 and is optional.  
8.1.3.2.1 
Treatment Period 3 
In order to continue into Treatment Period 3 the subject must sign the Part B informed consent 
form (ICF) or assent, as applicable. The ICF should be signed before the Day 85 Visit to allow 
for delivery of study drug for Treatment Period 3.  
Study visits will occur on Day 85 (also the last visit of Treatment Period 2) and Day 113 to allow 
for a full 28 days of study drug (inhaled study drug and oral ivacaftor). 
On Day 86 and Day 87, until the telephone call is no longer required by the IDMC, subjects will 
have a telephone call for safety purposes (e.g., inquire about AEs). If necessary, the subject may 
be asked to return to clinic to follow up on a new medical problem. 
The first dose of both ivacaftor and inhaled study drug in Treatment Period 3 will be 
administered at the Day 85 Visit, after completion of the Day 85 pre-dose assessments.  
If the first dose of study drug (inhaled study drug and oral ivacaftor) administered in the clinic on 
Day 85 is taken in the morning, the second dose will be taken that evening. The last home dose 
of the twice daily study regimen in Treatment Period 3 will be taken on the evening of Day 112 
and no dose will be taken on Day 113.  
If the first dose of study drug (inhaled study drug and oral ivacaftor) administered in the clinic on 
Day 85 is taken in the afternoon, a second dose will not be taken that evening. The last home 
dose of the twice daily study regimen in Treatment Period 3 will be taken on the morning of Day 
113, at least 4 hours before the Day 113 Visit. 
Subjects should only take study drug at a maximum of twice daily.  
Subjects will remain in the clinic for a total of 2 to 4 hours after dosing with study drug at the 
Day 85 Visit until the IDMC provides approval to only require subjects to remain in clinic for 
1 hour post-dosing. The duration (2 to 4 hours) each subject stays in clinic for observation will 
be left to the discretion of the investigator. If the IDMC does not approve reducing the 
observation period to 1 hour post-dosing, then subjects will continue to be observed in clinic for 
2 to 4 hours during the Day 85 Visit.  
Subjects randomized prior to IDMC approval to convert Day 99 Visit to telephone call:  
 If a subject reaches the Day 99 Visit prior to the IDMC approval to convert the Day 99 Visit 
to a telephone call, the Day 99 Visit must be completed to assess safety parameters, including 
AEs, vital signs, pulse oximetry, ECG, physical exam, clinical laboratory values, and 
spirometry. No telephone call is required on this day if a visit is conducted. The Day 99 Visit 
may occur at any time between Day 88 and Day 99. 
 If the IDMC does not approve to convert the Day 99 Visit to a telephone call, subjects will 
proceed as per the bullet above. 
Subjects randomized after IDMC approval to convert Day 99 Visit to telephone call:  
 The Day 99 Visit will be changed to a Day 99 Telephone Call to assess AEs. No visit is 
required on this day if a telephone call is conducted. The Day 99 Telephone Call may occur 
at any time between Day 88 and Day 99. 
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8.1.3.3 
Planned Pre-visit Subject Contacts 
There are 5 planned pre-visit contacts to the subject during the study; 4 will occur in Part A and 
1 will occur in Part B.  
These contacts are to occur:  
 Part A: 1 day before the Day 1, Day 29, Day 57, and Day 85 Visits 
 Part B: 1 day before the Day 113 Visit 
This planned pre-visit contact, which may occur via telephone call, text message, or email, is 
designed to ensure: 
 that subjects remember to withhold their morning dose of study drug in Part A before the 
Day 29 and Day 85 Visit and in Part B before the Day 113 Visit only if the clinic visit is 
scheduled within 4 hours after the time of the morning dose,    
 that subjects withhold their short-acting bronchodilator for 4 hours before spirometry is 
performed at the clinic in Part A at the Day 1, Day 29, Day 57, and Day 85 Visits, and in Part 
B before the Day 113 Visit,    
 that subjects withhold long-acting bronchodilators the night before the first and last visit of 
each treatment period 
 
 
 that subjects remember to bring their subject diary, all unused study drug, and 
 
 back to the clinic in Part A at the Day 29 and Day 85 
Visits, and in Part B at the Day 113 Visit, and ETT Visit, if applicable.  
All subjects will be asked to return their 
 at the Part A Day 29 and Day 
85 Visits, the Part B Day 113 Visit, 
 at 
the Part A Day 85 Visit, the Part B Day 113 Visit, or their ETT Visit, as applicable. 
Upon completion of the subject’s last study visit and all study procedures, the pre-study 
medication regimen may be resumed at the discretion of the investigator.  
8.1.4 
Follow-Up 
The Safety Follow-up Telephone Call is scheduled to occur 28 days (± 7 days) after the last dose 
of study drug for subjects who complete study drug dosing and for subjects who prematurely 
discontinue study drug dosing.  
Based on a clinical finding during either Treatment Period or during the 28-day Safety Follow-up 
Period, the investigator may decide to convert the Safety Follow-up Telephone Call into a Safety 
Follow-up Visit, whereby the subject would be asked to return to the clinic.  
8.1.5 
Early Termination of Treatment 
If the subject prematurely discontinues study drug treatment, an ETT Visit should be scheduled 
as soon as possible after the subject decides to terminate study drug treatment. Subjects who 
prematurely discontinue treatment will also be required to complete the Safety Follow-up 
Telephone Call, approximately 28 days (± 7 days) after their last dose of study drug.  
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If the subject withdraws consent for the study, no further evaluations will be performed, and no 
additional data will be collected. Parion Sciences may retain and continue to use any data 
collected before such withdrawal of consent. 
8.1.6 
Unscheduled Visits 
Subjects may need to be seen at times other than the scheduled study visits for additional safety 
assessments, to follow up on changes in clinical status, or to follow up on clinical laboratory or 
other findings. If an additional study visit occurs, the date and assessments completed during the 
visit will be documented. 
8.1.7 
Independent Data Monitoring Committee 
An IDMC will be formed for this study. The IDMC will conduct regular, planned reviews of 
study data with the primary goal of evaluating the safety of the study drug regimen to ensure the 
subjects’ safety (Section 12.3.5). Procedural details of the IDMC’s structure and function, 
frequency of meetings, and data planned for review will be included in the IDMC charter. The 
IDMC charter will be finalized before the first subject is screened.  
 
Rationale for Study Design and Study Drug Regimens 
8.2.1 
Study Design 
Part A of this Phase 2a, 2-part, randomized, double-blind, placebo-controlled, incomplete block, 
multicenter crossover study, in subjects with PCD ≥12 years of age is designed to evaluate the 
safety and efficacy of VX-371 formulated with or without HS. In Part B (optional), the safety 
and efficacy of ivacaftor and VX-371 formulated with or without HS will be evaluated. No 
controlled clinical study to evaluate the effect of a potential therapeutic agent has been 
completed at the time this protocol was written in subjects with PCD. Only recently have 
diagnostic criteria evolved that enable a confirmed diagnosis of PCD. Because many patients 
have been misdiagnosed in the past, this PCD study will restrict enrollment to only those subjects 
who meet the rigorous entry criteria.   
A randomized, double-blind, placebo-controlled study design was selected for Part A to avoid 
observer bias and reduce symptoms or outcomes arising from the investigator’s or the subject’s 
knowledge of treatment. An incomplete block crossover design wherein subjects are randomized 
to 1 of 4 treatment sequences (Table 8-1) will enable within-subject comparison of the treatment 
effects with increased statistical power while maximizing the power for the comparisons 
anticipated to be of greatest interest. In Part B, administration of ivacaftor will be open-label, but 
subjects will remain blinded to the inhaled study drug treatment regimen and sequence.  
During Part A, a 28-day Washout Period is judged to be of sufficient duration for all subjects to 
return to their baseline values for FEV1. Multiple comparisons will be made which will provide 
insight with respect to the effect of VX-371 and inform design options for future studies. Even 
though 2 different concentrations of saline will be used, the double-blind will be maintained with 
respect to both 0.17% saline (placebo) and 4.2% HS since each subject will receive treatment 
with only 1 saline concentration; no subject will cross over from 0.17% saline to 4.2% HS or 
vice versa. The double blind will also be maintained with regard to VX-371 because allocation to 
this component will remain unknown to both investigators and subjects. 
Given the absence of historical information from prior studies in PCD and the abundance of 
information in CF, another muco-obstructive disease, several extrapolations have been made 
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regarding the chosen endpoints from CF studies and applied to this PCD study. Change in 
ppFEV1 was selected as the primary assessment of efficacy, based on observed effects of 
hydrating agents in CF, and based on observations that oral antibiotics can increase ppFEV1 in 
treated PCD patients, which indicates that FEV1 may be an acceptable measure. In addition, 2 
quality of life instruments (i.e., questionnaires), the QOL-PCD and SGRQ, will be used. 
 
  
While chronic cycling antibiotics are not widely used in PCD patients, the scheduling of study 
drug with regard to the antibiotic schedule should be controlled while the subject is enrolled in 
the study as antibiotics may affect spirometry results in the PCD population (Section 8.1.1). 
A sample size of approximately 150 subjects randomized is considered feasible and is expected 
to provide sufficient data to evaluate the safety and efficacy of VX-371 formulated with and 
without HS in Part A along with the administration of oral ivacaftor in Part B.  
Part B was designed to evaluate whether the addition of oral ivacaftor will have an impact on the 
efficacy of inhaled VX-371. Therefore, no Washout Period between Treatment Period 2 and 
Treatment Period 3 is necessary.  
8.2.2 
Study Drug Dose and Duration 
 
 
 Thus, Part A of the current study is designed to 
demonstrate safety and efficacy of an 85 µg dose of VX-371 administered twice daily, with or 
without HS, by oral inhalation in patients with PCD.  
Parion Sciences Study PS-G201 was a randomized, double-blind, placebo-controlled, 
parallel-group study to evaluate the safety and efficacy of 85 µg VX-371 twice daily in subjects 
with CF. 
 
 
 
In Part B, subjects will continue on their inhaled study drug regimen from Treatment Period 2, 
and will also receive 150 mg of ivacaftor every 12 hours (q12h) for 28 days through Day 113 
(see the Ivacaftor Investigator’s Brochure for additional details supporting the efficacy, safety, 
and pharmacokinetic (PK) profile of ivacaftor).  
8.2.3 
Rationale for Study Assessments 
Spirometry: Spirometry (as measured by FEV1) is the most widely implemented standardized 
assessment to evaluate lung function.24 FEV1 obtained from spirometry is a reflection of the 
extent of airway obstruction and, as the most clinically accepted measure of disease progression 
in CF, indicates that FEV1 may be an equally acceptable measure in efficacy studies of the PCD 
population.  
QOL-PCD: The QOL-PCD is a subject-completed, disease-specific instrument designed to 
measure impact on overall health, daily life, perceived well-being and symptoms that has been 
developed specifically for use in subjects with a diagnosis of PCD.25,26  
SGRQ: The SGRQ is a 50-item questionnaire with 76 weighted responses. This questionnaire 
measures health status (quality of life) in patients with diseases of airway obstruction.27 It has 
good discriminative and evaluative properties and is responsive to therapeutic trials.  
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The items in the SGRQ are divided into 3 domains: “Symptoms,” which is concerned with 
frequency and severity of respiratory symptoms; “Activity,” which is concerned with activities 
that cause or are limited by breathlessness; and “Impacts,” which covers aspects concerned with 
social functioning and psychological troubles resulting from airway disease. A score will be 
calculated for each domain and a total score will also be calculated. For each domain and for the 
total score, the range of values is 0 to 100, with higher values corresponding with greater 
impairment of quality of life. A minimum change in score of 4 units was established as clinically 
relevant after patient and clinician testing.  
 
 
 
 
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are enrolled. 
 
Inclusion Criteria 
Subjects who meet all of the following inclusion criteria will be eligible. 
1. Subject (or subject’s legally appointed and authorized representative) will sign and date an 
informed consent form (ICF) and, where appropriate, assent form. 
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, contraceptive guidelines, and other study procedures. 
3. Willing and able to use the nebulization device as directed by the instructions for use.  
4. The subject must have evidence supportive of a PCD diagnosis, based on the following : 
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5. Subjects with ppFEV1 of ≥40 to <90 percentage points adjusted for age, sex, and height 
according to the Global Lung Function Initiative (GLI) predicted values at the Screening 
Visit, taken 4 hours or more after last dose of short-acting bronchodilators (β-agonists and/or 
anticholinergics)  
6. Non-smoker for the past 90 days prior to the Screening Visit and less than a 5 pack-year 
lifetime history of smoking, and willing to not smoke while enrolled in the study. 
7. Stable regimen of medications and chest physiotherapy for the 28 days prior to Day 1, and no 
anticipated need for changes during the study period (other than stopping inhaled HS). 
8. If currently using daily inhaled HS, must be able to discontinue its use for the duration of the 
study.  
9. If taking daily chronic or chronic cycling antibiotics, has been on a consistent regimen for at 
least 4 months prior to the Screening Visit. The cycling regimen of antibiotics can be either 
intermittent monotherapy (e.g., 28 days on/28 days off) or continuous alternating therapy 
(e.g., 28-day cycles of 2 alternating antibiotics).   
10. Clinically stable (as deemed by the investigator) for at least 14 days prior to the Screening 
Visit with no evidence of significant new or acute respiratory exacerbations, excluding 
symptoms of allergic (perennial or seasonal) or non-allergic rhinitis. 
11. Female subjects of childbearing potential must have a negative serum pregnancy test at the 
Screening Visit. Females of childbearing potential must have a negative urine pregnancy test 
at the Day 1, Day 57, and Day 85 Visits before receiving the first dose of study drug in each 
Treatment Period, respectively. Subjects of childbearing potential and who are sexually 
active must meet the contraception requirements outlined in Section 11.6.5.1. 
 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria will not be eligible. 
1. Diagnosis of CF, including at least 1 of the following: 
a. Documented sweat chloride test ≥60 mM by quantitative pilocarpine iontophoresis  
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b. Abnormal nasal potential difference (NPD) test  
c. 2 CF-causing mutations in the CFTR gene 
2. Subjects with only 1 mutation in the CFTR gene and a sweat chloride test ≥60 mM by 
quantitative pilocarpine iontophoresis. 
3. History of any organ transplantation or lung resection or chest wall surgery. 
4. Significant congenital heart defects, other than a laterality defect, at the discretion of the 
investigator. 
5. Diagnosis of Cri du chat syndrome (chromosome 5p deletion syndrome). 
6. Inability to withhold short-acting bronchodilator use for 4 hours prior to clinic visit and long-
acting bronchodilator use the night before the first and last clinic visit of each treatment 
period. 
7. History of any illness or any clinical condition that, in the opinion of the investigator, might 
confound the results of the study or pose an additional risk in administering study drug(s) to 
the subject. This may include, but is not limited to history of clinically significant and 
uncontrolled adrenal, neurologic, gastrointestinal, renal, hepatic, cardiovascular (including 
hyper/hypotension and tachy/bradycardia), psychological, pulmonary (other than PCD), 
metabolic, endocrine, or hematological/coagulation disorder or disease, or scoliosis of such 
severity that it impacts pulmonary function or any other major disorder or disease, in the 
opinion of the investigator.  
8. Use of diuretics (including amiloride) or renin-angiotensin antihypertensive drugs (e.g., 
spironolactone, angiotensin converting enzyme [ACE] and/or neural endopeptidase [NEP]-
inhibitors, or angiotensin receptor blockers [ARBs]) or trimethoprim or drospirenone in the 
28 days before Day 1 or anticipate need for these medications during the study. 
9. Had symptoms of acute upper or lower respiratory tract infection or had an acute pulmonary 
exacerbation requiring treatment or was treated with systemic antibiotics for ear or sinus 
disease within 28 days before Day 1 (topical otic antibiotics allowed). 
10. History of significant intolerance to inhaled HS, as determined by the investigator.  
11. History of drug or alcohol abuse, in the opinion of the investigator.  
12. Known hypersensitivity to any of the study drugs or amiloride. 
13. Used ivacaftor within 28 days prior to Day 1 or anticipate need for ivacaftor during the study. 
14. Pregnant and/or nursing females. 
15. Any clinically significant laboratory abnormalities at the Screening Visit as judged by the 
investigator, or any of the following:  
a. Plasma or serum potassium > upper limit of normal (ULN)  
b. Abnormal renal function, defined as creatinine clearance rate <50 mL/min using the 
Bedside Schwartz equation (for subjects 12 to 17 years of age)29 or <50 mL/min using the 
Cockcroft-Gault equation (for subjects ≥18 years of age).30  
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c. Abnormal liver function, defined as ≥3 × ULN for alanine aminotransferase (ALT) or 
aspartate aminotransferase (AST), or >2 × ULN for total bilirubin, unless accounted for by 
Gilbert’s syndrome (benign indirect hyperbilirubinemia)  
d. Hemoglobin concentration <10.0 g/dL 
16. Unwilling or unable to follow the contraception guidelines as outlined in Section 11.6.5.1.  
17. History of at least 2 sputum or throat swab cultures yielding B. cepacia complex or M. 
abscessus or M. avium within the previous 2 years.  
18. Has had surgery within 3 months of Day 1 that required general anesthesia and 
hospitalization. 
19. Has previously participated in an investigational study involving administration of any 
investigational compound or use of an investigational device within 28 days prior to the 
Screening Visit (Note: Participation in a past or concurrent observational study is 
acceptable). 
20. Has any surgical or medical condition which in the judgment of the investigator might 
interfere with the absorption, distribution, metabolism, or excretion of the study drug or with 
safety evaluations. 
21. Has any other condition or circumstances that, in the opinion of the investigator, should 
disqualify this subject for this study. 
22. The subject or a close relative of the subject is the investigator or a sub-investigator, research 
assistant, pharmacist, study coordinator, or other staff directly involved in the conduct of the 
study.  
9.2.1 
Additional Exclusion Criteria for Part B 
In addition to the exclusion criteria above, subjects who participate in Part B and meet any of the 
following exclusion criteria will not be eligible to continue into Part B. 
1. Unable to swallow tablets. 
2. Concomitant use of strong or moderate inhibitors or inducers of cytochrome P450 (CYP) 3A, 
including consumption of certain herbal medications (e.g., St. John's Wort), and 
grapefruit/grapefruit juice.  
3. Known hypersensitivity to ivacaftor. 
 
Study Restrictions 
Prohibited and restricted medications are not allowed in this study (Screening Period through the 
last study visit) as summarized in Table 9-1 and Table 9-2. 
 
 
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Table 9-1 
Prohibited Medications 
Prohibited 
Medication 
Screening 
Period 
Part A 
Part B 
 
Treatment 
Period 1 
Washout 
Period 
Treatment 
Period 2 
Treatment 
Period 3 
Until Safety 
Follow-Up 
Telephone 
Call 
 Hypertonic 
saline 
 Diuretics 
(including 
amiloride) 
 Renin-
angiotensin 
antihypertensiv
e drugs (ACE 
and/or NEP-
inhibitors or 
ARBs) 
 Trimethoprim 
 Drospirenone 
None 
allowed 
within 28 
days before 
Day 1  
None 
allowed  
None allowed  None 
allowed  
None 
allowed  
Used as 
prescribed by 
subject’s 
health care 
provider 
Medications with 
moderate or 
potent CYP3A 
inhibitor activity, 
as well as 
grapefruit/ 
grapefruit juice 
Used as 
prescribed by 
subject’s 
health care 
provider 
Used as 
prescribed 
by subject’s 
health care 
provider 
Used as 
prescribed by 
subject’s 
health care 
provider 
Used as 
prescribed 
by 
subject’s 
health care 
provider 
None 
allowed 
Used as 
prescribed by 
subject’s 
health care 
provider 
beginning 48 
hours after 
the subject’s 
last dose of 
ivacaftor 
Moderate or 
potent CYP3A 
inducers 
including certain 
herbal 
medications such 
as St. John's Wort 
Used as 
prescribed by 
subject’s 
health care 
provider 
Used as 
prescribed 
by subject’s 
health care 
provider 
Used as 
prescribed by 
subject’s 
health care 
provider 
Used as 
prescribed 
by 
subject’s 
health care 
provider 
None 
allowed 
Used as 
prescribed by 
subject’s 
health care 
provider 
beginning 48 
hours after 
the subject’s 
last dose of 
ivacaftor 
 
 
 
 
 
 
 
 
 
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 Table 9-2 
Antibiotic and Bronchodilator Restrictions 
Restricted 
Medication 
Screening 
Period 
Part A 
Part B 
 
Treatment 
Period 1 
Washout 
Period 
Treatment 
Period 2 
Treatment 
Period 3 
Until 
Safety 
Follow-up 
Telephone 
Call 
Chronic or 
chronic cycling 
antibiotics 
Must have 
been on a 
consistent 
regimen for 
at least 4 
months prior 
to the 
Screening 
Visit 
Must remain 
on the pre-
study regimen  
Must remain 
on the pre-
study 
regimen 
Must remain 
on the pre-
study 
regimen  
Must remain 
on the pre-
study 
regimen 
Used as 
prescribed 
by 
subject’s 
health care 
provider 
Long-acting 
bronchodilators 
Should be 
used at the 
same time of 
day, on the 
same 
schedule as 
during the 28 
days before 
Day 1, 
unless 
medically 
necessary  
 
Should be 
used at the 
same time of 
day, on the 
same 
schedule, 
every day 
Must be 
withheld the 
night before 
the clinic visit 
on Day 1 and 
Day 29, unless 
medically 
necessary.  
Should be 
used at the 
same time of 
day, on the 
same 
schedule, 
every day 
Must be 
withheld the 
night before 
the clinic 
visit on Day 
57, unless 
medically 
necessary. 
Should be 
used at the 
same time of 
day, on the 
same 
schedule, 
every day 
Must be 
withheld the 
night before 
the clinic 
visit on Day 
57 and Day 
85, unless 
medically 
necessary.  
Should be 
used at the 
same time of 
day, on the 
same 
schedule, 
every day 
Must be 
withheld the 
night before 
the clinic 
visit on Day 
85 and Day 
113, unless 
medically 
necessary. 
Used as 
prescribed 
by 
subject’s 
health care 
provider 
Short-acting 
bronchodilators 
Must be 
withheld for 
4 hours prior 
to spirometry 
performed at 
the clinic 
visit, unless 
medically 
necessary 
Must be 
withheld for 4 
hours prior to 
spirometry 
performed at 
the clinic visit, 
unless 
medically 
necessary 
Must be 
withheld for 
4 hours prior 
to 
spirometry 
performed at 
the clinic 
visit, unless 
medically 
necessary 
Must be 
withheld for 
4 hours prior 
to spirometry 
performed at 
the clinic 
visit, unless 
medically 
necessary 
Must be 
withheld for 
4 hours prior 
to spirometry 
performed at 
the clinic 
visit, unless 
medically 
necessary 
Used as 
prescribed 
by 
subject’s 
health care 
provider 
 
 
Prior and Concomitant Medications 
Subjects are to remain on a stable PCD medication regimen from 28 days before Day 1 through 
the last study visit. Those patients taking HS before the Screening Period will washout from HS 
during the Screening Period and will not be allowed to take HS for the duration of the study 
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through the end of the last study visit (other than as blinded study drug if allocated to an 
HS-containing treatment sequence).  
The following guidelines for bronchodilator use should be adhered to: 
 Throughout the study, short- and long-acting bronchodilators should be used on the same 
time of day and schedule as during the 28 days before Day 1. 
 Short-acting bronchodilators must be withheld for 4 hours prior to spirometry performed 
at the clinic visit and long-acting bronchodilators must be withheld the night before each 
clinic visit. Short- and long-acting bronchodilators may be taken by the subject if 
medically necessary.  
 
Information regarding all prior and concomitant medications, including the subject’s PCD 
medications, other medications, and herbal and naturopathic remedies administered from 28 days 
before the Screening Visit through the Safety Follow-up Telephone Call will be recorded in each 
subject’s source documents and electronic case report form (eCRF). For subjects who are 
screened but are not subsequently enrolled into the study, details of prior medication will only be 
documented in the subject’s source documents. 
9.4.1 
Prohibited Medications in Part B 
Prohibited and restricted medications are described in Table 9-1 and Table 9-2. 
Subjects who participate in Part B must not use medications with moderate or potent cytochrome 
P450 (CYP)3A inhibitor or inducer activity, and should not use certain herbal medications, 
grapefruit, or grapefruit juice beginning on Day 85 until 48 hours after the last dose of ivacaftor.  
Subjects must not use commercially-available ivacaftor during the study. 
A comprehensive list of restricted medications will be provided in the Study Reference Manual. 
Noncompliance with these restrictions will be addressed on a case-by-case basis with the Parion 
medical monitor.  
 
Removal of Subjects  
Subjects may withdraw from the study at any time at their own request. Subjects may be 
withdrawn from study drug treatment at any time at the discretion of the investigator or Parion 
Sciences for safety, behavior, noncompliance with study procedures, or administrative reasons. If 
a subject has been withdrawn from study drug treatment, the subject will continue to be 
followed, provided the subject has not withdrawn consent.  
Subjects who discontinue study drug early should continue to return for study assessments, as 
noted in Section 8.1.5.  
If a subject does not return for a scheduled visit, reasonable effort will be made to contact the 
subject. In any circumstance, reasonable effort will be made to document subject outcome. The 
investigator will inquire about the reason for withdrawal, request that the subject return all 
unused investigational product(s), request that the subject return for an ETT Visit, if applicable 
(see Section 8.1.5), and follow up with the subject regarding any unresolved AEs. The site staff 
should perform the Safety Follow-up Telephone Call with the subject 28 days (± 7 days) after the 
last dose of study drug.  
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If the subject withdraws consent for the study, no further evaluations will be performed and no 
additional data will be collected. Parion Sciences may retain and continue to use any data 
collected before such withdrawal of consent. 
A subject will be withdrawn from study drug for any of the following reasons: 
 Parion Sciences, regulatory authorities, or the site’s institutional review board (IRB) or 
independent ethics committee (IEC) close the study. 
 A female subject or a female partner of a male subject has a confirmed pregnancy. 
 A subject has persistent and severe bronchospasm related to study drug administration. 
 A subject’s treatment is unblinded by the investigator. 
 Development of a life-threatening AE or a serious adverse event (SAE) that places him/her at 
immediate risk, and discontinuation of study drug deemed necessary. 
A subject may be withdrawn from study drug after a discussion between the investigator 
and the Parion medical monitor for any of the following reasons: 
 Development of a medical condition that requires prolonged concomitant therapy with a 
prohibited medication or prolonged interruption of the study drug. 
 Noncompliance with study requirements. 
 A serum potassium level >1.1  ULN, confirmed by a plasma potassium level >1.1  ULN. 
A confirmatory serum and plasma potassium level may be drawn at the discretion of the 
investigator before making the decision to remove a subject from the study. Refer to 
Section 11.6.2.1 for further guidance on treatment of hyperkalemia.  
 The subject has a relative decline in ppFEV1 of ≥15% from their Day 1, Day 57, or Day 85 
Visit pre-dose value.  
 An increase in ALT or AST according to evaluations and management described in Section 
11.6.2.2. 
 
Replacement of Subjects 
Subjects who withdraw or are withdrawn during the study drug treatment period(s) or washout 
period will not be replaced. 
 
STUDY DRUG ADMINISTRATION AND MANAGEMENT 
 
Preparation and Dispensing 
Study drug may be dispensed only under the supervision of the investigator or an authorized 
designee and only for administration to the study subjects. 
 
Administration 
10.2.1 
Inhaled Study Drug Administration Via the Nebulizer 
Inhaled study drug will be administered twice daily by a PARI eFlow nebulizer. The nebulizer 
will be provided to the subject for use with the inhaled study drug, and has been customized to 
be used only with the inhaled study drug provided for this study and is not to be used for the 
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inhalation of other treatments. Additionally, it is important that the subject use the provided 
nebulizer for the inhalation of study drug and not use any other PARI eFlow nebulizer devices 
that they may have.  
Subjects will be given instruction by the site staff on the proper use and care of the nebulizer, 
and will also receive written instructions on the care, use, and cleaning requirements. The 
nebulizer device (nebulizer and handset/aerosol head) identification information will be 
documented for each subject. 
Subjects are required to use the correctly assembled device, into which inhaled study drug has 
been added, and to nebulize through oral inhalation sitting up, with the device held horizontally 
and breathing more deeply than normal tidal breathing. This should be continued until all study 
drug has been delivered.  
A replacement nebulizer and/or handset (aerosol head) may be provided at other times during the 
study, if necessary.  
10.2.2 
Ivacaftor 
For subjects enrolled in Part B of the study, the first dose of oral ivacaftor will be administered at 
the Day 85 Visit. A fat-containing meal or snack will be provided for ivacaftor dosing at the 
clinic. Subjects are required to take 150 mg of ivacaftor orally q12h with fat-containing food, 
such as a high-fat, high-calorie meal or snack. Examples of appropriate fat-containing foods will 
be provided in the Study Reference Manual.  
10.2.3 
Dosing in Clinic 
This study requires that the first dose of study drug during each Treatment Period be taken in the 
clinic (at the Day 1, Day 57, and Day 85 Visits) while the subject is under observation by the 
study staff for at least 1 hour after dosing.  
The post-dose observation period is generally anticipated to encompass the first hour after dosing 
at Day 1 and Day 57, at which time spirometry, chest auscultation, pulse oximetry, and vital 
signs will be repeated. If the subject is doing well and is in no respiratory distress, the subject 
will be allowed to leave the clinic after this period and will be given 28 days of the study drug 
for at-home administration. If, however, in the judgment of the investigator, the subject needs to 
continue to be observed or monitored, the length of the post-dose observation period may be 
extended.  
Until the IDMC allows a 1-hour post-dose observation period at Day 85, subjects who continue 
into Part B will remain in clinic during the Day 85 Visit for 2 to 4 hours after administration of 
study drug. The amount of time each subject remains in clinic for observation (2 to 4 hours) may 
be left up to the discretion of the investigator. Prior to discharge, spirometry, chest auscultation, 
pulse oximetry, and vital signs will be repeated. If the subject is doing well and is in no 
respiratory distress, the subject will be allowed to leave the clinic after this period and will be 
given 28 days of the study drug for at-home administration. If, however, in the judgment of the 
investigator, the subject needs to continue to be observed or monitored, the length of the post-
dose observation period may be extended. 
If the subject routinely uses a short-acting bronchodilator prior to any inhalation treatment(s) 
(i.e., pre-treat), this practice should be continued throughout the study prior to inhalation of the 
inhaled study drug. If the subject does not routinely pre-treat inhaled medications with a short-
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acting bronchodilator, but has demonstrated significant respiratory symptoms after the test-dose 
of HS at the Screening Visit, as determined by the investigator or an absolute decline in ppFEV1 
of ≥15 percentage points following the first dose of blinded inhaled study drug at Day 1, then the 
subject should be provided with a short-acting bronchodilator, as needed, and instructed to 
subsequently pre-treat with this medication prior to all subsequent doses of blinded inhaled study 
drug.   
10.2.4 
Dosing at Home 
If the first dose of study drug administered in the clinic on Day 1, Day 57, or Day 85 is taken in 
the morning, the second dose will be taken that evening. The last dose of the twice daily study 
regimen will be taken on the evening of Day 28, Day 84, or Day 112 and no dose will be taken 
before the morning visit on Day 29, Day 85, or Day 113.   
If the first dose on Day 1, Day 57, or Day 85 is taken in the clinic in the afternoon, a second dose 
will not be taken that evening. The last dose of the twice daily study regimen will be taken on the 
morning of Day 29, Day 85 or Day 113, at least 4 hours before the afternoon visit on Day 29, 
Day 85, or Day 113. 
Subjects will be instructed to administer the study drug (inhaled study drug and/or oral ivacaftor) 
twice daily approximately 12 hours apart. Whenever possible, subjects should take the study 
drug at the same time each day. For example, the morning dose could be taken at 8:00 AM every 
morning and the evening dose could be taken at 8:00 PM every evening. 
All inhaled study drug will be administered twice daily via the PARI eFlow nebulizer over an 
estimated 6 to 8 minutes.   
Subjects will be asked to record the time start and stop of study drug dosing in a subject diary 
provided to them at Day 1, Day 57, and Day 85.  
10.2.5 
Missed Doses 
On Non-Clinic Visit Days: 
 If a subject misses a dose of study drug (inhaled study drug and/or oral ivacaftor) and 
remembers the missed dose within 6 hours, the subject should take the dose of study drug 
(with a fat-containing food, if oral ivacaftor). 
 If more than 6 hours have elapsed after the usual dosing time, the subject should skip that 
dose of study drug and resume the normal schedule for the following dose. A double dose 
should not be taken to make up for the forgotten dose. 
On Clinic Visit Days: 
 If a subject misses a dose of study drug (inhaled study drug and/or oral ivacaftor) on a Study 
Visit day, the subject should take the dose (with a fat-containing food, if ivacaftor), unless it 
is within 4 hours of a clinic visit, and should alert site personnel upon arrival to the site.   
 
Method of Assigning Subjects to Treatment Groups 
Approximately 150 subjects will be randomized to 1 of 4 treatment sequences when they are 
determined to have met all eligibility criteria. Subjects will be randomized in a 2:2:1:1 ratio in 
Part A to one of the 4 treatment sequences, (Treatment Sequence 1 or Treatment Sequence 2; 
Treatment Sequence 3 or Treatment Sequence 4), stratifying for ppFEV1 severity (<70 or ≥70).  
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Randomization must only occur after all inclusion and exclusion criteria are met and before the 
first dose of inhaled study drug is administered in Part A on Day 1.  
An interactive web or voice response system (IXRS) will be used to assign subjects to treatment. 
The randomization code will be produced by a qualified randomization vendor. The Parion 
Sciences study biostatistician, or designee, will review and approve the dummy randomization 
list. The final randomization list will be reviewed and approved by a designated unblinded 
biostatistician.  
There is no randomization in Part B. Subjects will remain in the same treatment as in Treatment 
Period 2 of Part A and will also receive open-label oral ivacaftor. Subjects must be able to meet 
and comply with study drug restrictions for Part B as outlined in Table 9-1 and Table 9-2 and per 
the Study Reference Manual.  
 
Dose Modification for Toxicity 
Modifications of the study drug doses are prohibited. If any unacceptable toxicity arises, 
individual subjects will be withdrawn from the study and study drug dosing will be discontinued. 
Interruptions of study drug dosing may be considered on a case-by-case basis after discussion 
with the Parion medical monitor.  
Specific instructions for interruption for elevated liver function tests (LFTs) and elevated plasma 
and serum potassium are provided in Section 11.6.2. 
 
Packaging and Labeling 
Inhaled study drug (85 µg VX-371 in 4.2% HS; 4.2% HS; 85 µg VX-371 in 0.17% saline; and 
placebo [0.17% saline]) will be supplied in blow-fill seal vials that are filled to deliver 3 mL of 
inhaled study drug.  
Ivacaftor 150-mg tablets will be supplied in weekly, child resistant, blister cards. Study drug 
labeling will be in compliance with applicable local and national regulations. Additional details 
regarding packaging, labeling, and dispensing for inhaled study drug and oral ivacaftor will be 
included in the Pharmacy Manual. 
 
Study Drug Supply, Storage, and Handling 
Table 10-1 provides the study drug information. The investigator, or an authorized designee 
(e.g., a licensed pharmacist), will ensure that all investigational product is stored in a secured 
area, under recommended storage conditions, and in accordance with applicable regulatory 
requirements. To ensure adequate records, all study drugs, nebulizers, and handsets (aerosol 
heads) will be accounted for via the drug accountability forms as instructed by Parion Sciences. 
Table 10-1 
Study Drug  
Drug Name 
Formulation/ 
Route 
Dosage 
Packaging 
Storage 
Condition 
Placebo 
Liquid/ 
oral nebulized 
inhalation 
3 mL 0.17% saline 
Supplied as 3 mL 
blow-fill seal vials  
25°C (77°F) with 
excursions permitted from 
15 to 30°C (59 to 86°F) 
Hypertonic 
saline (HS) 
Liquid/ 
oral nebulized 
inhalation 
3 mL 4.2% HS 
Supplied as 3 mL 
blow-fill seal vials 
25°C (77°F) with 
excursions permitted from 
15 to 30°C (59 to 86°F) 
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Table 10-1 
Study Drug  
Drug Name 
Formulation/ 
Route 
Dosage 
Packaging 
Storage 
Condition 
VX-371 
Liquid/ 
oral nebulized 
inhalation 
85 µg VX-371 in 
3 mL 0.17% saline 
Supplied as 3 mL 
blow-fill seal vials  
25°C (77°F) with 
excursions permitted from 
15 to 30°C (59 to 86°F) 
VX-371 in HS 
Liquid/ 
oral nebulized 
inhalation 
85 µg VX-371 in 
3 mL 4.2% HS 
Supplied as 3 mL 
blow-fill seal vials  
25°C (77°F) with 
excursions permitted from 
15 to 30°C (59 to 86°F) 
Ivacaftor 
Blue, 
film-coated 
tablet with 
wax/oral 
150 mg 
Supplied as 150-mg 
tablets 
Store at ≤ 25°C (77°F)  
with excursions to 30°C 
(86°F)  
 
 
Drug Accountability 
The pharmacist or designated study site staff will maintain records documenting the dates and 
amounts of (1) study drug received; (2) study drug dispensed to the subjects; (3) nebulizer and/or 
handset (aerosol head) dispensed 
 by the subjects; and (4) study drug returned by the 
subjects. 
 
 These materials will be 
retained at the site according to instructions provided by Parion Sciences or its designee until 
inventoried by the study monitor. The study monitor will review study drug records and 
inventory throughout the study. 
 
Disposal, Return, or Retention of Unused Drug 
The study site staff or pharmacy personnel will retain all materials returned by the subjects until 
the study monitor has performed drug accountability. At the end of the study, the study monitor 
will provide instructions as to the disposition of any unused investigational product. If the study 
monitor authorizes destruction at the study site, the investigator will ensure that the materials are 
destroyed in compliance with applicable environmental regulations, institutional policy, and any 
special instructions provided by Parion Sciences. Destruction will be adequately documented. 
Procedures for destruction or return of the study drug will be detailed in the Pharmacy Manual. 
 
Compliance  
To maximize treatment compliance, the investigator or designee will supervise all study drug 
dosing that occurs at the site. At each visit, site personnel will review that the subject is 
compliant with study drug dosing and remind the subject of study drug dosing requirements.  
Compliance will also be assessed by ongoing count of study drug and evaluation of the subject 
diary.  
Discrepancies will be discussed with the subject. If subjects demonstrate continued 
noncompliance of study drug dosing despite educational efforts, the investigator will contact the 
Parion medical monitor to discuss discontinuing the subject from the study drug.  
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Blinding and Unblinding 
This is a double-blind study for the inhaled study drug and treatment assignment for Parts A and 
B. Treatment with ivacaftor in Part B will be unblinded (i.e., open-label).  
10.10.1 
Blinding  
All study personnel will be blinded to subject treatment assignments with the exception of the 
following:  
 Any site personnel for whom this information is important to ensure the safety of the subject 
in the event of a life-threatening medical emergency 
 Any site personnel for whom this information is important to ensure the safety of the subject 
and their fetus in the event of a pregnancy 
 Vertex Global Patient Safety (GPS) and Regulatory Affairs personnel to satisfy SAE 
processing and reporting regulations 
 External vendor (unblinded) statistician preparing the final (production) randomization list 
who is not part of the study team 
 Contract research organization (CRO) IXRS management 
 Clinical Supply Chain Vendor 
 IDMC 
 Vendor preparing the unblinded analysis for the IDMC  
 The bioanalytical laboratory/vendor personnel  
 Parion medical monitor may, for matters relating to safety concerns, unblind individual 
subjects at any time. 
10.10.2 
Unblinding 
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind. The unblinding method will be either a manual or electronic process. 
Unblinding of the individual subject’s treatment by the investigator will be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject’s study drug is 
necessary for clinical management. In such cases, investigators will use their best judgment as to 
whether to unblind without first attempting to contact the Parion medical monitor to discuss and 
agree to the need for unblinding. If investigators deem it not necessary to unblind immediately, 
they should first attempt to contact the Parion medical monitor to discuss and agree to the need 
for unblinding. If investigators have tried but are unable to reach the Parion medical monitor, 
they will use their best judgment, based on the nature and urgency of the clinical situation, and 
may proceed with unblinding without having successfully reached and discussed the situation 
with the Parion medical monitor. 
Contact information for the Parion medical monitor (or appropriate backup) will be provided in a 
separate document. 
If a subject’s treatment assignment has been unblinded for a medical emergency or urgent 
clinical situation, the Parion medical monitor will be notified within 24 hours of the unblinding 
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event. The reason and the date of the unblinding will be documented clearly in the subject’s 
study file. Information about the treatment assignment obtained from the unblinding will be 
maintained in a secure location with controlled access and will not be shared with Parion 
Sciences, Vertex Pharmaceuticals, CRO, or any site personnel (other than the physician treating 
the subject). In addition, the investigator will consider whether the clinical event that prompted 
unblinding will be considered an SAE, according to the regulatory definitions or criteria for 
SAEs, and if so, submit an SAE report to Vertex GPS and Parion Sciences or designee, per 
Section 13.1.2.2. 
Parion Sciences or designee will also unblind any SAE reports in compliance with regulatory 
reporting requirements. In addition, Parion Sciences may, for matters relating to safety concerns, 
unblind individual subjects at any time.  
 
ASSESSMENTS 
 
Timing of Assessments 
The schedule of assessments is shown in Table 3-1, Table 3-2, and Table 3-3.  
The QOL-PCD assessment must be completed before the start of any other assessments. The 
SGRQ should be completed immediately following the QOL-PCD.  
 
 
 
Subjects who have taken their morning dose of study drug may have a study visit and undergo 
visit assessments on that day, provided that the pre-dose assessments do not occur within 4 hours 
of the morning dose of study drug.  
 
 
   
 
Subject and Disease Characteristics 
Medical history will be elicited from each subject at the Screening Visit. Based on the medical 
history, the subject will be assessed for any disqualifying medical conditions as specified in the 
inclusion and exclusion criteria. The medical history shall include a complete review of systems, 
past medical and surgical histories, and any allergies. 
Subject and disease characteristics include the following: demographics, medical history, height, 
weight, nNO level, type of laterality defect (situs inversus totalis, situs ambiguous, or heterotaxy) 
confirmed by historical chest imaging (if applicable), and PCD genetic mutation (determined by 
central genetic testing laboratory). PCD diagnostic criteria listed in Section 9.1 will be reviewed 
centrally, as defined in the Study Reference Manual. 
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Efficacy 
11.5.1 
Spirometry 
Spirometry will be performed according to the ATS Guidelines (ATS, 2005) at the time points 
outlined in Table 3-1, Table 3-2, and Table 3-3. ATS criteria for acceptability will be determined 
via a central spirometry vendor. Spirometry assessments should be performed as closely as 
possible to the same time of day as the baseline assessments to minimize the impact of diurnal 
variation. 
The first spirometry assessment at each visit should occur at least 4 hours after use of any short-
acting β-adrenergic (e.g., albuterol) or anticholinergic (e.g., ipratropium) bronchodilator, and 
after a long-acting bronchodilator has been held from the previous evening, if applicable (see 
Section 9.4) 
The following parameters will be determined as part of the spirometry assessment (according to 
GLI-predicted values for age, sex, and height).31  
 Measured: 
o FEV1 (L)  
o Forced vital capacity (FVC) (L) 
o Forced midexpiratory flow rate (FEF25%-75%) (L/sec) 
 Derived from measured parameters: 
o ppFEV1 (percentage points)  
o ppFVC (L)  
o FEV1/FVC and ppFEV1/FVC 
o ppFEF25%-75% (L/sec) 
For each assessment time point, a minimum of 3 acceptable maneuvers should be done. The 
largest FVC and second largest FVC must not vary by more than 0.15 L and the largest FEV1 
and the second largest FEV1 must not vary by more than 0.15 L. Reproducibility criteria may 
require that up to 8 maneuvers be performed. Volume-time or flow-volume curves from the best 
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3 FVC maneuvers should be considered when entering the relevant spirometry data into the 
spirometry system.   
All sites will be provided with spirometers and associated materials to be used for all study 
assessments by the central spirometry service. Spirometry data will be transmitted to a 
centralized spirometry service for quality review. 
Records of all spirometry maneuvers must be retained in the subject’s source records.  
11.5.2 
QOL-PCD 
The QOL-PCD will be completed before the start of any other assessments, including the SGRQ, 
as noted in Table 3-2 and Table 3-3.  
Subjects aged 12 at Day 1 will complete the QOL-PCD-Child version themselves and their 
parents/caregivers will complete the QOL-PCD-Parent version on all visits, regardless of 
whether subjects subsequently become 13 years of age during the study. Subjects aged 13 to 17 
years at Day 1 will complete the Adolescent version of the questionnaire themselves at all visits. 
Subjects aged 18 years and older at Day 1 will complete the Adult version of the questionnaire 
themselves at all visits. The questionnaires provide information about demographics; general 
quality of life, school, work, or daily activities; and symptom difficulties (pertaining to PCD). 
Copies of the QOL-PCD used in this study will be provided in the Study Reference Manual. 
Translations of the QOL-PCD, if available, will be provided for participating centers in non-
English-speaking countries. 
11.5.3 
SGRQ 
The SGRQ will be completed immediately following the QOL-PCD and before the start of any 
other assessments, as noted in Table 3-2 and Table 3-3.  
Subjects aged 16 years or older at Day 1 will complete the SGRQ for themselves. 
 
 
 
 
. Copies of the SGRQ used in this study will be 
provided in the Study Reference Manual. Translations of the SGRQ, if available, will be 
provided for participating centers in non-English-speaking countries. 
 
Safety 
Safety evaluations will include AEs, airway reactivity (pre- to post-dose FEV1 change for first 
dose), clinical laboratory values, clinical evaluation of vital signs, ECGs, physical examinations, 
and pulse oximetry. 
11.6.1 
Adverse Events 
All AEs will be assessed, documented, and reported in accordance with ICH GCP guidelines. 
Section 13.1 outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting AEs. A separate document that details AE CRF completion 
guidelines for investigators as well as training will be provided. 
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11.6.2 
Clinical Laboratory Assessments 
Blood and urine samples will be analyzed at a central laboratory with the exception of urine 
pregnancy tests, which will be analyzed locally. At the Screening Visit, blood specimens will be 
collected for safety laboratory tests. On Day 1, Day 57, and Day 85, blood samples will be 
collected before the first dose of the study drug in the corresponding Treatment Period.  
Blood and urine samples for clinical laboratory assessments will be collected as shown in Table 
3-1, Table 3-2, and Table 3-3. Laboratory test results that are abnormal and considered clinically 
significant will be reported as AEs (see Section 13.1).  
The laboratory test panels are shown in Table 11-1. 
Table 11-1 
Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
Urine Testsa 
Glucose  
Blood urea nitrogen   
Creatinine 
Potassium 
Sodium  
Calcium  
Chloride  
Magnesium  
Bicarbonate  
Phosphorus  
Bilirubin, direct bilirubin  
Alkaline phosphatase  
Aspartate aminotransferase  
Alanine aminotransferase  
Amylase  
Lactate dehydrogenase 
Lipase  
Gamma-glutamyl transferase  
Protein  
Albumin  
Creatine kinase 
Plasma Chemistry 
Plasma potassium 
 
Hemoglobin  
Hematocrit 
Erythrocytes:  
Mean corpuscular hemoglobin  
Mean corpuscular hemoglobin 
concentration 
Mean corpuscular volume 
Platelets  
Reticulocytes (absolute)   
Leukocytes  
Differential (absolute and percent): 
Eosinophils  
Basophils  
Neutrophils  
Lymphocytes  
Monocytes  
Leukocyte esterase  
Nitrite  
Urobilinogen  
Urine protein  
pH 
Urine blood  
Specific gravity  
Urine ketones  
Urine bilirubin  
Urine creatinine 
Urine glucose  
Urine potassium 
Urine sodium 
a 
If urinalysis results are positive for leukocyte esterase, nitrite, protein, or blood, microscopic examination of 
urine will be performed and results will be provided for leukocytes, erythrocytes, crystals, bacteria, and casts. 
In order for the subject to receive inhaled study drug on Day 1, clinical laboratory assessments 
from the Screening Visit will have no clinically significant findings that preclude participation in 
the study, as judged by the investigator. 
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Pregnancy (beta-human chorionic gonadotropin [β-HCG]) Tests for Females of Childbearing 
Potential: Serum samples will be obtained as specified in Table 3-1 and analyzed at the central 
laboratory. Urine pregnancy tests will be performed at the site as specified in Table 3-1, Table 
3-2, and Table 3-3. The urine pregnancy test on Day 1, Day 57, and Day 85 must be confirmed 
to be negative before the first dose of study drug in the corresponding Treatment Period.  
If a urine pregnancy test is positive, all study drug dosing will stop and the pregnancy will be 
confirmed with a serum β-human chorionic gonadotropin test. If confirmed, the pregnancy will 
be reported and the subject will be permanently discontinued from study drug as discussed in 
Section 11.6.5.2. If a pregnancy test is positive, the procedures outlined in Section 11.6.5.2 will 
be followed.  
FSH (Screening Visit Only): Blood sample for FSH will be measured for any potentially 
postmenopausal female with at least 12 months of continuous spontaneous amenorrhea. Serum 
FSH levels must be ≥40 mIU/mL to be considered postmenopausal.  
PCD Genotype: PCD genotyping will be performed during the Screening Period.  
Specific instructions will be provided in the Study Reference Manual. Unless a confirmed PCD 
genotype is an inclusion criterion for a particular subject, the genotype result is not required in 
order for randomization to occur. If a confirmed PCD genotype is required for randomization, 
enough time should be given between collection of the sample and the Day 1 Visit to allow 
results to be received.   
Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged to be clinically appropriate.  
For purposes of study conduct, only laboratory tests done in the central laboratory may be used. 
Local laboratories may be used at the discretion of the local investigator for management of 
urgent medical issues. If a local laboratory test value is found to be abnormal and clinically 
significant, it will be verified by the central laboratory as soon as possible after the investigator 
becomes aware of the abnormal result. If it is not possible to send a timely specimen to the 
central laboratory (e.g., the subject was hospitalized elsewhere), the investigator may base the 
assessment of an AE on a local laboratory value.  
11.6.2.1 
Hyperkalemia 
The standard of care for management of hyperkalemia should be applied. A thorough 
investigation of potential causes should be conducted, and the subject’s potassium level should 
be followed closely.  
If hyperkalemia occurs, study drug should be interrupted until the serum and plasma potassium 
are in the normal range. If no convincing temporary or possibly reversible alternative etiology 
(e.g., oral intake of potassium, acute renal failure, metabolic acidosis, uncontrolled diabetes 
mellitus, admission of repeated fist-clenching during phlebotomy, hemolyzed sample) for the 
elevated potassium is identified, study drug treatment must be discontinued regardless of 
whether the level has improved; this decision should be made in consultation with the Parion 
medical monitor or authorized designee. Subjects in whom treatment is discontinued for elevated 
potassium should have their potassium levels monitored closely until levels normalize or return 
to baseline. 
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11.6.2.2 
Elevation of Liver Function Test Parameters 
It is strongly recommended that subjects with new 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 have subsequent close monitoring of ALT and AST levels, as 
clinically indicated. 
Study drug administration must be interrupted immediately and the Parion medical monitor must 
be notified if the following criterion is met: 
 ALT or AST levels >5  ULN  
A thorough investigation of potential causes should be conducted and the subject should be 
followed closely for clinical progression. 
If criteria for study drug interruption is met and no convincing alternative etiology 
(e.g., acetaminophen use, viral hepatitis, alcohol ingestion) for the elevated ALT or AST levels 
are identified, regardless of whether the levels have improved, the subject must be discontinued 
from the study, in consultation with the Parion medical monitor (Section 9.5). An ETT Visit 
should be scheduled as soon as possible. Subjects discontinued for elevated ALT or AST levels 
should be followed until their levels normalize or return to baseline. 
If a convincing alternative etiology is identified for the ALT and/or AST elevation, study drug 
may be resumed when both laboratory values return to baseline or are ≤2 × ULN, whichever is 
higher, after approval by the Parion medical monitor.  
Upon resumption of study drug, ALT and/or AST must be assessed weekly for the shorter of: 
 4 weeks 
 1 week following the last dose of study drug, if ALT and/or AST levels have returned to 
baseline or ≤2 × ULN 
Upon resumption of study drug, ALT and/or ALT levels must be assessed weekly for 4 weeks. If 
a repeat elevation of >5 × ULN occurs within 4 weeks of rechallenge with study drug, then study 
drug must be discontinued, regardless of the presumed etiology. 
11.6.3 
Physical Examinations and Vital Signs 
A complete physical examination will be performed at the Screening Visit, Day 1, Day 29, Day 
57, Day 85, Day 113, and ETT visits. At the Day 15, Day 71 and Day 99 visits (if completed), an 
abbreviated physical examination will be done. The complete physical examination will include 
the following components: HEENT (head, eyes, ears, nose, and throat), neck, chest and chest 
auscultation, cardiovascular, abdomen, skin, and musculoskeletal. The abbreviated physical 
examination will include the following components: HEENT, neck, chest auscultation, 
cardiovascular, and skin. Both the full and abbreviated physical examinations will exclude rectal 
and genitourinary examinations (see Table 3-1, Table 3-2, and Table 3-3). 
After the Screening Visit, any clinically significant abnormal findings in physical examinations 
will be reported as AEs. 
Vital signs include blood pressure (systolic and diastolic), body temperature, pulse rate (beats per 
minute), respiratory rate (breaths per minute), and pulse oximetry. These will be assessed 
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following at least a 5-minute rest in a sitting or supine position. After the Screening Visit, 
clinically significant abnormal findings in vital signs will be reported as AEs.  
11.6.4 
Electrocardiograms 
Twelve-lead ECGs will be performed using a machine with printout according to the Schedule of 
Assessments (Table 3-1, Table 3-2, and Table 3-3). Additional 12-lead ECGs will be performed 
at any other time if clinically indicated. The performance of all ECGs will adhere to the 
following guidelines: 
 The subject will be instructed to rest in a sitting or supine position for at least 5 minutes 
before having an ECG performed. 
 Prior to placing ECG leads, the record will be reviewed for the presence of dextrocardia. 
Subjects with dextrocardia will have all ECG limb and chest (V) leads reversed. 
The ECG traces will be manually read at the study site at the Screening Visit, Day 1, Day 15 (if a 
visit is conducted), Day 29, Day 57, Day 71 (if a visit is conducted), Day 85, Day 99 (if a visit is 
conducted), Day 113, and the ETT Visit. A printout of the ECG traces will be made for safety 
review by the investigator and maintained with source documentation. Clinically significant 
ECG abnormalities (taking into consideration anticipated abnormalities in subjects with 
dextrocardia) occurring during the study through the Day 113 Visit will be recorded as AEs.  
To ensure safety of the subjects, a qualified individual at the study site will make comparisons to 
baseline measurements. If the QTcF increases by >45 msec from the baseline or an absolute 
QTcF value is ≥500 msec for any scheduled ECG, 2 additional ECGs will be performed 
approximately 2 to 4 minutes apart to confirm the original measurement. If the QTcF value 
remains above the threshold value on the repeat ECG measurement with no identified alternative 
etiology for the increased QTcF, then study drug should not be administered on that day and 
must be immediately interrupted. An ECG should be repeated within 48 to 72 hours to monitor 
the QTcF interval. Discussion with the Parion medical monitor must occur to determine whether 
study drug may be resumed or whether discontinuation from study drug treatment is indicated. 
Subjects in whom treatment is discontinued for increased QTcF should have their QTcF 
monitored closely until it normalizes or returns to baseline. 
11.6.5 
Contraception and Pregnancy 
The effects of VX-371 on conception, pregnancy, and lactation of humans are not known. 
Ivacaftor did not show any effect in reproductive toxicology studies, including rat fertility, rat 
and rabbit embryo-fetal development, and rat peri/post-natal reproduction toxicity studies (refer 
to the Ivacaftor Investigator’s Brochure).  
 
 Results suggested that the clinical effects of the oral contraceptive would 
not likely be adversely impacted by coadministration with ivacaftor. Therefore, hormonal 
contraceptives are one acceptable means of contraception for female subjects of childbearing 
potential in this study. 
11.6.5.1 
Contraception 
Participation in this study requires a commitment from the subject and his/her partner to use at 
least 1 acceptable method of contraception, which must be used correctly with every act of 
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sexual intercourse. Methods of contraception should be in successful use from at least 14 days 
before the first dose of study drug (unless otherwise noted) and until 90 days following the last 
dose of study drug. 
Contraception for the couple is waived for the following: 
 True abstinence for the subject, when this is in line with the preferred and usual lifestyle of 
the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. 
 If the male is infertile (e.g., bilateral orchiectomy). Infertility may be documented through 
examination of a semen specimen or by demonstration of the absence of the vas deferens by 
ultrasound before the first dose of the study drug. 
 If the female is of non-childbearing potential, per the following: 
o Documented hysterectomy or a bilateral oophorectomy/salpingo-oophorectomy. 
o Postmenopausal: continuous amenorrhea for at least 12 months and serum FSH levels 
≥40 mIU/mL.  
o Has not achieved menarche (has not had her first menstrual period). If a female achieves 
menarche during the study, she will need to follow acceptable methods of contraception 
or abstinence. 
For subjects for whom contraception methods are not waived due to one of the reasons 
cited above, the following are acceptable contraceptive methods for male subjects and their 
female (non-study) partners, and for female subjects and their male (non-study) partners: 
Table 11-2 
Acceptable Methods of Contraception 
 Male vasectomy 6 months or more previously, with a negative post-vasectomy semen analysis for sperm. 
 Male or female condom with or without spermicide (either as a single product if commercially available and/or 
allowed according to local regulations; otherwise condom and spermicide as separate products). 
 Female bilateral tubal ligation performed at least 6 months previously. 
 Female diaphragm, cervical cap, or vaginal sponge, each with spermicide (where available). 
 Female continuous use of an intrauterine device (non-hormone releasing or hormone releasing) for at least 90 
days. 
 Female combined (estrogen and progestogen-containing) or progestogen-only hormonal contraception 
associated with inhibition of ovulation if successfully used for at least 60 days. 
 
Important notes: 
 Local requirements may prohibit the use of some of these acceptable methods listed above. 
Please contact the Parion medical monitor with any questions. 
 If applicable, additional contraception requirements may need to be followed according to 
local regulations and/or requirements. 
 Male and female subjects who are not sexually active at the time of screening must agree to 
follow the contraceptive requirements of this study if they become sexually active. 
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 Female condom used with male condom (as a double method of contraception) is not an 
acceptable method of contraception due to risk of tearing; a different acceptable method of 
birth control must be used as described in Table 11-2.  
 Male subjects must not donate sperm after the first dose of study drug, throughout the study, 
and for 90 days following the last dose of study drug. 
 Female subjects and female partners of male subjects should not plan to become pregnant 
during the study through 90 days following the last dose of study drug. 
 Female subjects should not nurse a child from the start of study drug dosing through 90 days 
following the last dose of study drug. 
Unique situations that may not fall within the above specifications may be discussed with the 
Parion medical monitor on an individual basis. 
11.6.5.2 
Pregnancy 
Subjects will be counseled to inform the investigator of any pregnancy that occurs during study 
drug treatment and for 90 days after the last dose of study drug(s). 
All pregnancies occurring during the study or within 90 days after discontinuation of study drug 
must be followed until resolution (i.e., birth or voluntary or spontaneous termination of the 
pregnancy). Any subject found to be pregnant at any time during the study will be withdrawn 
from the study immediately. Any pregnancy outcome that meets the criteria for an SAE will be 
reported as an SAE. 
If a subject or the female partner of a male subject becomes pregnant while participating in the 
study, study drug will be permanently discontinued immediately. The investigator will notify the 
Parion medical monitor and Vertex GPS and Parion Sciences within 24 hours of the site’s 
knowledge of the subject’s (or partner’s) pregnancy using the Pregnancy Information Collection 
Form. 
If confirmed to be on active drug, the subject or partner will be followed until the end of the 
pregnancy and the infant will be followed for 1 year after the birth, provided informed consent is 
obtained. A separate ICF will be provided to explain these follow-up activities. Pregnancy itself 
does not constitute an AE. 
 
STATISTICAL AND ANALYTICAL PLANS 
Parion Sciences or its designee will analyze the safety and efficacy data. 
This section presents a summary of the planned analyses for this protocol. Statistical analysis 
details will be provided in the Statistical Analysis Plan (SAP), which will be finalized before the 
clinical database lock for the study and treatment unblinding. 
 
Sample Size and Power 
Part A 
The primary efficacy objective of Part A of this study is to evaluate the efficacy of VX-371 with 
and without HS in subjects ≥12 years of age with PCD. For efficacy analysis, the statistical 
inferences will be based on change from study baseline. The null hypotheses to be tested are that 
the mean absolute change from study baseline in ppFEV1 after 28 days of treatment is the same 
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for 1) VX-371 in HS versus placebo; 2) VX-371 versus placebo; and 3) VX-371 in HS versus 
HS alone. 
To have a feasible sample size and study duration, a crossover design has been proposed for Part 
A of this study. Assuming an SD of 7 percentage points, 50 subjects each for Treatment 
Sequence 1 and Treatment Sequence 2 are needed to have approximately 81% power to detect a 
3-percentage point treatment difference in the mean absolute change in ppFEV1 from study 
baseline, after 28 days of treatment between VX-371 + HS and HS alone. Part A of the study will 
have approximately 87% power to detect a 4-percentage point change from baseline, after 28 
days of treatment in ppFEV1 between VX-371 + HS and placebo. The power to detect a 
3-percentage point difference between VX-371 and placebo is about 51%. The sample size 
estimate was based on 10000 simulation runs with an incomplete block design assuming no 
dropouts. In the simulation, the correlation between responses to the 2 treatments within a 
subject was assumed to be 0. Furthermore, a 2-sided significance level of 0.05 was used in the 
sample size determination with no multiplicity adjustment. The sample size also takes into 
consideration an assumed dropout rate of 10%. 
Part A of the study will enroll approximately 150 subjects. However, as no therapeutic 
intervention study has previously been completed in PCD patients, the ability to enroll all 150 
subjects is uncertain. Enrollment of less than 150 subjects will still provide useful information 
and could demonstrate an important difference between treatments. Enrollment into Part A will 
continue until approximately 150 subjects are randomized or the enrollment rate drops, despite 
suitable interventions, such that the planned enrollment cannot be achieved. 
Part B 
No formal sample size calculation was performed. All subjects who completed the assigned 
treatment in Part A and who meet the eligibility criteria for Part B will be offered enrollment in 
Part B.  
 
Analysis Sets 
Assignment of subjects to analysis sets will be done before the clinical database lock for the 
study.  
The All Subjects Set is defined as all subjects who were randomized or have received at least 1 
dose of study drug (i.e., all subjects in the study). All subject data listings will be referenced 
using the All Subjects Set, unless otherwise specified. 
Part A 
The Part A Full Analysis Set (FAS) is defined as all randomized subjects who have received at 
least 1 dose of study drug in Part A. The Part A FAS is to be used in Part A efficacy analyses in 
which subjects will be analyzed according to the treatment to which they were assigned or 
background data summary according to the treatment sequence to which they were randomized 
in Part A. All analyses of background data and efficacy data in Part A will be based on the Part 
A FAS. In efficacy analyses, data for a period will be used provided that the subject received at 
least 1 dose of study drug in the Treatment Period.  
The Part A Safety Set is defined as all subjects who received at least 1 dose of study drug in Part 
A. The Part A Safety Set is to be used for all Part A safety analyses in which subjects will be 
analyzed according to the treatment they received in each period of Part A. In safety analyses, 
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data for a period will be used provided that the subject received at least 1 dose of study drug in 
that Treatment Period. 
Part B 
The Part B FAS is defined as all subjects randomized in Part A and enrolled in Part B and  who 
have received at least 1 dose of study drug in Part B. The Part B FAS is to be used in Part B 
efficacy analyses in which subjects will be analyzed according to the treatment as  enrolled in 
Part B, which is ivacaftor plus the same treatment as assigned in Part A Treatment Period 2. All 
analyses of background data and efficacy data in Part B will be based on the Part B FAS. 
The Part B Safety Set is defined as all subjects who received at least 1 dose of study drug in Part 
B. The Part B Safety Set is to be used for all Part B safety analyses in which subjects will be 
analyzed according to the treatment as enrolled in Part B, which is ivacaftor plus the same 
treatment as assigned in Part A Treatment Period 2.  
 
Statistical Analysis 
12.3.1 
General Considerations 
All individual subject data for those randomized or exposed to study drug will be presented in 
data listings.  
Continuous variables will be summarized using the following descriptive summary statistics: 
number of subjects (n), mean, SD, SE, median, minimum value (min), and maximum value 
(max). The precision of the measurement for each continuous variable will be specified in the 
SAP.  
Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place. 
Treatment-emergent Period  
Treatment-Emergent Period for Part A Treatment Period 1: 
 For subjects who prematurely discontinue treatment in Part A Treatment Period 1, the 
Treatment-Emergent Period will be defined as the interval that occurs on or after first dose of 
Treatment Period 1 and up to 28 days after the last dose in Treatment Period 1. 
 For subjects who continue into Treatment Period 2, the treatment emergent period will be 
defined as the interval that occurs on or after first dose of study drug in Treatment Period 1 
and before first dose of study drug in Treatment Period 2. 
Treatment-Emergent Period for Part A Treatment Period 2: 
 For subjects who prematurely discontinue treatment in Treatment Period 2, the 
treatment-emergent period will be defined as the interval that occurs on or after first dose of 
study drug in Treatment Period 2 and up to 28 days after the last dose in Treatment Period 2. 
 For subjects who complete Treatment Period 2, the treatment-emergent period will be 
defined as the interval that occurs on or after first dose of Treatment Period 2 and before first 
dose of Part B (Treatment Period 3).  
Treatment-Emergent Period for Part B Treatment Period 3: 
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For subjects who receive treatment in Part B, the treatment-emergent period will be defined as 
the interval that occurs on or after first dose of study drug in Part B until the end of study. 
Baseline: 2 types of baselines will be defined for Part A. The study baseline is defined as the 
most recent nonmissing measurement (scheduled or unscheduled) collected before the first dose 
of study drug. The definition will be applied to all demographics, background, and baseline 
characteristics and also efficacy data analysis, including the primary endpoint analysis. The 
period baseline is defined as the most recent nonmissing measurement (scheduled or 
unscheduled) collected before the first dose of study drug in each Treatment Period. For Part A 
Treatment Period 2, the period baseline should be from an assessment measured after the last 
dose for Treatment Period 1. This definition will be applied to all safety data analysis. This 
definition will be applied to all safety data analysis in Part A and Part B.  
For Part B, 2 types of baseline will be defined. The study baseline is defined as the most recent 
nonmissing measurement (scheduled or unscheduled) collected before the first dose of study 
drug (i.e., same baseline as for Part A). The Part B baseline is defined as the most recent 
nonmissing measurement (scheduled or unscheduled) collected before the first dose of study 
drug in Part B. 
Change/Absolute Change from Study Baseline in Part A and Part B will be calculated as:  
post-baseline value - study baseline value  
Change/Absolute Change from Period Baseline in Part A and Part B will be calculated as: 
post-baseline value - period baseline value 
Change/Absolute Change from Part B Baseline will be calculated as:  
post-baseline value - Part B baseline value 
12.3.2 
Background Characteristics 
Subject disposition, demographic and baseline characteristics, prior and concomitant 
medications, study drug exposure and compliance, and other background characteristics (e.g., 
medical history) will be summarized. Additionally, all subject data will be presented in subject 
data listings. All Part A summaries will be based on the Part A FAS and all Part B summaries 
will be based on the Part B FAS unless otherwise specified in the SAP for the study. No 
statistical hypothesis testing will be performed on background characteristics. 
12.3.2.1 
Subject Disposition 
Part A 
The number and percentage of subjects in the Part A FAS will be summarized by treatment 
sequence in each of the following disposition categories: 
 Completed Part A study drug treatment  
 Prematurely discontinued Part A study drug treatment and the reasons for discontinuation 
 Last scheduled on-treatment visit completed in Part A for subjects who discontinued study 
drug treatment in Part A 
 Completed Part A 
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o Continued study in Part B 
o Did not enroll in Part B 
 Prematurely discontinued the study in Part A and the reasons for discontinuation  
Part B 
The number and percentage of subjects in the Part B FAS will be summarized by treatment in 
each of the following disposition categories: 
 Completed Part B study drug treatment  
 Prematurely discontinued Part B study drug treatment and the reasons for discontinuation 
 Completed study in Part B 
 Prematurely discontinued the study in Part B and the reasons for discontinuation 
12.3.2.2 
 Demographics and Baseline Characteristics 
Demographic, background (e.g., medical history), and baseline characteristics will be 
summarized by treatment sequence for Part A and Part B. Protocol deviations/violations will be 
provided as a subject data listing only. Important protocol deviations/violations will be 
summarized. 
The following demographics and study baseline characteristics will be summarized by treatment 
sequence for Part A FAS and by treatment for Part B FAS, respectively: sex, race, ethnicity, age, 
weight, height, body mass index (BMI), region, and study baseline ppFEV1.  
12.3.2.3 
Prior and Concomitant Medications 
Medications used in this study will be coded by using the World Health Organization Drug 
Dictionary-Enhanced and categorized as follows:  
Prior medication: any medication that started before the first dose of study drug in Part A, 
regardless of when it ended. 
Concomitant medication: medication continued or newly received during the 
Treatment-Emergent Period for Part A (Treatment Period 1 or Treatment Period 2), or Part B 
(Treatment Period 3).  
A given medication can be classified as a prior medication, a concomitant medication, or both 
prior and concomitant. If a medication has a missing or partial missing start/end date or time and 
it cannot be determined whether the medication was taken before initial dosing or concomitantly, 
it will be considered as prior and concomitant. 
Prior medications will be summarized by treatment sequence, Part A concomitant medications 
will be summarized by treatment based on the Part A FAS, and Part B concomitant medications 
will be summarized by treatment based on the Part B FAS.  
12.3.2.4 
Study Drug Exposure and Compliance 
Part A 
Exposure to study drug in Part A (i.e., duration of treatment) will be summarized by treatment 
for the Part A FAS in terms of duration of treatment a subject received (in days), defined as: 
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the last day of study drug - the first day of study drug + 1 within each Treatment Period.  Half 
days will be counted if the first dose is administered in the afternoon and/or the last dose is 
administered in the morning. 
Study drug compliance will be calculated for each Treatment Period of Part A as follows:  
100 × [(Total number of vials dispensed – the total number of unused vials returned – the total 
number of vials reported as lost or wasted in a Treatment Period of Part A) / (Duration of study 
drug exposure in the corresponding Treatment Period of Part A times 2)]. 
Duration of treatment and study drug compliance in Part A will be summarized by descriptive 
summary statistics by treatment. 
Part B 
Exposure to study drug in Part B (i.e., duration of treatment) will be summarized by treatment 
for the Part B FAS in terms of duration of treatment a subject received (in days), defined as the 
last day of study drug minus the first day of study drug in Part B plus 1.  Half days will be 
counted if the first dose is administered in the afternoon and/or the last dose is administered in 
the morning. 
Study drug compliance will be calculated for each study drug in Part B as follows:  
100 × [(Total number of doses dispensed – the total number of unused doses returned – the total 
number of doses reported as lost or wasted in Part B) / (Duration of study drug exposure in Part 
B times 2)]. 
Duration of treatment and study drug compliance in Part B will be summarized by descriptive 
summary statistics by treatment. 
12.3.3 
Efficacy Analysis 
For Part A efficacy analysis, the statistical inference will be based on change from study 
baseline. For Part B efficacy analysis, the statistical inference will be based on change from 
study baseline and change from Part B baseline.  
All Part A efficacy summaries and analysis will be based on the Part A FAS and all Part B 
efficacy summaries and analysis will be based on the Part B FAS unless otherwise specified. 
12.3.3.1 
Analysis of Primary Efficacy Variables 
Part A 
The primary efficacy endpoint for Part A is the absolute change in ppFEV1 from study baseline, 
after 28 days of treatment in each Treatment Period of Part A.   
The null hypotheses to be tested are that the mean absolute change from study baseline in 
ppFEV1 after 28 days of treatment is the same for 1) VX-371 in HS versus placebo; 2) VX-371 
versus placebo; and 3) VX-371 in HS versus HS alone. 
The primary efficacy analysis is based on a mixed-effects model. This model will include the 
absolute change from study baseline in ppFEV1 after 28 days of treatment as the dependent 
variable, treatment and period as fixed effects, and subject as a random effect. The within-subject 
covariance will be assumed to have the compound symmetry (CS) structure. Denominator 
degrees of freedom for the F-test for fixed effects will be estimated using the Kenward-Roger 
approximation.32 No imputation of missing data will be done. Assuming that the subjects have 
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dropped out at random, an estimate of treatment effect will be based on such subjects and will 
then be combined with the estimate from subjects who have data in both Treatment Periods with 
weights based on the precision of these estimates. 
The estimated mean of the dependent variable, a 95% CI, and a 2-sided P value will be provided 
for each treatment. There will be no adjustment for multiplicity. Similarly, the estimated 
between-treatment differences along with the corresponding 95% CI and 2-sided P values will be 
presented.  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
Part B 
For the Part B primary efficacy endpoints, absolute change in ppFEV1 from study baseline and from 
Part B baseline, after 28 days of treatment in Part B, and descriptive summary statistics (n, mean, SD, 
SE, median, minimum, and maximum) will be provided.  
The within-group P value and the 95% confidence interval based on normal approximation will be 
provided for absolute change in ppFEV1 
 
from study baseline, after 28 days of treatment in Part B  
 
from Part B baseline, after 28 days of treatment in Part B  
12.3.3.2 
Analysis of Secondary Efficacy Variables 
Part A 
For the Part A secondary efficacy endpoint, the primary analysis will be based on change from 
study baseline.  
 Change in quality of life score as measured by the QOL-PCD after 28 days of treatment in 
Part A 
 Change in the SGRQ after 28 days of treatment in Part A 
Analysis of the change in QOL-PCD and SGRQ will be similar to that of the primary analysis of 
the Part A primary efficacy endpoint. 
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Part B 
For the Part B secondary efficacy endpoint, the primary analysis will be based on change from 
study baseline as well as change from Part B baseline.  
 Change in quality of life score as measured by the QOL-PCD after 28 days of treatment in 
Part B 
 Change in the SGRQ after 28 days of treatment in Part B 
Analysis of the change in QOL-PCD and SGRQ will be similar to that of the primary analysis of 
the Part B primary efficacy endpoints. 
12.3.4 
Safety Analysis 
All safety analyses will be based on the set of data associated with the treatment emergent period 
for Part A Treatment Period 1, the treatment emergent period for Part A Treatment Period 2, and 
the treatment emergent period for Part B (Treatment Period 3). Part A safety analyses will be 
based on the Part A Safety Set. The summaries will be by treatment received in Part A. Part B 
safety analyses will be based on the Part B Safety Set. The summaries will be by treatment 
received in Part B. 
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For safety analysis, the period baseline will be used for Part A and the Part B baseline will be 
used for Part B. 
All safety data will be presented in individual subject data listings. 
The overall safety profile of study drug will be assessed in terms of the following safety and 
tolerability endpoints: 
 Incidence of treatment-emergent adverse event (TEAEs) 
 Clinical laboratory values (i.e., urine, serum and plasma chemistry, and hematology) 
 ECG results 
 Spirometry 
 Vital signs 
 Pulse oximetry 
12.3.4.1 
Adverse Events 
For analysis purposes, AEs will be classified as pre-treatment AEs or TEAEs, defined as follows:  
Pre-treatment AEs: Any AEs that started before the initial dosing of study drug. 
TEAE: any AE that increased in severity or that was newly developed during the treatment 
emergent period for Part A Treatment Period 1 or Part A Treatment Period 2 or Part B. An AE 
that starts (or increases in severity) during a specific Part A Treatment Period or Part B will be 
attributed to the study drug the subject was receiving during the corresponding Part A Treatment 
Period or Part B.  
For AEs with missing or partial start date, if there is no clear evidence that the AEs started (or 
increased in severity) before the first dose of Part A, the start date will be imputed to the first 
dosing date of Part A and the AE assigned to the treatment in Part A Treatment Period 1. For 
AEs with missing or partial start date, if there is no clear evidence that the AEs started (or 
increased in severity) before the first dose of Part B, the start date will be imputed to the first 
dosing date of Part B and the AE assigned to the treatment in Part A Treatment Period 1. 
Therefore, for AEs with missing or partial start date, it is possible the AE is considered 
treatment-emergent in both Part A Treatment Period 1 and Part B. 
Part A and Part B 
AE summary tables for Part A will be presented for TEAEs only and will include the following: 
 All TEAEs  
 TEAEs by worst/highest relationship  
 TEAEs by maximum severity 
 TEAEs leading to treatment discontinuation 
 Serious TEAEs 
 TEAEs leading to death 
 Frequently reported TEAEs 
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Summaries will be presented by treatment by MedDRA system organ class and preferred term 
using frequency counts and percentages (i.e., number and percentage of subjects with an event). 
When summarizing the number and percentage of subjects with an event, subjects with multiple 
occurrences of the same AE or a continuing AE will be counted once, only the maximum 
severity level will be presented in the severity summaries, and the worst/highest relationship 
level in the relationship summaries. An AE overview table will be provided. In addition, a listing 
containing individual subject AE data for all deaths and other serious AEs will be provided 
separately for Part A and Part B. 
All AEs, including pre-treatment AEs, will be presented in individual subject data listings. 
12.3.4.2 
Clinical Laboratory Assessments 
Part A 
The raw values and change from Part A period baseline values of the continuous laboratory 
parameters will be summarized in SI units by treatment at each scheduled time point.  
The number and percentage of subjects with at least 1 laboratory abnormality meeting the 
threshold analysis criteria during the Part A Treatment Emergent Period will be summarized by 
treatment. The threshold analysis criteria will be provided in the SAP.   
Part B 
The raw values and change from Part B baseline values of the continuous laboratory parameters 
will be summarized in SI units by treatment at each scheduled time point. 
The number and percentage of subjects with at least 1 laboratory abnormality meeting the 
threshold analysis criteria during the Part B treatment emergent period will be summarized by 
treatment. The threshold analysis criteria will be provided in the SAP.   
Part A and Part B 
Results of urinalysis and serum/urine pregnancy tests will be listed in individual subject data 
listings only. In addition, a listing containing individual subject laboratory measurements outside 
the reference ranges will be provided. This listing will include data from scheduled and 
unscheduled time points. 
Urine sodium to potassium ratios will be summarized by treatment. 
12.3.4.3 
Electrocardiogram 
Part A and Part B 
A summary of raw values and change from Part A and Part B period baseline values will be 
provided by treatment at each scheduled visit for the following ECG measurements: heart rate, 
QRS duration, PR, and QTcF intervals. The number and percentage of subjects with at least 1 
threshold analysis event during the treatment emergent period will also be tabulated. The 
threshold analysis criteria will be provided in the SAP.   
12.3.4.4 
Vital Signs 
Part A and Part B 
The summary of raw values and change from Part A and Part B period baseline values for the 
following vital signs will be presented by treatment at each scheduled time point: systolic and 
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diastolic blood pressure (mm Hg), body temperature, pulse rate (beats per minute), and 
respiratory rate (breaths per minute). The number and percentage of subjects with at least 1 
threshold analysis event during the treatment emergent period will also be tabulated. The 
threshold analysis criteria will be provided in the SAP.   
12.3.4.5 
Physical Examination 
For Parts A and B, physical examination results will be presented in individual subject data 
listings only. Clinically relevant results identified after the Screening Visit will be reported as 
AEs.  
12.3.4.6 
Spirometry 
Part A 
Spirometry data in Part A will be summarized based on the Part A Safety Set. This will include 
the number and percentage of subjects at each scheduled time point with predefined decreases in 
ppFEV1/FEV1 relative to Part A period baseline value.  
Part B 
Spirometry data in Part B will be summarized based on the Part B Safety Set. This will include 
the number and percentage of subjects at each scheduled time point with predefined decreases in 
ppFEV1/FEV1 relative to Part B baseline value.  
12.3.4.7 
Other Safety Analysis 
12.3.4.7.1 
Pulse Oximetry  
Part A 
The summary of raw values and change from Part A period baseline values will be presented by 
treatment at each scheduled time point for the percent of oxygen saturation by pulse oximetry.  
The number and percentage of subjects with shift changes from Part A period baseline 
(normal/missing and low according to the reference range) to the lowest percent of oxygen 
saturation during the Part A treatment emergent period will be tabulated by treatment. 
Part B 
The summary of raw values and change from Part B baseline values will be presented by 
treatment at each scheduled time point for the percent of oxygen saturation by pulse oximetry.  
The number and percentage of subjects with shift changes from Part B baseline (normal/missing 
and low according to the reference range) to the lowest percent of oxygen saturation during the 
Part B treatment emergent period will be tabulated by treatment. 
12.3.5 
Interim and IDMC Analyses 
12.3.5.1 
Interim Analysis 
Not applicable 
12.3.5.2 
IDMC Analysis 
An IDMC will be formed before study initiation. The IDMC’s objectives and operational details 
will be defined in a separate document (IDMC charter), which will be finalized before the first 
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subject is screened. The IDMC will conduct regular planned safety reviews of study data as 
outlined in the IDMC charter. 
 
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS 
 
Adverse Event and Serious Adverse Event Documentation, Severity 
Grading, and Reporting 
13.1.1 
Adverse Events 
13.1.1.1 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a subject during the study; the event 
does not necessarily have a causal relationship with the treatment. This includes any newly 
occurring event or worsening of a preexisting condition (e.g., increase in its severity or 
frequency) after the ICF is signed and study procedures have started.  
An AE is considered serious if it meets the definition in Section 13.1.2.1.  
13.1.1.2 
Clinically Significant Assessments 
Study assessments including laboratory tests, ECGs, physical exams, pulse oximetry, and vital 
signs, will be assessed and those deemed a clinically significant worsening from baseline 
documented as an AE. When possible, a clinical diagnosis for the study assessment will be 
provided, rather than the abnormal test result alone (e.g., urinary tract infection, anemia). In the 
absence of a diagnosis, the abnormal study assessment itself will be listed as the AE (e.g., 
bacteria in urine or decreased hemoglobin). 
An abnormal study assessment is considered clinically significant if the subject has 1 or more of 
the following: 
 Concomitant signs or symptoms related to the abnormal study assessment 
 Further diagnostic testing or medical/surgical intervention 
 Discontinuation from the study 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant will be made by the investigator. 
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13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time ICF is signed and study procedures have started until the 
following time points: 
 For subjects who are not randomized until time of screen failure (e.g., screen failure, 
withdrawal of consent) 
 For enrolled subjects who have a Safety Follow-up Telephone Call: through the Safety 
Follow-up Telephone Call 
 For subjects who Early Terminate from the study: through the Safety Follow-up Telephone 
Call 
All subjects will be queried, using non-leading questions, about the occurrence of AEs at each 
study visit. When possible, a constellation of signs and/or symptoms will be identified as 
1 overall event or diagnosis. All AEs for enrolled subjects will be recorded in the CRF and 
source document. AEs for subjects who are screened but not subsequently randomized in the 
study will be recorded only in the subject’s source documents. The following data will be 
documented for each AE: 
 Description of the event 
 Classification of “serious” or “nonserious” 
 Date of first occurrence and date of resolution (if applicable) 
 Severity  
 Causal relationship to study drug(s)  
 Action taken  
 Outcome  
 Concomitant medication or other treatment given 
13.1.1.4 
Adverse Event Severity 
The investigator will determine and record the severity of all serious and non-serious AEs. The 
guidance available at the following website will be consulted: Common Terminology Criteria for 
Adverse Events (CTCAE), Version 4.0, Cancer Therapy Evaluation Program, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed August 
2012). AEs of CTCAE Grades 4 and 5 will be documented as “life-threatening.” In considering 
the severity of an AE in a pediatric subject, the investigator will consider that reference ranges 
for pediatric clinical laboratory parameters may differ from those given in the CTCAE. The 
severity of an AE that does not appear in the CTCAE will be determined according to the 
definitions in Table 13-1. 
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Table 13-1 
Grading of AE Severity 
Classification 
Definition 
Mild (Grade 1) 
Mild level of discomfort and does not interfere with regular activities 
Moderate (Grade 2) 
Moderate level of discomfort and significantly interferes with regular activities 
Severe (Grade 3) 
Significant level of discomfort and prevents regular activities 
Life-threatening (Grade 4) 
Any adverse drug experience that places the subject, in the view of the 
investigator, at immediate risk of death  
 
13.1.1.5 
Adverse Event Causality 
Every effort will be made by the investigator to assess the relationship of the AE, if any, to the 
study drug(s). Causality will be classified using the categories presented in Table 13-2. 
Table 13-2 
Classifications for AE Causality 
Classification 
Definition 
Related 
There is an association between the event and the administration of investigational 
study drug, a plausible mechanism for the event to be related to the investigational 
study drug and causes other than the investigational study drug have been ruled out, 
and/or the event re-appeared on re-exposure to the investigational study drug. 
Possibly related 
There is an association between the event and the administration of the 
investigational study drug and there is a plausible mechanism for the event to be 
related to investigational study drug, but there may also be alternative etiology, 
such as characteristics of the subject’s clinical status or underlying disease. 
Unlikely related 
The event is unlikely to be related to the investigational study drug and likely to be 
related to factors other than investigational study drug.  
Not related 
The event is related to an etiology other than the investigational study drug (the 
alternative etiology will be documented in the study subject’s medical record). 
 
13.1.1.6 
Study Drug Action Taken 
The investigator will classify the study drug action taken with regard to the AE. The action taken 
will be classified according to the categories shown in Table 13-3.  
Table 13-3 
Classifications for Study Drug Action Taken with Regard to an AE 
Classification 
Definition 
Dose not changed 
Study drug dose not changed in response to an AE 
Drug interrupted 
Study drug administration interrupted in response to an AE  
Drug withdrawn 
Study drug administration permanently discontinued in response to an AE 
Not applicable 
Action taken regarding study drug administration does not apply.  
“Not applicable” will be used in circumstances such as when the investigational 
treatment had been completed before the AE began and no opportunity to decide 
whether to continue, interrupt, or withdraw treatment is possible. 
 
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13.1.1.7 
Adverse Event Outcome 
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories shown in Table 13-4. 
Table 13-4 
Classifications for Outcome of an AE 
Classification 
Definition 
Recovered/Resolved 
Resolution of an AE with no residual signs or symptoms 
Recovered/ Resolved 
With Sequelae 
Resolution of an AE with residual signs or symptoms 
Not Recovered/Not 
Resolved (Continuing) 
Either incomplete improvement or no improvement of an AE, such that it remains 
ongoing 
Fatal 
Outcome of an AE is death. “Fatal” will be used when death is at least possibly 
related to the AE. 
Unknown 
Outcome of an AE is not known (e.g., a subject lost to follow-up) 
 
13.1.1.8 
Treatment Given 
The investigator ensures adequate medical care is provided to subjects for any AEs, including 
clinically significant laboratory values related to study drug. In addition, the investigator will 
describe whether any treatment was given for the AE. “Yes” is used if any treatment was given 
in response to an AE, and may include treatments such as other medications, hospitalization, 
surgery, or physical therapy. “No” indicates the absence of any kind of treatment for an AE. 
13.1.2 
Serious Adverse Events 
13.1.2.1 
Definition of a Serious Adverse Event 
An SAE is any AE that meets any of the following outcomes: 
 Fatal (death, regardless of cause, that occurs during participation in the study or occurs after 
participation in the study and is suspected of being a delayed toxicity due to administration of 
the study drug) 
 Life-threatening, such that the subject was at immediate risk of death from the reaction as it 
occurred  
 Inpatient hospitalization or prolongation of hospitalization 
 Persistent or significant disability/incapacity (disability is defined as a substantial disruption 
of a person’s ability to conduct normal life functions) 
 Congenital anomaly or birth defect 
 Important medical event that, based upon appropriate medical judgment, may jeopardize the 
subject or may require medical or surgical intervention to prevent 1 of the outcomes listed 
above (e.g., an allergic bronchospasm requiring intensive treatment in an emergency room or 
at home)  
If a subject has a hospitalization or procedure (e.g., surgery) for an event or condition that 
occurred before the subject signed the ICF, and the hospitalization or procedure was planned 
before the subject signed the ICF, the hospitalization or procedure will not be considered to 
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indicate an SAE, unless an AE caused the hospitalization or procedure to be rescheduled sooner 
or to be prolonged relative to what was planned. In addition, hospitalizations clearly not 
associated with an AE (e.g. social hospitalization for purposes of respite care) will not be 
considered to indicate an SAE. 
Clarification will be made between the terms “serious” and “severe,” because they are not 
synonymous. The term “severe” is often used to describe the intensity (severity) 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 a severe headache. This is not the same as 
“serious,” which is based on subject/event outcome or action described above, and is usually 
associated with events that pose a threat to a subject’s life or functioning. Seriousness, not 
severity, serves as a guide for defining expedited regulatory reporting obligations.  
13.1.2.2 
Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent and assent (where applicable) through the 
Follow-up Visit, regardless of causality, will be reported by the investigator to Vertex GPS 
within 24 hours. In addition, all SAEs that occur after the Safety Follow-up Telephone Call and 
are considered related to study drug(s) will be reported to Vertex GPS and Parion Sciences 
within 24 hours. 
SAEs will be recorded on the Vertex Organized Safety Information Collection Form (hereafter 
referred to as the “SAE Form”) using a recognized medical term or diagnosis that accurately 
reflects the event. SAEs will be assessed by the investigator for relationship to the investigational 
study drug(s) and possible etiologies. On the Clinical Trials SAE Form, relationship to study 
drug(s) will be assessed only as related (includes possibly related) or not related (includes 
unlikely related), and severity assessment will not be required. For the purposes of study 
analysis, if the event has not resolved at the end of the study reporting period, it will be 
documented as ongoing. For purposes of regulatory safety monitoring, the investigator is 
required to follow the event to resolution and report to Vertex and Parion Sciences the outcome 
of the event using the Vertex Clinical Trials SAE Form. 
13.1.2.3 
Reporting Serious Adverse Events 
The investigator is responsible for notifying the sponsor within 24 hours of identifying an SAE, 
regardless of the presumed relationship to the investigational study drug. The Vertex Clinical 
Trial SAE Form will be completed for new/initial events as well as to report follow-up 
information on previously reported events. Investigators are asked to report follow-up 
information as soon as it becomes available to ensure timely reporting to health authorities.  
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Please send completed SAE Forms to Vertex GPS and Parion Sciences at the following: 
 
Vertex GPS 
Email: 
 
Fax: 
  
Contact Telephone: 
 
Parion Sciences 
Email: 
 
13.1.2.4 
Expedited Reporting and Investigator Safety Letters 
Vertex, as the IND sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions (SUSARs) involving the study drug(s) to all regulatory authorities and Parion Sciences.  
Parion Sciences will report these events to all participating investigators in accordance with ICH 
Guidelines and/or local regulatory requirements, as applicable. In addition, Parion Sciences, the 
study manager, or authorized designee, will be responsible for the submission of safety letters 
investigators and to central IECs.  
It is the responsibility of the investigator or designee to promptly notify the local IRB/local IEC 
of all unexpected serious adverse drug reactions involving risk to human subjects. 
13.1.3 
Adverse Device Effects 
13.1.3.1 
Definition of an Adverse Device Effect 
An adverse device effect (ADE) is an AE related to the use of an investigational medical device. 
This includes any AE resulting from insufficiencies or inadequacies in the Instructions for Use, 
the deployment, the installation, the operation, or any malfunction of the investigational medical 
device. This includes any event that is a result of a use error or intentional misuse. 
13.1.3.2 
Definition of Serious Adverse Device Effect  
A serious adverse device effect (SADE) is an ADE that: 
 Led to a death. 
 Led to a serious deterioration in health that either: 
o resulted in a life-threatening illness or injury, or 
o resulted in an injury or permanent impairment of a body structure or a body function, or 
o required in-subject hospitalization or prolongation of existing hospitalization, or 
o resulted in medical or surgical intervention to prevent life-threatening illness. 
 Led to fetal distress, fetal death, or a congenital abnormality or birth defect. 
13.1.3.3 
Reporting Adverse Device Effects 
All ADEs, including SADEs, that occur after obtaining informed consent and assent (where 
applicable), and prior to the return of the device by the subject, must be reported to Vertex GPS 
and Parion Sciences within 24 hours of identification. 
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The Adverse Device Effect Form will be completed for new/initial reports as well as to report 
follow-up information on previously reported ADEs. Investigators are asked to report follow-up 
information as soon as it becomes available.   
Please send completed Adverse Device Effect Form to Vertex GPS and Parion Sciences at 
the following: 
 
Vertex GPS 
Email: 
 
Fax: 
  
Contact Telephone: 
 
Parion Sciences 
Email: 
 
By definition, an ADE is also an AE and the investigator should also follow the documentation 
procedures outlined in Section 13.1.1.3. If the AE is also an SAE, the investigator will separately 
document and report the SAE (see Section 13.1.2.2). 
13.1.3.4 
Expedited Reporting and Investigator Safety Letters 
Vertex, as IND sponsor, is responsible for evaluating and reporting unanticipated adverse device 
effects (UADEs) involving the investigational device used in this study to all regulatory 
authorities.  Parion Sciences will report these events to all participating investigators in 
accordance with ICH Guidelines and/or local regulatory requirements, as applicable. In addition, 
Parion Sciences, the study manager, or authorized designee, will be responsible for the 
submission of safety letters to central IECs, as applicable.  
It is the responsibility of the investigator or designee to report all UADEs to their local IRB/local 
IEC, as applicable. 
 
Administrative Requirements 
13.2.1 
Ethical Considerations 
The study will be conducted in accordance with the current ICH GCP Guidelines, which are 
consistent with the ethical principles founded in the Declaration of Helsinki, and in accordance 
with local applicable laws and regulations. The IRB/IEC will review all appropriate study 
documentation to safeguard the rights, safety, and well-being of the subjects. The study will only 
be conducted at sites where IRB/IEC approval has been obtained. The protocol, Investigator’s 
Brochure, sample ICF, advertisements (if applicable), written information given to the subjects 
(including diary cards), safety updates, annual progress reports, and any revisions to these 
documents will be provided to the IRB/IEC by the investigator or Parion Sciences, the study 
manager, or authorized designee, as allowable by local applicable laws and regulations. 
13.2.2 
Subject Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from the 
subject or legal representative or guardian (if applicable), and assent will be obtained from 
pediatric subjects (if applicable), before study participation. The method of obtaining and 
documenting the informed consent and assent (if applicable) and the contents of the consent will 
comply with ICH GCP and all applicable laws and regulations and will be subject to approval by 
Parion Sciences or its designee. 
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13.2.3 
Investigator Compliance 
No modifications to the protocol will be made without the approval of both the investigator and 
Parion Sciences. Changes that significantly affect the safety of the subjects, the scope of the 
investigation, or the scientific quality of the study (i.e., efficacy assessments) will require 
IRB/IEC notification before implementation, except where the modification is necessary to 
eliminate an apparent immediate hazard to human subjects. Parion Sciences will submit all 
protocol modifications to the required regulatory authorities. 
When circumstances require an immediate departure from procedures set forth in the protocol, 
the investigator will contact Parion Sciences to discuss the planned course of action. If possible, 
contact will be made before the implementation of any changes. Any departures from protocol 
will be fully documented in the source documentation and in a protocol deviation log.  
13.2.4 
Access to Records 
The investigator will make the office and/or hospital records of subjects enrolled in this study 
available for inspection by Parion Sciences or its representative at the time of each monitoring 
visit and for audits. The records will also be available for direct inspection, verification, and 
copying, as required by applicable laws and regulations, by officials of the regulatory health 
authorities (FDA and others). The investigator will comply with applicable privacy and security 
laws for use and disclosure of information related to the research set forth in this protocol.  
13.2.5 
Subject Privacy 
To maintain subject confidentiality and to comply with applicable data protection and privacy 
laws and regulations, all CRFs, study reports, and communications relating to the study will 
identify subjects by assigned subject numbers and access to subject names linked to such 
numbers shall be limited to the site and the study doctor and shall not be disclosed to Parion 
Sciences. As required by applicable laws and regulations in the countries in which the study is 
being conducted, the investigator will allow Parion Sciences and/or its representatives access to 
all pertinent medical records to allow for the verification of data gathered in the CRFs/SAE 
forms and the review of the data collection process. The FDA and regulatory authorities in other 
jurisdictions, including the IRB/EC, may also request access to all study records, including 
source documentation, for inspection. 
For sites participating in the study in the US, and in accordance with the Health Insurance 
Portability and Accountability Act and associated regulations (HIPAA) an executed HIPAA 
authorization shall be obtained by the site from each subject (or the legal representative of the 
subject) before research activities may begin. Each HIPAA authorization shall comply with all 
HIPAA requirements including authorization allowing the site access to and use of the subject’s 
personally identifiable health information, authorization for the site to disclose such information 
to Vertex, Parion Sciences, the FDA, and other parties requiring access under the protocol, and 
statements as to the purpose for which such information may be used and for how long. 
13.2.6 
Record Retention 
The investigator will maintain all study records according to ICH GCP guidelines and/or 
applicable local regulatory requirement(s), whichever is longest, as described in the Clinical 
Trial Agreement. If the investigator withdraws from the responsibility of keeping the study 
records, custody will be transferred to a person willing to accept the responsibility and Parion 
Sciences will be notified. 
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13.2.7 
Study Termination 
At any time, Parion Sciences may terminate this study in its entirety or may terminate this study 
at any particular site. In addition, for reasonable cause, either the investigators or their 
IRBs/IECs may terminate the study at their center. 
Conditions that may lead to reasonable cause and warrant termination include, but are not limited 
to: 
 Subject or investigator noncompliance 
 Unsatisfactory subject enrollment 
 Lack of adherence to protocol procedures 
 Lack of evaluable and/or complete data 
 Potentially unacceptable risk to study subjects 
 Decision to modify drug development plan 
 Decision by the FDA or other regulatory authority 
Written notification that includes the reason for the clinical study termination is required. 
 
Data Quality Assurance 
Parion Sciences or its designated representative will conduct a study site visit to verify the 
qualifications of each investigator, inspect clinical study site facilities, and inform the 
investigator of responsibilities and procedures for ensuring adequate and correct study 
documentation. 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant. Study data for each randomized subject will be entered into a CRF by study site 
personnel using a secure, validated web-based electronic data capture (EDC) application. Parion 
Sciences will have read-only access to site-entered clinical data in the EDC application.  
Instances of missing, discrepant, or uninterpretable data will be queried with the investigator for 
resolution. Any changes to study data will be made to the CRF and documented in an audit trail, 
which will be maintained within the clinical database. 
 
Monitoring 
Monitoring and auditing procedures developed or approved by Parion Sciences will be followed 
to comply with GCP guidelines. On-site checking of the CRFs/SAE Forms for completeness and 
clarity, cross-checking with source documents, and clarification of administrative matters will be 
performed. 
The study will be monitored by Parion Sciences or its designee. Monitoring will be done by 
personal visits from a representative of Parion Sciences, or designee (study site monitor), who 
will review the CRFs/SAE Forms and source documents. The study site monitor will ensure that 
the investigation is conducted according to the protocol design and regulatory requirements. 
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Electronic Data Capture  
Parion Sciences will provide the study sites with secure access to and training on the EDC 
application sufficient to permit study site personnel to enter or correct information in the CRFs 
on the subjects for which they are responsible.  
A CRF will be completed for each enrolled study subject. It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the subject’s 
CRF. Source documentation supporting the CRF data will indicate the subject’s participation in 
the study and will document the dates and details of study procedures, AEs, other observations, 
and subject status. 
The investigator, or designated representative, will complete the CRF as soon as possible after 
information is collected.  
The audit trail entry will show the user’s identification information and the date and time of any 
correction. The investigator will provide formal approval of all the information in the CRFs, 
including any changes made to the CRFs, to endorse the final submitted data for the subjects for 
whom the investigator is responsible.  
Parion Sciences will retain the CRF data and corresponding audit trails. A copy of the final 
archival CRF in the form of a CD or other electronic media will be placed in the investigator’s 
study file. 
 
Publications and Clinical Study Report 
13.6.2 
Clinical Study Report  
A clinical study report, written in accordance with the ICH E3 Guideline, will be submitted in 
accordance with local regulations.
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Investigator Signature Page 
Protocol #: 
PS-G202 
Version #: 
6.0 
Version Date 
31 Oct 2016 
Study Title: A Phase 2a, 2-part, Randomized, Double-blind, Placebo-controlled, Incomplete 
Block Crossover Study to Evaluate the Safety and Efficacy of VX-371 Solution for 
Inhalation With and Without  Oral Ivacaftor in Subjects With Primary Ciliary Dyskinesia 
I have read Protocol PS-G202, Version 6.0 and agree to conduct the study according to its terms. 
I understand that all information concerning VX-371 and this protocol supplied to me by Parion 
Sciences Incorporated (Parion Sciences) is confidential.   
Printed Name 
Signature 
Date 
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SAP_001.pdf: 
Statistical Analysis Plan 
 
 
03.007A.01     
  
 
Page 1 of 76 
 
Sponsor Name: 
Parion Sciences Incorporated 
Protocol Number and Title: 
  
PS-G202: A Phase 2a, 2-part, Randomized, 
Double-blind, Placebo-controlled, Incomplete 
Block Crossover Study to Evaluate the Safety 
and Efficacy of VX-371 Solution for Inhalation 
With and Without Oral Ivacaftor in Subjects 
With Primary Ciliary Dyskinesia 
Protocol Version and Date: 
Version 6.0 31Oct2016 
 
1006696 
Author(s): 
 
 
 Lead Biostatistician 
SAP Version: 
 1.0 
SAP Version Date:  
24th July 2018 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Parion Sciences 
Incorporated. Acceptance of this document constitutes agreement by the recipient that no 
information contained herein will be published or disclosed without prior written authorization 
from an official of Parion Sciences Incorporated.  However, this document may be disclosed to 
appropriate Institutional Review Board and Ethics Committees or duly authorized representatives 
of a national regulatory authority under the condition that they are requested to keep it 
confidential. In the event of an actual or suspected breach of this obligation, 
 
should be notified promptly. 
 
 
Report P155, Version 1.0 
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Report P155, Version 1.0 
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TABLE OF CONTENTS 
1 
GLOSSARY OF ABBREVIATIONS ................................................................ 8 
2 
PURPOSE ..................................................................................................... 10 
2.1 
Responsibilities ................................................................................................................. 10 
2.2 
Timings of Analyses .......................................................................................................... 10 
3 
STUDY OBJECTIVES ................................................................................... 11 
3.1 
Part A................................................................................................................................... 11 
3.1.1 
Primary Objective ............................................................................................................ 11 
3.1.2 
Secondary Objective ....................................................................................................... 11 
3.2 
Part B................................................................................................................................... 11 
3.2.1 
Primary Objective ............................................................................................................ 11 
3.2.2 
Secondary Objective ....................................................................................................... 11 
3.3 
Brief Description ................................................................................................................ 11 
3.4 
Subject Selection ............................................................................................................... 12 
3.5 
Determination of Sample Size .......................................................................................... 12 
3.5.1 
Part A ............................................................................................................................... 12 
3.5.2 
Part B ............................................................................................................................... 13 
3.6 
Treatment Assignment & Blinding ................................................................................... 13 
3.7 
Administration of Study Medication ................................................................................ 14 
3.8 
Study Procedures and Flowchart ..................................................................................... 14 
4 
ENDPOINTS .................................................................................................. 16 
4.1 
Part A................................................................................................................................... 16 
4.1.1 
Primary Endpoints ........................................................................................................... 16 
4.1.2 
Secondary Endpoints ...................................................................................................... 16 
 
 
 
 
4.2 
Part B................................................................................................................................... 16 
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4.2.1 
Primary Endpoints ........................................................................................................... 16 
4.2.2 
Secondary Endpoints ...................................................................................................... 17 
 
 
 
 
5 
ANALYSIS SETS .......................................................................................... 18 
5.1 
Screened Subjects ............................................................................................................. 18 
5.2 
All Subjects Set .................................................................................................................. 18 
5.2.1 
Part A ............................................................................................................................... 18 
5.2.2 
Part B ............................................................................................................................... 18 
5.3 
Full Analysis Set ................................................................................................................ 18 
5.3.1 
Part A ............................................................................................................................... 18 
5.3.2 
Part B ............................................................................................................................... 18 
5.4 
Safety Set ............................................................................................................................ 19 
5.4.1 
Part A ............................................................................................................................... 19 
5.4.2 
Part B ............................................................................................................................... 19 
5.5 
Important Protocol Deviations ......................................................................................... 19 
6 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS ................................ 20 
6.1 
General Methods ................................................................................................................ 20 
6.2 
Key Definitions ................................................................................................................... 20 
6.2.1 
Baseline ........................................................................................................................... 20 
6.2.2 
Treatment Emergent Period ............................................................................................ 21 
6.3 
Missing Data ....................................................................................................................... 22 
6.4 
Visit Windows ..................................................................................................................... 22 
7 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION ....................................................................................................... 23 
7.1 
Subject Disposition and Withdrawals .............................................................................. 23 
7.2 
Subject Screened and Screen Failure ............................................................................. 24 
7.3 
Demographic and Other Baseline Characteristics ......................................................... 24 
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7.4 
Medical History .................................................................................................................. 25 
7.5 
Medication .......................................................................................................................... 25 
7.5.1 
Prior Medication ............................................................................................................... 25 
7.5.2 
Concomitant Medication .................................................................................................. 25 
7.5.3 
Medication during Wash-out and Follow-up Period ........................................................ 26 
7.6 
Study Drug Exposure and Compliance ........................................................................... 26 
8 
EFFICACY ..................................................................................................... 28 
8.1 
Primary Efficacy Endpoint and Analysis ......................................................................... 28 
8.2 
Secondary Efficacy Endpoints and Analyses ................................................................. 30 
 
 
 
 
8.5 
Summary of Efficacy Analyses ........................................................................................ 34 
 
 
10 
SAFETY ..................................................................................................... 38 
10.1 
Adverse Events .................................................................................................................. 38 
10.2 
Laboratory Evaluations ..................................................................................................... 40 
10.3 
Vital Signs ........................................................................................................................... 41 
10.4 
Eletrocardiogram ............................................................................................................... 41 
10.5 
Physical Examination ........................................................................................................ 41 
10.6 
Spirometry .......................................................................................................................... 41 
10.7 
Pulse Oximetry ................................................................................................................... 42 
10.8 
Summary of Safety Analysis ............................................................................................ 42 
11 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL ......................... 44 
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12 
REFERENCE LIST .................................................................................... 45 
13 
PROGRAMMING CONSIDERATIONS ...................................................... 46 
13.1 
Table, Listing, and Figure Format .................................................................................... 46 
13.1.1 
General ........................................................................................................................ 46 
13.1.2 
Headers and Footers .................................................................................................. 46 
13.1.3 
Display Titles ............................................................................................................... 47 
13.1.4 
Column Headers ......................................................................................................... 47 
13.1.5 
Body of the Data Display ............................................................................................. 48 
14 
QUALITY CONTROL ................................................................................. 51 
15 
INDEX OF TABLES ................................................................................... 52 
16 
INDEX OF LISTINGS ................................................................................. 53 
17 
INDEX OF FIGURES ................................................................................. 54 
 
 
APPENDIX III LIST OF THRESHOLD RANGE ANALYSIS CRITERIA ............... 60 
APPENDIX IV SCHEDULES OF ASSESSMENTS .............................................. 67 
APPENDIX V HANDLING MISSING DATE .......................................................... 73 
APPENDIX VI VISIT WINDOWS .......................................................................... 75 
 
 
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1 GLOSSARY OF ABBREVIATIONS 
 
Abbreviation 
Description 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CTCAE 
Common Terminology Criteria for Adverse Events 
CM 
Concomitant Medication 
CS 
Compound Symmetry 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
EU 
Europe 
FAS 
Full Analysis Set 
FEF25%-75% 
Forced Midexpiratory Flow Rate 
FEV1 
Forced Expiratory Volume in 1 Second 
FVC 
Forced Vital Capacity 
HS 
Hypertonic Saline 
IDMC 
Independent Data Monitoring Committee 
K+ 
Potassium 
max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
Minimum 
NA 
North America 
Na+ 
Sodium 
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Abbreviation 
Description 
PBO 
Placebo 
PCD 
Primary Ciliary Dyskinesia 
pp 
Percentage Predicted 
PT 
Preferred Term 
QTcF 
Corrected QT Interval by Fridericia’s Formula 
 
 
PR 
PR Interval, Segment 
QOL 
Quality of Life 
QOL-PCD 
PCD Quality of Life Questionnaire 
QRS 
The Portion of an ECG Comprising the Q, R, and S Waves, Together 
Representing Ventricular Depolarization 
QTc 
QT Interval Corrected 
QTcF 
QT Interval Corrected by Fridericia’s Formula 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SE 
Standard Error 
SGRQ 
St. George’s Respiratory Questionnaire 
SI 
Standard International System of Units 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TE 
Treatment-Emergent 
TEAE 
Treatment Emergent Adverse Event 
TLF 
Table, Listing and Figure 
ULN 
Upper Limit of Normal 
 
 
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2 PURPOSE 
The purpose of this statistical analysis plan (SAP) is to describe the planned statistical 
analyses of efficacy endpoints and safety endpoints for the final analysis. The SAP 
clarifies that analysis of Part A and Part B data will be presented separately. 
 
 
 
   
2.1 RESPONSIBILITIES 
 will perform the statistical analyses and are responsible for the production 
and quality control of all tables, figures and listings. 
2.2 TIMINGS OF ANALYSES 
The primary analysis of safety and efficacy and pharmacokinetics is planned after all 
subjects complete all three treatment periods for this study or terminate early from any 
of the treatment periods during the study. Unless otherwise specified, the analysis 
includes all data collected in the database through the time of the database lock.  
Periodic Independent Data Monitoring Committee Meetings (IDMC) have been held to 
monitor ongoing subject safety. The details of these analyses are specified in the IDMC 
charter and IDMC SAP. An unblinded team from 
 which is independent from 
the study team performed the analyses to maintain the blinding of the study. 
 
 
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3 STUDY OBJECTIVES 
3.1 PART A 
3.1.1 
Primary Objective 
To evaluate the safety and efficacy of treatment with VX-371, administered with and 
without 4.2% hypertonic saline (HS) in subjects with primary ciliary dyskinesia (PCD) 
who are ≥12 years of age. 
3.1.2 
Secondary Objective 
To evaluate the effect of VX-371, administered with and without 4.2% HS, on quality of 
life (QOL) in subjects with PCD who are ≥12 years of age. 
3.2 PART B 
3.2.1 
Primary Objective 
To evaluate the safety and efficacy of treatment with ivacaftor and VX-371, 
administered with and without 4.2% HS in subjects with PCD who are ≥12 years of age. 
3.2.2 
Secondary Objective 
To evaluate the effect of ivacaftor and VX-371, administered with and without 4.2% HS 
on QOL in subjects with PCD who are ≥12 years of age. 
3.3 BRIEF DESCRIPTION 
This is a Phase 2a, 2-part, multicenter, randomized, double-blind, placebo-controlled, 
incomplete block crossover study in subjects ≥12 years of age with PCD. Part A will 
consist of Treatment Period 1 and Treatment Period 2, separated by a Washout Period. 
Part B is optional and will consist of Treatment Period 3; subjects will complete Part A 
before beginning Part B. There will not be a Washout Period between Part A and Part B.  
Approximately 150 subjects will be randomized to 1 of 4 treatment sequences in a 
2:2:1:1 ratio in Part A, stratifying for percent predicted forced expiratory volume in 1 
second (ppFEV1) severity (<70 or ≥70) as described in Table 1. Subjects who enroll in 
Part B will have oral ivacaftor added to the treatment they were receiving in Treatment 
Period 2 of Part A, as described in Table 1.  
Table 1. 
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Part A 
Part B 
Sequence 
Treatment Period 1 
Treatment Period 2 
Treatment Period 3 
N 
1 
VX-371 in 4.2% HS 
4.2% HS 
4.2% HS + ivacaftor 
50 
2 
4.2% HS 
VX-371 in 4.2% HS 
VX-371 in 4.2% HS + ivacaftor 
50 
3 
VX-371 in 0.17% 
saline  
Placebo (0.17% saline) 
Placebo (0.17% saline) + ivacaftor 
25 
4 
Placebo (0.17% saline) 
VX-371 in 0.17% saline  
VX-371 in 0.17% saline + 
ivacaftor 
25 
 
Part A Study Duration 
Excluding the Screening Period, the planned study duration is 113 days from Day 1 to 
Safety Follow-up Telephone Call, approximately 28 days after the last dose of study 
drug.  
Part A + Part B Study Duration 
Excluding the Screening Period, the planned study duration is 141 days from Day 1 to 
Safety Follow-up Telephone Call, approximately 28 days after the last dose of study 
drug.  
3.4 
SUBJECT SELECTION 
Protocol V6.0 section 9 specifies the details of eligibility criteria. 
3.5 DETERMINATION OF SAMPLE SIZE 
3.5.1 
Part A 
The primary efficacy objective of Part A of this study is to evaluate the efficacy of VX-
371 with and without HS in subjects ≥12 years of age with PCD. For efficacy analysis, 
the statistical inferences will be based on change from study baseline. The null 
hypotheses to be tested are that the mean absolute change from study baseline in 
ppFEV1 after 28 days of treatment is the same for 1) VX-371 in HS versus placebo; 2) VX-
371 versus placebo; and 3) VX-371 in HS versus HS alone. 
To have a feasible sample size and study duration, a crossover design has been proposed 
for Part A of this study. Assuming an SD of 7 percentage points, 50 subjects each for 
Treatment Sequence 1 and Treatment Sequence 2 are needed to have approximately 
81% power to detect a 3 percentage point treatment difference in the mean absolute 
change in ppFEV1 from study baseline, after 28 days of treatment between VX-371 + HS 
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and HS alone. Part A of the study will have approximately 87% power to detect a 4-
percentage point change from baseline, after 28 days of treatment in ppFEV1 between 
VX-371 + HS and placebo. The power to detect a 3 percentage point difference between 
VX-371 and placebo is about 51%. The sample size estimate was based on 10000 
simulation runs with an incomplete block design assuming no dropouts. In the 
simulation, the correlation between responses to the 2 treatments within a subject was 
assumed to be 0. Furthermore, a 2-sided significance level of 0.05 was used in the 
sample size determination with no multiplicity adjustment. The sample size also takes 
into consideration an assumed dropout rate of 10%. 
Part A of the study will enroll approximately 150 subjects. However, as no therapeutic 
intervention study has previously been completed in PCD patients, the ability to enroll 
all 150 subjects is uncertain. Enrollment of less than 150 subjects will still provide 
useful information and could demonstrate an important difference between treatments. 
Enrollment into Part A will continue until approximately 150 subjects are randomized or 
the enrollment rate drops, despite suitable interventions, such that the planned 
enrollment cannot be achieved. 
3.5.2 
Part B  
No formal sample size calculation was performed. All subjects who completed the 
assigned treatment in Part A and who meet the eligibility criteria for Part B will be 
offered enrollment in Part B. 
3.6 TREATMENT ASSIGNMENT & BLINDING 
Approximately 150 subjects will be randomized to 1 of 4 treatment sequences in 
double-blind fashion when they are determined to have met all eligibility criteria. 
Subjects will be randomized in a 2:2:1:1 ratio, in Part A to one of the 4 treatment 
sequences, (Treatment Sequence 1 or Treatment Sequence 2; Treatment Sequence 3 or 
Treatment Sequence 4), stratifying for ppFEV1 severity (<70 or ≥70). Randomization 
must only occur after all inclusion and exclusion criteria are met and before the first 
dose of inhaled study drug is administered in Part A on Day 1.  
An interactive web or voice response system (IXRS) will be used to assign subjects to 
treatment based a centralized randomization scheme. The randomization code will be 
produced by 
. The Parion Sciences study biostatistician, or designee, will 
review and approve the dummy randomization list. The final randomization list will be 
reviewed and approved by a designated unblinded 
 biostatistician responsible for the 
IDMC analyses to maintain the study blind throughout the course of the study until the 
final database lock. 
There is no randomization in Part B. Subjects will remain in the same treatment as in 
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Treatment Period 2 of Part A and will also receive open-label oral ivacaftor. 
3.7 ADMINISTRATION OF STUDY MEDICATION 
Protocol V6.0 section 10 specifies the details of study drug administration. 
 
3.8 
STUDY PROCEDURES AND FLOWCHART 
A schematic of the study design is provided below: 
 
 
This study includes the following: 
1. Screening Period: Day of Screening Visit until Day 1 (first dose of study drug). 
The Screening Visit can occur Day -38 to Day -5, relative to the first dose of 
study drug 
2. Treatment Periods: 
Part A: 
 
Treatment Period 1: Day 1 (first dose of study drug) through Day 29 (28 days of 
treatment) 
 
Washout Period: Day 29 through Day 56 (28 days) 
 
Treatment Period 2: Day 57 through Day 85 (28 days of treatment) 
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Part B (Optional): 
 
Treatment Period 3: Day 85 (first dose of oral ivacaftor) through Day 113 (28 
days of treatment) 
3. Safety Follow-up Period: 28 days (± 7 days) after the last dose of study drug. 
If the subject prematurely discontinues study drug, an Early Termination of Treatment 
(ETT) Visit should be scheduled as soon as possible after the subject decides to 
terminate study drug treatment. Subjects who prematurely discontinue treatment will 
also be required to complete the Safety Follow-up Telephone Call approximately 28 
days (± 7 days) after their last dose of study drug. 
If the subject meets the criteria for study participation and is taking HS at the time of 
Screening, the subject will be instructed to stop their usual regimen of inhaled HS for 
the duration of the study, beginning at least 28 days before the first dose of study drug 
in the study and continued through completion of the last study visit. If a subject is not 
taking HS as part of their ongoing PCD treatment, the Day 1 Visit may be scheduled to 
occur as soon as 5 days after the Screening Visit, provided that results of all screening 
procedures have been received. Each subject will be instructed to use an appropriate 
airway clearance technique throughout the study. 
Schedules of Assessments are shown in Appendix IV Table 5, Table 6 and Table 7 
 
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4 ENDPOINTS 
4.1 PART A  
4.1.1 
Primary Endpoints 
 
Results of safety and tolerability assessments of adverse events (AEs), clinical 
laboratory values (urine, serum and plasma chemistry, and hematology), 12-lead 
electrocardiograms (ECGs), spirometry, vital signs, and pulse oximetry 
 
Absolute change in ppFEV1 from study baseline, after 28 days of treatment in 
Part A 
4.1.2 
Secondary Endpoints 
 
Change in QOL score as measured by the Quality of Life-PCD Questionnaire (QOL-
PCD) and the St. George’s Respiratory Questionnaire (SGRQ)[1] from study 
baseline, after 28 days of treatment in Part A 
4.2 PART B 
4.2.1 
Primary Endpoints 
 
Results of safety and tolerability assessments of AEs, clinical laboratory values 
(urine, serum and plasma chemistry, and hematology), 12-lead ECGs, 
spirometry, vital signs, and pulse oximetry 
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 
Absolute change in ppFEV1, from study baseline and Part B baseline after 28 
days of treatment in Part B 
4.2.2 
Secondary Endpoints 
 
Change in QOL score as measured by the QOL-PCD and SGRQ from study baseline 
and Part B baseline, after 28 days of treatment in Part B 
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5 ANALYSIS SETS 
5.1 SCREENED SUBJECTS  
Screened subject for Part A is defined as any subject who signed the study specific 
informed consent and had at least one study procedure performed during the screening 
period. 
5.2 ALL SUBJECTS SET 
5.2.1 Part A 
The Part A All Subjects Set is defined as all subjects who were randomized or received 
at least 1 dose of study drug in Part A. Part A subject data listings will be referenced 
using the Part A All Subjects Set, unless otherwise specified. 
5.2.2 Part B 
The Part B All Subjects Set is defined as all subjects who enrolled (signed the Part B 
informed consent) in Part B. 
5.3 FULL ANALYSIS SET  
5.3.1 Part A 
The Part A Full Analysis Set (FAS) is defined as all randomized subjects who received at 
least 1 dose of study drug in Part A and had a confirmed diagnosis of PCD. The Part A 
FAS subjects will be analyzed according to the treatment to which they were assigned in 
each period of Part A. Data for a period will be used provided that the subject received 
at least 1 dose of study drug in that Treatment Period. 
5.3.2 Part B  
The Part B FAS is defined as all subjects who had a confirmed diagnosis of PCD and 
received at least 1 dose of ivacaftor in Part B. The Part B FAS subjects will be analyzed 
according to the treatment as enrolled in Part B, which is ivacaftor plus the same 
treatment as assigned in Part A Treatment Period 2.  
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5.4 SAFETY SET 
5.4.1 Part A 
The Part A Safety Set is defined as all subjects who received at least 1 dose of study 
drug in Part A. The Part A Safety Set subjects will be analyzed according to the 
treatment they received in each period of Part A. Data for a period will be used 
provided that the subject received at least 1 dose of study drug in that Treatment 
Period. 
5.4.2 Part B 
The Part B Safety Set is defined as all subjects who received at least 1 dose of ivacaftor 
in Part B. The Part B Safety Set subjects will be analyzed according to the treatment 
they actually received in Part B. 
5.5 IMPORTANT PROTOCOL DEVIATIONS 
An important protocol deviation (IPD) is a deviation that may significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect 
a subject’s rights, safety, or well-being.  IPD rules will be developed and finalized prior 
to the database lock. 
The protocol deviations that should be considered as potential IPDs include, but are not 
limited to: 
 
Subject was randomized despite the violation of inclusion/exclusion criteria 
 
Subject was less than 80% compliant with study drug 
 
Subject received prohibited concomitant medications 
 
Subject received the wrong treatment or incorrect doses  
 
Subject remained in the study despite meeting withdrawal criteria 
Occurrence of any of these events should be considered as potential IPDs, but a blinded 
team should categorize them as IPDs only if they have the potential to significantly 
affect the completeness, accuracy, or reliability of the study data or that may 
significantly affect a subject’s rights, safety, or well-being. 
IPDs (from the clinical database or from the site deviation log) will be summarized 
descriptively based on the FAS and presented by treatment sequence in Part A and by 
treatment in Part B.  Additionally, IPDs will be provided in an individual subject data 
listing. 
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6 GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
6.1 GENERAL METHODS 
All analyses will be implemented using SAS Version 9.3 or higher. Data summaries will 
be presented by treatment . All data will be listed. 
Continuous variables will be summarized using the following descriptive summary 
statistics: number of subjects (n), mean, SD, median, minimum value (min), and 
maximum value (max).  
Categorical variables will be summarized using counts and percentages. Percentages 
will be presented to 1 decimal place. 
General rules of precision are as follows: 
 
Minimum and maximum values will be reported with the same precision as the 
reported measurement unless otherwise specified. For the calculated variables, 
two decimal places will be reported. 
 
Mean and median will be reported to 1 greater decimal place than the precision 
of the reported measurement unless otherwise specified. 
 
Standard deviation and standard error (to indicate standard error of an estimate 
from a statistical model) will be reported to 1 greater decimal place than the 
corresponding mean.  
 
Report p-values to 4 decimal places; report as “<0.0001”, when applicable.  
 
In general, the precision of mean, LS Mean, and 95% CI for a variable is the 
same, unless otherwise specified. 
6.2 KEY DEFINITIONS 
6.2.1 Baseline 
Two types of baseline will be defined for Part A. The study baseline is defined as the 
most recent nonmissing measurement (scheduled or unscheduled) collected before the 
first dose of study drug in the study. The definition will be applied to all demographics, 
background, and baseline characteristics and efficacy data analyses, including the 
primary endpoint analysis. The period baseline is defined as the most recent non-
missing measurement (scheduled or unscheduled) collected before the first dose of 
study drug in each Treatment Period. For Part A Treatment Period 2, the period 
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baseline will be the first assessment measured after treatment-emergent (TE) period for 
Period 1. This definition will be applied to all safety data analyses.  
For spirometry analysis in Part A, if Period 1 day 1 pre-dose data is not available, data 
collected at the screening visit before the test HS dose will be used as Period 1 baseline 
or study baseline instead of the last non-missing screening visit after the test HS dose. 
For weight, height and BMI, study baseline and Period 1 baseline will be defined as the 
most recent non-missing measurement (scheduled or unscheduled) collected before or 
on the day of the first dose of study drug in Part A, Period 1. Similarly, Period 2 baseline 
will consider the most recent non-missing measurement (scheduled or unscheduled) 
collected after the TE period for Period 1 and before or on the day of first dose of study 
drug in Part A, Period 2. 
For SGRQ and QOL-PCD, study baseline will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before or on the day of the first 
dose of study drug in Part A, Period 1. 
For Part B, two types of baseline, study baseline and Part B baseline, will be defined. 
The study baseline is defined the same as study baseline for Part A. The Part B baseline 
is defined as the most recent non-missing measurement (scheduled or unscheduled) 
collected before the first dose of ivacaftor in Part B and after the last dose in Period 2. 
 
Change/Absolute change from study baseline in Part A and Part B will be 
calculated as:  
post-baseline value – study baseline value. 
 
Change/Absolute change from period baseline in Part A will be calculated as: 
post-baseline value – period baseline value. 
 
Change/Absolute change from Part B Baseline will be calculated as:  
post-baseline value - Part B baseline value 
For weight, height and BMI, SGRQ and QOL-PCD, Part B baseline will be defined as the 
most recent non-missing measurement (scheduled or unscheduled) collected before or 
on the day of the first dose of ivacaftor in Part B and after the last dose in Period 2. 
6.2.2 Treatment Emergent Period 
Treatment-emergent (TE) period for Part A Treatment Period 1:  
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 
The Treatment-Emergent Period will correspond to the interval from the first 
dose date of Treatment Period 1 to 28 days after the last dose date of 
Treatment Period 1 or the date before the first dose date of Treatment Period 2 
or the safety follow-up visit, whichever occurs earlier. 
TE period for Part A Treatment Period 2:  
 
The treatment emergent period will correspond to the interval from the first 
dose date of Treatment Period 2 to 28 days after the last dose date of 
Treatment Period 2 or the date before the first dose date of Part B or the safety 
follow-up visit, whichever occurs earlier.  
Treatment-Emergent Period for Part B: 
 
The treatment emergent period will correspond to the interval from the first 
dose date of study drug in Part B to 28 days after the last dose date of Part B or 
the safety follow-up visit, whichever occurs earlier. 
6.3 MISSING DATA 
Imputations for missing or partially missing start/end dates for prior/concomitant 
medications and adverse events are described in Appendix V. 
Imputation for missing individual QOL-PCD scores is described in Appendix II. 
No other imputations will be performed for missing data. Observed data will be used in 
the analyses. 
6.4 VISIT WINDOWS 
Visit windows can be found in Appendix VI 
 
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7 DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION 
7.1 SUBJECT DISPOSITION AND WITHDRAWALS 
Part A 
The number of subjects in the following categories will be presented by treatment 
group:  
 
All Subjects Set (randomized or dosed) 
 
Randomized (defined as subjects who were assigned a treatment sequence but 
have not necessarily taken a dose of study drug). 
 
Randomized but not dosed 
 
Full Analysis Set (FAS) 
 
Safety Set 
The number of subjects in the following categories will be presented by treatment 
group for each period (Period 1 and Period 2):  
 
Full Analysis Set (FAS) 
 
Safety Set 
The number and percentage (based on Part A FAS) of subjects in each of the following 
disposition categories will be presented by treatment group for each period (Period 1 
and Period 2): 
 
Completed treatment regimen 
 
Prematurely discontinued the treatment and the reasons for discontinuation  
 
Prematurely discontinued the study and the reasons for discontinuation  
The number and percentage (based on the overall FAS) of subjects in each of the 
following disposition categories will be presented by treatment group: 
 
Completed treatment regimen in both periods 
 
Completed study in Part A 
 
Rolled-over to Part B 
A listing of subjects who discontinued study or discontinued treatment regimen for Part 
A will be provided. 
Part B 
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The number of subjects in the following categories will be presented by treatment 
group and overall:  
 
Full Analysis Set (FAS) 
 
Safety Set 
The number and percentage (based on Part B FAS) of subjects in each of the following 
disposition categories will be presented by treatment group and overall: 
 
Completed Part B study drug treatment  
 
Prematurely discontinued Part B study drug treatment and the reasons for 
discontinuation 
 
Completed study in Part B 
 
Prematurely discontinued the study in Part B and the reasons for discontinuation 
A listing of subjects who discontinued study or discontinued treatment regimen for Part 
B will be provided. 
7.2 SUBJECT SCREENED AND SCREEN FAILURE 
Screen failure for Part A is defined as any screened subject who was not dosed with 
study drug. 
Number of screened subjects and number and percentages of screen failures will be 
summarized, and all screen failures will be listed with their corresponding screen failure 
reason. 
A listing for randomized but not dosed subjects (a subset of screen failure subjects) will 
be provided. 
7.3  DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic and baseline characteristics will be summarized for Part A and Part B.  
The following demographics and study baseline characteristics will be summarized by 
Period 1 treatment and Period 2 treatment for Part A FAS and overall, treatment for 
Part B FAS and overall: sex, child bearing potential, race, ethnicity, age at baseline, age 
(<18 years old), weight, height, body mass index (BMI), region (North America and 
Europe), study baseline ppFEV1, nNO measurement (nNO level 1 and nNO level 2), 
laterality defect, ciliary ultrastructure defect, and PCD genetic mutation.  
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In addition, Part B baseline characteristics will also be summarized based on Part B FAS 
by treatment group and overall, including age at Part B baseline, weight, height, BMI 
and ppFEV1. 
7.4 MEDICAL HISTORY  
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), Version: 18.1. 
Medical history data will be summarized by Period 1 treatment and Period 2 treatment 
for Part A FAS and by treatment for Part B FAS.  
7.5 MEDICATION 
Medications will be coded using World Health Organization (WHO) DRUG dictionary, 
Version: WhoDrugDDEB2 201512 (ENG). 
7.5.1 Prior Medication 
Prior medication is defined as any medication that has a start date before the first dose 
of study drug in Part A, regardless of when it ended. 
If the medication end date is before the date of first dose of study drug, then the 
medication will be summarized as prior medication regardless of whether the 
medication start date is missing or not. 
Prior medications will be summarized by ATC level 1 and 2 term, preferred term (PT) 
and treatment for Part A and Part B separately.  
7.5.2 Concomitant Medication 
Concomitant medication is defined as any medication that is continued or newly 
received during the Treatment-Emergent (TE) period for Part A, or Part B.  
A medication that starts/ends on or after the start date of the Treatment Emergent 
Period, up through and before the start date of the next Treatment Emergent Period, 
will be assigned to the treatment group associated with the current Treatment 
Emergent Period.  
For the cases when Treatment Emergent Period 2 end of dosing is on the same day as 
the Treatment Emergent Period for Part B start of dosing date, any medication starting 
on the same day as the Treatment Emergent Period for Part B start of dosing date, will 
be assigned to the treatment in Period for Part B. 
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A given medication can be classified as a prior medication, a concomitant medication, 
or both prior and concomitant. If a medication has a missing or partial missing start/end 
date and it cannot be determined whether the medication was taken before initial 
dosing or concomitantly, it will be considered as prior and concomitant, and this 
medication will be assigned to all treatment groups.  
If the start date of the medication is the same as the date of the first dose date of the 
study drug in Period 1, then the medication is classified as a concomitant medication 
and will be assigned to Period 1 treatment group. 
Concomitant medications will be summarized by ATC level 1 and 2 term and preferred 
term (PT). Part A concomitant medications will be summarized by treatment based on 
the Part A FAS, and Part B concomitant medications will be summarized by treatment 
based on the Part B FAS.  
7.5.3 Medication during Wash-out and Follow-up Period 
The medication will also be summarized and listed for wash-out period and follow-up 
period overall. Washout Period will start on the day after the last dose date in Period 1 
and end on the day before dosing in Period 2. Follow-up Period will start on the day 
after the last dose of study drug in the study. 
7.6 STUDY DRUG EXPOSURE AND COMPLIANCE 
Exposure to study drug (i.e., duration of treatment) will be summarized by treatment 
for the Part A FAS and the Part B FAS in terms of duration of treatment a subject 
received (in days), defined as:  
 
If a patient takes the first dose of study drug in the morning and the last dose of 
study drug in the afternoon, then exposure (days) will be defined as: last day of 
study drug – first day of study drug + 1 
 
If a patient takes the first dose of study drug in the morning and the last dose of 
study drug in the morning, then exposure (days) will be defined as: last day of 
study drug – first day of study drug + 0.5 
 
If a patient takes the first dose of study drug in the afternoon and the last dose 
of study drug in the morning, then exposure (days) will be defined as: last day of 
study drug – first day of study drug 
 
If a patient takes the first dose of study drug in the afternoon and the last dose 
of study drug in the afternoon, then exposure (days) will be defined as: last day 
of study drug – first day of study drug + 0.5  
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Study drug compliance will be summarized by treatment based on Part A FAS and Part B 
FAS. Study drug compliance will be calculated for each treatment as follows: 
100 × [(Total number of vials dispensed – the total number of unused vials returned – 
the total number of vials reported as lost or wasted in a Treatment Period) / (Duration 
of study drug exposure in the corresponding Treatment Period times 2)]. 
For Part B ivacaftor, compliance will be calculated as follows: 
100 × [(Total number of tablets dispensed – the total number of unused tablets returned 
– the total number of tablets reported as lost or wasted in a Treatment Period) / 
(Duration of study drug exposure in the corresponding Treatment Period times 2)]. 
Duration of treatment and study drug compliance will be summarized by descriptive 
summary statistics by treatment. A separate categorical summary will be provided for 
the count and percent of subjects with the following compliance levels: <80% and 
>=80%. 
 
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8 EFFICACY 
For Part A efficacy analysis, the statistical inference will be based on change from study 
baseline. For Part B efficacy analysis, the statistical inference will be based on change 
from study baseline and change from Part B baseline. The change from study baseline 
will provide an assessment of the overall ivacaftor+VX-371 with and without HS effect. 
The change from Part B baseline will provide an assessment of additional effect of 
ivacaftor on top of the treatment in Part A treatment period 2 assuming that the effect 
of treatment in Part A treatment period 2 is stabilized by the time of ivacaftor 
treatment in Part B.  
All Part A efficacy summaries and analyses will be based on the Part A FAS, and all Part 
B efficacy summaries and analyses will be based on the Part B FAS unless otherwise 
specified.  
8.1 PRIMARY EFFICACY ENDPOINT AND ANALYSIS 
Part A  
The primary efficacy endpoint for Part A is the absolute change in ppFEV1 from study 
baseline, after 28 days of treatment in each Treatment Period of Part A. 
The null hypotheses to be tested are that the mean absolute change from study baseline 
in ppFEV1 after 28 days of treatment is the same for 1) VX-371 in HS versus placebo; 2) 
VX-371 versus placebo; 3) VX-371 in HS versus HS alone. The primary assessment of 
efficacy will be based on the comparison of VX-371 in HS versus HS alone. 
The primary efficacy analysis is based on a mixed-effects model. This model will include 
the absolute change from study baseline in ppFEV1 after 28 days (Visit Day 29 for Period 
1 and Day 85 for Period 2) of treatment as the dependent variable, treatment and 
period as fixed effects, study baseline as a covariate, and subject as a random effect. 
The within-subject covariance will be assumed to have the compound symmetry (CS) 
structure. Denominator degrees of freedom for the F-test for fixed effects will be 
estimated using the Kenward-Roger approximation. No imputation of missing data will 
be done.  
The estimated mean of the dependent variable, a 95% CI, and a 2-sided p-value will be 
provided for each treatment. There will be no adjustment for multiplicity. Similarly, 
the estimated between-treatment differences along with the corresponding 95% CI and 
2-sided p-values will be presented. 
A sample SAS code is provided below: 
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Waterfall plot of the change from study baseline in ppFEV1 at Day 29 will be plotted by 
treatment group. 
Summary statistics for the actual values and absolute changes from study baseline in 
pre-dose ppFEV1 will be summarized descriptively by treatment and visit based on Part 
A FAS.  
In addition, the actual values and absolute changes at post-HS screening from pre-HS 
screening visit as well as actual values and absolute changes at Day 1 post-dose from 
Day 1 pre-dose in each period will be summarized based on Part A Safety Set and Part B 
Safety Set.  
 
 
  
 
 
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Part B  
For the Part B primary efficacy endpoints, absolute changes in ppFEV1 from study 
baseline and from Part B baseline, after 28 days of treatment in Part B, descriptive 
summary statistics will be provided. 
The absolute change from study baseline in ppFEV1 at Day 29 of Part B (Visit Day 113) 
will be analyzed using an Analysis of Covariance (ANCOVA) model with treatment as an 
independent variable and study baseline as well as treatment-by-study baseline 
interaction as covariate. The same model will be repeated using the Part B baseline 
instead. The LS means along with the 95% CIs and the within-treatment 2-sided P-values 
will be provided by treatment group. An overall estimate of the mean change across the 
treatment groups will also be provided with sample size for each treatment group as the 
weight. 
Waterfall plot of the absolute change from study baseline and Part B baseline in ppFEV1 
at Day 29 will be plotted by treatment group. 
8.2 SECONDARY EFFICACY ENDPOINTS AND ANALYSES 
Part A  
SGRQ: 
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The SGRQ will have three domains (Symptoms, Activity, Impacts) and Total for age 
groups ≥ 16 
 
  
SGRQ total score for 
 will be analyzed using similar analyses as described 
in Section 8.1 Part A including mixed effect model and waterfall plot. Note that the 
mixed effect model will use study baseline for ppFEV1 as a baseline covariate. 
 
 
 
 
The summary statistics for the actual values and absolute changes from study baseline 
will be obtained for SGRQ total score 
. 
QOL-PCD: 
The QOL-PCD 
 – adult version, 
 
 
 
 
 
 Subjects aged 18 years and older at 
Day 1 of Part A will complete the Adult version of the questionnaire themselves at all 
visits.
 
 
 
 
 
 
 
 
 
The Lower Respiratory Symptoms domain focuses on lung symptoms and the treatments 
evaluated in this study are targeted toward the lungs. 
QOL-PCD Lower Respiratory Symptoms domain for each QOL-PCD questionnaire version 
will be analyzed using similar analyses for mixed effect model and waterfall plot as 
described in Section 8.1 Part A. Note that the mixed effect model will use study 
baseline for ppFEV1 as a baseline covariate. 
 
 
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The summary statistics for the actual values and absolute changes from study baseline 
will be obtained for Lower Respiratory Symptoms domain for 
 QOL-PCD 
questionnaire 
. 
Part B 
For the Part B secondary efficacy endpoint, the analysis will be based on change from 
study baseline as well as change from Part B baseline. 
SGRQ: 
SGRQ total score 
 will be analyzed using ANCOVA model and waterfall 
plot as described in Section 8.1 Part B.  
The summary statistics for the actual values and absolute changes from study baseline 
and changes from Part B baseline will be obtained for SGRQ total score 
 
. 
QOL-PCD: 
QOL-PCD Lower Respiratory Symptoms domain for 
 QOL-PCD questionnaire 
 
will be analyzed using ANCOVA model and waterfall plot as described in Section 8.1 Part 
B.  
The summary statistics for the actual values and absolute changes from study baseline 
and from Part B baseline will be obtained for Lower Respiratory Symptoms domain for 
 QOL-PCD questionnaire 
. 
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8.5 SUMMARY OF EFFICACY ANALYSES 
Table 2 below shows a brief summary of the efficacy analyses aforementioned in 
Section 8. 
Table 2. 
Summary of efficacy analysis 
Part A: 
Name 
Endpoint 
Analyses 
Primary 
efficacy 
endpoint and 
analysis 
Absolute change in ppFEV1 
from study baseline at Day 29 
within each treatment Period 
- 
Mixed-effects model 
- 
Waterfall plot 
 
 
- 
 
Secondary 
efficacy 
endpoint and 
analysis - 
SGRQ 
Change in SGRQ total score 
from study baseline, after 28 
days of treatment in Part A 
For SGRQ total score: 
- 
Mixed-effects model 
- 
Waterfall plot 
- 
Descriptive analysis 
- 
 
Secondary 
efficacy 
endpoint and 
analysis – 
QOL-PCD 
Change in QOL-PCD Lower 
Respiratory Symptoms domain 
score from study baseline, 
after 28 days of treatment in 
Part A 
For QOL-PCD Lower Respiratory 
Symptoms domain: 
- 
Mixed-effects model 
- 
Waterfall plot 
- 
Descriptive analysis 
- 
 
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Part B: 
Name 
Endpoint 
Analyses 
Primary 
efficacy 
endpoint and 
analysis 
Absolute change in ppFEV1 
from study baseline and Part 
B baseline at Day 29 
- 
ANCOVA model 
- 
Waterfall plot 
- 
Descriptive analysis 
Secondary 
efficacy 
endpoint and 
analysis - 
SGRQ 
Change in SGRQ total score 
from study baseline and Part 
B baseline, after 28 days of 
treatment in Part B 
For SGRQ total score: 
- 
ANCOVA model 
- 
Waterfall plot 
- 
Descriptive analysis 
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Secondary 
efficacy 
endpoint and 
analysis – 
QOL-PCD 
Change in QOL-PCD Lower 
Respiratory Symptoms domain 
score from study baseline and 
Part B baseline, after 28 days 
of treatment in Part B 
For QOL-PCD Lower Respiratory 
Symptoms domain: 
- 
ANCOVA model 
- 
Waterfall plot 
- 
Descriptive analysis 
 
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10 SAFETY 
All safety analyses will be based on the set of data associated with the treatment 
emergent period for Part A Treatment Period 1, the treatment emergent period for Part 
A Treatment Period 2, and the treatment emergent period for Part B. Part A safety 
analyses will be based on the Part A Safety Set. The summaries will be by treatment 
received in Part A. Part B safety analyses will be based on the Part B Safety Set. The 
summaries will be provided by treatment received in Part B. For subjects receiving 
study drug from more than one treatment group in the same treatment period for Part 
A, the treatment group allocation will be determined using the following order: VX-371 
+ HS > VX-371 + Placebo > HS > Placebo. 
 
For safety analysis, the period baselines will be used for Part A and the Part B baseline 
will be used for Part B. The overall safety profile of study drug will be assessed in terms 
of the following safety and tolerability endpoints: 
 
Treatment-emergent adverse event (TEAEs) 
 
Clinical laboratory values (i.e., urine, serum and plasma chemistry, and 
hematology) 
 
ECG results 
 
Spirometry 
 
Vital signs 
 
Pulse oximetry 
10.1 ADVERSE EVENTS 
For analysis purposes, AEs will be classified as pre-treatment adverse events (AEs) or 
TEAEs, defined as follows:  
Pre-treatment AEs are defined as any AEs that started before the initial dosing of study 
drug. 
TEAE: any AE that increased in severity or that was newly developed during the 
treatment emergent period for Part A Treatment Period 1 or Part A Treatment Period 2 
or Part B. An AE that starts (or increases in severity) during a specific Part A Treatment 
Period or Part B will be attributed to the study drug the subject was receiving during 
the corresponding Part A Treatment Period or Part B. 
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For AEs with missing or partial start date, if there is no clear evidence that the AEs 
started (or increased in severity) before the first dose of Part A, the start date will be 
imputed to the first dosing date of Part A and the AE assigned to the treatment in Part A 
Treatment Period 1. For AEs with missing or partial start date, if there is no clear 
evidence that the AEs started (or increased in severity) before the first dose of Part B, 
the start date will be imputed to the first dosing date of Part B and the AE assigned to 
the treatment in Part B.  
For the cases in which the end of treatment emergent Period 2 is on the same day as 
the start of treatment emergent Period for Part B, any AE starting on the same day as 
start of treatment emergent Period for Part B, will be assigned to the treatment in Part 
B. 
AE summary tables for Part A and B will be presented for TEAEs only and will include 
the following: 
 
All TEAEs 
 
TEAEs by worst/highest relationship (includes Related, Possibly Related, Unlikely 
Related and Not Related) 
 
TEAEs by maximum severity (includes Mild, Moderate, Severe, and Life 
threatening) 
 
TEAEs leading to treatment discontinuation 
 
TEAEs leading to drug interruption 
 
Serious TEAEs 
 
TEAEs leading to death 
 
Frequently reported TEAEs 
A frequently reported TEAE is defined as more than 2 subjects who have TEAE preferred 
term incidence for at least 1 treatment group. 
Summaries will be presented by treatment and by MedDRA (version 18.1) system organ 
class (SOC) and preferred term using frequency counts and percentages (i.e., number 
and percentage of subjects with an event). When summarizing the number and 
percentage of subjects with an event, subjects with multiple occurrences of the same 
AE or a continuing AE will be counted once, only the maximum severity level will be 
presented in the severity summaries, and the worst/highest relationship level in the 
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relationship summaries. An AE overview table will be provided for the following 
categories: 
 
TEAEs 
 
Related TEAEs (includes Related and Possibly Related)  
 
Serious TEAEs 
 
Related Serious TEAEs 
 
TEAEs Leading to Study Drug Interruption 
 
TEAEs Leading to Study Drug Discontinuation 
 
TEAEs with Outcome of Death 
In addition, a listing containing individual subject AE data for all deaths and other 
serious AEs will be provided separately for Part A and Part B. All AEs, including pre-
treatment AEs, will be presented in individual subject data listings.  
TEAEs related to study device will also be summarized by system organ class and 
preferred term using frequency counts and percentages (i.e., number and percentage of 
subjects with an event). 
10.2 LABORATORY EVALUATIONS 
The actual values and absolute changes from Part A period baseline and Part B baseline 
for the continuous laboratory parameters will be summarized in SI units by treatment at 
each scheduled visit for Part A and Part B respectively.  
The number and percentage of subjects with at least 1 laboratory abnormality meeting 
the threshold analysis criteria during the Treatment Emergent Period for Part A and Part 
B will be summarized by treatment. The Thresholds Range Analyses criteria are 
provided in Appendix III. 
Results of urinalysis and serum/urine pregnancy tests will be listed in individual subject 
data listings only. In addition, a listing containing individual subject laboratory 
measurements outside the reference ranges will be provided. This listing will include 
data from scheduled and unscheduled time points. 
Urine sodium, potassium and urine sodium to potassium ratios will be summarized by 
treatment. 
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Serum potassium exceeding 1.1 * upper limit of normal (ULN) and/or plasma potassium 
exceeding 1.1 * ULN will also be summarized and listed. 
10.3 VITAL SIGNS  
The actual values and absolute changes from Part A period baseline and Part B baseline 
for the following vital signs measurements will be presented by treatment at each 
scheduled visit for Part A and Part B respectively: systolic and diastolic blood pressure 
(mm Hg), body temperature, pulse rate (beats per minute), respiratory rate (breaths 
per minute), weight (kg), height (cm) and BMI (kg/m2). The number and percentage of 
subjects with at least 1 threshold analysis event during the treatment emergent period 
will also be tabulated.  
The Thresholds Range Analyses criteria are provided in Appendix III. 
10.4 ELETROCARDIOGRAM  
A summary of actual values and absolute changes from Part A period baseline and Part B 
baseline will be provided by treatment at each scheduled visit for Part A and Part B 
respectively for the following electrocardiogram (ECG) measurements: ventricular heart 
rate, QRS duration, PR duration, QT duration, RR interval, QTcF. In addition, the 
number and percentage of subjects with at least 1 threshold analysis event during the 
treatment emergent period will also be tabulated.  
The Thresholds Range Analyses criteria are provided in Appendix III. 
10.5 PHYSICAL EXAMINATION 
For Part A and Part B, abnormal physical examination results will be presented in 
individual subject data listings only.  
10.6 SPIROMETRY 
Spirometry data in Part A  and Part B will be summarized based on the Part A Safety Set 
and Part B Safety Set respectively. This will include the number and percentage of 
subjects at each scheduled time point relative to Part A period baseline value and Part 
B Baseline value for the following: 
 
Subjects with ≥10 percentage point decrease in ppFEV1 
 
Subjects with ≥15 percentage point decrease in ppFEV1 
 
Subjects with ≥ 20 percentage point decrease in ppFEV1 
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 
Subjects with ≥ 0.2 L decrease in FEV1 
10.7 PULSE OXIMETRY 
The summary of actual values and absolute changes from Part A period baseline values 
and Part B period baseline will be presented by treatment at each scheduled time point 
for the percent of oxygen saturation by pulse oximetry for Part A and Part B 
respectively. 
The number and percentage of subjects with shift changes from Part A period baseline 
and Part B baseline (normal/missing and low: Normal oxygen saturation: >95%, low 
oxygen saturation: <=95%) to the lowest percent of oxygen saturation during the Part A 
and B treatment emergent period will be tabulated by treatment. 
10.8 SUMMARY OF SAFETY ANALYSIS 
Table 3 below shows a brief summary of the safety analyses aforementioned in Section 
10. 
Table 3. 
Summary of safety analysis 
Part A: 
Name 
Analyses 
Adverse event 
Frequency of TEAEs for different categories 
Laboratory 
Using Period 1 and Period 2 Baseline: 
- 
Descriptive analysis 
- 
Threshold range analysis 
- 
Descriptive analysis for urine sodium, potassium and urine 
sodium to potassium ratios 
Vital sign 
Using Period 1 and Period 2 Baseline:  
- 
Descriptive analysis 
- 
Threshold  analysis 
Eletrocardiogram Using Period 1 and Period 2 Baseline:  
- 
Descriptive analysis 
- 
Threshold analysis 
Spirometry 
Using Period 1 and Period 2 Baseline:  
- 
Frequency of pre-specified ppFEV1 and FEV1 categories 
Pulse Oximetry 
Using Period 1 and Period 2 Baseline:  
- 
Descriptive analysis 
- 
Shift table 
Part B: 
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Name 
Analyses 
Adverse event 
Frequency of TEAEs for different categories 
Laboratory 
Using Part B Baseline:  
- 
Descriptive analysis 
- 
Threshold range analysis 
- 
Descriptive analysis for urine sodium, potassium and urine 
sodium to potassium ratios 
Vital sign 
Using Part B Baseline:  
- 
Descriptive analysis 
- 
Threshold  analysis 
Eletrocardiogram Using Part B Baseline:  
- 
Descriptive analysis 
- 
Threshold analysis 
Spirometry 
Using Part B Baseline:  
- 
Frequency of pre-specified ppFEV1 and FEV1 categories 
Pulse Oximetry 
Using Part B Baseline:  
- 
Descriptive analysis 
- 
Shift table 
 
 
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11 CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
Not applicable  
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12 REFERENCE LIST 
[1] St George’s respiratory questionnaire Manual, June 2009. 
 
 
 
[3] Laura Behan, Margaret W Leigh, Sharon D Dell, Audrey Dunn Galvin, Alexandra L 
Quittner, Jane S Lucas. Validation of a health-related quality of life instrument 
for primary ciliary dyskinesia (QOL-PCD). Thorax 2017 
 
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13 PROGRAMMING CONSIDERATIONS 
13.1 TABLE, LISTING, AND FIGURE FORMAT 
13.1.1 
General 
 
All TLFs will be produced in landscape format, unless otherwise specified. 
 
All TLFs will be produced using the Courier New font, size 9  
 
The data displays for all TLFs will have a 1-inch binding margin on top of a 
landscape oriented page and a minimum 1-inch margin on the other 3 sides. 
 
Headers and footers for figures will be in Courier New font, size 8. 
 
Legends will be used for all figures with more than 1 variable, group, or item 
displayed. 
 
TLFs will be in black and white (no color), unless otherwise specified 
 
Specialized text styles, such as bolding, italics, borders, shading, and 
superscripted and subscripted text, will not be used in the TLFs, unless 
otherwise specified. On some occasions, superscripts 1, 2, or 3 may be used (see 
below). 
 
Only standard keyboard characters will be used in the TLFs. Special characters, 
such as non-printable control characters, printer-specific, or font-specific 
characters, will not be used. Hexadecimal-derived characters will be used, 
where possible, if they are appropriate to help display math symbols (e.g., μ). 
Certain subscripts and superscripts (e.g., cm2, Cmax) will be employed on a case-
by-case basis. 
 
Mixed case will be used for all titles, footnotes, column headers, and 
programmer-supplied formats, as appropriate. 
13.1.2 
Headers and Footers 
All table and listing headers will be similar in content.   
Components of the header and footer include: 
 
Upper Left, Line 1: “Parion Sciences Incorporated” 
 
Upper Left, Line 2:  “PS-G202 : CLEAN-PCD. Final CSR analysis” 
 
Upper Right, Line 1:  “Page X of Y”, where X and Y are the current page number 
and the total number of pages, respectively 
Actual title of the table or listing should start at line 4. 
All table and listing footnotes should be consistent: 
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 
A solid line spanning the margins will separate the body of the data display from 
the footnotes.  
 
All footnotes will be left justified with single-line spacing immediately below the 
solid line underneath the data display. 
 
Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 
3, etc. if a reference footnote. Each new footnote should start on a new line 
where possible. 
 
Footnotes will be present on the page where they are first referenced and 
thereafter on each page of the table, unless the footnote is specific only to 
certain pages. Subject specific footnotes should be avoided. 
 
Footnotes will be used sparingly and must add value to the table, figure, or data 
listing. If more than six footnotes are planned, then a cover page may be used to 
display footnotes, and only those essential to comprehension of the data will be 
repeated on each page.  
 
The last line of the footnote section will be a standard source line that indicates 
the name of the program used to produce the data display, date the program 
was run, and the listing source: 
o Lower Left, Last Line: “Program Name: <\\path name>” 
o Lower Right, Last Line: “Creation Date and Time: <DDMMMYYYY HH:MM>” 
 
13.1.3 
Display Titles 
 
Each TLF should be identified by the designation and a numeral. (i.e., Table 
14.1.1). ICH E3 numbering will be used. A decimal system (x.y and x.y.z) should 
be used to identify TLFs with related contents. The title is centered. The 
analysis set should be identified on the line immediately following the title. The 
title and table designation are single spaced. A solid line spanning the margins 
will separate the display titles from the column headers. There will be 1 blank 
line between the last title and the solid line. 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
Safety Set 
 
13.1.4 
Column Headers 
 
Column headings should be displayed immediately below the solid line described 
above in initial upper-case characters.  
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 
In the case of efficacy tables, the variable (or characteristic) column will be on 
the far left followed by the treatment group columns and total column (if 
applicable). P-values may be presented under the total column or in separate p-
value column (if applicable). Within-treatment comparisons may have p-values 
presented in a row beneath the summary statistics for that treatment. 
 
For numeric variables, include “unit” in column or row heading when 
appropriate. 
 
Analysis set sizes will be presented for each treatment group in the column 
heading as (N=xx) (or in the row headings if applicable). This is distinct from the 
‘n’ used for the descriptive statistics representing the number of subjects in the 
analysis set. 
13.1.5 
Body of the Data Display 
13.1.5.1 
General Conventions 
Data in columns of a table or listing should be formatted as follows: 
• 
alphanumeric values are left-justified; 
• 
whole numbers (e.g., counts) are right-justified; and 
• 
numbers containing fractional portions are decimal aligned. 
13.1.5.2 
Table Conventions 
 
Units will be included where available 
 
If the categories of a parameter are ordered, then all categories between the 
maximum and minimum category should be presented in the table, even if n=0 
for all treatment groups in a given category that is between the minimum and 
maximum level for that parameter. For example, the frequency distribution for 
symptom severity would appear as: 
Severity 
Rating 
N 
severe 
0 
moderate 
8 
mild 
3 
Where percentages are presented in these tables, zero percentages will not be 
presented and so any counts of 0 will be presented as 0 and not as 0 (0%). 
 
If the categories are not ordered (e.g., Medical History etc.), then only those 
categories for which there is at least 1 subject represented in 1 or more groups 
should be included. 
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 
An Unknown or Missing category should be added to any parameter for which 
information is not available for 1 or more subjects.  
 
P-values should be output in the format: “0.xxxx”, where xxxx is the value 
rounded to 4 decimal places. Any p-value less than 0.0001 will be presented as 
<0.0001.  If the p-value is returned as >0.9999 then present as >0.9999 
 
Percentage values should be printed to one decimal places, in parentheses with 
no spaces, one space after the count (e.g., 7 (12.1%), 13 (5.3%)). Unless 
otherwise noted, for all percentages, the number of subjects in the analysis set 
for the treatment group who have an observation will be the denominator. 
Percentages equating to 100% should be presented as 100%, without any decimal 
places.  
 
For Part A: Tabular display of data for medical history and adverse events should 
be presented by the body system or SOC with the highest occurrence for VX-371 
in 4.2% hypertonic saline group in decreasing order, assuming all terms are 
coded. Within the body system or SOC, medical history (by preferred term), and 
adverse events (by preferred term) should be displayed in decreasing order for 
VX-371 in 4.2% hypertonic saline group. Tabular display of data for 
prior/concomitant medications  should be presented by the ATC level with 
highest occurrence for VX-371 in 4.2% hypertonic saline group in decreasing 
order. Within the ATC level prior/concomitant medications (by preferred term) 
should be displayed in decreasing order for VX-371 in 4.2% hypertonic saline 
group. If the incidence for more than 1 term is identical, they should then be 
sorted alphabetically. Missing descriptive statistics which cannot be estimated 
should be reported as “-”. 
 
For Part B: A similar approach will also apply for Part B using the overall column 
instead of VX-371 in 4.2% hypertonic saline group as the sorting order. 
 
The percentage of subjects is normally calculated as a proportion of the number 
of subjects assessed in the relevant treatment group (or overall) for the analysis 
set presented. However, careful consideration is required in many instances due 
to the complicated nature of selecting the denominator, usually the appropriate 
number of subjects exposed. Describe details of this in footnotes or 
programming notes. 
 
For categorical summaries (number and percentage of subjects) where a subject 
can be included in more than one category, describe in a footnote or 
programming note if the subject should be included in the summary statistics for 
all relevant categories or just 1 category and the criteria for selecting the 
criteria. 
 
Where a category with a subheading (such as system organ class) has to be split 
over more than one page, output the subheading followed by “(cont)” at the top 
of each subsequent page. The overall summary statistics for the subheading 
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should only be output on the first relevant page. 
13.1.5.3 
Listing Conventions 
 
Listings will be sorted for presentation in order of treatment groups, subject 
number, visit/collection day, and visit/collection time. 
 
Missing data should be represented on subject listings as either a hyphen (“-”) 
with a corresponding footnote (“- = unknown or not evaluated”), or as “N/A”, 
with the footnote “N/A = not applicable”, whichever is appropriate. 
 
Dates should be printed in ISO format (“YYYY-MM-DD”: 2000-07-01). If time is 
collected, the date and time will be presented in format: “YYYY-MM-
DDTHH:MM:SS: 2000-07-01T20:13:14”. Missing portions of dates should be 
represented on subject listings as dashes 2000-07--- or 2000-07-01T20:--:--). 
Dates or date and time that are missing because they are not applicable for the 
subject are output as “N/A”, unless otherwise specified. 
 
All observed time values must be presented using a 24-hour clock HH:MM or 
HH:MM:SS format (e.g., 11:26:45, or 11:26). Time will only be reported if it was 
measured as part of the study. 
 
Units will be included where available 
 
13.1.5.4 
Figure Conventions 
 
Unless otherwise specified, for all figures, study visits will be displayed on the X-
axis and endpoint (e.g., treatment mean change from Baseline) values will be 
displayed on the Y-axis. 
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14 QUALITY CONTROL 
SAS programs are developed to produce clinical trial output such as analysis data sets, 
summary tables, data listings, figures or statistical analyses. 
 
 provide an overview of the development of such SAS programs. 
 describes the quality control procedures that are performed 
for all SAS programs and output. Quality control is defined here as the operational 
techniques and activities undertaken to verify that the SAS programs produce the 
proper clinical trial output by checking for their logic, efficiency and commenting and 
by review of the produced output. 
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15 INDEX OF TABLES 
For table shells, see ATTACHMENT 1 
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16 INDEX OF LISTINGS 
For listing shells, see ATTACHMENT 2 
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17 INDEX OF FIGURES 
For figure shells, see ATTACHMENT 3 
    
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APPENDIX III LIST OF THRESHOLD RANGE ANALYSIS CRITERIA 
 
Threshold Criteria for Laboratory Tests 
Parameter 
Criteria 
Comments 
Clinical Chemistry 
CPK 
>ULN - ≤ 2.5 x ULN 
>2.5 - ≤ 5 x ULN 
>5 - ≤ 10x ULN  
>10 x ULN 
CTCAE grades 1-4 
Creatinine 
>ULN - ≤ 1.5 x ULN 
>1.5 - ≤ 3.0 x ULN 
>3.0 - ≤ 6.0 x ULN 
>6.0 x ULN 
CTCAE grades 1-4 
Blood Urea 
Nitrogen 
>ULN - ≤ 1.5 x ULN 
>1.5 - ≤ 3.0 x ULN 
>3.0 - ≤ 6.0 x ULN 
>6.0 x ULN 
Same criteria as creatinine  
 
No CTCAE  
Sodium 
Hyponatremia 
<LLN - ≥130 mmol/L 
<130 – ≥120 mmol/L  
<120 mmol/L  
CTCAE grade 1, 3, 4 
 
(No CTCAE grade 2) 
Hypernatremia 
>ULN - ≤ 150 mmol/L 
>150 mmol/L- ≤155 mmol/L  
>155 mmol/L - ≤ 160 mmol/L 
>160 mmol/L 
CTCAE grade 1-4 
Potassium 
(Plasma) 
Hypokalemia 
 <LLN – ≥ 2.5 mmol/L 
 <2.5 – ≥ 2.0 mmol/L 
 <2.0 mmol/L 
 
Hyperkalemia 
>ULN – ≤ 5.1 mmol/L 
CTCAE grade 1-4 
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>5.1 –  ≤ 5.6 mmol/L  
>5.6 – ≤ 6.0 mmol/L  
>6.0 mmol/L 
Potassium (Serum) 
Hypokalemia 
<LLN – ≥ 3.0 mmol/L 
<3.0 – ≥ 2.5 mmol/L 
<2.5 mmol/L 
CTCAE grade 1&2, 3, 4 
 
(Grade 1 and 2 are the same) 
Hyperkalemia 
>ULN – ≤ 5.5 mmol/L 
>5.5 –  ≤ 6.0 mmol/L  
>6.0 – ≤ 7.0 mmol/L  
>7.0 mmol/L 
CTCAE grade 1-4 
Glucose 
 
 
 
 
 
 
Hypoglycemia 
<3.0 – ≥ 2.2 mmol/L  
<2.2 - ≥ 1.7 mmol/L 
<1.7 mmol/L 
CTCAE grade 1-4 
Hyperglycemia  
>ULN - ≤ 8.9 mmol/L 
>8.9 – ≤ 13.9 mmol/L 
>13.9 – ≤ 27.8 mmol/L  
>27.8 mmol/L 
CTCAE grade 1-4 
Albumin 
<35 - ≥ 30 g/L 
<30 – ≥ 20 g/L 
<20 g/L  
CTCAE grade 1-3 
 
Amylase 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.0 x ULN  
>2.0 – ≤ 5.0 x ULN 
>5.0 x ULN 
CTCAE grade 1-4 
Lipase 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.0 x ULN  
>2.0 – ≤ 5.0 x ULN 
>5.0 x ULN 
CTCAE grade 1-4 
Direct bilirubin 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2 x ULN 
>2 – ≤ 3 x ULN  
>3 – ≤ 10 x ULN 
>10 x ULN 
Same Criteria as Total Bilirubin 
 
No CTCAE  
Not in DILI Guidance 
 
GGT  
>ULN - ≤ 2.5 x ULN 
>2.5 –  ≤ 5.0 x ULN 
>5.0 –  ≤ 20.0 x ULN  
>20.0 x ULN 
CTCAE grade 1-4 
Calcium 
Hypercalcemia 
>ULN - ≤ 2.9 mmol/L  
>2.9 – ≤ 3.1 mmol/L  
>3.1 – ≤ 3.4 mmol/L  
>3.4 mmol/L 
CTCAE grade 1-4 
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Hypocalcemia 
<LLN - ≥ 2.0 mmol/L 
<2.0 – ≥1.75 mmol/L  
<1.75 – ≥ 1.5 mmol/L  
<1.5 mmol/L  
CTCAE grade 1-4 
Magnesium 
 
Hypermagnesemia 
>ULN - ≤ 1.23 mmol/L 
>1.23 – ≤ 3.30 mmol/L 
>3.30 mmol/L 
CTCAE grade 1, 3, 4 
 
No CTCAE grade 2 
Hypomagnesemia 
<LLN - ≥ 0.5 mmol/L 
<0.5 – ≥ 0.4 mmol/L 
<0.4 – ≥ 0.3 mmol/L  
<0.3 mmol/L  
CTCAE grade 1-4 
ALT 
>ULN - ≤  3 xULN 
>3 – ≤  5 xULN 
>5 – ≤  8 xULN 
>8 – ≤  20.0 xULN 
>20.0 x ULN 
Per FDA DILI Guidance Jul 2009 and 
CTCAE 
 
AST 
>ULN - ≤  3 xULN 
>3 – ≤  5 xULN 
>5 – ≤  8 xULN 
>8 – ≤  20.0 xULN 
>20.0 x ULN 
FDA DILI Guidance and CTCAE 
 
ALT or AST 
(ALT>ULN and ALT ≤  3 xULN) or 
(AST>ULN and AST≤  3 xULN) 
(ALT>3 xULN and ALT ≤  5 xULN) or 
(AST>3xULN and AST≤  5 xULN) 
(ALT>5 xULN and ALT ≤  8 xULN) or 
(AST>5xULN and AST≤  8 xULN) 
(ALT>8 xULN and ALT ≤  20 xULN) or 
(AST>8xULN and AST≤  20 xULN) 
ALT>20 xULN 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 and CTCAE 
 
Total Bilirubin 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2 x ULN 
>2 – ≤ 3 x ULN  
>3 – ≤ 10 x ULN 
>10 x ULN 
FDA DILI Guidance and CTCAE 
 
 
ALT and Total 
Bilirubin 
ALT>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009  
 
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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  
 
Hematology 
WBC 
WBC decreased 
<LLN - ≥ 3.0 x 10e9 /L 
<3.0 – ≥ 2.0 x 10e9 /L  
<2.0 – ≥ 1.0 x 10e9 /L  
<1.0 x 10e9 /L 
CTCAE grade 1-4 
Leukocytosis 
>100 x 10e9 /L 
CTCAE grade 3 (only Grade available)  
Lymphocytes 
Lymphocyte decreased 
<LLN - ≥ 0.8 x10e9 /L 
<0.8 – ≥ 0.5 x10e9 /L  
<0.5 – ≥ 0.2 x10e9 /L  
<0.2 x10e9 /L 
CTCAE grade 1-4 
Lymphocyte increased 
>4 – ≤ 20 x10e9/L  
>20 x10e9/L  
CTCAE grade 2, 3 (only Grades available) 
Neutrophils 
Neutrophil decreased 
<LLN - ≥ 1.5 x10e9 /L 
<1.5 –  ≥ 1.0 x10e9 /L  
<1.0 –  ≥ 0.5 x10e9 /L  
<0.5 x10e9 /L 
CTCAE grade 1-4 
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 
 
 
 
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Threshold Criteria for ECGs 
Parameter 
Criteria 
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 
 
 
QTcF 
 
>450 ms (Male)  
>470 ms (Female) 
≥500 ms 
Increase from baseline >10 ms 
Increase from baseline >20 ms 
Increase from baseline >40 ms 
Increase from baseline >60 ms 
 
Threshold Criteria for Vital Signs 
Parameter 
Threshold Criteria 
Comments 
HR 
 
Same PCS as above in ECG category 
 
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SBP 
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 
 
DBP 
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 
809/770 analyses 
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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 
 
 
 
 
 
 
 
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APPENDIX IV SCHEDULES OF ASSESSMENTS 
Table 5. 
Study PS-G202: Screening Period 
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Table 6. 
Study PS-G202: Treatment Period 
 
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Table 7. 
Early Termination of Treatment Visit and Safety Follow-Up Telephone 
Call 
 
 
 
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APPENDIX V HANDLING MISSING DATE 
Prior/Concomitant medication: 
Missing or partial medication start date: 
 
If only day is missing, use the first day of the month.  
 
If day and month are both missing, use the first day of the year.  
 
If day, month and year are all missing, use a date before the first dose date (in 
practice, use Jan. 01, 2000 to impute). 
Missing or partial medication stop date: 
 
If only day is missing, use the last day of the month. 
 
If day and month are both missing, use the last day of the year. 
 
If day, month and year are all missing, assign ‘continuing’ status to stop date (in 
practice, use Dec. 31, 2050 to impute). 
Adverse Event: 
Imputation of missing AE start date: 
 
If AE start date is completely missing and AE end date is after the first dose date 
in Part A Period 1 but before first dose date in Part B, then use the first dose 
date in Part A Period 1 as the AE start date and classify the AE as a TEAE; if the 
AE end date is after the first dose date in Part B then  
1) Use the first dose date in Part A Period 1 as the AE start date 
2) Use the first dose date in Part B as the AE start date. 
 
If AE start date is completely missing, and AE end date is before the first dose 
date in Part A Period 1, then the AE is not a TEAE.  
 
If both AE start date and AE end date are completely missing then 
1) Use the first dose date as AE start date in Part A Period 1 and classify the AE 
as a TEAE for Part A 
2) Use the first dose date as AE start date in Part B and classify the AE as a TEAE 
for Part B 
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 
If only day is missing, use the first day of the month or the first dose date 
whichever is later, unless the AE start month is before the first dose date in 
which case, the AE start date remains missing and this AE is not a TEAE. 
 
If day and month are both missing, use the first day of the year or the first dose 
date whichever is later, unless the AE start year is before the first dose date.  In 
this case, the AE start date remains missing and this AE is not a TEAE. 
Imputed AE start date must be earlier than the original AE end date, otherwise set 
imputed start date = original AE end date and the AE is not a TEAE. 
Missing AE causality 
For summary tables of related AEs, report missing causality as ‘related’.  
Missing AE Severity 
There will be no imputation of missing AE severity. 
Missing SAE category 
There will be no imputation of missing SAE category. 
 
 
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APPENDIX VI VISIT WINDOWS 
The unscheduled or early withdrawal visit will be mapped to a scheduled visit for 
analysis using the date of collection/assessment as a basis to determine study day and 
then study day will be mapped to the intended visit. Table 8 and Table 9 below contain 
the analysis visit windows. 
Table 8. 
Study windows 
Study Period 
Scheduled 
Visit/Day  
Study Day Window 
Analysis Visit 
Period 1 
Day 15 Visit 
Day >1 – ≤ 22 
Day 15 
Day 29 Visit 
Day >22 – ≤ 36 
Day 29 
Period 2 
Day 71 Visit 
Period 2, Day >1 – ≤ 22 
Day 15 
Day 85 Visit 
Period 2, Day >22 – ≤ 36a 
Day 29 
Period 3 
Day 99 Visit 
Period 3, Day >1 – ≤ 22 
Day 15 
Day 113 Visit 
Period 3, Day >22 - ≤ 36 
Day 29 
a: all assessments should happen before Part B dosing time. 
For SGRQ, QOL-PCD 
 hematology, height and weight, 
 
 the following windows will be used: 
Table 9. 
Study windows for Day 1 and Day 29 only 
Study Period 
Scheduled Visit/Day  Study Day Window 
Analysis Visit 
Period 1 
Day 29 Visit 
Day >1 – ≤ 36 
Day 29 
Period 2 
Day 85 Visit 
Period 2, Day >1 – ≤ 36a 
Day 29 
Period 3b 
Day 113 Visit 
Period 3, Day >1  
Day 29 
a: all assessments should happen before Part B dosing time. 
b: visit windows for height and weight will only be applied for Period 1 and 2. Height and weight 
visit windows for Period 3 will be the same as table 6.  
Once analysis visit windows are assigned, all visits, including scheduled visits, 
unscheduled visits, and early termination visits will be eligible for being flagged as the 
“analyzed record” within the analysis visit window. Note that the scheduled visit should 
match with the visit for which the visit window is defined. For example: If Day 29 visit 
falls in the visit window for Day 15, then Day 15 will be assigned to this visit. If no 
numerical measurement is available within a visit window, the measurement will be 
considered missing for the visit. 
A subject’s individual analysis visit window could potentially contain more than one 
visit. In the event of multiple visits falling within an analysis visit window or in case of a 
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tie, the following rules will be used in sequence to determine the “analyzed record” for 
the analysis visit window: 
 
the data closest to the scheduled day will be used. 
 
If there are multiple measurements with the same distance from the target day, 
the latest measurement will be used. 
The data not flagged as the “analyzed record” will only be listed in subject listings. 
 
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