Clinical trial NCT02709109
Conditions: Cystic Fibrosis
Sponsor: Parion Sciences
Start date: 2016-02-01; Completion date: 2017-09-01
Enrollment: 147 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of treatment with VX-371 in hypertonic saline compared to hypertonic saline alone in subjects with cystic fibrosis (CF) who are ≥12 years of age, homozygous for the F508del-cystic fibrosis transmembrane conductance regulator (CFTR) mutation, and being treated with Orkambi

Detailed description:

Arms: arm 1: Participants received 85 microgram (mcg) VX-371 diluted in 3 milliliter (mL) 4.2 percent (%) HS through oral nebulized inhalation twice daily for 28 days (Day 1 to Day 28) in treatment period 1 followed by a 28 days washout period (Day 29 to Day 56) and then received 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days (Day 57 to Day 84) in treatment period 2. Participants also received a stable dose of 2 tablets of Orkambi (lumacaftor 400 milligram (mg)/ivacaftor 250 mg) orally every 12 hours with fat-containing food throughout the study as part of their cystic fibrosis (CF) standard of care. arm 2: Participants received 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days (Day 1 to Day 28) in treatment period 1 followed by a 28 days washout period (Day 29 to 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 (Day 57 to Day 84) in treatment period 2. Participants also received a stable dose of 2 tablets of Orkambi (lumacaftor 400 mg/ivacaftor 250 mg) orally every 12 hours with fat-containing food throughout the study as part of their CF standard of care. arm 3: Participants received 85 mcg VX-371 diluted in 3 mL 0.17% Saline (placebo) through oral nebulized inhalation twice daily for 28 days (Day 1 to Day 28) in treatment period 1 followed by a 28 days washout period (Day 29 to Day 56) and then received 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days (Day 57 to Day 84) in treatment period 2. Participants also received a stable dose of 2 tablets of Orkambi (lumacaftor 400 mg/ivacaftor 250 mg) orally every 12 hours with fat-containing food throughout the study as part of their CF standard of care. arm 4: Participants received 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days (Day 1 to Day 28) in treatment period 1 followed by a 28 days washout period (Day 29 to 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 (Day 57 to Day 84) in treatment period 2. Participants also received a stable dose of 2 tablets of Orkambi (lumacaftor 400 mg/ivacaftor 250 mg) orally every 12 hours with fat-containing food throughout the study as part of their CF standard of care.
Interventions: intervention 1: VX-371 + HS intervention 2: Hypertonic saline intervention 3: Placebo intervention 4: Orkambi intervention 5: VX-371
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 80 
1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Clinical Study Protocol 
A Phase 2a, Randomized, Double-blind, 
Placebo-controlled, Incomplete Block, Crossover 
Study to Evaluate the Safety and Efficacy of VX-371 
in Subjects Aged 12 Years or Older With Cystic 
Fibrosis, Homozygous for the F508del-CFTR 
Mutation, and Being Treated With Orkambi 
Vertex Study Number: VX15-371-101 
 
EudraCT Number: 2015-004841-13 
Date of Protocol: 22 July 2016 (Version 3.0)  
Vertex Pharmaceuticals Incorporated  
50 Northern Avenue 
Boston, MA 02210-1862, USA 
 
 
 
CONFIDENTIAL 
This document contains confidential information. Any use, distribution, or disclosure without the prior written consent 
of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under applicable laws or 
regulations. Persons to whom the information is disclosed must be informed that the information is confidential and 
may not be further disclosed by them. 


Protocol VX15-371-101, Version 3.0 
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Vertex Pharmaceuticals Incorporated 
 


Protocol VX15-371-101, Version 3.0 
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2 
PROTOCOL SYNOPSIS 
Title 
A Phase 2a, Randomized, Double-blind, Placebo-controlled, Incomplete Block, 
Crossover Study to Evaluate the Safety and Efficacy of VX-371 in Subjects Aged 12 
Years or Older With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation, 
and Being Treated With Orkambi 
Brief Title 
A Study to Evaluate the Efficacy and Safety of VX-371 in Subjects With Cystic 
Fibrosis Who Are Homozygous for the F508del-CFTR Mutation 
 
 
Clinical Phase and 
Clinical Study Type  
Phase 2a, safety and efficacy 
 
 
Objectives 
Primary 
To evaluate the safety and efficacy of treatment with VX-371 in hypertonic saline 
(HS) compared to HS alone in subjects with cystic fibrosis (CF) who are ≥12 years of 
age, homozygous for the F508del-CFTR mutation, and being treated with Orkambi 
Secondary 
• To evaluate the efficacy of treatment with VX-371 in HS compared with placebo 
in subjects with CF who are ≥12 years of age, homozygous for the F508del-CFTR 
mutation, and being treated with Orkambi 
• To evaluate the efficacy of treatment with VX-371 in HS compared with VX-371 
in placebo in subjects with CF who are ≥12 years of age, homozygous for the 
F508del-CFTR mutation, and being treated with Orkambi 
• To evaluate the efficacy of treatment with VX-371 in placebo compared with 
placebo in subjects with CF who are ≥12 years of age, homozygous for the 
F508del-CFTR mutation, and being treated with Orkambi 
• To investigate the pharmacokinetics (PK) of VX-371 in subjects with CF who are 
≥12 years of age, homozygous for the F508del-CFTR mutation, and being treated 
with Orkambi 
 
 
Endpoints 
Primary 
• Results of safety and tolerability assessments of adverse events, spirometry, 
clinical laboratory values (urine, serum, and plasma chemistry, hematology, and 
coagulation studies), standard 12-lead electrocardiograms (ECGs), vital signs, and 
ophthalmologic examinations 
• Absolute change in percent predicted forced expiratory volume in 1 second 
(ppFEV1) from baseline at Day 28 in each Treatment Period 
 
Secondary 
PK parameters for VX-371 
 
 
 
Number of Subjects 
Approximately 150 subjects will be randomized to 1 of 4 treatment sequences 
 
 


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Study Population 
Male and female subjects aged 12 years or older with CF who are homozygous for the 
F508del-CFTR mutation and being treated with Orkambi  
 
 
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 
(placebo), oral nebulized inhalation 
 
 
 
Active substance: VX-371 + HS 
 
Activity: ENaC inhibitor 
 
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 
 
 
 
Active substance: lumacaftor and ivacaftor (fixed-dose combination with lumacaftor 
and ivacaftor) 
 
Activity: CFTR corrector and potentiator (chloride ion [Cl-] secretion) 
 
Strength and Route of Administration: lumacaftor 200-mg/ivacaftor 125-mg tablets 
for oral administration 
 
 
Study Duration 
Excluding the Screening Period, the planned study duration is up to 115 days for 
Orkambi+/HS- subjects and up to 143 days for Orkambi-/HS-, Orkambi-/HS+, and 
Orkambi+/HS+ subjects.  
 
 
Study Design 
Phase 2a, randomized, double-blind, placebo-controlled, incomplete block, crossover, 
multicenter, study in subjects ≥12 years of age with CF who are homozygous for the 
F508del-CFTR mutation and who are being treated with Orkambi. 
Subjects will be randomized to 1 of 4 treatment sequences that will each be composed 
of: Treatment Period 1  Washout  Treatment Period 2. 
This study includes the following: 
• Screening Period:  
• Day -28 to Day -1 for Orkambi+/HS- subjects  
• Day -56 to Day -29 for Orkambi-/HS-, Orkambi-/HS+, and Orkambi+/HS+ 
subjects 
• Run-in Period: Day -28 to Day -1 for Orkambi-/HS-, Orkambi-/HS+, and 
Orkambi+/HS+ subjects  
• Treatment Period 1 through Treatment Period 2: 
o Treatment Period 1: Day 1 (first dose of inhaled study drug) through Day 28 
o Washout Period: Day 29 through Day 56 
o Treatment Period 2: Day 57 through Day 84 
• Early Termination of Treatment Visit for a subject who discontinues from study 


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drug treatment(s) but who does not complete the remaining assessments in the 
treatment period during which study drug treatment(s) is discontinued.  
• Safety Follow-up Telephone Contact: 28 days (+ 3 days) after the Day 84 Visit; or 
28 days (+ 3 days) after the Day 28 Visit for a subject who completes this visit but 
who will not be continuing into Treatment Period 2 (Note: Under certain 
circumstances, a safety Follow-up Telephone Contact may not be appropriate, and 
a Safety Follow-up Visit may be required.) 
• A Safety Follow-up Visit will occur 28 days (+ 3 days) after a subject’s last dose 
of study drug (whether inhaled study drug or lumacaftor/ivacaftor) in subjects 
who:  
o prematurely discontinue one or both study drugs during the course of either 
treatment period and do not complete the remaining assessments in the 
treatment period in which discontinuation occurred. In this circumstance, an 
ETT Visit is required in addition to the Safety Follow-up Visit (see 
Section 8.1.4). 
o have a clinical finding during the treatment period or during the 28-day Safety 
Follow-up Period that requires follow-up in the estimation of the PI. An ETT 
Visit may or may not be required in this circumstance (see Section 8.1.4). 
 
 
Assessments 
Efficacy: spirometry, 
 
Safety: adverse events, spirometry, clinical laboratory values (urine, serum and 
plasma chemistry, hematology, and coagulation studies), ECGs, physical 
examinations, vital signs, and ophthalmologic examinations (for subjects <18 years of 
age at Screening only) 
PK: VX-371,
 
 
 
 
 
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.  
The primary efficacy objective of this study is to evaluate the efficacy of treatment 
with VX-371 in HS compared to HS. For efficacy analysis, the statistical inference 
will be based on change from study baseline. The null hypothesis to be tested is that 
the mean change from study baseline in ppFEV1 to the Day 28 measurements is the 
same for VX-371 in combination with HS versus HS alone.  
To have a feasible sample size and study duration, this study uses a crossover design. 
Assuming a standard deviation (SD) of 7 percentage points, 50 subjects per sequence 
are needed to have an approximately 81% power to detect a 3 percentage point 
treatment difference in the mean absolute change in ppFEV1 from study baseline at 
Day 28 between VX-371 + HS and HS alone. The study will have approximately 
80% power to detect a 3 percentage point (within treatment) change from baseline at 
Day 28 in ppFEV1 for VX-371. A 2-sided significance level of 0.05 was used in the 
sample size calculations. 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 
at Day 28 in each Treatment Period. The primary efficacy analysis is based on a 
mixed-effects model. This model will include the absolute change from study 
baseline in ppFEV1 at Day 28 as the dependent variable, study baseline for ppFEV1, 
treatment, and period as fixed effects, and subject nested within sequence as a random 
effect. The within-subject covariance will be assumed to have the compound 
symmetry structure. Denominator degrees of freedom for the F-test for fixed effects 
will be estimated using the Kenward-Roger approximation. No imputation of missing 


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data will be done. Assuming that the subjects have 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. Similarly, the estimated between-treatment 
differences along with the corresponding 95% CI and 2-sided P values will be 
presented. Additionally, a mixed model of repeated measures (MMRM) will be used 
with period, study baseline for ppFEV1, visit, treatment, and treatment by visit, study 
baseline for ppFEV1 by visit, as fixed effects and subject nested within sequence as a 
random effect. The absolute change from study baseline in ppFEV1 will be the 
dependent variable. The repeated measures analysis will enable use of all post-
baseline available data and provide least square means estimates at each visit within a 
given treatment as well as estimates of treatment difference at each visit or across all 
visits.
 
 
 
 
IDMC Reviews 
The independent data monitoring committee (IDMC) will conduct regular planned 
safety reviews of study data as outlined in the IDMC charter. 


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3 
SCHEDULE OF ASSESSMENTS 
Schedules of Assessments are shown in Table 3-1, Table 3-2, Table 3-3, and Table 3-4.  
During the Screening Visit it should be determined whether the subject will have a Run-in 
Period. Table 8-2 outlines the assignment of subjects to a Run-in Period. 
Table 3-1 
Study VX15-371-101: Screening Period for All Subjects 
Event/Assessment 
Screening Period  
(Day-28 to Day -1 for Orkambi+/HS- Subjects 
or 
Day -56 to Day -29 for Orkambi-/HS+, Orkambi-/HS-, and 
Orkambi+/HS+ Subjectsa) 
Clinic visit 
X 
Informed consent/assent 
X 
Inclusion/exclusion criteria review 
X 
Demography 
X 
Medical history 
X 
Ophthalmologic history 
X 
Medications review 
X 
Height and weightb  
X 
Vital signs 
X 
Ophthalmologic examination (only for 
pediatric subjects <18 years of age) 
X 
Physical examinationc  
X 
 
 
a  
All Screening assessments must be completed before the Day 1 Visit for Orkambi+/HS- subjects and before the 
Day -28 Visit for Orkambi-/HS+, Orkambi-/HS-, and Orkambi+/HS+ subjects. Subjects may be rescreened after 
discussion with, and approval from, the medical monitor (see Section 8.1.1.2).   
b  
Height and weight will be measured with shoes off. 
c  
A full physical examination will be performed at the Screening Visit (see Section 11.6.3).  


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Table 3-1 
Study VX15-371-101: Screening Period for All Subjects 
Event/Assessment 
Screening Period  
(Day-28 to Day -1 for Orkambi+/HS- Subjects 
or 
Day -56 to Day -29 for Orkambi-/HS+, Orkambi-/HS-, and 
Orkambi+/HS+ Subjectsa) 
Standard 12-lead ECGd 
X 
Sweat chloridee 
X 
CFTR genotypef 
X 
Serum β-hCGg 
X 
Serum FSHh 
X 
Urine tests 
X 
Serum and plasma chemistry 
X 
Hematology  
X 
Coagulation 
X 
Spirometry  
X 
Lumacaftor/ivacaftor dosingi 
lumacaftor 400 mg/ivacaftor 250 mg q12h 
AEs and SAEs 
Continuous, from signing of ICF (and assent form, if applicable) 
through Safety Follow-up Telephone Contact 
 
 
d  
A standard 12-lead ECG will be performed after the subject has been seated or supine for at least 5 minutes 
(Section 11.6.4). 
e  
A sweat chloride test must be performed at the Screening Visit if an eligible sweat chloride value is not 
available in the subject’s medical records and the Screening Visit value is needed to establish eligibility. For 
subjects using sweat chloride values documented in their medical records to establish eligibility, the sweat 
chloride test at the Screening Visit is optional. Collection of sweat chloride will not overlap with any other 
study assessments. 
f  
CFTR genotyping will be performed to confirm that the subject is homozygous for the F508del-CFTR mutation 
and the results of the genotyping should be confirmed during the Screening Period. If the CFTR screening 
genotype result is not received before randomization, a previous CFTR genotype lab report may be used to 
establish eligibility. Note: Subjects who have been randomized and whose screening genotype does not confirm 
study eligibility must be discontinued from the study.  
g  
A 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  
Subjects are to take 2 tablets (each containing lumacaftor 200 mg/ivacaftor 125 mg) orally q12h with fat-
containing food (Section 10.2.2). 
 
 


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Table 3-2 
Study VX15-371-101: Run-in Period for Orkambi-/HS-, Orkambi-/HS+, and 
Orkambi+/HS+ Subjects 
Event/Assessment 
Run-in Perioda 
(Day -28 to Day -1) 
Day -28 
(± 2 days) 
Day -14 
(± 2 days) 
Clinic visit 
X 
X 
Vital signs 
X 
X 
Physical examinationb  
X 
X 
Meal or snack at study centerc 
X 
X 
Lumacaftor/ivacaftor dosingd 
lumacaftor 400 mg/ivacaftor 250 mg q12h 
Adverse events and serious adverse events 
Continuous, from signing of ICF (and assent form, if applicable) 
 through Safety Follow-up Telephone Contact 
 
 
 
a  
During the Run-in Period, all subjects who are receiving HS as part of their CF standard of care will washout 
from HS for 28 days before dosing with study drug and will remain off HS through the Safety Follow-up 
Telephone Contact.  
b  
An abbreviated physical examination will be performed at the Day -28 and Day -14 Visits (see Section 11.6.3).  
c  
At the scheduled visits indicated, if the subject has not taken the morning dose of lumacaftor/ivacaftor  before 
coming to the study visit, a fat-containing meal or snack will be provided with that dose. 
d  
Subjects are to take 2 tablets (each containing lumacaftor 200 mg/ivacaftor 125 mg) orally q12h with 
fat-containing food (Section 10.2.2). 
 
 


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Table 3-3 
Study VX15-371-101: Treatment Period 
Event/Assessment 
Treatment Perioda 
Treatment Period 1 
(Day 1 to Day 28) 
Washoutb  
(Day 29 to Day 56) 
(+ 3 days) 
Treatment Period 2 
(Day 57 to Day 84) 
Day 1 
Day 3 
(± 1 day) 
Day 14 
(± 3 days) 
Day 28 
(- 2 days) 
Day 57 
 
Day 59 
(± 1 day) 
Day 70 
(± 3 days) 
Day 84 
(- 2 days) 
Clinic visit 
X 
 
X 
X 
 
X 
 
X 
X 
Telephone contactc 
 
X 
 
 
 
 
X 
 
 
Inclusion/exclusion criteria review 
X 
 
 
 
 
 
 
 
 
Randomizationd 
X 
 
 
 
 
 
 
 
 
Height and weightf  
X 
 
 
X 
 
X 
 
 
X 
Vital signsg 
X 
 
X 
X 
 
X 
 
X 
X 
Physical examinationh  
X 
 
 
X 
 
X 
 
 
X 
Standard 12-lead ECGi 
X 
 
X 
X 
 
X 
 
X 
X 
 
 
a 
See Section 8.1.4 for guidance about discontinuation of study drug treatment.  
b  
The Washout Period may be for acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) upon 
discussion with and approval by the medical monitor (see Section 8.1.3.2). 
c  
A telephone contact will occur on Day 3 and Day 59 of the study for safety purposes (e.g., inquiry about adverse events).  
d  
Randomization will occur after all inclusion and exclusion criteria are met. If the screening genotype result is not received before randomization, a previous 
CFTR genotype lab report may be used to establish eligibility. Note: Subjects who have been randomized on the basis of a historical genotype lab report and 
whose screening genotype does not confirm study eligibility must be discontinued from the study. 
  
 
f  
Height and weight will be measured with shoes off. 
g  
All vital signs will be collected within 60 minutes before inhaled study drug dosing. Only pulse rate and blood pressure will be collected 90 (± 30) minutes 
after inhaled study drug dosing. Vital signs will be assessed after the subject has been seated or supine for at least 5 minutes (Section 11.6.3). 
h  
An abbreviated physical examination will be performed before dosing with inhaled study drug (see Section 11.6.3).  
i  
The ECG will be performed 60 (± 30) minutes after completion of inhaled study drug dosing and after the subject has been seated or supine for at least 
5 minutes (Section 11.6.4).  


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Table 3-3 
Study VX15-371-101: Treatment Period 
Event/Assessment 
Treatment Perioda 
Treatment Period 1 
(Day 1 to Day 28) 
Washoutb  
(Day 29 to Day 56) 
(+ 3 days) 
Treatment Period 2 
(Day 57 to Day 84) 
Day 1 
Day 3 
(± 1 day) 
Day 14 
(± 3 days) 
Day 28 
(- 2 days) 
Day 57 
 
Day 59 
(± 1 day) 
Day 70 
(± 3 days) 
Day 84 
(- 2 days) 
Spirometryk  
X 
 
X 
X 
 
X 
 
X 
X 
Urine pregnancy testl 
X 
 
 
X 
 
X 
 
 
X 
Urine testsm 
X 
 
X 
X 
 
X 
 
X 
X 
Serum and plasma chemistryo 
X 
 
X 
X 
 
X 
 
X 
X 
Hematology 
X 
 
 
X 
 
X 
 
 
X 
Coagulation 
X 
 
 
X 
 
X 
 
 
X 
 
 
  
 
 
k  
The spirometry assessment will be performed within 60 (± 10) minutes before and 30 (± 5) minutes) after the dose of inhaled study drug is administered.    
l  
Pregnancy tests will only be administered to female subjects of childbearing potential (see Section 11.6.2).  
m  
On Day 1 and Day 57, a urine sample will be collected 90 (+ 5) minutes before dosing with inhaled study drug. A urine sample will also be collected at 
90 (± 60) minutes after completion of dosing with inhaled study drug at the Day 14, Day 28, Day 70, and Day 84 Visits. 
  
 
o  
Subjects with a potassium level that is ≤0.4 units below the ULN at the Day 1 or Day 57 Visit will be required to have a blood sample collected for a repeat 
evaluation of plasma potassium within 7 (± 2) days (see Section 11.6.2.2). 


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Table 3-3 
Study VX15-371-101: Treatment Period 
Event/Assessment 
Treatment Perioda 
Treatment Period 1 
(Day 1 to Day 28) 
Washoutb  
(Day 29 to Day 56) 
(+ 3 days) 
Treatment Period 2 
(Day 57 to Day 84) 
Day 1 
Day 3 
(± 1 day) 
Day 14 
(± 3 days) 
Day 28 
(- 2 days) 
Day 57 
 
Day 59 
(± 1 day) 
Day 70 
(± 3 days) 
Day 84 
(- 2 days) 
Urine for PK analysisp  
X 
 
X 
X 
 
X 
 
X 
X 
Blood for PK analysisq 
X 
 
X 
X 
 
X 
 
X 
X 
Meal or snack at study centerr 
X 
 
X 
X 
 
X 
 
X 
X 
Inhaled study drug dosings  
X 
 
X 
Xt 
 
X 
 
X 
Xt 
Lumacaftor/ivacaftor dosingu 
lumacaftor 400 mg/ivacaftor 250 mg q12h 
Inhaled study drug count 
X 
 
X 
X 
 
X 
 
X 
X 
Lumacaftor/ivacaftor drug count 
X 
 
X 
X 
 
X 
 
X 
X 
 
 
p 
A urine sample for evaluation of VX-371 will be collected within 90 (+ 5) minutes before and 90 (± 60) minutes after completion of dosing with inhaled 
study drug at the Day 1, Day 14, Day 28, Day 57, Day 70, and Day 84 Visits (see Section 11.3.2). 
q 
Blood samples for the PK assessment will be analyzed for VX-371 
. For the evaluation of VX-371, a blood sample will be 
collected within 90 (+ 5) minutes before dosing with inhaled study drug and at 60 (± 30) minutes after completion of inhaled study drug dosing  at the Day 1, 
Day 14, Day 28, Day 57, Day 70, and Day 84 Visits.
 
 
r  
At the scheduled visits indicated, if the subject has not taken the morning dose of lumacaftor/ivacaftor before coming to the study visit, a meal or snack will 
be provided with that dose after all predose assessments have occurred.  
s  
Inhaled study drug will be administered from Day 1 to Day 28 and from Day 57 to Day 84. Inhaled study drug should be administered by nebulization twice 
daily (bid) approximately 10 to 12 hours apart for oral inhalation (see Section 10.2.1). Inhaled study drug will be administered at the clinic at the Day 1, 
Day 14, Day 28, Day 57, Day 70, and Day 84 Visits. 
t  
The last dose of inhaled study drug in Treatment Period 1 and Treatment Period 2 is the dose of study drug received at the Day 28 and Day 84 Visits, 
respectively. 
u  
Subjects are to take 2 tablets (each containing lumacaftor 200 mg/ivacaftor 125 mg) orally q12h with fat-containing food (Section 10.2.2). The last dose of 
Orkambi during the Run-in Period will be the morning dose of the Day 1 Visit (Section 8.1.2). 


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Table 3-3 
Study VX15-371-101: Treatment Period 
Event/Assessment 
Treatment Perioda 
Treatment Period 1 
(Day 1 to Day 28) 
Washoutb  
(Day 29 to Day 56) 
(+ 3 days) 
Treatment Period 2 
(Day 57 to Day 84) 
Day 1 
Day 3 
(± 1 day) 
Day 14 
(± 3 days) 
Day 28 
(- 2 days) 
Day 57 
 
Day 59 
(± 1 day) 
Day 70 
(± 3 days) 
Day 84 
(- 2 days) 
Dispense nebulizer and/or 
nebulizer handsetv 
X 
 
 
 
 
X 
 
 
 
Collect nebulizer and/or nebulizer 
handsetw 
 
 
 
X 
 
 
 
 
X 
Medications review 
X 
 
X 
X 
 
X 
 
X 
X 
Concomitant treatments and 
procedures 
X 
 
X 
X 
 
X 
 
X 
X 
Adverse events and serious 
adverse events 
Continuous, from signing of ICF (and assent form, if applicable) 
 through Safety Follow-up Telephone Contact 
 
 
 
v  
A nebulizer device (nebulizer and handset) will be dispensed at the Day 1 Visit. At the Day 57 Visit, a new nebulizer handset will be provided for 
 
replacement. 
w  
The nebulizer handset used during Treatment Period 1 will be collected at the Day 28 Visit. At the Day 84 Visit, the nebulizer device (nebulizer and handset 
 
used during Treatment Period 2) will be collected.  


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Table 3-4 
Study VX15-371-101: Early Termination of Treatment Visit, Safety Follow-
up Visit, and Safety Follow-up Telephone Contact 
Event/Assessment 
Early Termination of  
Treatment Visita 
Safety Follow-up Visit 
28 days (+ 3 days) 
After Last Dose of Study 
Drugb  
Safety Follow-up 
Telephone Contact 
28 days (+ 3 days) After 
the Day 28 or Day 84 Visitc 
Clinic visit 
X 
X 
 
Telephone contact 
 
 
X 
Height and weightd 
X 
X 
 
Vital signs 
X 
X 
 
Physical examination  
X 
X 
 
Ophthalmologic 
examinationse 
X 
X 
X 
Standard 12-lead ECGf 
X 
X 
 
Urine pregnancy testg 
X 
X 
 
Hematology 
X 
X 
 
Coagulation 
X 
X 
 
Urine tests 
X 
X 
 
Serum and plasma chemistry 
X 
X 
 
Urine for PK analysish 
X 
 
 
Blood for PK analysisi 
X 
 
 
Spirometry  
X 
X 
 
 
Inhaled study drug count 
X 
 
 
Lumacaftor/ivacaftor drug 
count 
X 
X 
 
Collect nebulizer and 
nebulizer handset 
X 
 
 
Concomitant medications 
X 
X 
 
Concomitant treatments and 
procedures 
X 
X 
 
 
 
a 
See Section 8.1.4 for guidance about discontinuation of study drug treatment.   
b  
See Section 8.1.6. 
c  
See Section 8.1.5. 
d  
Height and weight will be measured with shoes off. 
e  
Pediatric subjects <18 years of age at the Screening Visit who discontinue study drug treatment will have an 
ophthalmologic examination that is to occur between their last dose of study drug and completion of either the 
ETT Visit or the Safety Follow-up Visit. Pediatric subjects who complete the Day 84 Visit will have an 
ophthalmologic examination that is to occur between the Day 84 Visit and the Safety Follow-up Telephone 
Contact. See Section 11.6.5. 
f  
The ECG will be performed after the subject has been seated or supine for at least 5 minutes (Section 11.6.4).  
g  
Pregnancy tests will only be administered to female subjects of childbearing potential (see Section 11.6.2). 
h  
At the ETT Visit, a single urine sample for PK will be collected. 
i  
At the ETT Visit, 2 blood samples for PK will be collected, 1 for the evaluation of VX-371 
 
. 


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Table 3-4 
Study VX15-371-101: Early Termination of Treatment Visit, Safety Follow-
up Visit, and Safety Follow-up Telephone Contact 
Event/Assessment 
Early Termination of  
Treatment Visita 
Safety Follow-up Visit 
28 days (+ 3 days) 
After Last Dose of Study 
Drugb  
Safety Follow-up 
Telephone Contact 
28 days (+ 3 days) After 
the Day 28 or Day 84 Visitc 
Adverse events and serious 
adverse events 
Continuous, from signing of ICF (and assent form, if applicable) 
 through Safety Follow-up Telephone Contact 


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4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
 
2 
Protocol Synopsis ................................................................................................................... 3 
3 
Schedule of Assessments........................................................................................................ 7 
4 
Table of Contents ................................................................................................................. 16 
List of Tables............................................................................................................................ 20 
List of Figures .......................................................................................................................... 20 
Glossary of Terms .................................................................................................................... 20 
5 
Introduction.......................................................................................................................... 21 
5.1 
Background ..................................................................................................................... 21 
5.2 
VX-371 Solution for Inhalation ...................................................................................... 22 
5.3 
Completed and Ongoing Clinical Studies With VX-371 ............................................... 22 
 
 
5.3.2 
Phase 2a Study with VX-371.................................................................................. 23 
5.4 
Rationale for Present Study ............................................................................................ 24 
6 
Study Objectives .................................................................................................................. 24 
6.1 
Primary Objective ........................................................................................................... 24 
6.2 
Secondary Objectives ..................................................................................................... 24 
7 
Study Endpoints ................................................................................................................... 25 
7.1 
Primary Endpoints .......................................................................................................... 25 
7.2 
Secondary Endpoint ........................................................................................................ 25 
 
 
8 
Study Design ......................................................................................................................... 25 
8.1 
Overview of Study Design ............................................................................................. 25 
8.1.1 
Screening ................................................................................................................ 29 
8.1.1.1 
Repetition of Screening Assessment(s) ............................................................ 30 
8.1.1.2 
Rescreening ...................................................................................................... 30 
8.1.1.3 
Extension of Screening Period Window .......................................................... 30 
8.1.2 
Run-in Period .......................................................................................................... 30 
8.1.3 
Treatment Periods ................................................................................................... 31 
8.1.3.1 
Treatment Period 1 ........................................................................................... 31 
8.1.3.2 
Washout Period ................................................................................................ 31 
8.1.3.3 
Treatment Period 2 ........................................................................................... 31 
8.1.4 
Early Termination of Treatment ............................................................................. 32 
8.1.5 
Safety Follow-up Telephone Contact ..................................................................... 32 
8.1.6 
Safety Follow-up Visit............................................................................................ 32 
8.1.7 
Independent Data Monitoring Committee .............................................................. 33 
8.2 
Rationale for Study Design and Study Drug Regimens ................................................. 33 
8.2.1 
Study Design........................................................................................................... 33 
8.2.2 
Study Drug Dose and Duration .............................................................................. 33 
8.2.3 
Rationale for Study Assessments ........................................................................... 34 
9 
Study Population .................................................................................................................. 34 
9.1 
Inclusion Criteria ............................................................................................................ 35 
9.2 
Exclusion Criteria ........................................................................................................... 35 


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9.3 
Study Restrictions ........................................................................................................... 37 
9.4 
Prior and Concomitant Medications ............................................................................... 38 
9.4.1 
Prohibited Medications ........................................................................................... 39 
9.5 
Removal of Subjects ....................................................................................................... 39 
9.6 
Replacement of Subjects ................................................................................................ 40 
10 Study Drug Administration and Management ................................................................. 40 
10.1 Preparation and Dispensing ............................................................................................ 40 
10.2 Administration ................................................................................................................ 40 
10.2.1 
Nebulizer ................................................................................................................ 40 
10.2.2 
Lumacaftor in Combination With Ivacaftor ........................................................... 41 
10.3 Method of Assigning Subjects to Treatment Groups ..................................................... 41 
10.4 Dose Modification for Toxicity ...................................................................................... 42 
10.5 Study Drug Interruption ................................................................................................. 42 
10.6 Missed Doses .................................................................................................................. 42 
10.6.1 
Inhaled Study Drug ................................................................................................. 42 
10.6.2 
Lumacaftor in Combination With Ivacaftor ........................................................... 42 
10.7 Packaging and Labeling ................................................................................................. 42 
10.8 Study Drug Supply, Storage, and Handling ................................................................... 43 
10.9 Drug Accountability ....................................................................................................... 43 
10.10 Disposal, Return, or Retention of Unused Drug ............................................................. 43 
10.11 Compliance ..................................................................................................................... 44 
10.12 Blinding and Unblinding ................................................................................................ 44 
10.12.1 Blinding .................................................................................................................. 44 
10.12.2 Unblinding .............................................................................................................. 45 
11 Assessments .......................................................................................................................... 45 
11.1 Timing of Assessments ................................................................................................... 45 
11.2 Subject and Disease Characteristics ............................................................................... 46 
11.3 Pharmacokinetics ............................................................................................................ 46 
11.3.1 
Blood Sampling ...................................................................................................... 46 
11.3.2 
Urine Sampling ....................................................................................................... 46 
11.3.3 
Processing and Handling of Pharmacokinetic Samples ......................................... 47 
11.3.4 
Bioanalysis.............................................................................................................. 47 
 
11.5 Efficacy ........................................................................................................................... 48 
11.5.1 
Spirometry .............................................................................................................. 48 
 
 
 
 
 
 
11.6 Safety .............................................................................................................................. 50 
11.6.1 
Adverse Events ....................................................................................................... 50 
11.6.2 
Clinical Laboratory Assessments ........................................................................... 50 
11.6.2.1 Elevation of Liver Function Test Parameters................................................... 52 
11.6.2.2 Hyperkalemia ................................................................................................... 53 
11.6.3 
Physical Examinations and Vital Signs .................................................................. 53 
11.6.4 
Electrocardiograms ................................................................................................. 53 
11.6.5 
Ophthalmologic Examination ................................................................................. 54 


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11.6.6 
Spirometry .............................................................................................................. 55 
11.6.7 
Contraception and Pregnancy ................................................................................. 55 
11.6.7.1 Contraception ................................................................................................... 55 
11.6.7.2 Pregnancy ......................................................................................................... 57 
12 Statistical and Analytical Plans .......................................................................................... 57 
12.1 Sample Size and Power .................................................................................................. 57 
12.2 Analysis Sets .................................................................................................................. 58 
12.3 Statistical Analysis ......................................................................................................... 58 
12.3.1 
General Considerations ........................................................................................... 58 
12.3.2 
Background Characteristics .................................................................................... 59 
12.3.2.1 Subject Disposition .......................................................................................... 59 
12.3.2.2 Demographics, Medical History, and Baseline Characteristics ....................... 59 
12.3.2.3 Prior and Concomitant Medications................................................................. 60 
12.3.2.4 Study Drug Exposure and Compliance ............................................................ 60 
12.3.3 
Efficacy Analysis .................................................................................................... 60 
12.3.3.1 Analysis of Primary Efficacy Variables ........................................................... 60 
 
 
 
12.3.4 
Safety Analysis ....................................................................................................... 64 
12.3.4.1 Adverse Events................................................................................................. 64 
12.3.4.2 Clinical Laboratory Assessments ..................................................................... 65 
12.3.4.3 Electrocardiogram ............................................................................................ 65 
12.3.4.4 Vital Signs ........................................................................................................ 65 
12.3.4.5 Physical Examination ....................................................................................... 65 
12.3.4.6 Ophthalmologic Examinations ......................................................................... 66 
12.3.4.7 Spirometry ........................................................................................................ 66 
12.3.4.8 Other Safety Analysis ...................................................................................... 66 
12.3.5 
Interim and IDMC Analyses ................................................................................... 66 
12.3.5.1 Interim Analysis ............................................................................................... 66 
12.3.5.2 IDMC Analysis ................................................................................................ 66 
12.4 Clinical Pharmacology Analysis .................................................................................... 66 
12.4.1 
Pharmacokinetic Analysis ...................................................................................... 66 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 66 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 66 
13.1.1 
Adverse Events ....................................................................................................... 66 
13.1.1.1 Definition of an Adverse Event........................................................................ 66 
13.1.1.2 Clinically Significant Assessments .................................................................. 67 
13.1.1.3 Documentation of Adverse Events................................................................... 67 
13.1.1.4 Adverse Event Severity .................................................................................... 68 
13.1.1.5 Adverse Event Causality .................................................................................. 68 
13.1.1.6 Study Drug Action Taken ................................................................................ 69 
13.1.1.7 Adverse Event Outcome .................................................................................. 69 
13.1.1.8 Treatment Given............................................................................................... 69 


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13.1.2 
Serious Adverse Events .......................................................................................... 69 
13.1.2.1 Definition of a Serious Adverse Event............................................................. 69 
13.1.2.2 Documentation of Serious Adverse Events...................................................... 70 
13.1.2.3 Reporting Serious Adverse Events................................................................... 71 
13.1.2.4 Expedited Reporting and Investigator Safety Letters ...................................... 71 
13.1.3 
Adverse Device Effects .......................................................................................... 71 
13.1.3.1 Definition of an Adverse Device Effect ........................................................... 71 
13.1.3.2 Definition of Serious Adverse Device Effect................................................... 71 
13.1.3.3 Reporting Adverse Device Effects ................................................................... 71 
13.1.3.4 Expedited Reporting and Investigator Safety Letters ...................................... 72 
13.2 Administrative Requirements ......................................................................................... 72 
13.2.1 
Ethical Considerations ............................................................................................ 72 
13.2.2 
Subject Information and Informed Consent ........................................................... 72 
13.2.3 
Investigator Compliance ......................................................................................... 72 
13.2.4 
Access to Records ................................................................................................... 73 
13.2.5 
Subject Privacy ....................................................................................................... 73 
13.2.6 
Record Retention .................................................................................................... 73 
13.2.7 
Study Termination .................................................................................................. 74 
13.3 Data Quality Assurance .................................................................................................. 74 
13.4 Monitoring ...................................................................................................................... 74 
13.5 Electronic Data Capture ................................................................................................. 75 
13.6 Publications and Clinical Study Report .......................................................................... 75 
 
 
13.6.2 
Clinical Study Report ............................................................................................. 75 
14 References ............................................................................................................................. 76 
15 Protocol Signature Pages .................................................................................................... 79 
15.1 Sponsor Signature Page .................................................................................................. 79 
15.2 Investigator Signature Page ............................................................................................ 80 
 


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List of Tables 
Table 3-1 
Study VX15-371-101: Screening Period for All Subjects ...................................... 7 
Table 3-2 
Study VX15-371-101: Run-in Period for Orkambi-/HS-, Orkambi-/HS+, and 
Orkambi+/HS+ Subjects ......................................................................................... 9 
Table 3-3 
Study VX15-371-101: Treatment Period .............................................................. 10 
Table 3-4 
Study VX15-371-101: Early Termination of Treatment Visit, Safety Follow-up 
Visit, and Safety Follow-up Telephone Contact ................................................... 14 
 
 
Table 8-1 
Study VX15-371-101 Treatment Sequences ........................................................ 26 
Table 8-2 
Run-in Period Subject Assignment ....................................................................... 29 
Table 9-1 
Study Restrictions ................................................................................................. 37 
Table 10-1 
Study Drug ............................................................................................................ 43 
Table 11-1 
Acceptable Blood PK Sampling Windows ........................................................... 46 
Table 11-2 
Acceptable Urine PK Sampling Windows ............................................................ 46 
Table 11-3 
Safety Laboratory Test Panels .............................................................................. 51 
Table 11-4 
Acceptable Methods of Contraception.................................................................. 56 
Table 13-1 
Grading of AE Severity ........................................................................................ 68 
Table 13-2 
Classifications for AE Causality ........................................................................... 68 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 69 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 69 
List of Figures 
Figure 8-1 
Schematic of Study Design VX15-371-101 ......................................................... 27 
Glossary of Terms 
Term 
Definition 
 
 
HS- 
Subject is not being treated with hypertonic saline (HS) at Screening. 
HS+ 
Subject is being treated with HS at Screening. 
Inhaled study drug 
VX-371 + placebo, VX-371 + HS, HS, and placebo administered by nebulizer 
Orkambi® (lumacaftor/ivacaftor) 
Lumacaftor/ivacaftor is the same drug as commercially available Orkambi. 
These terms are used interchangeably throughout the document. 
Orkambi- 
Subject is not being treated with Orkambi at Screening. 
Orkambi+ 
Subject is being treated with Orkambi at Screening. 
P-1037 
VX-371 has been developed under the name P-1037 by Parion Sciences 
Incorporated. 
Study drug 
Unless otherwise specified, the term “study drug” includes both inhaled study 
drug and orally administered lumacaftor/ivacaftor. 
 


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5 
INTRODUCTION 
5.1 
Background 
Cystic fibrosis (CF) affects an estimated 70,000 children and adults worldwide1 and is the most 
common fatal genetic disease in persons of European descent.2 Despite progress in the treatment 
of CF with antibiotics and mucolytics, the predicted median age of survival for a person with CF 
is in the mid-40s.2,3 Although the disease affects multiple organs, most morbidity and mortality 
is caused by progressive loss of lung function.4 
CF is an autosomal recessive genetic disease caused by a defect in the gene encoding the cystic 
fibrosis transmembrane conductance regulator (CFTR), an epithelial chloride ion (Cl-) channel 
activated by cyclic AMP-dependent protein kinase A that is responsible for aiding in the 
regulation of salt and water absorption and secretion in various tissues.2 This function is 
defective in patients with CF due to a loss of either cell surface expression and/or function. 
More than 1900 mutations in the CFTR gene have been identified.5 The most prevalent mutation 
is an in-frame deletion in the CFTR gene resulting in a loss of phenylalanine at position 508 in 
the CFTR protein (F508del-CFTR).5 In the US, almost 87% of patients with CF have at least 
1 copy of the F508del-CFTR mutation, and approximately 47% have 2 copies.6 The 
F508del-CFTR mutation interferes with the ability of the CFTR protein to reach and remain at 
the cell surface, as well as to open and close, resulting in decreased Cl- transport.7,8 The 
combined effect is a marked reduction in F508del-CFTR-mediated Cl- secretion that impairs 
fluid regulation and promotes accumulation of thick sticky mucus in the airway. The mucus 
build-up obstructs the airways and predisposes the patient to chronic lung infections.9 
Mucociliary clearance (MCC) is an important airway defense mechanism that is essential for 
respiratory health. The primary function of MCC is to clear inhaled particles, including 
inflammatory and infectious agents, from the surface of the lung.10 MCC depends on the 
coordinated, high frequency beating action of the cilia that cover the inner surface of the airways. 
Efficient ciliary motion is in turn dependent on proper regulation of hydration on the epithelial 
surface. Volume depletion of the airway surface liquid (ASL) compromises the efficiency of 
MCC.11 Inhaled therapies available to improve MCC include Pulmozyme® (recombinant human 
dornase alfa, Roche/Genentech), which facilitates expectoration by breaking down DNA and 
decreasing sputum viscosity, and hypertonic saline (HS), which may improve airway surface 
hydration and improve MCC.  
Despite the availability of the above mentioned therapies to improve MCC, patients with CF 
experience progressive loss of lung function over time and remain at risk for suffering acute 
pulmonary exacerbations due to chronic bacterial airway infection, requiring hospitalization 
and/or treatment with antibiotics. Therefore, additional therapies to improve MCC are needed. 
For reasons that are not fully understood, CF is also associated with a paradoxically increased 
activity of epithelial sodium channels (ENaC). The resulting combination of inadequate secretion 
of chloride ions and excessive intracellular transport of sodium ions creates an osmotic gradient 
that results in relative dehydration of the secretions in the airway lumen.12,13 Inadequate 
clearance of secretions predisposes the airways to bacterial infection. Recurrent episodes of 
infection lead to a repetitive cycle of increasing inflammation, airway injury, mucociliary 


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impairment, hypersecretion, and chronic infection of the airway with mucoid strains of 
Pseudomonas aeruginosa. 
When applied topically to the airway, ENaC inhibitors such as amiloride can decrease ENaC 
activity, increase ASL height, and increase MCC.14 While amiloride’s low potency, 
hyperkalemia, and short half-life in the airway make it impractical as a clinical therapy, newer 
generations of inhaled ENaC inhibitors featuring an amiloride pharmacophore have been 
designed to potently inhibit ENaC function directly on the respiratory epithelium, while 
minimizing exposure to renal ENaC, thereby reducing the risk of hyperkalemia and increasing 
the therapeutic index.  
5.2 
VX-371 Solution for Inhalation 
VX-371 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.15 Sodium ions 
enter cells through apical ENaC and are transported out by the Na+/ K+ ATPase located at the 
basolateral membrane.16,17 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.18 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. Free neutrophil elastase activity is detectable 
in the sputum of patients with CF and chronic obstructive pulmonary disease (COPD), especially 
during acute exacerbations. The combination of water loss from the ASL due to ENaC over 
activity and the increase in mucus production by submucosal glands and goblet cells means that 
the solid fraction of airway secretions in CF exceeds the threshold required for optimal MCC. It 
is hypothesized that the inhibition of ENaC activity with VX-371 will increase hydration of 
airway secretions rendering them more susceptible to MCC and cough clearance in subjects with 
CF. 
 
and later by Parion Sciences Incorporated (Parion) where it was known as P-1037. 
 P-1037 is the same drug as VX-371. 
Additional information is available in the VX-371 Investigator’s Brochure. 
5.3 
Completed and Ongoing Clinical Studies With VX-371 
 
 


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5.3.2 
Phase 2a Study with VX-371 
Parion is conducting a Phase 2a study (Parion Study G201) with P-1037 (VX-371) in subjects 
with CF. The goal of Study G201 is to evaluate the safety and efficacy of VX-371 with and 
without 4.2% HS. The study plans to enroll 150 subjects with CF. 
The 2 major differences between the Parion Phase 2a study and the present study are: 


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• 
The Parion study is enrolling subjects with CF with no genotype restriction; the present study 
will enroll only subjects with CF who are homozygous for F508del-CFTR. 
• 
The Parion study excludes subjects being treated with any ivacaftor-containing regimen, 
which includes Orkambi, whereas the present study requires subjects to be treated with 
Orkambi throughout the study (see Section 5.4 for the rationale behind this requirement). 
5.4 
Rationale for Present Study 
 
 
 
 
 
 
 
 
 
 
 
   
The present study is designed to evaluate the safety and efficacy of VX-371 formulated with 
4.2% HS in comparison to 4.2% HS alone on lung function over 28 days of treatment in subjects 
with CF who are 12 years of age and older who are homozygous for the F508del-CFTR 
mutation. The treatment effect will be evaluated on top of the expected CF standard of treatment 
for this population, which includes lumacaftor and ivacaftor combination therapy (Orkambi), an 
FDA-approved treatment for CF in patients homozygous for the F508del-CFTR mutation.  
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 
lumacaftor/ivacaftor. Lumacaftor/ivacaftor is the same drug as commercially available Orkambi, 
and these terms are used interchangeably. 
6 
STUDY OBJECTIVES 
6.1 
Primary Objective 
To evaluate the safety and efficacy of treatment with VX-371 in HS compared to HS alone in 
subjects with CF who are ≥12 years of age, homozygous for the F508del-CFTR mutation, and 
being treated with Orkambi 
6.2 
Secondary Objectives 
• To evaluate the efficacy of treatment with VX-371 in HS compared with placebo in subjects 
with CF who are ≥12 years of age, homozygous for the F508del-CFTR mutation, and being 
treated with Orkambi 
• To evaluate the efficacy of treatment with VX-371 in HS compared with VX-371 in placebo 
in subjects with CF who are ≥12 years of age, homozygous for the F508del-CFTR mutation, 
and being treated with Orkambi 


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• To evaluate the efficacy of treatment with VX-371 in placebo compared with placebo in 
subjects with CF who are ≥12 years of age, homozygous for the F508del-CFTR mutation, 
and being treated with Orkambi 
• To investigate the pharmacokinetics (PK) of VX-371 in subjects with CF who are ≥12 years 
of age, homozygous for the F508del-CFTR mutation, and being treated with Orkambi 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoints 
• Results of safety and tolerability assessments of adverse events (AEs), spirometry, clinical 
laboratory values (urine, serum and plasma chemistry, hematology, and coagulation studies), 
standard 12-lead electrocardiograms (ECGs), vital signs, and ophthalmologic examinations 
• Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from 
study baseline at Day 28 in each Treatment Period 
7.2 
Secondary Endpoint 
• PK parameters for VX-371 
8 
STUDY DESIGN 
8.1 
Overview of Study Design 
This is a Phase 2a, randomized, double-blind, placebo-controlled, incomplete block, crossover, 
multicenter, study in subjects ≥12 years of age with CF who are homozygous for the 
F508del-CFTR mutation and who are being treated with Orkambi. All subjects must be receiving 
stable treatment with Orkambi before the first dose of inhaled study drug and through the Safety 
Follow-up Telephone Contact or Safety Follow-up Visit.  
Approximately 150 subjects will be randomized to 1 of the 4 treatment sequences as described in 
Table 8-1. Each treatment sequence will comprise:  
Treatment Period 1  Washout  Treatment Period 2 


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Table 8-1 
Study VX15-371-101 Treatment Sequences 
Sequence 
Treatment Period 1 
Treatment Period 2 
N 
1 
VX-371 + 4.2% HS 
4.2% HS 
50 
2 
4.2% HS 
VX-371 + 4.2% HS 
50 
3 
VX-371 + 0.17% saline (placebo) 
Placebo (0.17% saline) 
25 
4 
Placebo (0.17% saline) 
VX-371 + 0.17% saline (placebo) 
25 
 
A schematic of the study design is provided in Figure 8-1.  
The sponsor may decide to stop enrollment in the 2 treatment sequences containing 
VX-371 + placebo and placebo for administrative reasons (for example, unexpected difficulty 
with enrollment). Enrollment would continue in the 2 treatment sequences containing VX-371 + 
HS and HS to ensure adequate enrollment to maintain statistical power in the 2 treatment 
sequences yielding data for the study’s primary analysis. All planned analyses will be conducted 
regardless of number of subjects enrolled. 
 


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Figure 8-1 
Schematic of Study Design VX15-371-101 
 
 
 
This study includes the following periods: 
• Screening Period:  
o Day -28 to Day -1 relative to the first dose of inhaled study drug for Orkambi+/HS- 
subjects 
o Day -56 to Day -29 relative to the first dose of inhaled study drug for Orkambi-/HS-, 
Orkambi-/HS+, and Orkambi+/HS+ subjects  
• Run-in Period: Day -28 to Day -1 relative to the first dose of inhaled study drug (for 
Orkambi-/HS-, Orkambi-/HS+, and Orkambi+/HS+ subjects) 
• Treatment Period 
o Treatment Period 1: Day 1 (first dose of inhaled study drug) through Day 28 
o Washout Period: Day 29 through Day 56  
o Treatment Period 2: Day 57 through Day 84 
Screening 
Period 
 
Randomization 
Day  
1 
Safety 
Follow-up 
Telephone  
Contact 
Treatment 2 
Treatment Period 2 
Treatment Period 1 
Day 
57 
Day 
84 
Day 
14 
Day 
28 
Day 
70 
 
Treatment 1 
 
Day 
-28 
Day  
3 
Day 
59 
A.  For Orkambi+/HS- Subjects 
Screening 
Period 
 
Randomization 
Day  
1 
Safety 
Follow-up 
Telephone 
Contact 
Treatment 2 
Treatment Period 2 
Treatment Period 1 
Day 
57 
Day 
84 
Day 
-28 
Day 
14 
Day 
28 
Day 
70 
 
Treatment 1 
 
Day 
-14 
Run-in Period
Day 
-56 
Day  
3 
Day 
59 
B.  For Orkambi-/HS-, Orkambi-/HS+, and Orkambi+/HS+ Subjects 
28-day 
Washout 
Day  
112 
(+3 days) 
28-day 
Washout 
Day  
112 
(+3 days) 


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• Early Termination of Treatment Visit for a subject who discontinues from study drug 
treatment(s) and who does not complete the remaining assessments in the treatment period 
during which study drug treatment(s) is discontinued.  
• Safety Follow-up Telephone Contact will occur 28 days (+ 3 days) after the Day 84 Visit; or 
28 days (+ 3 days) after the Day 28 Visit for a subject who completes this visit but who will 
not be continuing into Treatment Period 2. (Note: Under certain circumstances, a safety 
Follow-up Telephone Contact may not be appropriate, and a Safety Follow-up Visit may be 
required.) 
• A Safety Follow-up Visit will occur 28 days (+ 3 days) after a subject’s last dose of study 
drug (whether inhaled study drug or lumacaftor/ivacaftor) in subjects who:  
o prematurely discontinue one or both study drugs during the course of either treatment 
period and do not complete the remaining assessments in the treatment period in which 
discontinuation occurred. In this circumstance, an ETT Visit is required in addition to the 
Safety Follow-up Visit (see Section 8.1.4). 
o have a clinical finding during the treatment period or during the 28-day Safety Follow-up 
Period that requires follow-up in the estimation of the PI. An ETT Visit may or may not 
be required in this circumstance (see Section 8.1.4). 
Maintenance of Stable Medication Regimen for CF: 
It is recommended that subjects remain on stable CF medication regimens from 28 days before 
Day 1 through the Safety Follow-up Telephone Contact with the exception of those subjects 
taking HS. Those subjects taking HS before the Screening Period will washout from HS during 
the Run-in Period from Day -28 to Day -1 and will not be allowed to take HS for through the 
Safety Follow-up Telephone Contact or Safety Follow-up Visit (other than as blinded inhaled 
study drug if allocated to a relevant treatment sequence). A stable medication regimen is defined 
as the current medication regimen that subjects have been following for at least 28 days before 
Day 1. Subjects are to be on stable CF medication (including Orkambi) for at least 28 days 
before dosing with inhaled study drug on Day 1. 
Specific requirements apply to certain CF medications: 
• Subjects must be on a stable regimen of lumacaftor/ivacaftor for a minimum of 28 days of 
treatment before the Day 1 Visit and continue this through the Safety Follow-up Telephone 
Contact. 
• Subjects who are on a stable regimen of a single inhaled antibiotic that is continuously 
administered should remain on this antibiotic through the Safety Follow-up Telephone 
Contact.  
• Subjects who are on a stable regimen of a single inhaled cycling antibiotic (e.g., Tobramycin 
Inhalation Solution [TOBI®] regimen) should remain on this antibiotic through the Safety 
Follow-up Telephone Contact. Inhaled cycling antibiotics should be administered in 
28-day-on/28-day-off cycles.  
Clinic visits on Day 1 and Day 57 should be timed to occur exactly at the start of an 
on-cycle; treatment during the on-cycle should then end after no more than 28 days.  


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• At the time of study entry, subjects who are on an alternating regimen of inhaled cycling 
antibiotics that comprise continuous administration of antibiotics (e.g., TOBI administration 
alternating with Cayston®) should remain on these antibiotics according to their alternating 
regimens through the Safety Follow-up Telephone Contact.  
The first dose of inhaled study drug in each Treatment Period should coincide exactly with 
the first dose of the same cycled inhaled antibiotic (e.g., if TOBI is being administered first 
and Cayston second in the cycle, the Day 1 and Day 57 Visit should coincide with the first 
dose of TOBI). 
8.1.1 
Screening 
Screening Visit assessments are listed in Table 3-1. All subjects will complete the Screening 
Visit.  
Screening will occur between Day -28 and Day -1 for Orkambi+/HS- subjects, and between 
Day -56 and Day -29 for Orkambi-/HS-, Orkambi-/HS+, and Orkambi+/HS+ subjects. Screening 
will occur before the first dose of inhaled study drug to confirm that subjects meet the selection 
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. During the 
Screening Visit it should be determined whether the subject will have a Run-in Period.  
Table 8-2 outlines the assignment of subjects to a Run-in Period. 
Table 8-2 
Run-in Period Subject Assignment  
Treatment at 
Screening Visit 
Run-in Perioda 
HS 
Source of Orkambi or 
Lumacaftor/Ivacaftor 
Orkambi 
HS 
+ 
- 
No; subjects go directly 
from Screening to Day 1 
N/A 
Subjects will take their commercial Orkambi 
during the Screening Period, and will be 
given sponsor-supplied lumacaftor/ivacaftor 
starting on Day 1 
+ 
+ 
Yes 
Washout from HS 
Subjects will take their commercial Orkambi 
during the Screening and Run-in Periods, 
and will be given sponsor-supplied 
lumacaftor/ivacaftor starting on Day 1 
- 
- 
Yes 
N/A 
Subjects will be given sponsor-supplied 
lumacaftor/ivacaftor starting on the first day 
of the Run-in Period 
- 
+ 
Yes 
Washout from HS 
Subjects will be given sponsor-supplied 
lumacaftor/ivacaftor starting on the first day 
of the Run-in Period 
a  
Subjects with a Run-in Period must complete both the Day -28 and Day -14 Visits. Further details about the 
Run-in Period are provided in Section 8.1.2. 
To prepare for study participation, subjects will be instructed on the study restrictions and use of 
concomitant medications (Section 9.3 and Section 9.4). 


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8.1.1.1 
Repetition of Screening Assessment(s) 
Repetition of individual screening assessment(s) that did not meet eligibility criteria is not 
permitted with the following exceptions:  
• If there is clear evidence of a laboratory error (e.g., hemolyzed sample) or equipment 
malfunction, collection of a repeat sample for the appropriate laboratory test or assessment 
may be permitted with the approval of the medical monitor. 
• Exclusionary liver function test (LFT) levels or plasma potassium levels, which may be 
retested within 14 days of the original screening date. 
If screening spirometry measurements fail to meet acceptability and repeatability criteria as 
specified by American Thoracic Society/European Respiratory Society guidelines,20 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. 
8.1.1.2 
Rescreening 
Subjects may be rescreened after discussion with, and approval from, the medical monitor. If a 
subject is rescreened, all Screening Visit assessments will be repeated except for CF genotyping, 
follicle-stimulating hormone (FSH) level (if serum FSH level was ≥40 mIU/mL during prior 
screening), sweat chloride level, and the ophthalmologic examination (if the ophthalmologic 
examination was performed within the last 3 months before the Rescreening Visit). Subjects may 
only be rescreened once. If a subject is rescreened, the screening window will begin once the 
first rescreening assessment has been initiated. 
8.1.1.3 
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 8.1.1.1) 
• Unexpected operational or logistic delays, or to meet the eligibility criteria 
• Additional time to conduct ophthalmologic examinations (Section 11.6.5) 
8.1.2 
Run-in Period 
Run-in Period assessments are listed in Table 3-2. 
As described in Section 8.1.1, subjects who are not already being treated with commercially 
available Orkambi as part of their CF standard of care will enter the Run-in Period, which will 
occur between Day -28 and Day -1 before the first dose of inhaled study drug. These subjects 
will be provided with lumacaftor 200 mg/ivacaftor 125 mg tablets and are to take 2 tablets orally 
every 12 hours (q12h) with fat-containing food for a minimum of 28 days before dosing with 
inhaled study drug on Day 1.    
Subjects who are receiving HS as part of their CF standard of care will washout from HS during 
the Run-in Period for at least 28 days before dosing with inhaled study drug on Day 1. 
Note: For subjects who are taking commercially available Orkambi as part of their CF standard 
of care (Orkambi+/HS+ subjects), the last dose of commercially available Orkambi will be the 


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morning dose of the Day 1 Visit. For subjects who are being provided Orkambi by Vertex during 
the Run-in Period (Orkambi-/HS- and Orkambi-/HS+ subjects), the last dose of Orkambi during 
the Run-in Period will be the morning dose of the Day 1 Visit. 
Study visits will occur on Day -28 and Day-14 relative to the first dose of inhaled study drug on 
Day 1.  
8.1.3 
Treatment Periods 
Treatment Period assessments are listed in Table 3-3. 
8.1.3.1 
Treatment Period 1 
The first dose of inhaled study drug will be administered after randomization on Treatment 
Period 1 Day 1. This must also be the first “on” day for single cycled inhaled antibiotics (e.g., 
TOBI) and the first day of a new “on” period for an inhaled antibiotic in a continuous alternating 
regimen,  
Inhaled study drug should be taken according to instructions provided. Study visits will occur on 
Day 1, Day 14, and Day 28. On Day 3, subjects will have a telephone contact for safety purposes 
(e.g., inquire about AEs). The last dose of inhaled study drug in Treatment Period 1 is the dose of 
inhaled study drug received at the Day 28 Visit.  
Note: All subjects, whether they are taking commercially available Orkambi or Vertex-supplied 
Orkambi, must take a dose of Orkambi on the morning of the Day 1 Visit. All remaining doses of 
lumacaftor/ivacaftor for the duration of the study will be supplied by Vertex at the Day 1 Visit 
(see Section 10.2.2). 
8.1.3.2 
Washout Period 
Subjects will undergo a Washout Period of 28 days (+ 3 days) between the 2 Treatment Periods 
and must have at least 14 days in their “off-period” for inhaled single cycled antibiotics or at 
least 14 days of the “alternate” antibiotic for a continuous cycled 2 antibiotic regimen.  
The Washout Period may be extended for acute upper or lower respiratory infection, pulmonary 
exacerbation, or changes in therapy (including antibiotics); extension of the Washout Period 
must be discussed with the medical monitor. 
8.1.3.3 
Treatment Period 2 
The first dose of inhaled study drug in Treatment Period 2 will be administered at the Day 57 
Visit. This must also be the first “on” day for single cycled inhaled antibiotics (e.g., TOBI) and 
the first day of a new “on” period for an inhaled antibiotic in a continuous alternating regimen, 
provided that at least 14 days have elapsed with no inhaled antibiotic (single cycled regimen) or 
the other antibiotic (continuous cycling of 2 antibiotics).  
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 (first dose of inhaled study drug in 
Treatment Period 2) and must not have any “non-CF-related” illness within 2 weeks before the 
Day 57 Visit (first dose of inhaled study drug in Treatment Period 2). “Illness” is defined as an 
acute (serious or non-serious) condition (e.g., gastroenteritis). If the subject does not meet these 
criteria, then the continuation of the subject into Treatment Period 2 should be discussed with the 
medical monitor.  


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Inhaled study drug should be taken according to instructions provided. The last dose of inhaled 
study drug in Treatment Period 2 is the dose of inhaled study drug at the Day 84 Visit.  
Study visits will occur on Day 57, Day 70, and Day 84. On Day 59, subjects will have a 
telephone contact for safety purposes (e.g., inquire about adverse events).  
8.1.4 
Early Termination of Treatment  
A subject who prematurely discontinues inhaled study drug will continue to take 
lumacaftor/ivacaftor. Conversely, a subject who discontinues lumacaftor/ivacaftor will continue 
to take inhaled study drug. Subjects who prematurely discontinue one or both study drugs will be 
asked to complete the remaining assessments in the treatment period during which treatment was 
discontinued. If all assessments are completed, an ETT Visit is not required.  
A subject who discontinues from study drug treatment(s) and who does not complete the 
remaining assessments in the treatment period during which study drug treatment(s) is 
discontinued is required to complete an ETT Visit, which is to be scheduled as soon as possible 
after it is confirmed that the subject does not intend to complete the remaining assessments.  
A subject who prematurely discontinues from one or both study drugs in Treatment Period 1 will 
not continue into Treatment Period 2. 
If the ETT Visit occurs 28 days or later following the last dose of study drug, then the ETT Visit 
will replace the Safety Follow-up Visit (Section 8.1.6), and neither a Safety Follow-up Visit nor 
a Safety Follow-up Telephone Contact is required.  
If the subject withdraws consent for the study, no further evaluations should be performed, and 
no additional data should be collected. Vertex may retain and continue to use any data collected 
before such withdrawal of consent. 
8.1.5 
Safety Follow-up Telephone Contact 
The Telephone Contact is a phone interview for the purpose of collecting information on AEs. A 
Safety Follow-up Telephone Contact is scheduled to occur 28 days (+3 days) after the Day 84 
Visit for subjects who complete this visit, or 28 days (+3 days) after the Day 28 Visit for subjects 
who complete this visit but who will not be continuing into Treatment Period 2 (see 
Section 8.1.4).  
Under certain circumstances, a safety Follow-up Telephone Contact may not be appropriate, and 
a Safety Follow-up Visit may be required, as delineated in Section 8.1.6. 
8.1.6 
Safety Follow-up Visit 
Safety Follow-up Visit assessments are listed in Table 3-4.  
A Safety Follow-up Visit will occur 28 days (+ 3 days) after a subject’s last dose of study drug 
(whether inhaled study drug or lumacaftor/ivacaftor) in subjects who:  
• prematurely discontinue one or both study drugs during the course of either treatment period 
and do not complete the remaining assessments in the treatment period in which 
discontinuation occurred. In this circumstance, an ETT Visit is required in addition to the 
Safety Follow-up Visit (see Section 8.1.4). 


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• have a clinical finding during the treatment period or during the 28-day Safety Follow-up 
Period that requires follow-up in the estimation of the PI. An ETT Visit may or may not be 
required in this circumstance (see Section 8.1.4).  
8.1.7 
Independent Data Monitoring Committee 
An independent data monitoring committee (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 inhaled study drug regimen to ensure the subjects’ safety (Section 12.3.4). Procedural 
details of the IDMC’s structure and function, frequency of meetings, and data planned for review 
will be included in the IDMC charter.  
8.2 
Rationale for Study Design and Study Drug Regimens 
8.2.1 
Study Design 
This Phase 2a, randomized, double-blind, placebo-controlled, incomplete block, crossover, 
multicenter study in subjects ≥12 years of age with CF who are homozygous for the 
F508del-CFTR mutation and receiving stable Orkambi treatment is designed to evaluate the 
safety, efficacy, and PK of treatment with VX-371 in 4.2% HS compared to 4.2% HS alone.  
A randomized, double-blind, placebo-controlled study design was selected to avoid observer bias 
and reduce symptoms or outcomes arising from the investigator’s or the subject’s knowledge of 
treatment. A crossover design in which subjects are randomized to 1 of 4 treatment sequences 
will enable within-subject comparison of selected treatment effects with increased statistical 
power. A 28-day washout period is judged to be of sufficient duration for all subjects to return to 
their baseline values for FEV1 and to accommodate synchronization with cycling inhaled 
antibiotics.  
There are 2 primary endpoints; the first is to evaluate safety and tolerability, and the second is to 
evaluate efficacy as measured by the absolute change in ppFEV1 from study baseline at Day 28 
in each Treatment Period. Although the primary objectives are to evaluate the safety and efficacy 
of VX-371 in 4.2% HS versus 4.2% HS alone, 2 additional treatment sequences will compare 
VX-371 in 0.17% saline (placebo) versus 0.17% saline (placebo). These comparisons will 
provide insight with respect to the effect of VX-371 alone 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 VX-371 because allocation to this component will remain unknown to 
both investigators and subjects. 
A sample size of approximately 150 subjects is considered feasible and is expected to provide 
sufficient data to evaluate the efficacy, safety, and PK of VX-371 formulated with and without 
HS. The unbalanced randomization ratio permits more subjects to be used to address the primary 
study objective. 
8.2.2 
Study Drug Dose and Duration 
 
 
Thus, the current study is designed to demonstrate safety and efficacy of an 85 µg dose of VX-
371 administered bid by oral inhalation in subjects with CF.  


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Parion Study PS-G201 is an ongoing randomized, double-blind, placebo-controlled, 
parallel-group study to evaluate the safety and efficacy of 85 µg VX-371 bid in subjects with CF. 
The recommendations of a planned IDMC review of safety data indicated that no safety-related 
changes to the study conduct were needed and supported enrollment of pediatric subjects 12 to 
17 years of age. Further, the nonclinical safety toxicology data (see the VX-371 Investigator’s 
Brochure for details) supports 28 days of continuous treatment of VX-371 in the current study.  
8.2.3 
Rationale for Study Assessments 
Spirometry: Lung function in CF declines with age and is a significant predictor of mortality.21 
Spirometry (as measured by FEV) is the most widely implemented standardized assessment to 
evaluate lung function.22,23 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, is the 
recommended primary clinical endpoint in efficacy studies for CF. 
 
 
 
 
 
 
9 
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are enrolled. 


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9.1 
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 study manual. 
4. Subjects (male and female) will be aged 12 years or older on the date of ICF or, where 
appropriate, date of assent. 
5. Subjects with confirmed diagnosis of CF,36 defined as a sweat chloride value ≥60 mmol/L by 
quantitative pilocarpine iontophoresis. A sweat chloride test must be performed at the 
Screening Visit if an eligible sweat chloride value is not available in the subject’s medical 
records and the Screening Visit value is needed to establish eligibility. For subjects using 
sweat chloride values documented in their medical records to establish eligibility, the sweat 
chloride test at the Screening Visit is optional. If both results are available, the result from the 
Screening Visit will be used to determine eligibility. 
6. Subjects who are homozygous for F508del-CFTR. If the CFTR screening genotype result is 
not received before randomization, a previous CFTR genotype lab report may be used to 
establish eligibility. Note: Subjects who have been randomized and whose screening 
genotype does not confirm study eligibility must be discontinued from the study as described 
in Section 9.5.  
7. Subjects with ppFEV1 of ≥40 to <90 percentage points adjusted for age, sex, and height 
according to the Global Lung Initiative (GLI)37 at the Screening Visit.  
8. Subjects with stable CF disease as deemed by the investigator. 
9. Subjects who are willing to remain on a stable CF medication regimen through the Safety 
Follow-up Telephone Contact.  
10. Subjects who are willing to discontinue physician-prescribed HS use. 
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 Visit before receiving the first dose of inhaled study drug. 
12. Subjects of childbearing potential and who are sexually active must meet the contraception 
requirements outlined in Section 11.6.7.1.  
9.2 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria will not be eligible. 
1. History of any comorbidity, which in the opinion of the investigator, might confound the 
results of the study or pose an additional risk in administering study drug to the subject. For 
example, clinically significant adrenal disease, or any present history of any clinically 
significant and uncontrolled neurologic, gastrointestinal, renal, hepatic, cardiovascular 
(including hyper/hypotension and tachy/bradycardia), psychological, pulmonary (other than 


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CF), metabolic, endocrine, or hematological disorder or disease, or any other major disorder 
or disease, in the opinion of the investigator.  
2. Any clinically significant laboratory abnormalities at the Screening Visit that would interfere 
with the study assessments or pose an undue risk for the subject (as deemed by the 
investigator). 
3. Any of the following abnormal laboratory values at the Screening Visit: 
• Hemoglobin <10 g/dL 
• Abnormal liver function defined as any 2 or more of the following:  
o ≥3 × upper limit of normal (ULN) aspartate aminotransferase (AST)  
o ≥3 × ULN alanine aminotransferase (ALT)  
o ≥3 × ULN gamma-glutamyl transpeptidase  
o ≥3 × ULN alkaline phosphatase  
• ALT or AST >5 × ULN  
• Total bilirubin >2 × ULN 
• Abnormal renal function, defined as creatinine clearance rate <50 mL/min/1.73 m2 using 
the Bedside Schwartz equation38 (for subjects 12 to 17 years of age) or <50 mL/min 
using the Cockcroft-Gault equation39 (for subjects ≥18 years of age)  
• Plasma potassium >ULN 
4. An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy 
(including antibiotics) for pulmonary disease within 28 days before Day 1 (first dose of 
inhaled study drug). 
5. A 12-lead ECG demonstrating QTcF >450 msec at the Screening Visit. If QTcF exceeds 
450 msec for the screening ECG, the ECG should be repeated 2 more times during the 
Screening Period, and the average of the 3 QTcF values should be used to determine the 
subject’s eligibility. 
6. History of solid organ or hematological transplantation. 
7. Used diuretics (including amiloride) or renin-angiotensin aldosterone system 
antihypertensive drugs (spironolactone, angiotensin converting enzyme [ACE] inhibitors, or 
angiotensin receptor blockers [ARBs]), drospirenone, or trimethoprim in the 28 days prior to 
Screening or an anticipated need for any of these medications during the study.  
8. Ongoing or prior participation in an investigational drug study within 30 days of the 
Screening Visit.  
• A washout period of 5 terminal half-lives of the previous investigational study drug, or 
30 days, whichever is longer, must elapse before the Screening Visit.  
• The duration of the elapsed time may be longer if required by local regulations.  
Note: Ongoing participation in a noninterventional study (including observational 
studies) is permitted. 


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9. Inability to withhold short-acting, long-acting, or once-daily, long-acting bronchodilator use 
for 4, 12, or 24 hours prior to clinic visit, respectively. 
10. History of significant intolerance to inhaled HS. 
11. Known hypersensitivity or history of intolerance to Orkambi. 
12. Known hypersensitivity to the VX-371 or amiloride. 
13. Use of restricted medication or food within specified duration before the first dose of study 
drug as defined in Section 9.3. 
14.  Pregnant and nursing females. 
15. Subjects who have participated in Parion Sciences Study PS-G201. 
16. The subject or a close relative of the subject is the investigator or a subinvestigator, research 
assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of 
the study. 
9.3 
Study Restrictions 
Prohibited medications and certain foods are not allowed in this study (Screening Period through 
Safety Follow-up Telephone Contact) as summarized in Table 9-1. A non-exhaustive list of 
study prohibitions and cautions for food and medication will be provided in the Study Reference 
Manual.  
Table 9-1 
Study Restrictions 
Restricted Medication/Food 
Study Period 
Screening Period 
Treatment Period Through 
Safety Follow-up Telephone 
Contact 
Strong CYP3A inducers 
None allowed within 14 days before 
the first dose of study drug 
None allowed 
Strong CYP3A inhibitors 
• For subjects who have been 
receiving Orkambi as background 
therapy for at least 7 days before 
the Screening visit, there is no 
restriction 
• For all others, none allowed within 
14 days before the first dose of 
lumacaftor/ivacaftor 
Use with caution 
Hypertonic saline 
None allowed within 28 days before 
the first dose of inhaled study drug 
 
None allowed  
Diuretics (including amiloride)   
None allowed  
 
 
None allowed  
Renin-angiotensin antihypertensive drugs 
(e.g. spironolactone, angiotensin-
converting-enzyme (ACE) inhibitors, or 
angiotensin receptor blockers)  
None allowed 
 
 
 
None allowed 


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Table 9-1 
Study Restrictions 
Restricted Medication/Food 
Study Period 
Screening Period 
Treatment Period Through 
Safety Follow-up Telephone 
Contact 
Drospirenone 
None allowed within 14 days before 
the first dose of inhaled study drug 
  
None allowed 
Trimethoprim 
None allowed within 14 days before 
the first dose of inhaled study drug 
None allowed 
Note: The use of restricted medication in subjects with a medical need will be addressed on a case-by-case basis 
with the medical monitor. 
 
9.4 
Prior and Concomitant Medications 
Information regarding all prior and concomitant medications, including the subject’s CF 
medications, other medications, and herbal and naturopathic remedies administered from 30 days 
before the Screening Period through the Safety Follow-up Telephone Contact 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. 
• Subjects must remain on a stable medication (and supplement) regimen for their CF from the 
Run-in Period through the Day 84 Visit, and, if applicable, through the Safety Follow-up 
Telephone Contact. Stable medication regimen is defined as the current medication regimen 
for CF that subjects have been following for at least 28 days before the Day 1 Visit; this 
includes treatment with Orkambi but excludes treatment with HS. Subjects must not initiate 
long-term treatment with new medication from 28 days before the Day 1 Visit through the 
Safety Follow-up Telephone Contact unless it is discussed and approved by the medical 
monitor. Guidelines for stable inhaled antibiotic regimens for CF are as follows: 
o Subjects who are taking daily inhaled tobramycin or other chronically inhaled antibiotics 
should remain on that regimen throughout the study. 
o Subjects who are on inhaled cycling antibiotics should continue on their prior schedule. 
The timing of the first dose of inhaled study drug in Treatment Periods 1 and 2 (i.e., the 
Day 1 and Day 57 Visits, respectively) should be timed to occur exactly at the start of an 
on-cycle synchronized; treatment during the on-cycle should then end after no more than 
28 days. 
o Subjects who alternate 2 different antibiotics monthly should remain on the same 
schedule during the study. The timing of the first dose of inhaled study drug in each 
Treatment Period should coincide exactly with the first dose of the same cycled inhaled 
antibiotic (e.g., if TOBI is being administered first and Cayston second in the cycle, the 
Day 1 and Day 57 Visit should coincide with the first dose of TOBI). 
• Information about bronchodilator use during the study will be collected and documented. 
Subjects who are using a bronchodilator must have their spirometry assessments performed 
according to the guidelines provided in Section 11.5.1. 


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9.4.1 
Prohibited Medications 
Prohibited medications are described in Table 9-1. 
The use of cytochrome P450 (CYP) 3A substrates is not prohibited in this study, but 
investigators need to be aware that lumacaftor appears to be a strong inducer of this CYP 
isoenzyme. Therefore, the efficacy of drugs extensively metabolized by this isoenzyme may be 
affected. Each investigator should evaluate the benefit/risk ratio of using such drugs with 
lumacaftor during this study. Investigators should discuss any concerns regarding the use of 
CYP3A substrates during this study with the medical monitor. 
The use of CYP2C and 2B6 substrates are not prohibited in this study, but investigators need to 
be aware that lumacaftor has been shown in vitro to induce CYP2B6, CYP2C8, CYP2C9, and 
CYP2C19; inhibition of CYP2C8 and CYP2C9 has also been observed in vitro. Additionally, in 
vitro studies suggest that ivacaftor may inhibit CYP2C9. Therefore, concomitant use of 
lumacaftor in combination with ivacaftor with CYP2B6, CYP2C8, CYP2C9, and CYP2C19 
substrates may alter the exposure of these substrates. Each investigator should evaluate the 
benefit to risk ratio of using such drugs with lumacaftor and ivacaftor during this study and 
discuss the use of these substrates during this study with the medical monitor. 
A non-exhaustive study prohibitions and cautions list for food and medications will be provided 
in the Study Reference Manual. 
9.5 
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 Vertex 
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 prematurely discontinue study drug treatment should continue to return for study 
assessments, as noted in Section 8.1.4.  
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 a Safety Follow-up Visit, if 
applicable (see Section 8.1.4), and follow up with the subject regarding any unresolved AEs. 
Subjects who are randomized on the basis of a historical genotyping lab result and whose 
screening genotype does not confirm eligibility will be discontinued from study drug treatment. 
These subjects will undergo ETT and/or Safety Follow-up Visits per Sections 8.1.4 and 8.1.6, 
and will then be discontinued from the study. After discontinuation from study drug treatment, 
these subjects will not undergo any further assessments other than those performed at the ETT 
and/or Safety Follow-up Visits.  
If the subject withdraws consent for the study, no further evaluations will be performed and no 
additional data will be collected. Vertex may retain and continue to use any data collected before 
such withdrawal of consent. 


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A subject will be withdrawn from study drug treatment for any of the following reasons: 
• Vertex, 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. 
• Development of a life-threatening AE or a serious adverse event (SAE) that places him/her at 
immediate risk, and discontinuation of study treatment deemed necessary. 
A subject may be withdrawn from study drug treatment after a discussion between the 
investigator and the 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. 
• An increase in transaminases (ALT or AST) according to evaluations and management 
described in Section 11.6.2.1. 
• A potassium level >ULN. A confirmatory 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 11.6.2.2 for further guidance on treatment of hyperkalemia.  
9.6 
Replacement of Subjects 
Subjects who withdraw or are withdrawn during the Screening or Run-in periods may be 
replaced at the discretion of the Sponsor. Subjects who withdraw or are withdrawn during the 
study drug Treatment Period(s) will not be replaced. 
10 
STUDY DRUG ADMINISTRATION AND MANAGEMENT 
10.1 
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. 
10.2 
Administration 
10.2.1 
Nebulizer 
Inhaled study drug will be administered bid approximately 10 to 12 hours apart (Section 8.2.2) 
by a PARI eFlow nebulizer. The nebulizer device (nebulizer and handset) will be provided to the 
subject for use with the inhaled study drug at the Day 1 Visit. This nebulizer has been 
customized to be used only with the inhaled study drug and is not to be used for the inhalation of 
other treatments. Additionally, it is important that the subjects use the provided nebulizer for 
inhalation of study drug and not use any other PARI eFlow 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 identification information will be documented for each subject. A new nebulizer 
handset will be provided for replacement at the Day 57 Visit. 


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Subjects are required to use the correctly assembled device, into which inhaled study drug has 
been added, and to nebulize through oral inhalation while sitting up, with the device held 
horizontally and breathing more deeply than normal tidal breathing. This should be continued 
until the nebulizer device indicates that all inhaled study drug has been delivered.  
A replacement nebulizer and/or handset may be provided at other times during the study if 
necessary (Section 10.9).  
10.2.2 
Lumacaftor in Combination With Ivacaftor 
All subjects are to be on a stable regimen of lumacaftor/ivacaftor for at least 28 days before the 
Day 1 Visit and are to continue taking lumacaftor/ivacaftor through the Safety Follow-up 
Telephone Contact.  
Subjects who are taking commercially available Orkambi at Screening (i.e., Orkambi+/HS- and 
Orkambi+/HS+ subjects) will continue to take their commercially available Orkambi during the 
Screening Period. Subjects who are Orkambi+/HS+ will continue to take their commercially 
available Orkambi during the Run-in Period while they washout from HS. The last dose of 
commercially available Orkambi for Orkambi+/HS- and Orkambi+/HS+ subjects will be the 
morning dose of the Day 1 Visit.  
Subjects not already being treated with commercially available Orkambi (i.e., Orkambi-) will be 
provided with lumacaftor/ivacaftor by Vertex at the start of the Run-in Period and must continue 
to take it for the remainder of the study (i.e., through the Safety Follow-up Telephone Contact); 
for these subjects, the last dose of lumacaftor/ivacaftor during the Run-in Period will be the 
morning dose of the Day 1 Visit.  
All subjects, whether they are taking commercially available Orkambi or Vertex-supplied 
lumacaftor/ivacaftor, must take a dose of Orkambi on the morning of the Day 1 Visit. All 
remaining doses of lumacaftor/ivacaftor for the duration of the study (i.e., through Safety 
Follow-up Telephone Contact) will be supplied by Vertex at the Day 1 Visit. Subjects must not 
take both commercially available Orkambi and Vertex-supplied lumacaftor/ivacaftor (i.e., double 
dosing must be avoided). 
Subjects are to take 2 tablets (each containing lumacaftor 200 mg/ivacaftor 125 mg) orally q12h 
with fat-containing food. Examples of appropriate fat-containing foods include eggs, avocados, 
nuts, butter, peanut butter, cheese pizza, whole-milk dairy products (such as whole milk, cheese, 
and yogurt), etc. If a subject misses a dose and remembers the missed dose within 6 hours, the 
subject should take the dose with fat-containing food. If more than 6 hours elapsed after the 
usual dosing time, the subject should skip that dose and resume the normal schedule for the 
following dose. A double dose should not be taken to make up for the forgotten dose 
(Section 10.6.2). 
Arrangements will be made for the return of any unused lumacaftor/ivacaftor for final 
accountability (refer to the Pharmacy Manual for more detail). 
10.3 
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 (VX-
371 + 4.2% HS versus 4.2% HS; 4.2% HS versus VX-371 + 4.2% HS; VX-371 + placebo versus 
placebo; placebo versus VX-371 + placebo), 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. 
An interactive web response system (IWRS) will be used to assign subjects to treatment 
sequence. Detailed instructions for randomization will be provided separately. 
10.4 
Dose Modification for Toxicity 
Modifications of study drug doses are prohibited. Interruptions of study drug dosing should be 
discussed with the medical monitor and may be considered on a case-by-case basis after 
discussion with the medical monitor. Specific instructions for interruption for elevated LFTs and 
plasma potassium are provided in Section 11.6.2. 
10.5 
Study Drug Interruption 
If study drug dosing must be interrupted for more than 72 hours, the medical monitor must be 
notified. In these instances, study drug dosing may only resume after signed approval by the 
medical monitor. Specific instructions for interruption for prohibited medications, elevated LFT 
levels, and hyperkalemia are provided in Sections 9.3 and 9.4.1, Section 11.6.2.1, and 
Section 11.6.2.2, respectively. 
10.6 
Missed Doses 
10.6.1 
Inhaled Study Drug 
On Non-Study Visit Days: 
• If a subject misses a dose of inhaled study drug and remembers the missed dose within 
6 hours, the subject should take the dose of inhaled study drug. 
• If more than 6 hours elapsed after the usual dosing time, the subject should skip that dose of 
inhaled 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 Study Visit Days (Afternoon Visits Only): 
• If a subject misses a dose of inhaled study drug and remembers the missed dose within 
6 hours of an afternoon study visit, the subject should NOT take the missed dose. If the 
missed dose is taken within 6 hours of the study visit, the subject should alert site personnel 
upon arrival to the site. 
10.6.2 
Lumacaftor in Combination With Ivacaftor 
If a subject misses a dose of lumacaftor/ivacaftor and remembers the missed dose within 6 hours, 
the subject should take the dose with fat-containing food. If more than 6 hours elapses after the 
usual dosing time, the subject should skip that dose and resume the normal schedule for the 
following dose. A double dose should not be taken to make up for the forgotten dose. 
10.7 
Packaging and Labeling 
Inhaled study drug (85 µg VX-371 in 4.2% HS; 4.2% HS; 85 µg VX-371 plus 0.17% saline 
[placebo]; and placebo [0.17% saline]) will be supplied by Vertex in blow-fill seal vials that are 
filled to deliver 3 mL of inhaled study drug.  
Vertex will supply the lumacaftor 200-mg/ivacaftor 125-mg tablets in child-resistant weekly 
blister cards. Study drug labeling will be in compliance with applicable local and national 


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regulations. Additional details regarding packaging, labeling, and dispensing for inhaled study 
drug and Orkambi will be included in the Pharmacy Manual. 
10.8 
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 will be accounted for as detailed in 
Section 10.9. 
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) 
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 + 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) 
Lumacaftor/ 
ivacaftor  
(fixed-dose) 
Fixed-dose 
tablet/ 
oral 
400-mg lumacaftor/ 
250-mg ivacaftor  
Supplied as 200-mg 
lumacaftor/125-mg 
ivacaftor tablets 
Store at ≤30°C (86°F) 
 
10.9 
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 and returned by the subjects; and 
(3) nebulizer and nebulizer handsets dispensed to and returned by the subjects. Subjects will be 
instructed to return all used and unused materials associated with the study drugs to the site. 
These materials will be retained at the site according to instructions provided by Vertex or its 
designee until inventoried by the study monitor. The study monitor will review study drug 
records and inventory throughout the study. 
10.10 
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 Vertex. Destruction will be adequately documented. 


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Procedures for destruction or return of the inhaled study drug and Vertex-supplied 
lumacaftor/ivacaftor will be detailed in the Pharmacy Manual. 
10.11 
Compliance  
To maximize treatment compliance during the study, the investigator or designee will supervise 
inhaled study drug dosing and nebulizer use at each visit. At each visit, site personnel will review 
subject compliance with study drug dosing and remind the subject of study drug dosing 
requirements. Compliance will also be assessed by ongoing study drug count. 
If a subject demonstrates continued noncompliance of study drug dosing despite educational 
efforts, the investigator should contact the medical monitor to discuss discontinuation of the 
subject from the study treatment. 
10.12 
Blinding and Unblinding 
This is a double-blind study. 
10.12.1 
Blinding  
The subjects and all site personnel, including the investigator, the site monitor, and the study 
team, will be blinded 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 the 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 
• Vertex IXRS Management for IXRS oversight and system administration 
• IDMC 
• Vendor preparing the unblinded analysis for the IDMC  
• The bioanalytical external vendor personnel assigned to the study and Vertex Bioanalysis 
CRO Monitors who will not be participating in the study team 
• The medical monitor may, for matters relating to safety concerns, unblind individual subjects 
at any time 
Spirometry Data Blinding 
Despite treatment blinding, knowledge of the spirometry results has the potential to suggest 
whether a subject has been administered active inhaled study drug or placebo. Therefore, during 
the conduct of the study, the Vertex study team will have no access to the postdose spirometry 
data. The vendor for central reading of the spirometry data will send only the blinded spirometry 
files (blinded treatment group, with real values for screening and baseline, but with dummy 
values for all the spirometry assessments after baseline) to Vertex to be used for developing the 
statistical programs. Furthermore, subjects and their caregivers should not be informed of their 


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study-related spirometry results during the Treatment Period regardless of whether the subject 
has prematurely discontinued treatment. 
10.12.2 
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 an 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 treatment 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 medical monitor to discuss and agree 
to the need for unblinding. If investigators deem it not necessary to unblind immediately, they 
will first attempt to contact the medical monitor to discuss and agree to the need for unblinding. 
If investigators have tried but are unable to reach the 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 medical 
monitor. 
Contact information for the medical monitor (or appropriate backup) will be provided in a 
separate document. 
In addition, the Vertex Medical Information Call Center 
 will answer calls 
24 hours a day, 7 days a week, 365 days of the year, and will triage these calls to the study 
medical monitor or appropriate backup. 
If a subject’s treatment assignment has been unblinded for a medical emergency or urgent 
clinical situation, the medical monitor will be notified within 24 hours of the unblinding 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 the sponsor (Vertex), contract 
research organization (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 or designee, per Section 13.1. 
Vertex GPS or designee will also unblind any SAE reports in compliance with regulatory 
reporting requirements. In addition, Vertex may, for matters relating to safety concerns, unblind 
individual subjects at any time.  
11 
ASSESSMENTS 
11.1 
Timing of Assessments 
The timing of assessments is shown in Table 3-1, Table 3-2, Table 3-3, and Table 3-4. 
 
  
Subjects who have taken their morning dose of inhaled study drug on the day of a study visit 
may have their study visit and undergo visit assessments provided that the predose assessments 
do not occur within 6 hours of the morning dose of inhaled study drug.  


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11.2 
Subject and Disease Characteristics 
Subject and disease characteristics include the following: demographics, medical history, height, 
weight, and sweat chloride. 
Medical history will be elicited from each subject during screening. 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. 
11.3 
Pharmacokinetics 
11.3.1 
Blood Sampling 
At the visits and time points indicated in Table 3-3 and Table 3-4, blood samples for PK analysis 
will be collected for the determination of the concentrations of VX-371, 
 
. Blood samples collected before dosing must be collected within 90 (+ 5) minutes 
before dosing. The acceptable windows for blood PK sampling time points are detailed in 
Table 11-1.  
Samples from the PK sampling will be kept frozen by Vertex or its designee until all analyses 
have been completed and then disposed of according to Vertex or designee standard operating 
procedures. 
For each visit with a PK blood draw, a record of study drug administration will be collected. The 
collection date and time that each PK blood sample is drawn will also be recorded.  
Table 11-1 
Acceptable Blood PK Sampling Windows 
Sampling Time 
Time From Sampling Schedule Allowed 
Predose 
Within 90 (+ 5) minutes before inhaled study drug dose on PK sampling 
days 
60 minutes after completion of inhaled 
study drug dosing 
± 30 minutes   
 
11.3.2 
Urine Sampling 
Urine samples for PK analysis will be collected according to Table 3-3 and Table 3-4.  
Urine samples will be collected for determination of urine levels of VX-371. Urine samples 
collected before dosing must be collected within 90 (+ 5) minutes before dosing. The acceptable 
windows for urine PK sampling time points are detailed in Table 11-2.  
Samples will be shipped to a Vertex designated laboratory via a central laboratory and analyzed 
with a validated method for the quantification of VX-371. The date and time of urine sampling 
will be collected as well as the date and time of the last dose of inhaled study drug taken before 
collection of the urine sample.  
Table 11-2 
Acceptable Urine PK Sampling Windows 
Sampling Time 
Time From Sampling Schedule Allowed 
Predose 
Within 90 (+ 5) minutes before inhaled study drug dose on PK sampling 
days  


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Table 11-2 
Acceptable Urine PK Sampling Windows 
Sampling Time 
Time From Sampling Schedule Allowed 
90 minutes after completion of inhaled 
study drug dosing  
± 60 minutes  
 
11.3.3 
Processing and Handling of Pharmacokinetic Samples 
Detailed procedures for the collection of blood and urine samples and further procedures for 
processing and handling of samples for PK analysis will be provided in the Sample Handling 
Guideline. The shipment address and assay laboratory contact information will be provided to 
the investigational site before initiation of the study.  
11.3.4 
Bioanalysis 
Samples will be analyzed using a validated analytical method in compliance with Vertex or 
designee standard operating procedures. A description of the assay and validation data will be 
provided in separate reports. 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  


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11.5 
Efficacy 
11.5.1 
Spirometry 
Spirometry will be performed according to the American Thoracic Society Guidelines20 at the 
time points noted in Table 3-1, Table 3-2, Table 3-3, and Table 3-4 according to the additional 
guidelines that follow.  
During the Treatment Period, spirometry will be performed within 60 (± 10) minutes before and 
30 (± 5) minutes after dosing with inhaled study drug. 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. 
With the exception of the Screening Visit, all predose spirometry assessments should be 
performed pre-bronchodilator. At the Screening Visit, the spirometry assessment may be 
performed pre- or post-bronchodilator. Pre-bronchodilator spirometry is defined as spirometry 
testing performed for subjects who have 
• withheld their short-acting bronchodilator (e.g., albuterol) or anticholinergic (e.g., Atrovent®) 
for more than 4 hours before the spirometry assessment; 
• withheld their long-acting bronchodilator (e.g., salmeterol) more than 12 hours before the 
spirometry assessment; and 
• withheld their once-daily, long-acting bronchodilator (e.g., tiotropium bromide [Spiriva®]) 
for more than 24 hours before the spirometry assessment. 
In the event that a subject forgets to withhold the bronchodilator(s), spirometry should be 
performed according to the following: 
• If a subject’s Day 1 predose spirometry is pre-bronchodilator, but on a subsequent visit, the 
subject forgets to withhold bronchodilator use, a post-bronchodilator spirometry will be 
obtained for that visit only, and the visit will not be rescheduled. Spirometry during 
subsequent visits will be performed as pre-bronchodilator assessments. 
• If on Day 1, the subject forgets to withhold his/her dose of bronchodilator, spirometry should 
be performed post-bronchodilator and all subsequent spirometric measurements (according to 
the Schedule of Assessments detailed in Section 3) should be performed post-bronchodilator. 
• Each spirometry assessment will be recorded in the source documents as pre-bronchodilator 
or post-bronchodilator. 
If, in the opinion of the investigator, pretreatment with a short-acting bronchodilator is needed 
before administration of inhaled study drug, this may be done in the clinic before the dose of 
inhaled study drug is administered but after the predose spirometry assessment has been 
completed.  
The parameters listed below will be normalized using the GLI:37  
• FEV1 (L) 
• Forced vital capacity (FVC) (L) 
• FEV1/FVC (ratio) 


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• Forced expiratory flow (FEF25%-75%) (L/s) 
All sites will be provided with spirometers and associated materials to be used for all study 
assessment by the central spirometry service. Spirometry data will be transmitted to a centralized 
spirometry service for quality review. 
Subjects and their parent/caregiver should not be informed of their study-related spirometry 
results during the study regardless of whether the subject has prematurely discontinued 
treatment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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11.6 
Safety 
Safety evaluations will include AEs, spirometry, clinical laboratory assessments of serum, 
plasma, and urine, clinical evaluation of vital signs, ECGs, physical examinations, and 
ophthalmologic examinations (for pediatric subjects <18 years of age only). 
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. 
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. Although blood samples are to be collected and 
analyzed at a central laboratory, a local laboratory may be used if a subject cannot return to the 
clinical study site for the mandatory liver function testing (Section 11.6.2.1). 
Blood and urine samples for clinical laboratory assessments will be collected as shown in 
Table 3-1, Table 3-3, and Table 3-4. Laboratory test results that are abnormal and considered 
clinically significant will be reported as AEs (see Section 13.1.1).  
The safety laboratory test panels are shown in Table 11-3.  


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Table 11-3 
Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
Urine Testsa 
Glucose  
Blood urea nitrogen   
Creatinine 
 
Sodium  
Calcium  
Chloride  
Magnesium  
Bicarbonate  
Inorganic phosphate  
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  
Erythrocytes:  
Mean corpuscular hemoglobin  
Mean corpuscular hemoglobin 
concentration 
Mean corpuscular volume 
Platelets  
Reticulocytes (absolute)   
Leukocytes  
Differential (absolute and percent): 
Eosinophils  
Basophils  
Neutrophils  
Lymphocytes  
Monocytes  
Coagulation 
Activated partial thromboplastin time  
Prothrombin time 
Prothrombin time International 
Normalized Ratio  
 
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. 
Clinical laboratory assessments from screening will have no clinically significant findings that 
preclude participation in the study, as judged by the investigator, for a subject to receive inhaled 
study drug on Day 1. 
Pregnancy (β-human chorionic gonadotropin) 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 3-3 and Table 3-4. The 
urine pregnancy test on Day 1 must be negative before the first dose of inhaled study drug.  
If a urine pregnancy test is positive, all study drug dosing will be stopped 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 withdrawn from study drug dosing as 
discussed in Section 11.6.7.2. If a pregnancy test is positive, the procedures outlined in 
Section 11.6.7.2 will be followed. 
FSH (Screening Period 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. 
CFTR genotype (Screening Period only): CFTR genotyping will be performed to confirm the 
subject is homozygous for F508del-CFTR. Note: Subjects who have been randomized on the 
basis of a historical genotype lab report and whose screening genotype does not confirm study 


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eligibility must be discontinued from the study. Specific instructions will be provided in the 
Laboratory Manual.  
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 make the 
determination of an AE on the basis of the local laboratory value. 
11.6.2.1 
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 performed by the 
central laboratory within 48 to 72 hours of the initial finding and subsequent close monitoring of 
ALT and AST levels, as clinically indicated. If a subject cannot return to the site for liver 
function testing, a local laboratory may be used. Elevations in LFTs at the local laboratory must 
be reported immediately to the medical monitor, and the subject must have the tests repeated and 
sent to the central laboratory as soon as possible (ideally within 48 to 72 hours). 
Study Drug Interruption 
Study drug administration must be interrupted immediately, and the medical monitor must be 
notified, if any of the following criteria is met: 
• ALT or AST ≥8 × ULN 
• ALT or AST ≥5 × ULN for more than 2 weeks 
• ALT or AST ≥3 × ULN in association with total bilirubin ≥2 × ULN and/or clinical jaundice 
A thorough investigation of potential causes should be conducted, and the subject should be 
followed closely for clinical progression. 
If no convincing alternative etiology (e.g., acetaminophen use, viral hepatitis, or alcohol 
ingestion) for the elevated transaminases is identified, regardless of whether ALT or AST levels 
have improved, study drug treatment must be discontinued, in consultation with the medical 
monitor. Subjects in whom treatment is discontinued for elevated transaminases should have 
their transaminases monitored closely until levels normalize or return to baseline. 


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Resumption of Study Drug 
If a convincing alternative etiology is identified for the elevated transaminases (ALT, AST, 
gamma glutamyl transpeptidase, alkaline phosphatase, and total bilirubin), study drug may be 
resumed when transaminases return to baseline or are ≤2 × ULN, whichever is higher. Approval 
of the medical monitor is required before resumption of study drug. Upon resumption of study 
drug, transaminases must be assessed weekly for 4 weeks. If a protocol-defined transaminase 
elevation occurs within 4 weeks of rechallenge with the study drugs, then the study drugs must 
be discontinued, regardless of the presumed etiology. 
11.6.2.2 
Hyperkalemia 
Subjects with a potassium level that is ≤0.4 units below the ULN at the Day 1 or Day 57 Visit 
will be required to have a blood sample collected for a repeat evaluation of plasma potassium 
within 7 (± 2) days. 
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, inhaled study drug should be interrupted until the plasma potassium has 
stabilized 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 medical 
monitor. Subjects in whom treatment is discontinued for elevated potassium should have their 
potassium levels monitored closely until levels normalize or return to baseline. 
11.6.3 
Physical Examinations and Vital Signs 
A full physical examination of all body systems and vital signs assessment will be performed at 
the Screening Visit, ETT Visit, and Safety Follow-up Visit (see Table 3-1 and Table 3-4). At 
other visits, abbreviated physical examinations will be performed before dosing with inhaled 
study drug (see Table 3-3). 
A physical examination includes a review of the following systems: head/neck/thyroid; 
eyes/ears/nose/throat (EENT); respiratory; cardiovascular; lymph nodes; abdomen; skin; 
musculoskeletal; and neurological. Breast, anorectal, and genital examinations will be performed 
when medically indicated. After screening, any clinically significant abnormal findings in 
physical examinations will be reported as AEs. 
The abbreviated physical examination will include an assessment of the following body systems: 
head/neck/thyroid, EENT, cardiovascular system, respiratory system, skin, and abdomen.  
Vital signs include blood pressure (systolic and diastolic), temperature, pulse rate, and 
respiration rate. These will be assessed following a 5-minute rest in the seated or supine position. 
11.6.4 
Electrocardiograms 
Standard 12-lead ECGs will be performed using a machine with printout according to the 
Schedule of Assessments (Table 3-1, Table 3-3, and Table 3-4). Additional standard 12-lead 
ECGs will be performed at any other time if clinically indicated. During the Treatment Period, 


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the ECG will be performed 60 (± 30) minutes after the completion of inhaled study drug dosing. 
The performance of all ECGs will adhere to the following: 
• The subject will be instructed to rest in the seated or supine position for at least 5 minutes 
before having an ECG performed. 
The ECG traces will be read manually at the study site at the Screening Visit and Safety 
Follow-up 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 occurring 
during the study through the Safety Follow-up 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 is increased 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 either of the QTcF 
values from these repeated ECGs remains above the threshold value (>45 msec from baseline or 
≥500 msec), a single ECG will be repeated at least hourly until QTcF values from 2 successive 
ECGs fall below the threshold value that triggered the repeat measurement. 
If the QTcF value remains above the threshold value (>45 msec from the average of the 
3 predose values on Day 1 or ≥500 msec) on repeated measurement or is noted on >2 occasions 
with no identified alternative etiology for the increased QTcF, then discontinuation from study 
drug treatment may be required after discussion with the medical monitor. 
Subjects in whom treatment is discontinued for increased QTc should have their QTc monitored 
closely until it normalizes or returns to baseline. 
11.6.5 
Ophthalmologic Examination 
All pediatric subjects <18 years of age will undergo an ophthalmologic examination at the 
Screening Visit. Pediatric subjects <18 years of age at the Screening Visit who complete the Day 
84 Visit will have an ophthalmologic examination that is to occur between the Day 84 Visit and 
the Safety Follow-up Telephone Contact. Pediatric subjects who discontinue from study drug 
treatment will have an ophthalmologic examination that is to occur between their last dose of 
study drug and completion of either the ETT Visit or the Safety Follow-up Visit. 
The ophthalmologic examination includes 
• measurement of best corrected distance visual acuity of each eye; 
• measurement of lens refracting power (e.g., autorefractor or ophthalmoscopy streak 
following cycloplegia); and 
• pharmacologically-dilated examination of the lens with a slit lamp. 
These examinations must be conducted by a licensed ophthalmologist or optometrist. The 
screening ophthalmologic examination must be completed and the results reviewed before 
enrollment. The Screening Visit ophthalmologic examination does not need to be repeated if 
there is documentation of an examination that met protocol criteria, and that it was conducted 
within 3 months before the Screening Period, or if there is documentation of bilateral lens 
removal.  
In addition, at the Screening Visit, the following history will be obtained for all subjects: 


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• History of steroid use 
• History or presence of diabetes 
• Any prior ophthalmologic or optometric examinations 
• History of trauma to the eye 
• Any family history of glaucoma, congenital cataracts, or cataracts arising later in life 
• Use of corrective lenses (contact lenses or eyeglasses) 
• History of prolonged exposure to sunlight or ultraviolet light and use of sunglasses 
• History of exposure to secondhand smoke 
If a clinically significant lens opacity or cataract is identified at Screening, the medical monitor 
must be notified. Additional ophthalmologic examinations may be required if a lens opacity or 
cataract is identified at Screening. The medical monitor should be notified of any additional 
ophthalmologic examinations. 
11.6.6 
Spirometry 
Refer to Section 11.5.1 for the spirometry assessment. 
11.6.7 
Contraception and Pregnancy 
The effects of VX-371 on conception, pregnancy, and lactation in humans are not known.  
The effects of lumacaftor/ivacaftor on conception, pregnancy, and lactation in humans are not 
known. Neither lumacaftor nor ivacaftor showed any genotoxic potential in a standard battery of 
in vitro (Ames, Chinese hamster ovary cell chromosomal aberration) and in vivo (mouse 
micronucleus) studies. Lumacaftor and ivacaftor were each found to be non-teratogenic in 
reproductive toxicology studies in rats and rabbits (see the lumacaftor/ivacaftor Investigator’s 
Brochure). However, a metabolite of lumacaftor, M28-lumacaftor, given to pregnant rats at very 
high levels far beyond levels observed in humans (>100-fold) produced fetal malformations. The 
significance of this finding in humans is unclear, but is highly unlikely to be of any clinical 
significance. Subjects should follow the contraception requirements outlined in this study 
protocol. The effects of lumacaftor/ivacaftor on the PK of hormonal contraceptives are not 
known; however, since lumacaftor is an inducer of CYP3A, it may reduce the effectiveness of 
hormonal contraceptives. 
11.6.7.1 
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 much be used correctly with every act of 
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, postovulation 
methods) and withdrawal are not acceptable methods of contraception. 


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• 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: 
Table 11-4 
Acceptable Methods of Contraception 
Male subjects and their female 
(non-study) partners 
• 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 
Female subjects and their male 
(non-study) partnersa 
• 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) 
for at least 90 days 
 
a 
Hormonal contraceptives are not considered an acceptable method in female study subjects because of the 
potential for a drug-drug interaction with lumacaftor/ivacaftor resulting in reduced exposure and contraception 
failure; however, female subjects are not required to discontinue their use of hormonal contraceptives as long as 
they agree to use an acceptable method of contraception as described above. 
Important notes: 
• Hormonal contraceptives are not considered an acceptable method in female study subjects 
because of the potential for a drug-drug interaction with lumacaftor/ivacaftor resulting in 
reduced exposure and contraception failure; however, female subjects are not required to 


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discontinue their use of hormonal contraceptives as long as they agree to use an acceptable 
method of contraception as described in Table 11-4. 
• Local requirements may prohibit the use of some of these acceptable methods listed above. 
Please contact the 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. 
• 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 11-4. 
• 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 
medical monitor on an individual basis. 
11.6.7.2 
Pregnancy 
Subjects will be counseled to inform the investigator of any pregnancy that occurs during study 
treatment and for 90 days after the last dose of study drug(s). 
If a subject or the female partner of a male subject becomes pregnant while participating in the 
study, study drug must be permanently discontinued immediately. The investigator must notify 
the medical monitor and Vertex GPS within 24 hours of the site’s knowledge of the subject’s (or 
partner’s) pregnancy using the Pregnancy Information Collection Form.  
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 (and 
assent form, if applicable) will be provided to explain these follow-up activities. Pregnancy itself 
does not constitute an AE.  
12 
STATISTICAL AND ANALYTICAL PLANS 
This section presents a summary of the planned analyses for this protocol. Statistical analysis 
details will be provided in the Statistical Analysis Plan (SAP), and clinical pharmacologic 
analysis details will be provided in the Clinical Pharmacology Analysis Plan (CPAP), both of 
which will be finalized before the clinical database lock for the study and treatment unblinding. 
12.1 
Sample Size and Power 
The primary efficacy endpoint is the absolute change in ppFEV1 from study baseline to the Day 
28 measurements in each Treatment Period.  


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The null hypothesis to be tested is that the mean change from study baseline in ppFEV1 to the 
Day 28 measurements is the same for VX-371 in combination with HS versus HS alone.  
To have a feasible sample size and study duration, this study uses a crossover design. Assuming 
a standard deviation (SD) of 7 percentage points, 50 subjects per sequence are needed to have an 
approximately 81% power to detect a 3 percentage point treatment difference in the mean 
absolute change in ppFEV1 from study baseline at Day 28 between VX-371 + HS and HS alone. 
The study will have an approximately 80% power to detect a 3 percentage point (within 
treatment) change from baseline at Day 28 in ppFEV1 for VX-371. A 2-sided significance level 
of 0.05 was used in the sample size calculations. The sample size also takes into consideration an 
assumed dropout rate of 10%. 
12.2 
Analysis Sets 
The All Subjects Set is defined as all subjects who were randomized or have received at least 1 
dose of inhaled study drug (i.e., all subjects in the study). All subject data listings will be 
referenced using the All Subjects Set, unless otherwise specified. 
The Full Analysis Set (FAS) is defined as all randomized subjects who carry the intended 
homozygous F508del-CFTR mutation and have received at least 1 dose of inhaled study drug. 
The FAS is to be used in efficacy analyses in which subjects will be analyzed according to the 
treatment sequence to which they were randomized. All analyses of background data and 
efficacy data will be based on the FAS. 
The Safety Set is defined as all subjects who received at least 1 dose of inhaled study drug. All 
analyses of safety data will be based on the Safety Set. Subjects will be analyzed according to the 
treatment sequence received.  
12.3 
Statistical Analysis 
The primary objective of this study is to evaluate the safety and efficacy of treatment with VX-
371 in HS compared to HS alone treatment in subjects with CF who are homozygous for the 
F508del-CFTR mutation and being treated with Orkambi. 
This section presents a summary of the planned statistical analyses of efficacy and safety for this 
study. The Vertex Biometrics department or a designated CRO will analyze the data derived 
from this study. SAS® Version 9.2 or higher will be used to generate all statistical outputs 
(tables, figures, listings, and data sets). 
Statistical analysis and presentation details will be provided in the SAP for the study. 
12.3.1 
General Considerations 
All individual subject data for those randomized or exposed to inhaled 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, standard error (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. 


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Treatment emergent (TE) period for Treatment Period 1 will correspond to data from the first 
dose of inhaled study drug in the first period to the safety evaluation visit (28 days after the last 
dose in the first period and prior to the first dose of Treatment Period 2). Similarly, the TE period 
for Treatment Period 2 will correspond to data from the first dose of inhaled study drug in 
Treatment Period 2 through the Safety Follow-up Telephone Contact, or 28 days after the last 
dose in the second period for subjects who do not have a Safety Follow-up Telephone Contact. 
Baseline: For this crossover study, 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 inhaled study drug in the study. Study baseline will be used for all summaries of 
demographics, background, and baseline characteristics as well as all efficacy data analyses, 
including the primary endpoint analysis. In addition, period baseline is defined as the most 
recent nonmissing measurement (scheduled or unscheduled) collected before the first dose of 
inhaled study drug in each treatment period. For Treatment Period 2, the baseline value should 
be from an assessment measured after the TE period for Treatment Period 1. Period baseline will 
be used for all safety data analyses. For ECG, baseline for Period 1 will be defined as the average 
of the 3 pretreatment measurements on Day 1. 
Absolute change from study baseline will be calculated as post-baseline  
value – study baseline value.   
Absolute change from period baseline will be calculated as post-baseline  
value – period 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 will be 
summarized. Additionally, all subject data will be presented in subject data listings. All 
summaries will be based on the 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 
The number and percentage of subjects in the FAS will be summarized by treatment sequence in 
each of the following disposition categories: 
• Completed inhaled study drug treatment 
• Prematurely discontinued treatment and the reasons for discontinuation 
• Last scheduled on-treatment visit completed for subjects who discontinued treatment 
• Completed study 
• Prematurely discontinued the study and the reasons for discontinuation 
• Last scheduled visit completed 
12.3.2.2 
Demographics, Medical History, and Baseline Characteristics 
Demographic, medical history, and baseline characteristics will be summarized by treatment 
sequence. Protocol deviations will be provided as a subject data listing only. Important protocol 
deviations will be summarized. 


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The following demographics and study baseline characteristics will be summarized by treatment 
sequence for the FAS: sex, race, ethnicity, age, weight, height, BMI, region, 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 inhaled study drug, 
regardless of when it ended. 
• Concomitant medication: medication continued or newly received during the TE period for 
Treatment Period 1 or Treatment Period 2.  
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, and concomitant medications will 
be summarized by treatment based on the FAS.  
12.3.2.4 
Study Drug Exposure and Compliance 
Exposure to study drug (i.e., duration of treatment) will be summarized by treatment for the FAS 
in terms of duration of treatment a subject received (in days), defined as the last day minus the 
first day of study drug plus 1 within the Treatment Period. 
Study drug compliance will be calculated as follows:  
100 × [1 – (Total number of days study drug interrupted) / (Duration of study drug exposure)] 
The total number of days of study drug interrupted is defined as the sum of (number of days of 
study drug interrupted in each interruption interval); where number of days of study 
drug interrupted in each interval is defined as the interruption end date – the 
corresponding interruption start date + 1. 
Duration of treatment and study drug compliance will be summarized by means of descriptive 
summary statistics. 
12.3.3 
Efficacy Analysis 
The primary efficacy objective of this study is to evaluate the efficacy of VX-371 plus HS versus 
HS alone. For efficacy analysis, the statistical inference will be based on change from study 
baseline.  
12.3.3.1 
Analysis of Primary Efficacy Variables 
The primary efficacy endpoint is the absolute change in ppFEV1 from study baseline at Day 28 
in each Treatment Period.  
The null hypothesis to be tested is that the mean change from study baseline in ppFEV1 at Day 
28 is the same for VX-371 with 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 at Day 28 as the dependent variable, study 


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baseline for ppFEV1, treatment, and period as fixed effects, and subject nested within sequence 
as a random effect. The within-subject covariance will be assumed to have the compound 
symmetry structure. Denominator degrees of freedom for the F-test for fixed effects will be 
estimated using the Kenward-Roger approximation.42 No imputation of missing data will be 
done. Assuming that the subjects have 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. Similarly, the estimated between treatment differences along with the 
corresponding 95% CI and 2-sided P values will be presented. Additionally, a mixed model of 
repeated measures (MMRM) will be used with period, study baseline for ppFEV1, visit, 
treatment, and treatment by visit, study baseline for ppFEV1 by visit, as fixed effects and subject 
nested within sequence as a random effect. The absolute change from study baseline in ppFEV1 
will be the dependent variable. The repeated measures analysis will enable use of all post-
baseline available data and provide least square means estimates at each visit within a given 
treatment as well as estimates of treatment difference at each visit or across all visits.  
 
 


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12.3.4 
Safety Analysis 
All safety analyses will be based on the set of data associated with the TE period for Treatment 
Period 1 and the TE period for Treatment Period 2. Safety analyses will be based on the Safety 
Set. The summaries will be by treatment received. 
For safety analysis, the period baseline will be used.  
All safety data will be presented in individual subject data listings. 
The overall safety profile of inhaled 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., hematology, serum and plasma chemistry, coagulation 
studies, and urine studies) 
• ECG results 
• Vital signs 
• Ophthalmologic examination results (for pediatric subjects <18 years of age only) 
• Spirometry 
12.3.4.1 
Adverse Events 
For analysis purposes, AEs will be classified as pretreatment AEs or TEAEs, defined as follows:  
Pre-treatment AEs are defined as AEs that started before the start of inhaled study drug dosing. 
TEAE: any AE that increased in severity or that was newly developed during the TE period for 
Treatment Period 1 or Treatment Period 2. An AE that starts (or increases in severity) during a 
specific Treatment Period will be attributed to the inhaled study drug the subject was receiving 
during the Treatment Period.  
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, the start date will be imputed to the first dosing date 
and the AE assigned to the treatment in Treatment Period 1. 
AE summary tables will be presented for TEAEs only and will include the following: 
• All TEAEs  
• TEAEs by relationship  
• TEAEs by maximal severity 
• TEAEs leading to treatment discontinuation 
• Serious TEAEs 
• TEAEs leading to death 


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• Frequently reported TEAEs 
Summaries will be presented 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 and significant AEs will be 
provided separately. All AEs, including pre-treatment AEs, will be presented in individual 
subject data listings. 
12.3.4.2 
Clinical Laboratory Assessments 
The raw values and change from period baseline values of the continuous laboratory parameters 
will be summarized in SI units by treatment group at each scheduled time point during the TE 
period. 
The number and percentage of subjects with at least 1 potentially clinically significant (PCS) 
event during the TE period will be summarized by treatment group. The PCS criteria and the 
parameter selection criteria will be provided in the SAP.   
Results of urinalysis and serum pregnancy test 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 group.  
Clinically significant abnormal laboratory findings will be reported as AEs. 
12.3.4.3 
Electrocardiogram 
A summary of raw values and change from period baseline values will be provided by dose 
group at each scheduled visit for the following ECG measurements: heart rate, PR, QT, QRS, 
and QTcF intervals. In addition, the number and percentage of subjects by maximum 
on-treatment value of QTcF intervals, categorized as ≤450 msec, >450 msec and ≤480 msec, 
>480 msec and ≤500 msec, and >500 msec, as well as maximum on-treatment change from 
baseline value of QTcF intervals, categorized as ≤30 msec, >30 msec and ≤60 msec, and 
>60 msec, will be provided. Clinically significant abnormal findings will be reported as AEs. 
12.3.4.4 
Vital Signs 
The following vital signs will be summarized by treatment group at each scheduled time point: 
systolic and diastolic blood pressure (mmHg), body temperature, pulse rate (beats per minute), 
and respiratory rate (breaths per minute). Clinically significant abnormal findings will be 
reported as AEs. 
12.3.4.5 
Physical Examination 
Physical examination results will be presented in individual subject data listings only. Clinically 
significant results identified after screening will be reported as AEs. 


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12.3.4.6 
Ophthalmologic Examinations 
The ophthalmologic exams for pediatric subjects <18 years of age will be presented as by-subject 
listings. 
12.3.4.7 
Spirometry 
Spirometry data will be summarized based on the Safety Set. This will include the number and 
percentage of subjects at each visit with predefined decreases in FEV1 relative to baseline on pre- 
and postdose spirometry. 
12.3.4.8 
Other Safety Analysis 
Not applicable 
12.3.5 
Interim and IDMC Analyses 
12.3.5.1 
Interim Analysis 
Not applicable 
12.3.5.2 
IDMC Analysis 
The IDMC’s objectives and operational details will be defined in a separate document (IDMC 
charter). The IDMC will conduct regular planned safety reviews of study data as outlined in the 
IDMC charter. 
12.4 
Clinical Pharmacology Analysis 
12.4.1 
Pharmacokinetic Analysis 
The PK Analysis Set will be used for all PK analyses.  
Urine concentrations of VX-371 and plasma concentrations of VX-371, 
 
 will be summarized using descriptive statistics by collection time and treatment group. 
Further details of the planned PK analysis will be provided in the CPAP. Any deviation from the 
reporting and analysis plan will be reported in the clinical study report. 
13 
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS 
13.1 
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 pre-existing condition (e.g., increase in its severity or 
frequency) after the ICF is signed.  
An AE is considered serious if it meets the definition in Section 13.1.2.1.  


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13.1.1.2 
Clinically Significant Assessments 
Study assessments including laboratory tests, ECGs, PEs, and vital signs will be assessed and 
those deemed to have clinically-significant worsening from baseline will be 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 
• A change in the dose of study drug or 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. 
A laboratory value that is Grade 4 will not automatically be an SAE. A Grade 4 laboratory value 
will be an SAE if the subject’s clinical status indicates a life-threatening AE. 
13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time ICF is signed until the following time points: 
• For subjects who do not enroll: until time of screen failure (e.g., screen failure, withdrawal of 
consent) 
• For enrolled subjects who have a Safety Follow-up Telephone Contact: through the Safety 
Follow-up Telephone Contact 
• For enrolled subjects who do not have a Safety Follow-up Visit, the earliest of: 
o 28 days after the last dose of inhaled study drug, or 
o the ETT Visit, if that visit is 28 days or later following the last dose of inhaled study drug 
(see Section 8.1.4). 
All subjects will be queried, using nonleading 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 enrolled 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  


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• 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 nonserious 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 
2015). 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.  
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 reappeared 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). 
 


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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 
Dose reduced 
Study drug dose reduced 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. 
 
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 drugs) 


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• 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 
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 
Safety Follow-up Telephone Contact, 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 Contact and are considered related to study drug(s) will be reported to Vertex GPS 
within 24 hours. 
SAEs will be recorded on the Vertex Clinical Trial 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 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 the outcome of the event using the 
SAE Form. 


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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 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.  
Please send completed SAE Forms to Vertex GPS via: 
Email: 
(Preferred Choice) 
Fax: 
  
Contact Telephone: 
 
13.1.2.4 
Expedited Reporting and Investigator Safety Letters 
Vertex, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions (SUSARs) involving the study drug(s) to all regulatory authorities and participating 
investigators in accordance with ICH Guidelines and/or local regulatory requirements, as 
applicable. In addition, Vertex, or authorized designee, will be responsible for the submission of 
safety letters 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 user 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  
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 before the return of the device by the subject, must be reported to Vertex GPS 
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 via: 
Email: 
 (Preferred Choice) 
Fax: 
  
Contact Telephone: 
 
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 study sponsor, is responsible for evaluating and reporting unanticipated adverse 
device effects (UADEs) involving the investigational device used in this study to all regulatory 
authorities and participating investigators in accordance with ICH guidelines and/or local 
regulatory requirements, as applicable. In addition, Vertex, 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. 
13.2 
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 Vertex, 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 the 
subject (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 Vertex or its 
designee. 
13.2.3 
Investigator Compliance 
No modifications to the protocol will be made without the approval of both the investigator and 
Vertex. 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 


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before implementation, except where the modification is necessary to eliminate an apparent 
immediate hazard to human subjects. Vertex 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 Vertex to discuss the planned course of action. If possible, contact 
will be made before the implementation of any changes. Any departures from the 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 Vertex 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 physician and shall not be disclosed to Vertex. 
As required by applicable laws and regulations in the countries in which the study is being 
conducted, the investigator will allow Vertex 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/IEC, 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, 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 Vertex 
will be notified. 


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13.2.7 
Study Termination 
At any time, Vertex 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. 
13.3 
Data Quality Assurance 
Vertex 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 screened subject will be entered into a CRF by study site 
personnel using a secure, validated, web-based electronic data capture (EDC) application. Vertex 
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. 
13.4 
Monitoring 
Monitoring and auditing procedures developed or approved by Vertex 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 Vertex or its designee. Monitoring will be done by personal 
visits from a representative of Vertex, 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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13.5 
Electronic Data Capture 
Vertex 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 whom they are responsible.  
A CRF will be completed for each randomized 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.  
Vertex 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. 
13.6 
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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14 
REFERENCES
 
 
1 
Cystic Fibrosis Foundation web site. Available at: http://www.cff.org/AboutCF/. 
Accessed 15 September 2015. 
2 
Kreindler JL. Cystic fibrosis: Exploiting its genetic basis in the hunt for new therapies. 
Pharmacol Ther. 2010;125:219-29. 
3 
Cystic Fibrosis Foundation. Patient Registry: 2012 Annual Data Report. Bethesda, MD: 
Cystic Fibrosis Foundation; 2013. 
4 
Flume PA, Van Devanter DR. State of progress in treating cystic fibrosis respiratory 
disease. BMC Medicine. 2012;10(1):88. 
5 
Cystic Fibrosis Mutation Database (CFTR1) [Internet]. Cystic Fibrosis Centre at the 
Hospital for Sick Children in Toronto. Available at: 
http://www.genet.sickkids.on.ca/cftr/StatisticsPage.html. Accessed 15 September 2015.  
6 
Cystic Fibrosis Foundation. Patient Registry: 2011 Annual Data Report. Bethesda, MD: 
Cystic Fibrosis Foundation; 2012. 
7 
Cheng SH, Gregory RJ, Marshall J, Sucharita P, Souza DW, White GA, et al. Defective 
intracellular transport and processing of CFTR is the molecular basis of most cystic 
fibrosis. Cell. 1990;63:827-34. 
8 
Dalemans W, Barbry P, Champigny G, Jallat S, Dott K, Dreyer D, et al. Altered chloride 
ion channel kinetics associated with the delta F508 cystic fibrosis mutation. Nature. 
1991;354:526-28. 
9 
Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. 2005;352:1992-2001. 
10  
Van der Schans CP. Bronchial mucus transport. Respir Care. 2007;52(9):1150-6. 
11  
Knowles MR, Boucher RC. Mucus clearance as a primary innate defense mechanism 
 
for mammalian airways. J Clin Invest 2002;109(5):571-7. 
12  
Berdiev BK, Qadri YJ, Benos DJ. Assessment of the CFTR and ENaC association. Mol 
BioSyst. 2009;5(2):123-7. 
13  
Boucher RC. New concepts of the pathogenesis of cystic fibrosis lung disease. Eur Respir 
J. 2004;23(1):146-58. 
14  
App EM, King M, Helfesrieder R, Kohler D, Matthys H. Acute and long-term amiloride 
inhalation in cystic fibrosis lung disease. A rational approach to cystic fibrosis therapy. 
Am Rev Respir Dis. 1990;141(3):605-12. 
15  
Kellenberger S, Schild L. Epithelial sodium channel/degenerin family of ion channels: a 
variety of functions for a shared structure. Physiol Rev. 2002;82(3):735-67. 
 
 


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16  
Beguin P, Wang X, Firsov D, Puoti A, Claeys D, Horisberger JD, et al. The gamma 
subunit is a specific component of the Na,K-ATPase and modulates its transport function. 
EMBO J. 1997;16(14):4250-60. 
17  
Kellenberger S, Gautschi I, Schild L. A single point mutation in the pore region of the 
 
epithelial Na+ channel changes ion selectivity by modifying molecular sieving. Proc 
 
Natl Acad Sci USA. 1999;96(7):4170-5. 
18  
Barker PM, Nguyen MS, Gatzy JT, Grubb B, Norman H, Hummler E, et al. Role of 
gamma-ENaC subunit in lung liquid clearance and electrolyte balance in newborn mice. 
Insights into perinatal adaptation and pseudohypoaldosteronism. J Clin Invest 
1998;102(8):1634-40. 
19  
 
 
20 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26:319-38. 
21 
Liou TG, Adler FR, Fitzsimmons SC, Cahill BC, Hibbs JR, Marshall BC. Predictive 5-
year survivorship model of cystic fibrosis. Am J Epidemiol. 2001;153(4):345-52. 
22  
Rosenfeld M. An overview of endpoints for cystic fibrosis clinical trials. Proc Am Thorac 
Soc. 2007;4(4):299-301. 
23  
Hayes D Jr, Kraman SS. The physiologic basis of spirometry. Respir Care. 
2009;54:1717-26. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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36 
Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus statement. 
Cystic Fibrosis Foundation Consensus Panel. J Pediatr. 1998;132(4):589-95. 
37  
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic 
reference values for spirometry for the 3-95-yr age range: the global lung function 2012 
equations. Eur Respir J. 2012;40(6):1324-43. 
38  
Schwartz GJ, Haycock GB, Edelmann CM Jr, Spitzer A. A simple estimate of 
 
glomerular filtration rate in children derived from body length and plasma creatinine. 
 
Pediatr. 1976;58:259-263. 
39  
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron. 1976;16:31-41. 
  
 
 
 
 
 
 
42 
Kenward MG, Roger JH. Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics. 1997;53:983-97. 
 


Protocol VX15-371-101, Version 3.0 
15 
PROTOCOL SIGNATURE PAGES 
15.1 
Sponsor Signature Page 
Protocol#: 
VX15-371-101 
I Version#: 
3.0 
I Version Date 
22 July 2016 
Study Title: A Phase 2a, Randomized, Double-blind, Placebo-controlled, Incomplete Block, 
Crossover Study to Evaluate the Safety and Efficacy ofVX-371 in Subjects Aged 12 Years or 
Older With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation, and Being Treated 
With Orkambi 
This Clinical Study Protocol has been reviewed and approved by the sponsor. 
Vertex Pharmaceuticals Incorporated 


Protocol VX15-371-101, Version 3.0 
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Vertex Pharmaceuticals Incorporated 
 
15.2 
Investigator Signature Page 
Protocol #: 
VX15-371-101 
Version #: 
3.0 
Version Date 
22 July 2016 
Study Title: A Phase 2a, Randomized, Double-blind, Placebo-controlled, Incomplete Block, 
Crossover Study to Evaluate the Safety and Efficacy of VX-371 in Subjects Aged 12 Years or 
Older With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation, and Being Treated 
With Orkambi 
 
 
I have read Protocol VX15-371-101, Version 3.0 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 
Vertex Pharmaceuticals Incorporated (Vertex) is confidential.  
 
 
Printed Name 
 
 
Signature 
 
Date 
 

SAP_001.pdf: 
1
TITLE PAGE 
VERTEX PHARMACEUTICALS INCORPORATED
Statistical Analysis Plan 
(Methods)
Protocol Number VX15-371-101, Version 3.0
(Final Analysis)
A Phase 2a, Randomized, Double-blind, Placebo-controlled, Incomplete Block, 
Crossover Study to Evaluate the Safety and Efficacy of VX-371 in Subjects Aged 12 
Years or Older With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation, 
and Being Treated With Orkambi
Author of SAP:  
Version: 1.0
Version Date of SAP: 27July2017
Vertex Pharmaceuticals Incorporated
50 Northern Avenue
Boston, MA, 02210, USA
CONFIDENTIAL
This document contains confidential information.  Any use, distribution, or disclosure without the prior written consent of 
Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under applicable laws or regulations.  
Persons to whom the information is disclosed must be informed that the information is confidential and may not be further 
disclosed by them.


Statistical Analysis Plan (Methods)
Page 2 of 60
Vertex Protocol VX15-371-101, Version 3.0
2
TABLE OF CONTENTS 
1
TITLE PAGE ...............................................................................................................1
2
TABLE OF CONTENTS .............................................................................................2
List of Tables....................................................................................................................4
List of Figures ..................................................................................................................4
4
INTRODUCTION........................................................................................................8
5
STUDY OBJECTIVES ................................................................................................8
5.1
Primary Objectives ..................................................................................................8
5.2
Secondary Objectives ..............................................................................................8
6
STUDY ENDPOINTS ..................................................................................................9
6.1
Primary Endpoint ....................................................................................................9
6.2
Secondary Endpoints...............................................................................................9
7
STUDY DESIGN..........................................................................................................9
7.1
Overall Design ........................................................................................................9
7.2
Sample Size and Power .........................................................................................11
7.3
Randomization ......................................................................................................12
7.4
Blinding and Unblinding .......................................................................................12
7.4.1
Blinding.........................................................................................................12
7.4.2
Unblinding.....................................................................................................13
8
ANALYSIS SETS.......................................................................................................14
9
STATISTICAL ANALYSIS ......................................................................................14
9.1
General Considerations..........................................................................................14
9.2
Background Characteristics ...................................................................................16
9.2.1
Subject Disposition........................................................................................16
9.2.2
Demographics and Baseline Characteristics ...................................................17
9.2.3
Medical History.............................................................................................19
9.2.4
Prior and Concomitant Medications ...............................................................19
9.2.5
Study Drug Exposure.....................................................................................19
9.2.6
Study Drug Compliance.................................................................................20
9.2.7
Important Protocol Deviations .......................................................................20
9.3
Efficacy Analysis ..................................................................................................21
9.3.1
Analysis of Primary Efficacy Endpoint ..........................................................21
27
9.3.4
Multiplicity Adjustment.................................................................................29
9.4
Safety Analysis......................................................................................................29
9.4.1
Adverse Events..............................................................................................30
9.4.2
Clinical Laboratory........................................................................................33
9.4.3
Electrocardiogram..........................................................................................34


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9.4.4
Vital Signs.....................................................................................................34
9.4.5
Physical Examination.....................................................................................35
9.4.6
Ophthalmologic Examinations .......................................................................35
9.4.7
Spirometry.....................................................................................................35
9.4.8
Other Safety Analyses....................................................................................35
10 INTERIM AND DMC ANALYSES...........................................................................36
10.1 Interim Analysis ....................................................................................................36
10.2 DMC Analysis.......................................................................................................36
11 REFERENCES...........................................................................................................37
12 APPENDICES ............................................................................................................38
12.1 Schedule of Assessments.......................................................................................38
12.2 Analysis Visit Windows for Safety and Efficacy Assessments...............................47
12.3 Imputation Rules for Missing Prior/Concomitant Medication Dates.......................50
12.4 Imputation Rules for Missing Adverse Event Dates...............................................51
12.5 Threshold Analysis Criteria ...................................................................................52
12.7 Standards for Efficacy and Safety Variable Display in TFLs..................................60


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List of Tables
Table 7-1
Study VX15-371-101 Treatment Sequences...................................................10
Table 12-1
Study VX15-371-101: Screening Period for All Subjects...............................38
Table 12-2
Study VX15-371-101: Run-in Period for Orkambi-/HS-, Orkambi-/HS+, and 
Orkambi+/HS+ Subjects..............................................................................................40
Table 12-3
Study VX15-371-101: Treatment Period........................................................41
Table 12-4
Study VX15-371-101: Early Termination of Treatment Visit, Safety Follow-up 
Visit, and Safety Follow-up Telephone Contact ...........................................................45
Table 12-5      Visit Window Mapping Rules for Efficacy Assessments...............................47
Table 12-6      Visit Window Mapping Rules for Safety Assessments..................................48
Table 12-7      Prior, Concomitant, and Post Categorization of a Medication........................50
Table 12-8      Threshold Criteria for Laboratory Tests ........................................................52
Table 12-9      Threshold Criteria for ECGs .........................................................................56
Table 12-10      Threshold Criteria for Vital Signs ...............................................................57
List of Figures
Figure 7-1
Schematic of Study Design VX15-371-101....................................................10


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LIST OF ABBREVIATIONS
Abbreviation
Term
AE
Adverse event
ATC
Anatomic class
ALP
Alkaline phosphatase
ALT
Alanine transaminase
AST
Aspartate transaminase
BMI
Body mass index (kg/m2)
Bid
Bis in die (twice a day)
Bpm
Beats per minute
CF
Cystic fibrosis
CFTR
Cystic fibrosis transmembrane conductance regulator gene
CI
Confidence Interval
CPAP
Clinical Pharmacology Analysis Plan
CRO
Contract research organization
CSP
Clinical study protocol
DMC
Data Monitoring Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
ETT
Early Termination of Treatment
FAS
Full Analysis Set
FEF25-75%
Forced midexpiratory flow rate (L/sec)
FEV1
Forced expiratory volume (L) in 1 second
FSH
Follicle-stimulating hormone
FVC
Forced vital capacity (L)
GLI
Global Lung Initiative
GPS
Global Patient Safety
HS
Hypertonic Saline
ICF
Informed consent form
IDMC
Independent Data Monitoring Committee
IPD
Important Protocol Deviation
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
LFT
Liver function test
LLN
Lower limit of normal 
max
Maximum value
MedDRA
Medical Dictionary for Regulatory Activities


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Vertex Protocol VX15-371-101, Version 3.0
Abbreviation
Term
min
Minimum value
MMRM
Mixed Model for Repeated Measures
PI
Principal Investigator
PK
Pharmacokinetic/pharmacokinetics
ppFEV1
Percent predicted forced expiratory volume in 1 second
PT
Preferred Term
q12h
Every 12 hours
QRS
Q, R, and S-wave define the QRS-complex in an ECG
QT
QT interval represents the duration of ventricular depolarization and 
subsequent repolarization; it is measured from the beginning of the 
QRS complex to the end of the T wave
QTcF
QT interval corrected for heart rate with Fridericia’s correction [QTcF 
= QT/RR0.33] 
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Standard deviation
SE
Standard error
SI
Système international
SOC
System organ class
TBILI
Total bilirubin
TE
Treatment Emergent
TEAE
Treatment-emergent adverse event
TFL
Tables, figures and listings
UB
Unblinded Biostatistician
ULN
Upper limit of normal


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Statistical Analysis Plan (Methods)
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Vertex Protocol VX15-371-101, Version 3.0
4
INTRODUCTION
This SAP, which describes the planned final analyses for the Study VX15-371-101 (Study 
101) data, is based on the following:

clinical study protocol (CSP) for Study 101 (Version 3.0, dated 22 July 2016).

approved electronic case report forms (eCRF) for Study 101 (Version 5.0, dated 4 April 
2017). 
Study 101 is a Phase 2a, randomized, double-blind, placebo-controlled, incomplete block, 
crossover, multicenter, study in subjects ≥12 years of age with cystic fibrosis (CF) who are 
homozygous for the F508del-CFTR mutation and who are being treated with Orkambi
(lumacaftor/ivacaftor). All subjects must be receiving stable treatment with Orkambi before 
the first dose of inhaled study drug and through the Safety Follow-up Telephone Contact or 
Safety Follow-up Visit. 
This SAP (Methods) documents the planned final statistical analyses of efficacy and safety 
endpoints defined in the study protocol for Study 101 and describes the corresponding data 
presentations. It also documents analyses for additional efficacy and safety variables not 
specified in the protocol, which will provide supportive information to enhance the scientific 
understanding of the drug entity.
The study will also evaluate the pharmacokinetic (PK) characteristics of VX-371, 
 
 in this patient population. PK analyses will be documented separately in the 
clinical pharmacology analysis plan (CPAP) for the study. 
The Vertex Biometrics department will perform the statistical analysis of the efficacy and 
safety data. SAS (Version 9.4) will be used to generate all statistical outputs (tables, figures, 
listings, and datasets). The SAP will be finalized and approved prior to the database lock and 
treatment unblinding for the study.
5
STUDY OBJECTIVES
5.1
Primary Objectives
To evaluate the safety and efficacy of treatment with VX-371 in hypertonic saline (HS)
compared to HS alone in subjects with CF who are ≥12 years of age, homozygous for the 
F508del-CFTR mutation, and being treated with Orkambi
5.2
Secondary Objectives

To evaluate the efficacy of treatment with VX-371 in HS compared with placebo in 
subjects with CF who are ≥12 years of age, homozygous for the F508del-CFTR mutation, 
and being treated with Orkambi

To evaluate the efficacy of treatment with VX-371 in HS compared with VX-371 in 
placebo in subjects with CF who are ≥12 years of age, homozygous for the 
F508del-CFTR mutation, and being treated with Orkambi


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Vertex Protocol VX15-371-101, Version 3.0

To evaluate the efficacy of treatment with VX-371 in placebo compared with placebo in 
subjects with CF who are ≥12 years of age, homozygous for the F508del-CFTR mutation, 
and being treated with Orkambi

To investigate the pharmacokinetics of VX-371 in subjects with CF who are ≥12 years of 
age, homozygous for the F508del-CFTR mutation, and being treated with Orkambi
6
STUDY ENDPOINTS
6.1
Primary Endpoint

Results of safety and tolerability assessments of adverse events (AEs), spirometry, 
clinical laboratory values (urine, serum and plasma chemistry, hematology, and 
coagulation studies), standard 12-lead electrocardiograms (ECGs), vital signs, and 
ophthalmologic examinations

Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) 
from study baseline at Day 28 in each Treatment Period
6.2
Secondary Endpoints

PK parameters for VX-371
7
STUDY DESIGN 
7.1
Overall Design 
This is a Phase 2a, randomized, double-blind, placebo-controlled, incomplete block, 
crossover, multicenter, study in subjects ≥12 years of age with CF who are homozygous for 
the F508del-CFTR mutation and who are being treated with Orkambi. All subjects must be 
receiving stable treatment with Orkambi before the first dose of inhaled study drug (i.e. VX-
371 + placebo, VX-371 + HS, HS and placebo administered by nebulizer) and through the 
Safety Follow-up Telephone Contact or Safety Follow-up Visit. 


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Vertex Protocol VX15-371-101, Version 3.0
Table 7-1
Study VX15-371-101 Treatment Sequences
Sequence
Treatment Period 1
Treatment Period 2
N
1
VX-371 + 4.2% HS
4.2% HS
50
2
4.2% HS
VX-371 + 4.2% HS
50
3
VX-371 + 0.17% saline (placebo)
Placebo (0.17% saline)
25
4
Placebo (0.17% saline)
VX-371 + 0.17% saline (placebo)
25
Approximately 150 subjects will be randomized (2:2:1:1) to 1 of the 4 treatment sequences as 
described in Table 7-1Study VX15-371-101 Treatment Sequences. Each treatment sequence 
will comprise:
Treatment Period 1 Washout Treatment Period 2
A schematic of the study design is provided in Figure 7-1.


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Vertex Protocol VX15-371-101, Version 3.0
Figure 7-1
Schematic of Study Design VX15-371-101
This study includes the following periods:

Screening Period: 
o
Day -28 to Day -1 relative to the first dose of inhaled study drug for Orkambi+/HS-
subjects
o
Day -56 to Day -29 relative to the first dose of inhaled study drug for Orkambi-/HS-, 
Orkambi-/HS+, and Orkambi+/HS+ subjects

Run-in Period: Day -28 to Day -1 relative to the first dose of inhaled study drug (for 
Orkambi-/HS-, Orkambi-/HS+, and Orkambi+/HS+ subjects)

Treatment Period
o
Treatment Period 1: Day 1 (first dose of inhaled study drug) through Day 28
o
Washout Period: Day 29 through Day 56 
Screening
Period
Randomization
Day 
1
Safety 
Follow-up
Telephone 
Contact
Treatment 2
Treatment Period 2
Treatment Period 1
Day
57
Day
84
Day
14
Day
28
Day
70
Treatment 1
Day
-28
Day 
3
Day
59
A.  For Orkambi+/HS- Subjects
Screening
Period
Randomization
Day 
1
Safety 
Follow-up
Telephone
Contact
Treatment 2
Treatment Period 2
Treatment Period 1
Day
57
Day
84
Day
-28
Day
14
Day
28
Day
70
Treatment 1
Day
-14
Run-in Period
Day
-56
Day 
3
Day
59
B.  For Orkambi-/HS-, Orkambi-/HS+, and Orkambi+/HS+ Subjects
28-day 
Washout
Day 
112 
(+3 days)
28-day 
Washout
Day 
112 
(+3 days)


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Vertex Protocol VX15-371-101, Version 3.0
o
Treatment Period 2: Day 57 through Day 84

Early Termination of Treatment (ETT) Visit for a subject who discontinues from study 
drug treatment(s) and who does not complete the remaining assessments in the treatment 
period during which study drug treatment(s) is discontinued. 

Safety Follow-up Telephone Contact will occur 28 days (+ 3 days) after the Day 84 Visit; 
or 28 days (+ 3 days) after the Day 28 Visit for a subject who completes this visit but 
who will not be continuing into Treatment Period 2. (Note: Under certain circumstances, 
a safety Follow-up Telephone Contact may not be appropriate, and a SFUV may be 
required.)

A SFUV will occur 28 days (+ 3 days) after a subject’s last dose of study drug (whether 
inhaled study drug or lumacaftor/ivacaftor) in subjects who: 
o
prematurely discontinue one or both study drugs during the course of either treatment 
period and do not complete the remaining assessments in the treatment period in 
which discontinuation occurred. In this circumstance, an ETT Visit is required in 
addition to the SFUV.
o
have a clinical finding during the treatment period or during the 28-day Safety 
Follow-up Period that requires follow-up in the estimation of the Principal 
Investigator (PI). An ETT Visit may or may not be required in this circumstance.
7.2
Sample Size and Power
The primary efficacy endpoint is the absolute change in ppFEV1 from study baseline to the 
Day 28 measurements in each Treatment Period. 
The null hypothesis to be tested is that the mean change from study baseline in ppFEV1 to the 
Day 28 measurements is the same for VX-371 in combination with HS versus HS alone. 
To have a feasible sample size and study duration, this study uses a crossover design. 
Assuming a standard deviation (SD) of 7 percentage points, 50 subjects per sequence (VX-
371 + 4.2% HS followed by 4.2% HS; 4.2% HS followed by VX-371 + 4.2% HS) 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 at Day 28 between VX-371 + HS and 
HS alone. The study will have approximately 80% power to detect a 3 percentage point 
(within treatment) change from study baseline at Day 28 in ppFEV1 for VX-371. A 2-sided 
significance level of 0.05 was used in the sample size calculations. The sample size took into 
account an assumed dropout rate of 10%.
7.3
Randomization
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 
(VX-371 + 4.2% HS followed by 4.2% HS; 4.2% HS followed by VX-371 + 4.2% HS; VX-
371 + placebo followed by placebo; placebo followed by VX-371 + placebo), stratifying by
ppFEV1 severity (<70 or ≥70). 
The 4 treatment sequences are provided in Table 7-1.


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An interactive web response system (IWRS) will be used for randomization following a list of 
randomization codes generated by a designated vendor (Cytel, Inc.).
7.4
Blinding and Unblinding
This is a double-blind study.
7.4.1
Blinding
The subjects and all site personnel, including the investigator, the site monitor, and the study 
team, will be blinded 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 the fetus in the event of a pregnancy

Vertex Global Patient Safety (GPS) and Regulatory Affairs personnel to satisfy 
Serious Adverse Event (SAE) processing and reporting regulations

External vendor (unblinded) statistician preparing the final (production) 
randomization list who is not part of the study team

Vertex IXRS Management for IXRS oversight and system administration

Independent Monitoring Committee (IDMC)

Vendor preparing the unblinded analysis for the IDMC 

The bioanalytical external vendor personnel assigned to the study and Vertex 
Bioanalysis Contract Research Organization (CRO) Monitors who will not be 
participating in the study team

The medical monitor may, for matters relating to safety concerns, unblind individual 
subjects at any time
Spirometry Data Blinding:
Despite treatment blinding, knowledge of the spirometry results has the potential to suggest 
whether a subject has been administered active inhaled study drug or placebo. Therefore, 
during the conduct of the study, the Vertex study team will have no access to the postdose 
(i.e. on or after Day 1) spirometry data. The vendor for central reading of the spirometry data 
will send only the blinded spirometry files (blinded treatment, with real values for screening 
and baseline, but with dummy values for all the spirometry assessments after baseline) to 
Vertex to be used for developing the statistical programs. However, approximately 2 weeks 
before database lock, during the process of locking the clinical database, a small group of 
individuals (a biostatistician, a statistical programmer, and a validation statistical 
programmer) who could be part of the Vertex study team will access the treatment-blinded 
post-dose spirometry data to ensure there are no significant data issues and to refine the 
statistical programs. These team members will not have access to the unblinded treatment 
codes until database lock occurred. Subjects and their caregivers should not be informed of 


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Vertex Protocol VX15-371-101, Version 3.0
their study-related spirometry results during the Treatment Period regardless of whether the 
subject has prematurely discontinued treatment.
7.4.2
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 an 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 treatment 
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 medical monitor to 
discuss and agree to the need for unblinding. If investigators deem it not necessary to unblind 
immediately, they will first attempt to contact the medical monitor to discuss and agree to the 
need for unblinding. If investigators have tried but are unable to reach the 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 medical monitor.
Contact information for the medical monitor (or appropriate backup) will be provided in a 
separate document.
In addition, the Vertex Medical Information Call Center 
 will answer calls 
24 hours a day, 7 days a week, 365 days of the year, and will triage these calls to the study 
medical monitor or appropriate backup.
If a subject’s treatment assignment has been unblinded for a medical emergency or urgent 
clinical situation, the medical monitor will be notified within 24 hours of the unblinding 
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 the 
sponsor (Vertex), 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 or designee, per section 13.1 of the CSP.
Vertex GPS or designee will also unblind any SAE reports in compliance with regulatory 
reporting requirements. In addition, Vertex may, for matters relating to safety concerns, 
unblind individual subjects at any time. 
8
ANALYSIS SETS
The following analysis sets will be defined: All Subjects Set, Randomized Set, Full Analysis 
Set (FAS), Safety Set and Run-in Subjects Set.
The All Subjects Set is defined as all subjects who have been randomized or have received 
at least 1 dose of inhaled study drug. 
The Randomized Set is defined as all subjects who have been randomized.


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Vertex Protocol VX15-371-101, Version 3.0
The Full Analysis Set (FAS) is defined as all randomized subjects who carry the intended 
homozygous F508del-CFTR mutation and have received at least 1 dose of inhaled study 
drug.  
The Safety Set is defined as all subjects who received at least 1 dose of inhaled study drug. 
The Run-in Subjects Set is defined as all subjects who received orkambi during the run-in 
period.
9
STATISTICAL ANALYSIS
9.1
General Considerations
All individual subject data for those randomized or exposed to inhaled study drug will be 
presented in data listings. Study drug exposure, discontinuations and adverse events during 
the run-in period will be listed. The Schedule of Assessments is provided in Section 12.1. 
The precision standards are provided in Section 12.7.
Continuous variables will be summarized using the following descriptive summary 
statistics: the number of subjects (n), mean, standard deviation (SD), median, minimum value 
(min), and maximum value (max).  
Categorical variables will be summarized using counts and percentages.     
Study periods: The study period will be divided into 3 segments based on the treatment of 
inhaled study drug:

Pre-treatment period is defined as the period after the informed consent/assent date 
and before the initial dosing of inhaled study drug in treatment period 1. For the 
Orkambi+/HS- subjects, this corresponds to the Screening Period. While for
Orkambi-/HS-, Orkambi-/HS+, and Orkambi+/HS+ subjects, it will also include the 
Run-in Period. 

Treatment emergent (TE) period

TE period for Treatment Period 1 will correspond to the period from the first dose 
of inhaled study drug in Treatment Period 1 to 28 days after the last dose of 
inhaled study drug in Treatment Period 1 and prior to the first dose of Treatment 
Period 2, or the Safety Follow-up Telephone Contact or Visit, whichever occurs
first. 

TE period for Treatment Period 2 will correspond to data from the first dose of 
inhaled study drug in Treatment Period 2 through the Safety Follow-up Telephone 
Contact or Visit , or 28 days after the last dose of inhaled study drug in Treatment
Period 2, whichever occurs first.

Post-treatment period is defined as the period after the last date of TE period for 
Treatment Period 2 to the date of the last study record in the clinical database or the 
period between the end of TE period for Treatment Period 1 and the start of TE period for 


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Treatment Period 2. For subjects who do not have Treatment Period 2, the period after 
the last date of TE period for Treatment Period 1 to the date of the last study record in the 
clinical database will be considered as post-treatment period. 
Baseline: For this crossover study, 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 inhaled study drug in the study. 
Study baseline will be used for all summaries of demographics, background, and 
baseline characteristics, ECG, as well as all efficacy data analyses, including the 
primary efficacy endpoint analysis.

The period baseline is defined as the most recent nonmissing measurement 
(scheduled or unscheduled) collected before the first dose of inhaled study drug in 
each treatment period. For Treatment Period 2, the baseline value should be from an 
assessment measured after the TE period for Treatment Period 1. Period baseline will 
be used for all safety data analyses except ECG. Since all ECG assessments will be 
performed 60 (± 30) minutes after completion of inhaled study drug dosing except 
measurements at Screening, the study baseline will be used for analysis for both 
periods.
Absolute change from study baseline will be calculated as post-baseline value - study 
baseline value.
Relative change from study baseline will be calculated as 100 x (post-baseline value -
study baseline value)/study baseline value.
Absolute change from period baseline will be calculated as post-baseline value - period 
baseline value.
Relative change from period baseline will be calculated as 100 x (post-baseline value -
period baseline value)/period baseline value.
Unscheduled Visits: Unscheduled visit measurements will be included in listings, for 
derivation of visit windows and computation of baseline, and for the analysis of 
maximum/minimum values and maximum/minimum changes from baseline values.
Visit Windows:  Section 12.2 defines the visit window mapping rules to derive the analysis
visits. 
Analysis visit selection rules:

For all efficacy parameters if there are multiple measurements within a visit window, 
the record at the corresponding scheduled visit will be used. If there is no 
measurement at the corresponding scheduled visit, then 1) the record closest to the 
target day will be used; or 2) if there are multiple records with the same distance to 
the target day, the earliest record will be used. 

For all safety parameters, if there are multiple measurements within a visit window, 
then 1) the record closest to the target day will be used; or 2) if there are multiple 
records with the same distance to the target day, the earliest record will be used.
Incomplete/Missing data: will not be imputed, unless otherwise specified. 


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Outliers: No formal statistical analyses will be performed to detect and/or remedy the 
presence of statistical outliers.
9.2
Background Characteristics 
Subject disposition, demographic and baseline characteristics, prior and concomitant
medications, study drug exposure and compliance, and other background characteristics will 
be summarized using descriptive statistics for continuous variables and counts and 
percentages for categorical variables. Additionally, all subject data will be presented in 
subject data listings. All summaries will be based on the FAS unless otherwise specified. No
statistical hypothesis testing will be performed on background characteristics.
9.2.1
Subject Disposition
The number of subjects in the run-in period who were not randomized or dosed with the 
inhaled study drug screen failures during the Run-in Period, number of subjects randomized 
or dosed with inhaled study drug, and the total number of subjects will be tabulated for the 
following groups and overall based on their Orkambi and HS status at Screening: 

Orkambi+/HS-

Orkambi-/HS-

Orkambi+/HS+

Orkambi-/HS+
The number of subjects in the following categories will be summarized by treatment group: 

All Subjects Set (Randomized or dosed with Inhaled Study Drug)

Randomized

Randomized but never 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): 

FAS

Safety Set
The number and percentage (based on Safety Set) 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 regimen and the reasons for discontinuations 

Prematurely discontinued inhaled study drug and the reasons for discontinuations 


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Vertex Protocol VX15-371-101, Version 3.0

Prematurely discontinued orkambi and the reasons for discontinuations 

Prematurely discontinued the study and the reasons for discontinuations 
The number and percentage (based on the overall Safety Set) of subjects in each of the 
following disposition categories will be presented by treatment group:

Completed treatment regimen in both periods

Completed study
A listing will be provided for subjects who discontinued treatment or who discontinued
study, along with reasons for discontinuations.
The number and percentage of randomized subjects will be summarized by stratification 
factor (ppFEV1 at screening), by country and by site, using the number of subjects being 
randomized in each treatment sequence as the denominator. A randomization listing ordered 
by randomization date also will be provided.
9.2.2
Demographics and Baseline Characteristics
Demographic and study baseline characteristics data will be summarized by treatment group
and overall based on the FAS for each period (Period 1 and Period 2).
Demographic data will include the following:

Age (years) at screening

Age group at screening (12 to <18 years vs ≥18 years)

Sex (Male and Female)
o
Female only: Child bearing potential

Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, not collected per local regulations, and Other)

Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local 
regulations)

Region (Europe or North America)
Study baseline characteristics will include the following:

Weight (kg)

Weight-for-age z-score (subjects < 20 years at screening)

Height (cm)

Height-for-age z-score (subjects < 20 years at screening)

BMI (kg/m2)

BMI-for-age z-score (subjects < 20 years at screening)

ppFEV1 at Screening (<70, ≥70)


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
ppFEV1 at study baseline (<40, ≥40 to <70, ≥70 to ≤90 and >90)

ppFEV1 at study baseline

FEV1 (L)

FVC (L)

ppFVC (%)

FEF25-75% (L/sec)

ppFEF25-75% (%)

FEV1/FVC

Orkambi and HS Use at Screening (Orkambi+/HS-, Orkambi+/HS+, Orkambi-/HS-, 
Orkambi-/HS+)

Use of Dornase Alfa

Use of inhaled antibiotic

Use of bronchodilator

Use of inhaled bronchodilator (short-acting only, [short-acting and long-acting] or long-
acting only) 

Use of inhaled corticosteroids
9.2.3
Medical History
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). For the FAS, medical history will be summarized descriptively by treatment 
group, system organ class (SOC) and preferred term (PT) for each period (Period 1 and 
Period 2). The corresponding data listing also will be provided.
Ophthalmology history will be presented in individual subject data listings only.
9.2.4
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 inhaled study drug
in the study, regardless of when it ended.

Concomitant medication: medication continued or newly received during the TE period 
for Treatment Period 1 or Treatment Period 2. 

Post-treatment medication: medication continued or newly received after the TE period 
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Period 2, or after the TE period for Treatment Period 1 for subjects who do not have 
Treatment Period 2.
A given medication can be classified as a prior medication, a concomitant medication, a post-
treatment medication, or both prior and concomitant, both concomitant and post-treatment, or 
prior, concomitant, and post-treatment. 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, concomitantly, or post-treatment, it will be considered as prior, concomitant, 
and post-treatment. Details for imputing missing or partial start and/or stop dates of 
medication are described in Section 12.3. 
For the FAS, prior medications and concomitant medications will be summarized 
descriptively by: 1) treatment group, preferred name (PN); and 2) treatment group, anatomic 
class (ATC) level 1, ATC level 2, and PN. Prior medication summaries will be by period 
(Period 1 and Period 2). The summary tables by treatment group and PN will be repeated to 
include prior and concomitant medications with a frequency of ≥5% at the PN level. Post-
treatment medications will be listed for each subject.
9.2.5
Study Drug Exposure
Exposure to inhaled study drug (i.e., duration of treatment in days) will be summarized by
treatment group based on the FAS.
Duration of inhaled study drug exposure is defined as follows: last dose date of inhaled study 
drug – first dose date of inhaled study drug + 1 day within the treatment period, regardless of 
any interruption in dosing between the first and the last dose.
If the last dose date of inhaled study drug in the treatment period is missing, the subject’s last 
available inhaled study drug administration date in that treatment period will be used for 
analysis purposes. 
Duration of inhaled study drug exposure will be summarized by treatment using descriptive 
summary statistics. Duration of inhaled study drug will also be summarized by time interval 
(>0 to ≤14 days, >14 to ≤28 days, and >28 days) using counts and percentages. 
Study drug administration information on Orkambi will be listed. 
9.2.6
Study Drug Compliance
Inhaled study drug compliance within each treatment period will be calculated as follows: 
    100 × [1 – (Total number of days inhaled study drug interrupted in a treatment 
period) / (Duration of inhaled study drug exposure in that treatment period)]
The total number of days of inhaled study drug interrupted in a treatment period is defined 
as:
   sum of (number of days of inhaled study drug interrupted in each interruption interval in 
that treatment period)


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where number of days of inhaled study drug interrupted in each interval is defined as the 
interruption end date – the corresponding interruption start date + 1.
Note: A subject may have treatment interruption first, followed by decision of permanent 
treatment discontinuation. In such cases, last dose date is collected as the date before that 
treatment interruption and drug interruption would appear to be after the last dose date. For 
calculating compliance, the interruption end date will be restricted to the last dose date.
Inhaled study drug compliance will be summarized by treatment group using descriptive 
summary statistics, and will also be summarized by category (<80%, ≥80%) using counts and 
percentages. A list of subjects with <80% compliance rate will be provided.
Compliance on Orkambi will be defined as follows:
    100 × [(Total number of days on Orkambi during the inhaled study drug exposure in a 
treatment period after excluding the number of days Orkambi was interrupted) / (Duration of 
inhaled study drug exposure in that treatment period)]
Note that the compliance for Orkambi will not consider the run-in period as well as the 
washout period. Compliance on Orkambi will be summarized using an approach similar to 
the inhaled study drug compliance.
Inhaled Study drug compliance and compliance on Orkambi will be summarized based on 
the FAS.
9.2.7
Important Protocol Deviations
Important protocol deviations (IPD) are a subset of protocol deviations that may significantly 
impact the completeness, accuracy, and/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 before database lock.
The protocol deviations that should be considered as potential IPDs include, but are not 
limited to:

Violation of subjects rights, safety or well-being

Subject entered the study despite violation of any inclusion or exclusion criteria

Subject was less than 80% compliant with study medications

Subject received excluded concomitant medications

Subject received the wrong treatment or incorrect doses

Subject remained in study despite meeting withdrawal criteria
Occurrence of any of these events should be considered as potential IPDs, but the blinded 
team should categorize them as IPDs only if they have the potential to affect interpretation of 
study results. 
IPDs (from the clinical database or from the site deviation log) will be summarized 
descriptively based on the FAS and presented by treatment sequence. Additionally, IPDs will 


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be provided as a subject data listing. No subjects with IPDs will be excluded from any 
analysis. 
9.3
Efficacy Analysis
The primary efficacy objective of this study is to evaluate the efficacy of VX-371+ HS 
versus HS alone. For efficacy analysis, the statistical inference will be based on change from 
study baseline. Unless otherwise defined, all efficacy analyses described in this section will
be based on FAS. The efficacy analyses will be performed according to the treatment to 
which the subject was assigned in each period. Data for a period will be used provided that 
the subject received at least one dose of study drug in that treatment period.
9.3.1
Analysis of Primary Efficacy Endpoint
9.3.1.1
Definition of Primary Efficacy Endpoint
The primary efficacy endpoint is the absolute change in ppFEV1 from study baseline at Day
28 in each treatment period. ppFEV1 is the ratio of FEV1 (L) to the predicted FEV1 (L), 
expressed as a percentage. The predicted FEV1 will be calculated according to the Global 
Lung Initiative (GLI) method1. The analysis will include all available measurements up to Day 
28 during each treatment period, both on-treatment measurements and measurements after 
treatment discontinuation.
9.3.1.2
Primary Analysis of Primary Efficacy Endpoint
The null hypothesis to be tested is that the mean change from study baseline in ppFEV1 at
Day 28 is the same for VX-371 with HS versus HS alone.
The primary analysis of the primary efficacy endpoint will be based on a mixed-effects 
model. This model will include the absolute change from study baseline in ppFEV1 at Day 28 
as the dependent variable and the following fixed effects: treatment, period and ppFEV1 at 
study baseline 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 performed. Subjects who have data only for one of the 
periods will have a data structure similar to a parallel-group trial. Assuming that these 
subjects have dropped out at random, an estimate of treatment effect based on such subjects 
will be combined with the estimate from subjects who have data in both treatment periods 
with weights based on the precision of these estimates2. 


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where “primary efficacy endpoint” is the absolute change from study baseline in ppFEV1 at 
day 28. 
Descriptive summary statistics including n, mean, SD, and least-square means (LS means), 
along with its SE, 95% CI and the within-treatment 2-sided P value will be provided by 
treatment group. The between-treatment LS mean differences [VX-371 + HS versus HS, VX-
371 + HS versus VX-371  + placebo, VX-371 + HS versus placebo, and VX-371 + placebo 
versus placebo] with the corresponding SE, 95% CIs and 2-sided P values will be presented. 
The cumulative distribution of the absolute change from study baseline in ppFEV1 at Day 28
will be plotted by treatment group.


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9.3.4
Multiplicity Adjustment
No multiplicity adjustment will be implemented. 
9.4
Safety Analysis
All safety analyses will be based on the set of data associated with the TE period for 
Treatment Period 1 and the TE period for Treatment Period 2. Safety analyses will use the 
Safety Set. Subjects will be analyzed according to the treatment they actually received in a 
given treatment period. For subjects receiving study drug from more than one treatment 
group in the same treatment period, the treatment group allocation will be the determined 
using the following order: VX-371 + HS > VX-371 + Placebo > HS  > Placebo. For safety 
analysis, the period baseline will be used.
All safety data will be presented in individual subject data listings.
The overall safety profile of inhaled 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., hematology, serum and plasma chemistry, coagulation
            studies, and urine studies)

ECG results

Vital signs

Ophthalmologic examination results (for pediatric subjects <18 years of age only)

Spirometry
Only descriptive analysis of the safety data will be performed; no statistical testing is 
planned.


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9.4.1
Adverse Events
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs or post-treatment 
AEs, defined as follows:
Pretreatment AE: any AE that started before the start of inhaled study drug dosing in the 
study.
TEAE: any AE that increased in severity or that was newly developed during the TE period
for Treatment Period 1 or Treatment Period 2. An AE that starts (or increases in severity)
during a specific treatment period will be attributed to the inhaled study drug the subject
was receiving during the treatment period.
Post-treatment AE: any AE that increased in severity or that was newly developed beyond 
the TE period for Treatment Period 2, or between the TE periods for Treatment Period 1 and 
Treatment Period 2, or beyond the TE period for Treatment Period 1 for subjects who do not 
have Treatment Period 2
For AEs with a missing or partially missing  start date, if there is no clear evidence that the 
AE started (or increased in severity) before the first dose in Treatment Period 1, the start date 
will be imputed to the first dosing date in Treatment Period 1 and the AE will be assigned to 
the treatment in Treatment Period 1. For AEs with partially missing start date that indicates 
the AE started (or increased in severity) after the TE period of Treatment Period 1, but no 
clear evidence that it started before the first dose in Treatment Period 2, the start date will be 
imputed to the first dosing date in Treatment Period 2 and the AE will be assigned to the 
treatment in Treatment Period 2. Details for imputing missing or partial start date of AEs are 
described in Section 12.4.
9.4.1.1
Over view of Treatment emergent AEs
An overview of all TEAEs will be summarized in the following categories:

All TEAEs 

Grade 3/4 TEAEs

TEAEs by relationship to study drug regimen

TEAEs by relationship to study device

TEAEs by maximum severity

TEAEs leading to treatment interruption (this will include TEAEs leading to 
treatment interruption of inhaled study drug, Orkambi, and either inhaled study drug
or Orkambi)

TEAEs leading to treatment discontinuation (this will include TEAEs leading to 
discontinuation of inhaled study drug, Orkambi, and either inhaled study drug or 
Orkambi)

Serious TEAEs

Related serious TEAEs


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
TEAEs leading to death
9.4.1.2
TEAEs and TE SAEs by System Organ Class and Preferred Term
The number and percentage of subjects with TEAEs will be summarized by treatment group, 
MedDRA system organ class (SOC) and preferred term (PT), where multiple occurrences of 
the same AE for the same subject will be counted only once. The summary table will be 
presented in descending order of frequencies in the VX-371 + HS treatment group. TE SAEs 
will be summarized similarly.
9.4.1.3
TEAEs and TE SAEs by PT
The number and percentage of subjects with TEAEs will be summarized by treatment group 
and PT, where multiple occurrences of the same AE for the same subject will be counted 
only once. TE SAEs will be summarized similarly.
9.4.1.4
Related TEAEs and TE SAEs by SOC, PT
The number and percentage of subjects with related TEAEs will be summarized by treatment 
group, SOC, and PT, where multiple occurrences of the same AE for the same subject will be 
counted only once. The summary table will be presented in descending order of frequencies 
in the VX-371 + HS treatment group. TEAEs in the following relationship to study drug 
regimen categories will be considered as related: Related, Possibly Related and Missing. TE 
SAEs will be summarized similarly.
In addition, related TEAEs pertaining to the study device will be summarized by treatment 
group and PT.
9.4.1.5
Grade 3/4 TEAEs by SOC, PT
The number and percentage of subjects with Grade 3/4 TEAEs will be summarized by 
treatment group, SOC, and PT, where multiple occurrences of the same AE for the same 
subject will be counted only once. The summary table will be presented in descending order 
of frequencies in the VX-371 + HS treatment group. Grade 3/4 TEAEs include severe and 
life-threatening adverse events. 


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9.4.1.6
Respiratory Events and Symptoms
Respiratory symptoms are defined as any TEAEs for the following 3 PTs:

Chest discomfort

Dyspnoea

Respiration abnormal
Respiratory events are defined as any of the afore-mentioned respiratory symptoms, or any 
TEAEs for the following 4 additional PTs:

Asthma

Bronchial hyperreactivity

Bronchospasm

Wheezing
A summary of TE respiratory symptoms and events will be presented:
1. Showing number and percentage of subjects overall as well as by PT;
2. Showing number and percentage of subjects by maximum severity;
3. Summary of time-to-first onset (relative to first dose date of inhaled study drug in the 
treatment period)
4. Summary of duration of events (days) with descriptive summary; 
5. Showing number and percentage of subjects with TEAE leading to treatment interruption 
of inhaled study drug, Orkambi, and either inhaled study drug or Orkambi; with TEAE 
leading to treatment discontinuation of inhaled study drug, Orkambi, and either inhaled 
study drug or Orkambi; with serious TEAEs; with related serious TEAEs; and with 
TEAE leading to death.
9.4.1.7
Hyperkalaemia
The following AE PTs will be selected for hyperkalaemia:

Hyperkalaemia

Blood potassium increased
A summary of hyperkalaemia will be presented using an approach similar to that for 
respiratory symptoms and events.


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9.4.2
Clinical Laboratory 
For treatment emergent laboratory measurements, the raw values and change from period 
baseline values of the continuous laboratory continuous laboratory measurements (chemistry, 
hematology, and coagulation) will be summarized in SI units using descriptive statistics by 
treatment group at each scheduled time point. Urine sodium to potassium ratios will be 
summarized by treatment group.
The number and percentage of subjects with abnormal high (>ULN) hematology and 
chemistry values will be summarized by visit, as will the number and percentage of subjects 
with abnormal low (<LLN) hematology and chemistry values. 
The number and percentage of subjects with laboratory measurements meeting the threshold 
analysis criteria during the TE period will be presented. The threshold analysis criteria are 
provided in Section 12.5 (Table 12-8      Threshold Criteria for Laboratory Tests).
The incidence of LFTs meeting the threshold analysis criteria during the TE period against 
the period baseline threshold criteria will also be summarized by treatment group (only 
worsening of the shift from period baseline will be presented).  
Mean values (± SD) will be plotted against visit for plasma potassium, ALT, AST, alkaline 
phosphatase, GGT, and total bilirubin.
A listing of subjects with elevated liver function test (LFT, alanine aminotransferase 
[ALT]>3 Upper Limit Normal [ULN], aspartate aminotransferase [AST]>3 ULN, serum 
alkaline phosphatase [ALP]>1.5 ULN, direct bilirubin>1.5 ULN, and total bilirubin>1.5 
ULN) results during the TE period will be presented. The listing will include all parameters 
of the LFT assessment at all visits.
A listing of subjects with elevated plasma potassium level at any time point during the TE 
period will be provided. The listing will include all plasma potassium measurements at all 
visits.


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Results of urinalysis and serum 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.
9.4.3
Electrocardiogram
For treatment-emergent ECG measurements, a summary of raw values and change from 
study baseline values will be provided by treatment group at each scheduled time point for 
the following standard 12-lead ECG measurements: PR, QTc for HR intervals (QTcF), QRS 
duration, and HR. In addition, the mean value at each time point will be plotted by treatment 
group for QTcF and heart rate.
The number and percentage of subjects with ECG measurements meeting the threshold 
analysis criteria during the TE period will be presented. The threshold analysis criteria are 
provided in Section 12.5 (Table 12-9      Threshold Criteria for ECGs).
9.4.4
Vital Signs
The raw values and change from period baseline values will be summarized by treatment 
group at each scheduled time point for the following treatment-emergent vital signs 
measurements: systolic and diastolic blood pressure (mm Hg), body temperature (oC), HR 
(beats per minute), weight, height, BMI and respiratory rate (breaths per minute). In addition, 
the mean value at each time point will be plotted by treatment group for systolic and diastolic 
blood pressure.
The number and percentage of subjects with vital signs meeting the threshold analysis 
criteria during the TE period will be presented. The threshold analysis criteria are provided in 
Section 12.5 (Table 12-10      Threshold Criteria for Vital Signs).
9.4.5
Physical Examination
Abnormal physical examination findings will be presented in a data listing.
9.4.6
Ophthalmologic Examinations
The results of ophthalmologic examinations for pediatric subjects <18 years of age will be 
presented in individual by-subject listings.
9.4.7
Spirometry
9.4.7.1
Decline in Postdose Spirometry
For the postdose measurements on Day 1, Day 14 and Day 28 of each treatment period, a 
summary of raw values for ppFEV1 will be provided by treatment group. The absolute 
change from the predose value of ppFEV1 to the postdose value on the same day will be 
provided by treatment group. In addition, a box plot by study day and treatment group will be 
provided. The above analyses will be repeated for FEV1.


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The following summaries regarding the decline in postdose spirometry will be provided:

Number and percentage of subjects with ≥10, ≥15 or ≥20 percentage points decrease in 
absolute change from predose value of ppFEV1.

Number and percentage of subjects with ≥0.2 L decrease in absolute change from predose 
value of FEV1.
Subjects with ≥10 percentage points decrease in absolute change from predose value of 
ppFEV1 or ≥0.2 L decrease in the absolute change from predose value of FEV1 will be listed. 
9.4.7.2
Decline in Predose Spirometry
The following summaries regarding the decline in predose spirometry will be provided:

Number and percentage of subjects with ≥10, ≥15 or ≥20 percentage points decrease in 
absolute change from period baseline in ppFEV1 at each post-baseline visit.

Number and percentage of subjects with ≥0.2 L decrease in absolute change from period 
baseline in FEV1 at each post-baseline visit.
Subjects with ≥10 percentage points decrease in absolute change from period baseline in 
ppFEV1 or ≥0.2 L decrease in the absolute change from period baseline in FEV1 will be 
listed. The listing will include raw values and absolute/relative changes from period baseline 
in ppFEV1 and FEV1 at each visit from the period in which the decline criteria was met.
9.4.8
Other Safety Analyses
Not applicable.
10
INTERIM AND DMC ANALYSES
10.1
Interim Analysis
No interim analysis is planned or conducted.
10.2
DMC Analysis
An independent data monitoring committee (DMC) was formed. The DMC objectives and 
operational details are defined in a separate document (DMC Charter), which was finalized 
before the first subject is screened in the study. The DMC conducted planned reviews of 
study data as outlined in the DMC Charter. The DMC meeting schedule is as below: 

After ≥40% of subjects (60 subjects) have completed Treatment Period 1.

Ad-hoc: Ad-hoc IDMC meetings will be teleconference on an as-needed basis. Timing of 
the data snapshot will be defined on an ad-hoc basis.
Overall, there is one DMC data review. Details of the DMC analyses are provided in the 
DMC Analysis Plan.


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11 REFERENCES
1          Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic 
reference values for spirometry for the 3-95-yr age range: the global lung function 2012 
equations. Eur Respir J. 2012;40(6):1324-43. 
2          Senn S. Cross-over Trials in Clinical Research. 2nd ed. Chichester, John Wiley & 
Sons. 2002. 
          
 
          
 
          
 
          
 


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12 APPENDICES
12.1
Schedule of Assessments
The Schedules of Assessments are shown in Tables 12-1 to 12-4.
All visits are to be scheduled relative to the Day 1 Visit (first dose of study drug). 
Table 12-1
Study VX15-371-101: Screening Period for All Subjects
Event/Assessment
Screening Period 
(Day-28 to Day -1 for Orkambi+/HS- Subjects
or
Day -56 to Day -29 for Orkambi-/HS+, Orkambi-/HS-, and 
Orkambi+/HS+ Subjectsa)
Clinic visit
X
Informed consent/assent
X
Inclusion/exclusion criteria review
X
Demography
X
Medical history
X
Ophthalmologic history
X
Medications review
X
Height and weightb
X
Vital signs
X
Ophthalmologic examination (only for 
pediatric subjects <18 years of age)
X
Physical examinationc
X
Standard 12-lead ECGd
X
Sweat chloridee
X
CFTR genotypef
X
Serum β-hCGg
X
Serum FSHh
X
                                               
a
All Screening assessments must be completed before the Day 1 Visit for Orkambi+/HS- subjects and before the 
Day -28 Visit for Orkambi-/HS+, Orkambi-/HS-, and Orkambi+/HS+ subjects. Subjects may be rescreened after 
discussion with, and approval from, the medical monitor (see section 8.1.1.2 of CSP).  
b
Height and weight will be measured with shoes off.
c
A full physical examination will be performed at the Screening Visit (see section 11.6.3 of CSP).
d
A standard 12-lead ECG will be performed after the subject has been seated or supine for at least 5 minutes
(see section 11.6.4 of CSP).
e
A sweat chloride test must be performed at the Screening Visit if an eligible sweat chloride value is not 
available in the subject’s medical records and the Screening Visit value is needed to establish eligibility. For 
subjects using sweat chloride values documented in their medical records to establish eligibility, the sweat 
chloride test at the Screening Visit is optional. Collection of sweat chloride will not overlap with any other 
study assessments.
f
CFTR genotyping will be performed to confirm that the subject is homozygous for the F508del-CFTR mutation 
and the results of the genotyping should be confirmed during the Screening Period. If the CFTR screening genotype 
result is not received before randomization, a previous CFTR genotype lab report may be used to establish 
eligibility. Note: Subjects who have been randomized and whose screening genotype does not confirm study 
eligibility must be discontinued from the study.
g
A pregnancy test will be performed for all female subjects of childbearing potential.


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Table 12-1
Study VX15-371-101: Screening Period for All Subjects
Event/Assessment
Screening Period 
(Day-28 to Day -1 for Orkambi+/HS- Subjects
or
Day -56 to Day -29 for Orkambi-/HS+, Orkambi-/HS-, and 
Orkambi+/HS+ Subjectsa)
Urine tests
X
Serum and plasma chemistry
X
Hematology
X
Coagulation
X
Spirometry 
X
Lumacaftor/ivacaftor dosingi
lumacaftor 400 mg/ivacaftor 250 mg q12h
 
AEs and SAEs
Continuous, from signing of ICF (and assent form, if applicable) 
through Safety Follow-up Telephone Contact
                                                                                                                                                      
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
Subjects are to take 2 tablets (each containing lumacaftor 200 mg/ivacaftor 125 mg) orally q12h with fat-
containing food (see section 10.2.2 of CSP).


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Table 12-2
Study VX15-371-101: Run-in Period for Orkambi-/HS-, Orkambi-/HS+, and 
Orkambi+/HS+ Subjects
Event/Assessment
Run-in Perioda
(Day -28 to Day -1)
Day -28
(± 2 days)
Day -14
(± 2 days)
Clinic visit
X
X
Vital signs
X
X
Physical examinationb
X
X
Meal or snack at study centerc
X
X
Lumacaftor/ivacaftor dosingd
lumacaftor 400 mg/ivacaftor 250 mg q12h
 
Adverse events and serious adverse events
Continuous, from signing of ICF (and assent form, if applicable)
through Safety Follow-up Telephone Contact
                                               
a
During the Run-in Period, all subjects who are receiving HS as part of their CF standard of care will washout 
from HS for 28 days before dosing with study drug and will remain off HS through the Safety Follow-up Telephone 
Contact. 
b
An abbreviated physical examination will be performed at the Day -28 and Day -14 Visits (see section 11.6.3 of 
CSP).
c
At the scheduled visits indicated, if the subject has not taken the morning dose of lumacaftor/ivacaftor before 
coming to the study visit, a fat-containing meal or snack will be provided with that dose.
d
Subjects are to take 2 tablets (each containing lumacaftor 200 mg/ivacaftor 125 mg) orally q12h with 
fat-containing food (see section 10.2.2 of CSP).


Statistical Analysis Plan (Methods)
Page 41 of 60
Vertex Protocol VX15-371-101, Version 3.0
Vertex Pharmaceuticals Incorporated
Table 12-3
Study VX15-371-101: Treatment Period
Event/Assessment
Treatment Perioda
Treatment Period 1
(Day 1 to Day 28)
Washoutb
(Day 29 to Day 56)
(+ 3 days)
Treatment Period 2
(Day 57 to Day 84)
Day 1
Day 3
(± 1 day)
Day 14
(3 days)
Day 28
(- 2 days)
Day 57
Day 59
(± 1 day)
Day 70
(3 days)
Day 84
(- 2 days)
Clinic visit
X
X
X
X
X
X
Telephone contactc
X
X
Inclusion/exclusion criteria review
X
Randomizationd
X
Height and weightf
X
X
X
X
Vital signsg
X
X
X
X
X
X
Physical examinationh
X
X
X
X
Standard 12-lead ECGi
X
X
X
X
X
X
                                               
a
See section 8.1.4 of CSP for guidance about discontinuation of study drug treatment. 
b
The Washout Period may be for acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) upon 
discussion with and approval by the medical monitor (see section 8.1.3.2 of CSP).
c
A telephone contact will occur on Day 3 and Day 59 of the study for safety purposes (e.g., inquiry about adverse events). 
d
Randomization will occur after all inclusion and exclusion criteria are met. If the screening genotype result is not received before randomization, a previous 
CFTR genotype lab report may be used to establish eligibility. Note: Subjects who have been randomized on the basis of a historical genotype lab report and 
whose screening genotype does not confirm study eligibility must be discontinued from the study.
.
f
Height and weight will be measured with shoes off.
g
All vital signs will be collected within 60 minutes before inhaled study drug dosing. Only pulse rate and blood pressure will be collected 90 (± 30) minutes 
after inhaled study drug dosing. Vital signs will be assessed after the subject has been seated or supine for at least 5 minutes ( see section 11.6.3 of CSP).
h
An abbreviated physical examination will be performed before dosing with inhaled study drug (see section 11.6.3 of CSP).
i
The ECG will be performed 60 (± 30) minutes after completion of inhaled study drug dosing and after the subject has been seated or supine for at least 
5 minutes ( see section 11.6.4 of CSP). 


Statistical Analysis Plan (Methods)
Page 42 of 60
Vertex Protocol VX15-371-101, Version 3.0
Vertex Pharmaceuticals Incorporated
Table 12-3
Study VX15-371-101: Treatment Period
Event/Assessment
Treatment Perioda
Treatment Period 1
(Day 1 to Day 28)
Washoutb
(Day 29 to Day 56)
(+ 3 days)
Treatment Period 2
(Day 57 to Day 84)
Day 1
Day 3
(± 1 day)
Day 14
(3 days)
Day 28
(- 2 days)
Day 57
Day 59
(± 1 day)
Day 70
(3 days)
Day 84
(- 2 days)
Spirometryk
X
X
X
X
X
X
Urine pregnancy testl
X
X
X
X
Urine testsm
X
X
X
X
X
X
Serum and plasma chemistryo
X
X
X
X
X
X
Hematology
X
X
X
X
Coagulation
X
X
X
X
                                               
 
k
The spirometry assessment will be performed within 60 (± 10) minutes before and 30 (± 5) minutes) after the dose of inhaled study drug is administered.   
l
Pregnancy tests will only be administered to female subjects of childbearing potential (see section 11.6.2 of CSP).
m
On Day 1 and Day 57, a urine sample will be collected 90 (+ 5) minutes before dosing with inhaled study drug. A urine sample will also be collected at 
90 (± 60) minutes after completion of dosing with inhaled study drug at the Day 14, Day 28, Day 70, and Day 84 Visits.
o
Subjects with a potassium level that is ≤0.4 units below the ULN at the Day 1 or Day 57 Visit will be required to have a blood sample collected for a repeat 
evaluation of plasma potassium within 7 (± 2) days (see section 11.6.2.2 of CSP).


Statistical Analysis Plan (Methods)
Page 43 of 60
Vertex Protocol VX15-371-101, Version 3.0
Vertex Pharmaceuticals Incorporated
Table 12-3
Study VX15-371-101: Treatment Period
Event/Assessment
Treatment Perioda
Treatment Period 1
(Day 1 to Day 28)
Washoutb
(Day 29 to Day 56)
(+ 3 days)
Treatment Period 2
(Day 57 to Day 84)
Day 1
Day 3
(± 1 day)
Day 14
(3 days)
Day 28
(- 2 days)
Day 57
Day 59
(± 1 day)
Day 70
(3 days)
Day 84
(- 2 days)
Urine for PK analysisp
X
X
X
X
X
X
Blood for PK analysisq
X
X
X
X
X
X
Meal or snack at study centerr
X
X
X
X
X
X
Inhaled study drug dosings
X
X
Xt
X
X
Xt
Lumacaftor/ivacaftor dosingu
lumacaftor 400 mg/ivacaftor 250 mg q12h
Inhaled study drug count
X
X
X
X
X
X
Lumacaftor/ivacaftor drug count
X
X
X
X
X
X
                                               
p
A urine sample for evaluation of VX-371 will be collected within 90 (+ 5) minutes before and 90 (± 60) minutes after completion of dosing with inhaled 
study drug at the Day 1, Day 14, Day 28, Day 57, Day 70, and Day 84 Visits (see section 11.3.2 of CSP).
q
Blood samples for the PK assessment will be analyzed for VX-371 
. For the evaluation of VX-371, a blood sample will be 
collected within 90 (+ 5) minutes before dosing with inhaled study drug and at 60 (± 30) minutes after completion of inhaled study drug dosing  at the Day 1, 
Day 14, Day 28, Day 57, Day 70, and Day 84 Visits.
 
r
At the scheduled visits indicated, if the subject has not taken the morning dose of lumacaftor/ivacaftor before coming to the study visit, a meal or snack will 
be provided with that dose after all predose assessments have occurred. 
s
Inhaled study drug will be administered from Day 1 to Day 28 and from Day 57 to Day 84. Inhaled study drug should be administered by nebulization twice 
daily (bid) approximately 10 to 12 hours apart for oral inhalation ( see section 10.2.1 of CSP). Inhaled study drug will be administered at the clinic at the
Day 1, Day 14, Day 28, Day 57, Day 70, and Day 84 Visits.
t
The last dose of inhaled study drug in Treatment Period 1 and Treatment Period 2 is the dose of study drug received at the Day 28 and Day 84 Visits, 
respectively.
u
Subjects are to take 2 tablets (each containing lumacaftor 200 mg/ivacaftor 125 mg) orally q12h with fat-containing food ( see section 10.2.2 of CSP). The 
last dose of Orkambi during the Run-in Period will be the morning dose of the Day 1 Visit ( see section 8.1.2 of CSP).


Statistical Analysis Plan (Methods)
Page 44 of 60
Vertex Protocol VX15-371-101, Version 3.0
Vertex Pharmaceuticals Incorporated
Table 12-3
Study VX15-371-101: Treatment Period
Event/Assessment
Treatment Perioda
Treatment Period 1
(Day 1 to Day 28)
Washoutb
(Day 29 to Day 56)
(+ 3 days)
Treatment Period 2
(Day 57 to Day 84)
Day 1
Day 3
(± 1 day)
Day 14
(3 days)
Day 28
(- 2 days)
Day 57
Day 59
(± 1 day)
Day 70
(3 days)
Day 84
(- 2 days)
Dispense nebulizer and/or 
nebulizer handsetv
X
X
Collect nebulizer and/or nebulizer 
handsetw
X
X
Medications review
X
X
X
X
X
X
Concomitant treatments and 
procedures
X
X
X
X
X
X
 
Adverse events and serious 
adverse events
Continuous, from signing of ICF (and assent form, if applicable)
through Safety Follow-up Telephone Contact
                                               
v
A nebulizer device (nebulizer and handset) will be dispensed at the Day 1 Visit. At the Day 57 Visit, a new nebulizer handset will be provided for 
replacement.
w
The nebulizer handset used during Treatment Period 1 will be collected at the Day 28 Visit. At the Day 84 Visit, the nebulizer device (nebulizer and handset 
used during Treatment Period 2) will be collected. 


Statistical Analysis Plan (Methods)
Page 45 of 60
Vertex Protocol VX15-371-101, Version 3.0
Vertex Pharmaceuticals Incorporated
Table 12-4
Study VX15-371-101: Early Termination of Treatment Visit, Safety 
Follow-up Visit, and Safety Follow-up Telephone Contact
Event/Assessment
Early Termination of 
Treatment Visit37
Safety Follow-up Visit
28 days (+ 3 days)
After Last Dose of Study 
Drug38
Safety Follow-up
Telephone Contact
28 days (+ 3 days) After 
the Day 28 or Day 84 
Visit39
Clinic visit
X
X
Telephone contact
X
Height and weight40
X
X
Vital signs
X
X
Physical examination 
X
X
Ophthalmologic 
examinations41
X
X
X
Standard 12-lead ECG42
X
X
Urine pregnancy test43
X
X
Hematology
X
X
Coagulation
X
X
Urine tests
X
X
Serum and plasma 
chemistry
X
X
Urine for PK analysis44
X
Blood for PK analysis45
X
Spirometry 
X
X
Inhaled study drug count
X
Lumacaftor/ivacaftor drug 
count
X
X
Collect nebulizer and 
nebulizer handset
X
Concomitant medications
X
X
Concomitant treatments 
and procedures
X
X
                                               
37 See 8.1.4 of CSP for guidance about discontinuation of study drug treatment.  
38
See  8.1.6 of CSP.
39
See 8.1.5 of CSP.
40
Height and weight will be measured with shoes off.
41 Pediatric subjects <18 years of age at the Screening Visit who discontinue study drug treatment will have an 
ophthalmologic examination that is to occur between their last dose of study drug and completion of either the 
ETT Visit or the Safety Follow-up Visit. Pediatric subjects who complete the Day 84 Visit will have an 
ophthalmologic examination that is to occur between the Day 84 Visit and the Safety Follow-up Telephone 
Contact. See 11.6.5 of CSP
42 The ECG will be performed after the subject has been seated or supine for at least 5 minutes (11.6.4 ). 
43
Pregnancy tests will only be administered to female subjects of childbearing potential (see 11.6.2 of CSP).
44
At the ETT Visit, a single urine sample for PK will be collected.
45
At the ETT Visit, 2 blood samples for PK will be collected, 1 for the evaluation of VX-371 
 
.


Statistical Analysis Plan (Methods)
Page 46 of 60
Vertex Protocol VX15-371-101, Version 3.0
Vertex Pharmaceuticals Incorporated
Table 12-4
Study VX15-371-101: Early Termination of Treatment Visit, Safety 
Follow-up Visit, and Safety Follow-up Telephone Contact
Event/Assessment
Early Termination of 
Treatment Visit37
Safety Follow-up Visit
28 days (+ 3 days)
After Last Dose of Study 
Drug38
Safety Follow-up
Telephone Contact
28 days (+ 3 days) After 
the Day 28 or Day 84 
Visit39
 
Adverse events and serious 
adverse events
Continuous, from signing of ICF (and assent form, if applicable)
through Safety Follow-up Telephone Contact


Statistical Analysis Plan (Methods)
Page 47 of 60
Vertex Protocol VX15-371-101, Version 3.0
Vertex Pharmaceuticals Incorporated
12.2
Analysis Visit Windows for Safety and Efficacy Assessments
Table 12-5      Visit Window Mapping Rules for Efficacy Assessments
* Day 1 post-dose measurement (unscheduled) in each period
Note: 
1. All assessments including early termination visits, safety follow-up and unscheduled 
visits will follow the individual visit window to be mapped to individual visits
2. For spirometry use only pre-dose assessments.
Assessments
Analysis
Period
Analysis Visit
Target 
Study 
Day
Visit Window 
(in study days)
Weight and Height
1
Baseline
1
[screening visit, Day 1]
1
Day 28
28
[2, 35]
2
Baseline
1
[end of TE period for first period 
+1 , Day 1]
2
Day 28
28
[2, 35]
Spirometry
1
Baseline
1
[screening visit, pre-dose Day 1]
1
Day 14
14
(1*, 21]
1
Day 28
28
[22, 35]
2
Baseline
1
[end of TE period for Period 1+1, 
pre-dose Day 1]
2
Day 14
14
(1*, 21] 
2
Day 28
28
[22, 35] 


Statistical Analysis Plan (Methods)
Page 48 of 60
Vertex Protocol VX15-371-101, Version 3.0
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Table 12-6      Visit Window Mapping Rules for Safety Assessments
Assessments
Analysis
Period
Analysis Visit
Target 
Study 
Day
Visit Window 
(in study days)
Serum and plasma 
chemistry
Urine tests(sodium and 
potassium)§
1
Baseline
1
[screening visit, pre-dose Day 1]
1
Day 14
14
(1*, 21]
1
Day 28
28
[22, 35]
2
Baseline
1
[end of TE period for first period 
+1 , pre-dose Day 1]
2
Day 14
14
(1*, 21]
2
Day 28
28
[22, 35]
Safety Follow-up 
Visit
NA
Use the nominal visit if study day 
greater than 35
Vital signs (respiratory 
rate and temperature)
1
Baseline
1
[screening visit, pre-dose Day 1]
1
Day 14
14
[2, 21]
1
Day 28
28
[22, 35]
2
Baseline
1
[end of TE period for first period 
+1 , pre-dose Day 1]
2
Day 14
14
[2, 21]
2
Day 28
28
[22, 35]
Safety Follow-up 
Visit
NA
Use the nominal visit if study day 
greater than 35
ECG
1
Baseline
1
[screening visit, pre-dose Day 1]
1
Day 1
1
1†
1
Day 14
14
(1*, 21]
1
Day 28
28
[22, 35]
2
Day 1
1
1†
2
Day 14
14
(1*, 21]
2
Day 28
28
[22, 35]
Safety Follow-up 
Visit
NA
Use the nominal visit if study day 
greater than 35
Hematology
Coagulation
1
Baseline
1
[screening visit, pre-dose Day 1]
1
Day 28
28
(1*, 35]
2
Baseline
1
[end of TE period for first period 
+1 , pre-dose Day 1]
2
Day 28
28
(1*, 35]
Safety Follow-up 
Visit
NA
Use the nominal visit if study day 
greater than 35


Statistical Analysis Plan (Methods)
Page 49 of 60
Vertex Protocol VX15-371-101, Version 3.0
Vertex Pharmaceuticals Incorporated
Assessments
Analysis
Period
Analysis Visit
Target 
Study 
Day
Visit Window 
(in study days)
Weight
1
Baseline
1
[screening visit, Day 1]
1
Day 28
28
[2, 35]
2
Baseline
1
[end of TE period for first period 
+1 , Day 1]
2
Day 28
28
[2, 35]
Safety Follow-up 
Visit
NA
Use the nominal visit if study day 
greater than 35
Spirometry
Vital Sign (HR, SBP, 
and DBP)
1
Baseline
1
[screening visit, pre-dose Day 1]
1
Day 1
1
1†
1
Day 14
14
(1*, 21]
1
Day 28
28
[22, 35]
2
Baseline
1
[end of TE period for Period 1+1, 
pre-dose Day 1]
2
Day 1
1
1†
2
Day 14
14
(1*, 21] 
2
Day 28
28
[22, 35] 
Safety Follow-up 
Visit
NA
Use the nominal visit if study day 
greater than 35
* Day 1 post-dose measurement (unscheduled) in each period
† Day 1 post-dose measurement (scheduled) in each period
§ Urine samples will also be collected post-dose on Day 14 and Day 28 in each period
Note: 
1. All assessments including early termination visits, safety follow-up and unscheduled 
visits will follow the individual visit window to be mapped to individual visits. 
2. Spirometry and vital sign assessments (heart rate, systolic blood pressure and diastolic 
blood pressure) taken at unscheduled visits or early termination visit or safety-follow-up 
visits will be considered as predose measurements and follow the visit window mapping 
rules to derive analysis visit. 


Statistical Analysis Plan (Methods)
Page 50 of 60
Vertex Protocol VX15-371-101, Version 3.0
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12.3
Imputation Rules for Missing Prior/Concomitant Medication Dates
Imputation rules for missing or partial medication start/stop dates are defined below:
1. Missing or partial medication start date:
a.
If only DAY is missing, use the first day of the month. 
b. If DAY and Month are both missing, use the first day of the year. 
c.
If DAY, Month and Year are all missing, use a date before the first dose date.
2. Missing or partial medication stop date:
a.
If only DAY is missing, use the last day of the month.
b. If DAY and Month are both missing, use the last day of the year.
c.
If DAY, Month and year are all missing, assign ‘continuing’ status to stop 
date.
In summary, the prior, concomitant or post categorization of a medication is described below.
Table 12-7      Prior, Concomitant, and Post Categorization of a Medication
Medication start 
date
Medication end date
< Start 
date of 
TE Period 
1
≥ Start date of TE 
Period 1 and ≤ End 
date of TE Period 1
> End date of TE 
Period 1 and < Start 
date of TE Period 2
≥ Start date of TE 
Period 2 and ≤ End 
date of TE Period 2
> End date 
of TE 
Period 2
< Start date of TE 
Period 1
P
PC1
PC1A
PC1C2
PC1C2A
≥ Start date of TE 
Period 1 and ≤ End 
date of TE Period 1
-
C1
C1A
C1C2A
C1C2A
> End date of TE 
Period 1 and < Start 
date of TE Period 2
-
-
A
C2A
C2A
≥ Start date of TE 
Period 2 and ≤ End 
date of TE Period 2
-
-
-
C2
C2A
> End date of TE 
Period 2
-
-
-
-
A
P – Prior; C1 – Concomitant for the Treatment in Period1; C2 – Concomitant for the Treatment in Period 2; A – Post-
Treatment.


Statistical Analysis Plan (Methods)
Page 51 of 60
Vertex Protocol VX15-371-101, Version 3.0
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12.4
Imputation Rules for Missing Adverse Event Dates
Imputation rules for missing or partial AE start date are defined below:
If only Day of AE start date is missing: 
If the AE start year and month are the same as that for the first dose date, then:

If the full (or  partial) AE end date is NOT before the first dose date or AE end date is 
missing, then impute the AE start day as the day of first dose date; otherwise, impute 
the AE start day as 1.

Otherwise, impute the AE start day as 1.
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE or post-treatment AE.
If Day and Month of AE start date are missing:
If AE start year = first dose year, then:

If the full (or partial) AE end date is NOT before the first dose date or AE end date is 
missing, then impute the AE start Month and Day as the Month and Day of first dose 
date; otherwise, impute the AE start Month as January and the Day as 1.

Otherwise, impute the AE start MONTH as January and the DAY as 1.
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE or post-treatment AE.
If Year of AE start date is missing:
If the year of AE start is missing or AE start date is completely missing then query site with 
no imputation. Also compare the full (or partial) AE end date to the first dose date. If the AE 
end date is before the first dose date then the AE should be considered as a pretreatment AE. 
Otherwise, the AE will be considered as TEAE.
The imputation rule will be applied with respect to treatment start date for both periods and 
preference will be given to treatment in period 1 in case the AE is assigned to treatments in 
both periods. Missing or partially missing AE end date will not be imputed.


Statistical Analysis Plan (Methods)
Page 52 of 60
Vertex Protocol VX15-371-101, Version 3.0
Vertex Pharmaceuticals Incorporated
12.5
Threshold Analysis Criteria
Table 12-8      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
Hypokalemia
<LLN – ≥ 2.5 mmol/L
<2.5 – ≥ 2.0 mmol/L
<2.0 mmol/L
Hyperkalemia
>ULN – ≤ 5.1 mmol/L
>5.1 –  ≤ 5.6 mmol/L 
>5.6 – ≤ 6.0 mmol/L 
>6.0 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


Statistical Analysis Plan (Methods)
Page 53 of 60
Vertex Protocol VX15-371-101, Version 3.0
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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
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
Inorganic 
phosphate
Hypophosphatemia
<0.74 – ≥ 0.6mmol/L
<0.6 – ≥ 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)
FDA DILI Guidance


Statistical Analysis Plan (Methods)
Page 54 of 60
Vertex Protocol VX15-371-101, Version 3.0
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ALT>20 xULN or AST> 20 xULN
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 
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
Coagulation
Activated partial 
thromboplastin time  
(PTT) 
>ULN - ≤ 1.5 x ULN
>1.5 – ≤ 2.5 x ULN
>2.5 x ULN
CTCAE grade 1-3


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Prothrombin time 
(PT) International
Normalized Ratio 
(INR)
>ULN - ≤ 1.5 x ULN
>1.5 – ≤ 2.5 x ULN
>2.5 x ULN
CTCAE grade 1-3


Statistical Analysis Plan (Methods)
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Table 12-9      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
QTc
>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


Statistical Analysis Plan (Methods)
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Table 12-10      Threshold Criteria for Vital Signs
Parameter
Threshold Criteria
Comments
HR
Same PCS as above in ECG category
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
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


Statistical Analysis Plan (Methods)
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Weight loss 
≥5 % decrease from baseline  
≥10 % decrease from baseline 
≥ 20% decrease from baseline 
CTCAE grade 1-3


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Statistical Analysis Plan (Methods)
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12.7
Standards for Efficacy and Safety Variable Display in TFLs
Continuous Variables
The precision for continuous variables has been specified in the Vertex Standard 
Programming Rules document (Version 1.0, December 2015):
The precision of the measurement in raw values for other continuous variables will be used 
to determine the number of decimal places to present in tables, figures, and derived listings.
Minimum and maximum values will be reported with the same precision as the units of 
measure. The mean, median, and SD will be reported to 1 greater decimal place. 
Categorical Variables: Percentages will be presented to 1 decimal place.