Clinical trial NCT04167345
Conditions: Alpha 1-Antitrypsin Deficiency
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2020-01-13; Completion date: 2020-11-14
Enrollment: 48 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the efficacy, safety and pharmacokinetics (PK) of VX-814 in PiZZ subjects.

Detailed description:

Arms: arm 1: Participants received placebo matched to VX-814 in the treatment period for 28 days. arm 2: Participants received VX-814 100 mg every 12 hours (q12h) in the treatment period for 28 days. arm 3: Participants received VX-814 200 mg q12h in the treatment period for 28 days. arm 4: Participants received VX-814 400 mg q12h in the treatment period for 28 days. arm 5: Participants received VX-814 600 mg q12h in the treatment period for 28 days.
Interventions: intervention 1: VX-814 intervention 2: Placebo
Intervention descriptions: intervention 1: Tablet for oral administration. intervention 2: Placebo matched to VX-814 for oral administration.

Protocol documents:
Prot_000.pdf: 
Page 1 of 68 
1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Clinical Study Protocol 
A Phase 2, Randomized, Double-blind, 
Placebo-controlled Study of the Efficacy and Safety 
of VX-814 in PiZZ Subjects 
Vertex Study Number: VX19-814-101 
 
 
EudraCT Number: 2019-003650-92 
Date of Protocol: 21 May 2020 (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 VX19-814-101, Version 3.0 
Page 4 of 68 
Vertex Pharmaceuticals Incorporated 
 
2 
PROTOCOL SYNOPSIS 
Title 
A Phase 2, Randomized, Double-blind, Placebo-controlled Study of the Efficacy 
and Safety of VX-814 in PiZZ Subjects 
  
Brief Title 
Evaluation of the Efficacy and Safety of VX-814 in Subjects With the PiZZ 
Genotype 
 
 
Clinical Phase and 
Clinical Study Type  
Phase 2; efficacy and safety  
 
 
Objectives 
Primary Objectives 
• 
To evaluate the efficacy of VX-814 in PiZZ subjects as measured by plasma 
functional alpha-1 antitrypsin (AAT) levels 
• 
To evaluate the safety and tolerability of VX-814 in PiZZ subjects 
Secondary Objectives 
• 
To evaluate the efficacy of VX-814 in PiZZ subjects as measured by plasma 
antigenic AAT levels  
• 
To evaluate the pharmacokinetics (PK) of VX-814 in PiZZ subjects 
Endpoints 
Primary Endpoints 
• 
Change from baseline in plasma functional AAT levels at Day 28 
• 
Safety and tolerability assessments based on adverse events (AEs), clinical 
laboratory values, standard 12-lead ECGs, vital signs, and pulse oximetry 
Secondary Endpoints 
• 
Change from baseline in plasma antigenic AAT levels at Day 28 
• 
PK parameters of VX-814 derived from plasma concentration-time data  
Number of Subjects 
Approximately 43 subjects with the PiZZ genotype 
 
 
Study Population 
Male subjects and female subjects 18 through 80 years of age, inclusive, with the 
PiZZ genotype 


Protocol VX19-814-101, Version 3.0 
Page 5 of 68 
Vertex Pharmaceuticals Incorporated 
 
Investigational Drug 
Active substance: VX-814 
 
Activity: AAT modulator 
 
Strength and route of administration: 100-mg tablet and matching placebo for oral 
administration. 
 
 
Study Duration 
Excluding the Screening Period, each subject will participate in the study for 
approximately 56 days: 28 days for the Treatment Period and 28 days for the 
Safety Follow-up Period.  
 
 
Study Design 
This is a Phase 2, randomized, double-blind, placebo-controlled study of VX-814. 
Schematics of the study design are shown below.  
Part A1: Approximately 15 subjects in total with the PiZZ genotype and antigenic 
AAT levels <8 µM at screening will be randomized (2:1:1:1) to 1 of 3 VX-814 
groups or the placebo group.  
Part A2: Approximately 8 subjects in total with the PiZZ genotype and antigenic 
AAT levels <8 µM at screening will be randomized (3:1) to a VX-814 group or 
the placebo group.  
Enrollment may be adjusted to ensure approximately 12 subjects receive VX-814 
400 mg q12h in Parts A1 and A2 combined. 
Part B: Approximately 20 subjects in total with the PiZZ genotype and antigenic 
AAT levels <8 µM at screening will be randomized (3:1) to a VX-814 group or 
the placebo group. 
Enrollment in Parts A2 and B may be initiated before Part A1 completes the 
planned enrollment. 
Randomization will be stratified by post-bronchodilator percent predicted forced 
expiratory volume in 1 second (ppFEV1) obtained either during the Screening 
Period or from a historical post-bronchodilator ppFEV1 value measured within 
1 year before screening (<50% versus ≥50%). 


Protocol VX19-814-101, Version 3.0 
Page 6 of 68 
Vertex Pharmaceuticals Incorporated 
 
 
Figure 2-1 
Parts A1, A2, and B: Schematic of Study Design for Subjects 
Who Have Never Been on Augmentation Therapy 
Part A1 
 
 
Part A2 
 
 
Part B 
 
 
N: number of subjects; q12h: every 12 hours 
Note: Figure is not drawn to scale.  
Subject numbers include subjects who have never been on augmentation therapy and 
subjects who have been on augmentation therapy at any time.  
Antigenic AAT levels must be drawn to confirm eligibility and sent to the central 
laboratory; results must be obtained and confirmed to be <8 µM before randomization. 
Once antigenic AAT levels have been confirmed to meet this eligibility criterion, 
randomization and Day 1 can occur any time within the remaining screening window. 
Sites should allow at least 14 days for sample processing and antigenic AAT level 
result reporting. 
Treatment Period 
28 days 
VX-814 600 mg q12h N = 15 
 
 
Screening  
up to 35 days 
Placebo N = 5 
VX-814 Washout Visit 
7 days after last dose 
Safety Follow-
up Visits 
14 and 28 days 
after last dose 
Treatment Period 
28 days 
VX-814 400 mg q12h N = 6 
 
 
Screening  
up to 35 days 
Placebo N = 2 
VX-814 Washout Visit 
7 days after last dose 
Safety Follow-
up Visits 
14 and 28 days 
after last dose 
Treatment Period 
28 days 
VX-814 400 mg q12h N = 6 
 
 
Screening  
up to 35 days 
VX-814 200 mg q12h N = 3 
VX-814 100 mg q12h N = 3 
Placebo N = 3 
VX-814 Washout Visit 
7 days after last dose 
Safety Follow-
up Visits 
14 and 28 days 
after last dose 


Protocol VX19-814-101, Version 3.0 
Page 7 of 68 
Vertex Pharmaceuticals Incorporated 
 
 
Figure 2-2 
Parts A1, A2, and B: Schematic of Study Design for Subjects 
Who Have Been on Augmentation Therapy at Any Time 
Part A1 
 
Part A2 
 
Treatment Period 
28 days 
VX-814 400 mg q12h N = 6 
 
 
Screening  
up to 70 days 
Placebo N = 2 
Safety Follow-
up Visits 
14 and 28 days 
after last dose 
Discontinue 
augmentation therapy 
>42 days before AAT 
levels are drawn for 
eligibility * 
Subjects may 
resume 
augmentation 
therapy after 
the last Safety 
Follow-up Visit 
VX-814 
Washout Visit 
7 days after last 
dose 
Antigenic AAT 
level for 
eligibility 
42 days 
Treatment Period 
28 days 
VX-814 400 mg q12h N = 6 
 
 
Screening  
up to 70 days 
VX-814 200 mg q12h N = 3 
VX-814 100 mg q12h N = 3 
Placebo N = 3 
Safety Follow-
up Visits 
14 and 28 days 
after last dose 
Discontinue 
augmentation therapy 
>42 days before AAT 
levels are drawn for 
eligibility * 
Subjects may 
resume 
augmentation 
therapy after 
the last Safety 
Follow-up Visit 
VX-814 
Washout Visit 
7 days after last 
dose 
Antigenic AAT 
level for 
eligibility 
42 days 


Protocol VX19-814-101, Version 3.0 
Page 8 of 68 
Vertex Pharmaceuticals Incorporated 
 
Part B 
 
N: number of subjects; q12h: every 12 hours 
Notes: Figure is not drawn to scale. Subject numbers include subjects who have never been 
on augmentation therapy and subjects who have been on augmentation therapy at any 
time. Subjects must discontinue augmentation therapy >42 days before antigenic AAT 
levels are drawn and sent to the central laboratory to confirm eligibility; results must 
be confirmed to be <8 µM before randomization. Once antigenic AAT levels have 
been confirmed to meet this eligibility criterion, randomization and Day 1 can occur 
any time within the remaining screening window. Sites should allow at least 14 days 
for sample processing and antigenic AAT level result reporting. Subjects can resume 
augmentation therapy after completion of assessments at the last Safety Follow-up 
Visit. 
*Blood samples will be obtained for antigenic and functional AAT levels at the same time 
that the other screening laboratory assessments are performed. If the subject received 
the last dose of augmentation therapy >42 days prior, this sample can be used to 
measure antigenic AAT level for eligibility. If samples are obtained ≤42 days after the 
last dose of augmentation therapy, another sample must be drawn >42 days after the 
last dose of augmentation therapy and sent to the central laboratory to confirm 
eligibility. 
 
 
Assessments 
Efficacy: 
Plasma functional and antigenic AAT levels  
Safety: 
AEs, clinical laboratory assessments, standard 12-lead ECGs, clinical evaluation 
of vital signs, pulse oximetry, spirometry, and physical examinations 
Pharmacokinetics: 
Plasma concentrations of VX-814 
Treatment Period 
28 days 
VX-814 600 mg q12h N = 15 
 
 
Screening  
up to 70 days 
Placebo N = 5 
Safety Follow-
up Visits 
14 and 28 days 
after last dose 
Discontinue 
augmentation therapy 
>42 days before AAT 
levels are drawn for 
eligibility * 
Subjects may 
resume 
augmentation 
therapy after 
the last Safety 
Follow-up Visit 
VX-814 
Washout Visit 
7 days after last 
dose 
Antigenic AAT 
level for 
eligibility 
42 days 


Protocol VX19-814-101, Version 3.0 
Page 9 of 68 
Vertex Pharmaceuticals Incorporated 
 
Statistical Analyses 
In Part A1, subjects will be randomized 2:1:1:1 to receive VX-814 400 mg every 
12 hours (q12h; n = 6), VX-814 200 mg q12h (n = 3), VX-814 100 mg q12h 
(n = 3), or placebo (n = 3). In Part A2, subjects will be randomized to receive 
VX-814 400 mg q12h (n = 6) or placebo (n = 2). In Part B, subjects will be 
randomized to receive VX-814 600 mg q12h (n = 15) or placebo (n = 5). 
Assuming 10% of the randomized subjects have a missing value at Day 28, this 
sample size provides adequate precision to estimate the plasma functional AAT 
levels at Day 28 for the VX-814 600-mg q12h group in Part B. 
The primary endpoint to assess efficacy is the change from baseline in plasma 
functional AAT levels at Day 28. 
 
 
 
 
 
 


Protocol VX19-814-101, Version 3.0 
Page 10 of 68 
Vertex Pharmaceuticals Incorporated 
 
3 
SCHEDULE OF ASSESSMENTS 
Schedules of assessments are in Table 3-1 (Parts A1, A2, and B Screening for subjects who have 
never been on augmentation therapy), Table 3-2 (Parts A1, A2, and B Screening for subjects who 
have been on augmentation therapy at any time), and Table 3-3 (Parts A1, A2, and B Treatment 
Period through Safety Follow-up). 
Table 3-1 
Study VX19̻814101 Parts A1, A2, and B: Screening for Subjects Who 
Have Never Been on Augmentation Therapy 
Event/Assessment 
Screening Period 
Day -35 through Day -1 
Comments 
Informed consent  
X 
 
Inclusion and exclusion criteria review 
X 
Sections 8.1 and 8.2 
Clinic visit 
X 
 
Demographics 
X 
 
Medical history 
X 
Section 11.1 
Medications review 
X 
Section 9.6 
Prior augmentation therapy review 
X 
Section 9.6  
Antigenic AAT level 
X 
Antigenic AAT levels must be drawn and 
confirmed to be <8 μM to establish 
eligibility before randomization can occur. 
Sites should allow at least 14 days for 
sample processing and antigenic AAT 
level result reporting. Section 8.1, 
inclusion criterion #7 and Section 11.3. 
Functional AAT level 
X 
Samples will be obtained for plasma 
functional AAT levels at the same time 
samples are obtained for antigenic AAT 
levels. Functional AAT level results will 
not be provided to site personnel. 
Section 11.3 
Standard 12-lead ECG 
X 
Will be performed in triplicate after the 
subject has rested for at least 5 minutes. 
When ECGs, vital signs, and blood draws 
are done on the same day, they should be 
performed in said order. Section 11.5.4 
Height and weight 
X 
Weight and height will be measured with 
shoes off.  
Vital signs 
X 
Vital signs will be performed after the 
subject has rested for at least 5 minutes. 
Section 11.5.3 
Pulse oximetry 
X 
Pulse oximetry will be performed after the 
subject has rested for at least 5 minutes. 
Section 11.5.3 
Complete physical examination 
X 
Section 11.5.3  
Serum FSH (postmenopausal female 
subjects only) 
X 
Section 11.5.2  
Serum β-hCG (all female subjects) 
X 
Section 11.5.2 
Serology (HBsAg, HCV Ab and RNA, 
HIV-1 and HIV-2 Abs) 
X 
Section 11.5.2 
PiZZ genotype 
X 
PiZZ genotype must be performed at the 
central laboratory. Section 8.1, inclusion 
criterion #6 
Serum chemistry 
X 
Section 11.5.2 


Protocol VX19-814-101, Version 3.0 
Page 11 of 68 
Vertex Pharmaceuticals Incorporated 
 
Table 3-1 
Study VX19̻814101 Parts A1, A2, and B: Screening for Subjects Who 
Have Never Been on Augmentation Therapy 
Event/Assessment 
Screening Period 
Day -35 through Day -1 
Comments 
Hematology 
X 
Section 11.5.2 
Coagulation 
X 
Section 11.5.2 
Urinalysis 
X 
Section 11.5.2 
Spirometry 
X 
Spirometry will be performed post-
bronchodilator and according to the 
American Thoracic Society 
Guidelines/European Respiratory Society 
Guidelines. If spirometry cannot be 
performed, historical post-bronchodilator 
ppFEV1 results measured within 1 year 
before screening can be used to determine 
eligibility. Section 8.2 exclusion criterion 
#7 and Section 11.5.5. 
Urine cotinine  
X 
Section 11.5.2 
AEs and SAEs 
Continuous from signing of ICF 
through last Safety Follow-up Visit 
Section 11.5.1 
AAT: alpha-1 antitrypsin; AE: adverse event; β-hCG: beta-human chorionic gonadotropin; FSH: follicle-stimulating hormone; 
HBsAg: hepatitis B surface antigen; HCV: hepatitis C virus; HIV-1/HIV-2 Abs: antibodies against human 
immunodeficiency viruses 1 and 2; ICF: informed consent form; ppFEV1: percent predicted forced expiratory volume in 
1 second; SAE: serious adverse event 
Note: Screening procedures (including informed consent) can be performed over more than 1 day. Informed consent must be 
obtained prior to any procedures. Repeat Screening assessments and Screening assessments that were not conducted at 
the initial visit during the Screening Period may be performed at the clinic or at home by a qualified visiting nurse, if 
permitted by ethical and regulatory authorities and agreed upon after investigator and subject consultation. 
 


Protocol VX19-814-101, Version 3.0 
Page 12 of 68 
Vertex Pharmaceuticals Incorporated 
 
Table 3-2 
Study VX19̻814101 Parts A1, A2, and B: Screening for Subjects Who 
Have Been on Augmentation Therapy at Any Time 
Event/Assessment 
Screening Period 
Day -70 through Day -1 
Comments 
Informed consent  
X 
 
Inclusion and exclusion criteria review 
X 
Sections 8.1 and 8.2 
Clinic visit 
X 
 
Demographics 
X 
 
Medical history 
X 
Section 11.1 
Medications review 
X 
Section 9.6 
Prior augmentation therapy review 
X 
Subjects must discontinue augmentation 
therapy >42 days before the antigenic 
AAT levels are obtained to determine 
eligibility. Subjects can resume 
augmentation therapy after completion 
of the Safety Follow-up Assessments. 
Section 9.6 
Antigenic AAT level (up to 2 samples 
obtained during screening)  
X 
Samples will be obtained for plasma 
antigenic AAT level and sent to the central 
laboratory at the same time other screening 
laboratory assessments are done. If the 
subject received the last dose of 
augmentation therapy >42 days prior, these 
results can be used to determine eligibility. 
If this sample is obtained ≤42 days after the 
last dose of augmentation therapy, another 
sample must be drawn >42 days after the 
last dose of augmentation therapy to 
confirm eligibility. Results must be 
confirmed to be <8 μM before 
randomization. 
This second sample can be drawn at a 
home or clinic visit. Sites should allow at 
least 14 days for sample processing and 
results reporting. Section 8.1, inclusion 
criterion #7 and Section 11.3. 
Functional AAT level (up to 2 samples 
obtained during screening) 
X 
Samples will be obtained for plasma 
functional AAT levels at the same time 
samples are obtained for antigenic AAT 
levels. If a second sample is obtained, the 
second sample can be drawn at a home 
or clinic visit. Results will not be provided 
to site personnel. Section 11.3 
Standard 12-lead ECG 
X 
Will be performed in triplicate after the 
subject has rested for at least 5 minutes. 
When ECGs, vital signs, and blood draws 
are done on the same day, they should be 
performed in said order. Section 11.5.4 
Height and weight 
X 
Weight and height will be measured with 
shoes off.  
Vital signs 
X 
Vital signs will be performed after the 
subject has rested for at least 5 minutes. 
Section 11.5.3 
Pulse oximetry 
X 
Pulse oximetry will be performed after the 
subject has rested for at least 5 minutes. 
Section 11.5.3 
Complete physical examination 
X 
Section 11.5.3  


Protocol VX19-814-101, Version 3.0 
Page 13 of 68 
Vertex Pharmaceuticals Incorporated 
 
Table 3-2 
Study VX19̻814101 Parts A1, A2, and B: Screening for Subjects Who 
Have Been on Augmentation Therapy at Any Time 
Event/Assessment 
Screening Period 
Day -70 through Day -1 
Comments 
Serum FSH (postmenopausal female 
subjects only) 
X 
Section 11.5.2  
Serum β-hCG (all female subjects) 
X 
Section 11.5.2 
Serology (HBsAg, HCV Ab and RNA, 
HIV-1 and HIV-2 Abs) 
X 
Section 11.5.2 
PiZZ genotype 
X 
PiZZ genotype must be performed at the 
central laboratory. Section 8.1, inclusion 
criterion #6 
Serum chemistry 
X 
Section 11.5.2 
Hematology 
X 
Section 11.5.2 
Coagulation 
X 
Section 11.5.2 
Urinalysis 
X 
Section 11.5.2 
Spirometry 
X 
Spirometry will be performed post-
bronchodilator and according to the 
American Thoracic Society 
Guidelines/European Respiratory Society 
Guidelines. If spirometry cannot be 
performed, historical post-bronchodilator 
ppFEV1 results within 1 year before 
screening can be used to determine 
eligibility. Section 8.2 exclusion criterion 
#7 and Section 11.5.5. 
Urine cotinine  
X 
Section 11.5.2 
AEs and SAEs 
Continuous from signing of ICF 
through last Safety Follow-up 
Visit 
Section 11.5.1 
AAT: alpha-1 antitrypsin; AE: adverse event; β-hCG: beta-human chorionic gonadotropin; FSH: follicle-stimulating hormone; 
HBsAg: hepatitis B surface antigen; HCV: hepatitis C virus; HIV-1/HIV-2 Abs: antibodies against human 
immunodeficiency viruses 1 and 2; ICF: informed consent form; ppFEV1: percent predicted forced expiratory volume in 
1 second; SAE: serious adverse event 
Notes: Screening procedures (including informed consent) can be performed over more than 1 day. Informed consent must be 
obtained prior to any procedures. Repeat Screening assessments and Screening assessments that were not conducted at 
the initial visit during the Screening Period may be performed at the clinic or at home by a qualified visiting nurse, if 
permitted by ethical and regulatory authorities and agreed upon after investigator and subject consultation. If a second 
blood sample is required >42 days after the last dose of augmentation therapy to measure antigenic AAT levels to 
confirm eligibility, this second blood sample (and the second functional AAT level drawn at the same time) can be drawn 
at a home visit or clinic visit.  
 


Protocol VX19-814-101, Version 3.0 
Page 14 of 68 
Vertex Pharmaceuticals Incorporated 
 
Table 3-3 
Study VX19̻814-101 Parts A1, A2, and B: Treatment Period and Follow-up Visits 
Event/ 
Assessment 
Treatment Period 
 
 
 
 
 
Day 1a 
Day 7 
(±1) b  
Day 14 
(±2)b  
Day 21 
(±2)b  
Day 28 
(-2)c 
VX-814 
Washout 
Visit 
7 (±2) Days 
After Last 
Dose of 
Study Drug 
ETT Visite 
Safety 
Follow-up 
Visit 
14 (±2) Days 
After Last 
Dose of Study 
Drug 
Safety 
Follow-up 
Visit 
28 (±2) Days 
After Last 
Dose of 
Study Drug 
Comments 
Inclusion and 
exclusion criteria 
confirmation 
X 
 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
Randomization may occur up 
to 7 days before Day 1 after all 
eligibility criteria including 
antigenic AAT levels <8 μM 
are confirmed. If 
randomization occurs before 
Day 1, eligibility must also be 
confirmed before the first dose 
of study drug on Day 1. 
Clinic visit 
X 
 
 
 
 
 
 
  
 
 
 
a 
On Day 1, all assessments must be completed before the first dose of study drug except for the post dose PK sampling, which is done at 3 and 6 hours (±30 minutes) after 
dosing in the clinic. 
b 
All assessments will be performed before administration of the morning or evening dose of study drug unless noted otherwise (Section 11). These visits may be performed 
in the morning or the evening in the clinic or at home by a qualified visiting nurse. If the visit is performed at home, it must be followed by a consultation between the subject and 
investigator (i.e., in person, telephone, or telemedicine video conference) within 1 day and may also include a separate follow-up with the study coordinator. 
c 
On Day 28, all assessments will be performed before administration of the morning dose of study drug unless noted otherwise (Section 11). The morning dose of study 
drug on the Day 28 Visit will be taken at home or in the clinic after the pre-dose PK sample has been drawn (within 60 minutes of dosing). Additional PK sampling will be done at 
3 and 6 hours (±30 minutes) after dosing. The last dose of study drug will be taken at home in the evening on Day 28, regardless of whether the Day 28 Visit occurs on Day 26 or 
Day 27. 
 
 
 
 
e 
If the subject prematurely discontinues study drug treatment, an ETT Visit should be scheduled as soon as possible after the decision to terminate study treatment. Subjects who 
prematurely discontinue treatment will be required to complete the Safety Follow-up Visits, approximately 14 (±2) and 28 (±2) days after their last dose of study drug. If the ETT 
Visit occurs between 12 and 21 days (inclusive) after the last dose of study drug, the ETT Visit will replace the Safety Follow-up Visit 14 days after the last dose of study drug, 
and a separate Safety Follow-up Visit 14 days after the last dose will not be required; the Safety Follow-up Visit 28 days after the last dose would still be required. If the ETT Visit 
occurs ≥22 days after the last dose of study drug, the ETT Visit will replace the Safety Follow-up Visit 28 days after the last dose, and a separate Safety Follow-up Visit 28 days 
after the last dose will not be required.  


Protocol VX19-814-101, Version 3.0 
Page 15 of 68 
Vertex Pharmaceuticals Incorporated 
 
Table 3-3 
Study VX19̻814-101 Parts A1, A2, and B: Treatment Period and Follow-up Visits 
Event/ 
Assessment 
Treatment Period 
 
 
 
 
 
Day 1a 
Day 7 
(±1) b  
Day 14 
(±2)b  
Day 21 
(±2)b  
Day 28 
(-2)c 
VX-814 
Washout 
Visit 
7 (±2) Days 
After Last 
Dose of 
Study Drug 
ETT Visite 
Safety 
Follow-up 
Visit 
14 (±2) Days 
After Last 
Dose of Study 
Drug 
Safety 
Follow-up 
Visit 
28 (±2) Days 
After Last 
Dose of 
Study Drug 
Comments 
Clinic or home health 
visit 
 
X 
X 
X 
X 
X 
X 
X 
X 
Subjects will have the option 
to complete these visits in the 
clinic or to have a home health 
visit. Home health visits are 
only an option if they receive 
approval from both ethical 
and regulatory authorities in 
the respective country. 
Telemedicine video 
conference or 
telephone contact 
 
X 
X 
X 
X 
X 
X 
X 
X 
Performed within 1 day after 
home health visit. Required 
only for subjects who have a 
home health visit; not required 
for subjects who have a clinic 
visit. 
Antigenic AAT level 
X 
X 
X 
 
X 
X 
X 
X 
X 
Section 11.3 
Functional AAT 
level 
X 
X 
X 
 
X 
X 
X 
X 
X 
Section 11.3 


Protocol VX19-814-101, Version 3.0 
Page 16 of 68 
Vertex Pharmaceuticals Incorporated 
 
Table 3-3 
Study VX19̻814-101 Parts A1, A2, and B: Treatment Period and Follow-up Visits 
Event/ 
Assessment 
Treatment Period 
 
 
 
 
 
Day 1a 
Day 7 
(±1) b  
Day 14 
(±2)b  
Day 21 
(±2)b  
Day 28 
(-2)c 
VX-814 
Washout 
Visit 
7 (±2) Days 
After Last 
Dose of 
Study Drug 
ETT Visite 
Safety 
Follow-up 
Visit 
14 (±2) Days 
After Last 
Dose of Study 
Drug 
Safety 
Follow-up 
Visit 
28 (±2) Days 
After Last 
Dose of 
Study Drug 
Comments 
Weight and height 
X 
 
 
 
  
 
 
  
 
Weight and height will be 
measured with shoes off. 
Standard 12-lead 
ECG 
X 
X 
 
 
X 
 
X 
X 
X 
Performed in triplicate after 
the subject has rested for at 
least 5 minutes 
When ECGs, vital signs, and 
blood draws are done on the 
same day, they should be 
performed in said order.  
Day 1: predose and 6 hours 
(±15 min) after dosing. 
Section 11.5.4 
Vital signs  
X 
X 
X 
 
X 
 
X 
X 
X 
Vital signs will be performed 
after the subject has rested for 
at least 5 minutes. Section 
11.5.3 
Pulse oximetry 
X 
X 
X 
 
X 
 
X 
X 
X 
Pulse oximetry will be 
performed after the subject has 
rested for at least 5 minutes. 
Section 11.5.3 
Pregnancy test 
(premenopausal 
female subjects of 
childbearing 
potential only) 
Urine 
and 
Serum 
 
Serum 
 
Urine 
 
Serum  
Serum 
Serum 
Subjects must have a negative 
urine pregnancy test result on 
Day 1 before starting dosing.  


Protocol VX19-814-101, Version 3.0 
Page 17 of 68 
Vertex Pharmaceuticals Incorporated 
 
Table 3-3 
Study VX19̻814-101 Parts A1, A2, and B: Treatment Period and Follow-up Visits 
Event/ 
Assessment 
Treatment Period 
 
 
 
 
 
Day 1a 
Day 7 
(±1) b  
Day 14 
(±2)b  
Day 21 
(±2)b  
Day 28 
(-2)c 
VX-814 
Washout 
Visit 
7 (±2) Days 
After Last 
Dose of 
Study Drug 
ETT Visite 
Safety 
Follow-up 
Visit 
14 (±2) Days 
After Last 
Dose of Study 
Drug 
Safety 
Follow-up 
Visit 
28 (±2) Days 
After Last 
Dose of 
Study Drug 
Comments 
Physical 
examination/ 
review of symptoms 
Abbrev 
PE 
 
 
 
Review of 
symptoms 
Review of 
symptoms 
Review of 
symptoms 
Review of 
symptoms 
Review of 
symptoms 
If there are any abnormal 
findings in the review of 
symptoms, the subject will be 
instructed to have a complete 
PE in the clinic. 
Section 11.5.3 
Spirometry (optional) 
X 
 
 
 
X 
 
 
 
 
Spirometry will be performed 
post-bronchodilator and 
according to the American 
Thoracic Society 
Guidelines/European 
Respiratory Society 
Guidelines. Section 11.5.5 
Sample for UGT1A1 
genotype 
X 
 
 
 
 
 
 
 
 
A single sample will be 
collected at any time on Day 1. 
Section 11.2.2 
Serum chemistry  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 11.5.2 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 11.5.2 
Coagulation 
X 
X 
X 
X 
X 
X  
X 
X 
X 
Section 11.5.2 
Urinalysis 
X 
X 
X 
X 
X 
 
X 
X 
X 
Section 11.5.2 


Protocol VX19-814-101, Version 3.0 
Page 18 of 68 
Vertex Pharmaceuticals Incorporated 
 
Table 3-3 
Study VX19̻814-101 Parts A1, A2, and B: Treatment Period and Follow-up Visits 
Event/ 
Assessment 
Treatment Period 
 
 
 
 
 
Day 1a 
Day 7 
(±1) b  
Day 14 
(±2)b  
Day 21 
(±2)b  
Day 28 
(-2)c 
VX-814 
Washout 
Visit 
7 (±2) Days 
After Last 
Dose of 
Study Drug 
ETT Visite 
Safety 
Follow-up 
Visit 
14 (±2) Days 
After Last 
Dose of Study 
Drug 
Safety 
Follow-up 
Visit 
28 (±2) Days 
After Last 
Dose of 
Study Drug 
Comments 
Blood for PK 
sampling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Day 1 and Day 28: predose 
(within 60 minutes before 
dosing) and at 3 and 6 hours 
(±30 minutes) after dosing 
(relative to the morning dose).  
Days 7, 14, and 21: predose 
(within 60 minutes before 
dosing, relative to the morning 
or evening dose) 
Safety Follow-up Visits: 
collected at any time during 
the visit. 
Section 11.2.1 
Study drug 
administration  
Day 1 through Day 28 
 
 
 
 
Section 9.7 
AEs and SAEs 
Continuous from signing of ICF through last Safety Follow-up Visit 
Section 11.5.1 
Medications review 
Continuous from signing of ICF through last Safety Follow-up Visit 
Section 9.6 
AAT: alpha-1 antitrypsin; Abbrev: abbreviated; AE: adverse event; 
; ETT: Early Termination of Treatment: ICF: informed 
consent form; 
 
 PK: pharmacokinetic; SAE: serious adverse event; 
 


Protocol VX19-814-101, Version 3.0 
Page 19 of 68 
Vertex Pharmaceuticals Incorporated 
 
4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
 
2 
Protocol Synopsis ................................................................................................................... 4 
3 
Schedule of Assessments...................................................................................................... 10 
4 
Table of Contents ................................................................................................................. 19 
List of Tables............................................................................................................................ 22 
List of Figures .......................................................................................................................... 22 
List of Abbreviations................................................................................................................ 23 
5 
Introduction.......................................................................................................................... 25 
5.1 
Background ..................................................................................................................... 25 
5.2 
Study Rationale .............................................................................................................. 25 
6 
Study Objectives .................................................................................................................. 25 
6.1 
Primary Objectives ......................................................................................................... 25 
6.2 
Secondary Objectives ..................................................................................................... 26 
 
 
7 
Study Endpoints ................................................................................................................... 26 
7.1 
Primary Endpoints .......................................................................................................... 26 
7.2 
Secondary Endpoints ...................................................................................................... 26 
 
 
8 
Study Population .................................................................................................................. 26 
8.1 
Inclusion Criteria ............................................................................................................ 27 
8.2 
Exclusion Criteria ........................................................................................................... 27 
9 
Study Implementation ......................................................................................................... 30 
9.1 
Study Design .................................................................................................................. 30 
9.1.1 
Screening ................................................................................................................ 33 
9.1.1.1 
Repetition of Screening Assessment(s) ............................................................ 34 
9.1.1.2 
Rescreening ...................................................................................................... 34 
9.1.1.3 
Extension of the Screening Period ................................................................... 34 
9.1.2 
Treatment Period .................................................................................................... 35 
 
 
9.1.3 
Follow-up................................................................................................................ 35 
9.1.4 
Early Termination of Treatment ............................................................................. 35 
9.2 
Lost to Follow-up ........................................................................................................... 36 
9.3 
Method of Assigning Subjects to Treatment Groups ..................................................... 36 
9.4 
Rationale for Study Elements ......................................................................................... 36 
9.4.1 
Rationale for Study Design..................................................................................... 36 
9.4.2 
Rationale for Study Population............................................................................... 36 
9.4.3 
Rationale for Study Drug Dose .............................................................................. 37 
9.4.4 
Rationale for Study Assessments ........................................................................... 37 
9.5 
Study Restrictions ........................................................................................................... 37 
9.5.1 
Exposure to Sunlight .............................................................................................. 38 
9.6 
Prior and Concomitant Medications ............................................................................... 39 
9.7 
Administration ................................................................................................................ 39 
9.8 
Dose Modification for Toxicity ...................................................................................... 40 


Protocol VX19-814-101, Version 3.0 
Page 20 of 68 
Vertex Pharmaceuticals Incorporated 
 
9.9 
Study Drug Interruption and Stopping Rules ................................................................. 40 
9.10 Removal of Subjects ....................................................................................................... 41 
9.11 Replacement of Subjects ................................................................................................ 42 
10 Study Drug Information and Management ....................................................................... 42 
10.1 Preparation and Dispensing ............................................................................................ 42 
10.2 Packaging and Labeling ................................................................................................. 42 
10.3 Study Drug Supply, Storage, and Handling ................................................................... 42 
10.4 Drug Accountability ....................................................................................................... 42 
10.5 Disposal, Return, or Retention of Unused Drug ............................................................. 43 
10.6 Compliance ..................................................................................................................... 43 
10.7 Blinding and Unblinding ................................................................................................ 43 
10.7.1 
Blinding .................................................................................................................. 43 
10.7.2 
Unblinding .............................................................................................................. 44 
11 Assessments .......................................................................................................................... 45 
11.1 Subject and Disease Characteristics ............................................................................... 45 
11.2 Pharmacokinetics ............................................................................................................ 45 
11.2.1 
Blood Sampling ...................................................................................................... 45 
11.2.2 
UGT1A1 Genotype................................................................................................. 46 
11.2.3 
Processing and Handling of Pharmacokinetic Samples ......................................... 46 
11.2.4 
Bioanalysis.............................................................................................................. 46 
11.3 Efficacy ........................................................................................................................... 46 
11.5 Safety .............................................................................................................................. 47 
11.5.1 
Adverse Events ....................................................................................................... 47 
11.5.2 
Clinical Laboratory Assessments ........................................................................... 48 
11.5.3 
Physical Examinations, Vital Signs, and Pulse Oximetry ...................................... 49 
11.5.4 
Electrocardiograms ................................................................................................. 49 
11.5.5 
Spirometry .............................................................................................................. 50 
11.5.6 
Contraception and Pregnancy ................................................................................. 50 
11.5.6.1 Contraception ................................................................................................... 50 
11.5.6.2 Pregnancy ......................................................................................................... 52 
12 Statistical and Analytical Plans .......................................................................................... 52 
12.1 Sample Size and Power .................................................................................................. 52 
12.2 Analysis Set .................................................................................................................... 53 
12.3 Statistical Analysis ......................................................................................................... 53 
12.3.1 
General Considerations ........................................................................................... 54 
12.3.2 
Demographics and Background Characteristics ..................................................... 54 
12.3.3 
Efficacy Analysis .................................................................................................... 55 
12.3.3.1 Analysis of the Primary Variable ..................................................................... 55 
12.3.3.2 Multiplicity Adjustment ................................................................................... 55 
12.3.3.3 Missing Data Handling .................................................................................... 55 


Protocol VX19-814-101, Version 3.0 
Page 21 of 68 
Vertex Pharmaceuticals Incorporated 
 
12.3.4 
Safety Analysis ....................................................................................................... 55 
12.3.5 
Interim and Independent Data Monitoring Committee Analyses ........................... 55 
12.3.5.1 Interim Analysis ............................................................................................... 55 
12.3.5.2 Independent Data Monitoring Committee Analysis ........................................ 56 
12.4 Clinical Pharmacology Analysis .................................................................................... 56 
12.4.1 
Pharmacokinetic Analysis ...................................................................................... 56 
12.4.2 
Pharmacokinetic/Pharmacodynamic Analyses ....................................................... 56 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 56 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 56 
13.1.1 
Adverse Events ....................................................................................................... 56 
13.1.1.1 Definition of an Adverse Event........................................................................ 56 
13.1.1.2 Clinically Significant Assessments .................................................................. 56 
13.1.1.3 Documentation of Adverse Events................................................................... 57 
13.1.1.4 Adverse Event Severity .................................................................................... 58 
13.1.1.5 Adverse Event Causality .................................................................................. 58 
13.1.1.6 Study Drug Action Taken ................................................................................ 59 
13.1.1.7 Adverse Event Outcome .................................................................................. 59 
13.1.1.8 Treatment Given............................................................................................... 59 
13.1.2 
Serious Adverse Events .......................................................................................... 60 
13.1.2.1 Definition of a Serious Adverse Event............................................................. 60 
13.1.2.2 Reporting and Documentation of Serious Adverse Events .............................. 60 
13.1.2.3 Expedited Reporting and Investigator Safety Letters ...................................... 61 
13.2 Administrative Requirements ......................................................................................... 61 
13.2.1 
Product Complaints ................................................................................................ 61 
13.2.2 
Ethical Considerations ............................................................................................ 61 
13.2.3 
Subject Information and Informed Consent ........................................................... 62 
13.2.4 
Investigator Compliance ......................................................................................... 62 
13.2.5 
Access to Records ................................................................................................... 62 
13.2.6 
Subject Privacy ....................................................................................................... 62 
13.2.7 
Record Retention .................................................................................................... 63 
13.2.8 
Study Termination .................................................................................................. 63 
13.2.9 
End of Study ........................................................................................................... 63 
13.3 Data Quality Assurance .................................................................................................. 63 
13.4 Monitoring ...................................................................................................................... 64 
13.5 Electronic Data Capture ................................................................................................. 64 
13.6 Confidentiality and Disclosure ....................................................................................... 64 
13.7 Publications and Clinical Study Report .......................................................................... 65 
 
 
13.7.2 
Clinical Study Report ............................................................................................. 65 
14 References ............................................................................................................................. 66 
15 Protocol Signature Pages .................................................................................................... 67 
15.1 Sponsor Signature Page .................................................................................................. 67 
15.2 Investigator Signature Page ............................................................................................ 68 
 


Protocol VX19-814-101, Version 3.0 
Page 22 of 68 
Vertex Pharmaceuticals Incorporated 
 
List of Tables 
Table 3-1 
Study VX19̻814101 Parts A1, A2, and B: Screening for Subjects Who Have 
Never Been on Augmentation Therapy ................................................................ 10 
Table 3-2 
Study VX19̻814101 Parts A1, A2, and B: Screening for Subjects Who Have 
Been on Augmentation Therapy at Any Time ...................................................... 12 
Table 3-3 
Study VX19̻814-101 Parts A1, A2, and B: Treatment Period and Follow-up 
Visits ..................................................................................................................... 14 
Table 9-1 
Study Restrictions ................................................................................................. 38 
Table 11-1 
Acceptable Pharmacokinetic Sampling Windows ................................................ 45 
Table 11-2 
Safety Laboratory Test Panels .............................................................................. 48 
Table 11-3 
Allowable Methods of Contraception ................................................................... 51 
 
 
Table 13-1 
Grading of AE Severity ........................................................................................ 58 
Table 13-2 
Classifications for AE Causality ........................................................................... 58 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 59 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 59 
List of Figures 
Figure 2-1 
Parts A1, A2, and B: Schematic of Study Design for Subjects Who Have Never 
Been on Augmentation Therapy ............................................................................. 6 
Figure 2-2 
Parts A1, A2, and B: Schematic of Study Design for Subjects Who Have Been on 
Augmentation Therapy at Any Time ...................................................................... 7 
Figure 9-1 
Parts A1, A2, and B: Schematic of Study Design for Subjects Who Have Never 
Been on Augmentation Therapy ........................................................................... 30 
Figure 9-2 
Parts A1, A2, and B: Schematic of Study Design for Subjects Who Have Been on 
Augmentation Therapy at Any Time .................................................................... 32 


Protocol VX19-814-101, Version 3.0 
Page 23 of 68 
Vertex Pharmaceuticals Incorporated 
 
List of Abbreviations  
Abbreviation 
Definition 
AAT 
alpha-1 antitrypsin 
AATD 
alpha-1 antitrypsin deficiency 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
β-hCG 
beta-human chorionic gonadotropin 
BMI 
body mass index 
CD 
compact disc 
COPD 
chronic obstructive pulmonary disease 
CPAP 
clinical pharmacology analysis plan 
CRF 
case report form 
CRO 
contract research organization 
 
 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
 
 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EENT 
eyes, ears, nose, and throat 
eGFR 
estimated glomerular filtration rate 
 
 
 
ETT 
Early Termination of Treatment 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLI 
Global Lung Function Initiative 
GLP 
Good Laboratory Practice 
GPP3 
Good Publication Practices 
GPS 
Global Patient Safety 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV-1/HIV-2 Abs 
antibodies against human immunodeficiency viruses 1 and 2 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
independent ethics committee 
 
 
IMP 
investigational medicinal product 


Protocol VX19-814-101, Version 3.0 
Page 24 of 68 
Vertex Pharmaceuticals Incorporated 
 
Abbreviation 
Definition 
IRB 
institutional review board 
IUD 
intrauterine device 
IWRS 
interactive web or voice response system 
 
 
Max 
maximum value 
MCP-Mod 
multiple-comparison procedures with modeling techniques 
Min 
minimum value 
MMRM 
mixed-effects model for repeated measures 
 
 
N 
size of subsample 
PC 
publication committee 
PD 
pharmacodynamics, pharmacodynamics 
PE 
physical examination 
 
 
PIs 
principal investigators 
PiZZ 
homozygous for the Z mutation in the SERPINA1 gene that encodes the AAT protein 
PK 
pharmacokinetic, pharmacokinetics 
ppFEV1 
percent predicted forced expiratory volume in 1 second 
q12h 
every 12 hours  
QTc 
QT interval corrected 
QTcF 
QT interval corrected by Fridericia's formula 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
steering committee 
SD 
standard deviation 
SERPINA1 
serine (or cysteine) proteinase inhibitor, clade A (alpha-1antiproteinase, antitrypsin), 
member 1 
SET 
study execution team 
 
 
SUSAR 
suspected, unexpected, serious adverse reaction 
TE 
treatment-emergent 
ULN 
upper limit of normal 
USA 
United States of America 
WHODrug 
World Health Organization-Drug Dictionary 
 


Protocol VX19-814-101, Version 3.0 
Page 25 of 68 
Vertex Pharmaceuticals Incorporated 
 
5 
INTRODUCTION 
5.1 
Background 
Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder characterized by low circulating 
levels of alpha-1 antitrypsin (AAT). AAT is produced primarily in the liver and secreted into the 
blood, although other cell types, including lung epithelial cells, monocytes, macrophages, and 
neutrophils, produce the protein locally.1, 2 AAT inhibits several serine proteinases secreted by 
inflammatory cells (most notably neutrophil elastase, cathepsin G, and proteinase-3) and thus 
protects organs such as the lung from damage by these proteinases, especially during periods of 
infection and increased inflammation. 
A single point mutation in the Z-allele of SERPINA1 (the gene encoding AAT) leads to protein 
misfolding, intracellular polymerization of misfolded mutant Z-AAT protein, and reduced 
secretion of active Z-AAT protein. Consequently, circulating AAT levels in individuals 
homozygous for the Z-allele (PiZZ) are markedly reduced; only approximately 15% of Z-AAT 
protein folds correctly and is secreted by the cell. The reduced levels of circulating, active AAT 
result in an imbalance between proteinase and antiproteinase activity, which has its greatest 
impact in the lung. Consequently, lung tissue is damaged over time, resulting in emphysema, a 
form of chronic obstructive pulmonary disease. This effect is most pronounced in PiZZ 
individuals and typically manifests in middle age, resulting in a decline in quality of life and 
shortened lifespan (mean 67 years of age).3 PiZZ individuals account for the majority of those 
with clinically relevant AATD lung disease. The accumulation of polymerized Z-AAT protein 
within hepatocytes causes cytotoxicity that can result in neonatal liver disease or progressive 
liver disease in adulthood that can lead to cirrhosis or liver cancer. 
VX-814 is being developed as a treatment for AATD. VX-814 has the potential to restore 
physiological levels of circulating AAT activity and thus reduce the risk of lung disease. By 
preventing Z-polymer formation in the liver, VX-814 may also reduce the risk of developing 
progressive liver disease (fibrosis and cirrhosis). 
5.2 
Study Rationale  
The purpose of this study is to evaluate the efficacy and safety profile of VX-814, including 
identification of an optimal VX-814 dose, to support further clinical development as a treatment 
for AATD. 
 
 
 
6 
STUDY OBJECTIVES 
6.1 
Primary Objectives 
• To evaluate the efficacy of VX-814 in PiZZ subjects as measured by plasma functional AAT 
levels 
• To evaluate the safety and tolerability of VX-814 in PiZZ subjects 


Protocol VX19-814-101, Version 3.0 
Page 26 of 68 
Vertex Pharmaceuticals Incorporated 
 
6.2 
Secondary Objectives 
• To evaluate the efficacy of VX-814 in PiZZ subjects as measured by plasma antigenic AAT 
levels  
• To evaluate the pharmacokinetics (PK) of VX-814 in PiZZ subjects 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoints 
• Change from baseline in plasma functional AAT levels at Day 28 
• Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, 
standard 12-lead ECGs, vital signs, and pulse oximetry 
7.2 
Secondary Endpoints 
• Change from baseline in plasma antigenic AAT levels at Day 28 
• PK parameters of VX-814 derived from plasma concentration-time data  
8 
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator's team before subjects are randomized and will also be confirmed before the first 
dose of study drug on Day 1. 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be eligible. 


Protocol VX19-814-101, Version 3.0 
Page 27 of 68 
Vertex Pharmaceuticals Incorporated 
 
8.1 
Inclusion Criteria 
1. Subject will sign and date an informed consent form (ICF).  
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, contraceptive guidelines, and other study procedures. 
3. Subjects will be 18 through 80 years of age, inclusive, at the time of signing of the ICF.  
4. All female subjects must have a negative pregnancy test at screening (serum test). 
Premenopausal female subjects of child-bearing potential must also have a negative 
pregnancy test on Day 1 (urine test) and must not be nursing or planning to become pregnant 
during the study or within 90 days after the last study drug dose.  
5. Body mass index (BMI) of 18.0 to 35.0 kg/m2, inclusive. 
6. Subjects must have a PiZZ genotype confirmed at screening.  
NOTE: PiZZ genotype must be tested at the central laboratory. Historical genotype results 
can be used to determine eligibility if they were obtained as part of a different Vertex study. 
In addition, if the screening PiZZ genotype result is not received before randomization, a 
previous non-Vertex PiZZ genotype laboratory report (approved by the medical monitor or 
designee) may be used to establish provisional eligibility. Subjects who have been 
randomized and whose screening genotype subsequently does not confirm study 
eligibility must be discontinued from the study (Section 9.10). 
7. Plasma antigenic AAT level <8 µM during screening.  
For subjects who have been on augmentation therapy at any time, results used to confirm 
eligibility must be drawn >42 days after the last dose of augmentation therapy. Antigenic 
AAT levels must be obtained from the central laboratory and results confirmed before 
randomization.  
8. Willing to remain off of augmentation therapy from >42 days before antigenic AAT levels 
are obtained for eligibility through the last Safety Follow-Up Visit  
8.2 
Exclusion Criteria 
1. History or presence of any illness or clinical condition that, in the opinion of the investigator, 
might affect the subject's safety or compliance or confound the results of the study or pose an 
additional risk in administering study drug(s) to the subject. This includes, but is not limited 
to, the following: 
• Solid organ, lung, or hematological transplantation or is currently on a transplant list  
• Subjects who have undergone gastrectomy or other gastrointestinal tract surgery, except 
appendectomy, cholecystectomy, and hemorrhoid surgery. 
• Cancer, except for squamous cell skin cancer, basal cell skin cancer, Stage 0 cervical 
carcinoma in situ, and stage 0 or 1 melanoma (all 4 with no recurrence during the last 
5 years)  


Protocol VX19-814-101, Version 3.0 
Page 28 of 68 
Vertex Pharmaceuticals Incorporated 
 
2. History of significant alcohol consumption for a period of more than 3 consecutive months 
within 1 year before screening, defined as more than 14 drinks/week for females or 
21 drinks/week for males (1 drink = 5 ounces (150 mL) of wine or 12 ounces (360 mL) of 
beer or 1.5 ounces (45 mL) of hard liquor). 
3. Illegal drug use within 1 year before screening as deemed by the investigator, including but 
not limited to cocaine, heroin, and other opioids. 
4. Ongoing or prior participation in a study of an investigational treatment within 28 days or 
5 terminal half-lives (whichever is longer) before screening. The duration of the elapsed time 
may be longer if required by local regulations.  
5. History of use of gene therapy or RNAi therapy at any time previously. 
6. Use of oral corticosteroids (at any dose) for a duration of greater than 3 months at any time 
within the 3 months before screening. 
7. A post-bronchodilator forced expiratory volume in 1 second (FEV1) value <30% of predicted 
mean for age, sex, and height (equations of the Global Lung Function Initiative [GLI]) during 
screening. Post-bronchodilator spirometry measurements must meet American Thoracic 
Society (ATS)/European Respiratory Society (ERS) criteria for acceptability and 
repeatability.4, 5, 6 
NOTE: if spirometry cannot be performed at screening, historical post-bronchodilator 
percent predicted FEV1 (ppFEV1) results within 1 year before screening can be used to 
determine eligibility. Historical post-bronchodilator spirometry measurements are <30% of 
predicted mean for age, sex, and height (equations of the GLI) and must meet ATS/ERS 
criteria for acceptability and repeatability. 
8. All clinically important pulmonary disease other than AATD-related COPD, including but 
not limited to physician-diagnosed COPD not related to AATD, interstitial lung disease, 
cystic fibrosis, pulmonary hypertension with or without cor pulmonale, history of pulmonary 
embolism, or malignant lung cancer.  
9. Unstable AATD-related COPD as deemed by the investigator.  
10. Documented chronic need for positive airway pressure therapy beyond nocturnal use. 
11. Documented medical history or diagnosis of clinically evident liver disease including but not 
limited to a prior diagnosis of hepatitis of any etiology, cirrhosis, portal hypertension, or 
confirmed or suspected esophageal varices.  
12. Any of the following abnormal laboratory values at screening: 
• Platelet count <150 × 109/L. 
• Albumin ≤3.5 g/dL 
• International normalized ratio ≥1.2 
• Hemoglobin <10 g/dL 
• Total bilirubin > upper limit of normal (ULN) 
• Aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase 
(GGT), or alkaline phosphatase (ALP) >2 × ULN 


Protocol VX19-814-101, Version 3.0 
Page 29 of 68 
Vertex Pharmaceuticals Incorporated 
 
• Estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73 m2 (calculated by the 
Modification of Diet in Renal Disease Study Equation)  
13. Risk factors for Torsade de Pointes (e.g., familial long QT syndrome, chronic hypokalemia, 
heart failure) or concomitant medications that prolong the QT/QTc interval or any history of 
unstable cardiac disorder that, in the opinion of the investigator, might put the subject at risk 
or may confound the results of the study.  
14. Any clinically significant ECG abnormality (as determined by the investigator) or median 
QTcF of triplicate standard 12-lead ECGs >450 msec at screening. 
15. History of Gilbert's Syndrome. 
16. Positive for HBsAg, HCV RNA, or HIV-1 and HIV-2 antibodies during screening.  
17. Use of the substances, activities, or devices during the time periods indicated in Section 9.5. 
18. Cigarette smoking during the past 6 months or a positive cotinine test at screening that is due 
to smoking or an electronic nicotine delivery system. Positive cotinine test due to nicotine 
replacement therapy for the purposes of smoking cessation, as attested by the investigator, is 
permitted.   
19. Male subjects who plan to donate sperm or who have a female partner who is pregnant, 
nursing, or planning to become pregnant during the study or within 90 days after the last 
study drug dose. 
20. The subject or a close relative of the subject is the investigator or a sub-investigator, research 
assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of 
the study. An adult (18 years of age or older) who is a relative of a study staff member may 
be enrolled in the study provided that 
• the adult lives independently of and does not reside with the study staff member, and 
• the adult participates in the study at a site other than the site at which the family member 
is employed. 
21. Hypersensitivity to any component of the investigational drug product or placebo 
(e.g., lactose). 
22. Subjects for whom discontinuation of augmentation therapy is not considered to be in their 
best interest, based on the clinical judgement of the treating physician. 


Protocol VX19-814-101, Version 3.0 
Page 30 of 68 
Vertex Pharmaceuticals Incorporated 
 
9 
STUDY IMPLEMENTATION 
9.1 
Study Design 
This is a Phase 2, randomized, double-blind, placebo-controlled study of VX-814. Schematics of 
the study design are shown in Figure 9-1 and Figure 9-2. 
Part A1: Approximately 15 subjects in total with the PiZZ genotype and antigenic AAT levels 
<8 µM at screening will be randomized (2:1:1:1) to 1 of 3 VX-814 groups or the placebo group. 
Part A2: Approximately 8 subjects in total with the PiZZ genotype and antigenic AAT levels 
<8 µM at screening will be randomized (3:1) to the VX-814 group or the placebo group.  
Enrollment may be adjusted to ensure approximately 12 subjects receive VX-814 400 mg q12h 
in Parts A1 and A2 combined. 
Part B: Approximately 20 subjects in total with the PiZZ genotype and antigenic AAT levels 
<8 µM at screening will be randomized (3:1) to the VX-814 group or the placebo group.  
Enrollment in Parts A2 and B may be initiated before Part A1 completes the planned enrollment. 
Randomization will be stratified by ppFEV1 obtained either during the Screening Period or from 
a historical ppFEV1 value (<50% versus ≥50%). 
Screening Visit assessments for subjects who have never been on augmentation therapy are listed 
in Table 3-1. Screening Visit assessments for subjects who have been on augmentation therapy at 
any time are listed in Table 3-2. Treatment Period assessments for all subjects are listed in 
Table 3-3. 
Figure 9-1 
Parts A1, A2, and B: Schematic of Study Design for Subjects Who Have 
Never Been on Augmentation Therapy 
Part A1 
 
 
 
 
 
Treatment Period 
28 days  
VX-814 400 mg q12h N = 6 
VX-814 200 mg q12h N = 3 
Placebo N = 3 
Safety 
Follow-up Visits 
14 and 28 days after last 
dose 
VX-814 100 mg q12h N = 3 
VX-814 Washout Visit 
7 days after last dose 
Screening 
up to 35 days 


Protocol VX19-814-101, Version 3.0 
Page 31 of 68 
Vertex Pharmaceuticals Incorporated 
 
Figure 9-1 
Parts A1, A2, and B: Schematic of Study Design for Subjects Who Have 
Never Been on Augmentation Therapy 
Part A2 
Part B 
 
N: number of subjects; q12h: every 12 hours 
Notes: Figure is not drawn to scale. Subject numbers include subjects who have never been on augmentation therapy 
and subjects who have been on augmentation therapy at any time. 
Antigenic AAT levels must be drawn to confirm eligibility and sent to the central laboratory; results must be 
obtained and confirmed to be <8 µM before randomization. Once antigenic AAT levels have been confirmed to 
meet this eligibility criterion, randomization and Day 1 can occur any time within the remaining screening 
window. Sites should allow at least 14 days for sample processing and antigenic AAT level result reporting. 
 
Treatment Period 
28 days  
VX-814 400 mg q12h N = 6 
Placebo N = 2 
Safety 
Follow-up Visits 
14 and 28 days after last 
dose 
VX-814 Washout Visit 
7 days after last dose 
Screening 
up to 35 days 
Treatment Period 
28 days  
VX-814 600 mg q12h N = 15 
Placebo N = 5 
Safety 
Follow-up Visits 
14 and 28 days after last 
dose 
VX-814 Washout Visit 
7 days after last dose 
Screening 
up to 35 days 


Protocol VX19-814-101, Version 3.0 
Page 32 of 68 
Vertex Pharmaceuticals Incorporated 
 
Figure 9-2 
Parts A1, A2, and B: Schematic of Study Design for Subjects Who Have Been on 
Augmentation Therapy at Any Time 
 
Part A 
Part A2 
Treatment Period 
28 days 
VX-814 400 mg q12h N = 6 
VX-814 200 mg q12h N = 3 
Placebo N = 3 
Safety 
Follow-up Visits 
14 and 28 days after last 
dose 
VX-814 100 mg q12h N = 3 
Discontinue 
augmentation 
therapy >42 days 
before AAT levels 
are drawn for 
eligibility * 
Subjects may 
resume 
augmentation 
therapy 
after the last 
Safety Follow-up 
Visit 
VX-814 
Washout Visit 
7 days after 
last dose 
Screening 
up to 70 days 
42 days 
Antigenic AAT 
level for 
eligibility 
Treatment Period 
28 days 
VX-814 400 mg q12h N = 6 
Placebo N = 2 
Safety 
Follow-up Visits 
14 and 28 days after last 
dose 
Discontinue 
augmentation 
therapy >42 days 
before AAT levels 
are drawn for 
eligibility * 
Subjects may 
resume 
augmentation 
therapy 
after the last 
Safety Follow-up 
Visit 
VX-814 
Washout Visit 
7 days after 
last dose 
Screening 
up to 70 days 
42 days 
Antigenic AAT 
level for 
eligibility 


Protocol VX19-814-101, Version 3.0 
Page 33 of 68 
Vertex Pharmaceuticals Incorporated 
 
Figure 9-2 
Parts A1, A2, and B: Schematic of Study Design for Subjects Who Have Been on 
Augmentation Therapy at Any Time 
 
Part B 
N: number of subjects; q12h: every 12 hours 
Notes: Figure is not drawn to scale. Subject numbers include subjects who have never been on augmentation therapy and 
subjects who have been on augmentation therapy at any time. Subjects must discontinue augmentation therapy 
>42 days before antigenic AAT levels are drawn and sent to the central laboratory to confirm eligibility; results must 
be confirmed to be <8 µM before randomization. Once antigenic AAT levels have been confirmed to meet this 
eligibility criterion, randomization and Day 1 can occur any time within the remaining screening window. Sites should 
allow at least 14 days for sample processing and antigenic AAT level results reporting. Subjects can resume 
augmentation therapy after completion of assessments at the last Safety Follow-up Visit. 
*Blood samples will be obtained for antigenic and functional AAT levels at the same time that the other screening 
laboratory assessments are performed. If the subject received the last dose of augmentation therapy >42 days prior, this 
sample can be used to measure antigenic AAT level for eligibility. If samples are obtained ≤42 days after the last dose 
of augmentation therapy, another sample must be drawn >42 days after the last dose of augmentation therapy and sent 
to the central laboratory to confirm eligibility. 
9.1.1 
Screening 
For subjects who have never been on augmentation therapy, the Screening Period (Day -35 
through Day -1) will occur up to 35 days before the first dose of study drug. 
For subjects who have been on augmentation therapy at any time, the Screening Period (Day -70 
through Day -1) will occur up to 70 days before the first dose of study drug. The last dose of 
augmentation therapy must have been given >42 days before the antigenic AAT levels are 
obtained to confirm eligibility. To establish eligibility, an antigenic AAT level must be drawn 
>42 days after the last dose of augmentation therapy and sent to the central laboratory. The 
antigenic AAT result must be reviewed to confirm eligibility before randomization. Subjects will 
remain off augmentation therapy thereafter until after the last Safety Follow-up Visit has been 
conducted.  
Screening assessments will be used to confirm that subjects meet the eligibility criteria. The 
investigator (or an appropriate authorized designee at the study site) will obtain informed consent 
from each subject before any study procedure takes place. Screening procedures (including 
informed consent) can be performed over more than 1 day. Informed consent must be obtained 
Treatment Period 
28 days  
VX-814 600 mg q12h N = 15 
Placebo N = 5 
Safety 
Follow-up Visits 
14 and 28 days after last 
dose 
Discontinue 
augmentation 
therapy >42 days 
before AAT levels 
are drawn for 
eligibility * 
Subjects may 
resume 
augmentation 
therapy 
after the last 
Safety Follow-up 
Visit 
VX-814 
Washout Visit 
7 days after 
last dose 
Screening 
up to 70 days 
42 days 
Antigenic AAT 
level for 
eligibility 


Protocol VX19-814-101, Version 3.0 
Page 34 of 68 
Vertex Pharmaceuticals Incorporated 
 
prior to any procedures. Screening assessments that were not conducted at the initial visit during 
the Screening Period may be performed at home by a qualified visiting nurse or at the clinic (if 
permitted by ethical and regulatory authorities and agreed upon after investigator and subject 
consultation). 
9.1.1.1 
Repetition of Screening Assessment(s) 
If screening spirometry measurements fail to meet acceptability and repeatability criteria as 
specified by American Thoracic Society/European Respiratory Society guidelines4, 5, 6, repeat 
spirometry evaluation may be performed. 
Otherwise, repeating individual screening assessment(s) that did not meet eligibility criteria is 
not permitted, with the following exceptions that require the approval of the medical monitor:  
• If there is clear evidence of a damaged sample, laboratory error, or equipment malfunction, 
collection of a repeat sample for the appropriate laboratory test or assessment may be 
permitted. 
• Exclusionary liver function, platelet, hemoglobin, albumin, or eGFR test results, which may 
be retested once. 
• Exclusionary ECG tests results, which may be retested once. 
The repeat screening assessment or blood sample may be conducted or drawn, respectively, at 
home by a qualified visiting nurse or at the clinic (if permitted by ethical and regulatory 
authorities and agreed upon after investigator and subject consultation). 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. 
9.1.1.2 
Rescreening 
Subjects may be rescreened only once. If a subject is rescreened, all screening assessments will 
be repeated, except for:  
• PiZZ genotyping 
• Follicle-stimulating hormone (FSH) level (if serum FSH level was in the postmenopausal 
range as determined by the laboratory performing the test during prior screening) 
If a subject is rescreened, a new screening window will begin when the first rescreening 
assessment has been initiated. 
9.1.1.3 
Extension of the Screening Period  
A subject may have the Screening Period window extended by 2 weeks without medical monitor 
approval for the following reasons: 
• Repetition of Screening Period assessments (Section 9.1.1.1) 
• Unexpected operational or logistic delays, or to meet the eligibility criteria. 
For subjects who have never been on augmentation therapy only, a subject may have the 
Screening Period window extended for an additional 2 weeks (total of 4 weeks extension) with 
medical monitor approval.  


Protocol VX19-814-101, Version 3.0 
Page 35 of 68 
Vertex Pharmaceuticals Incorporated 
 
9.1.2 
Treatment Period 
The Treatment Period will be randomized, double-blind, and placebo-controlled. It will last 
approximately 28 days. Study drug administration details are provided in Section 9.7. 
Subjects who prematurely discontinue study drug treatment will remain in the study from the 
time of discontinuation of study drug treatment through the last scheduled study visit and 
complete assessments for all study visits, as described in Section 9.1.4. 
9.1.3 
Follow-up 
Subjects will have a VX-814 Washout Visit 7 (± 2) days after the last dose of study drug and 
Safety Follow-up Visits 14 (± 2) and 28 (± 2) days after the last dose of study drug.  
9.1.4 
Early Termination of Treatment  
If a subject prematurely discontinues study treatment, an Early Termination of Treatment (ETT) 
Visit should be scheduled as soon as possible after the decision to terminate study treatment. 
Subjects who prematurely discontinue treatment will be required to complete the Safety 
Follow-up Visits 14 (± 2) and 28 (± 2) days after their last dose of study drug. The assessments 
performed at the ETT and Safety Follow-up Visits are listed in Table 3-3. 
If the ETT Visit occurs between 12 and 21 days (inclusive) after the last dose of study drug, then 
the ETT Visit will replace the Safety Follow-up Visit 14 days after the last dose of study drug, 
and a separate Safety Follow-up Visit 14 days after the last dose will not be required; the Safety 
Follow-up Visit 28 days after the last dose will be required. If the ETT Visit occurs ≥22 days 
after the last dose of study drug, the ETT Visit will replace the Safety Follow-up Visit 28 days 
after the last dose, and a separate Safety Follow-up Visit 28 days after the last dose will not be 
required. 
If a subject withdraws consent for the study, no further assessments will be performed. Vertex 
may retain and continue to use any data and samples collected before such withdrawal of 
consent. 


Protocol VX19-814-101, Version 3.0 
Page 36 of 68 
Vertex Pharmaceuticals Incorporated 
 
9.2 
Lost to Follow-up 
A subject will be considered lost to follow up if both of the following occur: 
• The subject misses 2 consecutive study visits (telephone contact, clinic, and/or home heath 
visit) and is subsequently unable to be contacted by telephone (3 documented attempts by 
telephone within 1 week following the second missed visit) 
• The subject does not respond within 1 week to a registered letter sent after the 3 attempted 
telephone contacts. 
9.3 
Method of Assigning Subjects to Treatment Groups 
In Part A1, subjects will be randomized (2:1:1:1) to 1 of 3 VX-814 groups or to the placebo 
group. In Part A2, subjects will be randomized (3:1) to the VX-814 group or to the placebo 
group. In Part B, subjects will be randomized (3:1) to the VX-814 group or to the placebo group. 
Each randomized subject will be assigned a unique subject number. Randomization will be 
stratified by ppFEV1 obtained either during the Screening Period or from a historical ppFEV1 
value (<50% versus ≥50%). 
An interactive web or voice response system (IWRS) will be used to assign subjects to treatment. 
The randomization code will be produced by Vertex Biostatistics or a qualified randomization 
vendor. The Vertex study biostatistician will review and approve the production of the final 
randomization list, which will be reviewed and approved by a designated unblinded 
biostatistician who is not a member of the study execution team (SET).  
9.4 
Rationale for Study Elements 
9.4.1 
Rationale for Study Design 
A parallel-group, randomized, placebo-controlled design was selected to minimize the imbalance 
in the distribution of the baseline characteristics of the different dosing groups. A double-blind 
design was included to prevent bias in endpoint assessment by the investigator or subject.  
The 28-day treatment duration is based on the estimated plasma half-life for AAT of 
approximately 5 days, indicating that plasma AAT levels will reach >95% of steady-state levels 
by the end of the treatment period. Therefore, it is expected that the 28-day treatment duration of 
VX-814 will be sufficient to evaluate the maximal effect of each dose level on plasma AAT. 
9.4.2 
Rationale for Study Population 
The study population will be comprised of subjects with a confirmed PiZZ genotype. This patient 
population was selected based on the proposed mechanism of action of VX-814.  


Protocol VX19-814-101, Version 3.0 
Page 37 of 68 
Vertex Pharmaceuticals Incorporated 
 
9.4.3 
Rationale for Study Drug Dose  
A total of 4 dose levels of VX-814 will be evaluated in this study (100 mg q12h, 200 mg q12h, 
400 mg q12h, and 600 mg q12h). The doses will be administered orally. 
 
 
  
 
 The doses selected 
will provide an adequate assessment of the dose-response relationship and safety profile of 
VX-814 in the exposure range of interest, with an adequate safety margin at the highest dose 
(Section 6 in the VX-814 IB). 
9.4.4 
Rationale for Study Assessments 
All safety and PK assessments are standard measurements for clinical studies in drug 
development. 
Blood samples will be collected to evaluate the effect of VX-814 on plasma functional and 
antigenic AAT levels in PiZZ subjects based on the mechanism of action of VX-814.  
UGT1A1 genotyping will be conducted to assess the impact of UGT1A1 polymorphism on PK 
exposure of VX-814, as UGT1A1 is the main enzyme metabolizing VX-814. 
9.5 
Study Restrictions 
Study restrictions and timing of restrictions are summarized in Table 9-1. Subjects may enroll in 
the study if they are receiving acceptable concomitant medications (according to Table 9-1). 
A non-exhaustive list of prohibited medications will be provided in the Study Reference Manual. 


Protocol VX19-814-101, Version 3.0 
Page 38 of 68 
Vertex Pharmaceuticals Incorporated 
 
Table 9-1 
Study Restrictions 
Restricted 
Medication/Food/Activitya 
Timing of Restriction 
Start 
Stop 
Other investigational drugs 
or devices 
28 days before screening, 5 half-lives before 
screening, or time determined by local 
requirements (whichever is longer) 
Completion of the last Safety 
Follow-up Visit assessments 
Augmentation therapy 
(human alpha-1 proteinase 
inhibitor) 
More than 42 days before antigenic AAT 
level is obtained for eligibility 
Completion of the last Safety 
Follow-up Visit assessments 
Sensitive CYP2C8 
substrates 
7 days or 5 half-lives (whichever is longer) 
before the first dose of study drug 
Completion of the last Safety 
Follow-up Visit assessments 
UGT1A1 moderate and 
strong inhibitors  
7 days or 5 half-lives (whichever is longer) 
before the first dose of study drug 
Completion of the last Safety 
Follow-up Visit assessments 
UGT1A1 moderate and 
strong inducers  
14 days before the first dose of study drug 
Completion of the last Safety 
Follow-up Visit assessments 
Tobacco productsc 
6 months before screening  
Completion of the last Safety 
Follow-up Visit assessments 
Alcohol: no more than 
14 drinks/week for females 
or 21 drinks/week for males 
(1 drink = 5 ounces 
(150 mL) of wine or 
12 ounces (360 mL) of beer 
or 1.5 ounces (45 mL) of 
hard liquor) 
Signing of ICF 
Completion of the last Safety 
Follow-up Visit assessments 
a 
See Section 9.6 for guidance on concomitant medications.  
 
Nicotine replacement therapy under the direction of a physician is allowed.  
9.5.1 
Exposure to Sunlight 
Subjects will take appropriate measures to minimize exposure to ultraviolet radiation 
(e.g., sunlight, tanning booths) from Day 1 through the last Safety Follow-up Visit.  


Protocol VX19-814-101, Version 3.0 
Page 39 of 68 
Vertex Pharmaceuticals Incorporated 
 
9.6 
Prior and Concomitant Medications 
Subjects will follow restrictions described in Table 9-1. 
In vitro data suggest that VX-814 acyl-glucuronide metabolite has the potential to inhibit 
CYP2C8, which may increase the exposure of medicinal products that are CYP2C8 substrates. 
Therefore, concomitant administration of sensitive CYP2C8 substrates is prohibited (Table 9-1).  
All medications taken from the Screening Visit through the last Safety Follow-up Visit will be 
recorded with indication, route of administration, and start and stop dates of administration. For 
subjects who are screened but not subsequently randomized, details of prior medication will only 
be documented in the subjects' source documents.  
Information about bronchodilator use during the study will be recorded for each subject. Use of 
short-acting and long-acting bronchodilators will be collected and documented in the source 
documents for each subject.  
Information about prior augmentation therapy, as applicable, will be recorded for each subject, 
including dose, frequency of administration, start and stop dates of last infusion. 
9.7 
Administration 
VX-814 will be administered orally, 2 times a day, approximately 12 hours apart. All subjects 
will receive the same number of tablets each day to maintain blinding. Additional information is 
provided in the Pharmacy Manual. 
Study drug will be administered according to the following guidelines: 
• Study drug will be taken with a meal (not a snack), preferably within 30 minutes of the start 
of the meal. 
• Each subject should take the study drug approximately 12 hours apart (±1 hours). Subjects 
will swallow the tablet(s) whole without chewing or crushing the tablets with approximately 
240 mL of water. Subjects may take additional water, as needed, to swallow tablets.  
• The date, amount taken, and time of study drug administration, including whether a meal was 
taken with each dose, will be recorded for the 2 doses before PK sample collection and the 
dose associated with PK sample collection. 


Protocol VX19-814-101, Version 3.0 
Page 40 of 68 
Vertex Pharmaceuticals Incorporated 
 
• If the subject’s scheduled clinic or home visit is to occur in the morning (i.e., before noon), 
study drug will be administered after predose assessments have been completed. If the visit is 
a clinic visit, a meal will be provided by the site.  
• If the subject's scheduled clinic or home visit is to occur in the afternoon, the following 
guidelines must be followed: 
o If the dose at the scheduled visit will be within 6 hours of the subject's scheduled 
morning dose, the subject should withhold the morning dose and the morning 
dose will be administered in the clinic with a meal provided by the site or 
witnessed by a home nurse at the home visit, with a meal. 
o If the dose at the scheduled visit will be more than 6 hours after the subject's 
scheduled morning dose, the subject should take the morning dose at home with a 
meal. 
• If the subject’s scheduled home visit is to occur in the evening, study drug will be 
administered with a meal after predose assessments have been completed.  
• The morning dose of study drug on the Day 28 Visit will be taken in the clinic or at home 
with a meal provided by the site after the predose PK sample has been drawn. The last dose 
of study drug will be taken at home with a meal in the evening on Day 28, regardless of 
whether the Day 28 Visit occurs on Day 26 or Day 27. 
Missed doses:  
If a subject misses a dose, the subject can take the missed dose within 6 hours of the usual dosing 
time and should take the dose as soon as possible with a meal. If more than 6 hours have elapsed 
after the usual dosing time, the subject should skip that dose and resume the normal schedule for 
the following dose.  
Morning and evening doses should not be taken at the same time. 
9.8 
Dose Modification for Toxicity 
No dose modifications for toxicity are allowed or required. If any unacceptable toxicity arises in 
the opinion of the investigator individual subjects will discontinue dosing (Section 9.1.4). 
9.9 
Study Drug Interruption and Stopping Rules 
The investigator has the discretion to discontinue study drug treatment at any time if the 
investigator feels that the subject's continued participation in the study jeopardizes their safety. 
Any subject with worsening of AATD or disease progression that, in the judgement of the 
treating physician, requires (re)initiation of standard of care treatment (per local guidelines) that 
is prohibited in this study (including augmentation therapy) will discontinue study drug 
treatment. 
Any subject with QTcF values above the threshold values as described in Section 11.5.4 will 
discontinue study drug treatment. 
Study drug treatment may be interrupted for safety concerns at discretion of the investigator. 


Protocol VX19-814-101, Version 3.0 
Page 41 of 68 
Vertex Pharmaceuticals Incorporated 
 
Study drug administration must be interrupted immediately (before confirmatory testing), and the 
medical monitor must be notified, if any of the following criteria are met: 
• ALT or AST >5 × ULN  
• Total bilirubin >3 × ULN  
• ALT or AST >3 × ULN associated with total bilirubin >2 × ULN and/or clinical jaundice 
Subjects with new treatment-emergent ALT or AST elevations of >3 × ULN, or total bilirubin 
>2 × ULN, must be followed closely, including confirmatory testing performed within 48 to 
72 hours of the initial finding and there must be close monitoring of ALT, AST, and bilirubin 
levels thereafter, as clinically indicated.  
If a subject cannot return to the site for confirmatory testing, a local laboratory may be used. 
Local laboratory results 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). 
In subjects who met above interruption criteria, a thorough investigation of potential causes 
should be conducted, and the subject must be followed closely for clinical progression. If an 
alternative, reversible cause of transaminase elevation and/or increased bilirubin has been 
identified, study drug administration may be resumed once transaminases and/or bilirubin return 
to baseline or are <ULN, whichever is higher. Approval of the medical monitor is required 
before resumption of study drug. Upon resumption of study drug, transaminases and bilirubin 
must be assessed weekly until 7 days after the last dose of study drug. If a protocol-defined 
transaminase and/or bilirubin elevation interruption threshold recurs, then study drugs must be 
permanently discontinued, regardless of the presumed etiology. 
All subjects for whom treatment is discontinued for elevated transaminases and/or bilirubin 
should have these levels monitored closely until levels normalize or return to baseline.  
9.10 
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. A subject 
who withdraws from study drug treatment will continue to be followed unless the subject 
withdraws consent.  
Subjects who are withdrawn from study drug dosing will complete assessments as described in 
Section 9.1.4. 
Subjects who have been randomized and whose screening PiZZ genotype does not confirm study 
eligibility must be discontinued from the study, even if a previous PiZZ genotype laboratory 
report was used to establish eligibility. 
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 have a Safety Follow-up Visit, if 
applicable (see Section 9.1.4), and follow up with the subject regarding any unresolved AEs. 


Protocol VX19-814-101, Version 3.0 
Page 42 of 68 
Vertex Pharmaceuticals Incorporated 
 
If a subject withdraws consent for the study, no further assessments will be performed. Vertex 
may retain and continue using the study data and samples after the study ends and may use the 
samples and information in the development of the study compound, for other drugs and 
diagnostics, in publications and presentations, and for education purposes. If a subject withdraws 
from the study, the study data and samples collected will remain part of the study. A subject will 
not be able to request the withdrawal of his/her information from the study data. A subject may 
request destruction of the samples collected from him/her during the study as long as those 
samples can be identified as his/her samples. 
9.11 
Replacement of Subjects 
Subjects who withdraw or are withdrawn before the first dose of study drug may be replaced.  
Subjects who withdraw or are withdrawn for nonsafety reasons during the study drug treatment 
period(s) may be replaced at Vertex's discretion.  
10 
STUDY DRUG INFORMATION 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 
Packaging and Labeling 
Vertex will supply the 100-mg VX-814 tablets and matching placebos. Study drug labeling will 
be in compliance with applicable local and national regulations. Additional details about 
packaging, labeling, and dispensing for VX-814 will be provided in the Pharmacy Manual. 
10.3 
Study Drug Supply, Storage, and Handling 
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 via the drug accountability forms as instructed by Vertex.  
VX-814 and matching placebo will be supplied as tablets of similar size and appearance 
containing 100 mg VX-814 and 0 mg VX-814, respectively. 
Detailed instructions regarding the storage, handling, and dispensation of the study drug will be 
provided in the Pharmacy Manual. 
10.4 
Drug Accountability 
The pharmacist or designated study site staff will maintain information regarding the dates and 
amounts of study drug received, study drug dispensed to the subjects, and study drug returned by 
the subjects. Subjects will be instructed to return all used and unused materials associated with 
the study drug 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. 
If a site uses a site-specific drug accountability system and/or process, including processes 
associated with the destruction of returned materials, the process must be documented and 
approved by Vertex. The study monitor must review the drug accountability documentation on a 


Protocol VX19-814-101, Version 3.0 
Page 43 of 68 
Vertex Pharmaceuticals Incorporated 
 
regular basis. The study monitor will promptly communicate to Vertex any discrepancies he/she 
is unable to resolve with the site. 
10.5 
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. 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. 
The principal investigator, study site staff, including pharmacy personnel will assist Vertex with 
any recall activities (as applicable) and place impacted investigational medicinal product (IMP) 
in quarantine when requested.  
10.6 
Compliance  
To ensure treatment compliance, the investigator or designee will supervise all study drug dosing 
that occurs at the site. At each visit, site personnel or approved home nurse will review that the 
subject is compliant with study drug dosing and remind the subject of study drug dosing 
requirements. Compliance will also be assessed by ongoing study drug count in the clinic or 
checked by home nurse for home visit. 
If a subject demonstrates continued noncompliance of study drug dosing despite educational 
efforts, the investigator will contact the medical monitor to discuss discontinuing the subject 
from the study. 
10.7 
Blinding and Unblinding 
This is a double-blind study. 
10.7.1 
Blinding  
All subjects, site personnel (including the investigator, the site monitor, and the study team), and 
the Vertex study team will be blinded to the treatment codes 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 her fetus in the event of a pregnancy 
• Vertex GPS and Regulatory Affairs personnel to satisfy SAE processing and reporting 
regulations 
• Unblinded statistician preparing the final (production) randomization list who is not part of 
the study team 
• Vertex IWRS Manager 
• Vertex Clinical Supply Chain 
• The bioanalytical CRO analyzing PK samples and the Vertex Bioanalytical personnel who is 
not a member of the SET but analyzes and reviews raw data from Bioanalytical CRO. The 
Vertex Bioanalytical SET member will continue to be blinded. 


Protocol VX19-814-101, Version 3.0 
Page 44 of 68 
Vertex Pharmaceuticals Incorporated 
 
Vertex medical monitor may, for matters relating to safety concerns, unblind individual subjects 
at any time. 
A limited Vertex team not directly involved in the conduct of the study may be unblinded to 
individual subject treatment assignments and have access to plasma AAT levels, PK, and/or 
safety data (e.g., adverse events, clinical laboratory assessments) for continuous monitoring 
purposes. No unblinded data or results of unblinded analyses will be shared with the study sites 
or with the Vertex study team. All instances of unblinding by Vertex personnel will be 
documented.  
Access to results of plasma functional and antigenic AAT data: 
During the conduct of the study, the Vertex study team will not have access to the plasma AAT 
level results until the study is unblinded for full review, with the exception of the screening 
plasma antigenic AAT levels. Antigenic AAT levels obtained during screening will be provided 
to study sites in order to confirm the subject’s eligibility to enroll in the study. Other AAT level 
results will not be disclosed to the study sites. 
Shortly before any planned efficacy analysis related to plasma AAT levels is conducted, plasma 
AAT data will be reviewed for data cleaning purposes by a biostatistician who does not have 
access to the treatment codes. 
Access to direct and indirect bilirubin results 
After screening, direct and indirect bilirubin results will not be disclosed to the study sites. After 
screening, the Vertex study team will not have access to the direct and indirect bilirubin results 
until the study is unblinded for full review. Study sites and the Vertex study team will receive 
total bilirubin results. 
Before the final data lock, direct and indirect bilirubin data will be reviewed for data cleaning 
purposes by a biostatistician who does not have access to the treatment codes. 
10.7.2 
Unblinding 
At the initiation of the study, study site personnel will be instructed on the method for breaking 
the blind. The unblinding method will be either manual or electronic. 
Unblinding of the individual subject's treatment by the investigator will be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject's study 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 unblinding. 
If investigators deem it unnecessary to unblind immediately, they will first attempt to contact the 
medical monitor to discuss 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. 
Contact information for the medical monitor (or appropriate backup) will be provided in a 
separate document. 


Protocol VX19-814-101, Version 3.0 
Page 45 of 68 
Vertex Pharmaceuticals Incorporated 
 
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 Vertex, the 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 13.1.2. 
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, unblind individual 
subjects at any time.   
11 
ASSESSMENTS 
The schedule of assessments is shown in Table 3-1, Table 3-2, and Table 3-3.  
11.1 
Subject and Disease Characteristics 
Subject and disease characteristics include the following: demographics, medical history, height, 
and weight. Cigarette and or e-cigarette smoking history (current smoker; ever smoker; never 
smoker) will be collected for each subject including time since quitting and pack-years and 
cartridge-years of smoking history (packs/day × number of years; cartridges/day × number of 
years).  
11.2 
Pharmacokinetics 
11.2.1 
Blood Sampling 
Blood samples will be collected for the evaluation of plasma concentrations of VX-814. 
 
 
  
Plasma concentration samples collected from subjects treated with placebo study drug will not be 
routinely analyzed.  
All efforts will be made to obtain the PK samples at the nominal time (±30 minutes) relative to 
dosing. Acceptable windows for sampling times are shown in Table 11-1. The exact time of the 
sample collection will be noted. 
Table 11-1 
Acceptable Pharmacokinetic Sampling Windows 
Sampling Time 
Time From Scheduled Sampling Allowed 
Predose 
Within 60 minutes before dosing 
All other time points 
± 30 minutes 
 
 
The following details will be recorded in the source document: date and time of study drug and 
meal administration for the 2 doses before the dose on PK sampling days and date and time of 
each of the PK blood samples. 


Protocol VX19-814-101, Version 3.0 
Page 46 of 68 
Vertex Pharmaceuticals Incorporated 
 
11.2.2 
UGT1A1 Genotype  
A single blood sample will be collected to assess the impact of UGT1A1 polymorphism on PK 
exposure of VX-814. 
11.2.3 
Processing and Handling of Pharmacokinetic Samples 
Detailed procedures for the collection of blood samples and further procedures for processing 
and handling of samples for PK analysis will be in the PK Sample Handling Guidelines.  
11.2.4 
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. 
11.3 
Efficacy 
Detailed procedures for the collection, processing, handling, and storage of blood samples for 
functional and antigenic AAT levels will be provided in the Clinical Biomarker Sample 
Handling Guidelines. 
Samples will be obtained for antigenic and functional AAT levels at the same time that other 
screening laboratory assessments are performed. These samples must be sent to the central 
laboratory. If the subject has never received augmentation therapy or if the subject received the 
last dose of augmentation therapy >42 days prior, this sample can be used to measure antigenic 
AAT level for eligibility. If samples are obtained ≤42 days after the last dose of augmentation 
therapy, another sample must be drawn >42 days after the last dose of augmentation therapy and 
sent to the central laboratory to determine eligibility. Sites should allow at least 14 days for 
sample processing and results reporting. Samples will be obtained for plasma functional AAT 
levels at the same time samples are obtained for antigenic AAT levels. Functional AAT level 
results will not be provided to site personnel. 


Protocol VX19-814-101, Version 3.0 
Page 47 of 68 
Vertex Pharmaceuticals Incorporated 
 
11.5 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, standard 12-lead ECGs, 
clinical evaluation of vital signs, pulse oximetry, spirometry, and physical examinations (PEs). 
11.5.1 
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. 


Protocol VX19-814-101, Version 3.0 
Page 48 of 68 
Vertex Pharmaceuticals Incorporated 
 
11.5.2 
Clinical Laboratory Assessments 
Blood and urine samples will be analyzed at a central laboratory.  
Laboratory test results that are abnormal and considered clinically significant will be reported as 
AEs (see Section 13.1). 
The safety laboratory test panels are shown in Table 11-2. 
Table 11-2 
Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
Urinalysisa 
Glucose  
Blood urea nitrogenb 
Creatinine 
Sodium 
Potassium  
Calcium  
Chloride  
Magnesium  
Bicarbonate  
Phosphate  
Total bilirubin (direct bilirubin, 
indirect bilirubin) 
Alkaline phosphatase  
Aspartate transaminase 
Alanine transaminase 
Amylase 
Lipase 
Gamma-glutamyl transferase  
Protein  
Albumin  
Creatine kinase 
Urate 
Cholesterol  
Triglycerides 
Low-density lipoprotein  
High-density lipoprotein 
Hemoglobin  
Erythrocytes 
Mean corpuscular volume 
Platelets  
Reticulocytes  
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  
Urine protein  
pH Urine 
Urine blood  
Specific gravity  
Urine ketones 
Urine glucose  
Urine cotinine 
a 
If urinalysis results are positive for leukocyte esterase, nitrite, protein, or blood, microscopic examination of 
urine will be done, and results will be provided for leukocytes, erythrocytes, crystals, bacteria, and casts. 
b 
If blood urea nitrogen cannot be collected, urea may be substituted. 
 
Additional Tests at Screening: 
• Serology test for HBsAg, HCV antibody and RNA, and HIV-1 and HIV-2 antibodies 
• Serum beta-human chorionic gonadotropin (β-hCG) for all female subjects  
• Serum FSH for postmenopausal female subjects with spontaneous amenorrhea for at least 
12 consecutive months without another reason, except for those who have documented 
bilateral oophorectomy or hysterectomy. Levels will be within the laboratory's range for 
postmenopausal for subjects to be considered of non-childbearing potential. 


Protocol VX19-814-101, Version 3.0 
Page 49 of 68 
Vertex Pharmaceuticals Incorporated 
 
Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged to be clinically appropriate for safety concerns. 
For purposes of study conduct, only safety laboratory tests done at the central laboratory may be 
used; however, the investigator has the discretion to use local laboratory in the event of safety 
concerns. If a local laboratory is used, results must be reported immediately to the medical 
monitor. If a local laboratory test value is found to be abnormal and clinically significant, it will 
be verified by the central laboratory as soon as possible after the investigator becomes aware of 
the abnormal result. If it is not possible to send a timely specimen to the central laboratory 
(e.g., the subject was hospitalized elsewhere), the investigator may base the assessment of an AE 
on the local laboratory value. 
11.5.3 
Physical Examinations, Vital Signs, and Pulse Oximetry 
A PE of all body systems, vital signs and pulse oximetry assessment will be performed at 
screening. At other visits, symptom-directed PEs and symptom-directed vital signs assessments 
can be performed at the discretion of the investigator or healthcare provider. 
A PE includes a review of the following systems: head, neck, and thyroid; eyes, ears, nose, and 
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 PEs will be reported as 
AEs. 
The abbreviated PE will include an assessment of the following body systems: head, neck, and 
thyroid; EENT; cardiovascular system; respiratory system; skin; and abdomen. 
The review of symptoms will include a verbal review of symptoms by body system. If there are 
any abnormal findings, the subject will be instructed to have a complete PE in the clinic. 
Vital signs include blood pressure (systolic and diastolic), temperature, pulse rate, and 
respiration rate. The subject will be instructed to rest for at least 5 minutes before vital signs are 
assessed.  
The subject will be instructed to rest for at least 5 minutes before pulse oximetry is assessed. 
11.5.4 
Electrocardiograms 
Standard 12-lead ECGs will be performed in triplicate. Additional standard 12-lead ECGs will be 
performed at any other time if clinically indicated. The performance of all ECGs will adhere to 
the following guidelines. Detailed instructions are provided in the Study Reference Manual: 
• The ECG will be done before any other procedures that may affect heart rate, such as blood 
draws. 
• The subject will be instructed to rest for at least 5 minutes before having an ECG. 
• The test should be performed in the supine position. 
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 last Safety Follow-up Visit will be recorded as AEs.  


Protocol VX19-814-101, Version 3.0 
Page 50 of 68 
Vertex Pharmaceuticals Incorporated 
 
To ensure safety of the subjects, a qualified individual at the study site or an approved home 
nurse at the home health visit will make comparisons of the QTcF value generated on the ECGs 
obtained at any time point after the first dose of drug administered in the treatment period to the 
pre-dose baseline QTcF value taken on Day 1 in the treatment period. If the median QTcF (of the 
safety ECGs performed in triplicate) is increased by >60 msec from the baseline (as defined in 
Section 12.3.1) or an absolute median QTcF value is ≥500 msec for any scheduled ECG 
assessment, triplicate ECGs will be repeated within 10 minutes of the initial assessment to 
confirm the original measurement. A subject with a confirmatory ECG that demonstrates a 
median QTcF (of the safety ECGs performed in triplicate) that has increased by >60 msec from 
the baseline or an absolute median QTcF value ≥500 msec will discontinue dosing. If the median 
QTcF (from the confirmatory ECGs repeated within 10 minutes of the initial assessment) falls 
below the threshold, the subject may continue dosing. If the confirmatory ECG is above the 
threshold then for safety monitoring, triplicate ECGs will be repeated at least every hour until the 
median QTcF value from 2 successive time points falls below the threshold value that triggered 
the repeat measurement. 
11.5.5 
Spirometry 
Spirometry will be performed post-bronchodilator and will be performed according to the 
American Thoracic Society (ATS) Guidelines/European Respiratory Society Guidelines.4, 5, 6 If 
spirometry cannot be performed at screening, historical post-bronchodilator ppFEV1 results 
within 1 year before screening can be used to determine eligibility. This assessment is optional at 
all other study visits. Further details will be provided in the Study Reference Manual. 
11.5.6 
Contraception and Pregnancy 
The effects of VX-814 on conception, pregnancy, and lactation in humans are not known. Refer 
to the VX-814 Investigator's Brochure for additional details. 
11.5.6.1 
Contraception 
Participation in this study requires a commitment from subjects and their partners to use methods 
of contraception outlined below, which must be used correctly with every act of sexual 
intercourse.  
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. True abstinence must 
be practiced from 28 days before Day 1 through 90 days after the last dose of study drug. 
• 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 without another reason for at least 
12 months and serum FSH levels within the laboratory’s range for postmenopausal 
females.  


Protocol VX19-814-101, Version 3.0 
Page 51 of 68 
Vertex Pharmaceuticals Incorporated 
 
• Same-sex relationships. 
For subjects for whom contraception methods are not waived for one of the reasons cited 
above, the following are highly effective contraceptive methods (Table 11-3) for male 
subjects and their female (non-study) partners and for female subjects and their male (non-
study) partners. In addition to the subject or partner using 1 method from Table 11-3, all 
male (non-study) partners and male subjects must use a condom, with spermicide (if 
available), from 28 days before Day 1 until 90 days after the last dose of study drug. 
Acceptable methods of contraception are listed in Table 11-3. 
Table 11-3 
Allowable Methods of Contraception 
Male subjects and their female 
(non-study) partners  
• Male vasectomy 6 months or more previously, with a documented 
negative post-vasectomy semen analysis for sperm 
• Female bilateral tubal ligation performed at least 6 months previously 
• Female continuous use of an intrauterine device for at least 90 days 
before the first dose of study drug, throughout study drug treatment, 
and until 90 days after the last dose of study drug. 
• Female hormonal contraceptives, if successfully used for at least 60 
days before the first dose of study drug, throughout study drug 
treatment, and until 90 days after the last dose of study drug. 
Female subjects and their male 
(non-study) partners 
• Female bilateral tubal ligation performed at least 6 months previously 
• Female continuous use of an intrauterine device (non-hormone 
releasing) for at least 90 days before the first dose of study drug, 
throughout study drug treatment, and until 90 days after the last dose 
of study drug. 
• Male vasectomy 6 months or more previously, with a documented 
negative post-vasectomy semen analysis for sperm. 
The effects of VX-814 on the PK of hormonal contraceptives are not known. Thus, hormonal contraception is 
NOT permitted as a highly effective method of contraception for female subjects. 
Important notes: 
• Male subjects must use a condom to avoid exposing a potential fetus to study drug via the 
seminal fluid. The female condom is not an acceptable method due to the increased risk of 
tearing when the female and male condoms are used at the same time. 
• 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. 
• 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 breastfeed a child from the start of study drug dosing through 
90 days following the last dose of study drug. 
• If applicable, additional contraception requirements may need to be followed according to 
local regulations and/or requirements. 


Protocol VX19-814-101, Version 3.0 
Page 52 of 68 
Vertex Pharmaceuticals Incorporated 
 
• Unique situations that may not fall within the above specifications may be discussed with the 
medical monitor on an individual basis. 
11.5.6.2 
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. 
If a subject or the female partner of a male subject becomes pregnant while participating in the 
study, study drug will be permanently discontinued immediately. The investigator will notify the 
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. 
A subject (or their partner, if relevant) who becomes pregnant while on study will be followed 
until the end of the pregnancy only if on blinded treatment, or if they have been unblinded and 
have received active drug. The infant will be followed for 1 year after birth, provided informed 
consent is obtained. A separate ICF will be provided to explain these follow-up activities. 
Pregnancy itself is not an AE.  
12 
STATISTICAL AND ANALYTICAL PLANS 
This section presents a summary of the principal features of the planned efficacy, safety, and PK 
analyses for the study. Safety and efficacy analysis details will be provided in the statistical 
analysis plan (SAP), and PK analysis details will be provided in the clinical pharmacology 
analysis plan (CPAP). Both the SAP and CPAP will be finalized before clinical data lock. 
 
 
 
Final analyses will take place after all subjects have completed the study, all data have been 
entered in the clinical study database, and the clinical data have been locked. 
12.1 
Sample Size and Power 
Approximately 43 subjects in total will be randomized to both parts of the study. In Part A1, 
subjects will be randomized to receive VX-814 400 mg q12h (n = 6), VX-814 200 mg q12h 
(n = 3), VX-814 100 mg q12h (n = 3), or placebo (n = 3). In Part A2, subjects will be 
randomized to receive VX-814 400 mg q12h (n = 6) or placebo (n = 2). In Part B, subjects will 
be randomized to receive VX-814 600 mg q12h (n = 15) or placebo (n = 5). 
Assuming approximately 10% of the randomized subjects have a missing value at Day 28, this 
sample size provides adequate precision to estimate the plasma functional AAT levels at Day 28 
for the VX-814 600 mg q12h group in Part B.  
Information regarding the sample size assessments is provided below. 


Protocol VX19-814-101, Version 3.0 
Page 53 of 68 
Vertex Pharmaceuticals Incorporated 
 
12.2 
Analysis Set 
The following analysis sets are defined: All Subjects Set, Full Analysis Set (FAS), and Safety 
Set. 
The All Subjects Set will include all subjects who were randomized or received at least 1 dose 
of study drug. This analysis set will be used for all individual subject data listings and disposition 
summary tables, unless otherwise specified. 
The FAS will include all randomized subjects who received at least 1 dose of study drug. The 
FAS will be used to summarize subject demographics and background characteristics, and for all 
efficacy analyses, unless otherwise specified. Subjects will be analyzed according to the 
treatment to which they were randomized. 
The Safety Set will include all subjects who received at least 1 dose of study drug. The Safety 
Set will be used for all safety analyses in which subjects will be analyzed according to the 
treatment they received, unless otherwise specified. 
12.3 
Statistical Analysis 
The primary objective of this study is to characterize the efficacy and safety of VX-814 in 
PiZZ subjects. This section summarizes the statistical analysis of efficacy and safety data. 
Methodological and related details (e.g., missing data) will be in the SAP. 


Protocol VX19-814-101, Version 3.0 
Page 54 of 68 
Vertex Pharmaceuticals Incorporated 
 
12.3.1 
General Considerations 
All individual subject data for subjects who were randomized or received at least 1 dose of study 
drug will be presented in individual subject data listings. Data from Parts A and B will be pooled 
for analysis, unless specified otherwise. 
Continuous variables will be summarized using the following descriptive summary 
statistics: the number of subjects (n), mean, SD, median, minimum value (min), and maximum 
value (max). 
Categorical variables will be summarized using counts and percentages. 
Baseline value, unless specified otherwise, will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of study drug. For 
ECGs, the baseline value will be defined as the average of the non-missing pretreatment 
measurements (triplicate) before the first dose of study drug. 
Change (absolute change) from baseline will be calculated as Post-baseline value – Baseline 
value. 
Relative change from baseline will be calculated and expressed in percentage as 
100% × (post-baseline value − Baseline value)/Baseline value. 
Treatment-emergent (TE) Period will include the time period starting from the date of the first 
dose of study drug to either (1) Safety Follow-up Visit 28 days after the last dose of study drug, 
(2) ETT Visit if it replaces the Safety Follow-up Visit 28 days after the last dose of study drug, 
or (3) 28 days after the last dose date for subjects who do not have a Safety Follow-up Visit 
28 days after the last dose or equivalent. The TE Period will be used for safety analyses unless 
specified otherwise. 
Incomplete/missing data will not be imputed, unless specified otherwise. 
12.3.2 
Demographics and Background Characteristics 
Subject disposition, e.g., completed treatment, prematurely discontinued the treatment and the 
reason for discontinuation, will be summarized by treatment group. 
Demographic and other baseline characteristics (e.g., plasma AAT levels and ppFEV1) will be 
summarized by treatment group. No statistical tests will be carried out to evaluate baseline 
imbalances between treatment groups.  
Medications used will be coded using the World Health Organization-Drug Dictionary 
(WHODrug) and summarized descriptively. Exposure to study drug (i.e., duration of treatment) 
and dosing compliance (i.e., percentage of days being compliant to treatment) will be 
summarized descriptively.  
Important protocol deviations will be provided in an individual subject data listing, and 
summarized, as appropriate. 
Additional details will be provided in the SAP. 


Protocol VX19-814-101, Version 3.0 
Page 55 of 68 
Vertex Pharmaceuticals Incorporated 
 
12.3.3 
Efficacy Analysis 
12.3.3.1 
Analysis of the Primary Variable 
The primary endpoint to assess efficacy is the change from baseline in plasma functional AAT 
levels at Day 28.
 
 
 
 
 
  
  
Details will be provided in the SAP. 
12.3.3.2 
Multiplicity Adjustment 
There is no multiplicity adjustment for the pairwise comparisons between different doses of 
VX-814 and placebo.  
12.3.3.3 
Missing Data Handling 
For the primary analysis of the primary endpoint, missing data will be assumed to be missing at 
random conditional on the observed data and covariate; consequently, no imputation of missing 
data will be performed. 
 
12.3.4 
Safety Analysis 
The overall safety profile of VX-814 will be assessed in terms of the following safety endpoints: 
• Incidence of treatment emergent adverse events (TEAEs) 
• Clinical laboratory values (i.e., hematology, serum chemistry, coagulation, and 
urinalysis) 
• Standard 12-lead ECG outcomes 
• Vital signs 
• Pulse oximetry 
For safety analyses, no statistical hypothesis testing will be conducted. Additional details will be 
provided in the SAP. 
12.3.5 
Interim and Independent Data Monitoring Committee Analyses 
12.3.5.1 
Interim Analysis 
Interim analyses may be performed at any time at the discretion of the sponsor for internal 
decision-making. Interim analyses will be performed and reviewed by an unblinded Vertex team 
not involved in the conduct of the study.  


Protocol VX19-814-101, Version 3.0 
Page 56 of 68 
Vertex Pharmaceuticals Incorporated 
 
12.3.5.2 
Independent Data Monitoring Committee Analysis 
Not applicable 
12.4 
Clinical Pharmacology Analysis 
12.4.1 
Pharmacokinetic Analysis 
The PK of VX-814 will be described using summary statistics. Preliminary review and analyses 
of the drug concentrations may be done before data lock under the conditions of masked 
identifications of the subject concentrations. 
Details of the analyses will be in the CPAP. 
12.4.2 
Pharmacokinetic/Pharmacodynamic Analyses 
A population PK analysis of plasma concentration versus time data of VX-814 may be 
performed using a non-linear mixed-effects modeling approach. Population PK/PD models may 
also be developed to help understand the relationship between VX-814 exposure and PD 
endpoints. A more detailed description of the methodology will be included in a separate 
population analysis plan. Results of these analyses, if conducted, will be presented in standalone, 
separate documents and will not be included in the CSR.  
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. 
13.1.1.2 
Clinically Significant Assessments 
Study assessments including clinical 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). 


Protocol VX19-814-101, Version 3.0 
Page 57 of 68 
Vertex Pharmaceuticals Incorporated 
 
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 the ICF is signed until the following times: 
• 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 Visit 28 days after the last dose: through 
the Safety Follow-up Visit 28 days after the last dose  
• For enrolled subjects who do not have a Safety Follow-up Visit 28 days after the last dose, 
through the ETT visit if that visit is ≥22 days after the last dose of study drug (see 
Section 9.1.4) or 28 days after the last dose of study drug for subjects who do not have an 
ETT visit. 
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 will be 
recorded only in the subject's source documents. The following data will be documented for each 
AE: 
• Description of the event 
• Classification of "serious" or "nonserious" 
• Date of first occurrence and date of resolution (if applicable) 
• Severity  
• Causal relationship to study drug(s)  
• Action taken  
• Outcome  
• Concomitant medication or other treatment given 


Protocol VX19-814-101, Version 3.0 
Page 58 of 68 
Vertex Pharmaceuticals Incorporated 
 
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 5.0, Cancer Therapy Evaluation Program, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed 
July 2018). AEs of CTCAE Grades 4 and 5 will be documented as “life-threatening.” The 
severity of an AE described by a term 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 event 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 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 subject's medical record). 
 


Protocol VX19-814-101, Version 3.0 
Page 59 of 68 
Vertex Pharmaceuticals Incorporated 
 
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 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 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, surgery, or physical 
therapy. "No" indicates the absence of any kind of treatment for an AE. 


Protocol VX19-814-101, Version 3.0 
Page 60 of 68 
Vertex Pharmaceuticals Incorporated 
 
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 and is suspected of being a delayed toxicity due to administration of the study 
drug) 
• Life-threatening, such that the subject was at immediate risk of death from the reaction as it 
occurred  
• Inpatient hospitalization or prolongation of hospitalization 
• Persistent or significant disability/incapacity (disability is defined as a substantial disruption 
of a person's ability to conduct normal life functions) 
• Congenital anomaly or birth defect 
• Important medical event that, based upon appropriate medical judgment, may jeopardize the 
subject or may require medical or surgical intervention to prevent 1 of the outcomes listed 
above (e.g., an allergic bronchospasm requiring intensive treatment in an emergency room or 
at home)  
If a subject has a hospitalization or procedure (e.g., surgery) for an event or condition that 
occurred before the subject signed the ICF, and the hospitalization or procedure was planned 
before the subject signed the ICF, the hospitalization or procedure will not be considered to 
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 
Reporting and Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent and assent (where applicable) through the 
last Safety Follow-up Visit, regardless of causality, will be reported by the investigator to Vertex 
GPS within 24 hours of identification. In addition, all SAEs that occur after the last Safety 
Follow-up Visit and are considered related to study drug(s) will be reported to Vertex GPS 
within 24 hours of identification.  


Protocol VX19-814-101, Version 3.0 
Page 61 of 68 
Vertex Pharmaceuticals Incorporated 
 
For SAEs that occur after obtaining informed consent and assent (where applicable) through the 
last Safety Follow-up Visit, 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: 
  
For technical issues related to submitting the form, contact telephone: 
 
SAEs that occur after the last Safety Follow-up Visit and are considered related to study drug(s) 
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 the outcome to Vertex using the SAE Form. 
13.1.2.3 
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, IECs, 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/ IEC of all 
unexpected serious adverse drug reactions involving risk to human subjects. 
13.2 
Administrative Requirements 
13.2.1 
Product Complaints 
A product complaint is defined as any verbal or written communication addressed to Vertex, or 
designee, of inquiry or dissatisfaction with the identity, strength, quality, or purity of a released 
drug product, IMP, or medical device. In addition, suspected counterfeit/falsified product is 
considered a product complaint.   
Product complaints are to be reported to Vertex.  
13.2.2 
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 be 
conducted only at sites where IRB/IEC approval has been obtained. The protocol, Investigator's 


Protocol VX19-814-101, Version 3.0 
Page 62 of 68 
Vertex Pharmaceuticals Incorporated 
 
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. 
13.2.3 
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) 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. 
13.2.4 
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., PD assessments) will require IRB/IEC notification 
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.  
13.2.5 
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.  
13.2.6 
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 will be limited to the site and the study physician and will 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. 


Protocol VX19-814-101, Version 3.0 
Page 63 of 68 
Vertex Pharmaceuticals Incorporated 
 
For sites participating in the US, and in accordance with the Health Insurance Portability and 
Accountability Act (HIPAA) and associated regulations, an executed HIPAA authorization will 
be obtained by the site from each subject (or the legal representative of the subject) before 
research activities may begin. Each HIPAA authorization will 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. 
13.2.7 
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. 
13.2.8 
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. 
13.2.9 
End of Study 
The end of study is defined as the last scheduled visit (or scheduled contact) of the last subject. 
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 subject. Study 
data for each enrolled subject will be entered into a CRF by study site personnel using a secure, 


Protocol VX19-814-101, Version 3.0 
Page 64 of 68 
Vertex Pharmaceuticals Incorporated 
 
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. 
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 which they are responsible.  
A CRF will be completed for each enrolled study subject. It is the investigator's responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the subject's 
CRF. Source documentation supporting the CRF data will indicate the subject's participation in 
the study and will document the dates and details of study procedures, AEs, other observations, 
and subject status. 
The investigator, or designated representative, will complete the CRF as soon as possible after 
information is collected.  
The audit trail entry will show the user's identification information and the date and time of any 
correction. The investigator will provide formal approval of all the information in the CRFs, 
including any changes made to them, 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 compact disc (CD) or other electronic media will be placed in the investigator's 
study file. 
13.6 
Confidentiality and Disclosure 
Any and all scientific, commercial, and technical information disclosed by Vertex in this 
protocol or elsewhere will be considered the confidential and proprietary property of Vertex. The 
investigator shall hold such information in confidence and shall not disclose the information to 
any third party except to such of the investigator's employees and staff as have been made aware 
that the information is confidential and who are bound to treat it as such and to whom disclosure 
is necessary to evaluate that information. The investigator shall not use such information for any 
purpose other than determining mutual interest in performing the study and, if the parties decide 
to proceed with the study, for the purpose of conducting the study. 


Protocol VX19-814-101, Version 3.0 
Page 65 of 68 
Vertex Pharmaceuticals Incorporated 
 
The investigator understands that the information developed from this clinical study will be used 
by Vertex in connection with the development of the study drug and other drugs and diagnostics, 
and therefore may be disclosed as required to other clinical investigators, business partners and 
associates, the FDA, and other government agencies. The investigator also understands that, to 
allow for the use of the information derived from the clinical study, the investigator has the 
obligation to provide Vertex with complete test results and all data developed in the study. 
13.7 
Publications and Clinical Study Report 
13.7.2 
Clinical Study Report  
A CSR, written in accordance with the ICH E3 Guideline, will be submitted in accordance with 
local regulations.  


Protocol VX19-814-101, Version 3.0 
Page 66 of 68 
Vertex Pharmaceuticals Incorporated 
 
14 
REFERENCES 
1 
Bergin DA, Reeves EP, Hurley K, Wolfe R, Jameel R, Fitzgerald S, et al. The circulating 
proteinase inhibitor alpha-1 antitrypsin regulates neutrophil degranulation and 
autoimmunity. Sci Transl Med. 2014;6(217):217ra1. 
2 
Geraghty P, Eden E, Pillai M, Campos M, McElvaney NG, Foronjy RF. Alpha1-
Antitrypsin activates protein phosphatase 2A to counter lung inflammatory responses. 
Am J Respir Crit Care Med. 2014;190(11):1229-42. 
3 
Piitulainen E, Tanash HA. The clinical profile of subjects included in the Swedish 
national register on individuals with severe alpha 1-antitrypsin deficiency. COPD. 
2015;12(suppl 1):36-41. 
4 
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. 
5 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26(2):319-38. 
6 
Culver BH, Graham BL, Coates AL, Wanger J, Berry CE, Clarke PK, et al. 
Recommendations for a standardized pulmonary function report. An official American 
Thoracic Society technical statement. Am J Respir Crit Care Med. 2017;196(11):1463-
72. 
7 
Anthonisen NR, Manfreda J, Warren CP, Hershfield ES, Harding GK, Nelson NA. 
Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern 
Med. 1987;106(2):196-204. 
11 
Battisti WP, Wager E, Baltzer L, Bridges D, Cairns A, Carswell CI, et al. Good 
publication practice for communicating company-sponsored medical research: GPP3. 
Ann Intern Med. 2015;163(6):461-4. 
12 
International Committee of Medical Journal Editors (ICMJE). December 2017. 
Recommendations for the conduct, reporting, editing, and publication of scholarly work 
in medical journals. Available at: http://www.icmje.org/recommendations/. Accessed 03 
August 2018. 
 


Protocol VX19-814-101, Version 3.0 
Page 67 of68 
15 
PROTOCOL SIGNATURE PAGES 
I 
15.1 
Sponsor Signatur-e Page 
, I 
Protocol#: 
VX19-814-101 I Version#: 
3.0 
I 
Date: 
21 May 2020 
Study Title: A Phase 
D,: ouble-blind, Placebo-control1'ed Study of the Efficacy 
and Safety of VX -814 m PzZZ 
, 
This clinical study protocol has beeh 
and approved by 
Vertex Pharmaceuticals Incorporated 
 


Protocol VX19-814-101, Version 3.0 
Page 68 of 68 
Vertex Pharmaceuticals Incorporated 
 
15.2 
Investigator Signature Page 
Protocol #:  
VX19-814-101 
Version #: 3.0 
Version Date: 
21 May 2020 
Study Title: A Phase 2, Randomized, Double-blind, Placebo-controlled Study of the Efficacy 
and Safety of VX-814 in PiZZ Subjects 
 
 
I have read Protocol VX19-814-101, Version 3.0, and agree to conduct the study according to its 
terms. I understand that all information concerning VX-814 and this protocol supplied to me by 
Vertex Pharmaceuticals Incorporated (Vertex) is confidential. 
 
 
Printed Name 
 
 
Signature 
 
Date 
 

SAP_001.pdf: 
Statistical Analysis Plan (Methods)  
Page 1 of 33 
Protocol Number: VX19-814-101 
 
 
Vertex Pharmaceuticals Incorporated 
 
1 
TITLE PAGE 
 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Statistical Analysis Plan 
(Methods) 
Protocol Number VX19-814-101, Version 3.0 
(Interim and Final Analysis) 
 
A Phase 2, Randomized, Double-blind, Placebo-controlled Study of 
the Efficacy and Safety of VX-814 in PiZZ Subjects  
 
Author of SAP: 
 
 
Version: 1.0 
Version Date of SAP: 11 November 2020 
 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, Massachusetts 02210-1862 
 
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 33                                
Protocol Number: VX19-814-101  
Vertex Pharmaceuticals Incorporated 
 
2 
TABLE OF CONTENTS 
1 
Title Page .............................................................................................................................. 1 
2 
Table of contents ................................................................................................................ 2 
4 
Introduction .......................................................................................................................... 5 
5 
Study Objectives ................................................................................................................. 5 
5.1 
Primary Objectives ........................................................................................................... 5 
5.2 
Secondary Objectives ....................................................................................................... 5 
 
 
6 
Study Endpoints .................................................................................................................. 6 
6.1 
Primary Endpoints ............................................................................................................ 6 
6.2 
Secondary Endpoints ........................................................................................................ 6 
 
 
7 
Study Design ........................................................................................................................ 6 
7.1 
Overall Design .................................................................................................................. 6 
7.2 
Sample Size and Power .................................................................................................. 10 
7.3 
Randomization ................................................................................................................ 11 
7.4 
Replacement ................................................................................................................... 11 
7.5 
Blinding and Unblinding ................................................................................................ 11 
8 
Analysis Sets ..................................................................................................................... 11 
8.1 
All Subjects Set .............................................................................................................. 11 
8.2 
Full Analysis Set ............................................................................................................. 11 
8.3 
Safety Set ........................................................................................................................ 11 
9 
Statistical Analysis ........................................................................................................... 12 
9.1 
General Considerations .................................................................................................. 12 
9.2 
Background Characteristics ............................................................................................ 13 
9.2.1 
Subject Disposition ................................................................................................. 13 
9.2.2 
Demographics and Baseline Characteristics ........................................................... 14 
9.2.3 
Medical History ...................................................................................................... 15 
9.2.4 
Prior and Concomitant Medications ....................................................................... 15 
9.2.5 
Study Drug Exposure and Compliance .................................................................. 16 


Statistical Analysis Plan (Methods)                                                                                                            Page 3 of 33                                
Protocol Number: VX19-814-101  
Vertex Pharmaceuticals Incorporated 
 
9.2.6 
Important Protocol Deviations ................................................................................ 16 
9.3 
Efficacy Analysis ............................................................................................................ 16 
9.3.1 
Analysis of Primary Efficacy Variable ................................................................... 16 
9.3.2 
Analysis of Secondary Efficacy Variable ............................................................... 17 
9.3.3 
Multiplicity Adjustment ......................................................................................... 17 
9.4 
Safety Analysis ............................................................................................................... 17 
9.4.1 
Adverse Events ....................................................................................................... 18 
9.4.2 
Clinical Laboratory ................................................................................................. 19 
9.4.3 
Electrocardiogram .................................................................................................. 19 
9.4.4 
Vital Signs .............................................................................................................. 20 
9.4.5 
Pulse Oximetry ....................................................................................................... 20 
9.4.6 
Spirometry .............................................................................................................. 20 
9.4.7 
Physical Examination ............................................................................................. 20 
10 Interim and IDMC Analyses ............................................................................................ 21 
10.1 Interim Analysis ............................................................................................................. 21 
10.2 Independent Data Monitoring Committee Analysis ....................................................... 21 
11 References .......................................................................................................................... 21 
12 Appendices ......................................................................................................................... 22 
 
Appendix B: Imputation Rules for Missing Prior/Concomitant Medication Dates ................. 25 
Appendix C: Imputation Rules for Missing AE dates ............................................................. 26 
 
Appendix E: Details of GLI Equations for Calculating ppFEV1 ............................................. 32 
 
 
 




Statistical Analysis Plan (Methods)                                                                                                            Page 5 of 33                                
Protocol Number: VX19-814-101  
Vertex Pharmaceuticals Incorporated 
 
4 
INTRODUCTION 
This statistical analysis plan (SAP) describes the efficacy, safety, 
 
and is based on the most recent approved 
clinical study protocol (CSP), the most recent approved electronic case report form (eCRF), and 
the most recent approved eCRF completion guidelines. SAP also documents analyses not 
specified in the protocol, which will provide supportive information for the scientific 
understanding of the drug entity. 
All analysis outputs (tables, figures, listings, and datasets) will be generated using SAS® 
Version 9.4 or higher (SAS Institute, Cary, North Carolina, USA). 
The SAP (Methods) will be finalized and approved before the clinical database lock. Any 
revisions to the approved SAP will be documented and approved in an amendment to the SAP 
prior to the clinical database lock. Any revisions made to the SAP after the clinical database lock 
will be documented in the clinical study report for this study. 
The analysis addressing the pharmacokinetic (PK) objective of the study will be described in the 
Clinical Pharmacology Analysis Plan (CPAP) which will be developed separately by the Clinical 
Pharmacology department at Vertex. 
 
 
5 
STUDY OBJECTIVES 
5.1 
Primary Objectives 
• To evaluate the efficacy of VX-814 in PiZZ subjects as measured by plasma functional AAT 
levels 
• To evaluate the safety and tolerability of VX-814 in PiZZ subjects 
5.2 
Secondary Objectives 
• To evaluate the efficacy of VX-814 in PiZZ subjects as measured by plasma antigenic AAT 
levels  
• To evaluate the pharmacokinetics (PK) of VX-814 in PiZZ subjects 


Statistical Analysis Plan (Methods)                                                                                                            Page 6 of 33                                
Protocol Number: VX19-814-101  
Vertex Pharmaceuticals Incorporated 
 
6 
STUDY ENDPOINTS 
6.1 
Primary Endpoints 
• Change from baseline in plasma functional AAT levels at Day 28 
• Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, 
standard 12-lead ECGs, vital signs, and pulse oximetry 
6.2 
Secondary Endpoints 
• Change from baseline in plasma antigenic AAT levels at Day 28 
• PK parameters of VX-814 derived from plasma concentration-time data  
7 
STUDY DESIGN 
7.1 
Overall Design 
This is a Phase 2, randomized, double-blind, placebo-controlled study of VX-814. Schematics of 
the study design are shown in Figure 7-1 and Figure 7-2. 
Part A1: Approximately 15 subjects in total with the PiZZ genotype and antigenic AAT levels 
<8 µM at screening will be randomized (2:1:1:1) to 1 of 3 VX-814 groups or the placebo group. 
Part A2: Approximately 8 subjects in total with the PiZZ genotype and antigenic AAT levels <8 
µM at screening will be randomized (3:1) to the VX-814 group or the placebo group.  


Statistical Analysis Plan (Methods)                                                                                                            Page 7 of 33                                
Protocol Number: VX19-814-101  
Vertex Pharmaceuticals Incorporated 
 
Enrollment may be adjusted to ensure approximately 12 subjects receive VX-814 400 mg q12h 
in Parts A1 and A2 combined. 
Part B: Approximately 20 subjects in total with the PiZZ genotype and antigenic AAT levels <8 
µM at screening will be randomized (3:1) to the VX-814 group or the placebo group.  
Enrollment in Parts A2 and B may be initiated before Part A1 completes the planned enrollment. 
Randomization will be stratified by ppFEV1 obtained either during the Screening Period or from 
a historical ppFEV1 value (<50% versus ≥50%). 
Screening Visit assessments for subjects who have never been on augmentation therapy are listed 
in Table 3-1 of the protocol. Screening Visit assessments for subjects who have been on 
augmentation therapy at any time are listed in Table 3-2 of the protocol. Treatment Period 
assessments for all subjects are listed in Table 3-3 of the protocol. 
Figure 7-1 
Parts A1, A2, and B: Schematic of Study Design for Subjects Who Have 
Never Been on Augmentation Therapy 
Part A1 
Part A2 
Treatment Period 
28 days  
VX-814 400 mg q12h N = 6 
VX-814 200 mg q12h N = 3 
Placebo N = 3 
Safety 
Follow-up Visits 
14 and 28 days after last 
dose 
VX-814 100 mg q12h N = 3 
VX-814 Washout Visit 
7 days after last dose 
Screening 
up to 35 days 
Treatment Period 
28 days  
VX-814 400 mg q12h N = 6 
Placebo N = 2 
Safety 
Follow-up Visits 
14 and 28 days after last 
dose
VX-814 Washout Visit 
7 days after last dose 
Screening 
up to 35 days 


Statistical Analysis Plan (Methods)                                                                                                            Page 8 of 33                                
Protocol Number: VX19-814-101  
Vertex Pharmaceuticals Incorporated 
 
Figure 7-1 
Parts A1, A2, and B: Schematic of Study Design for Subjects Who Have 
Never Been on Augmentation Therapy 
Part B 
N: number of subjects; q12h: every 12 hours 
Notes: Figure is not drawn to scale. Subject numbers include subjects who have never been on augmentation therapy 
and subjects who have been on augmentation therapy at any time. 
Antigenic AAT levels must be drawn to confirm eligibility and sent to the central laboratory; results must be 
obtained and confirmed to be <8 µM before randomization. Once antigenic AAT levels have been confirmed to 
meet this eligibility criterion, randomization and Day 1 can occur any time within the remaining screening 
window. Sites should allow at least 14 days for sample processing and antigenic AAT level result reporting. 
Figure 7-2 
Parts A1, A2, and B: Schematic of Study Design for Subjects Who Have Been on 
Augmentation Therapy at Any Time 
Part A 
 
 
Treatment Period 
28 days  
VX-814 600 mg q12h N = 15 
Placebo N = 5 
Safety 
Follow-up Visits 
14 and 28 days after last dose 
VX-814 Washout Visit 
7 days after last dose 
Screening 
up to 35 days 
Treatment Period 
28 days 
VX-814 400 mg q12h N = 6 
VX-814 200 mg q12h N = 3 
Placebo N = 3 
Safety 
Follow-up Visits 
14 and 28 days after last 
dose 
VX-814 100 mg q12h N = 3 
Discontinue 
augmentation 
therapy > 42 days 
before AAT levels 
are drawn for 
eligibility * 
Subjects may 
resume 
augmentation 
therapy 
after the last Safety 
Follow-up Visit 
VX-814 Washout 
Visit 
7 days after last 
dose 
Screening 
up to 70 days 
42 days 
Antigenic AAT 
level for 
eligibility 


Statistical Analysis Plan (Methods)                                                                                                            Page 9 of 33                                
Protocol Number: VX19-814-101  
Vertex Pharmaceuticals Incorporated 
 
Figure 7-2 
Parts A1, A2, and B: Schematic of Study Design for Subjects Who Have Been on 
Augmentation Therapy at Any Time 
Part A2 
Part B 
N: number of subjects; q12h: every 12 hours 
Notes: Figure is not drawn to scale. Subject numbers include subjects who have never been on augmentation therapy and 
subjects who have been on augmentation therapy at any time. Subjects must discontinue augmentation therapy >42 
days before antigenic AAT levels are drawn and sent to the central laboratory to confirm eligibility; results must be 
confirmed to be <8 µM before randomization. Once antigenic AAT levels have been confirmed to meet this eligibility 
criterion, randomization and Day 1 can occur any time within the remaining screening window. Sites should allow at 
least 14 days for sample processing and antigenic AAT level results reporting. Subjects can resume augmentation 
therapy after completion of assessments at the last Safety Follow-up Visit. 
*Blood samples will be obtained for antigenic and functional AAT levels at the same time that the other screening 
laboratory assessments are performed. If the subject received the last dose of augmentation therapy >42 days prior, this 
sample can be used to measure antigenic AAT level for eligibility. If samples are obtained ≤42 days after the last dose 
of augmentation therapy, another sample must be drawn >42 days after the last dose of augmentation therapy and sent 
to the central laboratory to confirm eligibility. 
Treatment Period 
28 days 
VX-814 400 mg q12h N = 6 
Placebo N = 2 
Safety 
Follow-up Visits 
14 and 28 days after last 
dose
Discontinue 
augmentation 
therapy >42 days 
before AAT levels 
are drawn for 
eligibility * 
Subjects may 
resume 
augmentation 
therapy 
after the last 
Safety Follow-up 
Visit 
VX-814 
Washout Visit 
7 days after 
last dose 
Screening 
up to 70 days 
42 days 
Antigenic AAT 
level for 
eligibility 
Treatment Period 
28 days  
VX-814 600 mg q12h N = 15 
Placebo N = 5 
Safety 
Follow-up Visits 
14 and 28 days after last 
dose 
Discontinue 
augmentation 
therapy >42 days 
before AAT levels 
are drawn for 
eligibility * 
Subjects may 
resume 
augmentation 
therapy 
after the last 
Safety Follow-up 
Visit 
VX-814 
Washout Visit 
7 days after 
last dose 
Screening 
up to 70 days 
42 days Antigenic AAT 
level for 
eligibility 


Statistical Analysis Plan (Methods)                                                                                                            Page 10 of 33                              
Protocol Number: VX19-814-101  
Vertex Pharmaceuticals Incorporated 
 
7.2 
Sample Size and Power 
Approximately 43 subjects in total will be randomized to both parts of the study. In Part A1, 
subjects will be randomized to receive VX-814 400 mg q12h (n = 6), VX-814 200 mg q12h (n = 
3), VX-814 100 mg q12h (n = 3), or placebo (n = 3). In Part A2, subjects will be randomized to 
receive VX-814 400 mg q12h (n = 6) or placebo (n = 2). In Part B, subjects will be randomized 
to receive VX-814 600 mg q12h (n = 15) or placebo (n = 5). 
Assuming approximately 10% of the randomized subjects have a missing value at Day 28, this 
sample size provides adequate precision to estimate the plasma functional AAT levels at Day 28 
for the VX-814 600 mg q12h group in Part B.  
Information regarding the sample size assessments is provided below. 


Statistical Analysis Plan (Methods)                                                                                                            Page 11 of 33                              
Protocol Number: VX19-814-101  
Vertex Pharmaceuticals Incorporated 
 
7.3 
Randomization 
Refer to Section 9.3 of the CSP for details. 
7.4 
Replacement 
Refer to Section 9.11 of the CSP for details. 
7.5 
Blinding and Unblinding 
Refer to Section 10.7 of the CSP for details.  
8 
ANALYSIS SETS 
The following analysis sets are defined: All Subjects Set, Full Analysis Set (FAS), and Safety 
Set. 
8.1 
All Subjects Set 
The All Subjects Set will include all subjects who were randomized or received at least 1 dose 
of study drug. This analysis set will be used for all individual subject data listings and disposition 
summary tables, unless otherwise specified. 
8.2 
Full Analysis Set 
The FAS will include all randomized subjects who received at least 1 dose of study drug. The 
FAS will be used to summarize subject demographics and background characteristics, and for all 
efficacy analyses, unless otherwise specified. Subjects will be analyzed according to the 
treatment to which they were randomized. 
8.3 
Safety Set 
The Safety Set will include all subjects who received at least 1 dose of study drug. The Safety 
Set will be used for all safety analyses in which subjects will be analyzed according to the 
treatment they received, unless otherwise specified. 


Statistical Analysis Plan (Methods)                                                                                                            Page 12 of 33                              
Protocol Number: VX19-814-101  
Vertex Pharmaceuticals Incorporated 
 
9 
STATISTICAL ANALYSIS 
9.1 
General Considerations 
The Schedule of Assessments is provided in Section 3 of CSP. The precision standards for 
reporting safety variables are provided in an internal Biometrics document that specifies the 
programming rules including the precision for derived variables.  
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, SD, median, minimum value (min), and maximum value 
(max). 
Categorical variables will be summarized using counts and percentages. 
Baseline value, unless specified otherwise, will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of study drug. For 
ECGs, the baseline value will be defined as the average of the non-missing pretreatment 
measurements (triplicate) collected before the first dose of study drug. For subjects who have 
ever been on augmentation therapy at any time, only functional and antigenic AAT levels 
collected >42 days after the last dose of augmentation therapy can be used to define baseline 
values. For functional and antigenic AAT levels, only the screening results obtained from the 
assay for Day 1 to Day 28 can be used to define baseline values if the Day 1 pre-dose results are 
missing. 
Change (absolute change) from baseline will be calculated as Post-baseline value – Baseline 
value. 
Relative change from baseline will be calculated and expressed in percentage as 100% × (post-
baseline value − Baseline value)/Baseline value. 
Treatment-emergent (TE) Period will include the time period starting from the date of the first 
dose of study drug to either (1) Safety Follow-up Visit 28 days after the last dose of study drug, 
(2) ETT Visit if it replaces the Safety Follow-up Visit 28 days after the last dose of study drug, 
or (3) 28 days after the last dose date for subjects who do not have a Safety Follow-up Visit 28 
days after the last dose or an equivalent ETT.  
For subjects consented to the study under CSP Versions 1.0, 1.1, and 1.2, the TE period will 
include the time period starting from the date of the first dose of study drug to either (1) Safety 
Follow-up Visit 14 days after the last dose of study drug, (2) ETT Visit if it replaces the Safety 
Follow-up Visit 14 days after the last dose of study drug, or (3) 14 days after the last dose date 


Statistical Analysis Plan (Methods)                                                                                                            Page 13 of 33                              
Protocol Number: VX19-814-101  
Vertex Pharmaceuticals Incorporated 
 
for subjects who do not have a Safety Follow-up Visit 14 days after the last dose of study drug or 
an equivalent ETT. 
Unscheduled visits: Data obtained from unscheduled visits will be included in the analysis as 
follows: 
• In scheduled visit windows per specified visit windowing rules 
• In the derivation of baseline and last on-treatment measurements 
• In the derivation of maximum and minimum values during TE period, and maximum and 
minimum change from baseline values during TE period for safety analyses 
• In individual subject data listings as appropriate 
Incomplete or missing data will not be imputed, unless specified otherwise. 
Outliers: No formal statistical analyses will be performed to detect and/or remedy the presence 
of statistical outliers, unless specified otherwise. 
Additional considerations: 
• Data collected for Parts A1, A2 and B will be pooled for analysis, unless specified otherwise. 
• An individual subject data listing will be provided for subjects’ visits impacted by COVID-
19. 
All individual subject data will be presented in individual subject data listings based on the All 
Subjects Set. 
9.2 
Background Characteristics 
9.2.1 
Subject Disposition 
Disposition summary will be provided by treatment group and overall. 
The number of subjects, based on the All Subjects Set, in the following disposition categories, 
will be summarized: 
• All Subjects Set 
• Full Analysis Set 
• Safety Set 
• Randomized 
• Randomized but not dosed 


Statistical Analysis Plan (Methods)                                                                                                            Page 14 of 33                              
Protocol Number: VX19-814-101  
Vertex Pharmaceuticals Incorporated 
 
The number and percentage of subjects, based on the FAS, in each of the following disposition 
categories, will be summarized: 
• Completed treatment 
• Discontinued treatment and the reason for discontinuation from treatment 
• Completed study 
• Discontinued study and the reason for discontinuation from study 
9.2.2 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized based on the FAS by treatment 
group and overall. 
Demographic data will include the following: 
• Age (in years) 
• Sex (female and male) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local regulations) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or Other Pacific Islander, Other, and Not Collected per Local Regulations) 
Baseline characteristics will include the following: 
• Weight (kg) 
• Height (cm) 
• BMI (kg/m2) 
• Prior Augmentation Therapy (Yes, No) 
• Smoking History (Yes, No) 
• ppFEV1 category determined during the Screening Period or from historical data (< 50%, 
≥50%) 
• ppFEV1 obtained during the Screening Period or from historical data (%) 
• FEV1 obtained during the Screening Period or from historical data (L) 
• FVC obtained during the Screening Period or from historical data (L) 
• Ratio of FEV1 and FVC obtained during the Screening Period or from historical data (%) 
• Functional AAT level (µM) 


Statistical Analysis Plan (Methods)                                                                                                            Page 15 of 33                              
Protocol Number: VX19-814-101  
Vertex Pharmaceuticals Incorporated 
 
• Antigenic AAT level (µM) 
9.2.3 
Medical History  
Medical history will be coded by using the Medical Dictionary for Regulatory Activities 
(MedDRA). Medical history will be summarized descriptively based on the FAS by MedDRA 
system organ class (SOC) and preferred term (PT). This summary will be provided by treatment 
group and overall. 
9.2.4 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization-Drug Dictionary (WHODrug) 
and categorized as the following for the purpose of analysis: 
Prior medication: Medication that started before the first dose of study drug 
Concomitant medication: Medication continued or newly received during the TE Period 
Post-treatment medication: Medication continued or newly received after the TE period 
A given medication may be classified as a prior medication, a concomitant medication or both a 
prior and a concomitant medication.  
If a medication start date is on or after the first dose date of study drug, then the medication will 
be classified as concomitant medication regardless of whether the medication end date is missing 
or not. If a medication end date is before the first dose date of study drug, then the medication 
will be classified as prior medication regardless of whether the medication start date is missing 
or not. Note that medication that started before the first dose of study drug and continued after 
the first dose will be classified as prior medication and separately as concomitant medication. 
If a medication has a missing or partially missing start/end date and it cannot be determined 
whether it was taken before the first dose of study drug, or concomitantly, it will be classified as 
prior and concomitant medication. 
Missing or partial dates will be imputed for medication. Details for imputing missing or partial 
start and/or stop dates of medication are described in Appendix B. 
Prior medications will not be summarized but will only be listed. Concomitant medications will 
be summarized based on the FAS by PT. This summary will be provided by treatment group and 
overall of VX-814 treatment groups. Bronchodilator will also be listed. 
Prior and concomitant non-drug therapy will be listed. 


Statistical Analysis Plan (Methods)                                                                                                            Page 16 of 33                              
Protocol Number: VX19-814-101  
Vertex Pharmaceuticals Incorporated 
 
9.2.5 
Study Drug Exposure and Compliance  
Study drug exposure (in days) will be calculated as (last date of dosing – first date of dosing) + 1, 
regardless of study drug interruption, and will be summarized descriptively based on the Safety 
Set by treatment group and overall. It will also be summarized in categories: ≤ 7 days, > 7 to ≤ 
14 days, > 14 to ≤ 21 days, > 21 to ≤ 28 days, and > 28 days, using counts and percentages. 
Study drug compliance will be calculated as 100 × [1 - (total number of days of study drug 
interruption) / (duration of study drug exposure in days)]. A study drug interruption on a given 
day is defined as any interruption of the study drug on that day. A study drug interruption that 
continues through the end of study participation (i.e., subject does not resume study drug before 
the end of study participation) will not be included in the compliance calculation. Study drug 
compliance will be summarized descriptively based on the FAS by treatment group and overall. 
It will also be summarized in categories: <80% and ≥80%, using counts and percentages. 
9.2.6 
Important Protocol Deviations 
An important protocol deviation (IPD) is a deviation that may significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a subject’s 
rights, safety, or well-being. IPD rules will be developed and finalized before the clinical 
database lock. IPDs will be identified by the PD review team according to the protocol deviation 
plan.  
IPDs will be summarized descriptively based on the FAS by treatment group and overall. 
9.3 
Efficacy Analysis 
All efficacy analyses described in this section will be based on the FAS, unless otherwise 
specified. Subjects will be analyzed according to the treatment to which they were randomized. 
9.3.1 
Analysis of Primary Efficacy Variable 
The primary efficacy variable is the change from baseline in plasma functional AAT levels at 
Day 28. 
The observed values and change from baseline of functional AAT levels will be summarized 
descriptively by treatment group at each visit. The treatment differences of VX-814 400 mg q12h 
versus placebo and VX-814 600 mg q12h versus placebo in change from baseline of functional 


Statistical Analysis Plan (Methods)                                                                                                            Page 17 of 33                              
Protocol Number: VX19-814-101  
Vertex Pharmaceuticals Incorporated 
 
AAT levels at Day 28 will be provided. If the sample size allows, the 2-sided P values and 95% 
confidence intervals of the treatment differences will also be provided based on the two-sample t 
test. 
 
9.3.2 
Analysis of Secondary Efficacy Variable 
The secondary efficacy variable is the change from baseline in plasma antigenic AAT levels at 
Day 28. 
The observed values and change from baseline of antigenic AAT levels will be summarized 
descriptively by treatment group at each visit. The treatment differences of VX-814 400 mg q12h 
versus placebo and VX-814 600 mg q12h versus placebo in change from baseline of antigenic 
AAT levels at Day 28 will be provided. If the sample size allows, the 2-sided P values and 95% 
confidence intervals of the treatment differences will also be provided based on the two-sample t 
test. 
 
9.3.3 
 Multiplicity Adjustment 
There is no multiplicity adjustment for the pairwise comparisons between different doses of VX-
814 and placebo. 
9.4 
Safety Analysis 
Safety is one of the primary objectives of this study. All safety analyses will be performed based 
on the Safety Set. Subjects will be analyzed according to the treatment they actually received in 
the treatment period. For subjects receiving more than one dose level, the treatment allocation 
will be the highest dose level. 
The overall safety profile of VX-814 will be assessed in terms of the following safety endpoints: 
• Incidence of treatment emergent adverse events (TEAEs) 
• Clinical laboratory values (i.e., hematology, serum chemistry, coagulation, and urinalysis) 
• Standard 12-lead ECG outcomes 
• Vital signs 


Statistical Analysis Plan (Methods)                                                                                                            Page 18 of 33                              
Protocol Number: VX19-814-101  
Vertex Pharmaceuticals Incorporated 
 
• Pulse oximetry 
Only descriptive analyses of safety will be performed and no statistical hypothesis testing will be 
performed. 
9.4.1 
Adverse Events 
AEs will be coded using MedDRA. The number and percentage of subjects experiencing an AE 
will be summarized by the MedDRA SOC and PT. AEs will be classified as pretreatment or 
treatment-emergent as follows: 
Pretreatment AEs: AEs that occurred before the first dose of study drug 
Treatment-emergent AEs: AEs that worsened or started on or after the first dose date of study 
drug through the end of the TE Period 
Post-treatment AE: AE that worsened or that was newly developed after the TE period 
For AEs with completely missing or partial start dates, if there is no clear evidence that the AEs 
started before or after the first dose of study drug, the AEs will be classified as TEAEs. 
Imputation rules for missing or partial AE start dates are defined as Appendix C. 
AE summary tables will be presented only for TEAEs by treatment group and overall of VX-814 
treatment groups, and will include the following: 
• Overview of TEAEs 
• All TEAEs 
• TEAEs by strongest relationship 
• TEAEs by maximum severity 
• TEAEs leading to death 
• Serious TEAEs 
• Related TEAEs 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption 
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 strongest relationship level in 
the relationship summaries.  


Statistical Analysis Plan (Methods)                                                                                                            Page 19 of 33                              
Protocol Number: VX19-814-101  
Vertex Pharmaceuticals Incorporated 
 
In addition, a listing containing individual subject level AE data for all deaths, SAEs, treatment 
discontinuations, and treatment interruptions will be provided separately. 
9.4.2 
Clinical Laboratory  
All statistical analyses of laboratory values will be performed using SI units. For treatment-
emergent laboratory measurements, the observed values and change from baseline values of the 
continuous hematology, chemistry, and coagulation results will be summarized by treatment 
group at each visit. 
The number and percentage of subjects with chemistry, hematology and coagulation values 
meeting threshold analysis criteria during the TE period will be summarized by treatment group. 
The threshold analysis criterion shift from baseline will also be summarized descriptively. 
 
 
In addition, listings containing individual subject hematology, chemistry, and coagulation values 
outside the reference ranges during the TE Period(s) will be provided. These listings will include 
data from scheduled and unscheduled visits. 
Results of urinalysis and the serum pregnancy test will be listed in individual subject data listings 
only. 
9.4.3 
Electrocardiogram 
For the treatment-emergent ECG measurements, a summary of observed values and change from 
baseline values will be provided by treatment group at each visit and time point, as applicable, 
for the following ECG measurements: RR interval (msec), PR interval (msec), QT interval 
(msec), QTcF interval (msec), QRS duration (msec), and heart rate (beats per minute).  
The number and percentage of subjects meeting threshold analysis criteria during the TE Period 
will be summarized by treatment group. 
 
  


Statistical Analysis Plan (Methods)                                                                                                            Page 20 of 33                              
Protocol Number: VX19-814-101  
Vertex Pharmaceuticals Incorporated 
 
Since ECGs are performed in triplicate, the mean of the ECGs will be used as the ECG value for 
summaries of observed values and change from baseline values, and all reported ECGs will be 
used to conduct threshold analyses. 
9.4.4 
Vital Signs 
For the treatment-emergent vital signs measurements, the observed values and change from 
baseline values will be summarized by treatment group at each visit. The following vital signs 
parameters will be summarized: systolic and diastolic blood pressure (mm Hg), pulse rate (beats 
per minute), body temperature (°C), and respiratory rate (breaths per minute).  
The number and percentage of subjects meeting threshold analysis criteria during the TE Period 
will be summarized by treatment group. 
 
 
9.4.5 
Pulse Oximetry 
For the treatment-emergent pulse oximetry measurements of the percentage of oxygen saturation, 
the observed values and change from baseline values will be summarized by treatment group at 
each visit. 
9.4.6 
 Spirometry 
Spirometry results, including FVC (L), FEV1 (L), and percent predicted FEV1 (ppFEV1, %), will 
be presented in an individual subject data listing only. The guideline for calculating ppFEV1 is 
provided in Appendix E. 
9.4.7 
Physical Examination 
Physical examination (PE) results will be presented in an individual subject data listing only. 


Statistical Analysis Plan (Methods)                                                                                                            Page 21 of 33                              
Protocol Number: VX19-814-101  
Vertex Pharmaceuticals Incorporated 
 
10 
INTERIM AND IDMC ANALYSES 
10.1 
Interim Analysis 
Interim analyses (IA) may be performed at any time at the discretion of the sponsor for internal 
decision-making. Interim analyses will be performed and reviewed by an unblinded Vertex team 
not involved in the conduct of the study.  
10.2 
 Independent Data Monitoring Committee Analysis 
Not applicable. 
11 
REFERENCES 
Not applicable. 
 
 








Statistical Analysis Plan (Methods)                                                                                                            Page 25 of 33                              
Protocol Number: VX19-814-101  
Vertex Pharmaceuticals Incorporated 
 
Appendix B: Imputation Rules for Missing Prior/Concomitant Medication Dates 
Missing or partial dates will be imputed for medication. Algorithm for missing or partial start 
date is: 
a. If day is missing, use the first day of the month; 
b. If month is missing, use January (1 January if day is also missing);  
c. If year is missing, no imputation is conducted. 
 Algorithm for missing or partial end date is: 
a. If day is missing, use the last day of the month;  
b. If month is missing, use December (31 December if day is also missing);  
c. If year is missing, no imputation is conducted. 
Missing data algorithms will be reviewed to ensure the algorithms work. For example, end date 
will not be before the start date after the imputation.  
In summary, the prior, concomitant, or post categorization of a medication is described below. 
Table 12-2 
Prior and Concomitant Categorization of a Medication 
Medication Start Date 
Medication Stop Date 
< First Dose Date of 
Study Drug 
≥ First Dose Date and ≤ 
End Date of TE Period 
> End Date of TE Period 
< First dose date of 
study drug 
P 
PC 
PCA 
 
 
 
 
≥ First dose date and ≤ 
End date of TE 
Period 
- 
C 
CA 
 
 
 
 
> End date of TE period 
- 
- 
A 
 C: Concomitant; P: Prior; A: Post 
 
Imputation rules for missing and/or partial dates of non-pharmacological treatment/procedure 
will follow the same imputation rule. 
 
 


Statistical Analysis Plan (Methods)                                                                                                            Page 26 of 33                              
Protocol Number: VX19-814-101  
Vertex Pharmaceuticals Incorporated 
 
Appendix C: Imputation Rules for Missing AE dates  
Imputation rules for missing or partial AE start date are defined below. If the imputed AE start 
date is before the study informed consent date, the AE start date will be imputed using the study 
informed consent date. 
• If only Day of AE start date is missing:  
o 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. 
o 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 or TEAE. 
• If Day and Month of AE start date are missing: 
o 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. 
o 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 or TEAE. 
• 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. 
Missing or partially missing AE end date will not be imputed. 
 
 












Statistical Analysis Plan (Methods)                                                                                                            Page 32 of 33                              
Protocol Number: VX19-814-101  
Vertex Pharmaceuticals Incorporated 
 
Appendix E: Details of GLI Equations for Calculating ppFEV1 
Percent predicted value will be calculated for parameters of FEV1, using the Quanjer GLI-2012 
Regression Equations and Lookup Tables. 
The regression equations and lookup tables required to implement the Quanjer GLI-2012 
predicted values are available in: 
Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, Janet Stocks. Quanjer GLI-2012 Regression 
Equation and Lookup Tables (Version 7 April 2013). Global Lung Function Initiative. [online] 
Available at: https://www.ers-education.org/guidelines/global-lung-function-
initiative/spirometry-tools/it-engineers-and-manufacturers.aspx [Accessed 16 August 2020]. 
The instructions and tools on how to implement the Quanjer GLI-2012 equations are:   
Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, Janet Stocks. Implementing GLI-2012 
regression equations (Version 19 July 2015). Global Lung Function Initiative. [online] Available 
at: https://www.ers-education.org/guidelines/global-lung-function-initiative/spirometry-tools/it-
engineers-and-manufacturers.aspx [Accessed 16 August 2018]. 
Sanja Stanojevic. GLI-2012 - SAS Macro (Version 2, 7 April 2013). Global Lung Function 
Initiative. [online] Available at: https://www.ers-education.org/guidelines/global-lung-function-
initiative/spirometry-tools/sas-macro/ [Accessed 16 August 2020]. 
Data handling rules for the ppFEV1 calculation are as follows:  
• Input age with at least 2 decimal places 
• For historical spirometry, use the height at the time of FEV1 measurement to calculate 
ppFEV1; for spirometry performed on or after informed consent, use height at screening 
for calculation. 
• For race, map the CRF reported Black or African American to Black, all other races in 
CRF (except White) are mapped to other, multiple checks for race in CRF are also 
mapped to other; white is a reference race in the equations and assumes 0 values for all 
race coefficients in the GLI equations.