Conditions: Alpha1-Antitrypsin Deficiency
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 44
Healthy volunteers: no

Brief summary:
This study will evaluate the efficacy, safety and pharmacokinetics (PK) of VX-864 in PiZZ subjects.

Detailed description:

Arms:
arm 1: Participants received placebo matched to VX-864 in the treatment period for 28 days. arm 2: Participants received VX-864 100 milligrams (mg) every 12 hours (q12h) in the treatment period for 28 days. arm 3: Participants received VX-864 300 mg q12h in the treatment period for 28 days. arm 4: Participants received VX-864 500 mg q12h in the treatment period for 28 days.

Interventions: intervention 1: VX-864 intervention 2: Placebo
Intervention descriptions: intervention 1: Tablets for oral administration. intervention 2: Placebo matched to VX-864 for oral administration.

Protocol document:
Prot_000.pdf: 
P a ge 1  of 6 4  
1  
 TI T L E P A G E  
 
 
V E R T E X P H A R M A C E U TI C A L S IN C O R P O R A T E D  
Cli ni c al St u d y Pr ot o c ol  
A P h a s e 2, R a n d o mi z e d, D o u bl e -bli n d, Pl a c e b o -
c o ntr oll e d St u d y of t h e Effi c a c y a n d S af et y of V X -8 6 4 
i n Pi Z Z  S u bj e ct s  
V ert e x St u d y N u m b er: V X 1 9 -8 6 4 -1 0 1  
  
 
E u dr a C T N u m b er: 2 0 1 9 -0 0 4 8 8 1 -1 6  
D ate of Pr ot oc ol:  1 2  J a n uar y 2 0 2 1 ( Versi o n 2. 0)  
Verte x P har mace uticals I nc or p orat e d  
5 0 N ort her n A ve n ue  
B ost o n, M A 0 2 2 1 0 -1 8 6 2, U S A  
 
 
 
 
 
 
C O N FI D E N TI A L  
T hi s d o c u m e nt c o nt ai n s c o nfi d e nti al i nf or m ati o n. A n y u s e, di stri b uti o n, or di s cl o s ur e wit h o ut t h e pri or writt e n c o n s e nt 
of V ert e x P h ar m a c e uti c al s I n c or p or at e d i s stri ctl y pr o hi bit e d e x c e pt t o t h e e xt e nt r e q uir e d u n d er a p pli c a bl e l a w s or 
r e g ul ati o n s. P er s o n s t o w h o m t h e i nf or m ati o n i s di s cl o s e d m u st b e i nf or m e d t h at t h e i nf or m ati o n i s c o nfi d e nti al a n d 
m a y n ot b e f urt h er di s cl o s e d b y t h e m.  




Pr ot oc ol V X 1 9 -8 6 4 -1 0 1 , Versi o n  2 . 0 
P a ge  3  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
2  
P R O T O C O L S Y N O P SI S  
Title  A P hase 2, Ra n d o mize d, D o u ble -bli n d, Place b o -c o ntr olle d St u d y of t he Efficac y 
a n d Safet y of V X -8 6 4 i n Pi Z Z  S u bj ects  
  
Brief Title  E val uati o n of t he Efficac y a n d Safet y of V X -8 6 4 i n S u bj ects Wit h t he Pi Z Z 
Ge n ot y pe  
  
Cli nic al P h ase a n d 
Cli nic al St u d y T y pe  
P hase  2; efficac y a n d safet y  
  
O bjecti ves  Pri mar y O bj ecti ves  
•  
T o e val uate t he efficac y of V X -8 6 4 i n Pi Z Z  s u bj ects as me as ure d b y plas ma 
f u ncti o nal al p ha -1 a ntitr y psi n  ( A A T) le vels 
•  
T o e val uate t he safet y a n d t olera bilit y of V X -8 6 4 i n Pi Z Z  s u bj ects 
Sec o n dar y O bj ecti ves  
•  
T o e val uate t he efficac y of V X -8 6 4 i n Pi Z Z  s u bj ects as me as ure d b y plas ma 
a nti ge nic A A T le ve ls  
•  
T o e val uate t he p har mac o ki netics ( P K) of V X -8 6 4 i n Pi Z Z  s u bj ects 
E n d p oi nts  Pri mar y E n d p oi nts  
•  
C ha n ge fr o m baseli ne i n plas ma f u ncti o nal A A T le vels at Da y 2 8  
•  
Safet y a n d t olera bilit y assess me nts base d o n a d verse e ve nts ( A Es), cli nical 
la b orat or y val ues, sta n dar d 1 2-lea d E C Gs, vital si g ns, a n d p ulse o xi metr y  
Sec o n dar y E n d p oi nts  
•  
C ha n ge fr o m baseli ne i n plas ma a nti ge nic A A T le vels at D a y 2 8  
•  
P K para meters of V X -8 6 4 deri ve d fr o m plas ma c o nce ntrati o n -ti me data  
  
N u m ber of S u bjects  A p pr o xi matel y 4 0 s u bj ects wit h t he Pi Z Z  ge n ot y pe  
  
St u d y P o p ul ati o n  Male a n d fe male s u bj ects 1 8 t hr o u g h 8 0  years of a ge, i ncl usi ve, wit h t he Pi Z Z  
ge n ot y pe  


Pr ot oc ol V X 1 9 -8 6 4 -1 0 1 , Versi o n  2 . 0 
P a ge  4  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
  
I n vesti g ati o n al Dr u g  Acti ve s u bsta nce: V X -8 6 4  
 Acti vit y: A A T m o d ulat or  
 Stre n gt h a n d r o ute of a d mi nistrati o n: 1 0 0 -m g a n d 2 5 0 -m g ta blets a n d matc hi n g 
place b o f or oral a d mi nistrati o n.  
  
St u d y D ur ati o n  E xcl u di n g t he Scree ni n g P eri o d, eac h s u bj ect will partici pate i n t he st u d y f or 
a p pr o xi matel y 5 6  da ys: 2 8  da ys f or t he Treat me nt P eri o d a n d 2 8  da ys f or t he 
Safet y F oll o w -u p P eri o d.  
  
St u d y Desi g n  T his is a P hase 2, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d st u d y of V X -8 6 4. 
Sc he matics of t he st u d y desi g n are s h o w n bel o w .  
A p pr o xi matel y 4 0 s u bj ects i n t otal wit h t he Pi Z Z  ge n ot y pe a n d a nti ge nic A A T 
le vels < 8 µ M at scree ni n g will be ra n d o mize d ( 2: 1: 1: 1) t o 1 of 3 V X-8 6 4 gr o u ps 
or place b o.  
Of t hese, a p pr o xi matel y 2 0 s u bj ects will be ra n d o mize d 2: 2: 1 t o V X -8 6 4 5 0 0 m g 
e ver y 1 2  h o urs ( q 1 2 h), V X -8 6 4 3 0 0 m g q 1 2 h, or place b o first. T he re mai ni n g 
s u bj ects (a p pr o xi matel y 2 0) will be ra n d o mize d 2: 2: 1 t o V X-8 6 4 5 0 0  m g q 1 2 h, 
V X -8 6 4 1 0 0 m g q 1 2 h, or place b o.  
Ra n d o mizati o n will be stratifi e d b y p ost -br o nc h o dilat or perce nt pre dicte d f orce d  
e x pirat or y v ol u me i n 1  sec o n d ( p p F E V 1) o btai ne d eit her d uri n g t he Scree ni n g 
P eri o d or fr o m a hist orical p ost -br o nc h o dilat or  p p F E V 1 val ue meas ure d wit hi n 
1  year bef ore scree ni n g  ( < 5 0 % vers us ≥5 0 %).  
Fi g ure  2 -1   
Sc he m atics of St u d y Desi g n f or S u bjects W h o H a ve Ne ver 
Bee n o n A u g me nt ati o n T her a p y  
 
A A T:  al p ha-1 a ntitr y psi n; N: n u m ber of s u bjects; q 1 2 h: e ver y 1 2 h o urs  
N otes: Fi g ure is n ot dra w n t o scale. S u bject n u m bers i ncl u de s u bjects w h o ha ve ne ver bee n 
o n a u g me ntati o n t hera p y a n d s u bjects w h o ha ve bee n o n a u g me ntati o n t h era p y at a n y 
ti me. A nti ge nic A A T le vels m ust be dra w n t o c o nfir m eli gi bilit y a n d se nt t o t he ce ntral 
la b orat or y; res ults m ust b e o btai ne d a n d c o nfir me d t o be < 8 µ M bef ore ra n d o mizati o n. 
O nce a nti ge nic A A T le vels ha ve bee n c o nfir me d t o meet t his eli gi bilit y criteri o n, 
ra n d o mizati o n a n d Da y 1 ca n occ ur a n y ti me wit hi n t he re mai ni n g scree ni n g wi n d o w. 
Sites s h o ul d all o w at le ast 1 4 d a ys f or s a m ple pr ocessi n g a n d a nti g e nic A A T le vel 
res ult r e p orti n g. 
Tr e at m e nt P eri o d  
2 8 d a y s  
V X -8 6 4 5 0 0 m g q 1 2 h N = 1 6  
 
 
S cr e e ni n g  
u p t o 3 5 d a y s  
V X -8 6 4 3 0 0 m g q 1 2 h N = 8  
V X -8 6 4 1 0 0 m g q 1 2 h N = 8  
Pl a c e b o N = 8  
V X -8 6 4 W a s h o ut Vi sit  
7 d a y s aft er l a st  d o s e  
S af et y F oll o w -
u p Vi sit s  
1 4 a n d 2 8 d a y s 
aft er l a st d o s e  


Pr ot oc ol V X 1 9 -8 6 4 -1 0 1 , Versi o n  2 . 0 
P a ge  5  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
Fi g ure  2 -2   
Sc he m atics of St u d y Desi g n f or S u bjects W h o H a ve Bee n o n 
A u g me nt ati o n T her a p y at A n y Ti me  
 
A A T:  al p ha-1 a ntitr y psi n; N: n u m ber of s u bjects; q 1 2 h: e ver y 1 2 h o urs  
N otes: Fi g ure is n ot dra w n t o scale. S u bject n u m bers i ncl u de s u bjects w h o ha ve ne ver bee n 
o n a u g me ntati o n t hera p y a n d s u bjects w h o ha ve bee n o n a u g me ntati o n t h era p y at a n y 
ti me. S u bjects m ust disc o nti n ue a u g me ntati o n t hera p y > 4 2  d a ys  bef ore a nti ge nic A A T 
le vels are dra w n a n d se nt t o t he c e ntr al l a b or at or y t o c o nfir m eli gi bilit y; res ults m ust 
be c o nfir me d t o be < 8  µ M bef ore ra n d o mizati o n. O nce a nti ge nic A A T le vels h a ve bee n 
c o nfir me d t o meet t his eli gi bilit y criteri o n, ra n d o mizati o n a n d Da y 1 ca n occ ur a n y t i me 
wit hi n t h e re mai ni n g scree ni n g wi n d o w. Sites s h o ul d all o w at le ast 1 4 d a ys f or s a m pl e 
pr ocessi n g a n d a nti g e nic A A T le vel res ult re p orti n g. S u bjects ca n res u me 
a u g me ntati o n t hera p y after c o m pleti o n of assess me nts at t h e last Safet y F oll o w -u p Visit.   
* Bl o o d sa m ples will be o btai ne d f or a nti ge nic a n d f u ncti o nal A A T le vels at t h e sa me ti me 
t h at t h e ot her scree ni n g la b orat or y assess me nts are perf or me d. If t h e s u bject recei ve d t he 
last d ose of a u g me ntati o n t h era p y > 4 2 da ys pri or, t his sa m ple ca n be use d t o meas ure 
a nti ge nic A A T le vel f or eli gi bilit y. If sa m ples ar e o btai ne d ≤4 2 da ys after t he last d ose of 
a u g me ntati o n t hera p y, a n ot h er sa m ple m ust  be dra w n > 4 2 da ys aft er t h e last d ose of 
a u g me ntati o n t hera p y a n d se nt t o t h e ce ntral la b orat or y t o c o nfir m eli g i bilit y.  
  
Assess me nts  Efficac y:  
Plas ma f u ncti o nal a n d a nti ge nic A A T le vels  
Safet y:  
A Es, cli nical la b orat or y assess me nts, sta n dar d 1 2 -lea d E C Gs, cli nical e val uati o n 
of vital si g ns, p ulse o xi metr y, s pir o metr y, a n d p h ysical e xa mi nati o ns  
P har mac o ki netics : 
Plas ma c o nce ntrati o ns of V X -8 6 4  
Tr e at m e nt P eri o d  
2 8 d a y s  
V X -8 6 4 5 0 0 m g q 1 2 h N = 1 6  
 
 
S cr e e ni n g  
u p t o 7 0 d a y s  
V X -8 6 4 3 0 0 m g q 1 2 h N = 8  
V X -8 6 4 1 0 0 m g q 1 2 h N = 8  
Pl a c e b o N = 8  
S af et y F oll o w -
u p Vi sit s  
1 4 a n d 2 8 d a y s 
aft er l a st d o s e  
Di s c o nti n u e 
a u g m e nt ati o n t h er a p y 
> 4 2  d a y s b ef or e A A T 
l e v el s ar e dr a w n f or 
eli gi bilit y * 
S u bj e ct s m a y 
r e s u m e 
a u g m e nt ati o n 
t h er a p y aft er 
t h e l a st S af et y 
F oll o w -u p Vi sit  
V X -8 6 4 
W a s h o ut Vi sit  
7 d a y s aft er l a st  
d o s e  
A nti g e ni c A A T 
l e v el f or 
eli gi bilit y  
4 2 d a y s  


Pr ot oc ol V X 1 9 -8 6 4 -1 0 1 , Versi o n  2 . 0 
P a ge  6  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
St atistic al A n al yses  S u bj ects will be ra n d o mize d 2: 1: 1: 1 t o recei ve V X -8 6 4 5 0 0 m g q 1 2 h ( n  = 1 6), 
V X -8 6 4 3 0 0 m g q 1 2 h ( n = 8), V X -8 6 4 1 0 0 m g q 1 2 h ( n = 8), or place b o ( n  =  8).  
Ass u mi n g 1 0 % of t he ra n d o mi ze d s u bj ects will ha ve a missi n g val ue at Da y 2 8, 
t his sa m ple size pr o vi des a de q uate precisi o n t o esti mate t he a bs ol ute plas ma 
f u ncti o nal A A T le vels at Day  2 8 f or t he V X -8 6 4 5 0 0 m g q 1 2 h gr o u p.  
T he pri mar y e n d p oi nt t o assess efficac y is t he c ha n ge fr o m b aseli ne i n plas ma 
f u ncti o nal A A T le vels at Da y 2 8. T his pri mar y a nal ysis will be base d o n a mi xe d-
effects m o del f or re peate d me as ures wit h c ha n ge fr o m basel i ne at Da ys 7,  1 4,  a n d 
2 8 as t he de pe n de nt varia ble. T he m o del will i ncl u de treat me nt gr o u p, visit, a n d 
treat me nt-b y -visit i nteracti o n as fi xe d effects. 
 
  


Pr ot oc ol V X 1 9 -8 6 4 -1 0 1 , Versi o n  2 . 0 
P a ge  7  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
3  
S C H E D U L E O F A S S E S S M E N T S  
Sc he d ules o f assess me nts are i n Ta bl e  3 -1  ( Scree ni n g f or s u bjects w h o ha v e ne ver bee n o n 
a u g m e ntati o n t hera p y), T a ble  3 -2  ( Scree ni n g f or s u bjects w h o ha ve b ee n o n a u g m e ntati o n 
t hera p y at a n y ti me), a n d Ta ble  3 -3  ( Treat me nt Peri o d t hr o u g h Safet y F oll o w-u p).  
T a ble  3 -1   
St u d y V X 1 9 ‑ 8 6 4 - 1 0 1: Scree ni n g f or S u bjects W h o H a ve Ne ver Bee n o n 
A u g me nt ati o n T her a p y  
E ve nt/ Assess me nt  
Scree ni n g Peri o d  
D a y  -3 5 t hr o u g h D a y  -1   
C o m me nts  
I nf or me d c o nse nt  
X  
Secti o n  1 3. 2. 3  
I ncl usi o n a n d e xcl usi o n criteria re vie w 
X  
Secti o ns  8. 1  a n d 8. 2  
Cli nic visit  
X  
 
De m o gra p hics  
X  
 
M e dical hist or y 
X  
Secti o n  1 1. 1  
Me dicati o ns re vie w  
X  
Secti o n  9. 6  
Pri or a u g me ntati o n t hera p y re vie w  
X  
Secti o n  9. 6   
A nti ge nic A A T le vel  
X  
A nti ge nic A A T le vels m ust b e dra w n a n d 
c o nfir me d t o be < 8 µ M t o esta blis h 
eli gi bilit y bef ore ra n d o mizati o n ca n occ ur. 
Sites s h o ul d all o w at le ast 1 4  d a ys f or 
s a m ple processi n g a n d a nti g e ni c A A T 
le vel res ult re p orti n g. Secti o n 8. 1 , 
i n cl usi o n criteri o n # 7 a n d Secti o n 1 1. 3   
F u ncti o nal A A T le vel  
X  
Sa m ples will be o btai ne d f or plas ma 
f u ncti o nal A A T le vels at t h e sa me ti me 
sa m ples are o btai ne d f or a nti ge nic A A T 
le vels. F u ncti o nal A A T le vel res ults will 
n ot be pr o vi d e d t o site pers o n nel. 
Secti o n  1 1. 3  
Sta n dar d 1 2 -lea d E C G 
X  
Will be perf or me d i n tri plicate after t he 
s u bject has reste d f or at least 5 mi n utes. 
W he n E C Gs, vital si g ns, a n d bl o o d dra ws 
are d o ne o n t h e sa me da y, t h e y s h o ul d be 
perf or me d i n sai d or der. Secti o n  1 1. 5. 4  
Hei g ht a n d wei g ht  
X  
Wei g ht a n d hei g ht will be meas ure d wit h 
s h oes off.  
Vital si g ns  
X  
Vital si g ns will be perf or me d after t h e 
s u bject has reste d f or at least 5 mi n utes. 
Secti o n 1 1. 5. 3  
P ulse o xi metr y  
X  
P ulse o xi metr y will be perf or me d after t he 
s u bject has reste d f or at least 5 mi n utes. 
Secti o n 1 1. 5. 3  
C o m plete p h ysic al e xa mi n ati o n  
X  
Secti o n 1 1. 5. 3   
Ser u m F S H ( p ost me n o pa usal fe male 
s u bjects o nl y) 
X  
Secti o n  1 1. 5. 2   
Ser u m β -h C G (all fe male s u bjects)  
X  
Secti o n  1 1. 5. 2  
Ser ol o g y ( H Bs A g, H C V A b a n d R N A, 
HI V -1 a n d HI V -2 A bs)  
X  
Secti o n  1 1. 5. 2  
Pi Z Z  ge n ot y pe  
X  
Pi Z Z  ge n ot y pe m ust b e perf or me d at t he 
ce ntral la b orat or y. Secti o n  8. 1 , i ncl usi o n 
criteri o n # 6 
Ser u m c he mistr y  
X  
Secti o n  1 1. 5. 2  
He mat ol o g y  
X  
Secti o n  1 1. 5. 2  


Pr ot oc ol V X 1 9 -8 6 4 -1 0 1 , Versi o n  2 . 0 
P a ge  8  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
T a ble  3 -1   
St u d y V X 1 9 ‑ 8 6 4 - 1 0 1: Scree ni n g f or S u bjects W h o H a ve Ne ver Bee n o n 
A u g me nt ati o n T her a p y  
E ve nt/ Assess me nt  
Scree ni n g Peri o d  
D a y  -3 5 t hr o u g h D a y  -1   
C o m me nts  
C oa g ulati o n  
X  
Secti o n  1 1. 5. 2  
Uri nal ysis  
X  
Secti o n  1 1. 5. 2  
S pir o metr y  
X  
S pir o metr y will be perf or me d p ost -
br o nc h o dilat or a n d acc or di n g t o t he 
A merica n T h oracic S ociet y 
G ui d eli nes/ E ur o pea n Res pirat or y S ociet y 
G ui d eli nes. If s pir o metr y ca n n ot be 
perf o r me d, hist orical p ost-br o nc h o dilat or 
p p F E V 1 res ults meas ure d wit hi n 1 year 
bef ore scree ni n g ca n be use d t o deter mi ne 
eli gi bilit y. Secti o n  8. 2  e xcl usi o n criteri o n 
# 7 a n d Secti o n  1 1. 5. 5 . 
Uri ne c oti ni ne  
X  
Secti o n  1 1. 5. 2  
A Es a n d S A Es  
C o nti n u o us fr o m si g ni n g of I C F 
t hr o u g h last Safet y F oll o w-u p Visit  
Secti o n 1 1. 5. 1  
Me dicati o ns re vie w  
C o nti n u o us fr o m si g ni n g of I C F 
t hr o u g h last Safet y F oll o w-u p Visit  
Secti o n  9. 6  
A A T: al p ha -1 a ntitr y psi n; A b:  a nti b o d y; A E: a d verse e ve nt; β -h C G : beta -h u ma n c h ori o nic g o na d otr o pi n; 
F S H:  f ollicle-sti m ulati n g h or m o ne; H Bs A g: he patitis  B s urface a nti ge n; H C V:  he patitis  C v ir us; 
HI V -1/ HI V -2  A bs:  a nti b o dies a gai nst h u ma n i m m u n o deficie nc y vir uses  1 a n d  2; I C F:  i nf or me d c o nse nt f or m; 
p p F E V 1: perce nt pre dicte d f orce d e x pirat or y v ol u me i n 1 sec o n d; S A E: seri o us a d verse e ve nt  
N ote: Scree ni n g pr oce d ures (i ncl u di n g i nf or me d c o nse nt)  ca n be perf or me d o ver m ore t h a n 1  da y. I nf or me d c o nse nt m ust b e 
o btai ne d pri or t o a n y pr oce d ures. Re peat Scree ni n g assess me nts a n d Scree ni n g assess me nts t hat wer e n ot c o n d ucte d at 
t he i nitial visit d uri n g t h e Scree ni n g P eri o d ma y be perf or me d at t he cli nic or at h o me b y a q ualifie d visiti n g n urse, if 
per mitte d b y et hical a n d re g ulat or y a ut h orities a n d a gree d u p o n after i n vesti gat or a n d s u bject c o ns ultati o n.  
 


Pr ot oc ol V X 1 9 -8 6 4 -1 0 1 , Versi o n  2 . 0 
P a ge  9  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
T a ble  3 -2   
St u d y V X 1 9 ‑ 8 6 4 - 1 0 1: Scree ni n g f or S u bjects W h o H a ve Bee n o n 
A u g me nt ati o n T her a p y at A n y Ti me  
E ve nt/ Assess me nt  
Scree ni n g Peri o d  
D a y  -7 0 t hr o u g h D a y  -1   
C o m me nts  
I nf or me d c o nse nt  
X  
Secti o n  1 3. 2. 3  
I ncl usi o n a n d e xcl usi o n criteria re vie w 
X  
Secti o ns  8. 1  a n d 8. 2  
Cli nic visit  
X  
 
De m o gra p hics  
X  
 
M e dical hist or y 
X  
Secti o n  1 1. 1  
Me dicati o ns re vie w  
X  
Secti o n  9. 6  
Pri or a u g me ntati o n t hera p y re vie w  
X  
S u bje cts m ust dis c o nti n ue a u g me nt ati o n 
t her a p y > 4 2 d a ys bef ore t he a nti g e nic 
A A T le vels a re o bt ai ne d t o dete r mi ne 
eli gi bilit y. S u bjects c a n res u me 
a u g me nt ati o n t he r a p y after c o m pleti o n 
of t he S afet y F oll o w -u p Assess me nts. 
Secti o n  9. 6  
A nti ge nic A A T le vel ( u p t o 2  sa m ples 
o btai ne d d uri n g scree ni n g)  
X  
Sa m ples will be o btai ne d f or plas ma 
a nti ge nic A A T le vel a n d se nt t o t he ce ntral 
la b orat or y at t h e sa me ti me ot h er scree ni n g 
la b orat or y assess me nts are d o ne. If t h e 
s u bject recei ve d t h e last d ose of 
a u g me ntati o n t hera p y > 4 2  da ys pri or, t hese 
res ults ca n be use d t o deter mi n e eli gi bilit y. 
If t his sa m ple is o btai ne d ≤4 2 da ys after t he 
last d ose of a u g me ntati o n t h era p y, a n ot her 
sa m ple m ust  be dra w n > 4 2  da ys after t he 
last d ose of a u g me ntati o n t h era p y t o 
c o nfir m eli gi bilit y. Res ults m ust be 
c o nfir me d t o be  < 8  µ M bef ore 
ra n d o mizati o n.  
T his sec o n d s a m ple c a n be dr a w n at a 
h o me or cli nic visit. Sites s h o ul d all o w at 
le ast 1 4 d a ys f or s a m pl e pr ocessi n g a n d 
res ults re p orti n g. Secti o n 1 1. 3  a n d 
Secti o n  8. 1 , i ncl usi o n criteri o n # 7. 
F u ncti o nal A A T le vel ( u p t o 2  sa m ples 
o btai ne d d uri n g scree ni n g)  
X  
Sa m ples will be o btai ne d f or plas ma 
f u ncti o nal A A T le vels at t h e sa me ti me 
sa m ples are o btai ne d f or a nti ge nic A A T 
le vels. If a sec o n d s a m ple is o bt ai ne d, t he 
sec o n d s a m ple c a n be dr a w n at a h o me 
or cli nic visit. Res ults will n ot be pr o vi de d 
t o site pers o n nel. Secti o n 1 1. 3  
Sta n dar d 1 2 -lea d E C G 
X  
Will be perf or me d i n tri plicate after t he 
s u bject has reste d f or at least 5 mi n utes. 
W he n E C Gs, vital si g ns,  a n d bl o o d dra ws 
are d o ne o n t h e sa me da y, t h e y s h o ul d be 
perf or me d i n sai d or der. Secti o n  1 1. 5. 4 . 
Hei g ht a n d wei g ht  
X  
Wei g ht a n d hei g ht will be meas ure d wit h 
s h oes off.  
Vital si g ns  
X  
Vital si g ns will be perf or me d after t h e 
s u bject has reste d f or at least 5 mi n utes. 
Secti o n 1 1. 5. 3 . 
P ulse o xi metr y  
X  
P ulse o xi metr y will be perf or me d after t he 
s u bject has reste d f or at least 5 mi n utes. 
Secti o n 1 1. 5. 3 . 
C o m plete p h ysic al e xa mi n ati o n  
X  
Secti o n 1 1. 5. 3 .  


Pr ot oc ol V X 1 9 -8 6 4 -1 0 1 , Versi o n  2 . 0 
P a ge  1 0  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
T a ble  3 -2   
St u d y V X 1 9 ‑ 8 6 4 - 1 0 1: Scree ni n g f or S u bjects W h o H a ve Bee n o n 
A u g me nt ati o n T her a p y at A n y Ti me  
E ve nt/ Assess me nt  
Scree ni n g Peri o d  
D a y  -7 0 t hr o u g h D a y  -1   
C o m me nts  
Ser u m F S H ( p ost me n o pa usal fe male 
s u bjects o nl y) 
X  
Secti o n  1 1. 5. 2   
Ser u m β -h C G (all fe male s u bjects)  
X  
Secti o n  1 1. 5. 2  
Ser ol o g y ( H Bs A g, H C V A b a n d R N A, 
HI V -1 a n d HI V -2 A bs)  
X  
Secti o n  1 1. 5. 2  
Pi Z Z  ge n ot y pe  
X  
Pi Z Z  ge n ot y pe m ust b e perf or me d at t he 
ce ntral la b orat or y. Secti o n  8. 1 , i ncl usi o n 
criteri o n # 6 
Ser u m c he mistr y  
X  
Secti o n  1 1. 5. 2  
He mat ol o g y  
X  
Secti o n  1 1. 5. 2  
C oa g ulati o n  
X  
Secti o n  1 1. 5. 2  
Uri nal ysis  
X  
Secti o n  1 1. 5. 2  
S pir o metr y  
X  
S pir o metr y will be perf or me d p ost -
br o nc h o dilat or a n d acc or di n g t o t he 
A merica n T h oracic S ociet y 
G ui d eli nes/ E ur o pea n Res pirat or y S ociet y 
G ui d eli nes. If s pir o metr y ca n n ot be 
perf or me d, hist orical p ost -br o nc h o dilat or 
p p F E V 1 res ults wit hi n 1 year bef ore 
scree ni n g ca n be use d t o deter mi n e 
eli gi bilit y. Secti o n 8. 2  e xcl usi o n criteri o n 
# 7 a n d Secti o n  1 1. 5. 5 . 
Uri ne c oti ni ne  
X  
Secti o n  1 1. 5. 2  
A Es a n d S A Es  
C o nti n u o us fr o m si g ni n g of I C F 
t hr ou g h last Safet y F oll o w -u p 
Visit  
Secti o n 1 1. 5. 1  
Me dicati o ns re vie w  
C o nti n u o us fr o m si g ni n g of I C F 
t hr o u g h last Safet y F oll o w-u p 
Visit  
Secti o n  9. 6  
A A T: al p ha -1 a ntitr y psi n; A b:  a nti b o d y; A E: a d verse e ve nt; β -h C G : beta -h u ma n c h ori o nic g o na d otr o pi n; 
F S H:  f ollicle-sti m ulati n g h or m o ne; H Bs A g: he patitis  B s urface a nti ge n; H C V:  he patitis  C vir us; 
HI V -1/ HI V -2  A bs:  a nti b o dies a gai nst h u ma n i m m u n o deficie nc y vir uses  1 a n d  2; I C F:  i nf or me d c o nse nt f or m; 
p p F E V 1: perce nt pre dicte d f orce d e x pirat or y v ol u me i n 1 sec o n d; S A E: seri o us a d verse e ve nt  
N otes: Scree ni n g pr oce d ures (i ncl u di n g i nf or me d c o nse nt) ca n be perf or me d o ver m ore t h a n 1  da y. I nf or me d c o nse nt m ust b e 
o btai ne d pri or t o a n y pr oce d ures. Re peat Scree ni n g assess me nts a n d Scree ni n g assess me nts t hat wer e n ot c o n d ucte d at 
t he i nitial visit duri n g t h e Scree ni n g P eri o d ma y be perf or me d at t he cli nic or at h o me b y a q ualifie d visiti n g n urse, if 
per mitte d b y et hical a n d re g ulat or y a ut h orities a n d a gree d u p o n after i n vesti gat or a n d s u bject c o ns ultati o n. If a sec o n d 
bl o o d sa m ple is re q uire d > 4 2 da y s after t he last d ose of a u g me ntati o n t hera p y t o meas ure a nti ge nic A A T le vels t o 
c o nfir m eli gi bilit y, t his sec o n d bl o o d sa m ple (a n d t h e sec o n d f u ncti o nal A A T le vel dra w n at t h e sa me ti me) c a n be dra w n 
at a h o me visit or cli nic visit.  
 


Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 1 1  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
T a ble  3 -3   
St u d y V X 1 9 ‑ 8 6 4 -1 0 1: Tre at me nt Peri o d a n d F oll o w -u p Visits  
E ve nt/  
Assess me nt  
Tre at me nt Peri o d  
 
 
 
 
 
D a y  1 a 
D a y  7 
( ± 1) b   
D a y  1 4 
( ± 2)b  
D a y  2 1 
( ± 2)b  
D a y  2 8 
(-2 )c 
V X -8 6 4 
W as h o ut 
Visit  
7 ( ± 2) D a ys  
After L ast 
D ose of 
St u d y Dr u g  
E T T 
Visit e 
S afet y 
F oll o w -u p 
Visit  
1 4 ( ± 2) 
D a ys  
After L ast 
D ose of 
St u d y 
Dr u g  
S afet y 
F oll o w -u p 
Visit  
2 8 ( ± 2) D a ys  
After L ast 
D ose of St u d y 
Dr u g  
C o m me nts  
I ncl usi o n a n d 
e xcl usi o n criteria 
c o nfir mati o n 
X   
  
  
 
 
 
 
  
 
 
 
a 
O n D a y 1, all assess me nts m ust be c o m plete d bef ore t he first d ose of st u d y dr u g e xce pt f or t he p ost d ose P K s a m pli n g, w hic h i s d o ne at 3, 5, a n d 8 h o urs ( ± 3 0  mi n utes) 
after d osi n g i n t he cli nic.  
b  
All assess me nts will be perf or me d bef ore a d mi nistr ati o n of t he m or ni n g or e ve ni n g d ose of st u d y dr u g u nless n ote d ot her wise ( Secti o n 1 1 ). T hese visits ma y be perf or me d 
i n t he m or ni n g or t he e ve ni n g i n t he cli nic or at h o me b y a q ualifie d visiti n g n urse. If t he visit is perf or me d at h o me, it m ust be f oll o we d b y a c o ns ultati o n bet wee n t he s u bj ect a n d 
i n vesti gat or (i.e., i n pers o n, tele p h o ne, or tele me dici ne vi de o c o nfere nce) wit hi n 1 da y a n d ma y als o i ncl u de a se parate f oll o w -u p wit h t he st u d y c o or di nat or . 
c  
O n D a y 2 8, all assess me nts will be perf or me d bef ore a d mi nistr ati o n of t he m or ni n g d ose of st u d y dr u g u nless n ote d ot her wise ( Secti o n 1 1 ). T he m or ni n g d ose of st u d y 
dr u g o n t he Da y 2 8 Visit will be ta ke n at h o me or i n t he cli nic after t he pre d ose P K sa m ple has bee n dra w n ( wit hi n 6 0 mi n utes  of d osi n g). A d diti o nal P K sa m pli n g will be d o ne  at 
3, 5 a n d 8 h o urs ( ± 3 0  mi n utes) after d osi n g. T he last d ose of st u d y dr u g will be ta ke n at h o me i n t he e ve ni n g o n Da y 2 8, re gar dless of w het her t he Da y 2 8 Visit occ urs o n Da y 2 6 
or Da y 2 7.  
e  
If t he s u bj ect pre mat urel y disc o nti n ues st u d y dr u g treat me nt, a n E T T Visit s h o ul d be sc he d ule d as s o o n as p ossi ble after t he decisi o n t o ter mi nate st u d y treat me nt. S u bj ects w h o 
pre mat urel y disc o nti n ue trea t me nt will be re q uire d t o c o m plete t he Safet y F oll o w-u p Visits, a p pr o xi matel y 1 4 ( ± 2) a n d 2 8 ( ± 2) da ys after t heir last d ose of st u d y dr u g. If t he E T T 
Visit occ urs bet wee n 1 2 a n d 2 1 da ys (i ncl usi ve) after t he last d ose of st u d y dr u g, t he E T T Visit will re p lace t he Safet y F oll o w-u p Visit 1 4 da ys after t he last d ose of st u d y dr u g, 
a n d a se parate Safet y F oll o w -u p Visit 1 4 da ys after t he last d ose will n ot be re q uire d; t he Safet y F oll o w -u p Visit 2 8 da ys after t he last d ose w o ul d still be re q uire d. If t he E T T Vi sit 
occ urs ≥2 2  da ys after t he last d ose of st u d y dr u g, t he E T T Visit will re place t he Safet y F oll o w -u p Visit 2 8 da ys after t he last d ose, a n d a se parate Safet y F oll o w -u p Visit 2 8 da ys 
after t he last d ose will n ot be re q uire d.  
 


Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 1 2  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
T a ble  3 -3   
St u d y V X 1 9 ‑ 8 6 4 -1 0 1: Tre at me nt Peri o d a n d F oll o w -u p Visits  
E ve nt/  
Assess me nt  
Tre at me nt Peri o d  
 
 
 
 
 
D a y  1 a 
D a y  7 
( ± 1) b   
D a y  1 4 
( ± 2)b  
D a y  2 1 
( ± 2)b  
D a y  2 8 
(-2 )c 
V X -8 6 4 
W as h o ut 
Visit  
7 ( ± 2) D a ys  
After L ast 
D ose of 
St u d y Dr u g  
E T T 
Visit e 
S afet y 
F oll o w -u p 
Visit  
1 4 ( ± 2) 
D a ys  
After L ast 
D ose of 
St u d y 
Dr u g  
S afet y 
F oll o w -u p 
Visit  
2 8 ( ± 2) D a ys  
After L ast 
D ose of St u d y 
Dr u g  
C o m me nts  
Ra n d o mizati o n   
X   
  
  
 
 
 
 
  
 
Ra n d o mizati o n ma y occ ur u p t o 
7  da ys bef ore Da y  1 after all 
eli gi bilit y criteria i ncl u di n g 
a nti ge nic A A T le vels < 8 µ M are 
c o nfir me d. If ra n d o mizati o n 
occ urs bef ore Da y 1, eli gi bilit y 
m ust als o be c o nfir me d bef ore 
t he first d ose of st u d y dr u g o n 
Da y 1.  
Cli nic visit  
X   
  
  
 
 
 
 
 
 
 
Cli nic or h o me 
healt h visit  
  
X   
X   
X   
X  
X  
X  
X  
X   
S u bjects will ha ve t he o pti o n t o 
c o m plete t hese visits i n t he 
cli nic or t o ha ve a h o me healt h 
visit.  H o me he alt h visits are 
o nl y a n o pti o n if t he y recei ve 
a p pr o v al fr o m b ot h et hic al 
a n d re g ul at or y a ut h orities i n 
t he res pecti ve c o u nt r y. 
Tele me dici ne 
vi de o c o nfere nce 
or tele p h o ne 
c o ntact 
  
X   
X   
X   
X  
X  
X  
X  
X   
Perf or me d wit hi n 1 d a y after 
h o me he alt h visit.  Re q uire d 
o nl y f or s u bjects w h o ha ve a 
h o me healt h visit; n ot re q uire d 
f or s u bjects w h o ha ve a cli nic 
visit.  
A nti ge nic A A T 
le vel 
X   
X   
X   
  
X  
X  
X  
X  
X   
Secti o n 1 1. 3  
F u ncti o nal A A T 
le vel 
X   
X   
X   
  
X  
X  
X  
X  
X   
Secti o n 1 1. 3  


Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 1 3  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
T a ble  3 -3   
St u d y V X 1 9 ‑ 8 6 4 -1 0 1: Tre at me nt Peri o d a n d F oll o w -u p Visits  
E ve nt/  
Assess me nt  
Tre at me nt Peri o d  
 
 
 
 
 
D a y  1 a 
D a y  7 
( ± 1) b   
D a y  1 4 
( ± 2)b  
D a y  2 1 
( ± 2)b  
D a y  2 8 
(-2 )c 
V X -8 6 4 
W as h o ut 
Visit  
7 ( ± 2) D a ys  
After L ast 
D ose of 
St u d y Dr u g  
E T T 
Visit e 
S afet y 
F oll o w -u p 
Visit  
1 4 ( ± 2) 
D a ys  
After L ast 
D ose of 
St u d y 
Dr u g  
S afet y 
F oll o w -u p 
Visit  
2 8 ( ± 2) D a ys  
After L ast 
D ose of St u d y 
Dr u g  
C o m me nts  
Wei g ht a n d 
hei g ht  
X   
  
  
 
 
 
 
 
  
Meas ure d wit h s h oes off.  
Sta n dar d 1 2 -lea d 
E C G  
X   
X   
  
  
X  
 
X  
X  
X  
P erf or me d i n tri plicate after t he 
s u bject has reste d f or at least 
5  mi n utes  
W he n E C Gs, vital si g ns, a n d 
bl o o d dra ws are d o ne o n t he 
sa me da y, t he y s h o ul d be 
perf or me d i n sai d or der.  
D a y 1 : pre d ose a n d 6 h o urs 
( ± 1 5 mi n) after d osi n g. 
S ecti o n  1 1. 5. 4  
Vital si g ns  
X   
X   
X   
  
X  
 
X  
X  
X  
P erf or me d after t he s u bject has 
reste d f or at least 5 mi n utes. 
Secti o n 1 1. 5. 3  


Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 1 4  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
T a ble  3 -3   
St u d y V X 1 9 ‑ 8 6 4 -1 0 1: Tre at me nt Peri o d a n d F oll o w -u p Visits  
E ve nt/  
Assess me nt  
Tre at me nt Peri o d  
 
 
 
 
 
D a y  1 a 
D a y  7 
( ± 1) b   
D a y  1 4 
( ± 2)b  
D a y  2 1 
( ± 2)b  
D a y  2 8 
(-2 )c 
V X -8 6 4 
W as h o ut 
Visit  
7 ( ± 2) D a ys  
After L ast 
D ose of 
St u d y Dr u g  
E T T 
Visit e 
S afet y 
F oll o w -u p 
Visit  
1 4 ( ± 2) 
D a ys  
After L ast 
D ose of 
St u d y 
Dr u g  
S afet y 
F oll o w -u p 
Visit  
2 8 ( ± 2) D a ys  
After L ast 
D ose of St u d y 
Dr u g  
C o m me nts  
P ulse o xi metr y   
X   
X   
X   
  
X  
 
X  
X  
X   
P erf or me d after t he s u bject has 
reste d f or at least 5 mi n utes. 
Secti o n 1 1. 5. 3  
Pre g na nc y test 
( pre me n o pa usal 
fe male s u bjects 
of c hil d beari n g 
p ote ntial o nl y)  
Uri ne 
a n d 
ser u m  
  
Ser u m   
  
Uri ne  
  
Ser u m   
Ser u m   
Ser u m   
S u bjects m ust h a ve a ne gati ve 
uri ne pre g na nc y test res ult o n 
Da y 1 bef ore d osi n g 
a d mi nistrati o n. 
P h ysical 
e xa mi nati o n/  
re vie w of 
s y m pt o ms 
A b bre v 
P E  
  
  
  
Re vie w of 
s y m pt o ms 
Re vie w of 
s y m pt o ms 
Re vie w of 
s y m pt o ms 
Re vie w of 
s y m pt o ms 
Re vie w of 
s y m pt o ms 
If t here are a n y a b n or mal 
fi n di n gs i n t he re vie w of 
s y m pt o ms, t he s u bject will be 
i nstr ucte d t o ha ve a c o m plete P E 
i n t he cli nic. Secti o n 1 1. 5. 3  
Ser u m c he mistr y   
X   
X   
X   
X   
X  
X  
X  
X  
X   
Secti o n 1 1. 5. 2  
He mat ol o g y   
X   
X   
X   
X   
X  
X  
X  
X  
X   
Secti o n 1 1. 5. 2  
C oa g ulati o n   
X   
X   
X   
X   
X  
X  
X  
X  
X   
Secti o n 1 1. 5. 2  


Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 1 5  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
T a ble  3 -3   
St u d y V X 1 9 ‑ 8 6 4 -1 0 1: Tre at me nt Peri o d a n d F oll o w -u p Visits  
E ve nt/  
Assess me nt  
Tre at me nt Peri o d  
 
 
 
 
 
D a y  1 a 
D a y  7 
( ± 1) b   
D a y  1 4 
( ± 2)b  
D a y  2 1 
( ± 2)b  
D a y  2 8 
(-2 )c 
V X -8 6 4 
W as h o ut 
Visit  
7 ( ± 2) D a ys  
After L ast 
D ose of 
St u d y Dr u g  
E T T 
Visit e 
S afet y 
F oll o w -u p 
Visit  
1 4 ( ± 2) 
D a ys  
After L ast 
D ose of 
St u d y 
Dr u g  
S afet y 
F oll o w -u p 
Visit  
2 8 ( ± 2) D a ys  
After L ast 
D ose of St u d y 
Dr u g  
C o m me nts  
Uri nal ysis  
X   
X   
X   
X   
X  
 
X  
X  
X   
Secti o n 1 1. 5. 2  
Bl o o d f or P K 
sa m pli n g 
X   
X   
X   
X   
X  
X  
X  
X  
X   
D a y 1 a n d D a y 2 8:  pre d ose 
( wit hi n 6 0 mi n utes bef ore 
d osi n g) a n d at 3, 5, a n d 8  h o urs 
( ± 3 0 mi n utes) after d osi n g 
(relati ve t o t he m or ni n g d ose).  
D a ys  7, 1 4, a n d 2 1:  pre d ose 
( wit hi n 6 0 mi n utes bef ore 
d osi n g, relati ve t o t he m or ni n g 
or e ve ni n g d ose).  
S afet y F oll o w -u p Visits:  
c ollecte d at a n y ti me d uri n g t he 
visit.  
Secti o n 1 1. 2. 1  
St u d y dr u g 
a d mi nistrati o n   
Da y 1 t hr o u g h Da y 2 8  
 
 
  
 
Secti o n  9. 7  
A Es a n d S A Es  
C o nti n u o us fr o m si g ni n g of I C F t hr o u g h last Safet y F oll o w -u p Visit  
Secti o n  1 1. 5. 1  
Me dicati o ns 
re vie w 
C o nti n u o us fr o m si g ni n g of I C F t hr o u g h last Safet y F oll o w -u p Visit  
Secti o n  9. 6  
A A T: al p ha -1 a ntitr y psi n; A b bre v: a b bre viate d; A E: a d verse e ve nt; 
; E T T: Earl y Ter mi nati o n of Treat me nt: I C F: i nf or me d 
c o nse nt f or m; 
P E;  p h ysic al e xa mi n ati o n; 
 P K: p har mac o ki netic; S A E: seri o us a d verse e ve nt; 
 
 


Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 1 6  of 6 4  
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4  
T A B L E O F C O N T E N T S  
1  
Title P a ge  ................................................................................................................................ 1  
 
2  
Pr ot oc ol S y n o psis  ................................................................................................................... 3  
3  
Sc he d ule of Assess me nts ........................................................................................................ 7  
4  
T a ble of C o nte nts  ................................................................................................................. 1 6  
List of Ta bl es ............................................................................................................................ 1 9  
List of Fi g ures  .......................................................................................................................... 1 9  
List of A b bre viati o ns ................................................................................................................ 2 0  
5  
I ntr o d uctio n .......................................................................................................................... 2 2  
5. 1  
Bac k gr o u n d  ..................................................................................................................... 2 2  
5. 2  
St u d y R ati o nale  .............................................................................................................. 2 2  
6  
St u d y O bject i ves .................................................................................................................. 2 2  
6. 1  
Pri mar y O bj ecti ves  ......................................................................................................... 2 2  
6. 2  
Sec o n dar y O bj ecti ves  ..................................................................................................... 2 3  
 
 
7  
St u d y E n d p oi nts  ................................................................................................................... 2 3  
7. 1  
Pri mar y E n d p oi nts  .......................................................................................................... 2 3  
7. 2  
Sec o n dar y E n d p oi nts  ...................................................................................................... 2 3  
 
 
8  
St u d y P o p ul ati o n  .................................................................................................................. 2 4  
8. 1  
I n cl usi o n Criteria ............................................................................................................ 2 4  
8. 2  
E x cl us i o n Criteria ........................................................................................................... 2 5  
9  
St u d y I m ple me nt ati o n  ......................................................................................................... 2 7  
9. 1  
St u d y Desi g n  .................................................................................................................. 2 7  
9. 1. 1  
Scree ni n g  ................................................................................................................ 2 8  
9. 1. 1. 1  
Re petiti o n of Scree ni n g Assess me nt(s)  ............................................................ 2 9  
9. 1. 1. 2  
Rescree ni n g  ...................................................................................................... 2 9  
9. 1. 1. 3  
E xte nsi o n of t he Scree ni n g Peri o d  ................................................................... 2 9  
9. 1. 2  
Treat me nt Peri o d  .................................................................................................... 3 0  
 
 
9. 1. 3  
Was h -o ut a n d F oll o w -u p Visits  .............................................................................. 3 0  
9. 1. 4  
Earl y Ter mi nati o n of Treat me nt  ............................................................................. 3 0  
9. 2  
L ost t o F oll o w -u p  ........................................................................................................... 3 1  
9. 3  
Met h o d of Assi g ni n g S u bjects t o Treat me nt Gr o u ps  ..................................................... 3 1  
9. 4  
Rati o nale f or St u d y El e me nts  ......................................................................................... 3 1  
9. 4. 1  
Rati o nale f or St u d y Desi g n ..................................................................................... 3 1  
9. 4. 2  
Rati o nale f or St u d y P o p ulati o n ............................................................................... 3 1  
9. 4. 3  
Rati o nale f or St u d y Dr u g D ose  .............................................................................. 3 1  
9. 4. 4  
Rati o nale f or St u d y Ass ess me nts  ........................................................................... 3 2  
9. 5  
St u d y R estricti o ns  ........................................................................................................... 3 2  
9. 5. 1  
E x p os ure t o S u nli g ht  .............................................................................................. 3 3  
9. 6  
Pri or a n d C o nc o mita nt Me dicati o ns  ............................................................................... 3 3  
9. 7  
A d mi nistrati o n  ................................................................................................................ 3 4  
9. 8  
D ose M o dif icati o n f or T o xicit y ...................................................................................... 3 5  


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9. 9  
St u d y Dr u g I nterr u pti o n a n d St o p pi n g R ules  ................................................................. 3 5  
9. 1 0  Re m o val of S u bjects  ....................................................................................................... 3 6  
9. 1 1  Re place me nt of S u bjects  ................................................................................................ 3 6  
1 0  S t u d y Dr u g I nf or m ati o n a n d M a n a ge me nt ....................................................................... 3 6  
1 0. 1  Pre parati o n a n d Dis pe nsi n g  ............................................................................................ 3 6  
1 0. 2  Pac ka gi n g a n d La b eli n g  ................................................................................................. 3 6  
1 0. 3  St u d y Dr u g S u p pl y, St or a ge, a n d Ha n dli n g  ................................................................... 3 7  
1 0. 4  Dr u g Acc o u nta bilit y  ....................................................................................................... 3 7  
1 0. 5  Dis p osal, Ret ur n, or Rete nti o n of U n use d Dr u g  ............................................................. 3 7  
1 0. 6  C o m plia nce  ..................................................................................................................... 3 7  
1 0. 7  Bli n di n g a n d U n bli n di n g  ................................................................................................ 3 8  
1 0. 7 . 1 
Bli n di n g  .................................................................................................................. 3 8  
1 0. 7. 2  
U n bli n di n g  .............................................................................................................. 3 9  
1 1  Assess me nts  .......................................................................................................................... 3 9  
1 1. 1  S u bject a n d Disease C haracteristics  ............................................................................... 3 9  
1 1. 2  P har mac o ki netics  ............................................................................................................ 4 0  
1 1. 2. 1  
Bl o o d Sa m pli n g  ...................................................................................................... 4 0  
1 1. 2. 2  
Pr ocessi n g a n d Ha n dli n g of P har mac o ki netic Sa m ples  ......................................... 4 0  
1 1. 2. 3  
Bi oa nal ysis .............................................................................................................. 4 0  
1 1. 3  Efficac y  ........................................................................................................................... 4 0  
1 1. 5  Safet y  .............................................................................................................................. 4 2  
1 1. 5. 1  
A d verse E v e nts  ....................................................................................................... 4 2  
1 1. 5. 2  
Cli nical La b orat or y Assess me nts  ........................................................................... 4 2  
1 1. 5. 3  
P h ysical E x a mi nati o ns, Vital Si g ns, a n d P ulse O xi metr y  ...................................... 4 4  
1 1. 5. 4  
Electr ocar di o gra ms  ................................................................................................. 4 4  
1 1. 5. 5  
S pir o metr y  .............................................................................................................. 4 5  
1 1. 5. 6  
C o ntrace pti o n a n d Pre g n a nc y  ................................................................................. 4 5  
1 1. 5. 6. 1  C o ntrace pti o n  ................................................................................................... 4 5  
1 1. 5. 6. 2  P re g n a nc y ......................................................................................................... 4 7  
1 2  St atistic al a n d A n al ytic al Pl a ns  .......................................................................................... 4 7  
1 2. 1  Sa m ple Size a n d P o wer  .................................................................................................. 4 7  
1 2. 2  A nal ysis Set  .................................................................................................................... 4 8  
1 2. 3  Statistical A nal ysis  ......................................................................................................... 4 8  
1 2. 3. 1  
Ge neral C o nsi derati o ns  ........................................................................................... 4 9  
1 2. 3. 2  
De m o gra p hics a n d Bac k gr o u n d C haracteristics  ..................................................... 4 9  
1 2. 3. 3  
Efficac y A nal ysis  .................................................................................................... 4 9  
1 2. 3. 3. 1  A nal ysis of t h e Pri mar y Varia ble  ..................................................................... 4 9  
1 2. 3. 3. 2  M ulti plicit y A dj ust me nt  ................................................................................... 5 0  
1 2. 3. 3. 3  Missi n g Data Ha n dli n g  .................................................................................... 5 0  
1 2 . 3. 4 
Safet y A nal ysis  ....................................................................................................... 5 0  


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P a ge 1 8  of 6 4  
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1 2. 3. 5  
I nteri m a n d I n de p e n de nt Data M o nit ori n g C o m mittee A nal yses ........................... 5 0  
1 2. 3. 5. 1  I nteri m A nal ysis ............................................................................................... 5 0  
1 2. 3. 5. 2  I n d e pe n de nt Data M o nit ori n g C o m mittee A nal ysis ........................................ 5 0  
1 2. 4  Cli nical P har mac ol o g y A nal ysis  .................................................................................... 5 1  
1 2. 4. 1  
P har mac o ki netic A n al ysis  ...................................................................................... 5 1  
1 2. 4. 2  
P har mac o ki netic/ P har mac o d y n a mic A nal yses  ....................................................... 5 1  
1 3  Pr o ce d ur al, Et hic al, Re g ul at or y, a n d A d mi nistr ati ve C o nsi der ati o ns  ........................... 5 1  
1 3. 1  A d verse E v e nt a n d Seri o us A d verse E ve nt D oc u me ntati o n, Se verit y Gra di n g, a n d 
Re p orti n g  ........................................................................................................................ 5 1  
1 3. 1. 1  
A d verse E v e nts  ....................................................................................................... 5 1  
1 3. 1. 1. 1  Defi niti o n of a n A d verse E ve nt ........................................................................ 5 1  
1 3. 1. 1. 2  Cli nicall y Si g nifica nt Assess me nts  .................................................................. 5 1  
1 3. 1. 1. 3  D oc u me ntati o n of A d verse E ve nts ................................................................... 5 2  
1 3. 1. 1. 4  A d verse E v e nt Se verit y  .................................................................................... 5 3  
1 3. 1. 1. 5  A d verse E v e nt  Ca usalit y  .................................................................................. 5 3  
1 3. 1. 1. 6  St u d y Dr u g Acti o n Ta ke n  ................................................................................ 5 4  
1 3. 1. 1. 7  A d verse E v e nt O utc o me  .................................................................................. 5 4  
1 3. 1. 1. 8  Treat me nt Gi ve n ............................................................................................... 5 4  
1 3. 1. 2  
S eri o us A d verse E v e nts  .......................................................................................... 5 5  
1 3. 1. 2. 1  Defi niti o n of a Seri o us A d verse E ve nt ............................................................. 5 5  
1 3. 1. 2. 2  Re p orti n g a n d D oc u me nt ati o n of Seri o us A d verse E ve nts  .............................. 5 5  
1 3. 1. 2. 3  E x pe dite d Re p orti n g a n d I n v esti gat or Safet y Lett ers  ...................................... 5 6  
1 3. 2  A d mi nistrati ve Re q uire me nts  ......................................................................................... 5 6  
1 3. 2. 1  
Pr o d uct C o m plai nts  ................................................................................................ 5 6  
1 3. 2. 2  
Et hical C o nsi derati o ns  ............................................................................................ 5 7  
1 3. 2. 3  
S u bject I nf or mati o n a n d I nf or me d C o nse nt  ........................................................... 5 7  
1 3. 2. 4  
I n v esti gat or C o m plia nce ......................................................................................... 5 7  
1 3. 2. 5  
Access t o Rec or ds  ................................................................................................... 5 7  
1 3. 2. 6  
S u bject Pri vac y  ....................................................................................................... 5 8  
1 3. 2. 7  
Rec or d Rete nti o n  .................................................................................................... 5 8  
1 3. 2. 8  
St u d y Ter mi nati o n  .................................................................................................. 5 8  
1 3. 2. 9  
E n d of St u d y  ........................................................................................................... 5 9  
1 3. 3  Data Q ualit y Ass ura nce  .................................................................................................. 5 9  
1 3. 4  M o nit ori n g  ...................................................................................................................... 5 9  
1 3. 5  Electr o nic Data Ca pt ure  ................................................................................................. 5 9  
1 3. 6  C o nfi de ntialit y a n d Discl os ure  ....................................................................................... 6 0  
1 3. 7  P u blicati o ns a n d Cli nical St u d y R e p ort  .......................................................................... 6 0  
 
 
1 3. 7. 2  
Cli nical St u d y Re p ort  ............................................................................................. 6 1  
1 4  Refere nces  ............................................................................................................................. 6 2  
1 5  Pr ot oc ol Si g n at ure P a g es  .................................................................................................... 6 3  
1 5. 1  S p o ns or Si g nat ure Pa ge  .................................................................................................. 6 3  
1 5. 2  In v esti gat or Si g nat ure Pa ge  ............................................................................................ 6 4  
 


Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 1 9  of 6 4  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
Li st of T a bl e s  
Ta ble  3 -1  
St u d y V X 1 9 ‑ 8 6 4 - 1 0 1: Scree ni n g f or S u bjects W h o Ha ve  Ne ver Bee n o n 
A u g me nt ati o n T hera p y  ........................................................................................... 7  
Ta ble  3 -2  
St u d y V X 1 9 ‑ 8 6 4 - 1 0 1: Scree ni n g f or S u bjects W h o Ha ve Bee n o n A u g me ntati o n 
T hera p y at A n y Ti me  .............................................................................................. 9  
Ta ble  3 -3  
St u d y V X 1 9 ‑ 8 6 4 -1 0 1: Treat me nt Peri o d a n d F oll o w -u p Visits  .......................... 1 1  
Ta ble  9 -1  
St u d y R estricti o ns  ................................................................................................. 3 2  
Ta ble  1 1 -1  
Acce pt a ble P har mac o ki netic Sa m pli n g Wi n d o ws  ................................................ 4 0  
Ta ble  1 1 -2  
Safet y La b orat or y Test P a nels  .............................................................................. 4 3  
Ta ble  1 1 -3  
All o wa ble Met h o ds of C o ntrace pti o n  ................................................................... 4 6  
 
 
Ta ble  1 3 -1  
Gra di n g of A E Se v erit y  ........................................................................................ 5 3  
Ta ble  1 3 -2  
Classificati o ns f or A E Ca usalit y  ........................................................................... 5 3  
Ta ble  1 3 -3  
Classificati o ns f or St u d y Dr u g Acti o n Ta k e n Wit h Re gar d t o a n A E  .................. 5 4  
Ta ble  1 3 -4  
Cla ssificati o ns f or O utc o me of a n A E .................................................................. 5 4  
Li st of Fi g ur e s  
Fi g ure  2 -1  
Sc he matics of St u d y Desi g n f or S u bjects W h o  Ha ve Ne ver Bee n o n 
A u g me nt ati o n T hera p y  ........................................................................................... 4  
Fi g ure  2 -2  
Sc he matics of St u d y Desi g n f or S u bjects W h o Ha ve Bee n o n A u g me ntati o n 
T hera p y a t A n y Ti me .............................................................................................. 5  
Fi g ure  9 -1  
Sc he matics of St u d y Desi g n f or S u bjects W h o Ha ve Ne ver Bee n o n 
A u g me nt ati o n T hera p y  ......................................................................................... 2 7  
Fi g ure  9 -2  
Sc he matics of St u d y Desi g n f or S u bjects W h o Ha ve Bee n o n A u g me ntati o n 
T hera p y at A n y Ti me  ............................................................................................ 2 8  


Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 2 0  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
Li st of A b br e vi ati o n s  
A b bre vi ati o n   
Defi niti o n  
A A T  
al p ha -1 a ntitr y psi n  
A A T D  
al p ha -1 a ntitr y psi n deficie nc y  
A b  
a nti b o d y 
A E  
a d verse e ve nt  
A L P  
al kali ne p h os p hatase  
A L T  
ala ni ne tra nsa mi nase  
A S T  
as partate tra nsa mi nase 
A T S  
A merica n T h oracic S ociet y  
β -h C G  
beta -h u ma n c h ori o nic g o na d otr o pi n  
B MI  
b o d y mass i n de x  
C D  
c o m pact disc  
CI  
c o nfi de nce i nter val  
C O P D  
c hr o nic o bstr ucti ve p ul m o nar y disease  
C P A P  
cli nical p har mac ol o g y a nal ysis pla n  
C R F  
case re p ort f or m  
C R O  
c o ntract researc h or ga nizati o n  
 
 
C S R  
cli nical st u d y re p ort  
C T C A E  
C o m m o n T er mi n ol o g y Criteri a f or A d verse E ve nts  
 
 
E C G  
electr ocar di o gra m  
E D C  
electr o nic data ca pt ure  
E E N T  
e yes, ears, n ose, a n d t hr oat  
e G F R  
esti mate d gl o mer ular filtrati o n rate  
E ma x  
ma xi m u m effect  
 
 
 
 
E T T  
Earl y T er mi nati o n of Treat me nt  
F A S  
F ull A nal ysis Set  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F E V 1 
f orce d e x pirat or y v ol u me i n 1 sec o n d 
FI H  
first-i n-h u ma n  
F S H  
f ollicle-sti m ulati n g h or m o ne 
G C P  
G o o d Cli nical Practice  
G G T  
ga m ma -gl uta m yl tra nsferase  
G LI  
Gl o bal L u n g F u ncti o n I nitiati ve  
 
 
G P S  
Gl o bal P atie nt Safet y  
H Bs A g  
he patitis B s urface a nti ge n  
H C V  
he patitis C vir us  
HI P A A  
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act  
HI V -1/ HI V -2 A bs   
a nti b o dies a gai nst h u ma n i m m u n o deficie nc y vir uses 1 a n d 2  
I B 
I n vesti gat or’s Br oc h ure 
I C F 
i nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o u ncil f or Har m o nizati o n 


Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 2 1  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
A b bre vi ati o n   
Defi niti o n  
I C MJ E 
I nter nati o nal C o m mittee of M e dical J o ur nal E dit ors 
I E C 
i n de pe n de nt et hics c o m mittee 
 
 
I M P 
i n vesti gati o nal me dici nal pr o d uct 
I R B 
i nstit uti o nal re vie w b oar d 
I W R S 
i nteracti ve we b or v oice res p o nse s yste m 
 
 
Ma x  
ma xi m u m val ue  
 
 
Mi n  
mi ni m u m val ue  
 
 
M M R M  
mi xe d -effects m o del f or re peate d meas ures  
N  
size of s u bsa m ple 
 
 
P D  
p har mac o d y na mic, p har mac o d y na mics  
P E  
p h ysical e xa mi nati o n  
 
 
PIs  
pri nci pal i n vesti gat ors  
Pi Z Z  
h o m oz y g o us f or t he Z m utati o n i n t he S E R PI N A 1  ge ne t hat e nc o des t he A A T pr otei n  
P K  
p har mac o ki netic, p har mac o ki netics  
p p F E V 1 
perce nt pre dicte d f orce d e x pirat or y v ol u me i n 1 sec o n d  
q 1 2 h  
e ver y 1 2 h o urs  
Q T  
Q T i nter val  
Q T c  
Q T i nter val c orrecte d  
Q T c F  
Q T i nter val c orrecte d b y Fri dericia's f or m ula  
R N A  
ri b o n ucleic aci d 
S A E  
seri o us a d verse e ve nt 
S A P  
statistical a nal ysis pla n 
 
 
S D  
sta n dar d de viati o n 
S E R PI N A 1  
seri ne ( or c ystei ne) pr otei nase i n hi bit or, cla de A (al p ha -1a nti pr otei nase, a ntitr y psi n), 
me m ber 1  
S E T  
st u d y e xec uti o n tea m 
 
 
S U S A R  
s us pecte d, u ne x pecte d, seri o us a d verse reacti o n 
T E  
treat me nt-e mer ge nt  
U L N  
u p per li mit of n or mal  
U S A  
U nite d States of A merica  
W H O Dr u g  
W orl d Healt h Or ga nizati o n -Dr u g Dicti o nar y  
 


Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 2 2  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
5  
I N T R O D U C TI O N 
5. 1   
B a c k gr o u n d  
Al p ha -1 a ntitr y psi n deficie nc y ( A A T D) is a ge n etic dis or der c h aracterize d b y l o w circ ulati n g 
le vels of al p ha-1 a ntitr y psi n ( A A T). A A T is pr o d uce d pri maril y i n t he li ver a n d secrete d i nt o t he 
bl o o d, alt h o u g h ot her cell t y pes, i ncl u di n g l u n g e pit helial cells, m o n oc ytes, macr o p ha ges, a n d 
ne utr o p hils, pr o d uce t he pr otei n l ocall y. 1 , 2 A A T i n hi bits se veral seri ne pr ote i nases secrete d b y 
i nfla m mat or y cells ( m ost n ota bl y ne utr o p hil el astase, cat he psi n G, a n d pr ot ei nase-3) a n d t h us 
pr otects or ga ns s u c h as t he l u n g fr o m da ma ge b y t hese pr otei nases, es peci all y d uri n g peri o ds of 
i nfecti o n a n d i ncrease d i nfla m mati o n. 
A si n gle p oi nt m utati o n i n t he Z -allele of S E R PI N A 1  (t he ge ne e nc o di n g A A T) lea ds t o pr otei n 
misf ol di n g, i ntracell ular p ol y merizati o n of misf ol de d m uta nt Z -A A T pr ot ei n, a n d re d uce d 
secreti o n of acti ve Z-A A T pr otei n. C o nse q ue ntl y, circ ulati n g A A T le v els i n i n di vi d ua ls 
h o m oz y g o us f or t he Z -all ele (Pi Z Z ) are m ar ke dl y re d uce d; o nl y a p pr o xi matel y 1 5 % of Z-A A T 
pr otei n f ol ds c orrectl y a n d is secrete d b y t he cell. T he re d u ce d le vels of circ ulati n g, acti ve A A T 
res ult i n a n i m bala nce b et wee n pr otei nas e a n d a nti pr otei nase activit y, w hic h has its greatest 
i m pact i n t he l u n g. C o ns e q ue ntl y, l u n g tiss ue is d a ma ge d o ver ti me, res ulti n g i n e m p h yse ma, a 
f or m of c hr o ni c o bstr ucti ve p ul m o nar y disease ( C O P D). T his effect is m ost pr o n o u nce d i n Pi Z Z  
i n di vi d uals a n d t y picall y ma nifests i n mi d dle a ge, res ulti n g i n a decli ne i n q ualit y of life a n d 
s h orte ne d lifes pa n ( mea n 6 7 years of a ge). 3 Pi Z Z  i n di vi d uals acc o u nt f or t h e maj orit y of t h ose 
wit h cli nicall y rele va nt A A T D l u n g disease. T he acc u m ulati o n of p ol y m erize d Z -A A T pr otei n 
wit hi n he pat oc yt es ca us es c yt ot o xicit y t hat ca n res ult i n ne o natal li ver disease or pr o gressi ve 
li ver disease i n a d ult h o o d t hat ca n lea d t o cirr h osis or li ver ca n cer. 
V X -8 6 4 is bei n g de vel o p e d as a tr eat me nt f or A A T D. V X -8 6 4 has t h e p ote ntial t o rest ore 
p h ysi ol o gical le vels of circ ulati n g A A T acti vit y a n d t h us re d uce t he ris k of l u n g diseas e. B y 
pre ve nti n g Z -p ol y mer f or mati o n i n t he li ver, V X -8 6 4 ma y als o re d uce t he ris k of de vel o pi n g 
pr o gressi ve li ver disease (fi br osis a n d cirr h osis).  
5. 2   
St u d y R ati o n al e  
T he p ur p ose of t his st u d y is t o e val uate t he efficac y a n d s afet y pr ofile of V X -8 6 4, i ncl u di n g 
i de ntificati o n of a n o pti mal V X-8 6 4 d ose, t o s u p p ort f urt her cli nical de ve l o p me nt as a treat me nt 
f or A A T D. 
 
 
 
6  
S T U D Y O B J E C TI V E S  
6. 1   
Pri m ar y O bj e cti v e s  
•  T o e val uate t he  effi cac y of V X -8 6 4 i n Pi Z Z  s u bjects as meas ure d b y plas ma f u ncti o nal A A T 
le vels 
•  T o e val uate t he s afet y a n d t olera bilit y of V X -8 6 4 i n Pi Z Z  s u bjects 


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6. 2   
S e c o n d ar y O bj e cti v e s  
•  T o e val uate t he effi cac y of V X -8 6 4 i n Pi Z Z  s u bjects as meas ure d b y plas ma a nti ge nic A A T 
le vels  
•  T o e val uate t he p har mac o ki netics ( P K) of V X -8 6 4 i n Pi Z Z  s u bjects 
7  
S T U D Y E N D P OI N T S  
7. 1   
Pri m ar y E n d p oi nt s  
•  C ha n ge fr o m bas eli ne i n  plas ma f u ncti o nal A A T l e vels at Da y 2 8  
•  Safet y a n d t olera bilit y assess me nts base d o n a d v erse e ve nts ( A Es), cli nical la b orat or y val u es, 
sta n dar d 1 2-lea d E C Gs, vital si g ns, a n d p ulse o xi metr y 
7. 2   
S e c o n d ar y E n d p oi nt s  
•  C ha n ge fr o m bas eli ne i n plas ma a nti ge nic A A T l e vels at Da y 2 8  
•  P K para meters of V X -8 6 4 deri ve d fr o m plas m a c o nce ntrati o n -ti me data  


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8  
S T U D Y P O P U L A TI O N  
Eli gi bilit y will be re vie we d a n d d oc u me nt e d b y a n a p pr o priatel y q u alifie d me m ber of t he 
i n vesti gat or's te a m bef ore s u bjects are ra n d o mize d a n d will als o be c o nfir me d bef ore t he first 
d ose of st u d y dr u g o n Da y  1.  
S u bjects w h o meet all of t he i ncl usi o n criteria a n d n o ne of t he e x cl usi o n criteria will be eli gi ble.  
8. 1   
I n cl u si o n Crit eri a 
1.  S u bject will si g n a n d dat e a n i nf or me d c o nse nt f or m (I C F).  
2.  Willi n g a n d a ble t o c o m pl y wit h sc he d ule d visits, treat me nt pla n, st u d y restricti o ns, 
la b orat or y tests, c o ntrace pti ve g ui deli nes, a n d ot h er st u d y pr oce d ures. 
3.  S u bjects will be 1 8 t hr o u g h 8 0  years o f a ge, i ncl usi ve, at t he ti me of si g ni n g of t he I C F.  
4.  All fe male s u bjects m ust ha ve a n e gati ve pre g na nc y test at scree ni n g (ser u m test). 
Pre me n o pa usal f e male s u bjects of c hil d -beari n g p ote ntial m ust als o ha ve a ne gati ve 
pre g na nc y t est o n Da y  1 ( uri ne test)  a n d m ust n ot be breastf ee di n g or pla n ni n g t o bec o m e 
pre g na nt d uri n g t he st u d y or wit hi n 9 0  da ys after t he last st u d y dr u g d ose.  
5.  B o d y mass i n de x ( B MI) of 1 8. 0 t o 3 5. 0 k g/ m 2, i ncl usi ve. 
6.  S u bjects m ust ha ve a Pi Z Z ge n ot y pe c o nfir me d at scree ni n g.  
N O T E: Pi Z Z  ge n ot y pe m ust be teste d at t he ce ntral la b orat or y. Hist orical ge n ot y p e res ults 
ca n be use d t o d eter mi ne eli gi bilit y if t he y were o btai ne d as part of a differe nt Verte x st u d y . 
I n a d diti o n, if t he scree ni n g Pi Z Z ge n ot y p e res ult is n ot recei ve d bef ore ra n d o m izati o n, a 
pre vi o us n o n -Verte x Pi Z Z ge n ot y pe la b orat or y re p ort (a p pr o ve d b y t he me dical m o nit or or 
desi g nee) ma y b e use d t o esta blis h pr o visi o nal eli gi bilit y. S u bjects w h o h a ve bee n 
r a n d o mize d a n d w h ose scree ni n g ge n ot y pe s u bse q ue ntl y d oes n ot c o nfir m st u d y 
eli gi bilit y m ust be disc o nti n ue d fr o m t he st u d y ( Secti o n 9. 1 0 ). 
7.  Plas ma a nti ge nic A A T le vel < 8 µ M d uri n g s cree ni n g.  
N O T E: F or s u bjects w h o ha ve bee n o n a u g me ntati o n t hera p y at a n y ti me, res ults use d t o 
c o nfir m eli gi bilit y m ust be dra w n > 4 2 da ys after t he last d ose of a u g me nt ati o n t hera p y. 
A nti ge nic A A T le vels m ust be o btai ne d fr o m t he ce ntral la b orat or y a n d res ults c o nf ir me d 
bef ore ra n d o mizati o n.  
8.  Willi n g t o re mai n off of a u g m e ntati o n t hera p y fr o m > 4 2 da ys bef ore a nti ge nic A A T le vels 
are o btai ne d f or eli gi bilit y t hr o u g h t he last Safet y F oll o w -U p Visit.  


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8. 2   
E x cl u si o n Crit eri a  
1.  Hist or y or prese n ce of a n y ill ness or cli nical c o n diti o n t hat, i n t he o pi ni o n of t he i n vesti gat or, 
mi g ht affect t he s u bject's safet y or c o m plia nce or c o nf o u n d t he res ults of t he st u d y  or p ose a n 
a d diti o nal ris k i n a d mi nisteri n g st u d y dr u g(s) t o t he s u bject. T his i ncl u des, b ut is n ot li mite d 
t o, t he f oll o wi n g: 
•  S oli d or ga n, l u n g, or he m at ol o gical tra ns pla ntati o n or is c urre ntl y o n a tra ns pla nt list  
•  S u bjects w h o ha ve u n der g o ne gastrect o m y or ot her gastr oi ntesti nal tract s ur ger y, e x ce pt 
a p pe n dect o m y, c h olec yst ect o m y, a n d he m orr h oi d s ur ger y.  
•  Ca ncer, e x ce pt f or basal cell s ki n ca ncer, Sta ge 0 cer vical carci n o ma i n sit u , a n d 
Sta ge  0  mel a n o ma  (re gar dless of rec urre n ce), or a de q uatel y treate d s q ua m o us cell s ki n 
ca ncer a n d S ta ge 1 m ela n o ma ( wit h n o rec urre n ce d uri n g t he last 5 years)  
2.  Hist or y of si g nifica nt alc o h o l c o ns u m pti o n f or a peri o d of m ore t ha n 3 c o nsec uti ve m o nt hs 
wit hi n 1 year bef ore scree ni n g, d efi ne d as m or e t h a n 1 4 dri n ks/ wee k f or fe males or 
2 1  dri n ks/ wee k f or m ales ( 1  dri n k  =  5  o u nces ( 1 5 0  m L) of wi ne or 1 2  o u n ces ( 3 6 0  m L) of 
beer or 1. 5  o u n ces ( 4 5  m L ) of har d li q u or). 
3.  Ille gal dr u g use wit hi n 1 year bef ore s cree ni n g as dee me d b y t he i n vesti gat or, i ncl u di n g b ut 
n ot li mite d t o c ocai ne, her oi n, a n d ot her o pi oi ds.  
4.  O n g oi n g or pri or partici p ati o n i n a st u d y of a n i n vesti gati o nal treat me nt wit hi n 2 8  da ys or 
5  ter mi nal half-li ves ( w hi c he ver is l o n ger) bef ore s cree ni n g. T he d urati o n of t he ela pse d ti me 
ma y b e l o n ger if re q uire d b y l ocal re g ulati o ns.  
5.  Hist or y of use of ge n e t h era p y or R N Ai t hera p y at a n y ti me pre vi o usl y.  
6.  Use of oral c ortic oster oi ds (at a n y d ose) f or a d urati o n of greater t ha n 3 m o nt hs at a n y ti me 
wit hi n t he 3  m o nt hs bef ore scree ni n g.  
7.  A p ost -br o nc h o dilat or f orce d e x pirat or y v ol u me i n 1 sec o n d ( F E V 1) val ue < 3 0 % of pre dicte d 
mea n f or a ge, se x, a n d hei g ht (e q u ati o ns of t he Gl o bal L u n g F u ncti o n I niti at i ve [ G LI]) d uri n g 
scree ni n g. P ost-br o nc h o dilat or s pir o metr y m eas ure me nts m ust meet A meri ca n T h oracic 
S ociet y ( A T S)/ E ur o pea n Res pirat or y S ociet y ( E R S) criteria f or acce pta bilit y a n d 
re peat a bilit y.4 , 5 , 6  
 
N O T E: if s pir o metr y ca n n ot be perf or me d at scree ni n g, hist orical p ost -br o nc h o dilat or 
perce nt pre dicte d F E V 1 ( p p F E V1) res ults wit hi n 1 year bef ore s cree ni n g ca n be use d t o 
deter mi ne eli gi bilit y. Hist orical p ost -br o nc h o dilat or s pir o metr y meas ure me nts  are < 3 0 % of 
pre dicte d mea n f or a ge, s e x, a n d hei g ht (e q u ati o ns of t he G LI) a n d m ust meet A T S/ E R S 
criteria f or acce pta bilit y a n d re peata bilit y.  
8.  All cli nicall y i m p orta nt p ul m o nar y disease ot her t ha n A A T D -relate d p ul m o nar y disease, 
i ncl u di n g b ut n ot li mite d t o i nterstitial l u n g disease, c ystic fi br osis, p ul m o nar y h y perte nsi o n 
wit h or wit h o ut c or p ul m o nale, hist or y of p ul m o nar y e m b olis m, or mali g n a nt l u n g ca ncer.  
9.  U nsta ble A A T D -relat e d C O P D as dee me d b y t he i n vesti gat or.  
1 0.  D oc u me nte d c hr o nic nee d f or p ositi ve a ir wa y press ure t hera p y b e y o n d n oct ur nal use. 


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1 1.  D oc u me nte d me dical hist or y or dia g n osis of cli nicall y e vi d e nt li ver disease i ncl u di n g b ut n ot 
li mite d t o a pri or dia g n osis of he patitis of a n y eti ol o g y, cirr h osis, p ortal h y p erte nsi o n, or 
c o nfir me d or s us p ecte d es o p ha geal varices.  
1 2.  A n y of t he f oll o wi n g a b n or mal la b orat or y v al ues at scree ni n g:  
•  Platelet c o u nt < 1 5 0 × 1 0 9/ L. 
•  Al b u mi n ≤3. 5 g/ d L  
•  I nter nati o nal n or malize d rati o ≥1. 2 
•  He m o gl o bi n < 1 0 g/ d L  
•  T otal bilir u bi n > u p per li mit of n or mal ( U L N)  
•  As partate tra nsa mi nase ( A S T), ala ni ne tra ns a mi nase ( A L T), ga m ma -gl uta m yl tra nsferas e 
( G G T), or al kali ne p h os p hatase ( A L P) > 2 × U L N  
•  Esti mate d gl o mer ular filtrati o n rate (e G F R) ≤3 0  m L/ mi n/ 1. 7 3  m 2 (calc ulate d b y t he 
M o dificati o n of Diet i n Re nal Diseas e St u d y E q uati o n)  
1 3.  Ris k fact ors f or T orsa de de P oi ntes (e. g., fa milial l o n g Q T s y n dr o me, c hr o nic h y p o k ale mia, 
heart fail ure) or c o nc o mita nt me dicati o ns t hat pr ol o n g t he Q T/ Q Tc i nter val or a n y hist or y of 
u nsta ble car di ac dis or der t hat, i n t he o pi ni o n of t he i n vesti gat or, mi g h t p ut t he s u bject at ris k 
or ma y c o nf o u n d t he res ults of t he st u d y.  
1 4.  A n y cli nicall y si g nifica nt E C G a b n or malit y (as det er mi ne d b y t he i n vesti gat or) or me dia n 
Q Tc F of tri plicate sta n d ar d 1 2 -lea d E C Gs > 4 5 0 msec at scree ni n g. 
1 5.  Hist or y of Gil bert's S y n dr o me.  
1 6.  P ositi ve f or he patitis B s urface a nti ge n ( H Bs A g), he patitis C vir us ( H C V) R N A , or HI V-1 
a n d HI V-2 a nti b o dies d uri n g scree ni n g.  
1 7.  Use of t he s u bsta nces, acti vities, or de vices d uri n g t he ti me peri o ds i n dicate d i n Secti o n  9. 5 . 
1 8.  Ci garette s m o ki n g d uri n g t he past 6 m o nt hs or a p ositi ve c oti ni ne test at scree ni n g t hat is d ue 
t o s m o ki n g or a n el ectr o nic nic oti ne deli ver y s yste m. P ositi ve c oti ni ne test d ue t o nic oti ne 
re place me nt t hera p y f or t he p ur p oses of s m o ki n g cessati o n, as atteste d b y t h e i n vesti gat or, is 
per mitte d.  
1 9.  Male s u bjects w h o pla n t o d o nate s per m or w h o ha ve a fe male p art ner w h o is pre g n a nt, 
breastfee di n g, or pla n ni n g t o bec o me pre g n a nt d uri n g t he  st u d y or wit hi n 9 0 da ys after t he 
last st u d y dr u g d ose. 
2 0.  T he s u bject or a cl ose relati ve of t he s u bject is t he i n vesti gat or or a s u b -i n vesti gat or, researc h 
assista nt, p har macist, st u d y c o or di nat or, or ot her staff directl y i n v ol ve d wit h t he c o n d uct of 
t he st u d y. A n a d ult ( 1 8 years of a ge or ol der) w h o is a relati ve of a st u d y st aff me m ber ma y 
be e nr olle d i n t he st u d y pr o vi de d t hat  
•  t he a d ult li ves i n de pe n de ntl y of a n d d o es n ot resi d e wit h t he st u d y staff me m ber, a n d 
•  t he a d ult partici pates i n t he st u d y at a site ot her t ha n t he site at w hic h t he fa mil y m e m ber 
is e m pl o ye d. 


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2 1.  H y p erse nsiti vit y  t o a n y c o m p o ne nt of t he i n vesti gati o nal dr u g pr o d uct or pl ace b o 
(e. g., lact ose). 
2 2.  S u bjects  f or w h o m disc o nti n uati o n of a u g me nt ati o n t hera p y is n ot c o nsi dere d t o be i n t heir 
best  i nterest, base d o n t h e cli nical j u d ge me nt of t h e treati n g p h ysicia n. 
9  
S T U D Y I M P L E M E N T A TI O N  
9. 1   
St u d y D e si g n  
T his is a P hase 2, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d st u d y of V X -8 6 4. Sc he matics of 
t he st u d y desi g n are s h o w n i n Fi g ure  9 -1  a n d Fi g ure  9 -2 .  
A p pr o xi matel y 4 0 s u bj ects i n t otal wit h t he Pi Z Z  ge n ot y p e a n d a nti ge ni c A A T le vels < 8  µ M at 
scree ni n g will be ra n d o mize d t o V X-8 6 4 or t he place b o 2: 1: 1: 1 t o V X -8 6 4 5 0 0 e ver y 1 2 h o urs 
( q 1 2 h), V X-8 6 4 3 0 0 m g q 1 2 h, V X -8 6 4 1 0 0 m g q 1 2 h, or place b o.  
Of t hese, a p pr o xi matel y 2 0 s u bjects will be ra n d o mize d 2 : 2: 1 t o V X-8 6 4 5 0 0 m g q 1 2 h, V X -8 6 4 
3 0 0 m g q 1 2 h, or place b o first. T he re mai ni n g s u bj ects (a p pr o xi matel y 2 0) will be ra n d o mize d 
2: 2: 1 t o V X -8 6 4 5 0 0 m g q 1 2 h, V X -8 6 4 1 0 0 m g q 1 2 h, or place b o.  
Ra n d o mizati o n will be stratifie d b y p ost -br o nc h o dilat or p p F E V 1 o bta i ne d eit her d uri n g t he 
Scree ni n g Peri o d or fr o m a hist orical p ost -br o nc h o dilat or p p F E V 1 val ue meas ure d wit hi n 1 year 
bef ore s cree ni n g ( < 5 0 % vers us ≥5 0 %).  
Scree ni n g ass ess me nts f or s u bjects w h o ha v e ne ver bee n o n a u g m e ntati o n t hera p y are liste d i n 
Ta ble  3 -1 . Scree ni n g ass ess me nts f or s u bjects w h o ha ve bee n o n a u g me ntati o n t hera p y at a n y 
ti me are liste d i n Ta ble  3 -2 . Treat me nt Peri o d assess me nts f or all s u bjects are liste d i n Ta ble  3 -3 . 
Fi g ure  9 -1   
Sc he m atics of St u d y Desi g n f or S u bjects W h o H a ve Ne ver Bee n o n 
A u g me nt ati o n T her a p y  
 
A A T:  al p ha-1 a ntitr y psi n; N: n u m ber of s u bj ects; q 1 2 h: e ver y 1 2 h o urs  
N otes: Fi g ure is n ot dra w n t o scale. S u bj ect n u m bers i ncl u de s u bj ects w h o ha ve ne ver bee n o n a u g me ntati o n t hera p y 
a n d s u bj ects w h o ha ve bee n o n a u g me ntati o n t hera p y at a n y ti me. A nti ge nic A A T le vels m ust be dra w n t o 
c o nfir m e li gi bilit y a n d se nt t o t he ce ntral la b orat or y; res ults m ust be o btai ne d a n d c o nfir me d t o be < 8 µ M 
bef ore ra n d o mizati o n. O nce a nti ge nic A A T le vels ha ve bee n c o nfir me d t o meet t his eli gi bilit y criteri o n, 
ra n d o mizati o n a n d Da y 1 ca n occ ur a n y ti me wit hi n t he re mai ni n g scree ni n g wi n d o w. Sites s h o ul d all o w at 
le ast 1 4 d a ys f or s a m ple pr o cessi n g a n d a nti ge nic A A T l e vel res ult re p orti n g. 
Tr e at m e nt P eri o d  
2 8 d a y s  
V X -8 6 4 5 0 0 m g q 1 2 h N = 1 6  
V X -8 6 4 3 0 0 m g q 1 2 h N = 8  
Pl a c e b o N = 8  
S af et y  
F oll o w -u p Vi sit s  
1 4 a n d 2 8 d a y s aft er l a st 
d o s e  
V X -8 6 4 1 0 0 m g q 1 2 h N = 8  
V X -8 6 4 W a s h o ut Vi sit  
7 d a y s aft er l a st d o s e  
S cr e e ni n g  
u p t o 3 5 d a y s  


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Fi g ure  9 -2   
Sc he m atics of St u d y Desi g n f or S u bjects W h o H a ve Bee n o n A u g me nt ati o n  
T her a p y at A n y Ti me  
 
A A T: al p ha -1 a ntitr y psi n; N: n u m ber of s u bj ects; q 1 2 h: e ver y 1 2 h o urs  
N otes: Fi g ure is n ot dra w n t o scale. S u bj ect n u m bers i ncl u de s u bj ects w h o ha ve ne ver bee n o n a u g me ntati o n t hera p y 
a n d s u bj ects w h o ha ve bee n o n a u g me ntati o n t hera p y at a n y ti me. S u bj ects m ust disc o nt i n ue a u g me ntati o n 
t hera p y >4 2 d a ys  bef ore a nti ge nic A A T le vels are dra w n a n d se nt t o t he ce ntr al l a b or at or y t o c o nfir m 
eli gi bilit y; res ults m ust be c o nfir me d t o be < 8  µ M bef ore ra n d o mizati o n. O nce a nti ge nic A A T le vels ha ve bee n 
c o nfir me d t o meet t his eli gi bilit y criteri o n, ra n d o mizati o n a n d Da y 1 ca n occ ur a n y ti me wit hi n t he re mai ni n g 
scree ni n g wi n d o w. Sites s h o ul d all o w at le ast 1 4  d a ys f or s a m ple pr ocessi n g a n d a nti ge nic A A T le vel 
res ults re p orti n g. S u bj ects ca n res u me a u g me ntati o n t hera p y after c o m pleti o n of assess me nts at t he last Safet y 
F oll o w -u p Visit.   
* Bl o o d sa m ples will be o btai ne d f or a nti ge nic a n d f u ncti o nal A A T le vels at t he sa me ti me t hat t he ot her scree ni n g 
la b orat or y assess me nts are perf or me d. If t he s u bj ect recei ve d t he last d ose of a u g me ntati o n t hera p y > 4 2 da ys 
pri or, t his sa m ple ca n be use d t o meas ure a nti ge nic A A T le vel f or eli gi bilit y. If sa m ples are o btai ne d ≤4 2  da ys 
after t he last d ose of a u g me ntati o n t hera p y, a n ot her sa m ple m ust  be dra w n > 4 2 da ys after t he last d ose of 
a u g me ntati o n t he ra p y a n d se nt t o t he ce ntral la b orat or y t o c o nfir m eli gi bilit y.  
9. 1. 1   
S cr e e ni n g  
F or s u bjects w h o h a ve n e ver bee n o n a u g me ntati o n t hera p y,  t he Scree ni n g Peri o d ( Da y -3 5 
t hr o u g h Da y -1) will occ ur u p t o 3 5  da ys b ef ore t he first d ose of st u d y dr u g.  
F or s u bjects w h o h a ve b ee n o n a u g me ntati o n t hera p y at a n y ti me, t he Scree ni n g Peri o d ( Da y  -7 0 
t hr o u g h Da y -1) will occ ur u p t o 7 0  da ys b ef ore t he first d ose of st u d y dr u g. T he l ast d ose of 
a u g m e ntati o n t hera p y m ust ha ve bee n gi ve n > 4 2 d a ys bef ore t he a nti ge nic A A T le vel s are 
o bt ai ne d t o c o nfir m eli gi bilit y. T o esta blis h eli gi bilit y, a n a nti ge nic A A T le vel m ust be dra w n 
> 4 2  d a ys after t he l ast d ose of a u g me nt ati o n t her a p y  a n d se nt t o t he ce ntral la b orat or y. T he 
a nti ge ni c A A T res ult m ust be re vie we d t o c o nfir m eli gi bilit y bef ore ra n d o mizati o n. S u bjects will 
re mai n off a u g me ntati o n t hera p y t hereafter u ntil after t he last Safet y F oll o w-u p Visit has bee n 
c o n d ucte d.  
Tr e at m e nt P eri o d  
2 8 d a y s  
V X -8 6 4 5 0 0 m g q 1 2 h N = 1 6  
V X -8 6 4 3 0 0 m g q 1 2 h N = 8  
Pl a c e b o N = 8  
S af et y  
F oll o w -u p Vi sit s  
1 4 a n d 2 8 d a y s aft er l a st 
d o s e  
V X -8 6 4 1 0 0 m g q 1 2 h  N = 8  
Di s c o nti n u e 
a u g m e nt ati o n 
t h er a p y > 4 2 d a y s 
b ef or e  A A T l e v el s 
ar e dr a w n f or 
eli gi bilit y *  
S u bj e ct s m a y 
r e s u m e 
a u g m e nt ati o n 
t h er a p y 
aft er t h e l a st 
S af et y F oll o w -u p 
Vi sit  
V X -8 6 4 
W a s h o ut Vi sit  
7 d a y s aft er 
l a st d o s e 
S cr e e ni n g  
u p t o 7 0 d a y s  
4 2  d a y s  
A nti g e ni c A A T 
l e v el f or 
eli gi bilit y  


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Scree ni n g ass ess me nts will be use d t o c o nfir m t hat s u bjects meet t he eli gi bilit y criteria. T he 
i n vesti gat or ( or a n a p pr o priate a ut h orize d desi g nee at t he st u d y site) will o btai n i nf or me d c o nse nt 
fr o m eac h s u bject bef ore a n y st u d y pr oce d ure ta kes place. Scree ni n g pr oce d ures (i ncl u di n g 
i nf or me d c o nse nt) ca n b e perf or me d o v er m ore t ha n 1 da y. I nf or m e d c o nse nt m ust be obtai ne d 
pri or t o a n y pr oce d ures. Scree ni n g ass ess me nts t hat were n ot c o n d ucte d at t he i nitial visit d uri n g 
t he Scree ni n g Peri o d ma y be p erf or me d at h o me b y a q u alifie d visiti n g n urse or at t he cli nic (if 
per mitte d b y et hical a n d re g ulat or y a ut h orities a n d a gree d u p o n after i n vesti gat or a n d s u bj ect 
c o ns ultati o n).  
9. 1. 1. 1   
R e p etiti o n of S cr e e ni n g A s s e s s m e nt( s)  
If scree ni n g s pir o metr y meas ure me nts fail t o meet acce pta bilit y a n d re p eata bilit y criteria as 
s pecifie d b y A T S/ E R S g ui deli nes 4 , 5 , 6, re peat s pir o metr y e val uati o n ma y b e perf or me d. 
Ot her wise, re peati n g i n di vi d ual scree ni n g assess me nt(s) t hat di d n ot meet eli gi bilit y criteria is 
n ot per mitte d, wit h t he f oll o wi n g e x ce pti o ns t hat re q uire t he a p pr o val of t h e me dical m o nit or:   
•  If t here is clear e vi de nce of a da ma ge d sa m ple, la b orat or y err or, or e q ui p me nt malf u ncti o n, 
c ollecti o n of a re peat s a m ple f or t he a p pr o priate l a b orat or y test or assess m e nt ma y b e 
per mitte d.  
•  E x cl usi o nar y li ver f u n cti o n, platelet, he m o gl o bi n, al b u mi n , or e G F R tests res ults, w hic h ma y 
be reteste d o n ce.  
•  E x cl usi o nar y E C G tests r es ults, w hic h ma y b e ret este d o nce.  
T he re p eat scree ni n g ass ess me nt or bl o o d sa m ple ma y b e c o n d uct e d or dra w n, res pecti vel y at 
h o me b y a q ualifie d visiti n g n urse (if per mitte d b y et hical a n d re g ulat or y a ut h orities a n d a gree d 
u p o n after i n vesti gat or a n d s u bject c o ns ultati o n) or at t he cli nic. If re peat val ues of t he i n di vi d ual 
assess me nt(s) are wit hi n t he eli gi bilit y criteria a n d c o m plete d wit hi n t he scree ni n g wi n d o w, t he n 
t he s u bject is eli gi ble f or t he st u d y.  
9. 1. 1. 2   
R e s cr e e ni n g  
S u bjects ma y be rescree n e d o nl y o n ce. If a s u bject is rescree ne d, all scree ni n g ass ess me nts will 
be re peate d, e x ce pt f or:  
•  Pi Z Z  ge n ot y pi n g  
•  F ollicle -sti m ulati n g h or m o ne ( F S H) le vel (if ser u m F S H le vel was i n t he p ost me n o pa usal 
ra n ge as d eter mi ne d b y t he la b orat or y p erf or mi n g t he test d uri n g pri or scree ni n g)  
If a s u bject is rescree ne d, a ne w scree ni n g wi n d o w will be gi n w he n t h e first rescree ni n g 
assess me nt has bee n i nitiate d . 
9. 1. 1. 3   
E xt e n si o n of t h e S cr e e ni n g P eri o d  
A s u bject ma y ha ve t h e Scree ni n g Peri o d wi n d o w e xte n de d b y 2 wee ks wit h o ut me dical m o nit or 
a p pr o val f or t h e f oll o wi n g reas o ns:  
•  Re petiti o n of Scree ni n g Peri o d assess me nts (Secti o n 9. 1. 1. 1 ) 
•  U ne x pecte d o perati o nal or l o gistic dela ys, or t o meet t he eli gi bilit y criteria.  


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F or s u bjects w h o h a ve n e ver bee n o n a u g me ntati o n t hera p y o nl y, a s u bject ma y h a ve t he 
Scree ni n g Peri o d wi n d o w e xte n de d f or a n a d diti o nal 2 wee ks (t otal of 4  wee ks e xte nsi o n) wit h 
me dical m o nit or a p pr o val.  
9. 1. 2   
Tr e at m e nt P eri o d  
T he Treat me nt Peri o d will be ra n d o mize d, d o u ble -bli n d, a n d place b o -c o ntr olle d. It will last 
a p pr o xi matel y 2 8 da ys. St u d y dr u g a d mi nistrati o n details are pr o vi de d i n Secti o n  9. 7 . 
S u bjects w h o pre mat urel y disc o nti n ue st u d y dr u g treat me nt will re mai n i n t he st u d y fr o m t he 
ti me of disc o nti n uati o n of st ud y dr u g treat me nt t hr o u g h t he last sc h e d ule d st u d y visit a n d 
c o m plete assess me nts f or all st u d y visits, as descri be d i n Secti o n  9. 1. 4 . 
9. 1. 3   
W a s h -o ut a n d F oll o w -u p Vi sit s  
S u bjects will ha ve a V X -8 6 4 Was h o ut Visit 7 ( ±  2)  da ys after t he last d ose of st u d y dr u g a n d 
Safet y  F oll o w -u p Visits 1 4  ( ± 2)  a n d 2 8 ( ± 2)  d a ys after t he last d ose of st u d y dr u g.  
9. 1. 4   
E arl y T er mi n ati o n of Tr e at m e nt   
If a s u bject pre mat urel y disc o nti n ues st u d y treat me nt, a n Earl y Ter mi nati o n of Treat me nt ( E T T) 
Visit s h o ul d be sc he d ule d as s o o n as p ossi ble after t he decisi o n t o ter mi nat e st u d y treat me nt. 
S u bjects w h o pre mat urel y disc o nti n ue treat me nt will be re q uire d t o c o m pl ete b ot h Safet y 
F oll o w -u p Visits. T he assess me nts perf or m e d at t he E T T a n d Safet y F oll o w -u p Visits are liste d 
i n Ta ble  3 -3 .  
If t he E T T Visit occ urs bet wee n 1 2 a n d 2 1 da ys (i ncl usi ve) after t he last d ose of st u d y dr u g, t he n 
t he E T T Visit will re place t he Safet y F oll o w-u p Visit 1 4 da ys after t he last d ose of st u d y dr u g, 
a n d a se parate Safet y F oll o w -u p Visit 1 4 da ys after t he last d ose will n ot be re q uire d; t he Safet y 
F oll o w -u p Visit 2 8 da ys after t he l ast d ose will be re q uire d. If t he E T T Visit occ urs ≥2 2  da ys 
after t he l ast d ose of st u d y dr u g, t h e E T T Visit will re place t h e Safet y F oll o w -u p Visit 2 8  da ys 
after t he l ast d ose, a n d a se parat e Safet y F oll o w -u p Visit 2 8 da ys after t he l ast d ose will n ot be 
re q uire d.  
If a s u bject wit h dra ws c o nse nt f or t he st u d y, n o f urt her assess me nts will be perf or me d. Verte x 
ma y retai n a n d c o nti n ue t o use a n y data a n d sa m pl es c ollecte d bef ore s uc h wit h dra wal of 
c o nse nt.  


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9. 2   
L o st t o F oll o w -u p  
A s u bject will be c o nsi dere d l ost t o f oll o w u p if b ot h of t he f oll o wi n g o cc ur:  
•  T he s u bject misses 2 c o nsec uti ve st u d y visits (tele p h o ne c o ntact, cli nic, a n d/ or h o me heat h 
visit) a n d is s u bse q ue ntl y u na ble t o be c o ntacte d b y tele p h o n e ( 3 d oc u m e nte d atte m pts b y 
tele p h o ne wit hi n 1 wee k f oll o wi n g t he sec o n d misse d visit)  
•  T he s u bject d oes n ot res p o n d wit hi n 1 wee k t o a re gistere d letter se nt after t he 3 atte m pte d 
tele p h o ne c o ntacts. 
9. 3   
M et h o d of A s si g ni n g S u bj e ct s t o Tr e at m e nt Gr o u p s  
A p pr o xi matel y 4 0 s u bj ects i n t otal will be ra n d o mize d t o recei ve V X -8 6 4 or place b o 2: 1: 1: 1 t o 
V X -8 6 4 5 0 0 m g e ver y 1 2 h o urs ( q 1 2 h), V X -8 6 4  3 0 0 m g q 1 2 h, V X -8 6 4 1 0 0 m g Q 1 2 h, or 
place b o.   
Of t hese, a p pr o xi matel y 2 0 s u bjects will be ra n d o mize d 2: 2: 1 t o V X -8 6 4 5 0 0 m g q 1 2 h, V X -8 6 4 
3 0 0 m g q 1 2 h, or place b o first. T he re mai ni n g s u bj ects (a p pr o xi matel y 2 0) will be ra n d o mize d 
2: 2: 1 t o V X -8 6 4 5 0 0 m g q 1 2 h, V X -8 6 4 1 0 0 m g q 1 2 h, or place b o.  
Eac h ra n d o mize d s u bject will be assi g ne d a u ni q u e s u bject n u m ber. Ra n d o mizati o n will be 
stratifie d b y p ost-br o nc h o dilat or p p F E V 1 o btai ne d eit her d uri n g t he Scree ni n g Peri o d or fr o m a 
p ost -br o nc h o dilat or hist orical p p F E V 1 val ue meas ure d wit hi n 1 year bef ore scree ni n g ( < 5 0 % 
vers us ≥5 0 %).  
A n i nteracti ve we b or v oi ce res p o ns e s yste m (I W R S) will be use d t o assi g n s u bjects t o treat me nt. 
T he ra n d o mizati o n c o de will be pr o d uce d b y Verte x Bi ostatistics or a q ualifie d ra n d o mizati o n  
ve n d or. T he Verte x st u d y bi ostatisticia n will re vie w a n d a p pr o ve t he pr o d u cti o n of t he fi nal 
ra n d o mizati o n list, w hic h will be re vie we d a n d a p pr o ve d b y a d esi g n ate d u n bli n de d 
bi ostatisticia n w h o is n ot a me m ber of t h e st u d y e x ec uti o n tea m ( S E T).  
9. 4   
R ati o n al e f or St u d y El e m e nt s  
9. 4. 1   
R ati o n al e f or St u d y D e si g n  
A parallel -gr o u p, ra n d o mize d, place b o -c o ntr olle d desi g n was selecte d t o mi ni mize t he i m bala nce 
i n t he distri b uti o n of t he baseli ne c haracteristics of t he differe nt d osi n g gr o u ps. A d o u ble-bli n d 
desi g n was i nc l u de d t o pre ve nt bias i n e n d p oi nt assess me nt b y t he i n vesti gat or or s u bject.  
T he 2 8 -da y tr eat me nt d ur ati o n is base d o n t he esti mate d plas ma half -life f or A A T of 
a p pr o xi matel y 5  da ys, i n dicati n g t hat plas ma A A T le vels will reac h > 9 5 % of stea d y -state l e vels 
b y t he e n d of t he treat me nt peri o d. T heref ore, it is e x pecte d t hat t he 2 8 -da y treat me nt d urati o n of 
V X -8 6 4 will be s uffici e nt t o e val uate t he ma xi mal effect of eac h d ose l e vel o n plas ma A A T.  
9. 4. 2   
R ati o n al e f or St u d y P o p ul ati o n  
S u bjects wit h a c o nfir me d Pi Z Z  ge n ot y p e were sel ecte d bas e d o n t he pr o p ose d mec ha nis m of 
acti o n of V X-8 6 4.  
9. 4. 3   
R ati o n al e f or St u d y Dr u g D o s e  
 
 


Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
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T he d oses sel ecte d will pr o vi de a n a de q uate assess me nt of 
t he d ose-res p o ns e rel ati o ns hi p a n d safet y pr ofile of V X-8 6 4 i n t he e x p os ure ra n ge of i nterest.  
9. 4. 4   
R ati o n al e f or St u d y A s s e s s m e nt s  
All safet y a n d P K assess me nts are sta n dar d meas ure me nts f or cli nical st u dies i n dr u g 
de vel o p me nt.  
Bl o o d sa m ples will be c ollecte d t o e val uate t h e effect of V X -8 6 4 o n plas ma f u ncti o nal a n d 
a nti ge ni c A A T le v els i n Pi Z Z  s u bjects base d o n t he mec ha nis m of acti o n of V X-8 6 4.  
9. 5   
St u d y R e stri cti o n s  
St u d y restricti o ns a n d ti mi n g of restricti o ns are s u m marize d i n Ta ble  9 -1 . S u bjects ma y e nr oll i n 
t he st u d y if t he y are recei vi n g acce pt a ble c o nc o mit a nt me dicati o ns (acc or di n g t o Ta ble  9 -1 ).  
A n o n -e x ha usti ve list of pr o hi bite d me dicati o ns will be pr o vi de d i n t he St u d y Refere n ce M a n ual.  
T a ble  9 -1   
St u d y Restricti o ns  
Restricte d 
M e dic ati o n/ F o o d/ Acti vit y
a 
Ti mi n g of Restricti o n  
St art  
St o p  
Ot her i n vesti gati o nal dr u gs or 
de vices  
2 8  da ys bef ore scree ni n g, 5  half -li ves 
bef ore scree ni n g, or ti me deter mi ne d 
b y l ocal re q uire me nts ( w hic he ver is 
l o n gest) 
C o m pleti o n of t he last Safet y 
F oll o w -u p Visit assess me nts  
A u g me ntati o n t hera p y ( h u ma n 
al p ha-1 pr otei nase i n hi bit or)  
M ore t ha n 4 2 da ys bef ore a nti ge nic 
A A T le vel is o btai ne d f or eli gi bilit y  
C o m pleti o n of t he last Safet y 
F oll o w -u p Visit assess me nts  
U G T 1 A 4/ U G T 1 A 1 m o derate 
a n d str o n g i n hi bit ors  
7 da ys or 5  half -li ves ( w hic he ver is 
l o n ger) bef ore t he first d ose of st u d y 
dr u g  
C o m pleti o n of t he last Safet y 
F oll o w -u p Visit assess me nts  
U G T 1 A 4/ U G T 1 A 1 m o derate 
a n d str o n g i n d ucers  
1 4 da ys bef ore t he first d ose of st u d y 
dr u g  
C o m pleti o n of t he last Safet y 
F oll o w -u p Visit assess me nts  
T o bacc o pr o d ucts c 
6  m o nt hs bef ore scree ni n g   
C o m pleti o n of t he last Safet y 
F oll o w -u p Visit  assess me nts  


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T a ble  9 -1   
St u d y Restricti o ns  
Restricte d 
M e dic ati o n/ F o o d/ Acti vit y
a 
Ti mi n g of Restricti o n  
St art  
St o p  
Alc o h ol: n o m ore t ha n 
1 4  dri n ks/ wee k f or fe males or 
2 1  dri n ks/ wee k f or males 
( 1 dri n k  =  5  o u nces ( 1 5 0  m L) of 
wi ne or 1 2  o u nces ( 3 6 0  m L) of 
beer or 1. 5  o u nces ( 4 5  m L) of 
har d li q u or)  
Si g ni n g of I C F  
C o m pleti o n of t he last Safet y 
F oll o w -u p Visit  assess me nts  
a  
See Secti o n  9. 6  f or g ui da nce o n c o nc o mita nt me dicati o ns.  
c  
Nic oti ne re p lace me nt t hera p y u n der t he directi o n of a p h ysicia n is all o we d.  
9. 5. 1   
E x p o s ur e t o S u nli g ht  
S u bjects will ta ke a p pr o priate meas ures t o mi ni mize e x p os ure t o ultra vi olet ra diati o n 
(e. g., s u nli g ht, ta n ni n g b o ot hs) fr o m Da y 1 t hr o u g h t he last Safet y F oll o w-u p Visit.  
9. 6   
Pri or a n d C o n c o mit a nt M e di c ati o n s  
S u bjects will f oll o w restricti o ns descri be d i n Ta bl e  9 -1 .
 
 
 
  
All me dicati o ns ta ke n fr o m t he si g ni n g of I C F t hr o u g h t he last Safet y F oll o w -u p Visit will be 
rec or de d wit h i n dicati o n, r o ute of a d mi nistrati o n, a n d start a n d st o p dates of a d mi nistrati o n. F or 
s u bjects w h o are scree ne d b ut n ot s u bse q ue ntl y ra n d o mize d, details of pri or me dicati o n will o nl y 
be d oc u me nte d i n t he s u bjects' s o urce d o c u me nts.  
I nf or mati o n a b o ut br o n c h o dilat or use d uri n g t h e st u d y will be rec or de d f or eac h s u bject. Use of 
s h ort-acti n g a n d l o n g-acti n g br o nc h o dilat ors will be c ollecte d a n d d oc u me nte d i n t he s o urce 
d oc u me nts f or eac h s u bject.  
I nf or mati o n a b o ut pri or a u g me ntati o n t hera p y, as a p plica ble, will be rec or de d f or eac h s u bject, 
i ncl u di n g d ose, fre q ue n c y of a d mi nistrati o n, start a n d st o p dates of last i nf usi o n. 


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9. 7   
A d mi ni str ati o n  
V X -8 6 4 will be a d mi nistere d orall y, 2  ti mes a d a y, a p pr o xi matel y 1 2 h o urs a part. All s u bjects 
will recei ve t he s a me n u m ber of ta blets eac h da y t o mai ntai n bli n di n g. A d diti o nal i nf or mati o n is 
pr o vi de d i n t he P har mac y Ma n u al. 
St u d y dr u g will be a d mi nistere d acc or di n g t o t he f oll o wi n g g ui deli nes:  
•  St u d y dr u g will be t a ke n u n der t he f aste d c o n diti o n .  
T he f aste d c o n diti o n  is defi ne d as f oll o ws: s u bjects m ust a bstai n fr o m all f o o d a n d dri n k 
(e x ce pt water) f or at least 2 h o urs bef ore a n d 2  h o urs after b ot h t he m or ni n g a n d t he e ve ni n g 
d ose of st u d y dr u g o n all st u d y da ys.  
•  Eac h s u bject s h o ul d ta ke t he st u d y dr u g a p pr o xi matel y 1 2 h o urs a part ( ±  2  h o urs). S u bjects 
will s wall o w t he ta blet(s) w h ole wit h o ut c he wi n g o r cr us hi n g t he ta blets wit h a p pr o xi matel y 
2 4 0 m L of water. S u bjects ma y ta ke a d diti o nal wat er ( b ut n o f o o d), as nee de d, t o s wall o w 
ta blets.  
•  If t he s u bject’s s c he d ule d cli nic or h o me visit is t o occ ur i n t he m or ni n g (i.e., bef ore n o o n), 
st u d y dr u g will be a d mi nistere d i n t he faste d c o n diti o n after pre d os e assess me nts ha ve bee n 
c o m plete d.  
•  If t he s u bject's sc he d ule d cli nic or h o me visit is t o occ ur i n t he after n o o n, t h e f oll o wi n g 
g ui deli nes m ust be f oll o we d:  
o  If t he d ose at t he s c he d ul e d visit will be wit hi n 6 h o urs of t he s u bject's sc he d ule d 
m or ni n g d ose, t he s u bject s h o ul d wit h h ol d t he m or ni n g d ose a n d t he m or ni n g d ose 
will be a d mi nistere d i n t he faste d c o n diti o n i n t he cli nic or wit nesse d b y a h o me n urse 
f or h o me visit. 
o  If t he d ose at t he s c he d ul e d visit will be m ore t ha n 6 h o urs after t he s u bject's 
sc he d ule d m or ni n g d ose, t he s u bject s h o ul d ta ke t h e m or ni n g d os e at h o me i n t he 
faste d c o n diti o n. 
•  If t he s u bject’s s c he d ule d h o me visit is t o occ ur i n t he e ve ni n g, st u d y dr u g will be 
a d mi nistere d after pre d os e assess me nts ha v e bee n c o m plete d.  
•  T he m or ni n g d os e of st u d y dr u g o n t h e Da y 2 8 Visit will be ta ke n i n t he cli nic or at h o me 
after t he pre d ose P K  s a m ple has bee n dra w n. T h e last d ose of st u d y dr u g will be ta ke n at 
h o me i n t he e ve ni n g o n Da y 2 8, re gar dless of w het her t he Da y 2 8 Visit occ urs o n Da y 2 6 or 
Da y 2 7.  
Misse d d oses:  
If a s u bject misses a d os e, t he s u bject ca n ta ke t he misse d d ose wit hi n 6 h o urs of t he us ual d osi n g 
ti me a n d s h o ul d ta ke t he d ose as s o o n as p ossi ble, pr o vi de d t he fasti n g re q uire me nts ca n b e met. 
If t he misse d d ose ca n n ot be ta ke n u n der t he re q uire d fastin g c o n diti o n wit hi n 6 h o urs of t he 
us ual d osi n g ti me, t he s u bject s h o ul d s ki p t hat d ose a n d res u m e t he n or mal sc he d ule f or t he 
f oll o wi n g d ose. If m ore t ha n 6 h o urs ha ve ela pse d after t he us u al d osi n g ti me, t he s u bject s h o ul d 
s ki p t hat d ose a n d res u m e t he nor mal sc he d ule f or t he f oll o wi n g d ose.  
M or ni n g a n d e ve ni n g d oses s h o ul d n ot be ta ke n at t he sa me ti me.  


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9. 8   
D o s e M o difi c ati o n f or T o xi cit y  
N o d ose m o dificati o ns f or t o xicit y are all o we d or re q uire d. If a n y u nacce pt a ble t o xicit y aris es i n 
t he o pi ni o n of t he i n vesti gat or i n di vi d ual s u bjects will disc o nti n ue d osi n g ( Secti o n 9. 1. 4 ). 
9. 9   
St u d y Dr u g I nt err u pti o n a n d St o p pi n g R ul e s  
T he i n vesti gat or has t he discreti o n  t o disc o nti n ue st u d y dr u g treat me nt at a n y ti me if t he 
i n vesti gat or feels t hat t he s u bject's c o nti n ue d parti ci pati o n i n t he st u d y je o par dizes t heir safet y. 
A n y s u bject wit h w orse ni n g of A A T D or disease pr o gressi o n t hat, i n t he j u d ge m e nt of t he 
treati n g p hysi cia n, re q uires (re)i nitiati o n of sta n dar d of care treat me nt ( per l ocal g ui d eli nes) t hat 
is pr o hi bite d i n t his st u d y (i ncl u di n g a u g m e ntati o n t hera p y) will disc o nti n ue st u d y dr u g 
treat me nt. 
A n y s u bject wit h Q Tc F v al ues a b o ve t he t hres h ol d val ues as des cri be d i n  Secti o n 1 1. 5. 4  will 
disc o nti n ue st u d y dr u g tr eat me nt.  
St u d y dr u g treat me nt ma y be i nterr u pte d f or safet y c o n cer ns at discreti o n of t he i n vesti g at or.  
St u d y dr u g a d mi nistrati o n m ust be i nterr u pte d i m me diatel y ( bef ore c o nfir mat or y testi n g), a n d t he 
me dical m o nit or m ust be n otifie d, if a n y of t he f oll o wi n g criteria are met:  
•  A L T or A S T > 5  ×  U L N  
•  T otal bilir u bi n > 3  ×  U L N  
•  A L T or A S T > 3  ×  U L N ass ociate d  wit h t otal bilir u bi n > 2  ×  U L N a n d/ or cli nical ja u n dice  
S u bjects wit h ne w treat m e nt -e mer ge nt A L T or A S T ele vati o ns of > 3  ×  U L N, or t otal bilir u bi n 
> 2  ×  U L N, m ust be f oll o we d cl osel y, i ncl u di n g c o nfir mat or y testi n g p erf or me d wit hi n 4 8 t o 
7 2  h o urs of t he i ni tial fi n di n g a n d t here m ust be cl ose m o nit ori n g of A L T, A S T, a n d bilir u bi n 
le vels t hereafter, as cli nicall y i n dicate d.  
If a s u bject ca n n ot r et ur n t o t he site f or c o nfir mat or y testi n g, a l o cal la b orat or y ma y be use d. 
L ocal la b orat or y res ults m ust be re p ort e d i m me di atel y t o t he m e dical m o nit or, a n d t he s u bject 
m ust ha ve t he tests re peate d a n d se nt t o t he ce ntral la b orat or y as s o o n as p ossi ble (i deall y wit hi n 
4 8 t o 7 2 h o urs).  
I n s u bjects w h o met a b o ve i nterr u pti o n criteria, a t h or o u g h i n v esti gati o n of p ote ntial ca uses 
s h o ul d be c o n d ucte d, a n d t he s u bject m ust be f oll o we d cl osel y f or cli nical pr o gressi o n. If a n 
alter nati ve, re versi ble ca use of tra nsa mi nas e ele vati o n a n d/ or i ncrease d bilir u bi n has bee n 
i de ntifie d, st u d y dr u g a d mi nistrati o n ma y be res u me d o nce tra ns a mi nases a n d/ or bilir u bi n ret ur n 
t o baseli ne or are < U L N, w hic he ver is hi g her. A p pr o v al of t he me dic al m o nit or is re q uire d 
bef ore res u m pti o n of st u d y dr u g.  U p o n res u m pti o n of st u d y dr u g, tra nsa mi nases a n d bilir u bi n 
m ust be assesse d wee kl y u ntil 7 da ys after t he last d ose of st u d y dr u g. If a pr ot oc ol -defi ne d 
tra nsa mi nase a n d/ or bilir u bi n ele vati o n i nterr u pti o n t hres h ol d rec urs, t he n st u d y dr u gs m ust be 
per ma n e ntl y disc o nti n ue d, re gar dl ess of t he pres u me d eti ol o g y.  
All s u bjects f or w h o m treat me nt is disc o nti n ue d f or ele vate d tra nsa mi nas es a n d/ or bilir u bi n 
s h o ul d ha ve t hese le vels m o nit ore d cl osel y u ntil le vels n or malize or ret ur n t o baseli ne.  


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9. 1 0   
R e m o v al of S u bj e c t s  
S u bjects ma y wit h dr a w fr o m t he st u d y at a n y ti me at t heir o w n re q u est. S u bjects ma y b e 
wit h dra w n fr o m st u d y dr u g treat me nt at a n y ti me at t he discreti o n of t he i n vesti gat or or Verte x 
f or safet y, b e ha vi or, n o n c o m plia nce wit h st u d y pr oce d ures, or a d mi nistrati ve reas o ns. A s u bject 
w h o wit h dra ws fr o m st u d y dr u g tr eat me nt will c o nti n ue t o be f oll o we d u nless t he s u bject 
wit h dra ws c o nse nt.  
S u bjects w h o are wit h dr a w n fr o m st u d y dr u g d osi n g will c o m plete assess me nts as descri be d i n 
Secti o n  9. 1. 4 .  
S u bjects w h o ha ve bee n ra n d o mize d a n d w h ose scree ni n g Pi Z Z ge n ot y p e d oes n ot c o nfir m st u d y 
eli gi bilit y m ust be disc o nti n ue d fr o m t he st u d y, e v e n if a pre vi o us Pi Z Z  ge n ot y pe la b orat or y 
re p ort was us e d t o esta blis h eli gi bilit y. 
If a s u bject d o es n ot ret ur n f or a sc h e d ule d visit, reas o na ble eff ort will be m a de t o c o ntact t he 
s u bject. I n a n y cir c u msta nce, reas o na ble eff ort will be ma de t o d oc u me nt s u bject o utc o me. T he  
i n vesti gat or will i n q uire a b o ut t he reas o n f or wit h dra wal, re q uest t hat t he s u bject ret ur n all 
u n use d i n vesti gati o nal pr o d uct(s), re q u est t hat t he s u bject ha ve a Safet y F oll o w -u p Visit, if 
a p plica ble (s ee Secti o n  9. 1. 4 ), a n d f oll o w u p wit h t he s u bject re gar di n g a n y u nres ol ve d A Es.  
If a s u bject wit h dra ws c o nse nt f or t he st u d y, n o f urt her assess me nts will be perf or me d. Vert e x 
ma y retai n a n d c o nti n ue usi n g t he st u d y data a n d sa m ples after t he st u d y e n ds a n d ma y use t he 
sa m ples a n d i nf or mati o n i n t he de vel o p me nt of t he st u d y c o m p o u n d, f or ot her dr u gs a n d 
dia g n ostics, i n p u blicati o ns a n d prese nt ati o ns, a n d f or e d ucati o n p ur p oses. If a s u bject wit h dra ws 
fr o m t he st u d y, t he st u d y data a n d sa m ples c ollecte d will re mai n part of t he st u d y. A s u bject will 
n ot be a ble t o re q u est t he wit h dra wal of his/ her i nf or mati o n fr o m t he st u d y data. A s u bject ma y 
re q uest destr u cti o n of t he sa m ples c ollecte d fr o m hi m/ her d uri n g the st u d y as l o n g as t h os e 
sa m ples ca n be i d e ntifie d as his/ her sa m ples. 
9. 1 1   
R e pl a c e m e nt of S u bj e ct s  
S u bjects w h o wit h dra w or are wit h dra w n bef ore t he first d ose of st u d y dr u g ma y b e re place d.  
S u bjects w h o wit h dra w or are wit h dra w n f or n o ns afet y reas o ns d uri n g  t he st u d y dr u g treat me nt 
peri o d(s) ma y b e re place d at Verte x's discreti o n.  
1 0   
S T U D Y D R U G I N F O R M A TI O N A N D M A N A G E M E N T  
1 0. 1   
Pr e p ar ati o n a n d Di s p e n si n g  
St u d y dr u g ma y be dis pe nse d o nl y u n d er t he s u per visi o n of t he i n vesti gat or or a n a ut h orize d 
desi g nee a n d o nl y f or a d mi nistrati o n t o t he st u d y s u bjects.  
1 0. 2   
P a c k a gi n g a n d L a b eli n g  
Verte x will s u p pl y t h e 1 0 0 - a n d 2 5 0-m g V X -8 6 4  ta blets a n d matc hi n g place b os. St u d y dr u g 
la beli n g will be i n c o m plia nce wit h a p plica ble l ocal a n d nati o nal re g ul ati o ns. A d diti o nal details 
a b o ut packa gi n g, la beli n g, a n d dis p e nsi n g f or V X -8 6 4  will be pr o vi de d i n t he P har mac y M a n ual.  


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1 0. 3   
St u d y Dr u g S u p pl y, St or a g e, a n d H a n dli n g  
T he i n vesti gat or, or a n a ut h orize d desi g nee (e. g.,  a lice nse d p har macist), will e ns ure t hat all 
i n vesti gati o nal pr o d u ct is st ore d i n a sec ure d area, u n der rec o m me n de d st ora ge c o n diti o ns, a n d i n 
acc or da nce wit h a p plica ble re g ulat or y re q uire m e nts. T o e ns ure a d e q uate rec or ds, all st u d y dr u gs 
will be acc o u nte d f or via t he dr u g acc o u nta bilit y f or ms as i nstr ucte d b y Verte x.  
V X -8 6 4 a n d mat c hi n g pl ace b o will be s u p plie d as ta blets of si milar size a n d a p peara nce 
c o ntai ni n g 1 0 0 - or 2 5 0 -m g V X -8 6 4 a n d 0 -m g V X -8 6 4, res p ecti vel y.  
Detaile d i nstr ucti o ns re gar di n g t h e st ora ge, h a n dli n g, a n d dis p e nsati o n of t he st u d y dr u g will be 
pr o vi de d i n t he P har mac y Ma n u al.  
1 0. 4   
Dr u g A c c o u nt a bilit y  
T he p har macist or desi g n ate d st u d y site staff will mai ntai n i nf or mati o n re gar di n g t h e dates a n d 
a m o u nts of st u d y dr u g recei ve d, st u d y dr u g dis pe nse d t o t he s u bjects, a n d st u d y dr u g ret ur ne d b y 
t he s u bjects. S u bjects will be i nstr ucte d t o ret ur n all use d a n d u n use d materials ass ociate d wit h 
t he st u d y dr u g t o t he site. T hese materials will be retai ned at t he site acc or di n g t o i nstr ucti o ns 
pr o vi de d b y Vert e x or its desi g nee u ntil i n ve nt orie d b y t he st u d y m o nit or. T he st u d y m o nit or will 
re vie w st u d y dr u g rec or ds a n d i n ve nt or y t hr o u g h o ut t he st u d y. 
If a site uses a site-s pecific dr u g acc o u nta bilit y s ystem a n d/ or pr ocess, i ncl u di n g pr ocesses 
ass ociate d wit h t he destr ucti o n of ret ur ne d m ateri als, t he pr ocess m ust be d oc u me nte d a n d 
a p pr o ve d b y Verte x. T he st u d y m o nit or m ust re vie w t he dr u g acc o u nta bilit y d oc u m e ntati o n o n a 
re g ular b asis. T he st u d y m o nit or will pr o m ptl y c o m m u nicate t o Verte x a n y discre pa n cies he/s he 
is u na ble t o res ol ve wit h t he site. 
1 0. 5   
Di s p o s al, R et ur n, or R et e nti o n of U n u s e d Dr u g  
T he st u d y site staff or p h ar mac y p ers o n nel will ret ai n all materials ret ur ne d b y t he s u bjects u ntil 
t he st u d y m o nitor has perf or me d dr u g acc o u nta bilit y. T he i n vesti gat or will e ns ure t hat t he 
materials are destr o ye d i n c o m plia nce wit h a p plica ble e n vir o n me ntal re g ul ati o ns, i nstit uti o nal 
p olic y, a n d a n y s peci al i nstr ucti o ns pr o vi de d b y Verte x. Destr ucti o n will be a de q uate l y 
d oc u me nte d.  
T he pri nci pal i n vesti gat or, st u d y site staff, i ncl u di n g p har mac y p ers o n nel, will assist Verte x wit h 
a n y recall acti vities (as a p plica ble) a n d place i m p acte d i n vesti gati o nal me dici nal pr o d uct (I M P) 
i n q uara nti ne w he n re q u este d. 
1 0. 6   
C o m pli a n c e  
T o  e ns ure tr eat me nt c o m plia nce, t he i n vesti gat or or desi g n ee will s u per vis e all st u d y dr u g d osi n g 
t hat occ urs at t he site. At eac h visit, site pers o n nel or a p pr o ve d h o m e n urse will re vie w t hat t he 
s u bject is c o m plia nt wit h st u d y dr u g d osi n g a n d re mi n d t he s ubject of st u d y dr u g d osi n g 
re q uire me nts. C o m plia nce will als o be assesse d b y o n g oi n g st u d y dr u g c o u nt i n t he cli nic or 
c hec k e d b y h o me n urse f or h o me visit.  
If a s u bject d e m o nstrates c o nti n ue d n o nc o m plia nce of st u d y dr u g d osi n g d es pite e d ucati o nal 
eff orts, t he i n vesti gat or will c o ntact t he me dical m o nit or t o disc uss disc o nti n ui n g t he s u bject 
fr o m t he st u d y. 


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1 0. 7   
Bli n di n g a n d U n bli n di n g  
T his is a d o u ble -bli n d st u d y.  
1 0. 7. 1   
Bli n di n g  
All s u bjects, site pers o n nel (i ncl u di n g t he i n v esti gat or, t he site m o nit or, a n d t he st u d y tea m), a n d 
t he Verte x st u d y tea m will be bli n de d t o t he treat me nt c o des wit h t he e x ce pti o n of t he f oll o wi n g:  
•  A n y site p ers o n nel f or w h o m t his i nf or mati o n is i m p orta nt t o e ns ure t he safet y of t he s u bject 
i n t he e ve nt of a life-t hreate ni n g m e dical e mer ge nc y 
•  A n y site p ers o n nel f or w h o m t his i nf or mati o n is i m p orta nt t o e ns ure t he safet y of t he s u bject 
a n d her fet us i n t he e ve nt of a pre g n a nc y  
•  Verte x Gl o bal Patie nt Safet y ( G P S) a n d Re g ulat or y Affairs p ers o n nel t o satisf y seri o us 
a d verse e ve nt ( S A E) pr o cessi n g  a n d re p orti n g re g ulati o ns  
•  U n bli n de d statisticia n pre pari n g t he fi n al ( pr o d ucti o n) ra n d o mizati o n list w h o is n ot part of 
t he st u d y tea m 
•  Verte x I W R S Ma na ger  
•  Verte x Cli nical S u p pl y C hai n  
•  T he bi oa nal ytical c o ntract researc h or ga nizati o n ( C R O) a nal yzi n g P K sa m ples a n d t he 
Verte x Bi oa nal ytical pers o n nel w h o is n ot a me m ber of t he S E T b ut a n al yzes a n d re vie ws 
ra w data fr o m Bi oa nal yti cal C R O. T he Verte x Bi oa nal yti cal S E T me m ber will c o nti n ue t o be 
bli n de d.  
Verte x me dical m o nit or ma y, f or matters relati n g t o saf et y c o ncer ns, u n bli n d i n di vi d ual s u bjects 
at a n y ti me. 
A li mite d Verte x tea m n ot directl y i n v ol ve d i n t he c o n d uct of t he st u d y ma y be u n bli n de d t o 
i n di vi d ual s u bject treat me nt assi g n me nts a n d h a ve access t o plas ma A A T le vels, P K/ P D, a n d/ or 
safet y data (e. g., a d v erse e ve nts, cli nical la b orat or y ass ess me nts) f or c o nti n u o us m o nit ori n g 
p ur p oses. N o u n bli n de d data or res ults of u n bli n de d a nal yses will be s hare d wit h t he st u d y sites 
or wit h t he Verte x st u d y tea m. All i nsta nces of u n bli n di n g b y Verte x pers o n nel wi ll be 
d oc u me nte d.  
Access t o res ults of plas ma f u ncti o nal a n d a nti ge nic A A T data : 
D uri n g t h e c o n d uct of t h e st u d y, t he Verte x st u d y tea m will n ot ha ve access t o t he plas ma A A T 
le vel res ults u ntil t he st u d y is u n bli n de d f or f ull re vie w, wit h t he e x ce pti o n of t he scree ni n g 
plas ma a nti ge nic A A T l e vels. A nti ge nic A A T le v els o btai ne d d uri n g scree ni n g will be pr o vi de d 
t o st u d y sites i n or der t o c o nfir m t he s u bject’s eli gi bilit y t o e nr oll i n t he st u d y. Ot her A A T le vel 
res ults will n ot be discl ose d t o t he st u d y sites.  
S h ortl y bef ore a n y pla n ne d effi cac y a nal ysis relat e d t o plas ma A A T le vels is c o n d ucte d, plas ma 
A A T data will be re vie we d f or dat a clea ni n g p ur p oses b y a bi ostatisticia n w h o d oes n ot ha ve 
access t o t he treat me nt c o des.  


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Access t o direct a n d i n dir ect bili r u bi n res ults: 
After scree ni n g, dir ect a n d i n direct bilir u bi n res ults will n ot be discl ose d t o t he st u d y sites. After 
scree ni n g, t he Verte x st u d y tea m will n ot ha ve access t o t he direct a n d i n direct bilir u bi n res ults 
u ntil t he st u d y is u n bli n d e d f or f ull r e vie w. St u d y sites a n d t he Verte x st u d y tea m will recei v e 
t otal bilir u bi n res ults. 
Bef ore t he fi nal data l oc k, direct a n d i n direct bilir u bi n data will be re vie we d f or data clea ni n g 
p ur p oses b y a bi ostatisticia n w h o d oes n ot ha ve access t o t he treat me nt c o d es. 
1 0. 7. 2   
U n bli n di n g  
At t he i nitiati o n of t he st u d y, st u d y site pers o n nel will be i nstr ucte d o n t he met h o d f or brea ki n g 
t he bli n d. T he u n bli n di n g met h o d will be eit her ma n ual or electr o nic. 
U n bli n di n g of t he i n di vi d ual s u bject's tr eat me nt b y t he i n vesti gat or wil l be li mite d t o me dical 
e mer ge n cies or ur ge nt cli nical sit uati o ns i n w hic h k n o wle d ge of t he s u bject's st u d y treat me nt is 
necessar y f or cli nical ma na ge me nt. I n s uc h cases, i n vesti gat ors will use t heir best j u d g me nt as t o 
w het her t o u n bli n d wit h o ut first att e m pti n g t o c o nt act t he me dical m o nit or t o disc uss u n bli n di n g. 
If i n vesti gat ors dee m it u n necessar y t o u n bli n d i m me diatel y, t he y will first atte m pt t o c o ntact t he 
me dical m o nit or t o disc uss u n bli n di n g. If i n vesti gat ors ha ve trie d b ut are u na ble t o reac h t he  
me dical m o nit or, t he y will use t heir best j u d g me nt, base d o n t he nat ure a n d ur ge nc y of t he 
cli nical sit uati o n, a n d ma y pr ocee d wit h u n bli n di n g.  
C o ntact i nf or mati o n f or t he me dical m o nit or ( or a p pr o priate bac k u p) will b e pr o vi de d i n a 
se parat e d oc u me nt. 
If a s u bject's tr eat me nt assi g n me nt has bee n u n bli n de d f or a m e dical e mer ge nc y or ur ge nt cli nical 
sit uati o n, t he me dical m o nit or will be n otifie d wit hi n 2 4 h o urs of t he u n bli n di n g e v e nt. T he 
reas o n a n d t h e date of t h e u n bli n di n g will be d oc u me nte d clearl y i n t he s u bject's st u d y file. 
I nf or mati o n a b o ut t he treat me nt assi g n me nt o btai n e d fr o m t he u n bli n di n g will be mai ntai ne d i n a 
sec ure l o cati o n wit h c o ntr olle d access a n d will n ot be s hare d wit h Verte x, t he C R O, or a n y site 
pers o n nel ( ot her t ha n t he p h ysicia n t reati n g t he s u bject). I n a d diti o n, t he i n vesti gat or will 
c o nsi der w het h er t he cli nical e ve nt t hat pr o m pte d u n bli n di n g will be c o nsi dere d a n S A E, 
acc or di n g t o t he re g ulat or y d efi niti o ns or criteria f or S A Es, a n d if s o, s u b mit a n S A E re p ort t o 
Verte x G P S or desi g nee, per  Secti o n 1 3. 1. 2 . 
Verte x G P S or desi g nee will als o u n bli n d a n y S A E re p orts i n c o m plia nce wit h re g ul at or y 
re p orti n g re q uir e me nts. I n a d diti o n, Verte x ma y, f or matters rel ati n g t o safet y, u n bli n d i n di vi d ual 
s u bjects at a n y ti me.  
1 1   
A S S E S S M E N T S  
T he sc he d ule of assess m e nts is s h o w n i n Ta ble  3 -1 , Ta ble  3 -2 , a n d Ta ble  3 -3 .  
1 1. 1   
S u bj e ct a n d Di s e a s e C h ar a ct eri sti c s  
S u bject a n d disease c haracteristics i ncl u de t he f oll o wi n g: de m o gra p hi cs, me dical hist or y, hei g ht, 
a n d wei g ht . Ci garette a n d or e-ci garette s m o ki n g hist or y (c urre nt s m o ker; e ver s m o ker; ne ver 
s m o ker) will be c ollect e d f or eac h s u bject i ncl u di n g ti me si nce q uitti n g a n d pac k-years a n d 
cartri d ge -years of s m o ki n g hist or y ( pac ks/ da y × n u m ber of years; cartri d ges/ da y × n u m ber of 
years).   


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1 1. 2   
P h ar m a c o ki n eti c s  
1 1. 2. 1   
Bl o o d S a m pli n g  
Bl o o d sa m ples will be c ollecte d f or t he e val uati o n of plas ma c o nce ntrati o n s of V X-8 6 4.   
 
 
  
Plas ma c o nce ntr ati o n sa m ples c ollecte d fr o m s u bjects treate d wit h place b o st u d y dr u g will n ot be 
r o uti nel y a n al yze d.  
All eff orts will be ma de t o o btai n t he P K sa m ples at t he n o mi nal ti me ( ± 3 0  mi n utes) relati ve t o 
d osi n g. Acce pta ble wi n d o ws f or sa m pli n g ti mes are s h o w n i n Ta ble  1 1 -1 . T he e x act ti me of t he 
sa m ple c ollecti o n will be n ote d. 
T a ble  1 1 -1  
Acce pt a ble P h ar m ac o ki netic S a m pli n g Wi n d o ws  
S a m pli n g Ti me  
Ti me Fr o m Sc he d ule d S a m pli n g All o w e d  
Pre d ose  
Wit hi n 6 0 mi n utes bef ore d osi n g  
All ot her ti me p oi nts  
±  3 0  mi n utes  
 
T he f oll o wi n g d etails will be rec or de d i n t he s o urce d oc u me nt: date a n d ti me of st u d y dr u g f or 
t he 2 d oses bef ore t he d ose o n P K sa m pli n g da ys; date a n d ti me of eac h of t he P K bl o o d 
sa m ples; a n d date a n d ti me of t he last meal bef ore t he d ose o n P K sa m pli n g  da ys . 
1 1. 2. 2   
Pr o c e s si n g a n d H a n dli n g of P h ar m a c o ki n eti c S a m pl e s  
Detaile d pr oce d ures f or t he c ollecti o n of bl o o d sa m ples a n d f urt her pr oce d ures f or pr ocessi n g 
a n d ha n dli n g of sa m ples f or P K a nal ysis will be i n t he P K Sa m ple Ha n dli n g G ui deli nes.  
1 1. 2. 3   
Bi o a n al y si s  
Sa m pl es will be a nal yze d usi n g a v ali date d a nal yti cal met h o d i n c o m plia nce wit h Verte x or 
desi g nee sta n dar d o perati n g pr oce d ures. A des cri pti o n of t he assa y a n d vali dati o n data will be 
pr o vi de d i n se parate re p orts.  
1 1. 3   
Effi c a c y  
Detaile d pr oce d ures f or t he c ollecti o n, pr ocessi n g, ha n dli n g, a n d st ora ge of bl o o d sa m ples f or 
f u ncti o nal a n d a nti ge nic A A T le vels will be pr o vi de d i n t he Cli nical Bi o mar ker Sa m ple 
Ha n dli n g G ui d eli nes.  
Sa m ples will be o btai ne d f or a nti ge nic a n d f u ncti o nal A A T le vels at t he s a me ti me t hat ot he r 
scree ni n g la b orat or y assess me nts are perf or me d. T hese sa m ples m ust be se nt t o t he ce ntral 
la b orat or y. If t he s u bject has ne ver recei ve d a u g m e ntati o n t hera p y or if t h e s u bject recei ve d t he 
last d ose of a u g me ntati o n t hera p y > 4 2 d a ys pri or, t his sa m ple ca n be use d t o meas ure a nti ge nic 
A A T le vel f or eli gi bilit y. If sa m ples are o btai ne d ≤4 2  da ys after t he last d ose of a u g me ntati o n 
t hera p y, a n ot her sa m ple m ust b e dra w n > 4 2 da ys after t he l ast d ose of a u g me ntati o n t hera p y a n d 
se nt t o t he ce ntral la b orat or y t o det er mi ne eli gi bilit y. Sites s h o ul d all o w at le ast 1 4  d a ys f or 
s a m ple pr ocessi n g a n d res ults re p orti n g. Sa m ples will be o btai ne d f or pl as ma f u ncti o nal A A T 
le vels at t he sa me ti me sa m ples are o btai ne d f or a nti ge nic A A T le vels. F u ncti o nal A A T le vel 
res ults will n ot be pr o vi de d t o site pers o n nel. 




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1 1. 5   
S af et y  
Safet y e val uati o ns will i ncl u de A Es, cli nical la b orat or y assess me nts, sta n dar d 1 2 -lea d E C Gs, 
cli nical e val uati o n of vital si g ns, p ulse o xi metr y, s pir o metr y, a n d p h ysical e x a mi nati o ns ( P Es).  
1 1. 5. 1   
A d v er s e E v e nt s  
All A Es will be assesse d, d oc u me nte d, a n d re p orte d i n acc or da nce wit h I C H  G C P G ui deli nes. 
S ecti o n 1 3. 1  o utli nes t he defi niti o ns, c ollecti o n peri o ds, criteria, a n d pr oce d ures f or 
d oc u me nti n g, gra di n g, a n d re p orti n g A Es. A se p arate d oc u me nt  t hat details A E C R F c o m pleti o n 
g ui deli nes f or i n vesti gat ors as well as tr ai ni n g will be pr o vi de d.  
1 1. 5. 2   
Cli ni c al L a b or at or y A s s e s s m e nt s  
Bl o o d a n d uri ne s a m ples will be a nal yze d at a ce ntral la b orat or y.  
La b orat or y test res ults t hat are a b n or mal a n d c o nsi dere d c li nicall y si g nifica nt will be re p orte d as 
A Es (see Secti o n  1 3. 1 ). 
T he safet y la b orat or y test pa nels are s h o w n i n Ta ble  1 1 -2 . 


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T a ble  1 1 -2  
S afet y L a b or at or y Test P a nels  
Ser u m C he mistr y  
He m at ol o g y  
Uri n al ysis a 
Gl uc ose  
Bl o o d urea nitr o ge n b 
Creati ni ne  
S o di u m  
P otassi u m  
Calci u m  
C hl ori de  
Ma g nesi u m  
Bicar b o nate  
P h os p hate  
T otal bilir u bi n ( direct bilir u bi n, 
i n direct bilir u bi n) 
Al kali ne p h os p hatase  
As partate tra nsa mi nase  
Ala ni ne tra nsa mi nase  
A m ylase  
Li pase  
Ga m ma -gl uta m yl tra nsferase   
Pr otei n  
Al b u mi n  
Creati ne ki nase  
Urate  
C h olester ol  
Tri gl yceri des  
L o w -de nsit y li p o pr otei n  
Hi g h -de nsit y li p o pr otei n  
He m o gl o bi n  
Er yt hr oc ytes  
Mea n c or p usc ular v ol u me  
Platelets  
Retic ul oc ytes  
Le u k oc ytes  
Differe ntial (a bs ol ute a n d perce nt):  
E osi n o p hils  
Bas o p hils  
Ne utr o p hil s 
L y m p h oc ytes  
M o n oc ytes  
C o a g ul ati o n  
Acti vate d partial t hr o m b o plasti n ti me  
Pr ot hr o m bi n ti me  
Pr ot hr o m bi n ti me I nter nati o nal 
N or malize d Rati o  
Le u k oc yte esterase  
Nitrite  
Uri ne pr otei n  
Uri ne bl o o d  
Uri ne c oti ni ne  
a  
If uri nal ysis res ults are p ositi ve f or le u k oc yte esterase, nitrit e, pr otei n or bl o o d, micr osc o pic e xa mi nati o n of 
uri ne will be d o ne, a n d res ults will be pr o vi de d f or le u k oc yt es, er yt hr oc ytes, cr ystals, bact eria, a n d casts.  
b  
If bl o o d urea nitr o ge n ca n n ot be c ollecte d, urea ma y be s u bstit ute d. 
A d diti o nal Tests at Scree ni n g : 
•  Ser ol o g y test f or H Bs A g, H C V a nti b o d y a n d R N A, a n d HI V -1 a n d HI V -2 a nti b o dies  
•  Ser u m beta -h u ma n c h ori o nic g o n a d otr o pi n ( β -h C G) f or all fe male s u bjects  
•  Ser u m F S H f or p ost me n o pa usal fe mal e s u bjects wit h s p o nta ne o us a me n orr hea wit h o ut 
a n ot her reas o n f or at least 1 2  c o nsec uti ve m o nt hs wit h o ut a n ot her reas o n, e x ce pt f or t h ose 
w h o ha ve d oc u m e nte d bilateral o o p h orect o m y or h ysterect o m y. Le v els will be wit hi n t h e 
la b orat or y's ra n ge f or p ost me n o pa usal f or s u bjects t o be c o nsi dere d of n o n-c hil d beari n g 
p ote ntial.  
A d diti o nal E val uati o ns : A d diti o nal cli nical la b orat or y e v al uati o ns will be perf or me d at ot her 
ti mes if j u d ge d t o be cli nicall y a p pr o priate f or safet y c o ncer ns. 
F or p ur p oses of st u d y c o n d uct, o nl y safet y la b orat or y tests d o n e at t he ce ntral la b orat or y m a y be 
use d; h o we ver, t h e i n vesti gat or h as t he discreti o n t o use l ocal la b orat or y i n t he e ve nt of s afet y 
c o ncer ns. If a l o cal la b orat or y is us e d, res ults m ust be re p orte d i m me diatel y t o t he me dical 
m o nit or. If a l ocal la b orat or y test val u e is f o u n d t o be a b n or mal a n d cli nicall y si g nifica nt, it will 


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be verifie d b y t h e ce ntr al la b orat or y as s o o n as p ossi ble after t he i n vesti gat or bec o mes a ware of 
t he a b n or mal r es ult. If it is n ot p ossi ble t o se n d a ti mel y s peci me n t o t he ce ntral la b orat or y 
(e. g., t he s u bject w as h os pitalize d else w here), t he i n vesti gat or ma y b ase t he assess me nt of a n A E 
o n t he l ocal la b orat or y val ue.  
1 1. 5. 3   
P h y si c al E x a mi n ati o n s, Vit al Si g n s, a n d P ul s e O xi m etr y  
A P E of all b o d y s yste ms, vital si g ns a n d p ulse o xi metr y assess me nt will be perf or me d at 
scree ni n g. At ot her visits, s y m pt o m-direct e d P Es a n d s y m pt o m -directe d vital si g ns assess me nts 
ca n be p erf or m e d at t he discreti o n of t he i n vesti gat or or healt hcar e pr o vi der . 
A P E i ncl u des a re vie w of t he f oll o wi n g s yste ms: hea d, nec k, a n d t h yr oi d; e yes, ears, n ose, a n d 
t hr oat ( E E N T); res pirat or y; car di o vasc ul ar; l y m p h n o des; a b d o me n; s ki n; m usc ul os keletal; a n d 
ne ur ol o gi cal. Breast, a n orectal, a n d ge nital e xa mi nati o ns will be perf or me d w he n me dicall y 
i n dicate d. After scree ni n g, a n y cli nicall y si g nifica nt a b n or mal fi n di n gs i n P Es will be re p orte d as 
A Es.  
T he a b bre viate d P E will i ncl u de a n ass ess me nt of t he f oll o wi n g b o d y s yste ms: hea d, nec k, a n d 
t h yr oi d; E E N T; car di o vasc ular s yste m; res pirat or y s yste m; s ki n; a n d a b d o me n.  
T he re vie w of s y m pt o ms will i ncl u de a ver bal re vi e w of s y m pt o ms b y b o d y s yste m. If t here are 
a n y a b n or mal fi n di n gs, t he s u bject will be i nstr ucte d t o ha ve a c o m plete P E i n t he cli nic.  
Vital si g ns i ncl u de bl o o d press ure (s yst olic a n d diast olic), te m perat ure, p ulse rate, a n d 
res pirati o n rat e. T he s u bj ect will be i nstr ucte d t o rest f or at least 5 mi n utes bef ore vital si g ns are 
assesse d.  
T he s u bject will be i nstr ucte d t o rest f or at least 5  mi n utes bef ore p ulse o xi metr y is ass esse d.  
1 1. 5. 4   
El e ctr o c ar di o gr a m s  
Sta n dar d 1 2 -lea d E C Gs will be perf or me d i n tri plicate. A d diti o nal sta n dar d 1 2-lea d E C Gs will be 
perf or me d at a n y ot her ti me if cli nicall y i n dicate d. T he perf or ma nce of all E C Gs will a d here t o 
t he f oll o wi n g g uideli nes. Detaile d i nstr ucti o ns are pr o vi de d i n t he St u d y Refere n ce Ma n u al : 
•  T he E C G will be d o ne bef ore a n y ot h er pr o ce d ures t hat ma y affect heart rat e, s uc h as bl o o d 
dra ws.  
•  T he s u bject will be i nstr ucte d t o rest f or at least 5  mi n utes bef ore ha vi n g a n E C G.  
•  T he test s h o ul d be perf or me d i n t he s u pi ne p ositi o n.  
A pri nt o ut of t he E C G traces will be ma de f or s afet y re vie w b y t he i n v esti gat or a n d mai ntai ne d 
wit h s o urce d oc u me nt ati o n. Cli nicall y si g nifica nt E C G a b n or malities occ urri n g d uri n g t he st u d y 
t hr o u g h t he Safet y F oll o w -u p Visit will be rec or de d as A Es.   
T o e ns ure safet y of t he s u bjects, a q ualifie d i n di vi d ual at t he st u d y site or a n a p pr o ve d h o me 
n urse at t he h o me healt h visit will ma ke c o m paris o ns of t he Q Tc F val ue ge nerate d o n t he E C Gs 
o btai ne d at a n y ti m e p oi nt after t he first d ose of dr u g a d mi nistere d i n t he treat me nt peri o d t o t he 
pre d ose bas eli ne Q Tc F v al ue ta ke n o n Da y  1 i n t he treat me nt peri o d. If t he me dia n Q Tc F ( of t he 
safet y E C Gs perf or me d i n tri plicate) is i ncrease d b y > 6 0 ms ec fr o m t he baseli ne (as defi ne d i n 
Secti o n  1 2. 3. 1 ) or a n a bs ol ute me dia n Q Tc F val ue is ≥5 0 0 msec f or a n y sc h e d ule d E C G 
assess me nt, tri plicate E C Gs will be re peate d wit hi n 1 0  mi n utes of t he i nitial assess me nt t o 
c o nfir m t he ori gi nal meas ure me nt. A s u bject wit h a c o nfir mat or y E C G t hat de m o nstrates a 


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me dia n  Q Tc F ( of t he s afet y E C Gs p erf or me d i n tri plicate) t hat has i ncrease d b y > 6 0 ms ec fr o m 
t he baseli ne or a n a bs ol ute me dia n Q Tc F val u e ≥5 0 0 msec will disc o nti n ue d osi n g. If t he me dia n 
Q Tc F (fr o m t he c o nfir mat or y E C Gs re peate d wit hi n 1 0  mi n utes of t he i nitial  assess me nt) falls 
bel o w t he t hres h ol d, t he s u bject ma y c o nti n ue d osi n g. If t he c o nfir m at or y E C G is a b o ve t he 
t hres h ol d t he n f or safet y m o nit ori n g, tri plicate E C Gs will be re peate d at least e ver y h o ur u ntil t he 
me dia n Q Tc F val ue fr o m 2 s uccessi ve ti me p oi n ts falls bel o w t he t hres h ol d val ue t hat tri g gere d 
t he re peat meas ure me nt. 
1 1. 5. 5   
S pir o m etr y  
S pir o metr y will be perf or me d p ost -br o nc h o dilat or a n d will be perf or me d acc or di n g t o t he 
A merica n T h oraci c S ociet y ( A T S) G ui deli nes/ E ur o pea n Res pirat or y S oci et y G ui deli nes.
4 , 5 , 6 If 
s pir o metr y ca n n ot be perf or me d at scree ni n g, hist orical p ost-br o nc h o dilat or p p F E V 1 res ults 
wit hi n 1 year bef ore scree ni n g ca n be us e d t o deter mi ne eli gi bilit y. T his ass ess me nt is o pti o nal at 
all ot her st u d y visits. F urt her details will be pr o vi de d i n t he St u d y Refere n ce Ma n ual.  
All sites will be pr o vi de d wit h s pir o meters t o be use d f or all st u d y assess m e nts. S pir o metr y dat a 
will be tra ns mitte d t o a ce ntralize d s pir o metr y ser vice f or q u alit y re vie w.  
1 1. 5. 6   
C o ntr a c e pti o n a n d Pr e g n a n c y  
T he effects of V X -8 6 4 o n c o nce pti o n, pre g n a nc y, a n d lactati o n i n h u ma ns are n ot k n o w n.  Refer 
t o t he V X-8 6 4 I B f or a d diti o nal details.  
1 1. 5. 6. 1   
C o ntr a c e pti o n  
Partici pati o n i n t his st u d y re q uires a c o m mit me nt fr o m s u bjects a n d t heir part ners t o use met h o ds 
of c o ntrace pti o n o utli ne d bel o w, w hic h m ust be use d c orrectl y wit h e ver y act of se x ual 
i nterc o urse.  
C o ntr ace pti o n f or t he c o u ple is w ai ve d f or t he f oll o wi n g:  
•  Tr ue a bsti ne nce f or t h e s u bject, w he n t his is i n li ne wit h t he preferre d a n d us ual lifest yle of 
t he s u bject. Peri o dic a bsti ne nce (e. g., cal e n dar, o v ulati o n, s y m pt ot her mal, p ost o v ulati o n 
met h o ds) a n d wit h dra wal are n ot acce pt a ble met h o ds of c o ntrace pti o n. Tr ue a bsti ne nce m ust 
be practice d fr o m 2 8 d a ys bef ore Da y 1 t hr o u g h 9 0  da ys after t he last d ose of st u d y dr u g.  
•  If t he male is i nfertile (e. g., bilateral orc hiect o m y). I nfertilit y ma y b e d oc u me nte d t hr o u g h 
e x a mi nati o n of a se me n s peci me n or b y de m o nstrati o n  of t he a bse nce of t he vas defere ns b y 
ultras o u n d bef ore t he first d ose of t he st u d y dr u g.  
•  If t he fe m ale is of n o n-c hil d beari n g p ot e ntial, per t he f oll o wi n g:  
o  D oc u me nte d h ysterect o m y or a bilat eral o o p h orect o m y/sal pi n g o -o o p h orect o m y.  
o  P ost me n o pa usal: c o nti n u o us a me n orr hea wit h o ut a n ot her reas o n f or at least 
1 2  m o nt hs wit h o ut a n ot her reas o n  a n d ser u m F S H le vels wit hi n t he la b orat or y’s ra n ge 
f or p ost me n o pa usal f e males.  
•  Sa me -se x relati o ns hi ps.  


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F or s u bjects f or w h o m c o ntr ace pti o n met h o ds are n ot w ai ve d f or o ne of t he re as o ns cite d 
a b o ve, t he f oll o wi n g are hi g hl y effecti ve c o ntr ace pti ve met h o ds ( T a ble  1 1 -3 ) f or m ale 
s u bjects a n d t heir fe m ale ( n o n-st u d y) p art ners a n d f or fe m ale s u bjects a n d t heir m ale 
( n o n-st u d y) p art ners. I n a d diti o n t o t he s u bject or p art ner usi n g 1 met h o d fr o m T a ble  1 1 -3 , 
all m ale ( n o n -st u d y) p art ners a n d m ale s u bjects m ust use a c o n d o m, wit h s per mi ci de (if 
a v ail a ble), fr o m 2 8 d a ys bef ore D a y 1 u ntil 9 0  d a ys after t he l ast d ose of st u d y dr u g. 
Acce pt a ble met h o ds of c o ntr ace pti o n are liste d i n T a ble  1 1 -3 . 
T a ble  1 1 -3  
All o w a ble Met h o ds of C o ntr ace pti o n  
M ale s u bjects a n d t heir fe m ale 
( n o n-st u d y) p art ners  
•  Male vasect o m y 6  m o nt hs or m ore pre vi o usl y, wit h a d oc u me nte d 
ne gati ve p ost -vasect o m y se me n a nal ysis f or s per m  
•  Fe male bilateral t u bal li gati o n perf or me d at least 6 m o nt hs pr e vi o usl y  
•  Fe male c o nti n u o us use of a n i ntra uteri ne de vice f or at least 9 0 da ys 
b ef ore t he first d ose of st u d y dr u g, t hr o u g h o ut s t u d y dr u g treat me nt, 
a n d u ntil 9 0 da ys after t he last d ose of st u d y dr u g.  
•  Fe male h or m o nal c o ntrace pti ves, if s uccessf ull y use d f or at l east 
6 0  da ys bef ore t he first d ose of st u d y dr u g, t hr o u g h o ut st u d y dr u g 
treat me nt, a n d u ntil 9 0 da ys after t he last d ose of st u d y dr u g.  
Fe m ale s u bjects a n d t heir m ale 
( n o n-st u d y) p art ners   
•  Fe male bilateral t u bal li gati o n perf or me d at least 6 m o nt hs pr e vi o usl y  
•  Fe male c o nti n u o us use of a n i ntra uteri ne de vice ( n o n -h or m o ne 
releasi n g) f or at least 9 0 da ys bef ore t he first d ose of st u d y dr u g, 
t hr o u g h o ut st u d y dr u g treat me nt, a n d u ntil 9 0 da ys after t he l ast d ose 
of st u d y dr u g.  
•  Male vasect o m y 6  m o nt hs or m ore pre vi o usl y, wit h a d oc u me nte d 
ne gati ve p ost -vasect o m y se me n a nal ysis f or s per m.  
N ote: T he effects of V X -8 6 4 o n t he P K of h or m o nal c o ntra ce pti ves are n ot k n o w n. T h us, h or m o nal c o ntrace pti o n 
is N O T per mitte d as a hi g hl y effecti ve met h o d of c o ntrace pti o n f or fe male s u bj ects. 
I m p ort a nt n otes: 
•  Male s u bjects m ust use a c o n d o m t o a v oi d e x p osi n g a p ot e ntial fet us t o st u d y dr u g vi a t he 
se mi nal fl ui d. T he fe mal e c o n d o m is n ot a n acce pta ble met h o d d ue t o t he i ncreas e d ris k of 
teari n g w he n t he fe mal e a n d male c o n d o ms are us e d at t he sa me ti me. 
•  Male a n d fe male s u bjects w h o are n ot se x uall y acti ve at t he ti me of scree ni n g m ust a gree t o 
f oll o w t he c o ntrace pti ve re q uire me nts of t his st u d y if t he y b ec o me se x uall y acti ve. 
•  Male s u bjects m ust n ot d o nate s per m after t he first d ose of st u d y dr u g, t hr o u g h o ut t he st u d y, 
a n d f or 9 0 da ys f oll o wi n g t he last d ose of st u d y dr u g.  
•  Fe male s u bjects a n d fe male part ners of male s u bj ects s h o ul d n ot pla n t o bec o me pre g n a nt 
d uri n g t he st u d y t hr o u g h 9 0  da ys f oll o wi n g t he l ast d ose of st u d y dr u g.  
•  Fe male s u bjects s h o ul d n ot breastfee d a c hil d fr o m t he start of st u d y dr u g d osi n g t hr o u g h 
9 0  da ys f oll o wi n g t he l a st d ose of st u d y dr u g. 
•  If a p plica bl e, a d diti o nal c o ntrace pti o n re q uire me nts ma y nee d t o be f oll o we d acc or di n g t o 
l ocal re g ulati o ns a n d/ or re q uire me nts. 
•  U ni q ue sit uati o ns t hat ma y n ot f all wit hi n t he a b o ve s pecificati o ns ma y b e disc usse d wit h t he 
me dical m o nit or o n a n i n di vi d ual basis.  


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1 1. 5. 6. 2   
Pr e g n a n c y  
S u bjects will be c o u nsele d t o i nf or m t he i n vesti gat or of a n y pre g na n c y t hat occ urs d uri n g st u d y 
treat me nt a n d f or 9 0 da ys after t he l ast d ose of st u d y dr u g.  
If a fe male s u bject or t he fe male part ner of a male s u bject bec o mes pre g na nt w hile partici pati n g 
i n t he st u d y, st u d y dr u g will be per ma ne ntl y disc o nti n ue d i m me diatel y. T he i n vesti gat or will 
n otif y t he me dical m o nit or a n d Verte x G P S wit hi n 2 4  h o urs of t he site's k n o wle d ge of t he 
s u bject's ( or part ner's) pre g n a nc y usi n g t he Pre g n a nc y I nf or mati o n C ollecti o n F or m. 
A s u bject ( or t heir p art ner, if rele va nt) w h o bec o m es pre g na nt w hile o n st u d y will be f oll o we d 
u ntil t he e n d of t he pre g n a nc y o nl y if o n bli n de d treat me nt, or if t he y h a ve b ee n u n bli n de d a n d 
ha ve recei ve d act i ve dr u g. T he i nfa nt will be f oll o we d f or 1 year after birt h, pr o vi de d i nf or me d 
c o nse nt is o btai ne d. A se parate I C F will be pr o vi d e d t o e x plai n t hese f oll o w -u p acti vities. 
Pre g n a nc y itself is n ot a n A E.  
1 2   
S T A TI S TI C A L A N D A N A L Y TI C A L P L A N S  
T his secti o n prese n ts a s u m mar y of t he pri nci pal feat ures of t he pla n ne d effi cac y, safet y, a n d P K 
a nal ys es f or t h e st u d y. Safet y a n d efficac y a n al ysis details will be pr o vi de d i n t he statistical 
a nal ysis pla n ( S A P), a n d P K a nal ysis det ails will be pr o vi de d i n t he cli nical p h ar mac ol o g y 
a nal ysis pla n ( C P A P). B ot h t he S A P a n d C P A P will be fi nalize d bef ore cli nical data l oc k. 
 
 
 
Fi nal a nal yses will ta ke place after all s u bjects ha ve c o m plete d t he st u d y, all data ha ve b ee n 
e ntere d i n t he cli nical st u d y dat a base, a n d t he cli ni cal data h a ve bee n l oc ke d.  
1 2. 1   
S a m pl e Si z e a n d P o w er  
S u bjects will be ra n d o m ize d 2: 1: 1: 1 t o recei ve V X-8 6 4 5 0 0 m g q 1 2 h ( n = 1 6), V X -8 6 4 3 0 0  m g 
q 1 2 h ( n  =  8), V X -8 6 4 1 0 0 m g q 1 2 h ( n = 8), or place b o ( n = 8).  
Ass u mi n g 1 0 % of t he ra n d o mize d s u bjects ha ve a missi n g val ue at D a y 2 8, t his sa m ple size 
pr o vi des a de q u ate precisi o n t o esti ma te t he a bs ol ute plas ma f u ncti o nal A A T le vels at Da y 2 8 f or 
t he V X-8 6 4 5 0 0 m g q 1 2 h d ose gr o u p.  
I nf or mati o n re gar di n g t h e sa m ple siz e assess me nts is pr o vi de d bel o w. 


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1 2. 2   
A n al y si s S et  
T he f oll o wi n g a nal ysis sets are d efi ne d: All S u bjects Set, F ull A nal ysis Set ( F A S), a n d Safet y 
Set.  
T he All S u bjects Set  will i ncl u de all s u bjects w h o were ra n d o mize d or recei ve d at least 1 d ose 
of st u d y dr u g. T his a nal ysis set will be use d f or all i n di vi d ual s u bject data listi n gs a n d dis p ositi o n 
s u m mar y ta bl es, u nless ot her wise s pecifie d. 
T he F A S  will i ncl u de a ll ra n d o mize d s u bjects w h o recei v e d at least 1 d ose of st u d y dr u g. T he 
F A S will be use d t o s u m marize s u bject de m o gra p hics a n d bac k gr o u n d c haracteristics, a n d f or all 
efficac y a n al ys es, u nless ot her wise s pecifie d. S u bjects will be a nal yz e d acc or di n g t o t he 
treat me nt t o w hic h t he y were ra n d o mize d. 
T he S afet y Set  will i ncl u de all s u bjects w h o recei ve d at least 1 d ose of st u d y dr u g. T he Safet y 
Set will be use d f or all safet y a nal yses i n w hic h s u bjects will be a nal yz e d acc or di n g t o t he 
treat me nt t he y recei ve d, unless ot her wise s pecifie d.  
1 2. 3   
St ati sti c al A n al y si s  
T he pri mar y o bjecti ves of t his st u d y are t o c haract erize t he effi cac y a n d safet y of V X -8 6 4 i n 
Pi Z Z  s u bjects. T his secti o n s u m marizes t he statistical a nal ysis of efficac y a n d safet y data.  
Met h o d ol o gical a n d re l ate d details (e. g., missi n g d ata) will be i n t he S A P.  


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1 2. 3. 1   
G e n er al C o n si d er ati o n s  
All i n di vi d ual s u bject data f or s u bjects w h o were ra n d o mize d or recei ve d at least 1 d ose of st u d y 
dr u g will be prese nte d i n i n di vi d ual s u bject data listi n gs.  
C o nti n u o us v ari a bles  will be s u m marize d usi n g t he f oll o wi n g d escri pti ve s u m mar y statistics: 
t he n u m ber of s u bjects ( n), mea n, S D, me dia n, mi ni m u m val ue ( mi n), a n d ma xi m u m val ue 
( ma x). 
C ate g oric al v a ri a bles  will be s u m marize d usi n g c o u nts a n d perce nta ges.  
B aseli ne v al ue , u nless s pecifie d ot her wise, will be defi ne d as t he m ost rece nt n o n-missi n g 
meas ure me nt (s c he d ule d or u nsc he d ule d) c ollecte d bef ore t h e first d ose of st u d y dr u g. F or 
E C Gs, t he baseli ne val ue will be defi ne d as t he a v era ge of t he n o n -missi n g pretreat me nt  
meas ure me nts (tri plicate) bef ore t h e first d ose of st u d y dr u g.  
C h a n ge ( a bs ol ute c h a n ge) fr o m b aseli ne  will be calc ulate d as p ost -baseli n e val ue –  bas eli ne 
val ue.  
Rel ati ve c h a n ge fr o m b aseli ne  will be calc ulate d a n d e x presse d i n perce nt a ge as 
1 0 0 %  ×  ( p ost-bas eli ne val ue − baseli ne v al ue)/ baseli ne val ue.  
Tre at me nt -e mer g e nt ( T E) Peri o d  will i ncl u de t he ti me peri o d starti n g fr o m t he date of t he first 
d ose of st u d y dr u g t o eit her ( 1) Safet y F oll o w -u p Visit 2 8 da ys after t he last d ose of st u d y dr u g, 
( 2) E T T Visit if it re places t he Safet y F oll o w-u p Visit 2 8 da ys after t he last d ose of st u d y dr u g, 
or ( 3) 2 8 da ys after t h e last d ose date f or s u bjects w h o d o n ot ha ve a Safet y F oll o w -u p Visit 
2 8  da ys after t h e last d ose of st u d y dr u g or e q ui v ale nt. T he T E Peri o d will  be use d f or s afet y 
a nal ys es u nless s pe cifie d ot her wise.  
I nc o m plete/ missi n g d at a will n ot be i m p ute d, u nless s pecifie d ot her wise.  
1 2. 3. 2   
D e m o gr a p hi c s a n d B a c k gr o u n d C h ar a ct eri sti c s  
S u bject dis p ositi o n (e. g., c o m plete d treat me nt, pre mat urel y dis c o nti n ue d t he treat me nt a n d t h e 
reas o n f or disc o nti n uati o n) will be s u m marize d b y treat me nt gr o u p. 
De m o gra p hic a n d ot her b aseli ne c haracteristics (e. g., plas ma A A T le vels a n d p p F E V
1) will be 
s u m marize d b y treat me nt gr o u p. N o statistical tests will be carrie d o ut t o e val uate baseli ne 
i m bala nces bet w ee n tr eat me nt gr o u ps.  
Me dicati o ns use d will be c o de d usi n g t he W orl d Healt h Or ga nizati o n -Dr u g Dicti o nar y 
( W H O Dr u g) a n d s u m marize d descri pti vel y. E x p os ure t o st u d y dr u g (i.e., d urati o n of treat me nt) 
a n d d osi n g c o m plia nce (i.e., perc e nta ge of da ys bei n g c o m plia nt t o treat me nt) will be 
s u m marize d descri pti vel y.  
I m p ort a nt pr ot oc ol de viati o ns will be pr o vi de d i n a n i n di vi d ual s u bject data listi n g, a n d 
s u m marize d, as a p pr o pri ate. 
A d diti o nal details will be pr o vi de d i n t he S A P.  
1 2. 3. 3   
Effi c a c y A n al y si s  
1 2. 3. 3. 1   
A n al y si s of t h e Pri m ar y V ari a bl e  
T he pri mar y e n d p oi nt t o assess effi cac y is t he c ha n ge fr o m baseli ne i n plas ma f u ncti o nal A A T 
le vels at Da y 2 8. T his pri mar y a nal ysis will be bas e d o n a mi x e d-effects m o del f or re p eate d 


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meas ures ( M M R M) wit h c ha n ge fr o m baseli ne at Da ys  7, 1 4, a n d 2 8 as t he de pe n de nt varia ble. 
T he m o del will i ncl u de treat me nt gr o u p, visit, a n d treat me nt -b y -visit i nteracti o n as fi x e d effects. 
T he m o del will be esti mate d usi n g restricte d ma xi m u m li keli h o o d. De n o mi nat or de grees of 
free d o m f or t he F -t est f or fi x e d effects will be esti mate d usi n g t he Ke n war d-R o ger 
a p pr o xi mati o n. A n u nstr uct ure d c o v aria n ce str uct ure will be use d t o m o del t he wit hi n -s u bject 
err ors. If t he m o del esti m ati o n d oes n ot c o n ver ge, a c o m p o u n d s y m metr y c o varia nce str uct ure 
will be use d i nstea d.  
 
Details will be pr o vi de d i n t he S A P.  
1 2. 3. 3. 2   
M ulti pli cit y A dj u st m e nt  
T here is n o m ulti plicit y a dj ust me nt f or t he pair wis e c o m paris o ns bet w ee n differe nt d os es of 
V X -8 6 4 a n d place b o.   
1 2. 3. 3. 3   
Mi s si n g D at a H a n dli n g  
F or t he pri mar y a nal ysis of t he pri mar y efficac y e n d p oi nt, missi n g data will be ass u me d t o be 
missi n g at ra n d o m c o n diti o nal o n t he o bser ve d d ata a n d c o v ariate; c o ns e q u e ntl y, n o i m p utati o n 
of missi n g data will be perf or me d.  
 
1 2. 3. 4   
S af et y A n al y si s  
T he o verall safet y pr ofile of V X -8 6 4 will be ass esse d i n ter ms of t he f oll o wi n g safet y e n d p oi nts:  
•  I n ci de nce of treat me nt e mer ge nt a d verse e v e nts ( T E A Es) 
•  Cli nical la b orat or y  val ues (i.e., he mat ol o g y, ser u m c he mistr y, c oa g ulati o n, a n d uri nal ysis)  
•  Sta n dar d 1 2 -lea d E C G o utc o mes 
•  Vital si g ns  
•  P ulse o xi metr y  
F or safet y a nal ys es, n o statistical h y p ot hesis testi n g will be c o n d u cte d. A d diti o nal details will be 
pr o vi de d i n t he S A P.  
1 2. 3. 5   
I nteri m a n d I n d e p e n d e nt D at a M o nit ori n g C o m mitt e e A n al y s e s  
1 2. 3. 5. 1   
I nt eri m A n al y si s 
I nteri m a nal yses ma y b e perf or me d at a n y ti me at t he discreti o n of t he s p o ns or f or i nter nal 
decisi o n -ma ki n g. I nteri m a nal ys es will be perf or m e d a n d re vi e we d b y a n u n bli n de d Verte x tea m 
n ot i n v ol ve d i n t he c o n d uct of t he st u d y.  
1 2. 3. 5. 2   
I n d e p e n d e nt D at a M o nit ori n g C o m mitt e e A n al y si s 
N ot a p plica ble  


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1 2. 4   
Cli ni c al P h ar m a c ol o g y A n al y si s  
1 2. 4. 1   
P h ar m a c o ki n eti c A n al y si s  
T he P K of V X -8 6 4  will be descri b e d usi n g s u m m ar y statistics. Preli mi nar y re vie w a n d a nal yses 
of t he dr u g c o n ce ntrati o ns ma y be d o ne bef ore d ata l oc k u n der t he c o n diti o ns of mas ke d 
i de ntificati o ns of t he s u bject c o nce ntrati o ns. 
Details of t he a n al ys es will be i n t he C P A P.  
1 2. 4. 2   
P h ar m a c o ki n eti c/ P h ar m a c o d y n a mi c A n al y s e s  
A p o p ulati o n P K a nal ysis of plas ma c o nce ntrati o n vers us ti me data of V X -8 6 4 ma y be 
perf or me d usi n g a n o n -li near mi x e d-effects m o deli n g a p pr oac h. P o p ulati o n P K/ P D m o dels ma y 
als o be de vel o pe d t o h el p u n dersta n d t he relati o ns hi p bet wee n V X -8 6 4 e x p os ure a n d P D 
e n d p oi nts. A m ore detail e d descri p ti o n of t he met h o d ol o g y will be i ncl u de d i n a se parate 
p o p ulati o n a nal ysis pla n. Res ults of t hese a nal yses, if c o n d ucte d, will be prese nte d i n sta n dal o ne, 
se parat e d oc u me nts a n d will n ot be i ncl u de d i n t he C S R.  
1 3   
P R O C E D U R A L, E T HI C A L,  R E G U L A T O R Y, A N D A D M I NI ST R A TI V E 
C O N SI D E R A TI O N S  
1 3. 1   
A d v er s e E v e nt a n d S eri o u s A d v er s e E v e nt D o c u m e nt ati o n, S e v erit y 
Gr a di n g, a n d R e p orti n g  
1 3. 1. 1   
A d v er s e E v e nt s  
1 3. 1. 1. 1   
D efi niti o n of a n A d v er s e E v e nt  
A n A E is defi ne d as a n y u nt o war d me dical o cc urre nce i n a s u bject d uri n g t he st u d y; t he e v e nt 
d oes n o t necess aril y h a ve a ca usal relati o ns hi p wit h t he treat me nt. T his i ncl u des a n y ne wl y 
occ urri n g e ve nt or w orse ni n g of a pre -e xisti n g c o n diti o n (e. g.,  i ncreas e i n its se verit y or 
fre q ue n c y) after t he I C F is si g ne d.  
A n A E is c o nsi dere d s eri o us if it meets t h e defi niti o n i n Secti o n  1 3. 1. 2. 1 .  
1 3. 1. 1. 2   
Cli ni c all y Si g nifi c a nt A s s e s s m e nt s  
St u d y assess me nts i ncl u di n g cli nical la b orat or y tests, E C Gs, P Es, a n d vital si g ns will be assess e d 
a n d t h ose dee me d t o h a v e cli nicall y si g nifica nt w orse ni n g fr o m baseli ne will be d oc u me nte d as 
a n A E. W he n p ossi ble, a cli nical dia g n osis f or t he st u d y assess me nt will be pr o vi de d, rat her t ha n 
t he a b n or mal test res ult al o ne (e. g., uri nar y tract i nfecti o n, a ne mia). I n t he a bse nce of a 
dia g n osis, t he a b n or mal st u d y assess me nt itself will be liste d as t he A E (e. g.,  bacteria i n uri ne or 
decrease d h e m o gl o bi n).  


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A n a b n or mal st u d y assess me nt is c o nsi dere d cli ni call y si g nifica nt if t he s u bject has 1  or m ore of 
t he f oll o wi n g: 
•  C o nc o mita nt si g ns or s y m pt o ms relate d t o t he a b n or mal st u d y ass ess me nt  
•  F urt her di a g n ostic testi n g or me dical/s ur gical i nter ve nti o n  
•  A c ha n ge i n t he d os e of st u d y dr u g or dis c o nti n uati o n fr o m t he st u d y  
Re peat testi n g t o d eter mi ne w het her t h e res ult is a b n or mal, i n t he a bse nce of a n y of t he a b o ve 
criteria, d o es n ot necess aril y meet cli nicall y si g nifica nt criteria. T he det er mi nati o n of w het her t he 
st u d y assess me nt res ults are cli nicall y si g nifica nt will be ma de b y t he i n ves ti gat or. 
A la b orat or y v al ue t hat is Gra de 4 will n ot a ut o maticall y be a n S A E. A Gra de 4  la b orat or y v al ue 
will be a n S A E if t he s u bject's cli nical stat us i n dicates a life -t hreate ni n g A E. 
1 3. 1. 1. 3   
D o c u m e nt ati o n of A d v er s e E v e nt s  
All A Es will be c ollecte d fr o m t he ti m e t he I C F is si g ne d u ntil t he f oll o wi n g ti mes:  
•  F or s u bjects w h o d o n ot e nr oll: u ntil ti me of scree n fail ure (e. g.,  scree n fail ure, wit h dra wal of 
c o nse nt)  
•  F or e nr olle d s u bjects w h o ha ve a Safet y F oll o w -u p Visit 2 8 da ys after t he l ast d ose : t hr o u g h 
t he Safety F oll o w -u p Visit 2 8 da ys after t he last d ose  
•  F or e nr olle d s u bjects w h o d o n ot ha ve a Safet y F oll o w -u p Visit 2 8 da ys after t he last d ose : 
t hr o u g h t he E T T Visit, if t hat visit is ≥2 2 da ys or later f oll o wi n g t he last d ose of st u d y dr u g 
(see Secti o n  9. 1. 4 ) or 2 8 da ys after t he last d ose of st u d y dr u g f or s u bjects w h o d o n ot ha ve 
a n E T T Visit.  
All s u bjects will be q uerie d, usi n g n o nlea di n g q u esti o ns, a b o u t t he occ urre nce of A Es at eac h 
st u d y visit. W he n p ossi ble, a c o nstellati o n of si g ns a n d/ or s y m pt o ms will be i de ntifie d as 
1  o verall e ve nt or dia g n osis. All A Es f or e nr olle d s u bjects will be rec or de d i n t he C R F a n d 
s o urce d oc u m e nt. A Es f or s u bjects w h o are scree n e d b ut n ot s u bse q ue ntl y e nr olle d will be 
rec or de d o nl y i n t he s u bject's s o urce d oc u me nts. T he f oll o wi n g d ata will b e d oc u me nte d f or eac h 
A E:  
•  Descri pti o n of t he e v e nt  
•  Classificati o n of "seri o us" or " n o nseri o us"  
•  Date of first o cc urre nce a n d date of re s ol uti o n (if a p plica ble) 
•  Se verit y  
•  Ca usal relati o ns hi p t o st u d y dr u g(s)  
•  Acti o n ta ke n  
•  O utc o me  
•  C o nc o mita nt me dicati o n or ot her treat me nt gi v e n  


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1 3. 1. 1. 4   
A d v er s e E v e nt S e v erit y  
T he i n vesti gat or will deter mi ne a n d rec or d t he se verit y of all seri o us a n d n o nseri o us A Es . T he 
g ui da nce a v aila ble at t he f oll o wi n g we bsite will be c o ns ulte d: C o m m o n Ter mi n ol o g y Criteria f or 
A d verse E v e nts ( C T C A E), Versi o n  5. 0, Ca ncer T h era p y E val uati o n Pr o gra m, 
htt p://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o nic _a p plicati o ns/ctc. ht m  ( Access e d 
J ul y 2 0 1 8 ). A Es of C T C A E Gra d es 4 a n d 5 will b e d oc u me nte d as "life -t hreate ni n g." T he 
se verit y of a n A E descri be d b y a ter m t hat d oes n ot a p pear i n t he C T C A E will be deter mi ne d 
acc or di n g t o t he d efi niti o ns i n Ta ble  1 3 -1 . 
T a ble  1 3 -1  
Gr a di n g of A E Se verit y  
Cl assific ati o n  
Defi niti o n  
Mil d ( Gr a de  1)  
Mil d le vel of disc o mf ort a n d d oes n ot i nterfere wit h re g ular acti vities  
M o der ate ( Gr a de  2)   
M o derate le vel of disc o mf ort a n d si g nifica ntl y i nterferes wit h re g ular acti vities 
Se vere ( Gr a de  3)  
Si g nifica nt le vel of disc o mf ort a n d pre ve nts re g ular acti vities  
Life -t hre ate ni n g 
( Gr a de 4)  
A n y a d verse dr u g e ve nt t hat places t he s u bj ect, i n t he vie w of t he i n vesti gat or, at 
i m me diate ris k of deat h  
 
1 3. 1. 1. 5   
A d v er s e E v e nt  C a u s alit y  
E ver y eff ort will be ma d e b y t h e i n vesti gat or t o assess t he relati o ns hi p of t he A E, if a n y, t o t he 
st u d y dr u g(s). Ca usalit y will be classifie d usi n g t h e cate g ories i n Ta ble  1 3 -2 . 
T a ble  1 3 -2  
Cl assific ati o ns f or A E C a us alit y  
Cl assific ati o n  
Defi niti o n  
Rel ate d  
T here is a n ass ociati o n bet wee n t he e ve nt a n d t he a d mi nistrati o n of i n vesti gati o nal 
st u d y dr u g, a pla usi ble mec ha nis m f or t he e ve nt t o be relate d t o t he i n vesti gati o nal 
st u d y dr u g a n d ca uses ot her t ha n t he i n vesti gati o nal st u d y dr u g ha ve bee n r ule d o ut, 
a n d/ or t he e ve nt rea p peare d o n re -e x p os ure t o t he i n vesti gati o nal st u d y dr u g.  
P ossi bl y rel ate d  
T here is a n ass ociati o n bet wee n t he e ve nt a n d t he a d mi nistrati o n of t he 
i n vesti gati o nal st u d y dr u g a n d t here is a pla usi ble mec ha nis m f or t he e ve nt t o be 
relate d t o i n vesti gati o nal st u d y dr u g, b ut t here ma y als o be alter nati ve etiol o g y, 
s uc h as c haracteristics of t he s u bj ect's cli nical stat us or u n derl yi n g disease.  
U nli kel y rel ate d   
T he e ve nt is u nli kel y t o be relate d t o t he i n vesti gati o nal st u d y dr u g a n d li kel y t o be 
relate d t o fact ors ot her t ha n i n vesti gati o nal st u d y dr u g.  
N ot rel ate d 
T he e ve nt is relate d t o a n eti ol o g y ot her t ha n t he i n vesti gati o nal st u d y dr u g (t he 
alter nati ve eti ol o g y will be d oc u me nte d i n t he s u bj ect's me dical rec or d).  
 


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St u d y Dr u g A cti o n T a k e n  
T he i n vesti gat or will classif y t he st u d y dr u g acti o n ta ke n wit h re gar d t o t he A E. T he acti o n ta ke n 
will be classifie d acc or di n g t o t he cate g ories i n Ta ble  1 3 -3 .  
T a ble  1 3 -3  
Cl assific ati o ns f or St u d y Dr u g Acti o n T a ke n Wit h Re g ar d t o a n A E  
Cl assific ati o n  
Defi niti o n  
D ose n ot c h a n ge d   
St u d y dr u g d ose n ot c ha n ge d i n res p o nse t o a n A E  
D ose re d uce d  
St u d y dr u g d ose re d uce d i n res p o nse t o a n A E  
Dr u g i nterr u pte d   
St u d y dr u g a d mi nistrati o n i nterr u pte d i n res p o nse t o a n A E  
Dr u g wit h dr a w n   
St u d y dr u g a d mi nistrati o n per ma ne ntl y disc o nti n ue d i n res p o nse t o a n A E  
N ot a p plic a ble  
Acti o n ta ke n re gar di n g st u d y dr u g a d mi nistrati o n d oes n ot a p pl y.  
" N ot a p plica ble" will be use d i n circ u msta nces s uc h as w he n t he i n vesti gati o nal 
treat me nt ha d bee n c o m plete d bef ore t he A E be ga n a n d n o o p p ort u nit y t o deci de 
w het her t o c o nti n ue, i nterr u pt, or wit h dra w treat me nt is p ossi ble.  
 
1 3. 1. 1. 7   
A d v er s e E v e nt O ut c o m e  
A n A E will be f oll o we d u ntil t he i n vesti gat or has deter mi ne d a n d pr o vi de d t he fi nal o utc o me. 
T he o utc o me will be classifie d acc or di n g t o t he cate g ories i n Ta ble  1 3 -4 . 
T a ble  1 3 -4  
Cl assific ati o ns f or O utc o me of a n A E  
Cl assific ati o n  
Defi niti o n  
Rec o vere d/res ol ve d   
Res ol uti o n of a n A E wit h n o r esi d ual si g ns or s y m pt o ms  
Rec o vere d/res ol ve d wit h 
se q uel ae 
Res ol uti o n of a n A E wit h resi d ual si g ns or s y m pt o ms  
N ot rec o vere d/ n ot 
res ol ve d (c o nti n ui n g)  
Eit her i nc o m plete i m pr o ve me nt or n o i m pr o ve me nt of a n A E, s uc h t hat it re mai ns 
o n g oi n g  
F at al  
O utc o me of a n A E is deat h. " Fatal" will be use d w he n deat h is at leas t p ossi bl y 
relate d t o t he A E. 
U n k n o w n  
O utc o me of a n A E is n ot k n o w n (e. g.,  a s u bj ect l ost t o f oll o w u p)  
 
1 3. 1. 1. 8   
Tr e at m e nt Gi v e n  
T he i n vesti gat or e ns ures a de q uate m e dical care is pr o vi de d t o s u bjects f or a n y A Es, i ncl u di n g 
cli nicall y si g nifica nt la b orat or y val ues relate d t o st u d y dr u g. I n a d diti o n, t he i n vesti gat or will 
descri be w het her a n y treat me nt was gi ve n f or t he A E. " Yes" is us e d if a n y treat me nt was gi ve n 
i n res p o nse t o a n A E, a n d ma y i ncl u d e treat me nts s uc h as ot her me dicati o ns, s ur ger y, or p h ysical 
t hera p y. " N o" i n dicates t he a bse nce of a n y ki n d of treat me nt f or a n A E. 


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1 3. 1. 2   
S eri o u s A d v er s e E v e nt s  
1 3. 1. 2. 1   
D efi niti o n of a S eri o u s A d v er s e E v e nt  
A n S A E is a n y A E t hat meets a n y of t he f oll o wi n g o utc o mes:  
•  Fatal ( deat h, r e gar dless of ca use, t h at occ urs d uri n g partici pat i o n i n t he st u d y or occ urs after 
partici pati o n a n d is s us pe cte d of bei n g a d ela ye d t o xicit y d ue t o a d mi nistrati o n of t he st u d y 
dr u g)  
•  Lif e -t hreate ni n g, s uc h t h at t he s u bject was at i m me diate ris k of deat h fr o m t he reacti o n as it 
occ urre d  
•  I n p atie nt h os pitalizati o n or pr ol o n gati o n of h os pitalizati o n 
•  Persiste nt or si g nifica nt disa bilit y/i nca pacit y ( disa bilit y is defi ne d as a s u bsta ntial disr u pti o n 
of a pers o n's a bilit y t o c o n d uct n or mal life f u ncti o ns)  
•  C o n ge nital a n o mal y or birt h defect  
•  I m p ort a nt me dical e ve nt t hat, base d u p o n a p pr o priate me dical j u d g me nt, m a y j e o par dize t he 
s u bject or ma y re q uire m e dical or s ur gical i nter ve nti o n t o pre ve nt 1 of t he o utc o mes liste d 
a b o ve (e. g.,  a n aller gic br o nc h os pas m re q uiri n g i nt e nsi ve treat me nt i n a n e mer ge nc y r o o m or 
at h ome)  
If a s u bject h as a h os pitalizati o n or pr oce d ure (e. g., s ur ger y) f or a n e ve nt or c o n diti o n t hat 
occ urre d bef ore t he s u bject si g ne d t he I C F, a n d t h e h os pitalizati o n or pr oce d ure was pla n n e d 
bef ore t h e s u bject si g ne d t he I C F, t he h os pitalizati o n or pr oce d ure will n ot be c o nsi dere d t o 
i n dicate a n S A E, u nless a n A E ca use d t h e h os pitalizati o n or pr oce d ure t o b e resc he d ul e d s o o ner 
or t o be pr ol o n ge d relati ve t o w hat was pla n n e d. I n a d diti o n, h os pitalizati o ns clearl y n ot 
ass ociate d wit h a n A E (e. g.,  s ocial h ospitalizati o n f or p ur p oses of res pite care) will n ot be 
c o nsi dere d t o i n dicat e a n S A E.  
Clarificati o n will be ma de bet wee n t he ter ms "seri o us" a n d "se v ere" b eca us e t he y are n ot 
s y n o n y m o us. T he ter m "se vere" is ofte n use d t o d escri be t he i nte nsit y (se v erit y) of a s p ecific 
e ve nt, as i n mil d, m o derate, or se vere m y ocar dial i nfarcti o n. T he e ve nt itself, h o we ver, ma y be 
of relati vel y mi n or me dical si g nifica nce, s u c h as a se vere h ea d ac he. T his is n ot t he sa me as 
"seri o us", w hic h is bas e d o n s u bject/e ve nt o utc o m e or  acti o n des cri be d a b o ve a n d is us uall y 
ass ociate d wit h e v e nts t hat p ose a t hreat t o a s u bject's life or f u ncti o ni n g. Seri o us ness, n ot 
se verit y, ser ves as a g ui d e f or defi ni n g e x pe dite d re g ul at or y re p orti n g o bli gati o ns.   
1 3. 1. 2. 2   
R e p orti n g a n d D o c u m e nt ati o n of S eri o u s A d v er s e E v e nt s  
All S A Es t hat occ ur aft er o btai ni n g i nf or me d c o ns e nt a n d asse nt ( w here a p plica ble) t hr o u g h t he 
last Safet y F oll o w-u p Visit, re gar dless of ca usalit y, will be re p orte d b y t he i n vesti gat or t o Verte x 
G P S wit hi n 2 4 h o urs of i de ntific ati o n . I n a d diti o n, all S A Es t hat occ ur after t he last Safet y 
F oll o w -u p Visit a n d are c o nsi dere d rel ate d t o st u d y dr u g(s) will be re p orte d t o Verte x G P S 
wit hi n 2 4  h o urs of i de ntific ati o n .  


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F or S A Es t hat occ ur after o btai ni n g i nf or me d c o ns e nt a n d asse nt ( w here a p plic a ble) t hr o u g h t he 
last Safet y F oll o w -u p Visit, t he S A E F or m will be c o m plete d f or ne w/i nitial e ve nts as well as t o 
re p ort f oll o w-u p i nf or mati o n o n pre vi o usl y re p orte d e ve nts. I n v esti gat ors are as ke d t o re p ort 
f oll o w-u p i nf or mati o n as s o o n as it bec o mes a va il a ble t o e ns ure ti mel y re p orti n g t o healt h 
a ut h orities.  
Please se n d c o m plete d S A E F or ms t o Verte x G P S via:  
E mail: 
 ( preferre d c h oice) 
Fa x: 
  
F or tec h ni cal iss ues rel ate d t o s u b mitti n g t he f or m, c o ntact tele p h o ne: 
 
S A Es t hat occ ur after t he last Safet y F oll o w-u p Visit a n d are c o nsi dere d rel ate d t o st u d y dr u g(s)  
will be rec or de d o n t he Verte x Cli nical Trial Safet y I nf or mati o n C ollecti o n F or m ( he reafter 
referre d t o as t he " S A E F or m") usi n g a rec o g nize d me dical ter m or dia g n osis t hat acc uratel y 
reflects t he e ve nt. S A Es will be assesse d b y t he i n vesti gat or f or relati o ns hi p t o t he i n vesti gati o nal 
st u d y dr u g(s) a n d p ossi ble eti ol o gies. O n t h e S A E F or m, rel ati o ns hi p t o st u d y dr u g(s) will be 
assesse d o nl y as relate d (i ncl u des p ossi bl y rel ate d) or n ot relate d (i ncl u des u nli kel y rel ate d), a n d 
se verit y assess me nt will n ot be re q uire d. F or t he p ur p oses of st u d y a nal ysis, if t he e ve nt has n ot 
res ol ve d at t he e n d of t he st u d y re p orti n g p eri o d, it will be d oc u me nte d as o n g oi n g. F or p ur p oses 
of re g ulat or y s afet y m o nit ori n g, t he i n vesti gat or is re q uire d t o f oll o w t he e v e nt t o res ol uti o n a n d 
re p ort t he o utc o me t o V erte x usi n g t he S A E F or m. 
1 3. 1. 2. 3   
E x p e dit e d R e p orti n g a n d I n v e sti g at or S af et y L ett er s  
Verte x, as st u d y s p o ns or, is res p o nsi ble f or re p orti n g s us pecte d, u ne x pecte d, seri o us a d verse 
reacti o ns ( S U S A Rs) i n v ol vi n g t he st u d y dr u g(s) t o all re g ulat or y a ut h orities, I E Cs, a n d 
partici pati n g i n v esti gat ors i n acc or da nce wit h I C H G ui deli nes a n d/ or l ocal re g ul at or y 
re q uire me nts, as a p plica ble. I n a d diti o n, Verte x, or a ut h orize d desi g n ee, will be res p o nsi ble f or 
t he s u b missi o n of safet y l etters t o ce ntral I E Cs.  
It is t he res p o nsi bilit y of t he i n vesti gat or or desi g n ee t o pr o m ptl y n otif y t he l ocal I R B/ I E C of all 
u ne x pecte d seri o us a d verse dr u g reacti o ns i n v ol vi n g ris k t o h u ma n s u bjects.  
1 3. 2   
A d mi ni str ati v e R e q uir e m e nt s  
1 3. 2. 1   
Pr o d u ct C o m pl ai nt s  
A pr o d uct c o m plai nt is defi ne d as a n y ver bal or writte n c o m m u nicati o n a d dresse d t o Verte x, or 
desi g nee, of i n q uir y or dissatisfacti o n wit h t he i de ntit y, str e n gt h, q ualit y, or p urit y of a release d 
dr u g pr o d uct, I M P, or me dical de vice. I n a d diti o n, s us pecte d c o u nterfeit/falsifie d pr o d uct is 
c o nsi dere d a pr o d uct c o m plai nt.  
Pr o d uct c o m plai nts are t o be re p ort e d t o Verte x.  


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1 3. 2. 2   
Et hi c al C o n si d er ati o n s  
T he st u d y will be c o n d ucte d i n acc or da nce wit h t he c urre nt I C H  G C P G ui deli nes, w hic h are 
c o nsiste nt wit h t he et hical pri nci ples f o u n de d i n t he Decl arati o n of Helsi n ki, a n d i n acc or da nce 
wit h l ocal a p plica ble la ws a n d  re g ulati o ns. T he I R B/I E C will re vie w all a p pr o priate st u d y 
d oc u me ntati o n t o safe g u ar d t he ri g hts, safet y, a n d well -bei n g of t he s u bjects. T he st u d y will be 
c o n d ucte d o nl y at sites w here I R B/I E C a p pr o v al h as bee n o btai ne d. T he pr ot oc ol, I B, sa m ple 
I C F, a d vertise me nts (if a p plica ble), writte n i nf or mati o n gi ve n t o t he s u bjects (i ncl u di n g diar y 
car ds), s afet y u p d ates, a n n ual pr o gress re p orts, a n d a n y re visi o ns t o t hese d oc u me nts will be 
pr o vi de d t o t he I R B/I E C b y t he i n vesti gat or or Verte x, as all o wa ble b y l oc al a p plica ble la ws a n d 
re g ulati o ns. 
1 3. 2. 3   
S u bj e ct I nf or m ati o n a n d I nf or m e d C o n s e nt  
After t he st u d y has b ee n f ull y e x plai ne d, writte n i nf or me d c o ns e nt will be o btai ne d fr o m t he 
s u bject or le gal r e pres e ntati ve or g uar dia n (if a p pli ca ble) b ef ore st u d y p artici pati o n . T he met h o d 
of o btai ni n g a n d d o c u me nti n g t he i nf or me d c o nse nt a n d asse nt (if a p plica ble) a n d t he  c o nt e nts of 
t he c o nse nt will c o m pl y wit h I C H G C P a n d all a p plica ble la ws a n d re g ulati o ns a n d will be 
s u bject t o a p pr o val b y Verte x or its desi g nee. 
I n t he e vent t hat s u bjects are u n willi n g or u na ble t o tra vel t o t he st u d y site d ue t o e xte n uati n g 
circ u msta nces (e. g., e ve nts relate d t o C O VI D -1 9), I C Fs ma y be pr o vi d e d el ectr o nicall y or b y 
p ost mail t o s u bjects or le gal re prese ntati ves or g uar dia ns (if a p plica ble).  T he s u bject a n d/ or le gal 
re pres e ntati ve or g u ar dia n will re vie w t he I C F wit h a n a p pr o priatel y q ualifie d me m ber of t h e 
i n vesti gat or’s t ea m via tele p h o ne c o ntact or vi de o call. After t his re vie w, t h e s u bject a n d/ or le gal 
re pres e ntati ve or g u ar dia n will c o nse nt, a n d/ or rec o nse nt ver ball y a n d b y si g ni n g a n d d ati n g t he 
I C F a n d ret ur ni n g it t o t he site via p ost mail. T he si g ne d a n d date d I C F will t he n be si g n e d a n d 
date d b y t he i n vesti gat or.  
1 3. 2. 4   
I n v e sti g at or C o m pli a n c e 
N o m o dificati o ns t o t he pr ot oc ol will be ma de w it h o ut t he a p pr o val of b ot h t he i n vesti gat or a n d 
Verte x. C ha n ges t hat si g nifica ntl y affect t he safet y of t he s u bj ects, t he sc o pe of t he i n vesti gati o n, 
or t he scie ntific q ualit y of t he st u d y (i.e.,  P D assess me nts) will re q uire I R B/I E C n otificati o n 
bef ore i m ple me nt ati o n, e x ce pt w here t he m o dificati o n is necessar y t o eli mi nate a n a p p are nt 
i m me diate hazar d t o h u ma n s u bjects. Verte x will s u b mit all pr ot oc ol m o dificati o ns t o t he 
re q uire d re g ulat or y a ut h orities. 
W he n circ u msta nces re q uire a n i m me diate de p art ure fr o m pr oce d ures set f ort h i n t he pr ot oc ol, 
t he i n vesti gat or will c o ntact Vert e x t o disc uss t he pla n ne d c o urse of acti o n. If p ossi ble, c o ntact 
will be ma de bef ore t he i m ple me ntati o n of a n y c h a n ges. A n y de p art ures fr o m t he pr ot oc ol will 
be f ull y d o c u me nte d i n t he s o urce d o c u me ntati o n a n d i n a pr ot oc ol de viati o n l o g.  
1 3. 2. 5   
A c c e s s t o R e c or d s  
T he i n vesti gat or will ma ke t he office a n d/ or h os pital rec or ds of s u bjects e nr olle d i n t his st u d y 
a vaila ble f or i ns pecti o n b y Verte x or its re pres e ntati ve at t he ti me of eac h m o nit ori n g visit a n d 
f or a u dits. T he rec or ds will als o be a vaila ble f or direct i ns pecti o n, verificati o n, a n d c o p yi n g, as 
re q uire d b y a p plica ble la ws a n d re g ulati o ns, b y officials of t he re g ulat or y h ealt h a ut h orities 
( F D A a n d ot hers). T he i n vesti gat or will c o m ply wit h a p plica ble pri vac y a n d sec urit y la ws f or use 
a n d discl os ure of i nf or mati o n relate d t o t he researc h set f ort h i n t his pr ot oc ol.  


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S u bj e ct Pri v a c y  
T o mai ntai n s u bject c o nfi de ntialit y a n d t o c o m pl y wit h a p plica ble data pr otecti o n a n d pri vac y 
la ws a n d reg ul ati o ns, all C R Fs, st u d y re p orts, a n d c o m m u nicati o ns relati n g t o t he st u d y will 
i de ntif y s u bjects b y assi g ne d s u bject n u m bers, a n d access t o s u bject na mes li n ke d t o s uc h 
n u m bers will be li mite d t o t he site a n d t he st u d y p h ysicia n a n d will n ot be discl ose d t o Verte x. 
As re q uire d b y a p plica bl e la ws a n d re g ulati o ns i n t he c o u ntries i n w hic h t h e st u d y is bei n g 
c o n d ucte d, t he i n vesti gat or will all o w Verte x a n d/ or its re prese nt ati ves access t o all perti ne nt 
me dical rec or ds t o all o w f or t he verificati o n of dat a gat here d i n t he C R Fs/ S A E F or ms a n d t h e 
re vie w of t h e data c ollecti o n pr ocess. T he F D A a n d re g ulat or y a ut h orities i n ot her j uris dicti o ns, 
i ncl u di n g t he I R B/I E C, ma y als o re q uest access t o all st u d y rec or ds, i ncl u di n g s o urce 
d oc u me ntati o n, f or i ns pecti o n.  
F o r sites partici p ati n g i n t he U S, a n d i n acc or da nce wit h t he Healt h I ns ura n ce P orta bilit y a n d 
Acc o u nta bilit y Act ( HI P A A) a n d ass ociate d re g ul ati o ns, a n e x ec ute d HI P A A a ut h orizati o n will 
be o btai ne d b y t he site fr o m eac h s u bject ( or t he l e gal re prese ntati ve of t he s u bject) bef ore 
researc h acti vities ma y b e gi n. E ac h HI P A A a ut h orizati o n will c o m pl y wit h all HI P A A 
re q uire me nts i ncl u di n g a ut h orizati o n all o wi n g t he site access t o a n d us e of t he s u bject's 
pers o nall y i de ntifia ble healt h i nf or mati o n, a ut h orizati o n f o r t he site t o discl ose s uc h i nf or mati o n 
t o Verte x, t he F D A, a n d ot her parties re q uiri n g access u n der t he pr ot oc ol, a n d state me nts as t o 
t he p ur p ose f or w hic h s u c h i nf or mati o n ma y be us e d a n d f or h o w l o n g. 
1 3. 2. 7   
R e c or d R et e nti o n  
T he i n vesti gat or will mai ntai n all  st u d y rec or ds acc or di n g t o I C H G C P G ui deli nes a n d/ or 
a p plica ble l ocal re g ulat or y re q uire me nt(s), w hic he ver is l o n gest, as descri be d i n t he Cli nical 
Trial A gree me nt. If t he i n vesti gat or wit h dra ws fr o m t he res p o nsi bilit y of kee pi n g t he st u d y 
rec or ds, c ust o dy will be tra nsferre d t o a pers o n willi n g t o acce pt t he res p o nsi bilit y a n d Verte x 
will be n otifie d.  
1 3. 2. 8   
St u d y T er mi n ati o n  
At a n y ti me, Verte x ma y ter mi nate t his st u d y i n its e ntiret y or ma y ter mi nat e t his st u d y at a n y 
partic ular site. I n a d diti o n, f or reas o na b le ca use, eit her t he i n vesti gat ors or t heir I R Bs/I E Cs ma y 
ter mi nate t he st u d y at t heir ce nter. 
C o n diti o ns t hat ma y lea d t o reas o na ble ca use a n d warra nt ter mi nati o n i ncl u de, b ut are n ot li mite d 
t o: 
•  S u bject or i n vesti gat or n o nc o m plia nce  
•  U nsatisfact or y s u bjec t e nr oll me nt 
•  Lac k of a d here nce t o pr ot oc ol pr oce d ures  
•  Lac k of e val ua ble a n d/ or c o m plete data  
•  P ote ntiall y u n acce pta ble ris k t o st u d y s u bjects  
•  Decisi o n t o m o dif y dr u g de vel o p me nt pla n  
•  Decisi o n b y t he F D A or ot her re g ulat or y a ut h orit y  
Writte n n otificati o n t hat i ncl u des t he reas o n f or t h e cli nical st u d y t er mi nati o n is re q uire d. 


Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 5 9  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
1 3. 2. 9   
E n d of St u d y  
T he e n d of st u d y is defi n e d as t he last sc he d ul e d visit ( or sc he d ule d c o ntact) of t he last s u bject.  
1 3. 3   
D at a Q u alit y A s s ur a n c e  
Verte x or its desi g nat e d re prese nt ati ve will c o n d uct a st u d y site visit t o verif y t he q ualificati o ns 
of eac h i n v esti gat or, i ns pect cli nical st u d y site facilities, a n d i nf or m t he i n vesti gat or of 
res p o nsi bilities a n d pr oce d ures f or e ns uri n g a de q u ate a n d c orrect st u d y d o c u me ntati o n. 
T he i n vesti gat or is re q uir e d t o pre pare a n d m ai ntai n a de q uate a n d acc urate case hist ories 
desi g ne d t o rec or d all o bser vati o ns a n d ot her d ata perti ne nt t o t he st u d y f or eac h s u bject. St u d y 
data f or eac h e nr olle d s u bject will be e ntere d i nt o a C R F b y st u d y site pers o n nel  usi n g a s ec ure, 
vali date d, we b -b ase d electr o nic data ca pt ure ( E D C) a p plicati o n. Verte x will ha ve rea d -o nl y 
access t o site -e ntere d cli nical data i n t he E D C a p plicati o n.  
I nsta n ces of missi n g, discre pa nt, or u ni nter preta bl e data will be q uerie d wit h t he i n vesti gat or f or 
res ol uti o n. A n y c ha n ges t o st u d y data will be ma de t o t he C R F a n d d oc u me nte d i n a n a u dit trail, 
w hic h will be mai ntai ne d wit hi n t he cli nical data b ase.  
1 3. 4   
M o nit ori n g  
M o nit ori n g a n d a u diti n g pr oce d ures de vel o p e d or a p pr o ve d b y Verte x will be f oll o we d t o 
c om pl y wit h G C P G ui deli nes. O n -site or re m ote (as a p plica ble b y l ocal re g ulati o n) c hec ki n g of 
t he C R Fs/ S A E F or ms f or c o m plete ness a n d clarit y, cr oss-c h ec ki n g wit h s o urce d oc u m e nts, a n d 
clarificati o n of a d mi nistrati ve matters will be perf or me d.  
T he st u d y will  be m o nit ore d b y Verte x or its desi g nee. M o nit ori n g will be d o ne b y p ers o nal or 
re m ote (as a p plica ble b y l ocal re g ulati o n) visits fr o m a re prese ntati ve of Verte x or desi g n ee 
(st u d y site m o nit or), w h o will re vie w t he C R Fs/ S A E F or ms a n d s o urce d o c u me nts. T he st u d y 
site m o nit or will e ns ure t hat t he i n vesti gati o n is c o n d ucte d acc or di n g t o t he pr ot oc ol desi g n a n d 
re g ulat or y re q uire me nts. 
1 3. 5   
El e ctr o ni c D at a C a pt ur e  
Verte x will pr o vi de t he st u d y sites wit h sec ure access t o a n d trai ni n g o n t h e E D C a p plicati o n 
s ufficie nt t o per mit st u d y site pers o n nel t o e nter or c orrect  i nf or mati o n i n t he C R Fs o n t he 
s u bjects f or w hic h t he y are res p o nsi ble.  
A C R F will be c o m plete d f or eac h e nr olle d st u d y s u bject. It is t he i n vesti gat or's res p o nsi bilit y t o 
e ns ure t he acc urac y, c o m plet e ness, clarit y, a n d ti meli ness of t he data re p orte d i n t he s u bject's 
C R F. S o urce d oc u me ntati o n s u p p orti n g t he C R F d ata will i n dicate t he s u bject's p artici pati o n i n 
t he st u d y a n d will d oc u me nt t he dates a n d d etails of st u d y pr oce d ures, A Es, ot her o bser vati ons, 
a n d s u bject stat us.  
T he i n vesti gat or, or desi g nate d re prese ntati ve, will c o m plete t he C R F as s o o n as p ossi ble after 
i nf or mati o n is c ollecte d.  
T he a u dit trail e ntr y will s h o w t he user's i de ntificati o n i nf or mati o n a n d t he date a n d ti me of a n y 
c orrecti o n . T he i n vesti gat or will pr o vi de f or mal a p pr o val of all t he i nf or mati o n i n t he C R Fs, 
i ncl u di n g a n y c ha n ges m a de t o t he m, t o e n d orse t he fi nal s u b mitte d data f or t he s u bjects f or 
w h o m t he i n vesti gat or is res p o nsi ble.  


Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 6 0  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
Verte x will retai n t he C R F data  a n d c orres p o n di n g a u dit trails. A c o p y of t he fi nal arc hi val C R F 
i n t he f or m of a c o m p act disc ( C D) or ot her electr o nic me dia will be place d i n t he i n vesti gat or's 
st u d y file. 
1 3. 6   
C o nfi d e nti alit y a n d Di s cl o s ur e  
A n y a n d all scie ntific, c o m mercial, a n d tec h nical i nf or mati o n discl ose d b y Verte x i n t his 
pr ot oc ol or else w h ere will be c o nsi dere d t h e c o nfi de ntial a n d pr o priet ar y pr o pert y of Verte x. T he 
i n vesti gat or s hall h ol d s u c h i nf or mati o n i n c o nfi de nce a n d s hall n ot discl ose t he i nf or mati o n t o 
a n y t hir d part y e x ce p t t o s uc h of t he i n vesti gat or's e m pl o yees a n d staff as h a ve bee n ma de a ware 
t hat t he i nf or mati o n is c o nfi de ntial a n d w h o are b o u n d t o treat it as s uc h a n d t o w h o m discl os ure 
is necessar y t o e val uate t hat i nf or mati o n. T he i n vesti gat or s hall n ot use s uc h i nfor mati o n f or a n y 
p ur p ose ot her t ha n deter mi ni n g m ut ual i nterest i n perf or mi n g t he st u d y a n d, if t he parties deci de 
t o pr ocee d wit h t he st u d y, f or t he p ur p ose of c o n d ucti n g t he st u d y. 
T he i n vesti gat or u n dersta n ds t hat t he i nf or mati o n de vel o pe d fr o m t his cli nical st u d y will be use d 
b y Verte x i n c o n necti o n wit h t he de vel o p me nt of t he st u d y dr u g a n d ot her dr u gs a n d dia g n ostics, 
a n d t heref ore ma y b e dis cl ose d as re q uire d t o ot her cli nical i n vesti gat ors, b usi ness part ners a n d 
ass ociates, t he F D A, a n d ot her g o v er n me nt a ge nci es. T he i n vesti gat or als o u n dersta n ds t hat, t o 
all o w f or t he use of t he i nf or mati o n deri ve d fr o m t he cli nical st u d y, t he i n v esti gat or has t he 
o bli gati o n t o pr o vi de Verte x wit h c o m plete test res ults a n d all data de vel o pe d i n t he st u d y.  
1 3. 7   
P u bli c ati o n s a n d Cli ni c al St u d y R e p ort  


Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 6 1  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
1 3. 7. 2   
Cli ni c al St u d y R e p ort  
A C S R, writte n i n acc or da nce wit h t he I C H E 3 G ui deli ne, will be s u b mitte d i n acc or da nce wit h 
l ocal re g ulati o ns.  


Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 6 2  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
1 4   
R E F E R E N C E S  
1   
Ber gi n D A, Ree v es E P, H urle y K, W olfe R, J a meel R, Fitz geral d S, et al . T he circ ul ati n g 
pr otei nase i n hi bit or al p ha -1 a ntitr y psi n r e g ulates n e utr o p hil de gra n ulati o n a n d 
a ut oi m m u nit y. Sci Tra nsl Me d. 2 0 1 4; 6( 2 1 7): 2 1 7ra 1.  
2   
Gera g ht y P, E de n E, Pillai M, Ca m p os M, Mc El va ne y N G, F or o nj y R F. Al p ha 1 -
A ntitr y psi n acti vat es pr ot ei n p h o s p hatase 2 A t o c o u nter l u n g i nfl a m mat or y res p o nses. 
A m J Res pir Crit Care Me d. 2 0 1 4; 1 9 0( 1 1): 1 2 2 9 -4 2.  
3   
Piit ulai ne n E, Ta nas h H A. T he cli nical pr ofile of s u bjects i ncl u de d i n t he S we dis h 
nati o nal re gister o n i n di vi d uals wit h se vere al p h a 1 -a ntitr y psi n defic ie nc y. C O P D. 
2 0 1 5; 1 2(s u p pl 1): 3 6 -4 1.  
4   
Q ua njer P H, Sta n oje vic S, C ole TJ, Ba ur X, Hall G L, C ul ver B H, et al. M ulti -et h nic 
refere nce val ues f or s pir o metr y f or t he 3-9 5 -yr a ge ra n ge: t he gl o bal l u n g f u ncti o n 2 0 1 2 
e q uati o ns. E ur Res pir J. 2 0 1 2; 4 0( 6): 1 3 2 4 -4 3.  
5   
Miller M R, Ha n ki ns o n J, Br usas c o V, B ur g os F, Casa b uri R, C oates A, et al. 
Sta n dar disati o n of s pir o metr y. E ur Res pir J. 2 0 0 5; 2 6( 2): 3 1 9 -3 8.  
6   
C ul ver B H, Gra ha m B L, C oates A L, Wa n ger J, Berr y C E, Clar ke P K, et al. 
Rec o m me n dati o ns f or a sta n dar dize d p ul m o na r y f u ncti o n re p ort. A n official A merica n 
T h oracic S oci et y t ec h nical state me nt. A m J Res pir Crit Care Me d. 2 0 1 7; 1 9 6( 1 1): 1 4 6 3 -
1 1   
Battis ti W P, Wa ger E, Baltzer L, Bri d ges D, C air ns A, Cars well CI, et al. G o o d 
p u blicati o n practice f or c o m m u nicati n g c o m pa n y -s p o ns ore d me dical researc h: G P P 3. 
A n n I nter n Me d. 2 0 1 5; 1 6 3( 6): 4 6 1 -4.  
1 2   
I nter nati o nal C o m mittee of Me dical J o ur nal E dit ors (I C MJ E). Decem ber 2 0 1 7. 
Rec o m me n dati o ns f or t h e c o n d uct, re p orti n g, e diti n g, a n d p u blicati o n of sc h olarl y w or k 
i n me dical j o ur nals. A vaila ble at: htt p:// w w w.ic mje. or g/rec o m me n dati o ns/ . Access e d 0 3 
A u g ust 2 0 1 8.  
 


Pr ot o c ol  V X 1 9- 8 6 4- 1 0l,  V ersi o n  2. 0 
P a g e 6 3 of 6 4 
1 6 
P R O T O C O L  SI G N A T U R E  P A G E S 
1 6. 1 
S p o n s or  Si g n at ur e  P a g e 
Pr ot o c ol #:  
V X 1 9- 8 6 4- 1 0 1 I V er si o n #:  
2. 0 
I V ersi o n  D at e: 
1 2 J a n u ar y 2 0 2 1 
St u d y  Titl e:  A  P h as e  2,  R a n d o mi z e d , D o u bl e- bli n d , Pl a c e b o- c o ntr oll e d  St u d y of t h e Effi c a c y 
a n d S af et y of V X- 8 6 4 i n Pi Z Z S u bj e cts 
T hi s  cli ni c al  st u d y  pr ot o c ol  h as  b e e n  r e vi e w e d a n d  a p pr o v e d  b y t h e s p o ns or. 
V ert e x  P h a n n a c e uti c al s  I n c or p or at e d 
 


Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 6 4  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
1 5. 2   
I n v e sti g at or Si g n at ur e P a g e 
Pr ot oc ol #:  V X 1 9 -8 6 4 -1 0 1  
Versi o n #:   
2. 0   
Versi o n Date:   
1 2  J a n uar y 2 0 2 1 
St u d y Title: A P hase 2, Ra n d o mize d, D o u ble -bli n d, Place b o -c o ntr olle d St u d y of t he Efficac y 
a n d Safet y of V X -8 6 4 i n Pi Z Z  S u bjects  
 
 
I h a ve rea d Pr ot oc ol V X 1 9-8 6 4 -1 0 1, Versi o n 2. 0, a n d a gree t o c o n d uct t he st u d y acc or di n g t o its 
ter ms. I u n dersta n d t hat all i nf or mati o n c o ncer ni n g V X-8 6 4 a n d t his pr ot oc ol s u p plie d t o me b y 
Verte x P har mace uticals I nc or p orat e d ( Verte x) is c o nfi de ntial.  
 
 
Pri nte d Na me  
  
 
Si g nat ure  
  
Date  
 
 
 

SAP_001.pdf: 
Statistical Analysis Plan (Methods)  
Page 1 of 34 
Protocol Number: VX19-864-101 
 
 
Vertex Pharmaceuticals Incorporated 
 
1 
TITLE PAGE 
 
 
VERTEX PHARMACEUTICALS INCORPORATED 
Statistical Analysis Plan 
(Methods) 
Protocol Number VX19-864-101, Version 1.0 
(Interim and Final Analysis) 
 
A Phase 2, Randomized, Double-blind, Placebo-controlled Study of 
the Efficacy and Safety of VX-864 in PiZZ Subjects  
 
Author of SAP:
 
 
Version: 1.0 
Version Date of SAP: 11 May 2021 
 
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 34                                
Protocol Number: VX19-864-101  
Vertex Pharmaceuticals Incorporated 
 
2 
TABLE OF CONTENTS 
1 
Title Page .............................................................................................................................. 1 
2 
Table of Contents ................................................................................................................ 2 
4 
Introduction .......................................................................................................................... 6 
5 
Study Objectives ................................................................................................................. 6 
5.1 
Primary Objectives ........................................................................................................... 6 
5.2 
Secondary Objectives ....................................................................................................... 6 
 
 
6 
Study Endpoints .................................................................................................................. 7 
6.1 
Primary Endpoints ............................................................................................................ 7 
6.2 
Secondary Endpoints ........................................................................................................ 7 
 
 
7 
Study Design ........................................................................................................................ 7 
7.1 
Overall Design .................................................................................................................. 7 
7.2 
Sample Size and Power .................................................................................................... 9 
7.3 
Randomization ................................................................................................................ 10 
7.4 
Replacement ................................................................................................................... 10 
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 ........................................................................................................... 11 
9.1 
General Considerations .................................................................................................. 11 
9.2 
Background Characteristics ............................................................................................ 13 
9.2.1 
Subject Disposition ................................................................................................. 13 
9.2.2 
Demographics and Baseline Characteristics ........................................................... 13 
9.2.3 
Medical History ...................................................................................................... 14 
9.2.4 
Prior and Concomitant Medications ....................................................................... 14 
9.2.5 
Study Drug Exposure and Compliance .................................................................. 15 


Statistical Analysis Plan (Methods)                                                                                                            Page 3 of 34                                
Protocol Number: VX19-864-101  
Vertex Pharmaceuticals Incorporated 
 
9.2.6 
Important Protocol Deviations ................................................................................ 15 
9.3 
Efficacy Analysis ............................................................................................................ 16 
9.3.1 
Analysis of Primary Efficacy Variable ................................................................... 16 
9.3.1.1 
Definition of Primary Efficacy Variable .......................................................... 16 
9.3.1.2 
Primary Analysis .............................................................................................. 16 
9.3.2 
Analysis of Secondary Efficacy Variable ............................................................... 17 
9.3.2.1 
Definition of Secondary Efficacy Variable ...................................................... 17 
9.3.2.2 
Analysis Method .............................................................................................. 17 
 
 
9.3.3 
Multiplicity Adjustment ......................................................................................... 18 
9.4 
Safety Analysis ............................................................................................................... 18 
9.4.1 
Adverse Events ....................................................................................................... 18 
9.4.2 
Clinical Laboratory ................................................................................................. 19 
9.4.3 
Electrocardiogram .................................................................................................. 20 
9.4.4 
Vital Signs .............................................................................................................. 20 
9.4.5 
Pulse Oximetry ....................................................................................................... 21 
9.4.6 
Spirometry .............................................................................................................. 21 
9.4.7 
Physical Examination ............................................................................................. 21 
10 Interim and IDMC Analyses ............................................................................................ 21 
10.1 Interim Analysis ............................................................................................................. 21 
10.1.1 
General Consideration ............................................................................................ 22 
10.1.2 
Background Characteristics .................................................................................... 22 
10.1.3 
Efficacy Analysis .................................................................................................... 22 
10.1.4 
Safety Analysis ....................................................................................................... 22 
 
 
10.2 Independent Data Monitoring Committee Analysis ....................................................... 22 
11 References .......................................................................................................................... 22 
12 Appendices ......................................................................................................................... 23 
 
Appendix B: Imputation Rules for Missing Prior/Concomitant Medication Dates ................. 26 


Statistical Analysis Plan (Methods)                                                                                                            Page 4 of 34                                
Protocol Number: VX19-864-101  
Vertex Pharmaceuticals Incorporated 
 
Appendix C: Imputation Rules for Missing AE Dates ............................................................ 27 
 
Appendix E: Details of GLI Equations for Calculating ppFEV1 ............................................. 33 
 
 
 




Statistical Analysis Plan (Methods)                                                                                                            Page 6 of 34                                
Protocol Number: VX19-864-101  
Vertex Pharmaceuticals Incorporated 
 
4 
INTRODUCTION 
This statistical analysis plan (SAP) describes the efficacy, safety, 
 
 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. 
 
 
 
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-864 in PiZZ subjects as measured by plasma functional 
alpha-1 antitrypsin (AAT) levels 
• To evaluate the safety and tolerability of VX-864 in PiZZ subjects 
5.2 
Secondary Objectives 
• To evaluate the efficacy of VX-864 in PiZZ subjects as measured by plasma antigenic AAT 
levels  
• To evaluate the pharmacokinetics (PK) of VX-864 in PiZZ subjects 


Statistical Analysis Plan (Methods)                                                                                                            Page 7 of 34                                
Protocol Number: VX19-864-101  
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-864 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-864. Schematics of 
the study design are shown in Figure 7-1 and Figure 7-2. 
Approximately 40 subjects in total with the PiZZ genotype and antigenic AAT levels <8 µM at 
screening will be randomized to VX-864 or placebo 2:1:1:1 to VX-864 500 mg q12h, VX-864 
300 mg q12h, VX-864 100 mg q12h, or placebo.  
Of these, approximately 20 subjects will be randomized 2:2:1 to VX-864 500 mg q12h, VX-864 
300 mg q12h, or placebo first. The remaining subjects (approximately 20) will be randomized 


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2:2:1 to VX-864 500 mg q12h, VX-864 100 mg q12h, or placebo. 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%).  
Screening assessments for subjects who have never been on augmentation therapy are listed in 
Table 3-1 of the protocol. Screening 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 
Schematics of Study Design for Subjects Who Have Never Been on 
Augmentation Therapy 
AAT: alpha-1 antitrypsin; 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. 
 
 
 


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Figure 7-2 
Schematics of Study Design for Subjects Who Have Been on 
Augmentation Therapy at Any Time 
AAT: alpha-1 antitrypsin; 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.  
 
7.2 
Sample Size and Power 
Subjects will be randomized 2:1:1:1 to receive VX-864 500 mg q12h (n = 16), VX-864 300 mg 
q12h (n = 8), VX-864 100 mg q12h (n = 8), or placebo (n = 8).  
Assuming 10% of the randomized subjects have a missing value at Day 28, this sample size 
provides adequate precision to estimate the absolute plasma functional AAT levels at Day 28 for 
the VX-864 500 mg q12h dose group. 
Information regarding the sample size assessments is provided below. 


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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. 


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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. 
9 
STATISTICAL ANALYSIS 
9.1 
General Considerations 
The Schedule of Assessments is provided in Section 3 of the CSP. The precision standards for 
reporting safety variables are provided in an internal Biometrics document that specifies 
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 


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ECGs, the baseline value will be defined as the average of the non-missing pre-dose 
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 antigenic AAT levels, only the screening results obtained from the on-treatment 
assay 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 a 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) Early Termination of Treatment (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.  
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 the TE period, and maximum and 
minimum change from baseline values during the 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: 
• For all model-based assessments, a dose group will only be included if ≥3 subjects have non-
missing data available. 
• An individual subject data listing will be provided for subject visits impacted by COVID-19. 


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• If appropriate and if needed, additional analysis of the functional and antigenic AAT 
endpoints may be performed excluding any AAT measurements influenced by a PEx and/or a 
COVID-19 vaccination. 
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 
The 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 
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) 


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• 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) 
• 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 purposes 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, a post-
treatment medication, or more than one of these categories.  


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If a medication start date is on or after the first dose date of study drug, then the medication will 
be classified as a 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 a prior medication regardless of whether the medication start 
date is missing or not. Note that a medication that started before the first dose of study drug and 
continued after the first dose will be classified as a prior medication and separately as a 
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 
a prior and a concomitant medication. 
Missing or partial dates will be imputed for medications. Details for imputing missing or partial 
start and/or stop dates of medications are described in Appendix B. 
Prior and post-treatment 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 across the VX-864 treatment groups. Bronchodilator 
usage will also be listed. 
Prior, concomitant, and post-treatment non-pharmacological therapy will be listed. 
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 


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rights, safety, or well-being. IPD rules will be developed and finalized before 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 
9.3.1.1 
Definition of Primary Efficacy Variable 
The primary efficacy variable is the change from baseline in plasma functional AAT levels at 
Day 28. 
9.3.1.2 
Primary Analysis 
The primary analysis of the primary efficacy variable includes data from VX-864 treatment 
groups and the placebo group. The primary comparison consists of the pairwise comparison 
between each dose of VX-864 and placebo. 
The primary analysis will be based on a mixed-effects model for repeated measures (MMRM) 
with change from baseline at Days 7, 14, and 28 as the dependent variable. The MMRM model 
will include the treatment group, visit, and treatment-by-visit interaction as fixed effects. An 
unstructured covariance structure will be used to model the within-subject errors. If the model 
estimation does not converge, a compound symmetry covariance structure will be used instead. 
The model will be estimated using restricted maximum likelihood. Denominator degrees of 
freedom for the F-test for fixed effects will be estimated using the Kenward-Roger 
approximation. Conditional on the observed data and covariates, missing data will be assumed to 
be missing at random; consequently, no imputation of missing data will be performed. 
The primary result obtained from the model will be the estimated treatment difference between 
each VX-864 treatment group in the model and the placebo group at Day 28. The adjusted means 
with 2-sided 95% confidence intervals and 2-sided P values will be provided. In addition, the 
estimated treatment differences, obtained from the model, between each VX-864 treatment group 


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in the model and the placebo group at each post-baseline visit will be provided, along with 2-
sided 95% confidence intervals and 2-sided P values. 
The observed values and change from baseline of functional AAT levels will also be summarized 
descriptively by treatment group at each visit. 
9.3.2 
Analysis of Secondary Efficacy Variable 
9.3.2.1 
Definition of Secondary Efficacy Variable 
The secondary efficacy variable is the change from baseline in plasma antigenic AAT levels at 
Day 28. 
9.3.2.2 
Analysis Method 
The analysis of the secondary efficacy variable includes data from VX-864 treatment groups and 
the placebo group. 
 
 
 
Analysis of the secondary efficacy variable will be based on an MMRM similar to the primary 
analysis of the primary efficacy variable, with change from baseline in plasma antigenic AAT 
levels at Days 7, 14, 28 as the dependent variables and the treatment group, visit, and treatment-
by-visit interaction as fixed effects. The adjusted means and the estimated treatment differences 
obtained from the model between each VX-864 treatment group in the model and the placebo 
group at Day 28, as well as at each post-baseline visit, will be provided, with 2-sided 95% 
confidence intervals and 2-sided P values. 


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The observed values and change from baseline of the antigenic AAT levels will be summarized 
descriptively by treatment group at each visit. 
9.3.3 
 Multiplicity Adjustment 
There is no multiplicity adjustment for the pairwise comparisons between each dose of VX-864 
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-864 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 
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 AEs: AEs that worsened or started after the TE Period 


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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 for only TEAEs by treatment group (including placebo and 
each VX-864 dose group) and overall across the VX-864 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.  
In addition, listings 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. 
 
 


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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 presented 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. 
 
  
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. 
 
 


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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. 
10 
INTERIM AND IDMC ANALYSES 
10.1 
Interim Analysis (Optional) 
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.  


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Interim analyses will be based on all data included in the IA data cuts. 
10.1.1 
 General Consideration 
General considerations, reporting conventions, and analysis methods specified for the final 
analysis apply to the IA, unless otherwise specified. 
For the IA, the 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, (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, or (4) the IA data cut date if subjects 
have not completed or discontinued the study at the time of the IA data cut. 
10.1.2 
Background Characteristics 
Refer to section 9.2 for the summary of background characteristics for the IA. In addition, 
“treatment ongoing” and “study ongoing” will be possible disposition categories for the IA. 
10.1.3 
Efficacy Analysis 
Descriptive statistics for the primary and secondary efficacy variables only will be presented for 
the IA. 
10.1.4 
Safety Analysis 
Refer to Section 9.4 for the safety analysis for the IA. 
10.2 
 Independent Data Monitoring Committee Analysis 
Not applicable. 
11 
REFERENCES 
Not applicable. 
 
 








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Appendix B: Imputation Rules for Missing Prior/Concomitant Medication Dates 
Missing or partial dates will be imputed for medications. The algorithm for a 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. 
 The algorithm for a 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. 
The missing data algorithms will be reviewed to ensure their accuracy. For example, after 
imputation, the end date will not precede the start date.  
In summary, the prior, concomitant, or post-treatment categorization of a medication is described 
below. 
Table 12-2 
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 
 A: Post-treatment; C: Concomitant; P: Prior 
 
Imputation of missing and/or partial dates for non-pharmacological treatments/procedures will 
follow the same imputation rule. 
 


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Appendix C: Imputation Rules for Missing AE Dates  
Imputation rules for missing or partial AE start dates 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 the 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 the TE period to determine whether the AE is a 
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 the AE end 
date is missing, then impute the AE start month and day as the month and day of the 
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 the TE period to determine whether the AE is a 
pretreatment AE or TEAE. 
• If Year of AE start date is missing: 
If the year of AE start date is missing or the AE start date is completely missing, then query 
the site with no imputation. 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 a TEAE. 
A missing or partially missing AE end date will not be imputed. 
 
 












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Appendix E: Details of GLI Equations for Calculating ppFEV1 
The 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 6 October 2020]. 
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 the FEV1 measurement to calculate 
ppFEV1; for spirometry performed on or after informed consent, use height at screening 
for the 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 selections for race in CRF are also 
mapped to Other. White is a reference race in the equations and assumes values of zero 
for all race coefficients in the GLI equations.