A Phase 2, Randomized, Double-blind, Placebo-controlled Study of the Efficacy and Safety of VX-864 in PiZZ Subjects
Phase: PHASE2
Conditions: Alpha1-Antitrypsin Deficiency
Sponsor: Vertex Pharmaceuticals Incorporated

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  
Verte x P har mace uticals I nc or p orate d  
 
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  

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 1 7  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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  

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 1 8  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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 

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 2 3  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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  

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 2 4  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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.  

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 2 5  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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. 

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 2 6  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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. 

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 2 7  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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  

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 2 8  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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  

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 2 9  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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.  

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 3 0  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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.  

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 3 1  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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  
P a ge 3 2  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
 
 
 
 
 
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  

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 3 3  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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. 

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 3 4  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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.  

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 3 5  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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.  

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 3 6  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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.  

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 3 7  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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. 

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 3 8  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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.  

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 3 9  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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).   

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 4 0  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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. 

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 4 2  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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 . 

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 4 3  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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 

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 4 4  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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 

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 4 5  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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.  

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 4 6  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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.  

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 4 7  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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. 

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 4 8  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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.  

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 4 9  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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 

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 5 0  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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  

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 5 1  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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).  

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 5 2  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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  

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 5 3  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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).  
 

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 5 4  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
1 3. 1. 1. 6   
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. 

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 5 5  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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 .  

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 5 6  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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.  

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 5 7  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
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.  

Pr ot oc ol V X 1 9 -8 6 4 -1 0 1, Versi o n  2. 0  
P a ge 5 8  of 6 4  
Verte x P har mace uticals I nc or p orate d  
 
1 3. 2. 6   
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