A Phase 2, Randomized, Double-blind, Active-controlled, Dose-ranging, Parallel-design Study of the Efficacy and Safety of VX-548 in Subjects With Painful Diabetic Peripheral Neuropathy
Phase: PHASE2
Conditions: Diabetic Peripheral Neuropathy
Sponsor: Vertex Pharmaceuticals Incorporated

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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, 
A cti v e -c o ntr oll e d, D o s e -r a n gi n g, P ar all el-d e si g n 
St u d y of t h e Effi c a c y a n d S af et y of V X -5 4 8 i n 
S u bj e ct s Wit h P ai nf ul Di a b eti c P eri p h er al 
N e ur o p at h y  
V ert e x St u d y N u m b er: V X 2 1 -5 4 8 -1 0 3  
 
D ate of Pr ot oc ol:  1 7  Fe br uar y 2 0 2 3  ( Versi o n 3. 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 p li 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 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 2  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 3  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
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, Acti ve -c o ntr olle d, D ose -ra n gi n g, 
Parallel -desi g n St u d y of t he Efficac y a n d Safet y of V X‑ 5 4 8 i n S u bjects Wit h Pai nf ul 
Dia betic Peri p heral Ne ur o pat h y  
  
Brief Title  E val uati o n of Efficac y a n d Safet y of V X -5 4 8 f or Pai nf ul Dia betic Peri p heral 
Ne ur o pat h y  
  
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 bjecti ves  
•   
T o e val uate t he efficac y of t hree V X -5 4 8 d oses i n treati n g s u bjects wit h pai nf ul 
dia betic peri p heral ne ur o pat h y ( D P N)  
•   
T o e val uate t he safet y a n d t olera bi lit y of V X-5 4 8  
  
E n d p oi nts  Pri mar y E n d p oi nt  
•   
C ha n ge fr o m baseli ne i n t he wee kl y a vera ge of dail y pai n i nte nsit y o n a n u meric 
pai n rati n g scale ( N P R S) at Wee k  1 2  
Sec o n dar y E n d p oi nts  
•   
C ha n ge fr o m baseli ne i n t he wee kl y a vera ge of t he Dail y Slee p I nterfere nce 
Scale ( D SI S) at Wee k  1 2  
•   
Pr o p orti o ns of s u bjects wit h ≥3 0 %, ≥5 0 %, a n d ≥7 0 % re d ucti o ns fr o m baseli ne i n 
t he wee kl y a vera ge of dail y pai n i nte nsit y o n t he N P R S at W ee k 1 2 
•   
Pr o p orti o n of s u bjects cate g orize d as m uc h i m pr o ve d or ver y m uc h i m pr o ve d at 
Wee k 1 2 o n t he patie nt gl o bal i m pressi o n of c ha n ge ( P GI C) assess me nt  
•   
Safet y a n d t ole ra bilit y base d o n t he i nci de nce a n d t y pe of a d verse e ve nts ( A Es) 
a n d c ha n ges fr o m baseli ne i n cli nicall y si g nifica nt la b orat or y test res ults, vital 
si g ns, a n d E C Gs at eac h visit 
  
N u m ber of S u bjects  A p pr o xi matel y 1 7 5 s u bjects  

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 4  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
  
St u d y P o p ul ati o n  Male a n d fe male s u bjects 1 8 t hr o u g h 8 0  years of a ge, i ncl usi ve, wit h prese nce of 
bilateral pai n i n l o wer e xtre m ities d ue t o D P N f or at least 1 year, a n d wee kl y a vera ge 
N P R S pai n sc ore of ≥4 wit h li mite d variati o n i n t he R u n -i n Peri o d 
  
I n vesti g ati o n al Dr u g Acti ve s u bsta nce: V X‑ 5 4 8  
 Acti vit y: Na V 1. 8 i n hi bit or  
 Stre n gt h a n d r o ute of a d mi nistrati o n: 2 3 -m g ta blets a n d matc hi n g place b o f or oral 
a d mi nistrati o n  
  
Refere nce Dr u g  Acti ve s u bsta nce: Pre ga bali n  
 Acti vit y: Calci u m c ha n nel (al p ha 2-delta site) i n hi bit or  
 Stre n gt h a n d r o ute of a d mi nistrati o n: 1 0 0 -m g ca ps ules 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 Peri o d ( w hic h i ncl u des a 7 -da y R u n -i n Peri o d), eac h s u bject 
will partici pate i n t he st u d y f or a p pr o xi matel y  1 4  wee ks: a 1 2 -wee k Treat me nt Peri o d 
a n d a Safet y F oll o w -u p Visit 1 4  ( ± 2) da ys after t he e n d of t he Treat me nt Peri 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, acti ve -c o ntr olle d, d ose -ra n gi n g, 4-ar m, 
parallel -desi g n st u d y. S u bjects w h o meet eli gi bilit y criteria d uri n g Scree ni n g Visits  
1  a n d 2 will e nter a 7 -da y R u n -i n Peri o d t o esta blis h t heir baseli ne N P R S pai n sc ore. 
S u bjects wit h a baseli ne a vera ge N P R S sc ore of ≥4  p oi nts wit h li mite d variati o n ( S D 
< 2 5 % of mea n) will be eli gi ble f or t he 1 2 -wee k Treat me nt Peri o d f oll o we d b y a 
Safet y F oll o w -u p Visit ( Fi g ure 2 -1 ).  
Fi g ure 2 -1   
V X 2 1 -5 4 8 -1 0 3  St u d y Desi g n  
 
N: n u m ber of s u bjects  
a  
At t h e e n d of t h e Treat me nt Peri o d ( Wee k 1 2), s u bjects will ta per off ca ps ule ( pre ga bali n 
refere nce or matc he d place b o) st u d y dr u g f or 7 da ys.  
A t otal of a p pr o xi matel y 1 7 5  s u bjects will be ra n d o mize d 2: 2: 1: 2 t o 4 treat me nt 
ar ms: V X -5 4 8 ( hi g h, mi d, or l o w d ose ) or pre ga bali n (refere nce ar m) (Ta ble  2 -1 ). 
Ra n d o mizati o n will be stratifie d b y se x (fe male a n d male) a n d b o d y mass i n de x 
( ≥3 0 a n d < 3 0 k g/ m 2). T o mai ntai n t he bli n d, all s u bjects will recei ve t he sa me 
n u m ber of ta blets o nce dail y ( q d) i n t he m or ni n g a n d t he sa me n u m ber of ca ps ules 
3  ti mes per da y i n a d o u ble-d u m m y desi g n. After t he Treat me nt Peri o d, s u bjects will 
ta per off ca ps ule (pre ga bali n  reference or matc he d place b o) st u d y dr u g f or 7  da ys 
( 4 da ys of d osi n g e ver y 1 2 h o urs, t he n 3 da ys of d osi n g q d), a n d t he Safet y 
F oll o w -u p Visit will occ ur a n a d diti o nal 7  ( ± 2) da ys later.  

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 5  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
T a ble  2 -1   
V X 2 1 -5 4 8 -1 0 3  T re at me nt Ar ms 
Tre at me nt  
Acti v e D ose  
N u m ber of S u bjects 
( Pl a n ne d) 
V X -5 4 8 ( hi g h d ose)   
6 9 m g q d  
5 0  
V X -5 4 8 ( mi d d ose)   
4 6 m g q d  
5 0  
V X -5 4 8 (l o w d ose)   
2 3 m g q d  
2 5  
Pre ga bali n  
1 0 0 m g ti d  
5 0  
q d: o nce dail y; ti d: 3 ti mes per da y  
N ote: T o mai ntai n t h e bli n d, all s u bjects will recei v e t he sa me n u m ber of ta blets a n d t h e 
sa me n u m ber of ca ps ules at t he sa me res pecti ve fre q ue nc y (i.e., q d f or ta blets a n d ti d 
f or ca ps ules d uri n g t h e Treat me nt Peri o d) i n a d o u ble-d u m m y desi g n.  
S u bjects will st o p ta ki n g pai n m e dicati o ns (i ncl u di n g pre ga bali n, if a p plica ble), 
e xce pt aceta mi n o p he n ( 5 0 0 m g), f or at least 1 4 da ys bef ore t he first d ose of st u d y 
dr u g.  
Aceta mi n o p he n will be per mitte d as a pai n resc ue me dicati o n as nee de d ( pr n) 
t hr o u g h o ut t he st u d y. S u bjects will be per mitte d t o ta ke 5 0 0 m g e ver y 4 t o 6 h o urs 
pr n, u p t o a ma xi m u m of 2 5 0 0  m g i n a n y 2 4 -h o ur peri o d. S u bjects will rec or d resc ue 
me dicati o n use, a n d t heir c urre nt pai n sc ore o n t he N P R S i m me diatel y bef ore eac h 
a d mi nistrati o n of resc ue me dicati o n.  
  
Assess m e nts  Efficac y : 1 1-p oi nt N P R S, D SI S, P GI C,   
 use of resc ue me dicati o n, a n d 
 
Safet y : A Es; cli nical la b orat or y assess me nts; cli nical e val uati o n of vital si g ns, E C Gs, 
a n d p h ysical e xa mi nati o n; a n d C ol u m bia S uici de Se verit y Rati n g Scale   
St atistic al A n al yses  T he pri mar y efficac y e n d p oi nt is t he c ha n ge fr o m baseli ne i n t h e wee kl y a vera ge of 
t he dail y pai n i nte nsit y o n a n N P R S at Wee k 1 2. T he pri mar y a nal ysis will be a 
wit hi n -gr o u p c o m paris o n i n a n y V X -5 4 8 d ose gr o u p.  
T he sa m ple size is base d o n t he pri mar y a nal ysis of t he pri mar y e n d p oi nt. Wit h 
3 7  e val ua ble s u bjects i n t he  V X -5 4 8 hi g h or mi d d ose gr o u p a n d 1 8 e val ua ble 
s u bjects i n t he V X-5 4 8 l o w d ose gr o u p, t here is m ore t ha n 9 0 %  p o wer i n a n y V X -
5 4 8 d ose gr o u p t o detect a mea n c ha n ge fr o m baseli ne of 3  wit h a si n gle gr o u p t-test 
at t he 2 -si de d 0. 0 5 si g nifica nce le vel, ass u mi n g t he S D is 2. 3. Wit h a n e val ua ble 
sa m ple size of 3 7, a 2-si de d 9 5 % CI f or t he mea n c ha n ge fr o m baseli ne i n t he hi g h or 
mi d d ose gr o u p will e xte n d 0. 7 7 o n eit her si de of t he o bser ve d mea n, ass u mi n g t he 
CI is base d o n t he t-statistic a n d t he o bser ve d S D is 2. 3. U n der t he sa me ass u m pti o ns 
a n d a n e val ua ble sa m ple size of 1 8, a 2 -si de d 9 5 % CI f or t he mea n c ha n ge fr o m 
baseli ne i n t he l o w d ose gr o u p will e xte n d 1. 1 4 o n eit her si de of t he o bser ve d mea n. 
T o acc o u nt f or a 2 5 % dr o p o ut rate, 5 0  s u bjects eac h will be e nr olle d i n t he V X -5 4 8 
hi g h d ose, V X -5 4 8 mi d d ose, a n d t he pre ga bali n gr o u ps; 2 5  s u bjects will be e nr olle d 
i n t he V X-5 4 8 l o w d ose gr o u p. T he t otal sa m ple size is 1 7 5 s u bjects.  
T he pri mar y efficac y a nal ysis will be base d o n a mi xe d -effects m o del f or re peat e d 
meas ures ( M M R M), wit h c ha n ge fr o m baseli ne i n wee kl y a vera ge of dail y pai n 
i nte nsit y sc ore as t he de pe n de nt varia ble; a n d fi xe d effects of treat me nt gr o u p, ti me 
(cate g orical), treat me nt gr o u p-b y -ti me i nteracti o n, baseli ne wee kl y a vera ge of dail y 
pai n i n te nsit y, a n d baseli ne wee kl y a vera ge of dail y pai n i nte nsit y-b y -ti me 
i nteracti o n. T he least s q uares ( L S) mea n c ha n ge fr o m baseli ne at Wee k 1 2 f or eac h 

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 6  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
gr o u p will be prese nte d wit h t he c orres p o n di n g S E, a n d t he c orres p o n di n g 9 5 % CI 
a n d P  val ue.  

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 7  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
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 of assess me nts are i n Ta bl e  3 -1  a n d Ta ble  3 -2 . 
T a ble  3 -1   
St u d y V X 2 1 -5 4 8 -1 0 3 : Scree ni n g Peri o d (I ncl u di n g 7-D a y R u n -i n Peri o d) 
E ve nt/ Assess me nt a 
D a y  -3 5 t o 
D a y  -9  
D a y  -8   
D a y -7 t o  D a y -1  
C o m me nts  
Scree ni n g 
Visit 1  
Scree ni n g 
Visit 2 b   
R u n -i n Peri o d 
I nf or me d c o nse nt  
X  
 
 
M ust be o btai ne d bef ore perf or mi n g a n y 
st u d y-relate d pr oce d ures. Re m ote c o nse nt 
ma y be use d if per mitte d b y l o cal re g ulati o ns; 
Secti o n  1 3. 2. 3 . 
Cli nic or h o me healt h visit   
X  
 
 
S u bjects will ha ve t he o pti o n t o c o m plete t his 
visit i n t he cli nic or t o ha ve a h o me healt h 
visit. H o me healt h visits are o nl y a n o pti o n if 
per mitte d b y l ocal re g ulati o ns. 
Secti o n  9. 1. 1. 1 . 
Tele me dici ne vi d e o 
c o nfere nce or tele p h o ne 
c o ntact 
X  
 
 
A c o ns ultati o n bet wee n t he s u bject a n d 
i n vesti gat or or q ualifie d dele gate ( LI P) m ust 
be perf or me d  wit hi n 2 b usi ness d a ys 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; Secti o n 9. 1. 5  
Cli nic visit  
 
X  
  
 
Disc o nti n ue s pecifie d 
me dicati o ns  
X   
X  
X   
Secti o n 9. 4  
De m o gra p hics  
X  
 
  
 
Me dical hist or y  
X  
 
  
 
Wei g ht, hei g ht, a n d B MI   
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 c ollecte d after t h e s u bject 
has bee n at rest (seate d or s u pi n e) f or at least 
5  mi n utes; Secti o n 1 1. 5. 3  
C o m plete p h ysical 
e xa mi n ati o n 
 
X  
  
At ti mes ot h er t ha n Scree ni n g Visit 2, 
s y m pt o m-directe d P Es ma y be perf or me d at 
t h e discreti o n of t he i n vesti gat or or healt h 
care pr o vi der; Secti o n 1 1. 5. 3  
Sta n dar d 1 2 -lea d E C G 
 
X  
  
Sta n dar d 1 2 -lea d E C Gs will be perf or me d i n 
tri plicate after s u bjects h a ve bee n at rest 
(s u pi n e) f or at least 5 mi n utes; Secti o n  1 1. 5. 4  
Ser u m β -h C G  
X  
 
 
All bi ol o gicall y fe male s u bjects; 
Secti o n  1 1. 5. 2  
Ser u m F S H  
X  
 
  
S us pecte d p ost me n o pa usal fe male s u bjects 
o nl y; Secti o n  1 1. 5. 2  
Ser ol o g y ( H Bs A g, H C V 
A b, a n d HI V -1/ HI V -2 A bs)  
X  
 
  
Secti o n  1 1. 5. 2  
Ser u m c he mistr y  
X  
 
 
He mat ol o g y  
X  
 
 
C oa g ulati o n  
X  
 
 
H b A 1c  
X  
  
 
T h yr oi d f u ncti o n test  
X  
 
 
Vita mi n B 1 2  
X  
 
 
Uri nal ysis  
X  
 
 

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 8  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
T a ble  3 -1   
St u d y V X 2 1 -5 4 8 -1 0 3 : Scree ni n g Peri o d (I ncl u di n g 7-D a y R u n -i n Peri o d) 
E ve nt/ Assess me nt a 
D a y  -3 5 t o 
D a y  -9  
D a y  -8   
D a y -7 t o  D a y -1  
C o m me nts  
Scree ni n g 
Visit 1  
Scree ni n g 
Visit 2 b   
R u n -i n Peri o d 
Uri ne dr u g test  
X   
( X) 
 
S u bjects w h o ha ve a p ositi ve scree n f or 
o pi oi ds (ac ute use o nl y) or marij ua na ma y 
re peat t h e test at Scree ni n g Visit 2, as n ote d 
b y ( X); t h e sec o n d test m ust be at least 7  da ys 
( marij ua na) or at least 3 da ys ( o pi oi d) after 
t h e first. Secti o n 1 1. 5. 2  
Uri ne alc o h ol test  
X  
 
  
Secti o n  1 1. 5. 2  
Pai n assess me nt trai ni n g  
   
X  
  
Secti o n  9. 1. 1. 1  
e-diar y a n d e P R O trai ni n g 
a n d de vice distri b uti o n  
 
X  
  
 
N P R S via dail y e -diar y  
 
 
X   
Eac h m or ni n g, s u bjects will rec or d t h eir 
a vera ge dail y N P R S sc ore fr o m t he pre vi o us 
2 4 h o urs. S u bjects will als o re p ort t h eir 
c urre nt pai n sc ore i m me diatel y bef ore eac h 
a d mi nistrati o n of resc ue me dicati o n, if 
a p plica ble. Secti o n  1 1. 3 . 
D SI S via dail y e -diar y  
 
 
X  
Eac h m or ni n g, s u bjects will re p ort o n t h e 
pre vi o us ni g ht’s slee p usi n g t h e D SI S; 
Secti o n  1 1. 3 . 
Resc ue me dicati o n use  
 
 
X   
S u bjects will r ec or d N P R S pai n sc ore 
i m me diatel y bef ore eac h a d mi nistrati o n a n d 
rec or d date a n d ti me of a d mi nistrati o n i n a n 
e-diar y; Secti o n  1 1. 3  
Me dicati o n 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 Safet y 
F oll o w -u p Visit  
All me dicati o ns ta ke n wit hi n 1 4 da ys bef ore 
Scree ni n g Visit 1 a n d selecte d pri or 
me dicati o ns ta ke n earlier; Secti o n  9. 5  
Treat me nt a n d pr oce d ures 
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 Safet y 
F oll o w -u p Visit  
 
A d verse e ve nts  
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 
Safet y F oll o w -u p Visit  
 
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; D SI S: Dail y Slee p I nterfere nce Scale; e -diar y:  electr o nic 
diar y; e P R O: electr o nic patie nt -re p orte d o utc o me; F S H: f ollicle-sti m ulati n g h or m o ne; H b A 1c: he m o gl o bi n A 1c 
( gl yc os ylate d he m o gl o bi n); H Bs A g: he patitis B s urface a nti ge n; H C V A b:  he patitis C vir us a nti b o d y; 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 u ses 1 a n d 2; I C F: i nf or me d c o nse nt f or m; N P R S: n u meric pai n 
rati n g scale; P E: p h ysical e xa mi nati o n  
a  
W he n assess me nt ti me p oi nts c oi nci d e, assess me nts will be perf or me d i n t he f oll o wi n g or der: vital si g ns, 1 2 -lea d E C G, 
P E, a n d bl o o d sa m ple c ollecti o n.  
b  
Sc ree ni n g Visit 2 ma y occ ur o nl y after la b orat or y res ults fr o m Scree ni n g Visit 1 are a vaila ble  a n d ha ve esta blis he d 
s u bject eli gi bilit y t o c o nti n ue st u d y partici pati o n. Scree ni n g Visit 2 will be c o nsi dere d as Da y  -8.  
 

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 9  of 6 0  
Verte x P har mace uticals I nc or p orate d  
 
C o nfi de ntial I nf or mati o n  
T a ble  3 -2   
St u d y V X 2 1 -5 4 8 -1 0 3 : Tre at me nt Peri o d a n d S afet y F oll o w-u p Visit  
 
Tre at me nt Peri o d  
  
  
S afet y F oll o w -u p 
Visit 1 4 ( ±  2)  D a ys  
After E n d of 
Tre at me nt Peri o d  
 
E ve nt/ Assess me nt a 
D a y 1 b  
Wee k 1  
( ± 1  D a y)  
Wee k 3  
( ± 3  D a ys)  
Wee k 5  
( ± 3  D a ys)  
Wee k 7  
( ± 3  D a ys)  
Wee k 9  
( ± 3  D a ys)  
Wee k 1 2  
( ± 3  D a ys)  
E T T  
Visit c  
T a per d  
C o m me nts  
Cli nic visit  
X   
X   
  
X   
  
  
X   
X   
 
X   
 
Cli nic or h o me healt h visit  
  
  
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 healt h 
visits are o nl y a n o pti o n if 
per mitte d b y l ocal 
re g ulati o ns; Secti o n 9. 1. 1  
Tele me dici ne vi de o c o nfere nce or 
tele p h o ne c o ntact 
  
  
X   
  
X   
X   
  
  
 
 
A c o ns ultati o n bet wee n t he 
s u bject a n d i n vesti gat or or 
q ualifie d dele gate ( LI P) m ust 
be perf or me d  wit hi n 2 
b usi ness d a ys 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; Secti o n 9. 1. 5  
Ra n d o mizati o n  
X   
  
  
  
  
  
  
  
 
 
Occ urs after eli gi bilit y is 
c o nfir me d, i ncl u di n g criteria 
f or a vera ge N P R S d uri n g 
7 -da y R u n -i n Peri o d. 
Wei g ht  
X   
X   
  
X   
  
  
X   
X   
 
 
Wei g ht will be meas ure d wit h 
s h oes off. 
Vital si g ns  
X   
X   
X   
X   
X   
X   
X   
X   
 
 
Vital si g ns will be c ollecte d 
after t he s u bject has bee n at 
rest (seate d or s u pi ne) f or at 
least 5 mi n utes a n d bef ore 
1 2 -lea d E C G assess me nt or 
bl o o d sa m pli n g. At t he Da y 1 
a n d Wee k 5 visits, vital si g ns 
will be c ollecte d pre d ose 
o nl y; Secti o n  1 1. 5. 3 . 
Sta n dar d 1 2 -lea d E C G 
X   
X   
  
X   
  
  
X   
X   
 
  
Sta n dar d 1 2 -lea d E C Gs will 
be perf or me d i n tri plicate 
after s u bjects h a ve bee n at 
rest (s u pi ne) f or at least 
5  mi n utes; 1 2 -lea d E C Gs will 
be d o ne after ta ki n g vital 
si g ns a n d bef ore a n y 
pr oce d ures t hat ma y affect 

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 1 0  of 6 0  
Verte x P har mace uticals I nc or p orate d  
 
C o nfi de ntial I nf or mati o n  
T a ble  3 -2   
St u d y V X 2 1 -5 4 8 -1 0 3 : Tre at me nt Peri o d a n d S afet y F oll o w-u p Visit  
 
Tre at me nt Peri o d  
  
  
S afet y F oll o w -u p 
Visit 1 4 ( ±  2)  D a ys  
After E n d of 
Tre at me nt Peri o d  
 
E ve nt/ Assess me nt a 
D a y 1 b  
Wee k 1  
( ± 1  D a y)  
Wee k 3  
( ± 3  D a ys)  
Wee k 5  
( ± 3  D a ys)  
Wee k 7  
( ± 3  D a ys)  
Wee k 9  
( ± 3  D a ys)  
Wee k 1 2  
( ± 3  D a ys)  
E T T  
Visit c  
T a per d  
C o m me nts  
heart rate (e. g.,  bl o o d 
sa m pli n g). At t he Da y 1 a n d 
Wee k 5 Visits, E C Gs will be 
c ollecte d pre d ose a n d at 2 a n d 
4  h o urs p ost d ose. At all ot her 
visits, E C Gs will be c ollecte d 
d uri n g t he visit wit h o ut re gar d 
t o d osi n g; Secti o n  1 1. 5. 4 . 
C o m plete P E  
X   
  
  
  
  
  
  
  
 
  
Secti o n  1 1. 5. 3  
A b bre viate d P E  
 
As a p plica ble  
S y m pt o m -directe d P Es will 
occ ur at a n y ti me d uri n g t he 
st u d y if tri g gere d b y A Es or if 
dee me d necessar y b y t he 
i n vesti gat or; Secti o n  1 1. 5. 3 . 
B S T K e val uati o n  
X   
  
 
  
  
  
X   
X   
 
  
Secti o n  1 1. 4  
N P R S via dail y e -diar y  
Da y 1 t hr o u g h Wee k 1 2  
  
 
  
Eac h m or ni n g, bef ore t he first 
dail y d ose, s u bjects will 
rec or d t heir a vera ge dail y 
N P R S sc ore fr o m t he 
pre vi o us 2 4  h o urs. S u bjects 
will als o re p ort t heir c urre nt 
pai n sc ore i m me diatel y bef ore 
eac h a d mi nistrati o n of resc ue 
me dicati o n, if a p plica ble. 
Secti o n  1 1. 3  
D SI S via dail y e -diar y  
Da y 1 t hr o u g h Wee k 1 2  
  
 
  
Eac h m or ni n g, bef ore t he first 
dail y d ose, s u bjects will 
re p ort o n t he pre vi o us ni g ht’s 
slee p usi n g t he D SI S. 
Secti o n  1 1. 3  
P GI C  
  
X   
 
X   
  
  
X   
X   
 
X   
Secti o n  1 1. 3  
C -S S R S  
X   
X   
 
X   
  
  
X   
X   
 
X   
Secti o n  1 1. 5. 5  
Uri nal ysis  
X   
  
X   
  
  
X   
X   
  
 
  
Secti o n  1 1. 5. 2  
Dr u g a n d alc o h ol testi n g  
X e  
  
X   
  
  
X   
X   
X   
 
 
Pre g na nc y test f 
uri n e e  
uri n e   
uri n e   
uri n e   
uri n e   
uri n e   
ser u m  
ser u m  
 
uri ne  

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 1 1  of 6 0  
Verte x P har mace uticals I nc or p orate d  
 
C o nfi de ntial I nf or mati o n  
T a ble  3 -2   
St u d y V X 2 1 -5 4 8 -1 0 3 : Tre at me nt Peri o d a n d S afet y F oll o w-u p Visit  
 
Tre at me nt Peri o d  
  
  
S afet y F oll o w -u p 
Visit 1 4 ( ±  2)  D a ys  
After E n d of 
Tre at me nt Peri o d  
 
E ve nt/ Assess me nt a 
D a y 1 b  
Wee k 1  
( ± 1  D a y)  
Wee k 3  
( ± 3  D a ys)  
Wee k 5  
( ± 3  D a ys)  
Wee k 7  
( ± 3  D a ys)  
Wee k 9  
( ± 3  D a ys)  
Wee k 1 2  
( ± 3  D a ys)  
E T T  
Visit c  
T a per d  
C o m me nts  
C oa g ulati o n  
   
  
  
  
  
  
X   
X   
 
 
He mat ol o g y  
X   
  
X   
  
  
X   
X   
X   
 
 
Ser u m c he mistr y 
X   
  
X   
  
  
X   
X   
  
 
 
H b A 1c  
  
  
  
  
  
  
X   
X   
 
 
D N A bl o o d sa m ple ( o pti o nal)  
X   
  
  
  
  
  
  
  
 
  
O pti o nal D N A sa m ple ma y be 
c ollecte d at a n y ti me o n 
Da y  1 after s u bject 
ra n d o mizati o n ( Secti o n 1 1. 4 ) 
Nf -L bi o mar ker sa m ple  
X   
X   
  
X   
  
  
X   
X   
 
  
Secti o n 1 1. 4  
Pai n assess me nt trai ni n g refres her   
  
  
  
X  
  
  
  
  
 
  
Secti o n 9. 1. 1. 1  
St u d y dr u g a d mi nistrati o n  
Da y 1 t hr o u g h Wee k 1 2 (ta blets q d i n t h e m or ni n g a n d ca ps ules ti d). Da y 1 a n d Wee k 5 
first dail y d oses will be a d mi nistere d at t h e cli nic. 
 
T h e last d ose of ta blet st u d y dr u g will be o n t he m or ni n g of t h e Wee k 1 2 Visit.  T he 
ta peri n g re gi me n f or t h e ca ps ule st u d y dr u g will be gi n t h e f oll o wi n g da y.  
  
X  
  
S u bjects will rec or d t he date 
a n d ti me of eac h d ose 
a d mi nistrati o n i n a n e -diar y. 
T o mai ntai n  t he bli n d, 
s u bjects will recei ve t he sa me 
n u m ber of ta blets a n d/ or 
ca ps ules at t he sa me 
res pecti ve fre q ue ncies i n eac h 
treat me nt gr o u p; Secti o n 9. 6  
St u d y dr u g c o u nt 
  
X   
X   
X   
X   
X   
X   
X   
  
X   
 
Resc ue me dicati o n use  
C o nti n u o us fr o m Da y 1 t hr o u g h Wee k 1 2  
  
 
  
S u bjects will r ec or d N P R S 
pai n sc ore i m me diatel y bef ore 
eac h a d mi nistrati o n a n d 
rec or d date a n d ti me of 
a d mi nistrati o n i n a n e -diar y; 
Secti o n  1 1. 3  

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 1 2  of 6 0  
Verte x P har mace uticals I nc or p orate d  
 
C o nfi de ntial I nf or mati o n  
T a ble  3 -2   
St u d y V X 2 1 -5 4 8 -1 0 3 : Tre at me nt Peri o d a n d S afet y F oll o w-u p Visit  
 
Tre at me nt Peri o d  
  
  
S afet y F oll o w -u p 
Visit 1 4 ( ±  2)  D a ys  
After E n d of 
Tre at me nt Peri o d  
 
E ve nt/ Assess me nt a 
D a y 1 b  
Wee k 1  
( ± 1  D a y)  
Wee k 3  
( ± 3  D a ys)  
Wee k 5  
( ± 3  D a ys)  
Wee k 7  
( ± 3  D a ys)  
Wee k 9  
( ± 3  D a ys)  
Wee k 1 2  
( ± 3  D a ys)  
E T T  
Visit c  
T a per d  
C o m me nts  
Me dicati o ns re vie w  
C o nti n u o us fr o m si g ni n g of t he I C F t hr o u g h t h e Safet y F oll o w -u p Visit  
 
C o nc o mita nt treat me nts a n d 
pr oce d ures  
C o nti n u o us fr o m si g ni n g of t he I C F t hr o u g h t h e Safet y F oll o w -u p Visit  
 
A d verse e ve nts  
C o nti n u o us fr o m si g ni n g of t he I C F t hr o u g h t h e Safet y F oll o w -u p Visit  
 
; B S T K: be dsi de se ns or y testi n g kit; C-S S R S: C ol u m bia S uici de Se verit y Rati n g Scale; D SI S: Dail y Slee p I nterfere nce Scale; e -diar y: electr o nic diar y; E T T: earl y 
ter mi nati o n of treat me nt; H b A 1c: he m o gl o bi n A 1c ( gl yc os ylate d he m o gl o bi n); I C F: i nf or me d c o nse nt f or m; LI P: lice nse d i n de pe n de nt practiti o ner; Nf -L: ne ur ofila me nt li g ht c hai n; N P R S: n u meric 
pai n rati n g scale; 
; P E: p h ysical e xa mi n ati o n; P GI C: patie nt gl o bal i m pressi o n of c ha n ge; 
; q 1 2 h: e ver y 1 2 h o urs; q d: o nce dail y; 
 ti d: 3 ti mes per da y 
a  
At eac h visit, d oc u me ntati o n of t he pre vi o us da y’s N P R S sc ore b y t he s u bject s h o ul d be c o nfir me d bef ore perf or mi n g a n y assess me nts. W he n assess me nt ti me p oi nts c oi nci de, assess me nts will be 
perf or me d i n t he f oll o wi n g or der: patie nt -re p orte d o utc o mes (e. g., N P SI), vital si g ns, 1 2-lea d E C G, P E, a n d bl o o d sa m ple c ollecti o n. 
b 
O n Da y 1 a n d t he Wee k 5 visit, all assess m e nts m ust b e c o m plete d bef ore t h e first dail y d ose of st u d y dr u g, e xce pt f or t he p ost d ose P K a n d E C G sa m pli n g. 
c 
If a s u bject pre mat urel y disc o nti n ues st u d y 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 h e s u bject  deci d es t o ter mi nate st u d y treat me nt; t he s u bject w ill be e nc o ura ge d t o 
c o m plete t he ca ps ule ( pre ga bali n  refere nce or matc he d place b o) st u d y dr u g ta per. S u bjects w h o pre mat urel y disc o nti n ue treat me nt will be e nc o ura ge d t o sta y i n t he st u d y, i ncl u di n g c o m pleti n g t he 
dail y diaries a n d ret ur ni n g f or cli nical visits t o c o m plete st u d y efficac y assess me nts (i.e., N P R S, P GI C, D SI S, N P SI, use of resc ue me dicati o n, a n d S F -M P Q -2). T hese s u bjects will als o be re q uire d t o 
c o m plete t he Safet y F oll o w -u p Visit. If t he E T T  Visit occ urs 1 4  da ys or later f oll o wi n g t he last t a blet 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, a n d a se parate Safet y 
F oll o w -u p Visit will n ot be re q uire d. If t he E T T Visit is wit hi n a wee k of a n y sc he d ule d visit i n t he Treat me nt Peri o d, it will re pl ace t hat sc he d ule d vi sit, a n d a se parate visit will n ot be re q uire d. 
d  
After t he Treat me nt Peri o d (ca ps ule d osi n g ti d), s u bjects will ta per off ca ps ule ( pre ga bali n  refere nce or matc he d place b o) st u d y dr u g as f oll o ws: 4 da ys of d osi n g q 1 2 h, t he n 3 da ys of d osi n g q d i n t he 
e ve nin g.  
e  
Res ults fr o m t he Da y 1 uri ne pre g na nc y, dr u g, a n d alc o h ol tests are re q uire d bef ore t he first d ose.  
f  
Pre g na nc y tests will o nl y be perf or me d f or fe male s u bjects of c hil d beari n g p ote ntial.  
 

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 1 3  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
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 m e nts ........................................................................................................ 7  
4  
T a ble of C o nte nts  ................................................................................................................. 1 3  
List of Ta bles ............................................................................................................................ 1 6  
List of Fi g ures  .......................................................................................................................... 1 6  
List of A b bre viati o ns ................................................................................................................ 1 7  
A b bre viati o n of St u d y N u m bers  .............................................................................................. 1 8  
5  
I ntr o d ucti o n.......................................................................................................................... 2 0  
5. 1  
Bac k gr o u n d  ..................................................................................................................... 2 0  
5. 2  
St u d y Rati o nale  .............................................................................................................. 2 0  
6  
St u d y O bjecti ves  .................................................................................................................. 2 0  
6. 1  
Pri mar y O bjecti ves  ......................................................................................................... 2 0  
7  
St u d y E n d p oi nts  ................................................................................................................... 2 1  
7. 1  
Pri mar y E n d p oi nt  ............................................................................................................ 2 1  
7. 2  
Sec o n dar y E n d p oi nts  ...................................................................................................... 2 1  
8  
St u d y P o p ul ati o n  .................................................................................................................. 2 1  
8. 1  
I n cl usi o n Criteria ............................................................................................................ 2 2  
8. 2  
E xcl usi o n Criteria  ........................................................................................................... 2 2  
9  
St u d y I m ple me nt ati o n  ......................................................................................................... 2 4  
9. 1  
St u d y Desi g n  .................................................................................................................. 2 4  
9. 1. 1  
Scree ni n g  ................................................................................................................ 2 5  
9. 1. 1. 1  
Scree ni n g Visits 1 a n d 2  ................................................................................... 2 5  
9. 1. 1. 2  
R u n -i n Peri o d ................................................................................................... 2 5  
9. 1. 1. 3  
Re petiti o n of Scree ni n g Assess me nt(s)  ............................................................ 2 6  
9. 1. 1. 4  
Rescree ni n g a n d Scree ni n g E xte nsi o ns  ............................................................ 2 6  
9. 1. 2  
Treat me nt Peri o d  .................................................................................................... 2 6  
9. 1. 3  
F oll o w -u p ................................................................................................................ 2 6  
9. 1. 4  
Earl y Ter mi nati o n of Treat me nt  ............................................................................. 2 7  
9. 1. 5  
H o me Healt h Visits  ................................................................................................ 2 7  
9. 2  
Met h o d of Assi g ni n g S u bjects t o Treat me nt Gr o u ps  ..................................................... 2 7  
9. 3  
Rati o nale f or St u d y Ele me nts  ......................................................................................... 2 7  
9. 3. 1  
St u d y Desi g n ........................................................................................................... 2 7  
9. 3. 2  
St u d y Dr u g D ose  .................................................................................................... 2 8  
9. 3. 3  
Rati o nale f or St u d y Assess me nts  ........................................................................... 2 8  
9. 4  
St u d y Restricti o ns  ........................................................................................................... 2 9  
9. 4. 1  
Treat me nts f or Pai n  ................................................................................................ 3 0  
9. 5  
Pri or a n d C o nc o mita nt Me dicati o ns  ............................................................................... 3 1  
9. 6  
A d mi nistrati o n  ................................................................................................................ 3 1  
9. 7  
D ose M o dificati o n f or T o xicit y  ...................................................................................... 3 2  
9. 8  
I n di vi d ual St o p pi n g R ules a n d Preca uti o ns .................................................................... 3 2  

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 1 4  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
9. 9  
Ge neral St u d y D r u g I nterr u pti o n a n d St o p pi n g R ules ................................................... 3 2  
9. 1 0  Re m o val of S u bjects  ....................................................................................................... 3 3  
9. 1 1  Re place me nt of S u bjects  ................................................................................................ 3 3  
1 0  St u d y Dr u g I nf or m ati o n a n d M a n a ge me nt  ....................................................................... 3 3  
1 0. 1  Pre parati o n a n d Dis pe nsi n g  ............................................................................................ 3 3  
1 0. 2  Pac ka gi n g a n d La b eli n g  ................................................................................................. 3 3  
1 0. 3  St u d y Dr u g S u p pl y, St ora ge, a n d Ha n dli n g  ................................................................... 3 4  
1 0. 4  Dr u g Acc o u nta b ilit y ....................................................................................................... 3 4  
1 0. 5  Dis p osal, Ret ur n, or Rete nti o n of U n use d Dr u g  ............................................................. 3 4  
1 0. 6  C o m plia nce  ..................................................................................................................... 3 4  
1 0. 7  Bli n di n g a n d U n bli n di n g  ................................................................................................ 3 5  
1 0. 7. 1  
Bli n di n g  .................................................................................................................. 3 5  
1 0. 7. 2  
U n bli n di n g  .............................................................................................................. 3 5  
1 1  Assess m e nts  .......................................................................................................................... 3 6  
1 1. 1  S u bject a n d Disease C haracteristics  ............................................................................... 3 6  
1 1. 3  Efficac y  ........................................................................................................................... 3 7  
1 1. 4  Ot her  ............................................................................................................................... 3 8  
1 1. 5  Safet y  .............................................................................................................................. 3 8  
1 1. 5. 1  
A d verse E v e nts  ....................................................................................................... 3 8  
1 1. 5. 2  
Cli nical La b orat or y Assess me nts  ........................................................................... 3 8  
1 1. 5. 3  
P h ysical E xa mi nati o ns a n d Vital Si g ns  .................................................................. 4 0  
1 1. 5. 4  
Electr ocar di o gra ms  ................................................................................................. 4 1  
1 1. 5. 5  
C ol u m bia S uici de Se verit y Rati n g Scale  ................................................................ 4 1  
1 1. 5. 6  
C o ntrace pti o n a n d Pre g n a nc y  ................................................................................. 4 1  
1 1. 5. 6. 1  C o ntrace pti o n  ................................................................................................... 4 1  
1 1. 5. 6. 2  Pre g na nc y  ......................................................................................................... 4 3  
1 2  St atistic al A n al ysis  ............................................................................................................... 4 3  
1 2. 1  Sa m ple Size a n d P o wer  .................................................................................................. 4 3  
1 2. 2  A nal ysis Sets  .................................................................................................................. 4 4  
1 2. 3  Statistical A nal ysis  ......................................................................................................... 4 4  
1 2. 3. 1  
Ge neral C o nsi derati o ns  ........................................................................................... 4 4  
1 2. 3. 2  
Bac k gr o u n d C haracteristics  .................................................................................... 4 4  
1 2. 3. 3  
Efficac y A nal ysis  .................................................................................................... 4 4  
1 2. 3. 3. 1  A nal ysis of Pri mar y E n d p oi nt  .......................................................................... 4 5  
1 2. 3. 3. 2  A nal ysis of Sec o n dar y Efficac y E n d p oi nts  ...................................................... 4 5  
1 2. 3. 3. 3  M ulti plicit y A dj ust me nt  ................................................................................... 4 5  
1 2. 3. 4  
Safet y A nal ysis  ....................................................................................................... 4 5  
1 2. 4  I nteri m A nal ysis ............................................................................................................. 4 6  
1 2. 5  Data M o nit ori n g C o m mittee A nal ysis  ............................................................................ 4 6  
1 2. 6  Cli nical P har mac ol o g y A nal ysis  .................................................................................... 4 6  

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 1 5  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
1 2. 6. 2  
/ P har mac o d yna mic A nal ysis  ....................................................... 4 6  
1 3  Pr oce 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  ........................... 4 6  
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  ........................................................................................................................ 4 6  
1 3. 1. 1  
A d verse E v e nts  ....................................................................................................... 4 6  
1 3. 1. 1. 1  Defi niti o n of a n A d verse E ve nt ........................................................................ 4 6  
1 3. 1. 1. 2  Cli nicall y Si g nifica nt Assess me nts  .................................................................. 4 6  
1 3. 1. 1. 3  D oc u me ntati o n of A d verse E ve nts ................................................................... 4 7  
1 3. 1. 1. 4  A d verse E v e nt Se verit y  .................................................................................... 4 8  
1 3. 1. 1. 5  A d verse E v e nt  Ca usalit y  .................................................................................. 4 8  
1 3. 1. 1. 6  St u d y Dr u g Acti o n Ta ke n  ................................................................................ 4 9  
1 3. 1. 1. 7  A d verse E v e nt O utc o me  .................................................................................. 4 9  
1 3. 1. 1. 8  Treat me nt Gi ve n ............................................................................................... 4 9  
1 3. 1. 2  
Seri o us A d verse E v e nts  .......................................................................................... 5 0  
1 3. 1. 2. 1  Defi niti o n of a Seri o us A d verse E ve nt ............................................................. 5 0  
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 0  
1 3. 1. 2. 3  E x pe dite d Re p orti n g a n d I n v esti gat or S afet y L etters  ...................................... 5 1  
1 3. 2  A d mi nistrati ve Re q uire me nts  ......................................................................................... 5 1  
1 3. 2. 1  
Pr o d uct C o m plai nts  ................................................................................................ 5 1  
1 3. 2. 2  
Et hical C o nsi derati o ns  ............................................................................................ 5 1  
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 2  
1 3. 2. 4  
I n v esti gat or C o m plia nce ......................................................................................... 5 2  
1 3. 2. 5  
Access t o Rec or ds  ................................................................................................... 5 2  
1 3. 2. 6  
S u bject Pri vac y  ....................................................................................................... 5 2  
1 3. 2. 7  
Rec or d Rete nti o n  .................................................................................................... 5 3  
1 3. 2. 8  
St u d y Ter mi nati o n  .................................................................................................. 5 3  
1 3. 2. 9  
E n d of St u d y  ........................................................................................................... 5 3  
1 3. 3  Data Q ualit y Ass ur a nce  .................................................................................................. 5 3  
1 3. 4  M o nit ori n g  ...................................................................................................................... 5 4  
1 3. 5  Electr o nic Data Ca pt ure  ................................................................................................. 5 4  
1 3. 6  C o nfi de ntialit y a n d Discl os ure  ....................................................................................... 5 4  
1 3. 7  P u blicati o ns a n d Cli nical St u d y Re p ort  .......................................................................... 5 5  
1 3. 7. 2  
Cli nical St u d y Re p ort  ............................................................................................. 5 5  
1 4  Refere nces  ............................................................................................................................. 5 6  
1 5  Pr ot oc ol Si g n at ure P a g es  .................................................................................................... 5 9  
1 5. 1  S p o ns or Si g nat ure Pa ge  .................................................................................................. 5 9  
1 5. 2  I n v esti gat or Si g nat ure Pa ge ............................................................................................ 6 0  
 

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 1 6  of 6 0  
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  2 -1  
V X 2 1 -5 4 8 -1 0 3 Treat me nt Ar ms  ............................................................................. 5  
Ta ble  3 -1  
St u d y V X 2 1 -5 4 8 -1 0 3: Scree ni n g Peri o d (I ncl u di n g 7 -Da y R u n -i n Peri o d) ........... 7  
Ta ble  3 -2  
St u d y V X 2 1 -5 4 8 -1 0 3: Treat me nt Peri o d a n d Safet y F oll o w -u p Visit  ................... 9  
Ta ble  9 -1  
V X 2 1 -5 4 8 -1 0 3 Treat me nt Ar ms  ........................................................................... 2 5  
Ta ble  9 -2  
St u d y Restricti o ns  ................................................................................................. 2 9  
Ta ble  9 -3  
Dail y St u d y Dr u g Ta blet a n d Ca ps ule A d mi nistrati o n b y Treat me nt Gr o u p  ....... 3 1  
Ta ble  1 0 -1  
St u d y Dr u g  ............................................................................................................ 3 4  
Ta ble  1 1 -2  
Safet y La b orat or y Test P a nels  .............................................................................. 3 9  
Ta ble  1 1 -3  
Acce pt a ble Met h o ds of C o ntrace pti o n .................................................................. 4 2  
Ta ble  1 3 -1  
Gra di n g of A E Se v erit y  ........................................................................................ 4 8  
Ta ble  1 3 -2  
Classificati o ns f or A E Ca usalit y  ........................................................................... 4 8  
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  .................. 4 9  
Ta ble  1 3 -4  
Classificati o ns f or O utc o me of a n A E  .................................................................. 4 9  
Li st of Fi g ur e s  
Fi g ure 2 -1  
V X 2 1 -5 4 8 -1 0 3 St u d y Desi g n  ................................................................................. 4  
Fi g ure 9 -1  
V X 2 1 -5 4 8 -1 0 3 St u d y Desi g n  ............................................................................... 2 4  
 

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 1 7  of 6 0  
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 A b br e vi ati o n s  
A b bre vi ati o n   
Defi niti o n  
A D L  
acti vities of dail y li vi n g  
A E  
a d verse e ve nt 
A M S A P  
a b bre viate d m o deli n g a n d si m ulati o n a nal ysis pla n  
A N C O V A  
a nal ysis of c o varia nce 
A U C 0 -2 4 
A U C fr o m t he ti me of d osi n g t o 2 4 h o urs  
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  
B S T K  
be dsi de se ns or y testi n g kit  
C D  
c o m pact disc 
CI  
c o nfi de nce i nter val  
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 S R S  
C ol u m bia S uici de Se verit y Rati n g Scale  
C T C A E  
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts  
C Y P  
c yt oc hr o me P 4 5 0  
D P N  
dia betic peri p heral ne ur o pat h y  
D SI S  
Dail y Slee p I nterfere nce Scale  
e-diar y  
electr o nic diar y  
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 T T  
Earl y Ter 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 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 L P  
G o o d La b orat or y Practice  
G P S  
Gl o bal Patie nt Safet y  
H 2  
hista mi ne t y pe 2 rece pt or  
H b A 1c  
he m o gl o bi n A 1c ( gl yc os ylate d he m o gl o bi n)  
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  
h u ma n i m m u n o deficie nc y vir us  
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 
I E C 
i n de pe n de nt et hics c o m mittee 
I M M P A C T 
I nitiati ve o n Met h o ds, Meas ure me nt, a n d Pai n Assess me nt i n Cli nical Trials 
I M P 
i n vesti gati o nal me dici nal pr o d uct 

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 1 8  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
A b bre vi ati o n   
Defi niti o n  
I N D 
I n vesti gati o nal Ne w Dr u g (a p plicati o n) ( U S) 
I R B 
i nstit uti o nal re vie w b oar d 
I X R S 
i nteracti ve res p o nse s yste m i n w hic h X re prese nts v oice or we b, s uc h as I W R S 
LI P  
lice nse d i n de pe n de nt practiti o ner 
L S  
least s q uares 
ma x  
ma xi m u m val ue  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
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 
Na v 
v olta ge -gate d s o di u m c ha n nels  
Nf -L  
ne ur ofila me nt li g ht c hai n  
N O A E L  
n o -o bser ve d -a d verse -effect le vel  
N P R S  
n u meric pai n rati n g scale  
N S AI D  
n o nster oi dal a nti -i nfla m mat or y dr u g 
P D  
p har mac o d y na mic  
P E  
p h ysical e xa mi nati o n  
P GI C  
patie nt gl o bal i m pressi o n of c ha n ge  
PI  
pri nci pal i n vesti gat or  
pr n  
as nee de d  
q 1 2 h  
e ver y 1 2 h o urs  
q d  
o nce dail y  
Q Tc F  
Q T i nter val c orrecte d b y Fri dericia’s f or m ula 
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  
sta n dar d err or 
S E T  
St u d y E xec uti o n Tea m  
S N RI  
selecti ve n ore pi ne p hri ne re u pta ke i n hi bit or 
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 
ti d 
3 ti mes per da y  
U S  
U nite d States  
 
 
A b br e vi ati o n of St u d y N u m b er s  
A b bre vi ati o n  
St u d y N u m ber  
St u d y 0 0 1  
St u d y V X 1 9 -5 4 8 -0 0 1  
St u d y 0 0 2  
St u d y V X 2 0 -5 4 8 -0 0 2  

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

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 2 0  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
5  
I N T R O D U C TI O N 
5. 1   
B a c k gr o u n d  
Ne ur o pat hic p ai n ma y be defi ne d as a pr ocess occ urri n g after a pri mar y lesi o n or disease of t he 
s o mat ose ns or y ner v o us s yste m. 1 It is a maj or ca us e of disa bilit y w orl d wi de, ne gati vel y affecti n g 
patie nt’s slee p, m o o d, a n d f u ncti o nalit y. 2 A nti de pressa nts a n d a ntic o n v ulsa nts re mai n t he first 
li ne treat me nt f or n e ur o pat hic pai n despite n ot bei n g desi g ne d f or s uc h p ur p ose. 3 T heir use is 
ofte n li mite d b y a n arse n al of si de effects or i n a de q uate pai n relief. Pre ga b ali n is a n 
a ntic o n v ulsa nt a p pr o ve d f or t he treat me nt of pai nf ul dia betic ne ur o pat h y; it is c o nsi dere d first -
li ne treat me nt i n m ost i nter nati o nal clinical g ui deli nes a n d f or ms a k e y part of ma na ge me nt of 
ne ur o pat hic pai n. 4 
Cli nical de vel o p me nt has e x hi bit e d a c o nsi dera ble lac k of rece nt pr o gress a n d i n n o vati o n of ne w 
me dicati o ns t o treat b ot h ac ute a n d c hr o nic p ai n. O ver t he last deca d es, m ost a p pr o ve d a n al gesic 
dr u gs f or t he tr eat me nt of ne ur o pat hic pai n eit her act o n t he ser ot o ni n -n ore pi ne p hri ne s yste m 
(s uc h as t he ser ot o ni n-n ore pi ne p hri ne re u pta ke i n hi bit or, d ul o xeti ne) or o n v olta ge -gate d calci u m 
c ha n nels (s uc h as t he ga b a pe nti n oi d, pre ga b ali n). 5 Gi ve n t he li mite d treat me nt o pti o ns, c o m bi ne d 
wit h t heir ris ks a n d relati ve i neffecti ve ness,  t he de vel o p me nt of a nal gesi cs tar geti n g s pecifi c 
pat h o p h ysi ol o g y mec ha nis ms wit h i m pr o ve d efficac y a n d safet y pr ofiles is vital f or better pai n 
ma na ge me nt a n d p atie nt healt h o utc o mes.  
V olta ge -gate d s o di u m c h a n nel 1. 8 ( Na V 1. 8) pla ys a critical r ole i n p ai n si g nali n g. 6 , 7 S u p p ort f or 
t his asserti o n arises fr o m ( 1) e val u ati o n of t he r ole Na V 1. 8 pla ys i n n or mal p h ysi ol o g y 8 -1 2, 
( 2) pat h ol o gical states arisi n g fr o m m utati o ns i n t he Na V 1. 8 g e ne ( S C N 1 0 A )1 3 , 1 4, ( 3) a ni mal 
m o dels 1 5 -1 8, a n d ( 4) p har mac ol o g y of k n o w n Na V 1. 8 -m o d ulati n g a ge nts. 1 9 -2 1 I n a d diti o n, beca use 
Na V 1. 8 e x pressi o n is restricte d t o peri p h eral ne ur o ns, partic ularl y t h ose t hat se nse pai n (e. g.,  t he 
d orsal r o ot ga n glia) 8 , 1 0, NaV 1. 8 i n hi bit ors are less li kel y t o be ass ociate d wit h t he si de effects 
c o m m o nl y o bser ve d wit h ot her s o di u m c ha n nel m o d ulat ors a n d t he a b use li a bilit y  ass ociate d 
wit h o pi oi d t hera pies. T heref ore, tar geti n g t he u n derl yi n g bi ol o g y of pai n t hr o u g h selecti ve 
Na V 1. 8 i n hi biti o n re prese nts a n o vel a p pr oac h t o a nal gesic dr u g de v el o p me nt t hat has t he 
p ote ntial t o a d dress a n ur ge nt u n met nee d f or safe a n d effecti ve ac ute a n d c hr o nic pai n t hera pies.  
V X -5 4 8 is bei n g de vel o p e d f or t he treat me nt of pai n. V X -5 4 8 is a Na V 1. 8 i n hi bit or t hat is hi g hl y 
selecti ve f or Na V 1. 8 relati ve t o ot her Na V  c ha n nels. Refer t o t he V X -5 4 8 I n vesti gat or’s Br oc h ure 
f or a d diti o nal details.2 2 
5. 2   
St u d y R ati o n al e  
Cli nical data fr o m 2 P has e 1 st u dies e val uati n g si n gle a n d m ulti ple asce n di n g d oses of V X -5 4 8 
de m o nstrate d t hat V X -5 4 8 is ge nerall y safe a n d well t olerate d i n healt h y s u bjects ( St u dies 0 0 1 
a n d 0 0 2, res pecti vel y). 2 2 
T his st u d y will e val uate t he effi cac y a n d safet y of t hree V X -5 4 8 d oses i n treati n g pai nf ul 
dia betic peri p heral ne ur o pat h y ( D P N). 
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 t hree V X -5 4 8 d oses i n treati n g s u bjects wit h pai nf ul D P N  

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 2 1  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
•  T o e val uate t he s afet y a n d t olera bilit y of V X -5 4 8  
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  
•  C ha n ge fr o m bas eli ne i n t he wee kl y a vera g e of dail y pai n i nte nsit y o n a n u meric pai n rati n g 
scale ( N P R S) at Wee k 1 2  
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 t he wee kl y a vera g e of t he Dail y Slee p I nterfere nce Scale ( D SI S) at 
Wee k  1 2  
•  Pr o p orti o ns of s u bjects wit h ≥3 0 %, ≥5 0 %, a n d ≥7 0 % re d ucti o ns fr o m baseli ne i n t he wee kl y 
a vera g e of dail y pai n i nte nsit y o n t he N P R S at Wee k 1 2  
•  Pr o p orti o n of s u bjects cate g orize d as m u c h i m pr o ve d or ver y m uc h i m pr o ve d at Wee k 1 2 o n 
t he patie nt gl o bal i m pressi o n of c ha n ge ( P GI C) assess me nt  
•  Safet y a n d t olera bilit y base d o n t he i nci de nce a n d t y pe of A Es a n d c ha n ges fr o m baseli ne i n 
cli nicall y si g nifica nt la b orat or y test res ults, vital s i g ns, a n d E C Gs at eac h visit 
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 tea m bef ore s u bjects are e nr olle d. 
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.  

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 2 2  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
8. 1   
I n cl u si o n Crit eri a 
1.  S u bject will si g n a n d date 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 her st u d y pr oce d ures. 
3.  S u bjects ( male a n d fe mal e) bet wee n t he a g es of 1 8 a n d 8 0  years, i n cl usi ve.  
4.  B o d y wei g ht ≥4 5 k g a n d b o d y mass i n de x ( B MI) of ≥1 8. 0  t o < 4 0. 0  k g/ m 2. 
5.  Dia g n osis of dia betes mellit us t y pe 1 or t y pe 2 wit h  
o  gl yc os ylate d he m o gl o bi n A 1c ( H b A 1c) ≤9 %;  
o  i n t he o pi ni o n of t he i n vesti gat or, o pti mize d gl yce mic c o ntr ol, a n d s u bject has bee n 
sta ble o n oral h y p o gl yce mics a n d/ or s u bc uta ne o us i ns uli n or dietar y treat me nt f or 
≥3  m o nt hs bef ore Scree ni n g Visit 1 ; a n d 
o  prese nce of bilateral pai n i n l o wer e xtre mities d ue t o D P N f or at least 1 year.  
6.  Wee kl y a vera g e of dail y N P R S ≥4 wit h li mite d variati o n i n t he 7 -da y R u n -i n Peri o d ( S D 
< 2 5 % of mea n).  
8. 2   
E x cl u si o n Crit eri a  
1.  M ore t ha n 3 missi n g dail y N P R S sc ores d uri n g t he 7 -da y R u n -i n Peri o d. 
2.  Pai nf ul ne ur o pat h y ot her t ha n D P N, s uc h as p ost -h er petic ne ural gia, p ost -tra u matic ner ve 
i nj ur y, dia betic a m y otr o p h y, h u ma n i m m u n o deficie nc y vir us ( HI V) ne ur o pat h y, i m m u ne 
se ns or y a n d a ut o n o mic p ol y ne ur o pat h y (e. g., Sj o gre n’s s y n dr o me), here ditar y se ns or y a n d 
a ut o n o mic p ol y ne ur o pat h y, f ocal dia betic n e ur o pat hies (e. g., pr o xi mal m ot or ne ur o pat h y, 
m o n o ne ur o pat h y, m o n o ne ur o pat h y m ulti ple x), or c hr o nic re gi o nal pai n s y n dr o me.  
3.  Hist or y of a n y ill ness or a n y 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 or t he 
s u bject’s ge neral practiti o ner, mi g ht 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 t o t he s u bject. T his ma y i ncl u de, b ut is n ot li mite d t o, hist or y 
of rele va nt dr u g or f o o d aller gies; hist or y of si g nifica nt res pir at or y, re nal, he patic, 
he mat ol o gic, car di o v asc ular, meta b olic, ne ur ol o gic, or ps yc hiatric dis ease; hist or y or 
prese nce of cli nica ll y si g nifica nt pat h ol o g y; a n d hist or y of ca ncer, e x ce pt f or s q ua m o us cell 
s ki n ca ncer, basal cell s ki n ca ncer, a n d Sta ge 0 cer vical carci n o ma i n sit u (all  3 wit h n o 
rec urre nce f or t h e last 5 years).  
4.  Hist or y of se vere ps yc hiatric dis or der, s uici dal i deati o n, a n d/ or at ris k of self -har m, har m t o 
ot hers, or s uici de atte m pt.  
5.  Hist or y of car di ac d ysr h yt h mias re q uiri n g a nti -arr h yt h mia treat me nt(s) wit hi n t he last 
2  years; hist or y or e vi de nce of a b n or mal E C Gs t hat i n t he o pi ni o n of t he i n vesti gat or or 
me dical m o ni t or w o ul d precl u de t he s u bj ect’s partici pati o n i n t he st u d y; hist or y of Q T 
pr ol o n gati o n or sta n dar d 1 2 -lea d E C G ( p erf or me d i n tri plicate) de m o nstrati n g me dia n Q Tc F 
> 4 5 0 msec at Scree ni n g Visit 2; or cli nical e vi de nce of str uct ural heart disease . 
6.  Hist or y of  a cli nical at h er oscler otic e v e nt, s uc h as m y ocar dial i nfarcti o n or str o ke, wit hi n t he 
past 1 2 m o nt hs bef ore Scree ni n g Visit  1  

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 2 3  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
7.  I m paire d re nal f u n cti o n defi ne d as eit her creati ni n e cleara nce < 6 0 m L/ mi n or re q uiri n g 
he m o dial ysis.  
8.  Hist or y of si g nifica nt he pat ic disease, i ncl u di n g b ut n ot li mite d t o he patic cirr h osis, p ortal 
h y perte nsi o n, m o derat e or se vere he patic i m pair m e nt ( defi ne d as C hil d -P u g h Class B or C). 2 3 
9.  Hist or y of n o n heali n g s ki n ulcer diseas e t hat, i n  t he o pi ni o n of t he i n vesti gat or or me dical 
m o nit or, w o ul d precl u de t he s u bject’s partici p ati o n i n t he st u d y.  
1 0.  S u bjects wit h a hist or y of se vere reti n o pat h y, defi ne d as Sta ge 3 or greater.  2 4 
1 1.  Hist or y of s u bsta nce a b use t hat, i n t he j u d g me nt of t he i n vesti gat or, c o ul d c o m pr o mise 
s u bject safet y, li mit t he s u bject’s a bilit y t o c o m plete t he st u d y, a n d/ o r c o m pr o mise t he 
o bjecti ves of t he st u d y.  
1 2.  Ala ni ne tra nsa mi nas e or as partate tra nsa mi nase v al ues > 2. 5  ×  u p per li mit of n or mal.  
1 3.  A n y ot her a b n or m al la b orat or y res ults i n dicati ve of si g nifica nt me dical disease t hat, i n t he 
o pi ni o n of t he i n vesti gat or, w o ul d precl u d e t he s u bject’s partici pati o n i n t h e st u d y.  
1 4.  A k n o w n or c li nicall y s us pecte d i nfecti o n wit h HI V or he patitis B or C vir uses. 
1 5.  S u bjects u n willi n g t o recei ve a n y pr ot oc ol -relat e d me dici ne (e. g., acet a mi n o p he n, 
pre ga bali n).  
1 6.  S u bjects wit h a hist or y of aller g y rel ate d t o pre g a b ali n a n d/ or aceta mi n o p he n.  
1 7.  F or bi ol o gical l y fe m ale s u bjects: Pre g na nt, n ursi n g, or pla n ni n g t o bec o me pre g na nt d uri n g 
t he st u d y or wit hi n 3 0 da ys after t he last st u d y dr u g d ose.  
F or bi ol o gicall y male s u bjects: Wit h a bi ol o gicall y fe male part ner w h o is pre g na nt, n ursi n g, 
or pla n ni n g t o bec o me pre g na nt d uri n g t he st u d y or wit hi n 3 0  da ys after t he last st u d y dr u g 
d ose.  
1 8.  Partici pati o n i n a pre vi o us st u d y i n vesti gati n g V X -5 4 8.  
1 9.  Partici pate d i n a n ot her i n vesti gati o nal st u d y  wit hi n 3 0  da ys of t he first d os e of st u d y dr u g.  
2 0.  A n y treat me nt wit h o pi o i ds f or c hr o nic (i ncl u di n g ne ur o pat hic) pai n d uri n g t he past 3 m o nt hs 
or use of o pi oi ds f or > 7 d a ys f or a n ac ute pai n c o n diti o n d uri n g t he past 3 m o nt hs bef ore 
Scree ni n g Visit  1.  
2 1.  E vi de nce of mis use, a berra nt use, or a d dicti o n t o alc o h ol or a n illicitl y use d dr u g of a b use i n 
t he past 3 years or a p ositi ve test f or dr u gs of a b us e as defi ne d i n Secti o n 1 1. 5. 2 . 
o  A p ositi ve dr u g scree n f or a k n o w n prescri be d c o n c o mita nt me dicati o n t hat is n ot 
ot her wise e x cl usi o nar y (e. g., be nz o diaze pi nes) will n ot dis q ualif y s u bjects.  
2 2.  Use of t he s u bsta nces, acti vities, or de vices, as defi ne d i n Ta ble  9 -2 , d uri n g t he s pecifie d 
ti mes. 
2 3.  S u bject, or cl ose rel ati ve of t he s u bject, is t he i n vesti gat or or a s u bi 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 at t hat site. 

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 2 4  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o 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, acti ve -c o ntr olle d, d ose -ra n gi n g, 4-ar m, 
parallel -d esi g n st u d y. S u bjects w h o meet eli gi bilit y criteria d uri n g Scree ni n g Visits 1 a n d 2 will 
e nter a 7 -da y R u n -i n Peri o d t o esta blis h t heir baseli ne N P R S pai n sc ore. S u bjects wit h a baseli ne 
a vera g e N P R S sc ore of ≥4  p oi nts wit h li mite d variati o n ( S D < 2 5 % of mea n) will be eli gi ble f or 
t he 1 2-wee k Treat me nt Peri o d f oll o we d b y a Safet y F oll o w -u p Visit ( Fi g ure 9 -1 ). 
Fi g ure 9 -1   
V X 2 1 -5 4 8 -1 0 3  St u d y Desi g n  
 
 
N: n u m ber of s u bjects  
a  
At t he e n d of t he Treat me nt Peri o d ( Wee k  1 2), s u bjects will ta per off ca ps ule ( pre ga bali n refere nce or matc h e d 
place b o) st u d y dr u g f or 7  da ys.  
A t otal of a p pr o xi matel y 1 7 5  s u bjects will be ra n d o mize d 2: 2: 1: 2 t o 4 treat me nt ar ms: V X-5 4 8 
( hi g h, mi d, or l o w d ose) or pre ga b ali n (refere nce ar m; Ta ble  9 -1 ). Ra n d o mizati o n will be 
stratifie d b y se x (fe male a n d male) a n d B MI ( ≥3 0 a n d < 3 0 k g/ m 2). T o mai ntai n t he bli n d, all 
s u bjects will recei ve t h e sa me n u m ber of ta bl ets o nce dail y ( q d) i n t he m or ni n g a n d t he sa me 
n u m ber of ca ps ules 3 ti mes per da y (ti d) i n a d o u ble -d u m m y desi g n. After t he Treat me nt Peri o d, 
s u bjects will ta per off ca ps ule (pre ga b ali n  refere n ce or matc he d place b o) st u d y dr u g f or 7 da y s 
( 4 da ys of d osi n g e ver y 1 2 h o urs, t he n 3  da ys of d osi n g q d), a n d t he Safet y F oll o w -u p Visit will 
occ ur a n a d diti o nal 7  ( ± 2) da ys later. 
S u bjects will st o p ta ki n g pai n me dicati o ns (i ncl u di n g pre ga bali n, if a p plica ble), e xce pt 
aceta mi n o p he n ( 5 0 0 m g), f or at least 1 4 da ys b ef ore t he first d ose of st u d y dr u g.   
Aceta mi n o p he n will be per mitte d as a pai n resc u e me dicati o n as nee d e d ( pr n) t hr o u g h o ut t he 
st u d y. S u bjects will be per mitte d t o ta ke 5 0 0 m g e ver y 4 t o 6 h o urs pr n, u p t o a ma xi m u m of 
2 5 0 0  m g i n a n y 2 4 -h o ur peri o d. S u bjects will rec or d resc u e me dicati o n use, a n d t heir c urre nt 
pai n sc ore o n t he N P R S i m me diatel y bef ore eac h a d mi nistrati o n of resc ue me dicati o n.  

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 2 5  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
T a ble  9 -1   
V X 2 1 -5 4 8 -1 0 3 Tre at me nt Ar ms  
Tre at m e nt  
Acti ve D ose  
N u m ber of S u bjects  
V X -5 4 8 ( hi g h d ose)  
6 9 m g q d  
5 0  
V X -5 4 8 ( mi d d ose)  
4 6 m g q d  
5 0  
V X -5 4 8 (l o w d ose)  
2 3 m g q d  
2 5  
Pre ga bali n  
1 0 0 m g ti d  
5 0  
q d: o nce dail y; ti d: 3 ti mes per da y  
N ote: T o mai ntai n t he bli n d, all s u bjects will recei ve t he sa me n u m ber of ta blets a n d t he sa me n u m ber of ca ps ules 
at t he sa me res pecti ve fre q ue nc y (i.e., q d f or ta blets a n d ti d f or ca ps ules d uri n g t he Treat me nt Peri o d) i n a 
d o u ble -d u m m y desi g n.  
9. 1. 1   
S cr e e ni n g  
Scree ni n g ass ess me nts are liste d i n Ta ble  3 -1 . 
Scree ni n g will occ ur wit hi n 3 5  da ys bef ore a d mi nistrati o n of st u d y dr u g. T he i n vesti gat or ( or a n 
a p pr o priate a ut h orize d d esi 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 
i n pers o n or re m otel y ( Secti o n 1 3. 2. 3 ) bef ore perf or mi n g a n y st u d y-relate d pr oce d ure. If nee d e d, 
Scree ni n g Visit 1 assess me nts ma y be perf or me d o n differe nt d a ys wit hi n t he Scree ni n g Peri o d 
(e. g., i nf or me d c o nse nt ma y be o btai ne d bef ore t he h o me healt h visit, if a p plica ble). 
T o pre pare f or st u d y p artici pati o n, s u bjects will be i nstr ucte d o n t he st u d y restr icti o ns 
( Secti o n 9. 4 ). D uri n g scree ni n g, s u bjects will disc o nti n ue t heir c urre nt pai n treat me nts as 
o utli ne d i n Secti o n  9. 4. 1 . S u bjects will be per mitte d t o ta ke aceta mi n o p he n pr n, f oll o wi n g t he 
g ui deli nes i n Secti o n  9. 4. 1 , as a res c ue me dicati o n f or i nter mitte nt pai n. 
9. 1. 1. 1   
S cr e e ni n g Vi sit s 1 a n d 2  
Scree ni n g Visit 1 ca n  o cc ur as earl y as Da y -3 5 a n d ma y occ ur i n t he cli nic or as a h o me healt h 
visit wit h a q ualifie d visiti n g n urse if per mitte d b y l ocal re g ulati o ns. Scree ni n g Visit  2 ma y occ ur 
o nl y after la b orat or y res ults fr o m Scree ni n g Visit 1 are a v aila ble a n d h a ve esta blis he d s u bject 
eli gi bilit y t o c o nti n ue st u d y partici pati o n per Secti o n 8 ; Scree ni n g Visit 2 m ust occ ur at t he cli nic 
a n d will be c o nsi dere d as Da y  -8.  
S u bjects will be i nstr ucte d d uri n g scree ni n g o n a p pr o priate e x p ectati o ns ar o u n d t heir 
partici pati o n i n a cli nical st u d y a n d t he i m p orta nce of c o nsiste ntl y a n d acc uratel y re p orti n g t heir 
pai n t hr o u g h o ut t he st u d y. At Scree ni n g Visit 2, s u bjects will re cei v e pai n assess me nt trai ni n gs 
o n acc urate pai n re p orti n g, bias re d ucti o n, use of t he electr o ni c diar y (e -diar y) a n d el ectr o nic 
patie nt -re p ort e d o utc o me assess me nts. A refres h er trai ni n g o n pai n assess me nt will occ ur at t he 
Wee k 5 Visit. A d diti o nal re vie w  of  t h ese e d u cati o nal materials ma y be re p eate d f or s o me or all 
s u bjects de pe n di n g o n t h e fi n di n gs of a n o n g oi n g bli n de d data re vie w (e. g., if pai n sc ore 
varia bilit y is i ncrease d o n a s u bject or site le vel).  
9. 1. 1. 2   
R u n -i n P eri o d 
T he R u n -i n Peri o d ( Da ys -7 t o -1) will be gi n t he da y f oll o wi n g Scree ni n g Visit 2 ( Da y -8). 
D uri n g t he R u n -i n Peri o d, s u bjects will re p ort t heir a vera ge d ail y pai n fr o m Da y -7 t o Da y -1 as 
descri be d i n Secti o n  1 1. 3  t o esta blis h t he baseli ne N P R S pai n sc ore. Pai n treat me nt restricti o ns 
a n d use of aceta mi n o p he n as a res c ue me dicati o n will c o nti n ue t o a p pl y d uri n g t he R u n -i n 
Peri o d. S u bjects will re p ort t heir use of aceta mi n o p he n.  

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 2 6  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
9. 1. 1. 3   
R e p etiti o n of S cr e e ni n g A s s e s s m e nt( s)  
Re petiti o n of a n y scree ni n g assess me nt t hat di d n ot meet eli gi bilit y criteria is n ot per mitte d, 
u nless s pecifie d i n t he pr ot oc ol, or t here is clear e vi de nce of a la b orat or y err or (e. g.,  he m ol ysis of 
sa m ple). I n all cases, t he me dical m o nit or m ust a ut h orize ret esti n g. 
9. 1. 1. 4   
R e s cr e e ni n g a n d S cr e e ni n g E xt e n si o n s  
S u bjects w h o d o n ot meet t he eli gi bilit y criteria ma y n ot be res cree ne d, wit h t he f oll o wi n g 
e xce pti o ns:  
•  S u bjects w h o met all eli gi bilit y criteria b ut ha d a n i nterc urre nt i ll ness (e. g., u p per res pir at or y 
i nfecti o n wit h fe ver) i n t he 5 da ys bef ore t he first d ose of st u d y dr u g t hat was pr o perl y 
e val uate d a n d w hic h res ol ve d f ull y  
•  S u bjects w h o met all eli gi bilit y criteria b ut were n ot a ble t o o btai n re q uire d d oc u me ntati o n 
wit hi n  t he all otte d scree ni n g wi n d o w 
•  S u bjects w h o met all eli gi bilit y criteria b ut tra nsie ntl y (f or pers o nal reas o ns) are u n a ble t o 
c o m mit t o all st u d y pr oce d ures  
•  S u bjects w h o met all eli gi bilit y criteria b ut were n ot ra n d o mize d f or a d mi nistrati ve reas o ns 
(e. g., i nteracti ve we b res p o nse s yste m is te m p oraril y i naccessi ble or n o nf u ncti o nal, or st u d y 
dr u g is n ot a vaila ble at t h e st u d y site)  
•  S u bjects w h o were s cree ne d u n der a pri or versi o n of t he pr ot oc ol a n d di d n ot meet a n y 
e xcl usi o n criteri o n, wit h t he e xce pti o n o f a criteri o n t hat was u p date d i n a s u bse q ue nt versi o n 
of t he pr ot oc ol  
Scree ni n g Wi n d o w E xte nsi o ns  
A n y s u bject w h o is gra nt e d a p pr o val b y t he m e dical m o nit or f or a n y of t he e xce pti o ns liste d 
a b o ve ma y ha v e t he scree ni n g wi n d o w e xte n de d b y 1  wee k bef ore n ee di n g t o u n der g o a n y 
rescree ni n g assess m e nts. If m ore t ha n 4 2 d a ys ha v e ela pse d fr o m scree ni n g bef ore first d ose of 
st u d y dr u g, all scree ni n g assess me nts nee d t o be re peate d. 
9. 1. 2   
Tr e at m e nt P eri o d  
Treat me nt Peri o d ass ess me nts are liste d i n Ta ble  3 -2 . 
All st u d y peri o ds will be c o n d ucte d as d escri be d i n Secti o n  9. 1 . D osi n g details are i n Secti o n 9. 6 . 
D uri n g t he Treat me nt Peri o d, s u bjects will f oll o w t he pai n treat me nt restricti o ns o utli ne d i n 
Secti o n  9. 4. 1 . S u bjects will be per mitte d t o ta ke aceta mi n o p he n pr n, f oll o wi n g t he g ui deli nes i n 
Secti o n  9. 4. 1 , as a res c ue me dicati o n f or i nter mitte nt pai n. 
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 u d y dr u g treat me nt t hr o u g h t he last sc he d ule d st u d y visit a n d 
c o m plete select e d 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   
F oll o w -u p  
After t he Treat me nt Peri o d, s u bjects will ta per off ca ps ule ( pre ga b ali n  refere nce or matc he d 
place b o) st u d y dr u g f or 7  da ys as descri be d i n Secti o n  9. 1 ; ta blet ( V X-5 4 8 or matc he d place b o) 
st u d y dr u g will n ot be pr o vi de d d uri n g t he ta per. S u bjects will ha ve a Safet y F oll o w -u p Visit 
1 4  ( ± 2)  da ys after t he e n d of t he Treat me n t Peri o d.  

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 2 7  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
Safet y F oll o w -u p assess me nts are liste d i n Ta ble  3 -2 . 
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 s u bject deci des t o ter mi nate st u d y 
treat me nt; t he s u bject will be e nc o ura ge d t o c o m pl ete t he ca ps ule (pre ga bali n  refere nce or 
matc he d place b o) st u d y dr u g ta per.  
S u bjects w h o pre mat urel y disc o nti n ue treat me nt will be e nc o ura g e d t o sta y i n t he st u d y, 
i ncl u di n g c o m pleti n g t he dail y diaries a n d ret ur ni n g f or cli nical visits t o c o m plete st u d y efficac y 
assess me nts (i.e., N P R S, P GI C, D SI S,   
 us e of resc u e me dicati o n, 
). T hes e 
s u bjects will als o be re q uire d t o c o m plete t he Safet y F oll o w-u p Visit, a p pr o xi matel y 
1 4  ( ± 2)  da ys after t heir l ast ta blet d ose of st u d y dr u g. T he assess me nts p erf or me d at t he Safet y 
F oll o w -u p Visit are liste d i n Ta ble  3 -2 . 
If t he E T T Visit occ urs 1 4 da ys or later f oll o wi n g t he last ta blet d ose of st u d y dr u g, t he n t he 
E T T  Visit will re place t h e Safet y F oll o w -u p Visit , a n d a se parate Safet y F oll o w-u p Visit will n ot 
be re q uir e d. If t he E T T Visit is wit hi n a wee k of a n y sc he d ule d visit i n t he Treat me nt Peri o d, it 
will re place t hat s c he d ule d visit, a n d a se parat e visit 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 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 nal 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 
( Secti o n 9. 1 0 ). 
9. 1. 5   
H o m e H e alt h Vi sit s  
H o me healt h visits are o nl y a n o pti o n if per mitte d b y l ocal re g ulati o ns. A n y visits t hat occ ur via 
h o me healt h m ust ha ve a c o ns ultati o n (i.e.,  tele me dici ne vi de o c o nfere n ce or tele p h o ne c o nt act) 
bet wee n t he s u bject a n d i n vesti gat or or q ualifie d d ele gate (lice nse d i n de pe n de nt practiti o ner 
[ LI P]) wit hi n 2 b usi ness da ys after t h e h o me healt h visit i n or der t o c hec k-i n a n d c ollect A Es, 
a n d ma y als o i ncl u de a s e parat e f oll o w u p wit h t he st u d y c o or di nat or.  
9. 2   
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 n i nteracti ve we b or v oi ce res p o ns e s yste m (I X 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 nate 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 xec uti o n Tea m  ( S E T).  
9. 3   
R ati o n al e f or  St u d y El e m e nt s  
9. 3. 1   
St u d y D e si g n  
T his st u d y is desi g ne d t o e val uate t he efficac y of V X -5 4 8 f or treat me nt of pai n i n s u bjects wit h 
pai nf ul D P N. T he ra n d o mize d, d o u ble -bli n d st u d y desi g n will li mit o bser ver bias a n d re d uce t he 
p ossi bilit y f or u n bli n di n g. F or t he  pri mar y e n d p oi nt, dail y N P R S pai n sc ores will be a vera ge d 
o ver a wee kl y peri o d t o re d uce t he i m pact o n t he a nal yses of i n di vi d ual hi g h or l o w pai n sc ores.  

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 2 8  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
9. 3. 2   
St u d y Dr u g D o s e  
V X -5 4 8 d oses ( T a ble  9 -1 ) were select e d base d o n fa v ora bl e safet y a n d P K data fr o m healt h y 
v ol u nteers i n St u d y  0 0 1 (si n gle asce n di n g d ose st u d y) a n d St u d y 0 0 2 ( m ulti ple asce n di n g d ose 
st u d y). M ulti ple oral d oses u p t o 6 5 m g a d mi nistere d i n s ol uti o n/s us pe nsi o n u n der faste d 
c o n diti o ns e ver y 2 4 h o urs f or 1 4 da ys ha v e bee n e val uate d a n d f o u n d t o b e safe a n d well 
t olerate d.2 2 T he selecte d V X -5 4 8 d oses are pre dicte d t o ac hie ve c o nce ntrati o ns t hat are a ble t o 
pr o d uce 8 0 % (l o w d ose) t o 9 0 % ( hi g h d ose) Na V 1. 8 i n hi biti o n i n t he i n vitr o h u ma n d or sal r o ot 
ga n glia assa y.  
Base d o n o bser ve d d ata, t he mea n e x p os ures ( A U C 0 -2 4 a n d C ma x ) f or V X-5 4 8 a n d its maj or 
meta b olite, M 6 -5 4 8, at t he hi g hest d ose i n t his st u d y ( 6 9 m g q d wit h o ut re gar d t o f o o d 
a d mi nistere d as ta blets) are pre di cte d t o pr o vi de t h e f oll o wi n g safet y mar gi ns t o t he 
n o -o bser ve d -a d verse-effect le vel ( N O A E L) o bser ve d i n m o n ke y i n t he 1 3 -wee k G L P t o xicit y 
st u d y:2 2  
•  V X -5 4 8: 2. 8 -f ol d a n d 4. 5-f ol d bel o w t he N O A E L f or A U C0 -2 4 a n d C ma x , res pecti vel y 
•  M 6 -5 4 8: 2. 8 -f ol d a n d 5. 9-f ol d bel o w t he N O A E L f or A U C0 -2 4 a n d C ma x , res pecti vel y 
T he safet y ma r gi ns were calc ulate d usi n g o bser ve d P K data f or t he s us pe nsi o n/s ol uti o n 
f or m ulati o n of V X-5 4 8 a n d a dj uste d base d o n t he relati ve bi oa vaila bilit y bet wee n t he ta blet a n d 
s ol uti o n f or m ulati o ns of V X-5 4 8 a n d relati ve bi oa vaila bilit y bet wee n faste d c o n diti o ns a n d fe d 
c o n diti o ns wit h hi g h -fat meal f or t he ta blet f or m ulati o n. 
9. 3. 3   
R ati o n al e f or St u d y A s s e s s m e nt s  
1 1 -p oi nt N P R S: Pai n i nte nsit y is t he F D A -rec o m me n de d efficac y e n d p oi nt f or st u dies of pai n 
dr u gs. 2 5 , 2 6 T his e val uati o n is a sta n dar d pai n ass ess me nt scale use d i n ma n y pai n re gistrati o n 
st u dies. T he 1 1 -p oi nt scale ra n ges fr o m 0 ( n o pai n) t o 1 0 ( w orst i ma gi na ble pai n).  
D SI S: Pai n fre q ue ntl y i nterferes wit h sl ee p, a n d sl ee p is i m p orta nt t o q ualit y of life. T he F D A 
rec o m me n ds e v al uati n g t he effect of a nal gesics o n slee p. 2 5 , 2 6 D SI S is c o m m o nl y use d i n 
ne ur o pat hic pai n st u dies a n d is assesse d o n a n 1 1 -p oi nt n u meric rati n g scal e. T he 1 1 -p oi nt scal e 
ra n ges fr o m 0 ( n o ne) t o 1 0 (se vere). 
P GI C:  T he P GI C is c o m m o nl y use d i n ne ur o pat hic pai n st u dies, a n d t he I nitiati ve o n Met h o ds, 
Meas ure me nt, a n d Pai n Assess me nt i n Cli nical Trials (I M M P A C T) gr o u p rec o m me n ds it as a 
c ore o utc o me m eas ure  f or c hr o nic p ai n st u dies.2 6 T here is s o me e vi d e nce t hat P GI C ma y be m ore 
se nsiti ve i n ne ur o pat hic pai n st u dies t ha n pai n i nte nsit y assess me nts beca use it ma y assess 
a d diti o nal q ualit y of life meas ures. 2 7 T he assess me nt c o nsists of a si n gle ite m o n a 7 -p oi nt scale 
fr o m 1 ( ver y m u c h i m pr o ve d) t o 7 ( ver y m uc h w orse). 
Use of resc ue me dic ati o ns: Data o n t he use of res c ue me dicati o ns are c ollecte d f or descri pti ve 
a nal ysis.  

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 2 9  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
C ol u m bi a S uici de Se verit y R ati n g Sc ale ( C -S S R S): T he F D A rec o m me n ds t he e val uati o n of 
s uici dalit y i n cli nical st u dies i n v ol vi n g dr u gs wit h C N S acti vit y. T he C-S S R S e val uates t his 
t hr o u g h a series of q uesti o ns a b o ut s uici dal t h o u g hts a n d be ha vi ors. 
Be dsi de Se ns or y Testi n g Kit ( B S T K):  T he B S T K is use d f or t he p ur p os e of sta n dar dize d 
assess me nt a n d p he n ot y pi n g of s u bjects’ pai n, u si n g t he us ual c o m p o ne nts of a ne ur ose ns or y 
e xa mi nati o n.  
9. 4   
St u d y R e stri cti o n s  
St u d y restricti o ns are s u m marize d i n Ta ble  9 -2 . A n o n-e x ha usti ve list of st u d y restricti 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 -2   
St u d y Restricti o ns  
Restricte d 
Me dic ati o n/ F o o d / Acti vit y a 
Ti mi n g of Restricti o n  
St a rt  
St o p  
Ot her i n vesti gati o nal dr u gs or 
de vices  
3 0  da ys bef ore first d ose of st u d y dr u g, 
5  half -li ves bef ore first d ose of st u d y 
dr u 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 ger) 
C o m pleti o n of S F U 
assess me nts  
A n y o pi oi d use f or c hr o nic 
(i ncl u di n g ne ur o pat hic) pai n; f or 
ac ute use, refer t o Secti o n  8. 2  a n d 
Secti o n  1 1. 5. 2  
3  m o nt hs bef ore S cree ni n g V isit 1   
C o m pleti o n of Wee k 1 2 or 
E T T Visit assess me nts  
Marij ua na or marij ua na pr o d ucts   
1 4 da ys bef ore first d ose of st u d y dr u g   
C o m pleti o n of Wee k 1 2 or 
E T T Visit assess me nts  
Pre ga bali n (e xce pt use of refere nce 
st u d y dr u g) a n d ga ba pe nti n 
1 4 da ys bef ore first d ose of st u d y dr u g   
C o m pleti o n  of st u d y dr u g 
ta per (i.e., 7 da ys after 
Wee k  1 2 or E T T Visit)  
Ca psaici n patc h  
9 0 da ys bef ore first d ose of st u d y dr u g   
C o m pleti o n of Wee k 1 2 or 
E T T Visit assess me nts  
La m otri gi ne, car ba maze pi ne, 
o xcar baze pi ne, p he n yt oi n, 
t o pira mate, val pr oic aci d, 
me xilet i ne, a n d t o pical a ge nts bei n g 
prescri be d f or pai n c o ntr ol  
1 4 da ys bef ore first d ose of st u d y dr u g   
C o m pleti o n of Wee k 1 2 or 
E T T Visit assess me nts  

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 3 0  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
T a ble  9 -2   
St u d y Restricti o ns  
Restricte d 
Me dic ati o n/ F o o d / Acti vit y a 
Ti mi n g of Restricti o n  
St a rt  
St o p  
All S N RIs a n d tric yclic 
a nti de pressa nts  
1 4 da ys bef ore first d ose of st u d y dr u g   
C o m pleti o n of Wee k 1 2 or 
E T T Visit assess me nts  
All ot her treat me nts f or pai n, e xce pt 
aceta mi n o p he n ( 5 0 0 m g) a n d st u d y 
dr u g (as o utli ne d i n Secti o n  9. 4. 1 ), 
i ncl u di n g n o n p harmace utical 
i nter ve nti o ns 
1 4 da ys bef ore first d ose of st u d y dr u g   
C o m pleti o n of Wee k 1 2 or 
E T T Visit assess me nts  
Oral ster oi ds  
5 half -li ves or 2 da ys ( w hic he ver is 
l o n ger) bef ore first d ose of st u d y dr u g  
U ntil last d ose of st u d y dr u g is 
ta ke n 
Me dicati o ns, her bal a n d dietar y 
s u p ple me nts (i ncl u di n g St. J o h n’s 
w ort) k n o w n t o be m o derate or 
str o n g i n d ucers of C Y P 3 A 
1 4  da ys bef ore first d ose of st u d y dr u g   
C o m pleti o n of S F U 
assess me nts  
Pr ot o n P u m p I n hi bit ors  
7 2 h o urs bef ore first d ose of st u d y dr u g   
U ntil last d ose of st u d y dr u g is 
ta ke n 
H 2 bl oc kers  
1 2 h o urs bef ore eac h m or ni n g d ose of 
st u d y dr ug  
6  h o urs after eac h m or ni n g 
d ose of st u d y dr u g  
A ntaci ds  
2 h o urs  bef ore eac h d ose of st u d y dr u g  
2 h o urs after eac h d ose of 
st u d y dr u g  
Gra pefr uit or gra pefr uit j uice, 
p o mel os, star fr uit, Se ville ora n ges 
a n d t heir j uices, ve geta bles fr o m t he 
m ustar d gree n fa mil y (e. g., kale, 
br occ oli, watercress, c ollar d gree ns, 
k o hlra bi, Br ussels s pr o uts, m ustar d), 
a n d c har br oile d meats  
7  da ys bef ore fir st d ose of st u d y dr u g   
C o m pleti o n of S F U 
assess me nts  
E T T: Earl y Ter mi nati o n of Treat me nt ; H 2: hista mi ne t y pe 2 rece pt or; S F U: Safet y F oll o w -u p; S N RI: selecti ve 
n ore pi ne p hri ne re u pta ke i n hi bit or  
a  
Refer t o t he St u d y Refere nce Ma n ual f or a m ore c o m plete list of me dicati o ns pr o hi bite d/restricte d i n t he 
st u d y. See Secti o n 9. 5  f or g ui da nce o n c o nc o mita nt me dicati o ns. 
9. 4. 1   
Tr e at m e nt s f or P ai n  
•  S u bjects will a bstai n fr o m all treat me nt f or pai n (i ncl u di n g me dicati o ns, s u p ple me nts, a n d 
n o n -p har mace utic al t hera pies) starti n g fr o m 1 4  da ys bef ore t he first d ose of st u d y dr u g, or as 
i n dicate d i n Ta ble  9 -2 , a n d c o nti n ui n g t hr o u g h t he ti me peri o ds i n dicate d i n Ta ble  9 -2 . F or 
treat me nts t hat re q uir e a t a per pri or t o disc o nti n uati o n, t he a p pr o priate t a per s h o ul d be 
c o m plete d b y 1 4 da ys bef ore t he first d ose of st u d y dr u g. S u bjects ta ki n g as piri n f or 
car di o vas c ular healt h ma y re mai n o n t heir sta ble d ose t hr o u g h o ut t he st u d y.  
•  S u bjects are n ot re q uire d t o st o p ta ki n g aceta mi n o p he n ( 5 0 0 m g) d uri n g t he 1 4 -da y peri o d 
bef ore t h e first d ose of st u d y dr u g. Acet a mi n o p h e n will be per mitte d as a p ai n resc u e 
me dicati o n pr n t hr o u g h o ut t he st u d y. S u bjects will be per mitte d t o ta ke 5 0 0  m g e ver y 4 t o 
6  h o urs pr n, u p t o a ma xi m u m of 2 5 0 0  m g i n a n y 2 4 -h o ur peri o d. S u bjects will rec or d resc ue 
me dicati o n use, a n d t heir c urre nt p ai n sc ore o n t h e N P R S i m me diatel y bef ore eac h 
a d mi nistrati o n of resc ue me dicati o n.  

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 3 1  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
9. 5   
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 a bstai n fr o m all c o nc o mita nt me dicati o ns as descri be d i n t he e xcl usi o n criteria 
( Secti o n 8. 2 ) a n d st u d y restricti o ns (Ta ble  9 -2 ). 
•  All me dicati o ns ta ke n f or t he treat me nt of pai n wit hi n 1 2 m o nt hs of Scree ni n g Visit 1 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 a n y disc o nti n ue d me dicati o ns, t he reas o n f or disc o nti n uati o n will als o be rec or de d. 
•  All o pi oi d me dicati o ns ta ke n wit hi n 1 2  m o nt hs of Scree ni n g Visit 1 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. 
•  All me dicati o ns ta ke n fr o m 1 4  da ys bef ore Scree ni n g Visit 1 t hr o u g h t he 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. All s u bjects will be q uesti o ne d a b o ut me dicati o ns at eac h st u d y visit.   
9. 6   
A d mi ni str ati o n  
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:  
•  S u bjects will rec or d t he d ate a n d ti me of eac h d os e a d mi nistrati o n i n a n e -diar y.  
•  T o mai ntai n t he bli n d, all s u bjects will recei ve t h e sa me n u m ber of ta bl ets a n d/ or ca ps ules i n 
a d o u ble-d u m m y desi g n as s u m marize d bel o w a n d i n Ta ble  9 -3 : 
o  V X -5 4 8 acti ve or V X -5 4 8 place b o (as 3 ta blets) will be a d mi nistere d t o all s u bjects 
q d i n t he m or ni n g ( wit h t he first dail y d ose of pre ga bali n acti ve or place b o ca ps ul e).  
o  Pre ga bali n acti ve or pre g a bali n place b o (as 1 ca ps ule) will be a d mi nistere d t o all 
s u bjects ti d a p pr o xi matel y 6 t o 8 h o urs a part (i.e., 3 ti mes d uri n g wa ki n g h o urs dail y).  
T a ble  9 -3   
D ail y St u d y Dr u g T a blet a n d C a ps ule A d mi nistr ati o n b y Tre at me nt Gr o u p  
Tre at m e nt Ar m  
N u m ber of T a blets  
N u m ber of C a ps ules a 
V X -5 4 8 Acti ve   
V X -5 4 8 Pl ace b o   
Pre g a b ali n Acti ve  
Pre g a b ali n 
Pl ace b o  
V X -5 4 8 ( hi g h d ose)  
3  
0  
0  
3  
V X -5 4 8 ( mi d d ose)  
2  
1  
0  
3  
V X -5 4 8 (l o w d ose)  
1  
2  
0  
3  
Pre ga bali n  
0  
3  
3  
0  
ti d: t hree ti mes per da y 
a  
Pre ga bali n ca ps ules (acti ve or place b o) will be a d mi nistere d ti d a p pr o xi matel y 6 t o 8 h o urs a part.  
•  S u bjects will ta ke st u d y dr u g at a p pr o xi matel y t h e sa me ti me eac h da y a n d will a d mi nister 
orall y wit h a p pr o xi matel y 2 4 0 m L ( 8 fl ui d o u nces) of water. St u d y dr u g ma y be ta ke n wit h 
or wit h o ut f o o d.  
•  S u bjects will s wall o w t he st u d y dr u g w h ole a n d will n ot c he w it bef ore s wall o wi n g.  
•  T he Da y 1 a n d Wee k 5 first dail y d oses will be a d mi nistere d at t he cli nic, a n d b ot h pre d ose 
a n d p ost d ose P K sa m ples, a n d pre d ose a n d p ost d ose 1 2 -lea d E C Gs, will be c ollecte d; 
t heref ore, t hese 2 visits s h o ul d be sc he d ule d t o start i n t he m or ni n g, a n d t he s u bject s h o ul d 
n ot ta ke t he m or ni n g d ose (ta blets a n d ca ps ule) at h o me. O n all ot her da ys (i ncl u di n g visit 
da ys, re gar dless of sc h e d ule d visit ti me) t he m or ni n g d ose will be ta ke n at h o me.  

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 3 2  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
Misse d D oses  
•  If a s u bject f or gets t he m or ni n g d ose (ta blets a n d ca ps ule) a n d re me m b ers wit hi n 2 h o urs of 
t he sc he d ule d d ose, t h e y will ta ke t he d ose at t hat ti me a n d res u me t heir n or mal sc he d ule f or 
t he f oll o wi n g d oses.  
•  If a s u bject f or gets t he m or ni n g d ose (ta blets an d ca ps ule), a n d m ore t ha n 2 h o urs ha ve 
ela pse d, t he y are t o s ki p t hat ca ps ule d ose a n d res u me at t he ne xt sc he d ul e d d ose, b ut s h o ul d 
ta ke t he ta blets wit h t he mi d da y ca ps ule d ose. If a s u bject c o nti n ues t o f or g et t he ta blet d ose 
a n d m ore t ha n 2 h o urs h a ve  passe d si nce t he sc he d ule d mi d da y ca ps ule d os e, t he s u bject 
s h o ul d s ki p t hat ta blet d ose a n d res u me at t he ne xt sc he d ule d ta blet d ose (i.e., t he ne xt da y).  
•  A ca ps ule s h o ul d n ot be t a ke n wit hi n 4 h o urs of t h e last ca ps ule, a n d 2  ca ps ules s h o ul d n ot be 
ta ken t o get her. T h eref ore, ass u mi n g a sc he d ule of e ver y 6  h o urs d uri n g wa ki n g h o urs, if a 
s u bject f or gets t he mi d da y d ose (ca ps ul e), a n d m ore t ha n 2 h o urs h a ve ela pse d, t he y are t o 
s ki p t hat ca ps ule d ose a n d res u me at t he n e xt sc he d ule d d ose. 
L ast D ose  
T he las t d ose of ta blet st u d y dr u g will be ta ke n o n t he m or ni n g of t he Wee k 1 2 Visit acc or di n g t o 
t he s u bject’s dail y sc he d ule, al o n g wit h t he m or ni n g d ose of ca ps ul e st u d y dr u g f or t hat da y. T he 
mi d da y a n d e ve ni n g d oses of ca ps ule st u d y dr u g will be ta ke n as us u al t hat da y. 
T a per  
T he ta per re gi me n f or t he ca ps ule st u d y dr u g will be gi n t he da y after t he Wee k 1 2 Visit. D osi n g 
f or t his 7-da y ta per is as f oll o ws: 1 ca ps ule i n t he m or ni n g a n d 1 ca ps ule i n t he e ve ni n g f or 
4  da ys, f oll o we d b y 1 ca ps ule i n t he e ve ni n g f o r 3 da ys; t he ta per is t he n c o m plete. 
9. 7   
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. If a n y u nacce pta ble t o xicit y arises, 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. 8   
I n di vi d u al St o p pi n g R ul e s a n d Pr e c a uti o n s 
D osi n g of st u d y dr u g i n a n i n di vi d ual s u bject will be disc o nti n ue d if t he s u bject has  
•  a seri o us a d verse e ve nt ( S A E) of heart fail ure t h at is c o nsi dere d relate d or p ossi bl y 
relate d t o V X-5 4 8 b y t he i n vesti gat or or Verte x; or  
•  a n S A E of ve ntric ular arr h yt h mia t hat is c o nsi dere d relate d or p ossi bl y rel ate d t o V X -5 4 8 
b y t he i n vesti gat or or Verte x.  
T he i n vesti gat or m ust i m me diatel y n otif y t he Verte x me di cal m o nit or if eit her of t he a b o ve S A E s 
occ ur. All S A Es, re g ar dl ess of t he pres u m e d relati o ns hi p t o st u d y dr u g, m ust als o be re p orte d t o 
Verte x Gl o bal Patie nt Safet y ( G P S) wit hi n 2 4  h o urs ( Secti o n  1 3. 1. 2 ). 
9. 9   
G e n er al 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  
E nr oll me nt a n d d osi n g will be pa use d if a n y of t he f oll o wi n g e ve nts occ ur a n d are c o nsi d ere d 
relate d or p ossi bl y rel ate d t o V X-5 4 8 b y t he i n vesti gat or or Verte x : 

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 3 3  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
•  ≥3 S A Es of Q Tc pr ol o n g ati o n  
•  1 S A E of T orsa des d e P oi ntes  
•  Deat h  
Verte x will n otif y re g ulat or y a ut h orities acc or di n g t o a p plica ble re g ul ati o ns. A re vie w of safet y 
data will be c o n d uct e d b y Verte x t o deter mi ne w het her t o: ( 1)  c o nti n ue t o p a use e nr oll me nt a n d 
d osi n g f or f urt her e val uati o n; ( 2)  res u me e nr oll me nt a n d d osi n g wit h o ut m o dificati o n t o st u d y 
c o n d uct; ( 3) res u me e nr oll me nt a n d d osi n g wit h m o dificati o n t o st u d y c o n d uct; or ( 4) ter mi nat e 
t he st u d y. 
9. 1 0   
R e m o v al of S u bj e ct s  
S u bjects ma y wit h dra 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 be 
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, be 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 treat 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 disc o nti n ue st u d y treat me nt earl y will be e nc o ura ge d t o c o m pl ete t he ta per a n d t o 
c o nti n ue t o ret ur n f or st u d y  efficac y ass ess me nts; a d diti o nal details are pr o vi de d i n Secti o n 9. 1. 4 .  
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 ret ur n f or 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 g ar 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 t he st u d y as l o n g as t h ose 
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 dr a w n d uri n g t h e st u d y dr u g treat me nt peri o d will n ot be 
re place d. 
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 der t he s u per visi o n of t he i n vesti gat or or a n a ut h ori ze 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 he 2 3 -m g V X‑ 5 4 8  ta blets, 1 0 0-m g pre ga b ali n ca ps ules, a n d matc hi n g 
place b os (ta bl ets a n d ca ps ules). 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 

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 3 4  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
a n d nati o n al re g ulati o ns. A d diti o nal details a b o ut pac ka gi n g, la b eli n g, a n d dis pe nsi n g f or 
V X‑ 5 4 8  will be i n t he P har mac y M a n ual.  
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 a ll 
i n vesti gati o nal pr o d uct 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. 
St u d y dr u g s u p pl y details are liste d i n Ta ble  1 0 -1 . Detaile d i nstr ucti o ns re g ar di n g t he st ora ge, 
ha n dli n g, a n d dis pe 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 ual.  
T a ble  1 0 -1  
St u d y Dr u g  
Dr u g N a m e  
D osi n g F or m/  
R o ute  
D os a ge  
H o w S u p plie d  
V X‑ 5 4 8  
Ta blet/ oral  
2 3, 4 6, or 6 9 m g q d   
S u p plie d as 2 3 -m g ta blets  
V X -5 4 8 place b o   
Ta blet/ oral  
0 m g q d  
S u p plie d as ta blets  
Pre ga bali n  
Ca ps ule/ oral  
1 0 0 m g ti d  
S u p plie d as 1 0 0 -m g ca ps ules  
Pre ga bali n place b o   
Ca ps ule/ oral  
0 m g ti d  
S u p plie d as ca ps ules  
q d: o nce dail y; ti d: 3 ti mes per da y  
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 a b o ut t he dates a n d 
a m o u nts of ( 1) st u d y dr u g recei v e d; ( 2) st u d y dr u g dis pe nse d t o t he s u bjects; a n d ( 3) 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 used 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 m aterials will be ret ai ne d at t he site acc or di n g t o 
i nstr ucti o ns pr o vi de d b y Verte x or its desi g nee. 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 dy. If a site uses a site -s p ecific dr u g acc o u nta bilit y 
s yste m a n d/ or pr ocess, i n cl u di n g pr ocesses ass ociate d wit h t he destr ucti o n of ret ur ne d m aterials, 
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 nt a bi lit y d oc u me ntati o n o n a re g ular basis. T he st u d y m o nit or will pr o m ptl y 
c o m m u nicate t o Vert e 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 a ll materials ret ur ne d b y t he s u bjects u ntil 
t he st u d y m o nit or 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 n str ucti o ns pr o vi de d b y Verte x. Destr u cti o n will be a de q uatel y 
d oc u me nte d.  
T he pri nci pal i n vesti gat or ( PI), st u d y site staff, i ncl u di n g p har mac y pers o n nel will assist Verte x 
wit h a n y recall acti vities (as a p plica bl e) a n d place i m pacte d i n vesti gati o nal me dic i nal pr o d uct 
(I M P) i n q uara nti ne w he n re q ueste 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 nee 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 

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 3 5  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
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 u bject 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 d uri n g h o me visits.  
If a s u bject d e m o nstrates c o nti nue d n o nc o m plia nce of st u d y dr u g d osi n g des 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.   
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 st u d y pers o n nel  will be bli n de d t o s u bject treat me nt assi g n me nts e xce pt f or t he f oll o wi n g 
i n di vi d uals:  
•  A n y site pers 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 a s u bject i n 
t he e ve nt of a life-t hreate ni n g me dical e mer ge nc y 
•  A n y site pers 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 a s u bject 
a n d a fet us i n t he e ve nt of a pre g n a nc y  
•  Verte x G P S a n d Re g ulat or y Affairs pers o n nel t o satisf y S A E pr ocessi n g a n d re p orti n g 
re g ulati o ns 
•  E xter nal ve n d or ( u n bli n de d) statisticia n pre p ari n g  t he fi nal ( 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 X R S Ma na ge me nt f or I X R S o versi g ht a n d s yste m a d mi nistrati o n  
•  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) la b orat or y/ ve n d or pers o n nel 
ma na ge d b y Verte x Bi oa nal ysis   
•  T he Vert e x bi oa nal ytical pers o n nel res p o nsi ble f or re vie wi n g ra w data fr o m t he bi oa nal ytical 
C R O, w h o is n ot a me m ber of t he S E T (t he Verte x bi oa nal ytical 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 safet y, 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 ha ve access t o P K, efficac y, a n d/ or safet y data 
(e. g., A Es, cli nical la b orat or y assess me nts) f or c o nti n u o us m o nit ori n g p ur p oses. T hese 
i n di vi d uals will n ot be me m bers of t he st u d y tea m a n d will n ot i nteract wit h t he st ud y pers o n nel. 
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 bli n de d Verte x p ers o n nel. 
Mas ke d i de ntificati o ns will be use d f or P K a nal ys es. All i nsta nces of u n bli n di n g b y Verte x 
pers o n nel will be d oc u m e nte d.  
1 0. 7. 2   
U n bli n di n g  
At t he i nitia ti 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. 

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 3 6  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
U n bli n di n g of t he i n di vi d ual s u bject’s treat me nt b y t he i n vesti gat or will be li mite d t o me dical 
e merge 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 atte m pti n g t o c o ntact t he me dic al 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 g at 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 i n a se parate 
d oc u me nt.  
If a s u bject’s treat me nt assi g n me nt has bee n u n bli n de d f or a m e dical e m er 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 ve nt. 
T he reas o n a n d t he dat e of t he 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 on a b o ut t he tr eat me nt assi g n me nt o btai ne 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 treati 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 defi 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 ne e, per Secti o n  1 3. 1. 2 . 
Verte x G P S or desi g ne e 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 ulat 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  a n d Ta ble  3 -2 .  
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 hics, me dical hist or y, hei g ht, 
a n d wei g ht . 

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 3 7  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
1 1. 2. 3   
Bi o a n al y si s  
Sa m ples will be a nal yze d usi n g a vali 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  
1 1 -p oi nt N P R S: Pai n i nte nsit y will be e val uate d usi n g t he 1 1 -p oi nt N P R S. Fr o m Da y -7 t hr o u g h 
Wee k 1 2, s u bjects will re p ort t heir a vera ge d ail y pai n d uri n g t he last 2 4  h o urs o n t he N P R S via 
e-diar y; d uri n g t he tr eat me nt peri o d, t he N P R S s h o ul d be c o m plete d i n t he m or ni n g bef ore t he 
first dail y d ose. S u bjects will als o re p ort t heir c urre nt pai n sc ore b ef ore eac h a d mi nistrati o n of 
resc ue m e dicati o n. T he N P R S sc ores fr o m t he dail y e-diar y will be use d i n t he pri mar y e n d p oi nt 
a nal ysis, a n d t he pr o p orti o n of s u bjects wit h ≥3 0 %, ≥5 0 %, a n d ≥7 0 % re d ucti o n fr o m ba seli ne i n 
wee kl y a vera g e sc ores as re p orte d i n t he d ail y e -di ar y will be use d i n t he sec o n dar y e n d p oi nt 
a nal yses.  
D SI S: T he D SI S will be c o m plete d eac h m or ni n g bef ore t h e first dail y d ose (a n d d uri n g t he r u n -
i n peri o d) i n a n e-di ar y t o descri be h o w pai n i n terfere d wit h t he s u bject’s slee p. 
P GI C:  T he P GI C will be c o m plete d at selecte d st u d y visits t o q ua ntif y t he c ha n ge i n s u bjects’ 
o verall stat us.  
Use of resc ue me dic ati o ns:  S u bjects will rec or d resc ue me dicati o n use, a n d t heir pai n o n t he 
N P R S i m me diatel y bef ore eac h a d mi nistrati o n of resc ue me dicati o n i n a n e -diar y.  

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 3 8  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
Access t o N P R S a n d D SI S Sc ores  
I n di vi d ual N P R S a n d D SI S sc ores will n ot be discl ose d t o t he st u d y sites. 
S u bjects s h o ul d n ot ha ve access t o t heir pre vi o us st u d y -relate d N P R S a n d D SI S sc ores u ntil 
Verte x has d eter mi ne d t h at t he st u d y has c o m plete d (i.e., cli nical st u d y re p ort [ C S R] 
fi nalizati o n), re g ar dless of w het her t h e s u bject per ma ne ntl y disc o nti n ues treat me nt. 
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; cli nical e val uati o n of vital 
si g ns, E C Gs, a n d p h ysical e xa mi nati o ns ( P Es), a nd C -S S R S.  
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 c urre nt I C H  E 6 G C P 
G ui deli nes. Secti 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.  
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 sa m ples will be a nal yze d at a ce ntral la b orat or y, u nl ess ot her wise s pecifie d. O n 
Da y  1, bl o o d sa m ple s will be c ollecte d bef ore t h e first d ose of t he st u d y dr u g. At all ot her 
sc he d ule d visits, t hese sa m ples will be c ollecte d at a n y ti me d uri n g t he visit. 
La b orat or y test res ults t hat are a b n or mal a n d c o nsi dere d cli nicall y si g nifica nt will be re p orte d as 
A E s (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 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 3 9  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
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  
Al kali ne p h os p hatase  
As partate tra nsa mi nase  
Ala ni ne tra nsa mi nase  
Li pase  
Ga m ma -gl uta m yl tra nsferase   
Pr otei n  
Al b u mi n  
Creati ne ki nase  
Urate  
He m o gl o bi n  
Platelets  
Le u k oc ytes  
Differe ntial ( perce nt):  
E osi n o p hils  
Bas o p hils  
Ne utr o p hils  
L y m p h oc ytes  
M o n oc ytes  
Ur o bili n o ge n  
Uri ne pr otei n  
p H  
Uri ne bl o o d  
S pecific gra vit y  
Uri ne ket o nes  
Uri ne bilir u bi n  
Uri ne gl uc ose  
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  
a  
If uri nal ysis res ults are p ositi ve f or pr otei n or bl o o d, micr osc o pic e xa mi nati o n of uri ne will be perf or me d a n d 
res ults pr o vi de d f or le u k oc ytes, er yt hr oc ytes, cr ystals, bacteria, 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.  
Cli nical la b orat or y assess me nts fr o m Scree ni n g Visit 1 m ust ha ve n o cli nicall y si g nifica nt 
fi n di n gs t hat precl u de partici pati o n i n t he st u d y, as j u d ge d b y t he i n vesti gat or, f or a s u bject t o 
pr ocee d t o Scree ni n g Visit 2 a n d t o recei ve st u d y dr u g o n Da y  1.  
A d diti o nal tests at scree ni n g : T he f oll o wi n g a d diti o nal tests will be perf or me d d uri n g scree ni n g 
(at Scree ni n g Visit 1) t o assess eli gi bilit y: 
•  Ser u m β -h u ma n c h ori o ni c g o na d otr o pi n ( β -h C G)  t est f or all bi ol o gicall y fe male s u bjects  
•  Ser u m f ollicle -sti m ulati n g h or m o ne ( F S H) f or fe male s u bjects w h o are s us pecte d t o be 
p ost me n o pa usal; f or a s u bject t o be c o nsi dere d of n o nc hil d beari n g p ote ntial, t he ser u m F S H 
le vels will be wit hi n t he la b orat or y’s ra n ge f or p ost me n o pa usal fe mal es 
•  Ser ol o g y will i ncl u de testi n g f or he patitis B s urface a nti ge n, he p atitis C vir us a nti b o d y, a n d 
a nti b o dies a gai nst HI V -1/ HI V -2. C o nfir mat or y HI V -1/ 2 A b differe ntiati o n a n d HI V -1 R N A 
Q ualitati ve T M A will be perf or me d f or p ositi ve a nti b o dies a gai nst HI V -1/ HI V -2. 
C o nfir mat or y He p C R N A P C R will be perf or me d f or p ositi ve he patitis C vir us a nti b o d y.  
•  H b A 1c  
•  T h yr oi d f u ncti o n test  
•  Vita mi n B 1 2  
•  Dr u g a n d alc o h ol testi n g  

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 4 0  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
Dr u g a n d alc o h ol testi n g:  O pi oi ds, met ha d o ne, ca n na bi n oi ds, c ocai ne, a m p heta mi nes/ 
met ha m p heta mi nes, bar bit urates, a n d be n z o diaze pi nes will be assesse d b y a uri ne test at 
Scree ni n g Visit  1 a n d o n Da y  1. Alc o h ol will be assesse d b y a uri ne t est at Scree ni n g Visit 1 a n d 
b y a uri ne, bl o o d, or breat h test o n Da y 1 a n d t hereafter. D uri n g treat me nt, dr u g a n d alc o h ol 
testi n g will be perf or me d per Ta ble  3 -2 . S u bjects ma y als o u n der g o ra nd o m uri ne dr u g scree ni n g 
a n d alc o h ol testi n g if dee me d a p pr o priat e b y t he i n vesti gat or.  
Dr u g a n d alc o h ol test res ults m ust be ne gati ve f or s u bjects t o recei v e st u d y dr u g. H o we v er, 
s u bjects w h o ha ve a p ositi ve scree n f or o pi oi ds (ac ute use o nl y) or marij uan a at Scree ni n g Visit 1 
ma y re peat t he test at Scree ni n g Visit 2; t he sec o n d test m ust be at least 7 da ys ( marij ua na) or at 
least 3 da ys ( o pi oi d) aft er t he first. A p ositi ve dr u g scree n f or a k n o w n pres cri be d c o n c o mita nt 
me dicati o n t hat is n ot ot her wise e x cl usi o nar y (e. g.,  be nz o diaze pi nes) will n ot dis q ualif y s u bjects.  
Pre g na nc y testi n g f or fe male s u bjects of c hil d beari n g p ote ntial (as defi ne d i n Secti o n 1 1. 5. 6. 1 ): 
All bi ol o gicall y fe male s u bjects will ha ve a ser u m pre g na nc y t est at Scree ni n g Visit 1. 
S u bse q ue nt pre g na n c y tests will be perf or me d o nl y f or fe mal e s u bjects of c hil d beari n g p ote ntial 
(as defi ne d i n Secti o n 1 1 . 5. 6. 1) as f oll o ws: 
•  A ser u m pre g n a nc y test will be perf or me d at t he Wee k 1 2 or E T T Visit.  
•  Uri ne pre g n a nc y tests will be perf or me d at all ot her visits t hat re q uire pre g na nc y testi n g . At 
Wee ks  3,  7, a n d 9, t he uri ne pre g na n c y test ma y b e d o ne eit her at h o me or at t he st u d y site.  
B ot h t he scree ni n g (ser u m) a n d Da y  1 ( uri ne) pre g na nc y ( β -h C G)  tests m ust be ne gati ve f or a 
s u bject t o recei ve st u d y dr u g. D uri n g treat me nt, if a uri ne pre g na nc y t est is p ositi ve, all st u d y 
dr u g d osi n g will st o p, a n d t he pre g na n c y will be c o nfir me d wit h a ser u m β -h C G test. If 
pre g na nc y is c o nfir me d, t he pr oce d ures o utli ne d i n Secti o n 1 1. 5. 6. 2  will be f oll o we d.  
A d diti o nal e val uati o ns:  A d diti o nal cli nical la b orat or y e val 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. 
O nl y la b orat or y tests d o n e i n t he ce ntr al la b orat or y ma y be use d f or t he safet y pa nels 
(Ta ble  1 1 -2 ), t he ser u m pre g na nc y t ests, a n d t he Scree ni n g Visit 1 uri ne dr u g a n d alc o h ol tests; 
l ocal la b orat ories a n d i n -cli nic ( or i n -h o me, w h ere i n dicate d) testi n g ma y b e use d f or dr u g a n d 
alc o h ol tests after Scree ni n g Visit 1 a n d f or all uri ne β -h C G pre g n a nc y tests. I n a d diti o n, l ocal 
la b orat ories ma y b e use d at t he discreti o n of t he l o cal i n vesti gat or f or m a na ge me nt of ur ge nt 
me dical iss ues. If a l o cal la b orat or y test val ue 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 be verifie d b y t he ce ntral la b orat or y as s o o n as p ossi ble after t he i n v esti gat or bec o mes 
a ware of t he a b n or mal r es ult. If it i s 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 was h os pitalize d else w here), t he i n vesti gat or ma y base 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 a n d Vit al Si g n s  
A P E of all b o d y s yste ms will be perf or me d at Scree ni n g Visit 2 a n d Da y 1. At ot her visits, 
s y m pt o m-directe d P Es ca n be perf or me d at t he dis creti o n of t he i n vesti gat or or healt hcare 
pr o vi der. Vital si g ns assess me nts will be perf or me d at Scree ni n g Visit 1 a n d at eac h cli nic or 
h o me healt h visit.  
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 gical. Breast, a n orectal, a n d g e nital e xa m i nati o ns will be perf or me d w he n me dicall y 

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 4 1  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
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 a P E will be re p orte d 
as A Es. If t here is a P E fi n di n g d uri n g a h o me visit, de pe n di n g o n its se verit y a n d at i n vesti gat or 
discreti o n, t he s u bject ma y be i nstr ucte d t o ha ve a P E or ot her e val uati o n 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 (seate d or s u pi ne) f or at least 5 m i n utes 
bef ore vital si g ns are 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 usi n g a mac hi n e wit h pri nt o ut. 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 n ce o f all E C Gs will a d here t o t he f oll o wi n g g ui deli 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 ( s u pi ne) f or at least 5 mi n utes bef ore h a 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.  
T he acce pta ble wi n d o w f or t he 2 - a n d 4 -h o ur p ost d ose E C Gs  o n  Da y 1 a n d Wee k 5 is 
±  3 0  mi n utes relati ve t o t he sc he d ule d n o mi nal ti me.  
A pri nt o ut of t h e 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 will ma ke c o m paris o ns t o 
baseli ne meas ure me nts. If t he me dia n Q Tc F is i ncrease d b y > 6 0  msec fr o m t he baseli ne or t he 
me dia n a bs ol ute Q Tc F v al ue is ≥5 0 0  msec f or a n y sc he d ule d or u ns c he d ul e d E C Gs ( perf or me d 
i n tri plicate), 2 a d diti o nal E C Gs ( perf or me d i n tri plicate) will be perf or me d a p pr o xi matel y 2  t o 
4  mi n utes a part t o c o nfir m t he ori gi nal meas ure m e nt. If t he me dia n Q Tc F val ue fr o m eit her of 
t hese re p eate d E C Gs re m ai ns a b o ve t he t hres h ol d val ue ( > 6 0  msec fr o m b aseli ne or ≥5 0 0  msec), 
t he s u bject s h o ul d disc o nti n ue d osi n g. F or safet y m o nit ori n g after disc o nti n uati o n, a si n gle E C G 
will be re peat e d at least h o url y u ntil Q Tc F val ues fr o m 2  s uccessi ve E C Gs fall bel o w t he 
t hres h ol d val ue t hat tri g g ere d t he re peat meas ure me nt.  
1 1. 5. 5   
C ol u m bi a S ui ci d e S e v erit y R ati n g S c al e  
T he C -S S R S will be perf or me d as o utli ne d i n Ta ble  3 -2 .  
1 1. 5. 6   
C o ntr a c e pti o n a n d Pr e g n a n c y  
1 1. 5. 6. 1   
C o ntr a c e pti o n  
St u d y partici pati o n re q uires c o m plia nce wit h t he c o ntrace pti o n g ui deli nes o utli ne d bel o w.  
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. T he s u bject m ust c o nfir m t hat t he y will practice tr ue 
a bsti ne nce fr o m Scree ni n g Visit 1 t hr o u g h 3 0  da ys after t he l ast d ose of st u d y dr u g. Tr ue 
a bsti ne nce is i m p orta nt t o differe ntiat e fr o m peri o dic a bsti ne nce (e. g.,  cale n dar, o v ulati o n, 

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 4 2  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati 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, w hic h are n ot acce pta ble met h o ds of 
c o ntrace pti o n.  
•  If t he male is i nfertile (e. g., bilateral orc hiect o m y). I nfertilit y ma y be d oc u me nte d t hr o u g h 
e xa mi nati o n of a se m e n s peci me n.  
•  If t he fem ale is of n o n -c hil d beari n g p ote ntial. T o be c o nsi dere d of n o n -c hil d beari n g p ote ntial, 
t he fe male m ust meet at l east 1 of t he f oll o wi n g criteria: 
o  P ost me n o pa usal: A me n orr heic f or at least 1 2 c o ns ec uti ve m o nt hs a n d a ser u m F S H 
le vel wit hi n t he la b orat or y's refere nce ra n ge f or p ost me n o pa usal fe males  
o  D oc u me nte d bilateral o o p h orect o m y a n d/ or h ysterect o m y  
•  Sa me bi ol o gical se x relati o ns hi ps.  
F or s u bjects f o r w h o m t he c o ntr ace pti o n re q uire me nt is n ot w ai ve d , st u d y partici pati o n 
re q uires a c o m mit me nt fr o m t he s u bject t hat at least 1 acce pta bl e met h o d  of c o ntrace pti o n, as 
o utli ne d i n Ta ble  1 1 -3 , is use d as a c o u pl e fr o m Scree ni n g Visit 1 t hr o u g h 3 0 da ys after t he last  
d ose of st u d y dr u g.  
T a ble  1 1 -3  
Acce pt a ble Met h o ds of C o ntr ace pti o n  
S u bjects a n d t heir 
n o n -st u d y p art ners a  
At least 1 of t he f oll o wi n g acce pta ble met h o ds m ust be use d as a c o u ple fr o m Scree ni n g 
Visit 1 t hr o u g h 3 0 da ys after t he last 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 b 
•   Fe male bilateral t u bal li gati o n perf or me d at least 6 m o nt hs pre 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 st u d y dr u g treat me nt, a n d u ntil 3 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 least 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 30  da ys after 
t he last d ose of st u d y dr u g. 
•   Male or fe male c o n d o m ( wit h or wit h o ut s per mici de)
c 
•   Fe male barrier c o ntrace pti o n (s uc h as dia p hra g m, cer vical ca p, or s p o n ge) wit h 
s per mici de 
a 
A p plica ble t o s u bjects a n d t heir n o n -st u d y part ners of t he o p p osite bi ol o gical se x f or w h o m t he c o ntrace pti o n 
re q uire me nt is n ot wai ve d. 
b  
Me dical rec or d d oc u me ntati o n of c o ntrace pti o n f or n o n -st u d y part ners is n ot re q uire d. T he s u bject m ust 
c o nfir m t hat t heir part ner has d oc u me nte d pr o of, a n d t he s u bject’s c o nfir mati o n s h o ul d be d oc u me nte d.  
c  
Fe male c o n d o m ca n n ot be use d wit h male c o n d o m d ue t o ris k of teari n g.  
A d diti o n al n otes:  
•  If o ver t he c o urse of t he st u d y t he s u bject meets t he criteria f or wai vi n g t he c o ntrace pti o n 
re q uire me nts, t he s u bject d oes n ot nee d t o f oll o w t he c o ntrace pti ve met h o ds liste d i n 
Ta ble  1 1 -3 . 
•  Male s u bjects m ust n ot d o nate s per m fr o m t he first st u d y dr u g d ose, 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.  
•  Male a n d fe male s u bjects w h o are n ot se x u all y acti ve at t he ti me of scre e 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 bec o me se x uall y acti ve. 

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 4 3  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
•  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 fall wit hi n t he a b o ve s pecificati o ns ma y be disc usse d wit h t he 
Verte x me dical m o nit or or desi g nee o n a n i n di vi d ual basis.  
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 ta bl et st u d y dr u g.  
If a s u bject, or t he fe m ale 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, t he st u d y dr u g will be per ma n e ntl y disc o nti n ue d i m me diatel y. T he i n vesti gat or will 
(1)  n otif y t he me di cal 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 na nc y, a n d (2) se n d t he Pre g na nc y I nf or mati o n C ollecti o n F or m t o 
Verte x G P S.  
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 acti ve dr u g. T he i nfa nt will be f oll o we d f or 1  y ear 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 de d t o e x plai n t hese f oll o w -u p acti vities. 
Pre g na nc y itself is n ot a n A E.  
1 2   
S T A TI S TI C A L A N A L Y SI S  
T his secti o n prese nts a s u m mar y of t he pri nci pal feat ures of t he pla n ne d statistical a nal yses. 
Statistical a nal ysis details will be pr o vi de d i n t he statist ical a nal ysis pla n ( S A P), a n d cli nical 
p har mac ol o gic a nal ysis details will be pr o vi de d i n t he cli nical p har mac ol o g y a nal ysis pla n 
( C P A P), b ot h of w hic h will be fi nalize d bef ore cli nical data bas e l oc k. 
1 2. 1   
S a m pl e Si z e a n d P o w er  
T he pri mar y efficac y e n d p oi nt is t he c ha n ge fr o m baseli ne i n t he wee kl y a vera ge of t he dail y 
pai n i nte nsit y o n a n N P R S at Wee k 1 2. T he pri mar y a nal ysis will be a wit hi n -gr o u p c o m paris o n 
(i.e., c ha n g e fr o m bas eli ne) i n a n y V X-5 4 8 d ose gr o u p.  
T he sa m ple size is bas e d o n t he pri mar y a n al ysis  of t he pri mar y e n d p oi nt. Wit h 3 7  e val ua ble 
s u bjects i n t he V X-5 4 8 hi g h or mi d d ose gr o u p a n d 1 8 e val ua ble s u bjects i n t he V X -5 4 8 l o w 
d ose gr o u p, t here is m ore t ha n 9 0 %  p o wer i n a n y V X -5 4 8 d ose gr o u p t o d etect a mea n c ha n ge 
fr o m baseli ne of 3 wit h a si n gle  gr o u p t-test at t he 2-si de d 0. 0 5 si g nifica nce le vel, ass u mi n g t he 
S D is 2. 3. Wit h a n e val ua ble sa m ple size of 3 7, a 2 -si de d 9 5 % CI f or t h e mea n c h a n ge fr o m 
baseli ne i n t he hi g h or mi d d ose gr o u p will e xte n d 0. 7 7 o n eit her si de of t he o bser ve d mea n, 
ass u mi n g t he CI is base d o n t he t-statistic a n d t he o bser ve d S D is 2. 3. U n der t he sa me 
ass u m pti o ns a n d a n e val ua ble sa m ple size of 1 8, a 2 -si de d 9 5 % CI f or t he mea n c ha n g e fr o m 
baseli ne i n t he l o w d ose gr o u p will e xte n d 1. 1 4 o n eit her si de of t he o bs er ve d mea n. T o acc o u nt 
f or a 2 5 % dr o p o ut rate, 5 0 s u bjects eac h will be e nr olle d i n t he V X-5 4 8 hi g h d ose, V X -5 4 8 mi d 
d ose, a n d t he pre ga bali n gr o u ps; 2 5  s u bjects will be e nr olle d i n t he V X-5 4 8 l o w d ose gr o u p. T he 
t otal sa m ple size is a p pr o xi matel y 1 7 5 s u bjects. 
T he st u d y is n ot p o were d f or c o m paris o n b et wee n t he V X -5 4 8 d oses a n d t he pre ga b ali n 
refere nce ar m. 

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 4 4  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
1 2. 2   
A n al y si s S et s  
T he All S u bjects Set is defi ne d as all s u bjects w h o ha ve bee n ra n d o mize d or ha ve 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 i n s u bject listi n gs, u nless ot her wise 
s pecifie d, a n d t h e dis p ositi o n s u m mar y ta ble. 
T he F ull A nal ysis Set ( F A S) is defi ne d as all ra n d o mize d s u bjects w h o ha v e recei ve d at least 
1  d ose of st u d y dr u g. T he F A S is t o be use d t o s u m marize s u bject d e m o gra p hics a n d bas eli ne 
c haracteristics, a n d f or all efficac y a n al yses, u nless ot her wise s pecifie d. S u bjects will be 
a nal yze 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 Safet y Set is defi ne d as all s u bjects w h o ha ve recei v e d at least 1 d ose of st u d y dr u g. T he 
Safet y Set is t o be use d f or all safet y a nal yses i n w hic h s u bjects will be a n al yze d acc or di n g t o t he 
treat me nt t he y recei ve d, u nless ot her wise s pecifie d. 
1 2. 3   
St ati sti c al A n al y si s  
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 p rese 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 descri 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 ues  f or t he N P R S dail y pai n i nte nsit y sc ores a n d D SI S will b e defi ne d as t he 
a vera g e sc ore fr o m D a y -7 t o Da y -1. F or E C Gs, t he baseli ne val u e will be defi ne d as t he 
a vera g e of t he n o n -missi n g pretre at me nt meas ure me nts (tri plicate) o n Da y 1. F or all ot her 
varia bles, bas eli ne val ues will be defi ne d as t he m ost rece nt n o n -missi n g meas ure m e nt c ollecte d 
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.  
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) t he Safet y F oll o w -u p Visit, ( 2) t he E T T Visit if it re places t he 
Safet y F oll o w -u p Visit, or ( 3 ) 1 4 da ys after t he 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 or e q ui vale nt. T he T E Peri o d will be use d f or safet y a nal yses u nless 
s pecifie d ot her wise.  
1 2. 3. 2   
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, de m o gra p hic a n d b aseli ne c h a ract eristics, pri or a n d c o nc o mita nt 
me dicati o ns, e x p os ure, c o m plia nce, a n d i m p orta nt pr ot oc ol de viati o ns will be s u m marize d.  
1 2. 3. 3   
Effi c a c y A n al y si s  
All efficac y e n d p oi nts will be a nal yze d b ase d o n t he F A S. O nl y t he pri nci pal feat ures of t he 
efficac y a n al ysis wi ll be prese nte d i n t his secti o n. Details of all a nal yses will be pr o vi de d i n t he 
S A P.  

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1 2. 3. 3. 1   
A n al y si s of Pri m ar y E n d p oi nt  
T he pri mar y efficac y e n d p oi nt is t he c ha n ge fr o m baseli ne i n t he wee kl y a vera ge of t he dail y 
pai n i nte nsit y o n a n N P R S at Wee k 1 2. T he pri mar y a nal ysis will be a wit hi n -gr o u p c o m paris o n 
i n a n y V X-5 4 8 d ose gr o u p.  
T he pri mar y efficac y a n al ysis will be base d o n a mi xe d -effects m o del f or re peat e d meas ures 
( M M R M), wit h c ha n ge fr o m baseli ne i n wee kl y a vera ge of dail y pai n i nte nsit y sc ore as t he 
de pe n de nt varia ble; a n d fi xe d effects of treat me nt gr o u p, ti me (cate g orical), treat me nt 
gr o u p -b y -ti me i nteracti o n, baseli ne wee kl y a vera ge of dail y pai n i nte nsit y, baseli ne wee kl y 
a vera g e of dail y pai n i nte nsit y -b y -ti me i nteracti o n. T he least s q uares ( L S) mea n c ha n g e fr o m 
baseli ne at Wee k 1 2 f or eac h gr o u p will be prese nt e d wit h t he c orres p o n di n g S E a n d t he 
c orres p o n di n g 9 5 % CI a n d P  val ue.  
1 2. 3. 3. 2   
A n al y si s of S e c o n d ar y Effi c a c y E n d p oi nt s  
T he pr o p orti o n of s u bjects wit h ≥3 0 % re d ucti o n fr o m baseli ne i n t he wee kl y a vera g e  of dail y 
pai n i nte nsit y o n t he N P R S at Wee k 1 2 will be s u m marize d des cri pti vel y b y treat me nt gr o u p a n d 
a nal yze d usi n g t he C oc hra n -Ma ntel -Hae ns zel test (stratifie d b y se x a n d B MI). T he pr o p orti o n of 
s u bjects wit h ≥5 0 % a n d ≥7 0 % re d ucti o n fr o m b as eli ne will be a nal yze d si milarl y.  
T he pr o p orti o n of s u bjects cate g orize d as m uc h i m pr o ve d or ver y m uc h i m pr o ve d at Wee k 1 2 o n 
t he P GI C ass ess me nt will be s u m marize d des cri pti vel y b y treat me nt gr o u p a n d a nal yze d usi n g 
t he C oc hra n-M a ntel -Hae nszel test (stratifie d b y se x a n d B MI).  
T he c ha n g e fr o m bas eli ne i n t he wee kl y a vera ge of t he D SI S at Wee k  1 2 will be a nal yze d 
si milarl y t o t he pri mar y e n d p oi nt.  
1 2. 3. 3. 3   
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 his P hase 2 st u d y.  
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 -5 4 8 will be ass esse d i n ter ms of t he f oll o wi n g safet y a n d 
t olera bilit y e n d p oi nts: 
•  I n ci de nce of treat me nt-e mer ge nt A Es  
•  Cli nical la b orat or y val ues  
•  Sta n dar d 1 2 -lea d E C G o utc o mes 
•  Vital si g ns  
•  C -S S R S  

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Safet y e n d p oi nts will be a nal yze d b ase d o n t he Safet y Set. N o statistical testi n g will be 
c o n d ucte d. All safet y dat a will be prese nt e d i n i n di vi d ual s u bject data listi n gs. A d diti o nal details 
will be pr o vi de d i n t he S A P.  
1 2. 4   
I nt eri m A n al y si s 
N ot a p plica ble.  
1 2. 5   
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.  
1 2. 6   
Cli ni c al P h ar m a c ol o g y A n al y si s  
1 2. 6. 2  
/ P h ar m a c o d y n a mi c A n al y si s 
A p o p ulati o n  
 a nal ysis of plas ma c o nce ntrati o n vers us ti me data of V X -5 4 8 a n d M 6 -5 4 8 ma y 
be perf or me d usi n g t he n o nli near mi xe d -effects m o deli n g a p pr oac h. A p o p ulati o n a p pr oac h ma y 
als o be use d t o i n vesti gate t he e x p os ure -res p o nse relati o ns hi p f or t he efficac y a n d safet y 
varia bles. A m or e detaile d descri pti o n of t he met h o d ol o g y t o be f oll o we d will be prese nte d i n t he 
m o deli n g a n d si m ulati o n a nal ysis pla n ( M S A P). T he res ults of t he p o p ulati o n  
 a n d 
/ p har mac o d y na mic ( P D) a nal ysis (if d o n e) will be re p orte d i n a se parate d oc u me nt. 
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 MI NI S T 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 ve nt 
d oes n ot necess aril y ha 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 he 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 asse ss me nts i ncl u di n g la b orat or y tests, E C Gs, P Es, a n d vital si g ns will be assesse d a n d 
t h ose dee me d t o ha 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 d e d, rat her t ha n t he 
a b n or mal test res ult al o n e (e. g.,  uri n ar y tract i nfecti o n, a ne mia). I n t he a bse nce of a di a g n osis, 

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C o nfi de ntial I nf or mati o n  
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 decreas e d 
he m o gl o bi n).  
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 assess 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 disc o nti n uati o n fr o m t he st u d y  
Re peat testi n g t o deter 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 results are cli nicall y si g nifica nt will be ma de b y t he i n vesti 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 val 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 me 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: t hr o u g h t he Safet y F oll o w -u p Visit  
•  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, t he earliest of  
o  1 4  da ys after t h e last d ose of ta blet st u d y dr u g, or  
o  t he E T T Visit, if t hat visit is 1 4 da ys or later f oll o wi n g t he last d ose of ta bl et st u d y 
dr u g (see Secti o n  9. 1. 4 ). 
All s u bjects will be q uerie d, usi n g n o nlea di n g q uesti o ns, a b o ut 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 data 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 res ol uti o n (if a p plica ble)  
•  Se veri t 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 ve n  

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1 3. 1. 1. 4   
A d v er s e E v e nt S e v erit y  
 T he i n vesti gat or will deter mi ne a n d rec or d t he se verit y of all seri o us a n d n o nseri o us A Es. T he 
g ui da nce a v aila ble at t h e 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/ p r ot oc ol De vel o p me nt/electr o nic _a p plicati o ns/ctc. ht m ( Access e d Ma y 
2 0 2 2). T he se v erit 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 defi 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  
Descri pti o n  
Gr a de  1 ( Mil d)  
Mil d; as y m pt o matic or mil d s y m pt o ms; cli nical or dia g n ostic o bser vati o ns o nl y; 
i nter ve nti o n n ot i n dicate d 
Gr a de  2 ( M o der ate)   
M o derate; mi ni mal, l ocal, or n o ni n vasi ve i nter ve nti o n i n dicate d; li miti n g a ge -
a p pr o priate i nstr u me ntal A D L a 
Gr a de  3 ( Se vere)  
Se vere or me dicall y si g nifica nt b ut n ot i m me diatel y life-t hreate ni n g; 
h os pitalizati o n or pr ol o n gati o n of h os pitalizati o n i n dicate d; disa bli n g; li miti n g 
self-care A D L b 
Gr a de  4 ( Life -
t hre ate ni n g) 
Life -t hreate ni n g c o nse q ue nces; ur ge nt i nter ve nti o n i n dicate d  
Gr a de  5 ( De at h)  
Deat h relate d t o a d verse e ve nt 
S o urce: 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  ( Accesse d Ma y 2 0 2 2) 
A D L: acti vities of dail y li vi n g; A E: a d verse e ve nt  
N ote: A se mi -c ol o n i n dicates ‘ or’ wit hi n t he descri pti o n of t he gra de.  
a  
I nstr u me ntal A D L refer t o pre pari n g meals, s h o p pi n g f or gr oceries or cl ot hes, usi n g t he tele p h o ne, ma na gi n g 
m o ne y, etc.  
b  
Self -care A D L refer t o bat hi n g, dressi n g a n d u n dressi n g, fee di n g self, usi n g t he t oilet, ta ki n g me dicati o ns, 
a n d n ot be dri d de n.  
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 he 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 he 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 bject’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 et i ol o g y will be d oc u me nte d i n t he s u bject’s me dical rec or d). 
A E: a d verse e ve nt  

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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 a 
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 u se 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.  
A E: a d verse e ve nt  
a  
Refer t o Secti o n 9. 7  f or directi o ns re gar di n g w hat dr u g acti o ns are per mitte d per pr ot oc ol.  
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 resi 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 bject l ost t o f oll o w u p)  
A E:  a d verse e ve nt 
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 h e A E. “ Yes ” is use 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 de 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 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
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Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
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 o cc urs d uri n g partici pati 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 dela 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)  
•  Life -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 ur re 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 je 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 o me)  
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 os pitalizati 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 “s eri o us” a n d “se v ere” beca 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 hi c h is base 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 n cti o ni n g. Seri o us ness, n ot 
se verit y, ser v es as a g ui d e f or defi ni n g e x pe dite d re g ulat 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 
Safet y F oll o w -u p Visit, r e gar dless of ca usalit y, will be re p orte d b y t he i n v esti gat or t o Verte x 
G P S wit hi n 2 4 h o urs o f i de ntific ati o n. I n a d diti o n, all S A Es t hat occ ur after t he 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 .  
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 plica ble) t hr o u g h  t he 
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 

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 5 1  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
f oll o w-u p i nf or mati o n as s o o n as it bec o mes a vail 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: gl o bal patie ntsafet y @ vrt x.c o m  ( preferre d c h oice) 
Fa x: + 1 -6 1 7 -3 4 1 -6 1 5 9  
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: + 1 -6 1 7 -3 4 1 -6 6 7 7  
S A Es t hat occ ur after t he Safet y F oll o w-u p Visit a n d are c o nsi d ere d relate 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 ( hereafter 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 urat el 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 relat i 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 he S A E F or m, relati 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 n cl u des p ossi bl y relate d) or n ot relate d (i ncl u des u nli kel y relate d), a n d se verit y 
assess me nt will n ot b e 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 peri 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 safet 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 ve 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 p ecte 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 C, a n d 
partici pati n g i n vesti gat ors i n acc or da nce wit h c urre nt I C H E 2 A G ui deli nes a n d/ or l ocal 
re g ulat 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 d esi g nee, will be 
res p o nsi ble f or t he s u b missi o n of safety letters 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 s eri 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, stre 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.  
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  E 6 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 n v esti gat or’s 
Br oc h ure, 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 dates, a n n ual pr o gress re p orts, a n d a n y re visi o ns t o t hese 

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 5 2  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
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 ocal 
a p plica ble la ws a n d re g ul ati 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 bef ore st u d y parti ci pati o n a n d bef ore perf or mi n g a n y st u d y-relate d pr oce d ures. Re m ote 
c o nse nt ma y be use d. Re m ote c o nse nt w o ul d i ncl u de a p h o ne call or tele m e dici ne visit bet wee n 
t he site a n d s u bject f or t h e c o nse nt disc ussi o n. T he met h o d of o btai ni n g a n d d oc u me nti n g t he 
i nf or me d c o nse nt a n d t h e c o nte nts of t he c o nse nt will c o m pl y wit h c urre nt I C H  E 6 G C P 
G ui deli nes 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. 
1 3. 2. 4   
I n ve 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 wit 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 g es t hat si g nifica ntl y affect t he safet y of t he s u bjects, 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.,  efficac y 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 xce 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 reg ulat or y a ut h orities.  
W he n cir c 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 oc 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 bl e 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 pl y 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.  
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 ntia lit 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 re g 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 wi ll 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 acce ss 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 or 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 xec ut e d HI P A A a ut h orizati o n wi ll 
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 

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 5 3  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
researc h acti vities ma y be gi n. Eac 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 or 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 c urre nt I C H  E 6 G C P G ui deli nes 
a n d/ or a p plica ble l o cal re g ulat or y re q uire m e 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 d y 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 hi s 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 ble 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 bject 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 nacce 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 ter mi nati o n is re q uire 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 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 oc u me ntati o n per 
c urre nt I C H E 6 G C P G ui deli nes.  
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 sec 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 da ta i n t he E D C a p plicati o n.  

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 5 4  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati 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 o m pl y wit h G C P G ui deli nes. O n -site or re m ote 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 pers o nal or 
re m ote visits fr o m a re prese ntati ve of Verte x or desi g nee (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 oc u m e 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 acc ess t o a n d trai ni n g o n t he 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 o r’s res p o nsi bilit y t o 
e ns ure t he acc urac y, c o m plete 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 data will i n dicate t he s u bject’s partici 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 o ns, 
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.  
Verte x will ret ai 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 h e 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 uc 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 pt 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 on. T he i n vesti gat or s hall n ot use s uc h i nf or 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 h at 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, 

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 5 5  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
a n d t heref ore ma y be 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 ver 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 vesti 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 a ll 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  
1 3. 7. 2   
Cli ni c al St u d y R e p ort  
A cli nical st u d y re p ort writte n i n acc or da nce wit h t he c urre nt I C H E 3 G ui d eli ne, will be 
s u b mitte d i n acc or da n ce wit h l ocal re g ulati o ns. 

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 5 6  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
1 4   
R E F E R E N C E S  
1   
Je nse n T S, Bar o n R, Haa n pää M, Kals o E, L o eser J D, Rice A S C, et al. A ne w defi niti o n 
of ne ur o pat hic p ai n. Pai n. 2 0 1 1; 1 5 2( 1 0): 2 2 0 4 -0 5.  
2   
I q b al Z, Az mi S, Ya da v R, Fer d o usi M, K u mar M, C ut h berts o n DJ, et al. Dia betic 
peri p heral ne ur o pat h y: e pi de mi ol o g y, dia g n osis, a n d p har mac o t hera p y. Cli n T her. 
2 0 1 8; 4 0( 6): 8 2 8 -4 9.  
3   
K h d o ur M R. Treat me nt of dia betic peri p heral n e ur o pat h y: a re vie w. J P har m P har mac ol. 
2 0 2 0; 7 2( 7): 8 6 3 -7 2.  
4   
Ca valli E, Ma m ma na S, Nic oletti F, Bra ma nti P, Mazz o n E. T he ne ur o pat hic pai n: a n 
o ver vie w of t h e c urre nt tre at me nt a n d f ut ure t hera pe utic a p pr oac hes. I nt J I m m u n o pat h ol 
P har mac ol. 2 0 1 9; 3 3: 2 0 5 8 7 3 8 4 1 9 8 3 8 3 8 3.  
5   
Gilr o n I, B ar o n R, Je nse n T. Ne ur o pat hic p ai n: pri nci ples of dia g n osis a n d treat me nt. 
Ma y o Cli n Pr oc. 2 0 1 5; 9 0( 4): 5 3 2 -4 5.  
6   
E n gla n d S. V olta ge -gate d s o di u m c ha n nels: t he searc h f or s u bt y pe -s electi ve a nal gesics. 
E x pert O pi n I n vesti g Dr u gs. 2 0 0 8; 1 7( 1 2): 1 8 4 9 -6 4.  
7   
Krafte D, Ba n n o n A. S o di u m c ha n nels a n d n ocice pti o n: rece nt c o nce pts a n d t hera pe utic 
o p p ort u nities. C urr O pi n P har mac ol. 2 0 0 8; 8( 1): 5 0 -6.  
8   
A k o pia n A N, Si vil otti L, W o o d J N. A tetr o d ot o xi n -resista nt v olta ge-g ate d s o di u m 
c ha n nel e x presse d b y s e ns or y ne ur o ns. Nat ure. 1 9 9 6; 3 7 9( 6 5 6 2): 2 5 7 -6 2.  
9   
S hiel ds S D, A h n H S, Ya n g Y, Ha n C, Seal R P, W o o d J N, et al. Na v 1. 8 e x pressi o n is n ot 
restricte d t o n ocice pt ors i n m o use peri p heral ner v o us s yste m. Pai n. 2 0 1 2; 1 5 3( 1 0): 2 0 1 7 -
3 0.  
1 0   
A ma ya F, Dec ost er d I, S a ma d T A, Pl u m pt o n C, Tate S, Ma n ni o n RJ, et al. Di versit y of 
e x pressi o n of t he s e ns or y ne ur o n -s pecific T T X-resista nt v olta ge-gate d s o di u m i o n 
c ha n nels S N S  a n d S N S 2. M ol Cell Ne ur osci. 2 0 0 0; 1 5( 4): 3 3 1 -4 2.  
1 1   
Blair N T, Bea n B P. R oles of tetr o d ot o xi n ( T T X) -s e nsiti ve Na + c urre nt, T T X-resista nt 
Na + c urre nt, a n d Ca 2 + c urre nt i n t he acti o n p ote ntials of n ocice pti ve se ns or y ne ur o ns. J 
Ne ur osci. 2 0 0 2; 2 2( 2 3): 1 0 2 7 7 -9 0.  
1 2   
B uc k nill A T, C o war d K, Pl u m pt o n C, Tate S, B o u ntra C, Birc h R, et al. Ner ve fi bers i n 
l u m bar s pi ne str uct ures a n d i nj ure d s pi nal r o ots e x press t he se ns or y ne ur o n-s pecific 
s o di u m c ha n nels S N S/ P N 3 a n d Na N/ S N S 2. S pi ne ( P hila Pa 1 9 7 6). 2 0 0 2; 2 7( 2): 1 3 5 -4 0.  
1 3   
Fa ber C G, La uri a G, Mer kies I SJ, C he n g X, Ha n C, A h n H S, et al. Gai n -of -f u ncti o n 
Na v 1. 8 m utati o ns i n pai nf ul ne ur o pat h y. Pr oc Natl Aca d Sci U S A. 2 0 1 2; 1 0 9( 4 7): 1 9 4 4 4 -
4 9.  
1 4   
Ha n C, Vas yl ye v D, M acala LJ, Gerrits M M, H oeij ma kers J G, Be kelaar KJ, et al. T he  
G 1 6 6 2 S Na V 1. 8 m utati o n i n s mall fi bre ne ur o pat h y: i m paire d i nacti vati o n u n derl yi n g 
D R G ne ur o n h y pere xcita bilit y. J Ne ur ol Ne ur os ur g Ps yc hiatr y. 2 0 1 4; 8 5( 5): 4 9 9 -5 0 5.  
1 5   
A bra ha mse n B, Z h a o J, Asa nte C O, Ce n da n C M, Mars h S, Marti nez -B ar bera J P, et al. 
T he cel l a n d m olec ular b asis of mec ha nical, c ol d, a n d i nfla m mat or y pai n. S cie nce. 
2 0 0 8; 3 2 1( 5 8 8 9): 7 0 2 -5.  
1 6   
R oza C, Lair d J M, S o usl o va V, W o o d J N, Cer ver o F. T he tetr o d ot o xi n -resista nt Na + 
c ha n nel N a v 1. 8 is esse ntial f or t he e x pressi o n of s p o nta ne o us acti vit y i n d a ma ge d 
se ns or y a x o ns of mice. J P h ysi ol. 2 0 0 3; 5 5 0( Pt 3): 9 2 1-6.  
1 7   
Stric kla n d I T, M arti n dale J C, W o o d ha ms P L, Ree ve AJ, C hessell I P, Mc Q uee n D S. 
C ha n ges i n t he e x pressi o n of Na V 1. 7, Na V 1. 8 a n d Na V 1. 9 i n a disti nct p o p ulati o n of 

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 5 7  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
d orsal r o ot ga n glia i n ner vati n g t he rat k nee j oi nt i n a m o del of c hr o nic i nfla m mat or y j oi nt 
pai n. E ur J Pai n. 2 0 0 8; 1 2( 5): 5 6 4 -7 2.  
1 8   
Qi u F, Jia n g Y, Z ha n g H, Li u Y, Mi W. I ncrease d e x pressi o n of tetr o d ot o xi n -resista nt 
s o di u m c ha n nels Na v 1. 8 a n d Na v 1. 9 wit hi n d orsal r o ot ga n glia i n a rat m o d el of b o ne 
ca ncer pai n. N e ur osci L ett. 2 0 1 2; 5 1 2( 2): 6 1 -6.  
1 9   
Jar vis M F, H o n ore P, S hie h C C, C ha p ma n M, J os hi S, Z ha n g X F, et al. A-8 0 3 4 6 7, a 
p ote nt a n d selecti ve Na v 1. 8 s o di u m c ha n nel bl oc ker, atte n uat es ne ur o pat hic a n d 
i nfla m mat or y pai n i n t he rat. Proc Natl Aca d Sci U S A. 2 0 0 7; 1 0 4( 2 0): 8 5 2 0 -5.  
2 0   
R us h A M, C u m mi ns T R. Pai nf ul researc h: i de ntificati o n of a s mall -m olec ul e i n hi bit or 
t hat selecti vel y tar gets N a v 1. 8 s o di u m c ha n nels. M olec ular I nter ve nti o ns. 2 0 0 7; 7( 4): 1 9 2-
5.  
2 1   
Pa y ne C E, Br o w n A R, T heile J W,  L o ucif AJ, Ale xa n dr o u AJ, F uller M D, et al. A n o vel 
selecti ve a n d orall y bi oa vaila ble Na v 1. 8 c ha n nel bl oc ker, P F-0 1 2 4 7 3 2 4, atte n uates 
n ocice pti o n a n d se ns or y ne ur o n e xcita bilit y. Br J P har mac ol. 2 0 1 5; 1 7 2( 1 0): 2 6 5 4 -7 0.  
2 2   
Verte x P har m ace uticals I nc or p orat e d. V X -5 4 8 I n vesti gat or's Br oc h ure.  
2 3   
U nite d States De part me nt of Healt h a n d H u ma n S er vices. F o o d a n d Dr u g A d mi nistrati o n. 
Ce nter f or Dr u g E val uati o n a n d Researc h ( C D E R). Ce nter f or Bi ol o gics E val uati o n 
Researc h ( C B E R). G ui da nce f or i n d ustr y: p har mac o ki ne tics i n patie nts wit h i m paire d 
he patic f u ncti o n: st u d y d esi g n, data a nal ysis, a n d i m pact o n d osi n g a n d la beli n g. 
R oc k ville, M D: Ma y 2 0 0 3.  
2 4   
U. S. De part me nt of Healt h & H u ma n Ser vices, Nati o nal I nstit utes of Healt h, Nati o nal 
E ye I nstit ute. Dia betic reti n o p at h y: w hat y o u s h o ul d k n o w. Bet hes da, M D: 2 0 1 5.  
2 5   
U nite d States De part me nt of Healt h a n d H u ma n S er vices. F o o d a n d Dr u g A d mi nistrati o n. 
Ce nter f or Dr u g E val uati o n a n d Researc h ( C D E R). Draft g ui da nce f or i n d ustr y: a nal gesic 
i n dicati o ns: de vel o pi n g dr u g a n d bi ol o gical pr o d ucts. R oc k ville, M D: Fe br uar y 2 0 1 4.  
2 6   
D w or ki n R H, T ur k D C, W yr wic h K W, Beat o n D, Cleela n d C S, Farrar J T, et al. 
I nter preti n g t he cli nical i m p orta nce of treat me nt o utc o mes i n c hr o nic pai n cli nical trials: 
I M M P A C T rec o m me n dati o ns. J Pai n. 2 0 08; 9( 2): 1 0 5 -2 1.  
2 7   
Attal N. Assess me nt of n e ur o pat hic pai n i n t he setti n g of i nter ve nti o n trials. Cli nical 
I n v esti gati o n. 2 0 1 1; 1( 4): 5 0 1-0 7.  
2 8   
B o u hassira D, Attal N, Fer ma nia n J, Alc haar H, Ga utr o n M, Mas q uelier E, et al. 
De vel o p me nt a n d vali dati o n of t he n e ur o pat hic p ai n s y m pt o m i n ve nt or y. Pai n. 
2 0 0 4; 1 0 8( 3): 2 4 8 -5 7.  
2 9   
Attal N, B o u hassira D, B ar o n R. Dia g n osis a n d assess me nt of ne ur o pat hic pai n t hr o u g h 
q uesti o n naires. La n cet N e ur ol. 2 0 1 8; 1 7( 5): 4 5 6 -6 6.  
3 0   
D w or ki n R H, T ur k D C, Re vic ki D A, Har di n g G, C o y ne K S, Peirce -Sa n d n er S, et al. 
De vel o p me nt a n d i nitial vali dati o n of a n e x pa n d e d a n d re vise d versi o n of t he S h ort -f or m 
Mc Gill Pai n Q uesti o n naire ( S F -M P Q -2). Pai n. 2 0 0 9; 1 4 4( 1 -2): 3 5 -4 2.  
3 1   
Bec k A T, Rial W Y, Ric k els K. S h ort f or m of de pressi o n i n ve nt or y: cr oss -v ali dati o n. 
Ps yc h ol Re p. 1 9 7 4; 3 4( 3): 1 1 8 4 -6.  
3 2   
M or ge nster n J, Gr o e ner J B, Je n de J M E, K urz F T, Str o m A, G ö pfert J, et al. Ne ur o n -
s pecific bi o mar kers pre dict h y p o- a n d h y peral gesi a i n i n di vi d uals wit h dia betic peri p heral 
ne ur o pat h y. Dia bet ol o gia. 2 0 2 1; 6 4( 1 2): 2 8 4 3 -5 5.  
3 3   
Battisti 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.  

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 5 8  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
3 4   
I nter nati o nal C o m mittee of Me dical J o ur n al E dit ors (I C MJ E). Dece m 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 oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 5 9  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
1 5   
P R O T O C O L SI G N A T U R E P A G E S  
1 5. 1   
S p o n s or Si g n at ur e P a g e  
Pr ot oc ol #:   
V X 2 1 -5 4 8 -1 0 3   
Versi o n #:   
3. 0   
Versi o n Date:   
1 7 Fe br uar y 
2 0 2 3  
St u d y Title: A P hase 2, Ra n d o mize d, D o u ble -bli n d, Acti ve -c o ntr olle d, D ose -ra n gi n g, Parallel-
desi g n St u d y of t he Efficac y a n d Safet y of V X -5 4 8 i n S u bjects Wit h Pai nf ul Dia betic 
Peri p heral N e ur o pat h y  
T his cli nical st u d y pr ot oc ol has bee n re vie we d a n d a p pr o ve d b y t he s p o ns or.  
Pri nte d Na me  
  
Title  
Si g nat ure  
  
Date  

Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0  
Pa ge 6 0  of 6 0  
Verte x P har mace uticals I nc or p orate d  
C o nfi de ntial I nf or mati o n  
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 2 1 -5 4 8 -1 0 3   
Versi o n #:   
3. 0   
Versi o n Date:   
1 7 Fe br uar y 
2 0 2 3  
St u d y Title: A P hase 2, Ra n d o mize d, D o u ble -bli n d, Acti ve -c o ntr olle d, D ose -ra n gi n g, Parallel-
desi g n St u d y of t he Efficac y a n d Safet y of V X -5 4 8 i n S u bjects Wit h Pai nf ul Dia betic 
Peri p heral N e ur o pat h y  
 
 
I h a ve rea d Pr ot oc ol V X 2 1 -5 4 8 -1 0 3 , Versi o n 3. 0 , an 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‑ 5 4 8  a n d t his pr ot oc ol s u p plie d t o me b y 
Verte x P har m ace 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