Clinical trial NCT05660538
Conditions: Diabetic Peripheral Neuropathy
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2022-12-20; Completion date: 2023-10-25
Enrollment: 194 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of VX-548 doses in treating Painful DPN.

Detailed description:

Arms: arm 1: Participants received Pregabalin 100 mg 3 times per day (tid) for 12 weeks arm 2: Participants received SUZ 23 mg tablet once daily (qd) for 12 weeks. arm 3: Participants received SUZ 46 mg tablet qd for 12 weeks. arm 4: Participants received SUZ 69 mg tablet qd for 12 weeks.
Interventions: intervention 1: Suzetrigine intervention 2: Pregabalin intervention 3: Placebo (matched to SUZ) intervention 4: Placebo (matched to pregabalin)
Intervention descriptions: intervention 1: Tablets for oral administration. intervention 2: Capsules for oral administration. intervention 3: Placebo matched to SUZ for oral administration. intervention 4: Placebo matched to pregabalin for oral administration.

Protocol documents:
Prot_000.pdf: 
Pa ge 1  of 6 0  
 
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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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  
Pa ge 5 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 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  
 
 
 
 
 

SAP_001.pdf: 
Statistical Analysis Plan (Methods)  
Page 1 of 33 
Protocol Number: VX21-548-103 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
 
 
1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan 
(Methods) 
Protocol Number VX21-548-103 
(Final Analysis) 
 
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 
 
 
 
Version: 1.0 
Version Date of SAP: 08 Nov 2023   
 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, Massachusetts 02210-1862 
 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written 
consent of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under 
applicable laws or regulations.  Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 


Statistical Analysis Plan (Methods)  
Page 2 of 33 
Protocol Number: VX21-548-103 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
2 
TABLE OF CONTENTS 
 
1 
Title Page .......................................................................................................................... 1 
2 
Table of Contents ............................................................................................................. 2 
 
 
 
4 
Introduction...................................................................................................................... 5 
5 
Study objectives ............................................................................................................... 6 
5.1 
Primary Objective ....................................................................................................... 6 
 
6 
Study Endpoints ............................................................................................................... 6 
6.1 
Primary Endpoint ........................................................................................................ 6 
6.2 
Secondary Endpoints .................................................................................................. 6 
 
7 
Study Design ..................................................................................................................... 7 
7.1 
Overall Design ............................................................................................................ 7 
7.2 
Sample Size and Power .............................................................................................. 8 
7.3 
Randomization ............................................................................................................ 8 
7.4 
Blinding and Unblinding ............................................................................................ 9 
8 
Analysis Sets ..................................................................................................................... 9 
8.1 
All Subjects Set .......................................................................................................... 9 
8.2 
Full Analysis Set ......................................................................................................... 9 
8.3 
Safety Set .................................................................................................................... 9 
9 
Statistical Analysis ........................................................................................................... 9 
9.1 
General Considerations .............................................................................................. 9 
9.2 
Background Characteristics ...................................................................................... 10 
9.2.1 
Subject Disposition ........................................................................................... 10 
9.2.2 
Demographics and Baseline Characteristics ..................................................... 11 
9.2.3 
Medical History ................................................................................................ 12 
9.2.4 
Prior and Concomitant Medications ................................................................. 12 
9.2.5 
Study Drug Exposure and Study Drug Compliance ......................................... 13 
9.2.6 
Important Protocol Deviations .......................................................................... 13 
9.3 
Efficacy Analysis ...................................................................................................... 13 
9.3.1 
Analysis of Primary Endpoint .......................................................................... 13 
9.3.2 
Analysis of Secondary Efficacy Variables ....................................................... 14 
 
9.3.4 
Multiplicity Adjustment ................................................................................... 16 
9.4 
Safety Analysis ......................................................................................................... 16 
9.4.1 
Adverse Events ................................................................................................. 17 
9.4.2 
Clinical Laboratory Assessments ..................................................................... 18 
9.4.3 
Electrocardiogram ............................................................................................ 18 
9.4.4 
Vital Signs ........................................................................................................ 19 


Statistical Analysis Plan (Methods)  
Page 3 of 33 
Protocol Number: VX21-548-103 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
9.4.5 
Physical Examination ....................................................................................... 19 
9.4.6 
Columbia-Suicide Severity Rating Scale ......................................................... 19 
10 Summary of Interim and IDMC Analyses .................................................................. 19 
11 List of Appendices.......................................................................................................... 20 
Appendix A 
Analysis Visit Windows for Safety and Efficacy Assessments ................. 20 
Appendix B 
Scoring of NPSI, SF-36, SF-MPQ-2, and BDI-2 ....................................... 23 
Appendix C 
Imputation Rules for Missing Prior/Concomitant Medication Dates ........ 27 
Appendix D 
Imputation Rules for Missing AE Dates and Times .................................. 28 
Appendix E 
Threshold Value Criteria ............................................................................ 29 
12 References ....................................................................................................................... 33 
 
 


Statistical Analysis Plan (Methods)  
Page 4 of 33 
Protocol Number: VX21-548-103 
Vertex Pharmaceuticals Incorporated 
Confidential Information 


Statistical Analysis Plan (Methods)  
Page 5 of 33 
Protocol Number: VX21-548-103 
Vertex Pharmaceuticals Incorporated 
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4 
INTRODUCTION 
This statistical analysis plan (SAP) for the final analysis is based on the most recent approved 
clinical study protocol (CSP), the most recent approved electronic case report form (eCRF), 
and the most recent approved eCRF completion guidelines. This SAP documents the planned 
statistical analysis of efficacy and safety endpoints defined in the study protocol of VX21-
548-103 and provides additional details and clarifications.  
The Vertex Biometrics Department will perform the final statistical analysis of the efficacy 
and safety data; SAS® Version 9.4 Software (SAS Institute, Cary, North Carolina, USA) or 
higher will be used to generate all statistical outputs (tables, figures, listings and datasets).   
The SAP (Methods) will be finalized and approved before the clinical data lock for the final 
analysis. Any revisions to the approved SAP will be documented and approved in an 
amendment to the SAP prior to the clinical database lock. Any revisions made to the SAP 
after the clinical data lock will be documented in the clinical study report for this study. 
Analyses addressing the pharmacokinetic (PK) objective of the study will be described in the 
Clinical Pharmacology Analysis Plan (CPAP) which will be developed separately by the 
Vertex Clinical Pharmacology department. 


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5 
STUDY OBJECTIVES 
 
5.1 
Primary Objective 
• To evaluate the efficacy of three VX-548 doses in treating subjects with painful diabetic 
peripheral neuropathy (DPN) 
• To evaluate the safety and tolerability of VX-548 
6 
STUDY ENDPOINTS 
6.1 
Primary Endpoint 
• Change from baseline in the weekly average of daily pain intensity on a numeric pain 
rating scale (NPRS) at Week 12 
6.2 
Secondary Endpoints 
• Change from baseline in the weekly average of the Daily Sleep Interference Scale 
(DSIS) at Week 12 
• Proportions of subjects with ≥30%, ≥50%, and ≥70% reductions from baseline in the 
weekly average of daily pain intensity on the NPRS at Week 12 
• Proportion of subjects categorized as much improved or very much improved at Week 
12 on the patient global impression of change (PGIC) assessment 
• Safety and tolerability based on the incidence and type of adverse events (AEs) and 
changes from baseline in clinically significant laboratory test results, vital signs, and 
ECGs at each visit 


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7 
STUDY DESIGN  
7.1 
Overall Design 
This is a Phase 2, randomized, double-blind, active-controlled, dose-ranging, 4-arm parallel-
design study evaluating the efficacy and safety of three different doses of VX-548 in treating 
diabetic peripheral neuropathy.  
Subjects who meet eligibility criteria during Screening Visits 1 and 2 will enter a 7-day Run-
in Period to establish their baseline NPRS pain score. Subjects with a baseline average NPRS 
score of ≥4 points with limited variation (SD <25% of mean) will be eligible for the 12-week 
Treatment Period followed by a Safety Follow-up Visit (Figure 7-1). 
 
Figure 7-1 
VX21-548-103 Study Design 
 
 
N: number of subjects 
a At the end of the Treatment Period (Week 12), subjects will taper off capsule (pregabalin 
reference or matched placebo) study drug for 7 days. 
 
A total of approximately 175 subjects will be randomized 2:2:1:2 to 4 treatment arms: VX-
548 (high, mid, or low dose) or pregabalin (reference arm) (Table 7-1). Randomization will 
be stratified by sex (female and male) and body mass index (≥30 and <30 kg/m2). To 
maintain the blind, all subjects will receive the same number of tablets once daily (qd) in the 
morning and the same number of capsules 3 times per day in a double-dummy design. After 
the Treatment Period, subjects will taper off capsule (pregabalin reference or matched 
placebo) study drug for 7 days (4 days of dosing every 12 hours, then 3 days of dosing qd), 
and the Safety Follow-up Visit will occur an additional 7 (± 2) days later. 
 
 
 
 
 


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Table 7-1          VX21-548-103 Treatment Arms 
 
qd: once daily; tid: 3 times per day 
Note: To maintain the blind, all subjects will receive the same number of tablets and the 
same number of capsules at the same respective frequency (i.e., qd for tablets and tid 
for capsules during the Treatment Period) in a double-dummy design. 
 
Subjects will stop taking pain medications (including pregabalin, if applicable), except 
acetaminophen (500 mg), for at least 14 days before the first dose of study drug. 
Acetaminophen will be permitted as a pain rescue medication as needed (prn) throughout the 
study. Subjects will be permitted to take 500 mg every 4 to 6 hours prn, up to a maximum of 
2500 mg in any 24-hour period. Subjects will record rescue medication use, and their current 
pain score on the NPRS immediately before each administration of rescue medication. 
Rescue medication usage will only be documented up to treatment discontinuation. 
 
7.2 
Sample Size and Power 
The sample size is based on the primary analysis of the primary endpoint. With 37 evaluable 
subjects in the VX-548 high or mid dose group and 18 evaluable subjects in the VX-548 low 
dose group, there is more than 90% power in any VX-548 dose group to detect a mean 
change from baseline of 3 with a single group t-test at the 2-sided 0.05 significance level, 
assuming the SD is 2.3. With an evaluable sample size of 37, a 2-sided 95% CI for the mean 
change from baseline in the high or mid dose group will extend 0.77 on either side of the 
observed mean, assuming the CI is based on the t-statistic and the observed SD is 2.3. Under 
the same assumptions and an evaluable sample size of 18, a 2-sided 95% CI for the mean 
change from baseline in the low dose group will extend 1.14 on either side of the observed 
mean. To account for a 25% dropout rate, 50 subjects each will be enrolled in the VX-548 
high dose, VX-548 mid dose, and the pregabalin groups; 25 subjects will be enrolled in the 
VX-548 low dose group. The total sample size is approximately 175 subjects. 
The study is not powered for comparison between the VX-548 doses and the pregabalin 
reference arm. 
 
7.3 
Randomization 
Refer to Section 9.2 of the CSP for details.  
 


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7.4 
Blinding and Unblinding 
Refer to Section 10.7 of the CSP for details. 
 
8 
ANALYSIS SETS 
8.1 
All Subjects Set 
The All Subjects Set is defined as all subjects who have been randomized or have received 
at least 1 dose of study drug. This analysis set will be used in subject listings and disposition 
summary table, unless otherwise specified. 
8.2 
Full Analysis Set 
The Full Analysis Set (FAS) is defined as all randomized subjects who have received at 
least 1 dose of study drug. The FAS is to be used to summarize subject demographics and 
baseline characteristics. It is also to be used in all efficacy analyses, in which subjects will be 
analyzed according to their randomized treatment group. 
8.3 
Safety Set 
The Safety Set is defined as all subjects who have received at least 1 dose of study drug. The 
Safety Set is to be used for all safety analyses in which subjects will be analyzed according to 
the treatment they received. 
9 
STATISTICAL ANALYSIS 
9.1 
General Considerations 
The Schedule of Assessments is provided in Section 3 of the CSP. The precision standards 
for reporting variables are provided in an internal Biometrics document that specifies the 
programming rules including the precision for derived variables. 
All individual subject data for subjects who were randomized or received at least 1 dose of 
study drug will be presented in individual subject data listings. 
Continuous variables will be summarized using the following descriptive summary 
statistics: the number of subjects (n), mean, standard deviation (SD), median, minimum value 
(min), and maximum value (max), unless otherwise specified.  
Categorical variables will be summarized using counts and percentages.  
Baseline value: The baseline for the weekly average of NPRS and DSIS will be defined as 
average of the non-missing scores from Day -7 to Day -1. For the weekly average of NPRS, 
baseline values will be calculated if there are at least 4 non-missing scores. For weekly 
average of DSIS, baseline values will be calculated if there are at least 3 non-missing scores. 
For ECGs, the baseline values will be defined as the most recent average of non-missing 
triplicate measurements collected before the first dose of the study drug. For all other 
variables, baseline values will be defined as the most recent non-missing measurement 
collected before the first dose of study drug, unless otherwise specified.  


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Change (absolute change) from baseline will be calculated as post-baseline value – 
baseline value.  
Treatment-emergent (TE) Period will include the time period from the date of the first 
dose of study drug to either (1) the Safety Follow-up Visit, (2) the ETT Visit if it replaces the 
Safety Follow-up Visit, or (3) 14 days after the last dose for subjects who do not have a 
Safety Follow-up Visit or equivalent.  
Unscheduled visits: Unscheduled visit measurements will be included in the analysis as 
follows: 
• In scheduled visit windows per specified visit windowing rules 
• In the derivation of baseline 
• In the derivation of maximum and minimum values during the TE period, and 
maximum and minimum change from baseline values during the TE period for safety 
analyses 
• In individual subject data listings as appropriate 
Visit windowing rules: The analysis visit windows for protocol-defined visits are provided 
in Appendix A.  
Incomplete/missing data: Details on how to handle missing data are described in 
subsequent sections when applicable. 
Outliers: No formal statistical analyses will be performed to detect and/or remedy the 
presence of statistical outliers. 
Multiplicity: There is no multiplicity adjustment for this Phase 2 study. 
 
9.2 
Background Characteristics  
9.2.1 
Subject Disposition 
The disposition summary will be provided by treatment group and overall. 
The number of subjects in the following categories will be summarized:  
• All Subjects Set 
• Randomized 
• Full Analysis Set (FAS) 
• Safety Set 
• Randomized but not dosed 
The number and percentage (based on the FAS) of subjects in each of the following 
disposition categories will be summarized: 
• Completed treatment 


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• Prematurely discontinued treatment and the reason for discontinuation from treatment 
• Completed study 
• Prematurely discontinued the study and the reason for discontinuation from study 
• Complete taper 
• Did not complete taper 
A disposition listing and a randomization listing of subjects will be provided.  
9.2.2 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized based on the FAS by 
treatment group and overall. 
Demographic data will include the following: 
• Age at screening (in years) 
• Age at screening category (≥18 to <65, ≥65) 
• Sex (male, female) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local 
regulations) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, not collected per local regulations, Other 
and Multiracial [if 2 or more races reported from a subject]) 
Baseline characteristics will include the following: 
• Weight (kg) 
• Height (cm) 
• BMI (kg/m2) 
• BMI category (≥ 30 and < 30 kg/m2) 
• Baseline HbA1c (%) 
• Baseline HbA1c category (<7 and ≥ 7%) 
• Baseline weekly average of NPRS  
• Baseline weekly average of NPRS category (<8, ≥8) 
• Baseline weekly average of DSIS 
• Baseline NPSI total score 
• Baseline SF-36 physical component summary score 
• Baseline SF-36 mental component summary score 
• Baseline SF-MPQ-2 total score 


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• Baseline BDI-2 total score  
The scoring of NPSI, SF-36, SF-MPQ-2 and BDI-2 are included in Appendix B.  
In addition to demographic data and baseline characteristics, data listings will also be 
provided for: 
• Informed consent 
• Inclusion/exclusion criteria violation for subjects with any such violations 
9.2.3 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Medical history will be summarized descriptively based on the FAS by 
MedDRA system organ class (SOC) and preferred term (PT). This summary will be provided 
by treatment group and overall. The corresponding data listing will also be provided. 
9.2.4 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization Drug Dictionary and 
categorized as the following for the purposes of analysis: 
Prior medication: Medication that started before the first dose of study drug, regardless of 
when dosing of the medication ended 
Concomitant medication: Medication continued or newly received after the date and time 
of the first dose of study drug through the end of the TE Period 
A given medication may be classified as a prior medication, a concomitant medication, or 
both a prior and a concomitant medication.  
If a medication start date/time is on or after the first dose of study drug, then the medication 
will be classified as a concomitant medication regardless of whether the medication end 
date/time is missing. If a medication end date/time is before the first dose of study drug, then 
the medication will be classified as a prior medication regardless of whether the medication 
start date/time is missing.  
Note that a medication that started before the first dose of study drug and continued after the 
first dose will be classified as a prior medication and separately as a concomitant medication. 
If a medication has a missing or partially missing start or end date/time and it cannot be 
determined whether it was taken before the first dose of study drug or concomitantly, it will 
be classified as a prior and a concomitant medication. 
Details for imputing missing or partial start/end date and time of medication are described in 
Appendix C. 
Prior and concomitant medications will be summarized based on the FAS by Preferred Name 
and listed. This summary will be provided by treatment group and overall. Prior pain 
medications will be included in the summary of prior medications and will also be 
summarized and listed separately. Concomitant analgesic medications other than rescue 
medication will be included in the summary of concomitant medications and will also be 
summarized and listed separately. Rescue medication, as collected in the e-diary, will not be 


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included in the summary of concomitant medications and will be summarized separately. 
Prior and concomitant non-pharmacological treatments or procedures will be listed. 
9.2.5 
Study Drug Exposure and Study Drug Compliance 
Study drug exposure and study drug compliance will be summarized based on data collected 
in eCRF.  
Duration of study drug exposure (in days) will be calculated as (last date of dosing in the 
treatment period – first date of dosing +1). Duration of study drug exposure in weeks will be 
summarized by treatment group (based on FAS) using descriptive summary statistics and by 
frequency count and percentages for the following categories: ≤1 week, >1 and ≤ 2 weeks, 
>2 and ≤ 3 weeks, …, >11 weeks and ≤ 12 weeks and >12 weeks.   
Study drug compliance rate will be calculated as 100× [1- (total number of days of study 
drug interruption between the last dose date in the treatment period and first dose date)/ 
(duration of study drug exposure in days)]. Study drug compliance rate will be summarized 
descriptively (based on FAS) by treatment group and overall and into the categories of 
<80%, and ≥80%. 
9.2.6 
Important Protocol Deviations  
An important protocol deviation (IPD) is a deviation that may significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a 
subject’s rights, safety, or well-being. IPD rules will be developed and finalized before 
database lock. IPDs will be identified by the PD review team according to the protocol 
deviation plan.  
IPDs will be summarized descriptively based on FAS by treatment group and overall, as well 
as presented in an individual data listing. 
 
9.3 
Efficacy Analysis 
All efficacy analyses described in this section will be based on the FAS. Subjects will be 
analyzed according to their randomized treatment assignment. 
9.3.1 
Analysis of Primary Endpoint 
9.3.1.1           Definition of Primary Estimand 
The primary endpoint is the change from baseline in the weekly average of daily pain 
intensity on an NPRS at Week 12. The primary estimand is defined as the following: 
• Treatment: VX-548 + rescue medication (if used)  
• Population: Study population defined by the study inclusion and exclusion criteria 
• Variable: change from baseline in the weekly average of daily pain intensity on an 
NPRS at Week 12 


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• Handling of intercurrent events:  
o The hypothetical strategy will be used to handle treatment discontinuation, which 
means that the observed NPRS scores up to treatment discontinuation will be 
used.  
o The treatment policy strategy will be used to handle rescue medication use, which 
means that the observed NPRS scores on the days when subjects take rescue 
medication will be used. 
• Population level summary: Variable mean 
9.3.1.2           Primary Analysis 
The primary analysis of the primary estimand will be a within-group comparison in any VX-
548 dose group.  
The weekly average of daily pain intensity on an NPRS (hereafter referred to as “weekly 
average of NPRS”) will be calculated as the average of the non-missing NPRS scores at the 
baseline and in each week during the treatment period as defined in Appendix A. The 
baseline score will be calculated if there are at least 4 non-missing NPRS scores during Days 
-7 to -1. The Week 1 to Week 12 scores will be calculated if there are at least 3 non-missing 
NPRS scores in each week. The NPRS scores collected up to treatment discontinuation will 
be used in the calculation of the weekly average of NPRS. 
The primary efficacy analysis will be based on a mixed-effects model for repeated measures 
(MMRM), with change from baseline in weekly average of NPRS at each week as the 
dependent variable; and fixed effects of treatment group, week (categorical), treatment 
group-by-week interaction, baseline weekly average of NPRS, baseline weekly average of 
NPRS-by-week interaction. The model will be estimated using restricted maximum 
likelihood. The Kenward-Roger approximation will be used to estimate denominator degrees 
of freedom and adjust standard errors (SE). An unstructured co(variance) structure will be 
used to model the within-subject errors. If there is a convergence issue, then a compound 
symmetric covariance matrix will be used to model the within-subject errors. The least 
squares (LS) mean change from baseline at Week 12 for each treatment group will be 
presented with the corresponding SE, 95% CI and P-value.  
9.3.2 
Analysis of Secondary Efficacy Variables 
Change from baseline in the weekly average of the DSIS at Week 12: The change from 
baseline in the weekly average of DSIS at Week 12 will be analyzed similarly to the primary 
analysis as specified in Section 9.3.1.2. The model will include the change from baseline in 
weekly average of DSIS scores as the dependent variable; and fixed effects of treatment 
group, time (categorical), treatment group-by-time interaction, baseline weekly average of 
DSIS, baseline weekly average of DSIS-by-time interaction. The LS mean change from 
baseline at Week 12 for each treatment group will be presented with the corresponding SE 
and95% CI. In addition, the LS mean change from baseline at each week will also be 
presented together with the corresponding SE and 95% CI by treatment group. The LS mean 


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change from baseline and SE at each week will also be presented in figure by treatment 
group. 
The weekly average of DSIS will be calculated by averaging the non-missing DSIS scores at 
the baseline and in each week during the treatment period as defined in Appendix A. They 
will be calculated if there are at least 3 non-missing DSIS scores for each week, including the 
baseline. The DSIS scores collected up to treatment discontinuation will be used in the 
calculation of the weekly average of DSIS. 
Proportion of subjects with ≥ 30%, ≥ 50%, and ≥ 70% reduction from baseline in the weekly 
average of daily pain intensity on the NPRS at Week 12: 
The percentage reduction in the weekly average of NPRS at Week 12 will be calculated as 
100% × (weekly average at baseline  ̶  weekly average at Week 12) / weekly average at 
baseline. The weekly average at baseline and at Week 12 are the scores used for the primary 
analysis. 
Subjects with ≥30% reduction from baseline at Week 12 will be defined as “responders”. 
Subjects with <30% reduction from baseline at Week 12 or subjects who discontinued 
treatment early will be defined as “non-responders”. Subjects who complete treatment but 
have missing weekly average at Week 12 will have the data imputed based on the last 
available weekly average and their response status will be determined based on the imputed 
score. The proportion of subjects with ≥30% reduction from baseline in the weekly average 
of NPRS at Week 12 will be summarized descriptively by treatment group. 
The proportion of subjects with ≥50% and ≥70% reduction from baseline will be defined and 
summarized similarly. 
Proportion of subjects categorized as much improved or very much improved at Week 12 on 
the PGIC assessment: The proportion of subjects categorized as much improved or very 
much improved at Week 12 on the PGIC assessment will be summarized descriptively by 
treatment group. Subjects who complete treatment but have missing data at Week 12 will 
have the data imputed from the last available measurement. Subjects who discontinue 
treatment will be considered as “non-responders”. 


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9.3.4 
Multiplicity Adjustment 
There is no multiplicity adjustment for this Phase 2 study.  
 
9.4 
Safety Analysis 
The overall safety profile of VX-548 will be assessed in terms of the following safety and 
tolerability endpoints:  
• Incidence of treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values (hematology, serum chemistry, coagulation, and urinalysis) 
• ECG outcomes 
• Vital signs 


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• Physical examination test values 
• C-SSRS 
All safety analyses will be performed based on the Safety Set based on actual treatment. In 
the unexpected scenario that a subject receives more than one treatment in the study, the 
following algorithm will be used to define actual treatment: for any dosed subjects, the actual 
treatment is defined as the VX-548 highest dose level among all received VX-548 treatment 
if the subject received any VX-548 treatment, regardless of the randomized treatment 
assignment; the actual treatment is defined as pregabalin if the subject did not receive any 
VX-548 treatment but did receive any pregabalin. 
Only descriptive analyses of safety will be performed, and no statistical hypothesis testing 
will be performed. 
9.4.1 
Adverse Events  
AEs will be coded according to MedDRA. For analysis purposes, AEs will be classified as 
pretreatment AEs and TEAEs as follows: 
Pretreatment AEs: AEs that occurred before the first dose of study drug 
Treatment-emergent AEs: AEs that worsened or started after the first dose of study drug 
through the end of the TE Period 
For AEs with completely missing or partial start dates/times, if there is no clear evidence that 
the AEs started before or after the first dose of study drug, the AEs will be classified as 
TEAEs. 
Imputation rules for missing or partial AE start dates/times are defined as Appendix D. 
AE summary tables will be presented for TEAEs by treatment group, and will include the 
following: 
• All TEAEs 
• TEAEs by strongest relationship 
• TEAEs by maximum severity 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption 
• Related TEAEs 
• Serious TEAEs 
• Related serious TEAEs 
• TEAEs leading to death 
Summaries will be presented by MedDRA SOC and PT using frequency counts and 
percentages (i.e., number and percentage of subjects with an event). When summarizing the 
number and percentage of subjects with an event, subjects with multiple occurrences of the 
same AE or a continuing AE will be counted once, and only the maximum severity level will 


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be presented in the severity summaries, and the strongest relationship level in the relationship 
summaries.  
All AEs, including pretreatment AEs and TEAEs, will be presented in an individual subject 
data listing. In addition, listings containing individual subject AE data for TEAEs leading to 
treatment discontinuation, TEAEs leading to treatment interruption, SAEs and all deaths will 
be provided separately. 
9.4.2 
Clinical Laboratory Assessments 
All statistical analyses of laboratory values will be performed using SI units. For treatment-
emergent laboratory measurements, the observed values and change from baseline values of 
the continuous hematology, chemistry, and coagulation results will be summarized at each 
visit. 
The number and percentage of subjects with selected test values meeting threshold analysis 
criteria during the TE period will be summarized. The threshold analysis shift from baseline 
criteria will also be summarized for selected chemistry measurements. The threshold analysis 
criteria are provided in Appendix E.  
Results of urinalysis and the urine/serum pregnancy test will be in individual subject data 
listings only. 
In addition, listings of individual subject hematology, chemistry, and coagulation values 
outside the normal reference ranges will be provided. These listings will include data from 
both scheduled and unscheduled visits. 
9.4.3 
Electrocardiogram 
For the treatment-emergent ECG measurements, a summary of observed values and change 
from baseline values will be provided at each visit and time point, as applicable, for the 
following ECG measurements: heart rate (HR; beats per minute [bpm]), PR interval (msec), 
RR interval (msec), QRS duration (msec), QT interval (msec), and QT corrected for HR 
intervals (QTcF [msec]).  
The number and percentage of subjects meeting threshold analysis criteria during the TE 
period will be summarized. The threshold analysis criteria are provided in Appendix E. A 
listing containing individual subject measurements meeting the threshold value criteria at any 
time point will be provided. This listing will include data from both scheduled and 
unscheduled visits. 
In addition, the number and percentage of subjects by maximum treatment-emergent value of 
QT/QTcF intervals, categorized as ≤450 msec, >450 msec and ≤480 msec, >480 msec and 
≤500 msec, and >500 msec, as well as maximum treatment-emergent change from baseline 
value of QT/QTcF intervals, categorized as ≤0 msec, and >0 and ≤30 msec, >30 and ≤60 
msec, and >60 msec, will be provided. 
Since ECGs are performed in triplicate, the mean of the ECG measurements will be used as 
the ECG value for summaries of observed values and change from baseline values, and all 
reported ECG measurements will be used to conduct threshold analyses and to assess 
maximum treatment-emergent values. 


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9.4.4 
Vital Signs 
For the treatment-emergent vital signs measurements, the observed values and change from 
baseline values will be summarized at each visit. The following vital signs parameters will be 
summarized: systolic and diastolic blood pressure (mm Hg), pulse rate (beats per minute), 
body temperature (°C), and respiratory rate (breaths per minute).  
The number and percentage of subjects meeting threshold analysis criteria during the TE 
Period will be summarized. The threshold analysis criteria are provided in Appendix E.  
In addition, a listing containing individual subject vital signs values will be provided. This 
listing will include data from both scheduled and unscheduled visits. 
9.4.5 
Physical Examination  
Physical examination (PE) results will be presented in an individual subject data listing only. 
9.4.6 
Columbia-Suicide Severity Rating Scale 
The proportion of subjects with at least one event during the TE Period of suicidal ideation, 
suicidal behavior, suicidal ideation or behavior, or self-injurious behavior without suicidal 
intent, as recorded on the Columbia-Suicide Severity Rating Scale (C-SSRS), will be 
summarized. C-SSRS results for subjects with responses of "Yes" at any visit will also be 
presented in an individual subject data listing. 
10 
SUMMARY OF INTERIM AND IDMC ANALYSES 
Not applicable. 


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11 
LIST OF APPENDICES 
Appendix A Analysis Visit Windows for Safety and Efficacy Assessments  
Table 12-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit/Time point1 
Target Study Day 
/Time point per 
the protocol 
Analysis Visit Window 
(in study days/time points) 2, 3, 4 
Safety Assessment 
Hematology 
Serum 
Chemistry 
 
Baseline 
Week 3 
Week 9 
Week 12 
 
Day 1 
Day 22 
Day 64 
Day 85 
 
[Screening Visit 1, Pre-dose Day 1] 
[Day 1 post-dose, 43] 
[44,74] 
[75,99] 
 
Coagulation 
Baseline  
Week 12 
N/A 
Day 85 
 
[Screening Visit 1, Pre-dose Day 1] 
[Day 1 post-dose,99] 
Standard 12-
Lead ECG 
 
Baseline 
Day 1  
Day 1 2 hrs post-dose 
Day 1 4 hrs post-dose 
Week 1 
Week 5 
Week 5 Pre-dose 
Week 5 2 hrs post-dose 
Week 5 4 hrs post-dose 
Week 12 
Day 1 
Day 1 
Day 1 
Day 8 
Day 36 
Day 36 
Day 36 
Day 36 
Day 85 
 
[Screening Visit 2, Pre-dose Day 1] 
Nominal  
Nominal 
Nominal 
[Day 2, 21] 
Nominal 
Nominal 
Nominal 
Nominal 
[61,99] 
 
Vital Signs 
Baseline 
Week 1 
Week 3 
Week 5 
Week 7 
Week 9 
Week 12 
Day 1 
Day 8 
Day 22 
Day 36 
Day 50 
Day 64 
Day 85 
[Screening Visit 1, Pre-dose Day 1] 
[Post-dose Day 1,14] 
[15,29] 
[30,43] 
[44,57] 
[58,74] 
[75,99] 
Efficacy Assessment 


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Table 12-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit/Time point1 
Target Study Day 
/Time point per 
the protocol 
Analysis Visit Window 
(in study days/time points) 2, 3, 4 
NPRS via daily 
e-diary 
DSIS via daily 
e-diary 
Baseline 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Week 7 
Week 8 
Week 9 
Week 10 
Week 11 
Week 12 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
[-7, -1] 
[1, 7] 
[8, 14] 
[15,21] 
[22,28] 
[29,35] 
[36,42] 
[43,49] 
[50,56] 
[57,63] 
[64,70] 
[71,77] 
[78,84] 
Rescue 
medication via 
daily e-diary 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Week 7 
Week 8 
Week 9 
Week 10 
Week 11 
Week 12 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
[1*, 7] 
[8, 14] 
[15,21] 
[22,28] 
[29,35] 
[36,42] 
[43,49] 
[50,56] 
[57,63] 
[64,70] 
[71,77] 
[78,84] 
PGIC 
Week 1 
Week 5 
Week 12 
Safety Follow-up 
Day 8 
Day 36 
Day 85 
N/A 
[Post-dose Day 1, 15] 
[29,43] 
[78,92] 
Nominal 
Notes: * only include Day 1 post-dose measurements. 
1 Visit/time point names for analysis purposes are used to report data in tables and figures. 
2The analysis visit windows will be applied using the following rules for both scheduled and unscheduled visits: 
a. 
If no numerical measurement is available within a visit window, the measurement will be considered 
missing for the visit.  
b. If there is more than 1 numerical measurement available within the same visit window, use the 
following rules:  


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i. 
The measurement closest to the target day/time point will be used; or  
ii. 
If there are multiple measurements within the same distance from the target day/time point, 
the latest measurement will be used. 
3For measurements collected on the date of the first dose of study drug, if it cannot be determined whether the 
measurement is before or after the first dose: 
a. 
If a scheduled measurement is pre-dose in the CSP, it will be treated as a pre-dose observation. If a 
scheduled measurement is post-dose in the CSP, it will be treated as a post-dose observation. 
b. Unscheduled measurements will be treated as post-dose observations. 
4When defining baseline for efficacy and safety, refer to the generic baseline definition in Section 9.1.  
 
 


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Appendix C Imputation Rules for Missing Prior/Concomitant Medication Dates 
Imputation rules for missing or partial medication start/stop dates are defined below: 
1. Missing or partial medication start date: 
a. If day is missing, use the first day of the month.  
b. If day and month are both missing, use the first day of the year.  
c. If day, month and year are all missing, use a date before the first dose date. 
2. Missing or partial medication stop date and time: 
a. If day is missing, use the last day of the month. 
b. If day and month are both missing, use the last day of the year. 
c. If day, month and year are all missing, assign ‘continuing’ status to stop date. 
 
Table 12-2 
Prior and/or Concomitant Categorization of a Medication 
Medication Start Date 
Medication Stop Date 
< First Dose Date/Time of 
Study Drug 
≥ First Dose Date/Time 
and ≤ End Date of TE 
Period 
< First dose date/time of study drug 
P 
PC 
≥ First dose date/time and ≤ end date of TE 
period 
- 
C 
C: Concomitant; P: Prior 
 
 


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Appendix D Imputation Rules for Missing AE Dates and Times 
Imputation rules for missing or partial AE start dates and times are defined below: 
If Hour and/or Minute of AE start time are missing, do not impute:  
• If the AE start date is before the first dose date, the AE will be classified as a 
pretreatment AE. 
• If the AE start date is on or after the first dose date, the AE will be classified as a 
TEAE. 
If only Day of AE start date is missing:  
o If the AE start year and month are the same as that for the first dose date, then: 
▪ If the full (or partial) AE end date is NOT before the first dose date or AE end 
date is missing, then impute the AE start day as the day of the first dose date 
▪ Otherwise, impute the AE start day as 1. 
o Otherwise, impute the AE start day as 1. 
Compare the imputed AE start date with the TE period to determine whether the AE is a 
pretreatment AE or TEAE. 
If Day and Month of AE start date are missing: 
o If AE start year is the same as the year of the first dose date, then: 
▪ If the full (or partial) AE end date is NOT before the first dose date or the AE end 
date is missing, then impute the AE start month and day as the month and day of 
the first dose date; 
▪ Otherwise, impute the AE start month as January and the day as 1. 
o Otherwise, impute the AE start month as January and the day as 1. 
Compare the imputed AE start date with TE period to determine whether the AE is a 
pretreatment AE or TEAE. 
If Year of AE start date is missing: 
If the year of AE start is missing or AE start date is completely missing, then query the site 
with no imputation. Compare the full (or partial) AE end date to the first dose date. If the AE 
end date is before the first dose date, then the AE should be considered as a pretreatment AE. 
Otherwise, the AE will be considered as a TEAE. 
If Hour and/or Minute of first dose time are missing: 
• If the AE start date is before the first dose date, the AE will be classified as a 
pretreatment AE. 
• If the AE start date is on or after the first dose date, the AE will be classified as a 
TEAE. 
A missing or partially missing AE end date will not be imputed. 


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Appendix E Threshold Value Criteria 
Table 11-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry 
ALT 
>ULN - ≤3xULN 
>3x - ≤5xULN 
>5x - ≤8xULN 
>8x - ≤20xULN 
>20xULN 
FDA DILI Guidance Jul 2009.  
AST 
>ULN - ≤3xULN 
>3x - ≤5xULN 
>5x - ≤8xULN 
>8x - ≤20xULN 
>20xULN 
FDA DILI Guidance Jul 2009. 
ALT or AST 
 (ALT>ULN - ≤ 3xULN) or (AST>ULN - 
≤3xULN) 
(ALT>3x - ≤5xULN) or  (AST>3x - 
≤5xULN) 
(ALT>5x - ≤8xULN) or  (AST>5x - 
≤8xULN) 
(ALT>8x - ≤20xULN) or (AST>8x - 
≤20xULN) 
ALT>20xULN or AST>20xULN 
FDA DILI Guidance Jul 2009. 
Alkaline Phosphatase 
>ULN - ≤1.5xULN 
>1.5 - ≤2.5xULN 
>2.5 - ≤5xULN 
>5 - ≤20xULN 
>20xULN 
FDA DILI Guidance Jul 2009.  
Total Bilirubin 
>ULN - ≤1.5xULN 
>1.5 - ≤2xULN 
>2 - ≤3xULN  
>3 - ≤10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
Direct Bilirubin 
>ULN - ≤1.5xULN 
>1.5 - ≤2xULN 
>2 - ≤3xULN  
>3 - ≤10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
ALT and Total Bilirubin 
ALT>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
 
AST and Total Bilirubin 
AST>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
 
(ALT or AST) and Total Bilirubin (ALT>3xULN or AST>3xULN) and 
TBILI>2×ULN 
FDA DILI Guidance Jul 2009. 


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Table 11-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
GGT 
>ULN - ≤2.5xULN 
>2.5 - ≤5xULN 
>5 - ≤20xULN  
>20xULN 
CTCAE grade 1-4 
Albumin 
<LLN - ≥30 g/L 
<30 - ≥20 g/L 
<20 g/L 
CTCAE grade 1-3 
Creatinine 
>ULN - ≤1.5xULN 
>1.5 - ≤3xULN 
>3 - ≤6xULN 
>6xULN 
CTCAE grades 1-4 
Lipase 
>ULN - ≤1.5xULN 
>1.5x - ≤2xULN 
>2x - ≤5xULN 
>5xULN 
Criteria based upon CTCAE 
Total protein 
 
<LLN  
>ULN 
No CTCAE 
Creatine kinase 
>ULN - ≤2.5xULN 
>2.5 - ≤5xULN 
>5 - ≤10xULN  
>10xULN 
CTCAE grades 1-4 
 
Hematology 
Hemoglobin 
Hgb decreased (anemia) 
<LLN - ≥100 g/L 
<100 - ≥80 g/L  
<80 g/L 
CTCAE grade 1-3 
 
Hgb increased 
>ULN - ≤20 g/L above ULN 
>20 g/L above ULN - ≤40 g/L above 
ULN 
>40 g/L above ULN 
CTCAE grade 1-3 
Platelets 
Platelet decreased 
<LLN - ≥75 x 10e9 /L 
<75 - ≥50 x 10e9 /L  
<50 - ≥25 x 10e9 /L  
<25 x 10e9 /L 
CTCAE grade 1-4 
 
Platelet increased   
>ULN 
No CTCAE available 
 
Coagulation 
 
 
Activated partial thromboplastin 
time (PTT)  
 
>ULN - ≤1.5xULN 
>1.5 - ≤2.5xULN 
>2.5xULN 
CTCAE grade 1-3 


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Table 11-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Prothrombin time (PT) 
International 
Normalized Ratio (INR) 
>ULN - ≤1.5xULN 
>1.5 - ≤2.5xULN 
>2.5 x ULN 
CTCAE grade 1-3 
 
Table 11-4 
Threshold Analysis Criteria for ECGs 
Parameter 
Threshold Analysis 
Comments 
HR 
Bradycardia 
<50 bpm  
<45 bpm 
Decrease from baseline ≥10 bpm 
Decrease from baseline ≥20 bpm 
<50 bpm and decrease from baseline ≥10 bpm 
<50 bpm and decrease from baseline ≥20 bpm 
Per HV grade 2, 3, plus shift change 
 
 
 
Tachycardia 
>100 bpm 
>115 bpm  
>130 bpm  
Increase from baseline ≥10 bpm 
Increase from baseline ≥20 bpm  
>100 bpm and increase from baseline ≥10 bpm 
>100 bpm and increase from baseline ≥20 bpm 
Per HV grade 1, 2, 3, plus shift change 
 
 
PR 
≥240 ms 
≥300 ms 
≥200 ms and increase from baseline ≥40 ms 
≥200 ms and increase from baseline ≥100 ms 
 
QRS 
>110 ms 
>160 ms 
Increase from baseline ≥20 ms 
Increase from baseline ≥40 ms 
 
QTc 
 
>450 to <500ms (Male) or >470 to <500ms (Female) 
≥500 ms 
Increase from baseline 
Increase from baseline >10 ms 
Increase from baseline >20 ms 
Increase from baseline >40 ms 
Increase from baseline >60 ms 
To be applied to any kind of QT 
correction formula.  
 
 
 
 
 


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Table 11-5   Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
Pulse Rate 
Same as above in ECG category 
 
SBP increased 
 
>140 mmHg 
>160 mmHg 
>10 mmHg increase from baseline 
>20 mmHg increase from baseline 
 
>140 mmHg & >10 mmHg increase from baseline 
>140 mmHg & >20 mmHg increase from baseline 
>160 mmHg & >10 mmHg increase from baseline 
>160 mmHg & >20 mmHg increase from baseline 
 
SBP decrease 
 
<90 mmHg 
<80 mmHg 
>10 mmHg decrease from baseline 
>20 mmHg decrease from baseline 
 
<90 mmHg and >10 mmHg decrease from baseline 
<90 mmHg and >20 mmHg decrease from baseline 
<80 mmHg and >10 mmHg decrease from baseline 
<80 mmHg and >20 mmHg decrease from baseline 
Per HV grade 1, 3, plus shift change 
DBP 
increased 
>90 mmHg 
>100 mmHg 
>5 mmHg increase from baseline 
>10 mmHg increase from baseline 
 
>90 mmHg and >5 mmHg increase from baseline 
>90 mmHg and >10 mmHg increase from baseline 
>100 mmHg and >5 mmHg increase from baseline 
>100 mmHg and >10 mmHg increase from baseline 
 
DBP 
decreased 
 
<60 mmHg 
<45 mmHg 
>5 mmHg decrease from baseline 
>10 mmHg decrease from baseline 
 
<60 mmHg and >5 mmHg decrease from baseline 
<60 mmHg and >10 mmHg decrease from baseline 
<45 mmHg and >5 mmHg decrease from baseline 
<45 mmHg and >10 mmHg decrease from baseline 
 
Oxygen 
saturation 
decreased 
<88% 
<95% and decrease from baseline >5% of absolute 
oxygen saturation 
  
 
 
 
 


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12 
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