A Phase 3b Open-label Study Evaluating the Effects of Elexacaftor/Tezacaftor/Ivacaftor on Cough and Physical Activity in Cystic Fibrosis Subjects 12 Years of Age and Older Who Are Heterozygous for the F508del Mutation and a Minimal Function Mutation (F/MF)
Phase: PHASE3
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated



Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  2  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
2 
P R O T O C O L  S Y N O P SI S  
Titl e   A  P h as e  3 b  O p e n -l a b el  St u d y  E v al u ati n g t h e  Eff e cts  of 
El e x a c aft or/ T e z a c aft or/I v a c aft or  o n  C o u g h  a n d  P h ysi c al  A cti vit y i n  C ysti c 
Fi br osis  S u bj e cts  1 2  Y e ars  of  A g e  a n d  Ol d er  W h o  Ar e  H et er o z y g o us f or t h e 
F 5 0 8 d el  M ut ati o n  a n d  a  Mi ni m al  F u n cti o n  M ut ati o n ( F/ M F)  
  
B ri ef  Titl e   A  St u d y t o  E v al u at e  E L X/ T E Z/I V A  o n  C o u g h  a n d  P h ysi c al  A cti vit y i n  S u bj e cts 
wit h  C ysti c  Fi br osis ( C F)  
   
Cli ni c al  P h as e  a n d 
Cli ni c al  St u d y  T y p e   
P h as e  3 b, i n v esti g ati o n  of  c o u g h  a n d  p h ysi c al  a cti vit y  
  
O bj e cti v e   T o  e v al u at e t h e  eff e cts  of  el e x a c aft or/t e z a c aft or/i v a c aft or ( E L X/ T E Z/I V A)  o n 
c o u g h  a n d  p h ysi c al  a cti vit y  usi n g  w e ar a bl e t e c h n ol o g y   
  
E n d p oi nts   Pri m ar y  E n d p oi nt  
P er c e nt r e d u cti o n fr o m  b as eli n e i n  c o u g h fr e q u e n c y ( c o u g h  e v e nts  p er  d a y) t o t h e 
a v er a g e  of  W e e k  8 t hr o u g h  W e e k  1 2   
S e c o n d ar y  E n d p oi nt  
A bs ol ut e  c h a n g e fr o m  b as eli n e i n t ot al st e p  c o u nt  p er  d a y t o t h e  a v er a g e  of 
W e e k  8 t hr o u g h  W e e k  1 2  

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  5  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
3 
S C H E D U L E  O F  A S S E S S M E N T S  
S c h e d ul es  of  ass ess m e nts  ar e i n  T a bl e   3- 1  a n d T a bl e   3- 2. 
 
T a bl e  3- 1  
St u d y  V X 2 0 - 4 4 5- 1 2 6:  S c r e e ni n g 
E v e nt/ Ass ess m e nt  
S c r e e ni n g  Visit  
D a y  -4 2 t o  D a y  -1 5  
 
C o m m e nts  
St u d y  visit  
X  
T h e  S cr e e ni n g  Visit  m ust  b e  p erf or m e d i n t h e  cli ni c.  
I nf or m e d c o ns e nt ( a n d  ass e nt, if 
a p pli c a bl e)  
X  
El e ctr o ni c  c o ns e nt  m a y  b e  us e d,  as  a p pli c a bl e, if 
p er mitt e d  b y l o c al r e g ul ati o ns. If  n ot  p er mitt e d  or if 
s u bj e ct  d e cli n es  el e ctr o ni c  c o ns e nt, s u bj e cts  will si g n  a 
p a p er  c o ns e nt f or m.   
D e m o gr a p hi cs  
X  
S e cti o n  1 1. 1  
M e di c al  hist or y  
X  
S e cti o n  1 1. 1  
M e di c ati o ns  r e vi e w 
X  
I nf or m ati o n r e g ar di n g  m e di c ati o ns t a k e n  wit hi n  5 6 d a ys 
b ef or e t h e  S cr e e ni n g  Visit  will  b e  c oll e ct e d ( S e cti o n  9. 5 ) 
H ei g ht  a n d  w ei g ht  
X  
M e as ur e d  wit h s h o es  off ( S e cti o n  1 1. 1 ) 
C o m pl et e  P E  
X  
S e cti o n  1 1. 4. 3  
C F  g e n ot y p e  
X  
If t h e C F T R  g e n ot y p e r es ult is  n ot r e c ei v e d  b ef or e t h e 
first  d os e  of st u d y  dr u g,  a  pr e vi o us C F T R   g e n ot y p e 
l a b or at or y r e p ort  m a y  b e  us e d t o  est a blis h  eli gi bility 
( S e cti o n 8. 1 )  S u bj e cts  w h o  h a v e  b e e n  e nr oll e d a n d  w h os e 
s cr e e ni n g  g e n ot y p e  d o es  n ot  c o nfir m st u d y  eli gi bilit y 
m ust  b e  dis c o nti n u e d fr o m t h e st u d y  ( S e cti o n 9. 9 ). 
F S H  
X  
P erf or m e d f or  a n y s us p e ct e d  m e n o p a us al f e m al e  wit h  at 
l e ast  1 2  m o nt hs  of  c o nti n u o us s p o nt a n e o us  a m e n orr h e a 
( S e cti o n 1 1. 4. 2 ) 
S er u m  pr e g n a n c y ( all f e m al e 
s u bj e cts) 
X  
S e cti o n  1 1. 4. 2  
S er u m  c h e mistr y (i n cl u di n g  cr e ati n e 
ki n as e)  
X  
H e m at ol o g y  
X  
A d v ers e  e v e nts  
C o nti n u o us, fr o m t h e 
d at e  of i nf or m e d  c o ns e nt 
t hr o u g h  c o m pl eti o n  of 
st u d y  p arti ci p ati o n 
S e cti o n  1 3. 1 ;  c o m pl eti o n  of st u d y  p arti ci p ati o n is  d efi n e d 
i n  S e cti o n 9. 1. 6 . 
F S H: f olli cl e sti m ul ati n g  h or m o n e;  P E:  p h ysi c al  e x a mi n ati o n  

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 , V ersi o n  1. 0  
P a g e  7  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
T a bl e  3- 2  
St u d y  V X 2 0 - 4 4 5- 1 2 6:  B as eli n e  P e ri o d,  T r e at m e nt  P e ri o d,  a n d  S af et y  F oll o w-u p  Visit  
E v e nt/ Ass ess m e nt a 
B as eli n e 
P e ri o d  
T r e at m e nt  P e ri o d  
E T T 
Visit   
S af et y 
F oll o w- u p 
Visit   
( 2 8 
±  7  D a ys 
Aft e r  L ast 
D os e  of 
St u d y 
D r u g) b  
C o m m e nts  
D a y  -1 4 
t o 
D a y  -1   
D a y  1  
W e e ks  2, 
3,  5,  6,  7, 
9   1 0   1 1   
W e e k  4   
W e e k  8   
W e e k  1 2   
W e e k  1 3  
Pr e g n a n c y t est ( all 
f e m al e s u bj e cts) 
  
Uri n e   
  
Uri n e   
Uri n e   
Uri n e   
  
Uri n e   
Uri n e   
D uri n g t h e  Tr e at m e nt  P eri o d, 
a  uri n e  pr e g n a n c y t est  will  b e 
p erf or m e d  wit h  a  h o m e  kit 
pr o vi d e d  b y t h e st u d y  sit e. 
R es ults  will  b e r e p ort e d t o t h e 
sit e ( S e cti o n 1 1. 4. 2 ). 
S er u m  c h e mistr y   
  
X   
 
  
 
 
X   
X   
X   
S e cti o n  1 1. 4. 2  

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 , V ersi o n  1. 0  
P a g e  8  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
T a bl e  3- 2  
St u d y  V X 2 0 - 4 4 5- 1 2 6:  B as eli n e  P e ri o d,  T r e at m e nt  P e ri o d,  a n d  S af et y  F oll o w-u p  Visit  
E v e nt/ Ass ess m e nt a 
B as eli n e 
P e ri o d  
T r e at m e nt  P e ri o d  
E T T 
Visit   
S af et y 
F oll o w- u p 
Visit   
( 2 8 
±  7  D a ys 
Aft e r  L ast 
D os e  of 
St u d y 
D r u g) b  
C o m m e nts  
D a y  -1 4 
t o 
D a y  -1   
D a y  1  
W e e ks  2, 
3,  5,  6,  7, 
9,  1 0,  1 1   
W e e k  4   
W e e k  8   
W e e k  1 2   
W e e k  1 3  
C o u g h  m e as ur e m e nts   
D a y  -1 4, 
D a y  - 7 
  
X   
X  
X   
X  
  
  
  
C o u g h  m o nit ori n g s yst e m  will 
b e  us e d f or  a si n gl e  d a y 
( d efi n e d  b y  2 4  c o nti n u o us 
h o urs)  at  e a c h ti m e  p oi nt 
( S e cti o n 1 1. 2. 1 ). S u bj e cts  will 
p ut t h e  c o u g h  d e vi c e  o n  u n d er 
dir e ct  o bs er v ati o n  at t h e ti m e 
of  c o nt a ct  b et w e e n t h e s u bj e ct 
a n d i n v esti g at or  or sit e 
p ers o n n el (i. e., i n  p ers o n  or 
t ele m e di ci n e  c o nt a ct ). 
A cti vit y 
m e as ur e m e nts 
C o nti n u o us fr o m  D a y  -1 4 t hr o u g h  W e e k  1 3  Visit  
  
  
  
Wrist -w or n  a cti gr a p h y s e ns or 
will  b e  w or n  2 4  h o urs  p er  d a y 
d uri n g t h e  B as eli n e  P eri o d 
a n d  Tr e at m e nt  P eri o d 
( S e cti o n 1 1. 2. 2 ). 
A d v ers e  e v e nts  
C o nti n u o us fr o m  d at e  of i nf or m e d  c o ns e nt t hr o u g h  c o m pl eti o n  of st u d y  p arti ci p ati o n  
C o m pl eti o n  of st u d y 
p arti ci p ati o n is  d efi n e d i n 
S e cti o n  9. 1. 6 . 
M e di c ati o ns r e vi e w  
C o nti n u o us fr o m  d at e  of i nf or m e d  c o ns e nt t hr o u g h  c o m pl eti o n  of st u d y  p arti ci p ati o n  
Tr e at m e nt  a n d 
pr o c e d ur es r e vi e w  
C o nti n u o us fr o m  d at e  of i nf or m e d  c o ns e nt t hr o u g h  c o m pl eti o n  of st u d y  p arti ci p ati o n  

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  1 0  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
4 
T A B L E  O F  C O N T E N T S  
1  
Titl e  P a g e  ................................................................................................................................  1 
2  
P r ot o c ol  S y n o psis  ...................................................................................................................  2 
3  
S c h e d ul e  of  Ass ess m e nts  ........................................................................................................  5 
4  
T a bl e  of  C o nt e nts  .................................................................................................................  1 0 
List  of  T a bl es  ...........................................................................................................................  1 3 
List  of  Fi g ur es ..........................................................................................................................  1 3  
List  of  A b br e vi ati o ns ...............................................................................................................  1 4  
5  
I nt r o d u cti o n ..........................................................................................................................  1 6 
5. 1  
B a c k gr o u n d .....................................................................................................................  1 6  
5. 2  
St u d y  R ati o n al e ..............................................................................................................  1 6  
6  
St u d y  O bj e cti v e  ....................................................................................................................  1 6 
7  
St u d y  E n d p oi nts  ...................................................................................................................  1 7 
7. 1  
Pri m ar y  E n d p oi nt ............................................................................................................  1 7  
7 2  
S e c o n d ar y  E n d p oi nt 
  1 7 
8  
St u d y  P o p ul ati o n ..................................................................................................................  1 7  
8. 1  
I n cl usi o n  Crit eri a ............................................................................................................  1 8 
8. 2  
E x cl usi o n  Crit eri a  ...........................................................................................................  1 8 
9  
St u d y I m pl e m e nt ati o n  .........................................................................................................  2 0 
9. 1  
St u d y  D esi g n ..................................................................................................................  2 0  
9. 1. 1  
S cr e e ni n g  ................................................................................................................  2 0 
9. 1. 1. 1  
R e p etiti o n  of  S cr e e ni n g  Ass ess m e nt(s)  ............................................................  2 0 
9. 1. 1. 2  
R es cr e e ni n g  ......................................................................................................  2 0 
9. 1. 1. 3  
E xt e nsi o n  of  S cr e e ni n g  P eri o d  Wi n d o w ..........................................................  2 1  
9. 1. 2  
Tr e at m e nt  P eri o d  ....................................................................................................  2 1 
9. 1. 3  
F oll o w- u p ................................................................................................................  2 1  
9. 1. 4  
E arl y  T er mi n ati o n  of  Tr e at m e nt  .............................................................................  2 1 
9. 1. 5  
L ost t o  F oll o w- u p ...................................................................................................  2 1  
9. 1. 6  
C o m pl eti o n  of  St u d y  P arti ci p ati o n .........................................................................  2 2  
9. 1. 7  
Us e  of  R e m ot e  M e as ur es  ........................................................................................  2 2 
9. 2  
M et h o d  of  Assi g ni n g  S u bj e cts t o  Tr e at m e nt  Gr o u ps .....................................................  2 2  
9. 3  
R ati o n al e  f or  St u d y  El e m e nts .........................................................................................  2 2 
9. 3. 1  
St u d y  D esi g n ...........................................................................................................  2 2  
9. 3. 2  
St u d y  P o p ul ati o n.....................................................................................................  2 3  
9. 3. 3  
St u d y  Dr u g  D os e ....................................................................................................  2 3  
9. 3. 4  
R ati o n al e f or  St u d y  Ass ess m e nts  ...........................................................................  2 3 
9. 4  
St u d y  R estri cti o ns ...........................................................................................................  2 4  
9. 5  
Pri or  a n d  C o n c o mit a nt  M e di c ati o ns ...............................................................................  2 4  
9. 6  
A d mi nistr ati o n  ................................................................................................................  2 5 
9. 6. 1  
D osi n g .....................................................................................................................  2 5  
9. 6. 2  
Miss e d  D os es  ..........................................................................................................  2 6 
9. 7  
D os e  M o difi c ati o n f or  T o xi cit y ......................................................................................  2 6  
9. 8  
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 es .................................................................  2 6  
9. 8. 1  
Li v er  F u n cti o n  T ests  ...............................................................................................  2 6 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  1 1  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
9. 8. 2  
R as h  ........................................................................................................................  2 7 
9. 9  
R e m o v al  of  S u bj e cts  .......................................................................................................  2 7 
9. 1 0  R e pl a c e m e nt  of  S u bj e cts  ................................................................................................  2 8 
1 0  St u d y  D r u g I nf o r m ati o n  a n d  M a n a g e m e nt  .......................................................................  2 8 
1 0. 1  Pr e p ar ati o n  a n d  Dis p e nsi n g  ............................................................................................  2 8 
1 0. 2  P a c k a gi n g  a n d  L a b eli n g .................................................................................................  2 8  
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 ...................................................................  2 8  
1 0. 4  Dr u g  A c c o u nt a bilit y .......................................................................................................  2 9  
1 0. 5  Dis p os al,  R et ur n,  or  R et e nti o n  of  U n us e d  Dr u g .............................................................  2 9  
1 0. 6  C o m pli a n c e .....................................................................................................................  2 9  
1 0. 7  Bli n di n g  a n d  U n bli n di n g ................................................................................................  3 0  
1 1  Ass ess m e nts  ..........................................................................................................................  3 0 
1 1. 1  S u bj e ct  a n d  Dis e as e  C h ar a ct eristi cs  ...............................................................................  3 0 
1 1. 2  Effi c a c y  ...........................................................................................................................  3 0 
1 1. 2. 1  
C o u g h  M e as ur e m e nts  .............................................................................................  3 0 
1 1. 4  S af et y  ..............................................................................................................................  3 2 
1 1. 4. 1  
A d v ers e  E v e nts .......................................................................................................  3 2  
1 1. 4. 2  
Cli ni c al  L a b or at or y  Ass ess m e nts  ...........................................................................  3 2 
1 1. 4. 3  
P h ysi c al  E x a mi n ati o ns 
 ..................................................................  3 4 
1 1. 4. 6. 1  C o ntr a c e pti o n ...................................................................................................  3 5  
1 1. 4. 6. 2  Pr e g n a n c y .........................................................................................................  3 6  
1 2  St atisti c al  A n al ysis  ...............................................................................................................  3 7 
1 2. 1  S a m pl e  Si z e  a n d  P o w er  ..................................................................................................  3 7 
1 2. 2  A n al ysis  S ets  ..................................................................................................................  3 7 
1 2. 3  St atisti c al  A n al ysis  .........................................................................................................  3 7 
1 2. 3. 1  
G e n er al  C o nsi d er ati o ns  ...........................................................................................  3 7 
1 2. 3. 2  
B a c k gr o u n d  C h ar a ct eristi cs ....................................................................................  3 8  
1 2. 3. 3  
Effi c a c y  A n al ysis  ....................................................................................................  3 8 
1 2. 3. 3. 1  A n al ysis  of  Pri m ar y  E n d p oi nt ..........................................................................  3 8  
1 2. 3. 3. 2  A n al ysis  of  S e c o n d ar y  E n d p oi nt ......................................................................  3 8  
1 2. 3. 3. 3  M ulti pli cit y  A dj ust m e nt  ...................................................................................  3 9 
1 2. 3. 3. 4  Missi n g  D at a  H a n dli n g ....................................................................................  3 9  
1 2. 3. 4  
S af et y  A n al ysis  .......................................................................................................  3 9 
1 2. 4  I nt eri m  A n al ysis .............................................................................................................  3 9 
1 2. 5  D at a  M o nit ori n g  C o m mitt e e  A n al ysis  ............................................................................  3 9 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  1 2  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
1 3  P r o c e d u r al,  Et hi c al,  R e g ul at o r y,  a n d  A d mi nist r ati v e  C o nsi d e r ati o ns  ...........................  3 9 
1 3. 1  A d v ers e  E v e nt  a n d  S eri o us  A d v ers 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 ........................................................................................................................  3 9  
1 3. 1. 1  
A d v ers e  E v e nts .......................................................................................................  3 9  
1 3. 1. 1. 1  D efi niti o n  of  a n  A d v ers e  E v e nt........................................................................  3 9  
1 3. 1. 1. 2  Cli ni c all y  Si g nifi c a nt  Ass ess m e nts  ..................................................................  4 0 
1 3. 1. 1. 3  D o c u m e nt ati o n  of  A d v ers e  E v e nts...................................................................  4 0  
1 3. 1. 1. 4  A d v ers e  E v e nt  S e v erit y  ....................................................................................  4 1 
1 3. 1. 1. 5  A d v ers e  E v e nt  C a us alit y  ..................................................................................  4 1 
1 3. 1. 1. 6  St u d y  Dr u g  A cti o n  T a k e n ................................................................................  4 2  
1 3. 1. 1. 7  A d v ers e  E v e nt  O ut c o m e ..................................................................................  4 2  
1 3. 1. 1. 8  Tr e at m e nt  Gi v e n ...............................................................................................  4 2 
1 3. 1. 2  
S eri o us  A d v ers e  E v e nts  ..........................................................................................  4 3 
1 3. 1. 2. 1  D efi niti o n  of  a  S eri o us  A d v ers e  E v e nt.............................................................  4 3  
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 us  A d v ers e  E v e nts ..............................  4 3  
1 3. 1. 2. 3  E x p e dit e d  R e p orti n g  a n d I n v esti g at or  S af et y  L ett ers ......................................  4 4  
1 3. 2  A d mi nistr ati v e  R e q uir e m e nts  .........................................................................................  4 4 
1 3. 2. 1  
Pr o d u ct  C o m pl ai nts ................................................................................................  4 4  
1 3. 2. 2  
Et hi c al  C o nsi d er ati o ns  ............................................................................................  4 4 
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 ns e nt  ...........................................................  4 5 
1 3. 2. 4  
I n v esti g at or C o m pli a n c e .........................................................................................  4 5  
1 3. 2. 5  
A c c ess t o  R e c or ds  ...................................................................................................  4 5 
1 3. 2. 6  
S u bj e ct  Pri v a c y  .......................................................................................................  4 5 
1 3. 2. 7  
R e c or d  R et e nti o n ....................................................................................................  4 5  
1 3. 2. 8  
St u d y  T er mi n ati o n ..................................................................................................  4 6  
1 3. 2. 9  
E n d  of  St u d y ...........................................................................................................  4 6  
1 3. 3  D at a  Q u alit y  Ass ur a n c e  ..................................................................................................  4 6 
1 3. 4  M o nit ori n g ......................................................................................................................  4 6  
1 3. 5  El e ctr o ni c  D at a  C a pt ur e  .................................................................................................  4 7 
1 3. 6  C o nfi d e nti alit y  a n d  Dis cl os ur e .......................................................................................  4 7  
1 3. 7  P u bli c ati o ns  a n d  Cli ni c al  St u d y  R e p ort ..........................................................................  4 8  
1 3. 7. 2  
Cli ni c al  St u d y  R e p ort  .............................................................................................  4 9 
1 4  R ef e r e n c es  .............................................................................................................................  5 0 
A P P E N DI X  A  Eli gi bl e  M F  C F T R  M ut ati o ns .......................................................................  5 2  
1 5  P r ot o c ol  Si g n at u r e  P a g es ....................................................................................................  5 5  
1 5. 1  S p o ns or  Si g n at ur e  P a g e ..................................................................................................  5 5  
1 5. 2  I n v esti g at or  Si g n at ur e  P a g e ............................................................................................  5 6 
 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  1 3  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
Li st  of  T a bl e s  
T a bl e  3 - 1 
St u d y  V X 2 0- 4 4 5- 1 2 6:  S cr e e ni n g ............................................................................  5 
T a bl e  3 - 2 
St u d y  V X 2 0- 4 4 5- 1 2 6:  B as eli n e  P eri o d,  Tr e at m e nt  P eri o d,  a n d  S af et y  F oll o w- u p 
Visit  .........................................................................................................................  6 
T a bl e  9 - 1 
Pr o hi bit e d  M e di c ati o ns  .........................................................................................  2 4 
T a bl e  1 0- 1  
St u d y  Dr u g ............................................................................................................  2 9  
T a bl e  1 1- 1  
S af et y  L a b or at or y  T est  P a n els  ..............................................................................  3 3 
T a bl e   1 1- 2 
A c c e pt a bl e  M et h o ds  of  C o ntr a c e pti o n  ..................................................................  3 6 
T a bl e  1 2- 1  
9 5 %  C o nfi d e n c e I nt er v als f or  P er c e nt  R e d u cti o n i n  C o u g h  Fr e q u e n c y  p er  D a y 
Fr o m  B as eli n e  .......................................................................................................  3 7 
T a bl e   1 3- 1 
Gr a di n g  of  A E  S e v erit y  ........................................................................................  4 1 
T a bl e   1 3- 2 
Cl assifi c ati o ns f or  A E  C a us alit y  ...........................................................................  4 1 
T a bl e   1 3- 3 
Cl assifi c ati o ns f or  St u d y  Dr u g  A cti o n  T a k e n  Wit h  R e g ar d t o  a n  A E ..................  4 2  
T a bl e   1 3- 4 
Cl assifi c ati o ns f or  O ut c o m e  of  a n  A E  ..................................................................  4 2 
Li st  of  Fi g ur e s  
Fi g ur e  2- 1  
V X 2 0 - 4 4 5- 1 2 6  St u d y  D esi g n .................................................................................  3 
Fi g ur e  9- 1  
V X 2 0 - 4 4 5- 1 2 6  St u d y  D esi g n ...............................................................................  2 0 
 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  1 4  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
Li st  of  A b br e vi ati o n s  
A b b r e vi ati o n   
D efi niti o n  
A D L  
a cti viti es  of  d ail y li vi n g  
A Es  
a d v ers e  e v e nts  
A L P  
al k ali n e  p h os p h at as e  
A L T  
al a ni n e tr a ns a mi n as e  
A S T  
As p art at e tr a ns a mi n as e  
β  
b et a,  a p p ar e nt  eli mi n ati o n r at e  c o nst a nt  
C D  
c o m p a ct  dis c  
C F  
C ysti c  Fi br osis  
C F T R  
C F  tr a ns m e m br a n e  c o n d u ct a n c e r e g ul at or  pr ot ei n 
C F T R  
C F tr a ns m e m br a n e  c o n d u ct a n c e r e g ul at or  g e n e  
C R F  
c as e r e p ort f or m  
C S R  
cli ni c al st u d y r e p ort  
C T C A E  
C o m m o n  T er mi n ol o g y  Crit eri a f or  A d v ers e  E v e nts  
C Y P  
C yt o c hr o m e  P 4 5 0  
E D C  
el e ctr o ni c  d at a  c a pt ur e  
E E N T  
e y es,  e ars,  n os e,  a n d t hr o at  
E L X  
el e x a c aft or  
E T T  
E arl y  T er mi n ati o n  of  Tr e at m e nt  
E U  
E ur o p e a n  U ni o n  
F/ M F  
F 5 0 8 d el  m ut ati o n  a n d  a  mi ni m al f u n cti o n  m ut ati o n  
F 5 0 8 d el  
C F T R  g e n e  m ut ati o n  wit h  a n i n -fr a m e  d el eti o n  of  a  p h e n yl al a ni n e  c o d o n 
c orr es p o n di n g t o  p ositi o n  5 0 8  of t h e  wil d -t y p e  pr ot ei n 
F A S  
F ull  A n al ysis  S et  
F D A  
F o o d  a n d  Dr u g  A d mi nistr ati o n  
F D C  
fi x e d-d os e  c o m bi n ati o n  
F E F 2 5 %- 7 5 % 
f or c e d  e x pir at or y fl o w, mi d e x pir at or y  p h as e  
F E V 1 
f or c e d  e x pir at or y  v ol u m e i n  1 s e c o n d 
F S H  
f olli cl e-sti m ul ati n g  h or m o n e 
F V C  
f or c e d  vit al  c a p a cit y 
G C P  
G o o d  Cli ni c al  Pr a cti c e  
G G T  
g a m m a -gl ut a m yl tr a nsf er as e  
G LI  
Gl o b al  L u n g  F u n cti o n I niti ati v e  
G P P 3  
G o o d  P u bli c ati o n  Pr a cti c e  
G P S  
Gl o b al  P ati e nt  S af et y  
I C F 
i nf or m e d  c o ns e nt f or m 
I C H 
I nt er n ati o n al  C o u n cil f or  H ar m o ni z ati o n 
I C MJ E 
I nt er n ati o n al  C o m mitt e e  of  M e di c al J o ur n al  E dit ors 
I E C 
i n d e p e n d e nt  et hi cs  c o m mitt e e 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  1 5  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
A b b r e vi ati o n   
D efi niti o n  
I M P 
i n v esti g ati o n al  m e di ci n al  pr o d u ct 
I N D 
I n v esti g ati o n al  N e w  Dr u g ( a p pli c ati o n) ( U S) 
I R B 
i nstit uti o n al r e vi e w  b o ar d 
I V A 
i v a c aft or 
I W R S 
i nt er a cti v e  w e b r es p o ns e s yst e m 
L U M  
l u m a c aft or 
m a x  
m a xi m u m  v al u e  
M F  
mi ni m al f u n cti o n  
mi n  
mi ni m u m  v al u e  
M M R M  
mi x e d -eff e cts  m o d el f or r e p e at e d  m e as ur es  
P  
pr o b a bilit y  
P C  
p u bli c ati o n  c o m mitt e e  
P E  
p h ysi c al  e x a mi n ati o n  
P -g p  
P -gl y c o pr ot ei n  
PI  
pri n ci p al i n v esti g at or  
p p F E V 1 
p er c e nt  pr e di ct e d f or c e d  e x pir at or y  v ol u m e i n  1 s e c o n d  
q 1 2 h  
e v er y  1 2  h o urs  
q d  
o n c e  d ail y  
Q T c F  
Q T i nt er v al  c orr e ct e d  b y  Fri d eri ci a’s f or m ul a  
S A E  
s eri o us  a d v ers e  e v e nt  
S A P  
st atisti c al  a n al ysis  pl a n  
S C  
st e eri n g  c o m mitt e e  
S D  
st a n d ar d  d e vi ati o n  
S U S A Rs  
s eri o us  a d v ers e r e a cti o ns  
T E  
Tr e at m e nt -e m er g e nt  
T E A Es  
tr e at m e nt  e m er g e nt  a d v ers e  e v e nts 
T E Z  
t e z a c aft or 
U L N  
u p p er li mit  of  n or m al  
U S  
U nit e d  St at es  
 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  1 6  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati 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  
C ysti c fi br osis ( C F) is  a n  a ut os o m al r e c essi v e  g e n eti c  dis e as e  wit h s eri o us  m or bi diti es  a n d 
fr e q u e nt  pr e m at ur e  m ort alit y.  C F  aff e cts  m or e t h a n  8 0, 0 0 0 i n di vi d u als  w orl d wi d e 
( a p pr o xi m at el y  3 1, 0 0 0 i n t h e  U S  a n d  4 9, 0 0 0 i n t h e  E U).1- 4  
C F is  c a us e d  b y  d e cr e as e d  q u a ntit y  a n d/ or f u n cti o n  of t h e  C F T R  pr ot ei n  d u e t o  m ut ati o ns i n t h e 
C F T R   ge n e. 5 C F T R is  a  c h a n n el t h at r e g ul at es  t h e fl o w  of  c hl ori d e  a n d  ot h er  a ni o ns  a cr oss 
e pit h eli a i n  m ulti pl e  or g a ns  a n d tiss u es, i n cl u di n g t h e l u n gs,  p a n cr e as  a n d  ot h er  g astr oi nt esti n al 
or g a ns,  a n d s w e at  gl a n ds. 6 D es pit e  pr o gr ess i n t h e tr e at m e nt  of  C F  wit h s y m pt o m ati c t h er a pi es, 
t h e  c urr e nt  m e di a n  a g e  at  d e at h  a m o n g  p e o pl e  wit h  C F is  a ppr o xi m at el y  3 0  y e ars,  a n d t h e 
pr e di ct e d  m e di a n  a g e  of s ur vi v al is  a p pr o xi m at el y  4 7  y e ars. 1 , 2 M or e  eff e cti v e tr e at m e nts  ar e 
n e e d e d f or  C F.  
T h e  m ost  c o m m o n  dis e as e- c a usi n g  m ut ati o n is  F 5 0 8 d el :  a p pr o xi m at el y  8 5. 3 %  of  p e o pl e  wit h  C F 
i n t he  U S  a n d  8 0. 6 % i n  E ur o p e  h a v e  at l e ast  o n e  F 5 0 8 d el  all el e. 1 , 2 
At  pr es e nt  C F  d o es  n ot  h a v e  a  c ur e.  C F T R  m o d ul at ors (i. e.,  c orr e ct ors  a n d  p ot e nti at ors) r e pr es e nt 
a  m aj or  a d v a n c e m e nt i n t h e tr e at m e nt  of  C F  b e c a us e t h e y  ar e s yst e mi c t h er a pi es t h at t ar g et t h e 
u n d erl yi n g  c a us e  of t h e  dis e as e  a n d  h a v e  b e e n s h o w n t o i m pr o v e  C F s ur vi v al  b y  m o dif yi n g t h e 
c o urs e  of  dis e as e. 7 , 8  T h e  cli ni c al t esti n g  a n d r e g ul at or y  a p pr o v al  of  C F T R  m o d ul at ors i n  c ert ai n 
c o u ntri es f or t h e tr e at m e nt  of  p e o pl e  wit h  C F  c a us e d  b y s p e cifi c  C F T R  g e n ot y p es  h a v e 
est a blis h e d t h e t h er a p e uti c  v al u e  of s p e cifi c r e gi m e ns  d e v el o p e d  b y  V ert e x.  T h es e tr e at m e nt 
r e gi m e ns i n cl u d e i v a c aft or (I V A)  m o n ot h er a p y ( K al y d e c o ™), l u m a c aft or ( L U M)/I V A  d u al 
c o m bi n ati o n t h er a p y ( Or k a m bi ™ ), t e z a c aft or ( T E Z)/I V A  d u al  c o m bi n ati o n t h er a p y 
( S y m d e k o ™,  S y m k e vi ™), a n d  el e x a c aft or ( E L X)/ T E Z/I V A tri pl e  c o m bi n ati o n t h er a p y 
( Tri k aft a™ ,  K aftri o™).  
T h e  E L X/ T E Z/I V A r e gi m e n is t h e first  m e di ci n e t o  d e m o nstr at e  cli ni c al  b e n efit i n  p ati e nts  wit h 
a si n gl e  F 5 0 8 d el  all el e, r e g ar dl ess  of t h e  m ut ati o n  of t h e s e c o n d  all el e.  A  pi v ot al  P h as e  3 
pr o gr a m i n  C F s u bj e cts  1 2  y e ars  of  a g e  or  ol d er  d e m o nstr at e d t h at  E L X/ T E Z/I V A  pr o vi d es 
s u bst a nti al i m pr o v e m e nts i n l u n g f u n cti o n,  C F T R f u n cti o n,  a n d  n utriti o n al st at us,  a n d  w as 
g e n er all y s af e  a n d  w ell t ol er at e d  wit h  a l o w r at e  of tr e at m e nt  dis c o nti n u ati o n.  
5. 2   
St u d y  R ati o n al e  
W e ar a bl e t e c h n ol o gi es  c a n  pr o vi d e  v al u a bl e i nf or m ati o n  o n  a s u bj e ct’s  c o u g h fr e q u e n c y, 
p h ysi c al  a cti vit y, 
 i n  a r e al- w orl d s etti n g;  h o w e v er, t h es e t e c h n ol o gi es  h a v e  n ot 
b e e n  wi d el y  us e d i n t h e  C F  p o p ul ati o n,  es p e ci all y i n t h os e  o n  hi g hl y  eff e cti v e  C F T R  m o d ul at or 
t h er a p y.  T h e  p ur p os e  of t his st u d y is t o  e v al u at e t h e  eff e ct  of  E L X/ T E Z/I V A  o n  c o u g h  a n d 
p h ysi c al  a cti vit y  usi n g  w e ar a bl e t e c h n ol o g y i n  C F s u bj e cts  h et er o z y g o us f or  F 5 0 8 d el   a n d  a 
s e c o n d C F T R  all el e  c arr yi n g  a  mi ni m al f u n cti o n ( M F)  m ut ati o n t h at is  n ot r es p o nsi v e t o I V A  or 
T E Z/I V A ( F / M F  g e n ot y p es).  
6 
S T U D Y  O B J E C TI V E  
T o  e v al u at e t h e  eff e cts  of  E L X/ T E Z/I V A  o n  c o u g h  a n d  p h ysi c al  a cti vit y  usi n g  w e ar a bl e 
t e c h n ol o g y 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  1 7  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
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  
P er c e nt r e d u cti o n fr o m  b as eli n e i n  c o u g h fr e q u e n c y ( c o u g h  e v e nts  p er  d a y) t o t h e  a v er a g e  of 
W e e k  8 t hr o u g h  W e e k  1 2 
7. 2   
S e c o n d ar y  E n d p oi nt  
A bs ol ut e  c h a n g e fr o m  b as eli n e i n t ot al st e p  c o u nt  p er  d a y t o t h e  a v er a g e  of  W e e k  8 t hr o u g h 
8 
S T U D Y  P O P U L A TI O N  
Eli gi bilit y  will  b e r e vi e w e d  a n d  d o c u m e nt e d  b y  a n  a p pr o pri at el y  q u alifi e d  m e m b er  of t h e 
i n v esti g at or’s t e a m  b ef or e s u bj e cts  ar e  e nr oll e d. 
S u bj e ct s  w h o  m e et  all  of t h e i n cl usi o n  crit eri a  a n d  n o n e  of t h e  e x cl usi o n  crit eri a  will  b e  eli gi bl e.  

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  1 8  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
8. 1   
I n cl u si o n  Crit eri a 
1.   S u bj e ct ( or  his  or  h er l e g all y  a p p oi nt e d  a n d  a ut h ori z e d r e pr es e nt ati v e)  will si g n  a n d  d at e  a n 
i nf or m e d  c o ns e nt f or m (I C F),  a n d,  w h e n  a p pr o pri ate,  a n  ass e nt f or m.  
2.   Willi n g  a n d  a bl e t o  c o m pl y  wit h s c h e d ul e d  visits, tr e at m e nt  pl a n, st u d y r estri cti o ns, 
l a b or at or y t ests,  c o ntr a c e pti v e  g ui d eli n es,  a n d  ot h er st u d y  pr o c e d ur es. 
3.   S u bj e cts ( m al e  a n d f e m al e)  1 2  y e ars  of  a g e  or  ol d er  o n t h e  d at e  of i nf or m e d  c o n s e nt. 
4.   S u bj e cts  h et er o z y g o us f or  F 5 0 8 d el   a n d  a n  M F  m ut ati o n ( F/ M F  g e n ot y p es, s e e A p p e n di x  A  
f or  d efi niti o n  a n d  n o n-e x h a usti v e list  of  eli gi bl e  M F  m ut ati o ns).  
a.   G e n ot y p e s h o ul d  b e  c o nfi r m e d  at t h e  S cr e e ni n g  Visit.  
b.   If t h e s cr e e ni n g C F T R   g e n ot y p e r es ult is  n ot r e c ei v e d  b ef or e t h e first  d os e  of st u d y  dr u g, 
a  pr e vi o us  C F T R   g e n ot y p e l a b or at or y r e p ort  m a y  b e  us e d t o  est a blis h  eli gi bilit y.  
c.   S u bj e cts  w h o  h a v e  b e e n  e nr oll e d  a n d  w h os e s cr e e ni n g  g e n ot y p e  d o es  n ot  c o nfir m st u d y 
eli gi bilit y  m ust  b e  dis c o nti n u e d fr o m t h e st u d y ( S e cti o n  9. 9 ). 
5.   F or c e d  e x pir at or y  v ol u m e i n  1 s e c o n d ( F E V 1)  v al u e  ≥ 3 0 %  a n d  ≤ 9 0 %  of  pr e di ct e d  m e a n f or 
a g e, s e x,  a n d  h ei g ht ( e q u ati o ns  of t h e  Gl o b al  L u n g  F u n cti o n I niti ati v e [ G LI]) 9 at t h e 
S cr e e ni n g  Visit (s pir o m etr y  m e as ur e m e nts  m ust  m e et  A m eri c a n  T h or a ci c  S o ci et y/ E ur o p e a n 
R es pir at or y  S o ci et y  crit eri a 1 0 f or  a c c e pt a bilit y  a n d r e p e at a bilit y)  a n d st a bl e  C F  dis e as e  as 
j u d g e d  b y t h e i n v esti g at or. 
6.   Willi n g t o r e m ai n  o n  a st a bl e  C F tr e at m e nt r e gi m e n ( ot h er t h a n  C F T R  m o d ul at ors) t hr o u g h 
c o m pl eti o n  of st u d y  p arti ci p ati o n. 
8. 2   
E x cl u si o n  Crit eri a  
1.   Hist or y  of  a n y ill n ess  o r  a n y  cli ni c al  c o n diti o n t h at, i n t h e  o pi ni o n  of t h e i n v esti g at or,  mi g ht 
c o nf o u n d t h e r es ults  of t h e st u d y  or  p os e  a n  a d diti o n al ris k i n  a d mi nist eri n g st u d y  dr u g(s) t o 
t h e s u bj e ct.  T his i n cl u d es,  b ut is  n ot li mit e d t o, t h e f oll o wi n g: 
•   Cli ni c all y  si g nifi c a nt li v er  cirr h osis  wit h  or  wit h o ut  p ort al  h y p ert e nsi o n  
•   S oli d  or g a n  or  h e m at ol o gi c al tr a ns pl a nt ati o n ( or  o n  a tr a ns pl a nt list)   
•   Al c o h ol  or  dr u g  a b us e i n t h e  p ast  y e ar, i n cl u di n g,  b ut  n ot li mit e d t o,  c a n n a bis,  c o c ai n e, 
a n d  o pi at es,  as  d e e m e d  b y  t h e i n v esti g at or 
•   C a n c er,  e x c e pt f or s q u a m o us  c ell s ki n  c a n c er,  b as al  c ell s ki n  c a n c er,  a n d  St a g e  0  c er vi c al 
c ar ci n o m a i n sit u ( all  3  wit h  n o r e c urr e n c e f or t h e l ast  5  y e ars)  
•   N o n - a m b ul at or y st at us 
2.   A n y  cli ni c all y si g nifi c a nt l a b or at or y  a b n or m aliti es  at t h e  S cr e e ni n g  Visit t h at  w o ul d i nt erf er e 
wit h t h e st u d y  ass ess m e nts  or  p os e  a n  u n d u e ris k f or t h e s u bj e ct ( as  d e e m e d  b y t h e 
i n v esti g at or). 
3.   A n y  of t h e f oll o wi n g  a b n or m al l a b or at or y  v al u es  at s cr e e ni n g:  
•   H e m o gl o bi n  < 1 0  g/ d L 
•   T ot al  bilir u bi n  ≥ 2  ×  u p p er li mit  of  n or m al ( U L N)  

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  1 9  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
•   As p art at e tr a ns a mi n as e ( A S T),  al a ni n e tr a ns a mi n as e ( A L T),  g a m m a -gl ut a m yl tr a nsf er as e 
( G G T),  or  al k ali n e  p h os p h at as e ( A L P)  ≥ 3  × U L N  
•   A b n or m al r e n al f u n cti o n  d efi n e d  as  gl o m er ul ar filtr ati o n r at e  ≤ 5 0   m L/ mi n/ 1. 7 3  m2 
( c al c ul at e d  by t h e  M o difi c ati o n  of  Di et i n  R e n al  Dis e as e  St u d y  E q u ati o n) 1 1 , 1 2 f or s u bj e cts 
≥ 1 8  y e ars  of  a g e  a n d  ≤ 4 5  m L/ mi n/ 1. 7 3   m2 ( c al c ul at e d  b y t h e  C o u n a h a n-B arr att 
e q u ati o n) 1 3 f or s u bj e cts  < 1 8  y e ars  of  a g e. 
4.   A n  a c ut e  u p p er  or l o w er r es pir at or y i nf e cti o n,  p ul m o n ar y  e x a c er b ati o n,  or  c h a n g es i n t h er a p y 
(i n cl u di n g  a nti bi oti cs) f or  p ul m o n ar y  dis e as e  wit hi n  2 8  d a ys  b ef or e  D a y  1 (first  d os e  of st u d y 
dr u g). 
5.   L u n g i nf e cti o n  wit h  or g a nis ms  ass o ci at e d  wit h  a  m or e r a pi d  d e cli n e i n  p ul m o n ar y st at us 
(i n cl u di n g,  b ut  n ot li mit e d t o, B ur k h ol d eri a  c e n o c e p a ci a , B ur k h ol d eri a  d ol os a ,  a n d 
M y c o b a ct eri u m  a bs c ess us ).  F or s u bj e cts  w h o  h a v e  h a d  a  hist or y  of  a  p ositi v e  c ult ur e, t h e 
i n v esti g at or  will  a p pl y t h e f oll o wi n g  crit eri a t o  est a blis h  w h et h er t h e s u bj e ct is fr e e  of 
i nf e cti o n  wit h s u c h  or g a nis ms: 
•   T h e s u bj e ct  h as  n ot  h a d  a r es pir at or y tr a ct  c ult ur e  p ositi v e f or t h es e  or g a nis ms  wit hi n t h e 
1 2  m o nt hs  b ef or e t h e  d at e  of i nf or m e d  c o ns e nt. 
•   T h e s u bj e ct  h as  h a d  at l e ast  2  r es pir at or y tr a ct  c ult ur es  n e g ati v e f or s u c h  or g a nis ms 
wit hi n t h e  1 2  m o nt hs  b ef or e t h e  d at e  of i nf or m e d  c o ns e nt,  wit h t h e first  a n d l ast  of t h es e 
s e p ar at e d b y  at l e ast  3   m o nt hs,  a n d t h e  m ost r e c e nt  o n e  wit hi n t h e  6 m o nt hs  b ef or e t h e 
d at e  of i nf or m e d  c o ns e nt. 
6.   A n  a c ut e ill n ess  n ot r el at e d t o  C F ( e. g.,  g astr o e nt eritis)  wit hi n  1 4  d a ys  b ef or e t h e first  d os e  of 
st u d y  dr u g ( D a y  1). 
7.   O n g oi n g  or  pri or  p arti ci p ati o n i n  a n i n v esti g ati o n al  dr u g st u d y  wit hi n  2 8  d a ys  of t h e 
S cr e e ni n g  Visit.   
•   A  w as h o ut  p eri o d  of  5 t er mi n al  h alf -li v es  of t h e  pr e vi o us i n v esti g ati o n al st u d y  dr u g,  or 
2 8  d a ys,  w hi c h e v er is l o n g er,  m ust  el a ps e  b ef or e t h e  S cr e e ni n g  Visit.   
•   T h e  d ur ati o n  of t h e  el a ps e d ti m e  m a y  b e l o n g er if r e q uir e d  b y l o c al r e g ul ati o ns.  
8.   Us e  of r estri ct e d  m e di c ati o n  wit hi n s p e cifi e d  d ur ati o n  b ef or e t h e first  d os e  of st u d y  dr u g  as 
d efi n e d i n  T a bl e  9- 1 . 
9.   Pr e g n a nt  a n d  br e ast -f e e di n g f e m al es.  All f e m al e s u bj e cts r e g ar dl ess  of  c hil d b e ari n g  p ot e nti al 
( S e cti o n 1 1. 4. 6 )  m ust  h a v e  a  n e g ati v e  pr e g n a n c y t est  at t h e  S cr e e ni n g  Visit  a n d t h e  D a y  1 
Visit.  
1 0.  T h e s u bj e ct  or  a  cl os e r el ati v e  of t h e s u bj e ct is t h e i n v esti g at or  or  a s u bi n v esti g at or, r es e ar c h 
assist a nt,  p h ar m a cist, st u d y  c o or di n at or,  or  ot h er st aff  dir e ctl y i n v ol v e d  wit h t h e  c o n d u ct  of 
t h e st u d y  at t h at sit e.  H o w e v er,  a n  a d ult ( a g e d  1 8  y e ars  or  ol d er)  w h o is  a r el ati v e  of  a st u d y 
st aff  m e m b er  m a y  b e  e nr oll e d i n t h e st u d y  pr o vi d e d t h at 
•   t h e  a d ult li v es i n d e p e n d e ntl y  of  a n d  d o es  n ot r esi d e  wit h t h e st u d y st aff  m e m b er,  a n d 
•   t h e  a d ult  p arti ci p at es i n t h e st u d y  at  a sit e  ot h er t h a n t h e sit e  at  w hi c h t h e f a mil y  m e m b er 
is  e m pl o y e d. 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  2 1  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
•   C F T R   g e n ot y pi n g 
•   F olli cl e -sti m ul ati n g  h or m o n e ( F S H) l e v el (if s er u m  F S H l e v el  w as i n t h e  p ost m e n o p a us al 
r a n g e  as  d et er mi n e d  b y t h e l a b or at or y  p erf or mi n g t h e t est  d uri n g  pri or s cr e e ni n g) 
•   O p ht h al m ol o gi c  e x a mi n ati o n (if  p erf or m e d  wit hi n  3  m o nt hs  b ef or e t h e  d at e  of i nf or m e d 
c o ns e nt) 
If  a s u bj e ct is r es cr e e n e d,  a  n e w s cr e e ni n g  wi n d o w  will  b e gi n  w h en t h e first r es cr e e ni n g 
ass ess m e nt  h as  b e e n i niti at e d.  
9. 1. 1. 3   
E xt e n si o n  of  S cr e e ni n g  P eri o d  Wi n d o w  
A s u bj e ct  m a y  h a v e t h e  S cr e e ni n g  P eri o d  wi n d o w  e xt e n d e d  b y  2  w e e ks f or t h e f oll o wi n g 
r e as o ns: 
•   R e p etiti o n  of t h e  S cr e e ni n g  P eri o d  ass ess m e nts ( S e cti o n  9. 1. 1. 1 ) 
•   U n e x p e ct e d  o p er ati o n al  or l o gisti c  d el a ys,  or t o  m e et t h e  eli gi bilit y  crit eri a  
•   S c h e d uli n g  of  o p ht h al m ol o gi c  e x a mi n ati o n ( S e cti o n  1 1. 4. 5 ) 
9. 1. 2   
Tr e at m e nt  P eri o d  
Tr e at m e nt  P eri o d  ass ess m e nts  ar e list e d i n  T a bl e   3- 2. 
T h e  Tr e at m e nt  P eri o d  will l ast  a p pr o xi m at el y  1 3  w e e ks.  St u d y  dr u g  a d mi nistr ati o n  d et ails  ar e 
pr o vi d e d i n  S e cti o n  9. 6 . 
9. 1. 3   
F oll o w -u p  
T h e  S af et y  F oll o w - u p  Visit is s c h e d ul e d t o  o c c ur  2 8 ( ±  7)  d a ys  aft er t h e l ast  d os e  of st u d y  dr u g. 
T h e  S af et y  F oll o w - u p  Visit is  n ot r e q uir e d f or s u bj e cts  w h o  c o m pl et e t h e  W e e k 1 3  Visit  a n d 
e nr oll i n t h e  o p e n- l a bel  e xt e nsi o n s af et y st u d y ,  or  w h o tr a nsiti o n t o  a  c o m m er ci all y  a v ail a bl e 
C F T R  m o d ul at or r e gi m e n,   wit hi n  2 8  d a ys  aft er t h e l ast  d os e  of st u d y  dr u g. 
9. 1. 4   
E arl y  T er mi n ati o n  of  Tr e at m e nt  
If  a s u bj e ct  pr e m at ur el y  dis c o nti n u es st u d y tr e at m e nt,  a n  E arl y  T er mi n ati o n  of Tr e at m e nt ( E T T) 
Visit s h o ul d  b e s c h e d ul e d  as s o o n  as  p ossi bl e  aft er t h e s u bj e ct  d e ci d es t o t er mi n at e st u d y 
tr e at m e nt.  S u bj e cts  w h o  pr e m at ur el y  dis c o nti n u e tr e at m e nt  will  als o  b e r e q uir e d t o  c o m pl et e t h e 
S af et y  F oll o w -u p  Visit.  
If t h e  E T T  Visit  o c c urs  3  w ee ks  or l at er f oll o wi n g t h e l ast  d os e  of st u d y  dr u g, t h e n t h e  E T T  Visit 
will r e pl a c e t h e  S af et y  F oll o w - u p  Visit,  a n d  a s e p ar at e  S af et y  F oll o w-u p  Visit  will  n ot  b e 
r e q uir e d. 
If  a s u bj e ct  wit h dr a ws fr o m t h e st u d y  a n d  als o  wit h dr a ws  c o ns e nt  or  ass e nt,  n o f urt her 
ass ess m e nts  will  b e  p erf or m e d.  V ert e x  m a y r et ai n  a n d  c o nti n u e t o  us e  a n y  d at a  a n d s a m pl es 
c oll e ct e d  b ef or e s u c h  wit h dr a w al  of  c o ns e nt  or  ass e nt.  
W e ar a bl e  d e vi c es  m ust  b e r et ur n e d t o t h e sit e  d uri n g t h e  E T T  Visit.  
9. 1. 5   
L o st t o  F oll o w -u p  
A s u bj e ct  will  b e  c o ns i d er e d l ost t o f oll o w- u p if  b ot h  of t h e f oll o wi n g  o c c ur: 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  2 2  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
•   T h e s u bj e ct  miss es  2  c o ns e c uti v e st u d y  visits (t el e m e di ci n e  c o nt a ct  or  cli ni c  visit)  a n d is 
s u bs e q u e ntl y  u n a bl e t o  b e  c o nt a ct e d  b y t el e p h o n e ( 3  d o c u m e nt e d  att e m pts  b y t el e p h o n e 
wit hi n  2   w e e ks f oll o win g t h e s e c o n d  miss e d  visit)  
•   T h e s u bj e ct  d o es  n ot r es p o n d  wit hi n  2  w e e ks t o  a r e gist er e d l ett er s e nt  aft er t h e  3  att e m pt e d 
t el e p h o n e  c o nt a cts. 
9. 1. 6   
C o m pl eti o n  of  St u d y  P arti ci p ati o n  
C o m pl eti o n  of st u d y  p arti ci p ati o n f or  e a c h i n di vi d u al s u bj e ct is  d efi n e d  as  1  of t h e f oll o wi n g: 
•   F or s u bj e cts  w h o  c o m pl et e t h e  Tr e at m e nt  P eri o d  a n d  e nt er  a n  o p e n- l a b el  e xt e nsi o n s af et y 
st u d y  wit hi n  2 8 d a ys  of t h e  W e e k  1 3  Visit: t h e  W e e k   1 3  Visit  
•   F or s u bj e cts  w h o  c o m pl et e t h e  Tr e at m e nt  P eri o d  a n d  d o  n ot  e nt er  a n  o p e n-l a b el  e xt e nsi o n 
s af et y st u d y  wit hi n  2 8  d a ys  of t h e  W e e k 1 3  Visit: t h e  S af et y  F oll o w - u p  Visit 
•   F or s u bj e cts  w h o  pr e m at ur el y  dis c o nti n u e st u d y  dr u g tr e at m e nt  b ut  d o  n ot  wit h dr a w  c o ns e nt 
( a n d  ass e nt,  as  a p pli c a bl e): t h e l at er  of t h e  E T T  Visit  or  S af et y  F oll o w-u p  Visit (if r e q ui r e d) 
•   F or s u bj e cts  w h o  wit h dr a w  c o ns e nt  or  ass e nt:  d at e  of  wit h dr a w al  of  c o ns e nt  or  ass e nt, 
w hi c h e v er is  e arli er ( S e cti o n  9. 9 ) 
If s u bj e cts  ar e l ost t o f oll o w- u p ( S e cti o n 9. 1. 5 ), t h e  d at e  of  c o m pl eti o n  of st u d y  p arti ci p ati o n will 
b e  d efi n e d  as t h e  d at e  of t h e l ast  c o nt a ct.   
T h e  e n d  of st u d y is  d efi n e d i n  S e cti o n  1 3. 2. 9 . 
9. 1. 7   
U s e  of  R e m ot e  M e a s ur e s  
St u d y  visits  m ust  b e  p erf or m e d i n t h e  cli ni c  as s p e cifi e d i n  T a bl e  3- 1   a n d T a bl e  3- 2 .  A  n u m b er  of 
ot h er  c o nt a cts  will  b e  p erf or m e d r e m ot el y  vi a t el e m e di ci n e  c o nt a ct.  U n d er  e xt e n u ati n g 
cir c u mst a n c es,  c ert ai n r e m ot e  m e as ur es  m a y  b e i m pl e m e nt e d ( e. g.,  d u e t o s af et y  c o n c er ns  a n d/ or 
l o c al r estri cti o ns r el at e d t o  C O VI D- 1 9  or  ot h er  e m er gi n g  e v e nts).  E v e n  u n d er  e xt e n u ati n g 
cir c u mst a n c es, t h e  S cr e e ni n g (i n cl u di n g i niti al  c o ns e nt),  D a y  1,  W e e k  1 3,  E T T,  a n d  S af et y 
F oll o w- u p  visits  m ust still  b e  p erf or m e d i n t h e  cli ni c.  
T h e f oll o wi n g r e m ot e  m e as ur es  m a y  b e i m pl e m e nt e d.  A d diti o n al  d et ails  c a n  b e f o u n d i n t h e 
St u d y  R ef er e n c e  M a n u al.  
•   St u d y  dr u g  m a y  b e s hi p p e d  dir e ctl y fr o m t h e sit e t o t h e s u bj e ct,  as  a p pli c a bl e  a n d  as  all o w e d 
p er l o c al r e g ul ati o ns.  
•   R e m ot e  m o nit ori n g  visits  m a y  b e i m pl e m e nt e d , as  a p pli c a bl e (i n cl u di n g r e m ot e s o ur c e  d at a 
v erifi c ati o n)  a n d  as  all o w e d  p er l o c al r e g ul ati o ns.    
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  
T his is  a n  o p e n -l a b el st u d y.  
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  o p e n- l a b el st u d y  will  e v al u at e t h e  eff e cts  of  E L X/ T E Z/I V A  o n  c o u g h  a n d  p h ysi c al  a cti vit y 
i n  C F s u bj e cts.  W e ar a bl e t e c h n ol o g y  will  b e  us e d t o  m e as ur e  c o u g h fr e q u e n c y,  d ail y  p h ysi c al 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  2 4  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
9. 4   
St u d y  R e stri cti o n s  
T a bl e  9- 1  lists  pr o hi bit e d  m e di c ati o ns.  A  n o n- e x h a usti v e list  of st u d y  pr o hi biti o ns  a n d  c a uti o ns 
f or  m e di c ati o n  will  b e  pr o vi d e d i n t h e  St u d y  R ef er e n c e  M a n u al. 
T a bl e  9- 1  
P r o hi bit e d  M e di c ati o ns  
M e di c ati o n  
Ti mi n g  of  R est ri cti o n  
R ati o n al e  
St a rt  of  R est ri cti o n  
E n d  of 
R est ri cti o n  
M o d er at e  a n d str o n g 
C Y P 3 A i n d u c ers  
N o n e  all o w e d  wit hi n 
1 4  d a ys  b ef or e t h e 
first  d os e  of t h e 
st u d y  dr u g  o n  D a y  1  
N o n e  all o w e d 
t hr o u g h 
c o m pl eti o n  of 
st u d y  p arti ci p ati o n  
 
 
E L X,  T E Z,  a n d I V A  ar e  m et a b oli z e d 
e xt e nsi v el y  vi a  C Y P 3 A 4.  T h er ef or e,  us e 
of  m o d er at e  a n d str o n g i n d u c ers  a n d 
i n hi bit ors  of  C Y P 3 A,  w hi c h h a v e t h e 
p ot e nti al t o  alt er t h e  e x p os ur e  of  E L X, 
T E Z,  or I V A,  ar e  pr o hi bit e d.  
 
M o d er at e  a n d str o n g 
C Y P 3 A i n hi bit ors 
( e x c e pt  ci pr ofl o x a ci n)a 
N o n e  all o w e d  wit hi n 
1 4  d a ys  b ef or e t h e 
first  d os e  of t h e 
st u d y  dr u g  o n  D a y  1 
N o n e  all o w e d 
t hr o u g h 
c o m pl eti o n  of 
st u d y  p arti ci p ati o n  
C F T R  m o d ul at ors 
(i n v esti g ati o n al  or 
a p pr o v e d),  e x c e pt f or 
st u d y  dr u gs 
N o n e  all o w e d  wit hi n 
6  m o nt hs  b ef or e 
D a y  - 1 4 
N o n e  all o w e d 
u ntil  aft er t h e l ast 
d os e  of st u d y  dr u g  
T h es e  a g e nts  m a y  c o nf o u n d t h e r es ults  of 
t his st u d y. 
C Y P:  c yt o c hr o m e  P 4 5 0;  E L X:  el e x a c aft or; I V A:  i v a c aft or;  T E Z: t e z a c aft or 
a  
Ci pr ofl o x a ci n is  n ot  a  m o d er at e  C Y P 3 A i n hi bit or  o n t h e  b asis  of r es ults  of  a  dr u g -dr u g i nt er a cti o n st u d y 
c o n d u ct e d  wit h I V A,  a s e nsiti v e  C Y P 3 A s u bstr at e ( K al y d e c o [i v a c aft or]  U S  P a c k a g e I ns ert).  
 
9. 5   
Pri or  a n d  C o n c o mit a nt  M e di c ati o n s  
I nf or m ati o n r e g ar di n g  pri or  a n d  c o n c o mit a nt  m e di c ati o ns, i n cl u di n g  C F m e di c ati o ns,  ot h er 
m e di c ati o ns,  a n d  h er b al  a n d  n at ur o p at hi c r e m e di es ,  will  b e  c oll e ct e d fr o m  e a c h s u bj e ct’s s o ur c e 
d o c u m e nt ati o n f or  m e di c ati o ns t a k e n  wit hi n  5 6  d a ys  b ef or e t h e  S cr e e ni n g  Visit  t hr o u g h 
c o m pl eti o n  of st u d y  p arti ci p ati o n,  as  d efi n e d i n  S e cti o n  9. 1. 6 . 
F or s u bj e cts  w h o  ar e s cr e e n e d  b ut  ar e  n ot s u bs e q u e ntl y  e nr oll e d,  d et ails  of  pri or  m e di c ati o n  will 
b e  d o c u m e nt e d  o nl y i n t h e s u bj e cts’ s o ur c e  d o c u m e nts.  
•   S u bj e cts s h o ul d r e m ai n  o n  a st a bl e tr e at m e nt r e gi m e n f or t h eir  C F fr o m  2 8   d a ys  b ef or e t h e 
D a y  1  Visit t hr o u g h  c o m pl eti o n  of st u d y  p arti ci p ati o n .  St a bl e tr e at m e nt r e gi m e n is  d efi n e d  as 
t h e  c urr e nt tr e at m e nt r e gi m e n f or  C F t h at s u bj e cts  h a v e  b e en f oll o wi n g f or  at l e ast  2 8   d a ys 
b ef or e t h e  D a y   1  Visit.  S u bj e cts s h o ul d  n ot i niti at e l o n g-t er m tr e at m e nt  wit h  n e w  m e di c ati o n 
fr o m  2 8 d a ys  b ef or e t h e  D a y  1  Visit t hr o u g h  c o m pl eti o n  of st u d y  p arti ci p ati o n.  G ui d eli n es 
f or st a bl e tr e at m e nt r e gi m e ns f or  C F  ar e as f oll o ws:  
o   S u bj e cts  w h o  ar e t a ki n g i n h al e d t o br a m y ci n  or  ot h er  c hr o ni c all y i n h al e d  a nti bi oti cs 
s h o ul d r e m ai n  o n t h at r e gi m e n t hr o u g h o ut t h e st u d y. 
o   S u bj e cts  w h o  c y cl e  o nt o  a n d  off  of  a n i n h al e d  a nti bi oti c s h o ul d  c o nti n u e  o n t h eir  pri or 
s c h e d ul e.  T h e ti mi ng  of t h e first  d os e  of st u d y  dr u g  o n t h e  D a y  1  Visit s h o ul d  b e 
s y n c hr o ni z e d  as  cl os el y  as  p ossi bl e ( e. g.,  n ot  m or e t h a n  ±  3  d a ys) t o t h e first  d a y i n 
t h e  c y cl e  o nt o t h e i n h al e d  a nti bi oti c. 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  2 5  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
o   S u bj e cts  w h o  alt er n at e  b et w e e n  2  diff er e nt i n h al e d  a nti bi oti cs s h o u l d r e m ai n  o n t h e 
s a m e  c y cli n g s c h e d ul e  d uri n g t h e st u d y.  T h e ti mi n g  of t h e first  d os e  of st u d y  dr u g  o n 
t h e  D a y  1  Visit s h o ul d  b e s y n c hr o ni z e d  as  cl os el y  as  p ossi bl e ( e. g.,  n ot  m or e t h a n 
±  3  d a ys) t o t h e first  d a y i n t h e  c y cl e  o nt o  1  of t h e i n h al e d  a nti bi ot i cs. 
•   S u bj e cts  m a y r e c ei v e  d os es  of  pr e d nis o n e  or  pr e d nis ol o n e  of  u p t o  1 0  m g/ d a y  c hr o ni c all y,  or 
u p t o  6 0  m g  d ail y f or  u p t o  5   d a ys. 
•   E L X  m a y i n hi bit  O A T P 1 B 1  a n d  O A T P 1 B 3,  w hi c h  m a y i n cr e as e t h e  e x p os ur e  of  m e di ci n al 
pr o d u cts t h at  ar e s u bstr at es f or t h es e tr a ns p ort ers.  S u bstr at es s u c h  as st ati ns,  gl y b uri d e, 
n at e gli ni d e,  a n d r e p a gli ni d e s h o ul d  b e  us e d  wit h  c a uti o n.  
•   I V A is  a  w e a k i n hi bit or  of  P-gl y c o pr ot ei n ( P -g p).  A d mi nistr ati o n  of I V A  m a y i n cr e as e 
s yst e mi c  e x p os ur e  of  m e di ci n al  pr o d u cts t h at  ar e s e nsiti v e s u bstr at es  of  P - g p,  w hi c h  m a y 
i n cr e as e  or  pr ol o n g t h eir t h er a p e uti c  eff e ct  a n d  a d v ers e r e a cti o ns.  Di g o xi n  or  ot h er s u bstr at es 
of  P- g p  wit h  a  n arr o w t h er a p e uti c i n d e x, s u c h  as  c y cl os p ori n e,  e v er oli m us, sir oli m us,  a n d 
t a cr oli m us, s h o ul d  b e  us e d  wit h  c a uti o n  a n d  a p pr o pri at e  m o nit ori n g.  
•   I V A  m a y i n hi bit  C Y P 2 C 9; t h er ef or e,  d uri n g  c o a d mi nistr ati o n  wit h  w arf ari n,  a d diti o n al 
m o nit ori n g  of t h e i nt er n ati o n al  n or m ali z e d r ati o is r e c o m m e n d e d.  Ot h er  m e di ci n al  pr o d u cts 
t h at  ar e  C Y P 2 C 9 s u bstr at es f or  w hi c h  e x p os ur e  m a y  b e in cr e as e d i n cl u d e  gli m e piri d e  a n d 
gli pi zi d e; t h es e s h o ul d  b e  us e d  wit h  c a uti o n. 
•   I nf or m ati o n  a b o ut  br o n c h o dil at or  us e  d uri n g t h e st u d y  will  b e  c oll e ct e d  a n d  d o c u m e nt e d. 
S u bj e cts  w h o  ar e  usi n g  a  br o n c h o dil at or s h o ul d  h a v e t h eir s pir o m etr y  ass ess m e nts  p erf or m e d 
a c c or di n g t o t h e  g ui d eli n es  pr o vi d e d i n  S e cti o n  1 1. 3. 4 . 
9. 6   
A d mi ni str ati o n  
9. 6. 1   
D o si n g  
St u d y  dr u g t a bl ets  will  b e  a d mi nist er e d  or all y  as  E L X  2 0 0  m g  q d/ T E Z  1 0 0  m g  q d/I V A  1 5 0  m g 
q 1 2 h  ( e. g.,  2  E L X/ T E Z/I V A fi x e d- d os e  c o m bi n ati o n [ F D C] t a bl ets i n t h e  m or ni n g  a n d  1 I V A 
t a bl et i n t h e  e v e ni n g).  A d diti o n al i nf or m ati o n is  pr o vi d e d i n t h e  P h ar m a c y  M a n u al. 
St u d y  dr u g s h o ul d  b e  a d mi nist er e d  wit h  a f at- c o nt ai ni n g  m e al  or s n a c k, s u c h  as  a 
st a n d ar d “ C F ”  m e al  or s n a c k  or  a st a n d ar d  m e al   a c c or di n g t o t h e f oll o wi n g  g ui d eli n es: 
1.  It is r e c o m m e n d e d t h at t h e  d os e  b e t a k e n  wit hi n  a p pr o xi m at el y  3 0  mi n ut es  of t h e st art  of t h e 
m e al  or s n a c k.  
2.   All  d os es  of st u d y  dr u g ( m or ni n g  a n d  e v e ni n g,  as  a p pli c a bl e) s h o ul d  b e  a d mi nist er e d 
a p pr o xi m at el y  e v er y  1 2  h o urs ( ±  2  h o urs)  o n  e a c h  d osi n g  o c c asi o n ( e. g., if t h e  m or ni n g  d os es 
of st u d y  dr u g  ar e  a d mi nist er e d  at  0 8: 0 0  h o ur  o n  D a y  1,  all s u bs e q u e nt  m or ni n g  d os es s h o ul d 
b e  a d mi nist er e d  b et w e e n  0 6: 0 0  h o ur  a n d  1 0: 0 0  h o ur). 
3.   At t h e  D a y   1  Visit,  all s u bj e cts  will  b e  o bs er v e d f or  2  h o urs  aft er t h e  m or ni n g  d os e  of t h e 
st u d y  dr u g. 
4.   At t h e  D a y  1  Visit , t h e  m or ni n g  d os e  of st u d y  dr u g  will  b e  a d mi nist er e d  u n d er t h e s u p er visi o n 
of sit e  m e di c al st aff  aft er  pr e d os e  ass ess m e nts  h a v e  b e e n  c o m pl et e d.  T h e  m e al  or s n a c k  will 
b e  pr o vi d e d  b y t h e sit e  o n  D a y  1  f or t h e  m or ni n g  d os e  of st u d y  dr u g. 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  2 6  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
5.   St u d y  dr u g  will  b e  dis p e ns e d  at t h e  D a y  1  Visit.  S u bj e cts  will  b e i nstr u ct e d t o r et ur n  all  us e d 
a n d  u n us e d st u d y  dr u g  t o t h e sit e at t h e  W e e k  1 3  Visit.  
6.   At t h e  W e e k   1 3  Visit, t h e  m or ni n g  d os e  of st u d y  dr u g  will N O T  b e  a d mi nist er e d.  T h e l ast 
d os e  of st u d y  dr u g  will  b e t h e  e v e ni n g  d os e  a d mi nist er e d t h e  d a y  b ef or e t h e  W e e k  1 3  Visit.  
9. 6. 2   
Mi s s e d  D o s e s  
If  6 h o urs  or l ess  h a v e  p ass e d si n c e t h e  miss e d   m or ni n g  or  e v e ni n g  d os e, t h e s u bj e ct s h o ul d t a k e 
t h e  miss e d  d os e  as s o o n  as  p ossi bl e  a n d  c o nti n u e  o n t h e  ori gi n al s c h e d ul e. 
M o r ni n g  d os e:  If  m or e t h a n  6 h o urs  h a v e  p ass e d si n c e t h e  miss e d  m o r ni n g  d os e, t h e s u bj e ct 
s h o ul d t a k e t h e  miss e d  d os e  as s o o n  as  p o ssi bl e  a n d s h o ul d  n ot t a k e t h e  e v e ni n g  d os e. 
E v e ni n g  d os e:  If  m or e t h a n  6 h o urs  h a v e  p ass e d si n c e t h e  miss e d  e v e ni n g   d os e, t h e s u bj e ct 
s h o ul d  n ot t a k e t h e  miss e d  d os e.  T h e  n e xt s c h e d ul e d  m or ni n g  d os e s h o ul d  b e t a k e n  at t h e  us u al 
ti m e. 
M or ni n g  a n d  e v e ni n g  d os es s h o ul d  n ot  b e t a k e n  at t h e s a m e ti m e.  
9. 7   
D o s e  M o difi c ati o n f or  T o xi cit y  
N o  d os e  m o difi c ati o ns f or t o xi cit y  ar e  all o w e d. If  a n y  u n a c c e pt a bl e t o xi cit y  aris es, i n di vi d u al 
s u bj e cts  will  dis c o nti n u e  d osi n g ( S e cti o n  9. 1. 4 ). 
9. 8   
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  
I n s u bj e cts  w h o  h a v e i nt err u pt e d st u d y  dr u g f or  > 7 2  h o urs f or  a n y r e as o n, t h e i n v esti g at or s h o ul d 
r es u m e st u d y  dr u g  o nl y  aft er  a t h or o u g h i n v esti g ati o n  of t h e  c a us e f or i nt err u pti o n.  T h e 
i n v esti g at or  will  e v al u at e t h e s u bj e ct’s  cli ni c al st a bilit y  a n d s h o ul d  c o nsi d er r es u m pti o n  of st u d y 
dr u g  o nl y  aft er t h e s u bj e ct is  cli ni c all y st a bl e  a n d t h er e is  n o  c o m or bi dit y  or  c o n diti o n t h at, i n t h e 
o pi ni o n  of t h e i n v esti g at or,  mi g ht  c o nf o u n d t h e r es ults  of t h e st u d y  or  p os e  a n  a d diti o n al ris k i n 
a d mi nist eri n g st u d y  dr u g t o t h e s u bj e ct.  
T h e  m e di c al  m o nit or s h o ul d  b e  n otifi e d  of  a n i nt err u pti o n  of st u d y  dr u g t h at l asts  > 7 2  h o urs f or 
a n y r e as o n  a n d  of t h e r es u m pti o n  of st u d y  dr u g  aft er s u c h i nt err u pti o n. I n s u bj e cts f or  w h o m 
st u d y  dr u g  w as  pr e vi o usl y i nt err u pt e d, t h e  m e di c al  m o nit or s h o ul d  b e  n otifi e d  of  a n y  pl a n t o 
dis c o nti n u e st u d y  dr u g,  b ef or e t h e  dis c o nti n u ati o n  h as  o c c urr e d, if  p ossi bl e. 
9. 8. 1   
Li v er  F u n cti o n  T e st s  
T h e  c e ntr al l a b or at or y  will  n otif y t h e  m e di c al  m o nit or  of  A L T  or  A S T  > 3   × U L N  a n d t ot al 
bilir u bi n  > 2  ×  U L N t h at  ar e  d eri v e d fr o m  c e ntr all y s u b mitt e d s a m pl es.  
S u bj e cts  wit h  n e w  tr e at m e nt-e m er g e nt  A L T   or A S T  el e v ati o ns  of  > 3   × U L N,  wit h  or  wit h o ut 
t ot al  bilir u bi n  > 2  ×  U L N,  m ust  b e f oll o w e d  cl os el y, i n cl u di n g  c o nfir m at or y t esti n g  p erf or m e d  b y 
t h e  c e ntr al l a b or at or y  wit hi n  4 8 t o  7 2  h o urs  of t h e i niti al fi n di n g  a n d s u bs e q u e nt  cl os e 
m o nit ori n g  of  A L T,   A S T,  a n d  bilir u bi n l e v els,  as  cli ni c all y i n di c at e d. 
If  a s u bj e ct  c a n n ot r et ur n t o t h e sit e f or  c o nfir m at or y t esti n g,  a l o c al l a b or at or y  m a y  b e  us e d. 
L o c al l a b or at or y r es ults  m ust  b e r e p ort e d i m m e di at el y t o t h e  m e di c al  m o nit or,  a n d t h e s u bj e ct 
m ust  h a v e t h e t ests r e p e at e d  a n d s e nt t o t h e  c e ntr al l a b or at or y  a s s o o n  as  p ossi bl e (i d e all y  wit hi n 
4 8 t o  7 2  h o urs).  
St u d y  dr u g  a d mi nistr ati o n  m ust  b e i nt e r r u pt e d  i m m e di at el y ( pri or t o  c o nfir m at or y t esti n g) if 
a n y  of t h e f oll o wi n g  crit eri a  ar e  m et:  

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  2 7  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
•   A L T   or A S T  > 8   × U L N  
•   A L T   or A S T  > 5   × U L N  f or  m or e t h a n  2 w e e ks  
•   A L T   or A S T  > 3   ×  U L N, i n  ass o ci ati o n  wit h t ot al  bilir u bi n  > 2  × U L N   a n d/ or  cli ni c al j a u n di c e 
A t h or o u g h i n v esti g ati o n  of  p ot e nti al  c a us es s h o ul d  b e  c o n d u ct e d,  a n d t h e s u bj e ct s h o ul d  b e 
f oll o w e d  cl os el y f or  cli ni c al  pr o gr essi o n. 
St u d y  dr u g  a d mi nistr ati o n  m ust  b e  d is c o nti n u e d if t h e f oll o wi n g  crit eri o n is  m et: 
•   S u bs e q u e nt  A L T   or A S T  v al u es  c o nfir m t h e i niti al  el e v ati o n t h at s atisfi e d t h e i nt err u pti o n 
r ul e ( a b o v e),  a n d  n o  c o n vi n ci n g  alt er n ati v e  eti ol o g y ( e. g.,  a c et a mi n o p h e n  us e,  vir al  h e p atitis, 
al c o h ol i n g esti o n) is i d e ntifi e d, r e g ar dl ess  of  w h et h er tr a ns a mi n as e l e v els  h a v e i m pr o v e d. 
All s u bj e cts i n  w h o m tr e at m e nt is  dis c o nti n u e d f or  el e v at e d tr a ns a mi n as es ( a n d  bilir u bi n,  as 
a p pli c a bl e) s h o ul d  h a v e t h es e l e v els  m o nit or e d  cl os el y  u ntil l e v els  n o r m ali z e  or r et ur n t o 
b as eli n e.  
If  a n  alt er n ati v e, r e v ersi bl e  c a us e  of tr a ns a mi n as e  el e v ati o n  wit h  or  wit h o ut i n cr e as e d  bilir u bi n  or 
cli ni c al j a u n di c e  h as  b e e n i d e ntifi e d, s u bj e cts  m a y r e c ei v e st u d y  dr u g  o n c e tr a ns a mi n as es r et ur n 
t o  b as eli n e  or  ar e  ≤ 2  × U L N ,  w hi c h e v er is  hi g h er.  R e g ar dl ess  of t h e  d ur ati o n  of i nt err u pti o n, t h e 
m e di c al  m o nit or s h o ul d  b e  n otifi e d  pri or t o r es u m pti o n  of st u d y  dr u g.  U p o n r es u m pti o n  of st u d y 
dr u g, tr a ns a mi n as es  a n d  bilir u bi n s h o ul d  b e  ass ess e d  w e e kl y f or  4  w e e ks. If  a  pr ot o c ol - d efi n e d 
tr a ns a mi n as e el e v ati o n i nt err u pti o n t hr es h ol d r e c urs  wit hi n  4   w e e ks  of r e c h all e n g e  wit h t h e st u d y 
dr u g ( wit h  c o nfir m ati o n  of t h e i niti al  el e v ati o n  b y r e p e at t esti n g  wit hi n  4 8  t o  7 2  h o urs), t h e n t h e 
st u d y  dr u g  m ust  b e  p er m a n e ntl y  dis c o nti n u e d, r e g ar dl ess  of t h e  pr es u m e d  eti ol o g y.   
9. 8. 2   
R a s h  
I n di vi d u als  w h o  d e v el o p  a  g e n er ali z e d r as h  will  b e  m o nit or e d  cl os el y.  St u d y  dr u g  d osi n g s h o ul d 
b e i nt err u pt e d if  a s u bj e ct  d e v el o ps  a  g e n er ali z e d r as h  of  Gr a d e  3  or  hi g h er ( S e cti o n  1 3. 1. 1. 4 ),  or 
a r as h t h at is  c o nsi d er e d  a s eri o us  a d v ers e  e v e nt ( S A E).  T h e i n v esti g at or  will  n otif y t h e  m e di c al 
m o nit or  of  a n y r as h t h at r es ults i n i nt err u pti o n  of st u d y  dr u g, is  Gr a d e  3  or  hi g h er 
( S e cti o n 1 3. 1. 1. 4 ),  or is  a n  S A E. I n v esti g at ors s h o ul d  c o nsi d er  a d diti o n al  e v al u ati o n i n cl u di n g 
l a b or at or y t esti n g ( e. g.,  c o m pl et e  bl o o d  c o u nt  wit h  diff er e nti al, li v er f u n cti o n t ests),  p h ot o gr a p hs 
of t h e r as h,  a n d  d er m at ol o g y  c o ns ult ati o n.  T h e i n v esti g at or  m a y  c o nsi d er r es u m pti o n  of st u d y 
dr u g if  c o nsi d er e d  cli ni c all y  a p pr o pri at e. 
9. 9   
R e m o v al  of  S u bj e ct s   
S u bj e cts ( or s u bj e cts’  p ar e nt/l e g al  g u ar di a n)  m a y  wit h dr a w fr o m t h e st u d y  at  a n y ti m e  at t h eir 
o w n r e q u est.  S u bj e cts  m a y  b e  wit h dr a w n fr o m st u d y  dr u g tr e at m e nt  at  a n y ti m e  at t h e  dis cr eti o n 
of t h e i n v esti g at or  or  V ert e x f or s af et y,  b e h a vi or,  n o n c o m pli a n c e  wit h st u d y  pr o c e d ur es,  or 
a d mi nistr ati v e r e as o ns.  A s u bj e ct  w h o  wit h dr a ws ( or is  wit h dr a w n  b y  p ar e nt/l e g al  g u ar di a n) 
fr o m st u d y  dr u g tr e at m e nt  will  c o nti n u e t o  b e f oll o w e d  u nl ess t h e s u bj e ct ( or  p ar e nt/l e g al 
g u ar di a n  wit h dr a ws  c o ns e nt.  
I n  a d diti o n,  a s u bj e ct  m ust  b e  dis c o nti n u e d fr o m st u d y  dr u g tr e at m e nt if t h e s u bj e ct  m e ets  a n y  of 
t h e f oll o wi n g  crit eri a: 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  2 8  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
•   H as  a s cr e e ni n g  C F T R   g e n ot y p e t h at  d o es  n ot  c o nfir m st u d y  eli gi bilit y if  a  pr e vi o us C F T R  
g e n ot y p e l a b or at or y r e p ort  w as  us e d t o  est a blis h  eli gi bilit y.  T h es e s u bj e cts  m ust  b e 
dis c o nti n u e d fr o m t h e st u d y ( S e cti o n  8. 1 ) 
•   M e ets  a n y  of t h e st o p pi n g ( dis c o nti n u ati o n)  crit eri a ( S e cti o n  9. 8 ) 
•   B e c o m es  pr e g n a nt ( S e cti o n  1 1. 4. 6. 2 ) 
If  a s u bj e ct  d o es  n ot r et ur n f or  a s c h e d ul e d  visit, r e as o n a bl e  eff ort  will  b e  m a d e t o  c o nt a ct t h e 
s u bj e ct. I n  a n y  cir c u mst a n c e, r e as o n a bl e  eff ort  will  b e  m a d e t o  d o c u m e nt s u bj e ct  o ut c o m e.  T h e 
i n v esti g at or  will i n q uir e  a b o ut t h e r e as o n f or  wit h dr a w al, r e q u est t h at t h e s u bj e ct r et ur n  all 
u n us e d i n v esti g ati o n al  pr o d u ct(s), r e q u est t h at t h e s u bj e ct r et ur n f or  a n  E T T  Visit  a n d  S af et y 
F oll o w- u p  Visit, if  a p pli c a bl e (s e e  S e cti o n  9. 1. 4 ),  a n d f oll o w  u p  wit h t h e s u bj e ct r e g ar di n g  a n y 
u nr es ol v e d  A Es.  
If  a s u bj e ct  wit h dr a ws  c o ns e nt f or t h e st u d y,  n o f urt h er  ass ess m e nts  will  b e  p erf or m e d.  V ert e x 
m a y r e t ai n  a n d  c o nti n u e  usi n g t h e st u d y  d at a  a n d s a m pl es  aft er t h e st u d y  e n ds,  a n d  m a y  us e t h e 
s a m pl es  a n d i nf or m ati o n i n t h e  d e v el o p m e nt  of t h e st u d y  c o m p o u n d, f or  ot h er  dr u gs  a n d 
di a g n osti cs, i n  p u bli c ati o ns  a n d  pr es e nt ati o ns,  a n d f or  e d u c ati o n  p ur p os es. If  a  s u bj e ct  wit h dr a ws 
fr o m t h e st u d y, t h e st u d y  d at a  a n d s a m pl es  c oll e ct e d  will r e m ai n  p art  of t h e st u d y.  A s u bj e ct  will 
n ot  b e  a bl e t o r e q u est t h e  wit h dr a w al  of  his/ h er i nf or m ati o n fr o m t h e st u d y  d at a.  A s u bj e ct  m a y 
r e q u est  d estr u cti o n  of t h e s a m pl es  c oll e ct ed fr o m  hi m/ h er  d uri n g t h e st u d y  as l o n g  as t h os e 
s a m pl es  c a n  b e i d e ntifi e d  as  his/ h er s a m pl es.  
9. 1 0   
R e pl a c e m e nt  of  S u bj e ct s  
S u bj e cts  w h o  wit h dr a w  or  ar e  wit h dr a w n  d uri n g t h e  B as eli n e  P eri o d  or st u d y  dr u g  T r e at m e nt 
P eri o d  will  n ot  b e r e pl a c e 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  m a y  b e  dis p e ns e d  o nl y  u n d er t h e s u p er visi o n  of t h e i n v esti g at or  or  a n  a ut h ori z e d 
d esi g n e e  a n d  o nl y f or  a d mi nistr ati o n t o t h e st u d y s u bj e cts.  A n i nt er a cti v e  w e b r es p o ns e s yst e m 
(I W R S)  will  b e  us e d t o  dis p e ns e st u d y  dr u g. 
1 0. 2   
P a c k a gi n g  a n d  L a b eli n g  
St u d y  dr u g t a bl ets  will  b e s u p pli e d i n  blist er  c ar ds  b y  V ert e x.  St u d y  dr u g l a b eli n g  will  b e i n 
c o m pli a n c e  wit h  a p pli c a bl e l o c al  a n d  n ati o n al r e g ul ati o ns.  A d diti o n al  d et ails r e g ar di n g 
p a c k a gi n g, l a b eli n g,  a n d  dis p e nsi n g f or st u d y  dr u g  will  b e i n t h e  P h ar m a c y  M a n u al. 
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 a bl e  1 0- 1   pr o vi d es t h e st u d y  dr u g i nf or m ati o n.  T h e i n v esti g at or,  or  a n  a ut h ori z e d  d esi g n e e 
( e. g., a li c e ns e d  p h ar m a cist),  will  e ns ur e t h at  all i n v esti g ati o n al  pr o d u ct is st or e d i n  a s e c ur e d 
ar e a,  u n d er r e c o m m e n d e d st or a g e  c o n diti o ns,  a n d i n  a c c or d a n c e  wit h  a p pli c a bl e r e g ul at or y 
r e q uir e m e nts.  T o  e ns ur e  a d e q u at e r e c or ds,  all st u d y  dr u gs  will  b e  a c c o u nt e d f or  vi a t h e  dr u g 
a c c o u nt a bilit y f or ms  as i nstr u ct e d  b y  V ert e x.  
D et ail e d i nstr u cti o ns r e g ar di n g t h e st or a g e,  h a n dli n g,  a n d  dis p e ns ati o n  of t h e st u d y  dr u g  will  b e 
pr o vi d e d i n t h e  P h ar m a c y  M a n u al. 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  2 9  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
T a bl e  1 0- 1  
St u d y  D r u g   
D r u g  N a m e,  D osi n g  F o r m,  R o ut e  
T a bl et  St r e n gt h  
E L X/ T E Z/I V A,  F D C t a bl et,  or al  
    
E L X 
    
T E Z 
  
I V A 
 
1 0 0  m g  
5 0  m g  
7 5  m g  
I V A, t a bl et,  or al 
1 5 0  m g  
E L X:  el e x a c aft or;  F D C: fi x e d -d os e  c o m bi n ati o n; I V A: i v a c aft or;  T E Z: t e z a c aft or  
N ot e:  S e e  S e cti o n  9. 6  f or  d et ails  o n st u d y  dr u g  a d mi nistr ati o n. 
1 0. 4   
Dr u g  A c c o u nt a bilit y  
T h e  p h ar m a cist  or  d esi g n at e d st u d y sit e st aff  will  m ai nt ai n i nf or m ati o n  a b o ut t h e  d at es  a n d 
a m o u nts  of ( 1) st u d y  dr u g r e c ei v e d; ( 2) st u d y  dr u g  dis p e ns e d t o t h e s u bj e cts;  a n d ( 3) st u d y  dr u g 
r et ur n e d  b y t h e s u bj e cts.  S u bj e cts  will  b e i nstr u ct e d t o r et ur n  all  us e d  a n d  u n us e d  m at eri als 
ass o ci at e d  wit h t h e st u d y  dr u g t o t h e sit e.  T h es e  m at eri als  will  b e r et ai n e d  at t h e sit e  a c c or di n g t o 
i nstr u cti o ns  pr o vi d e d  b y  V ert e x  or its  d esi g n e e.  T h e st u d y  m o nit or  will r e vi e w st u d y  dr u g 
r e c or ds  a n d i n v e nt or y t hr o u g h o ut t h e st u d y.  
If  a sit e  us es  a sit e-s p e cifi c  dr u g  a c c o u nt a bilit y s yst e m  a n d/ or  pr o c ess, i n cl u di n g  pr o c ess es 
ass o ci at e d  wit h t h e  d estr u cti o n  of r et ur n e d  m at eri als, t h e  pr o c ess  m ust  b e  d o c u m e nt e d  a n d 
a p pr o v e d  b y  V ert e x.  T h e st u d y  m o nit or  m ust r e vi e w t h e  dr u g  a c c o u nt a bilit y  d o c u m e nt ati o n  o n  a 
r e g ul ar  b asis.  T h e st u d y  m o nit or  will  pr o m ptl y  c o m m u ni c at e t o  V ert e x  a n y  dis cr e p a n ci es  h e/s h e 
is  u n a bl e t o r es ol v e  wit h t h e sit e. 
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 h e st u d y sit e st aff  or  p h ar m a c y  p ers o n n el  will r et ai n  all  m at eri als r et ur n e d  b y t h e s u bj e cts  u ntil 
t h e st u d y  m o nit or  h as  p erf or m e d  dr u g  a c c o u nt a bilit y.  T h e i n v esti g at or  will  e ns ur e t h at t h e 
m at eri als  ar e  d estr o y e d i n  c o m pli a n c e  wit h  a p pli c a bl e  e n vir o n m e nt al r e g ul ati o ns, i nstit uti o n al 
p oli c y,  a n d  a n y s p e ci al i nstr u cti o ns  pr o vi d e d  b y  V ert e x.  D estr u cti o n  will  b e  a d e q u at el y 
d o c u m e nt e d. 
T h e  pri n ci p al i n v esti g at or, st u d y sit e st aff, i n cl u di n g  p h ar m a c y  p ers o n n el  will  assist  V ert e x  wit h 
a n y r e c all  a cti viti es ( as  a p pli c a bl e)  a n d  pl a c e i m p a ct e d i n v esti g ati o n al  m e di ci n al  pr o d u ct (I M P) 
i n  q u ar a nti n e  w h e n r e q u est e d. 
1 0. 6   
C o m pli a n c e   
T o  e ns ur e tr e at m e nt  c o m pli a n c e, t h e i n v esti g at or  or  d esi g n e e  will s u p er vis e  all st u d y  dr u g  d osi n g 
t h at  o c c urs  at t h e sit e  at r e q uir e d  visits.  At  e a c h  visit, sit e  m e di c al st aff will r e vi e w t h at t h e 
s u bj e ct is  c o m pli a nt  wit h st u d y  dr u g  d osi n g  a n d r e mi n d t h e s u bj e ct ( a n d t h eir  p ar e nt  or l e g al 
g u ar di a n,  as  a p pli c a bl e)  of st u d y  dr u g  d osi n g r e q uir e m e nts.  C o m pli a n c e  will  als o  b e  ass ess e d  b y 
o n g oi n g st u d y  dr u g  c o u nt. 
If  a s u bj e ct  or s ubj e ct’s  p ar e nt  or l e g al  g u ar di a n  d e m o nstr at es  c o nti n u e d  n o n c o m pli a n c e  of st u d y 
dr u g  d osi n g  d es pit e  e d u c ati o n al  eff orts, t h e i n v esti g at or s h o ul d  c o nsi d er  dis c o nti n ui n g t h e 
s u bj e ct fr o m t h e st u d y. 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  3 0  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
1 0. 7   
Bli n di n g  a n d  U n bli n di n g  
T his is  a n  o p e n -l a b el st u d y;  h o w e v er, s u bj e cts  a n d t h eir  p ar e nt/l e g al  g u ar di a n s h o ul d  n ot  b e 
i nf or m e d  of t h eir st u d y-r el at e d   
 c o u g h,  a cti vit y, 
 
 r es ults d uri n g t h e  Tr e at m e nt  P eri o d, r e g ar dl ess if t h e s u bj e ct  p er m a n e ntl y 
dis c o nti n u es. 
1 1   
A S S E S S M E N T S  
T h e s c h e d ul e  of  ass ess m e nts is s h o w n i n  T a bl e  3- 1   a n d T a bl e  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 bj e ct  a n d  dis e as e  c h ar a ct eristi cs i n cl u d e t h e f oll o wi n g:  d e m o gr a p hi cs,  m e di c al  hist or y,  h ei g ht, 
a n d  w ei g ht. 
M e di c al  hist or y  will  b e  eli cit e d fr o m  e a c h s u bj e ct  a n d  e xtr a ct e d fr o m  m e di c al r e c or ds  d uri n g 
s cr e e ni n g.  B as e d  o n t h e  m e di c al  hist or y, t h e s u bj e ct  will  b e  ass ess e d f or  a n y  dis q u alif yi n g 
m e di c al  c o n diti o ns  as s p e cifi e d i n t h e i n cl usi o n  a n d  e x cl usi o n  crit eri a  ( S e cti o n 8 ).  T h e  m e di c al 
hist or y  will i n cl u d e  a  c o m p l et e r e vi e w  of s yst e ms,  m e di c al  a n d s ur gi c al  hist ori es,  a n d  a n y 
all er gi es.  
H ei g ht  a n d  w ei g ht  will  b e  m e as ur e d  wit h s h o es  off.  F oll o wi n g s cr e e ni n g,  h ei g ht  will  b e  c oll e ct e d 
o nl y f or s u bj e cts  ≤ 2 1  y e ars  of  a g e  o n t h e  d at e  of i nf or m e d  c o ns e nt.  
1 1. 2   
Effi c a c y  
1 1. 2. 1   
C o u g h  M e a s ur e m e nt s  
S u bj e cts  will  b e  pr o vi d e d  wit h  a  n o n-i n v asi v e, s e mi- a ut o m at e d,  a m b ul at or y  c o u g h  m o nit ori n g 
s yst e m t o r e c or d  c o u g h fr e q u e n c y.  T h e s yst e m  will  b e  us e d f or  a si n gl e  d a y ( d efi n e d  b y 
2 4  c o nti n u o us  h o urs)  at ti m e  p oi nts s p e cifi e d i n  T a bl e  3- 2 .  S u bj e cts  will  p ut t h e  c o u g h  d e vi c e  o n 
u n d er  dir e ct  o bs er v ati o n  at t h e ti m e  of  c o nt a ct  b et w e e n t h e s u bj e ct  a n d i n v esti g at or  or sit e 
p ers o n n el (i. e., i n  p ers o n  o r t el e m e di ci n e c o nt a ct ). 
1 1. 2. 2   
A cti vit y  M e a s ur e m e nt s  
S u bj e cts  will  b e  pr o vi d e d  wit h  a  wrist- w or n  a cti gr a p h y s e ns or (si mil ar t o  a  w at c h) t o  m e as ur e 
b e h a vi or al  o ut c o m es ( e. g., st e p  c o u nt,  c a d e n c e, ti m e s p e nt i n  p h ysi c al  a cti vit y i nt e nsit y 
c at e g ori es,
  et c.).  T h e  wrist- w or n  d e vi c e  will  b e  w or n  2 4  h o urs  p er  d a y  d uri n g t h e 
B as eli n e  P eri o d  a n d t h e  Tr e at m e nt  P eri o d ( e x c e pt f or  pr e -s p e cifi e d  c h ar gi n g ti m e  p oi nts)  a n d 
will  b e r et ur n e d t o t h e st u d y sit e  u p o n  c o m pl eti o n  of t h e st u d y ( S e cti o n  9. 1. 6 ). 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  3 1  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  3 2  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
1 1. 4   
S af et y  
S af et y  e v al u ati o ns  will i n cl u d e  A Es,  cli ni c al l a b or at or y  ass ess m e nts,  p h ysi c al  e x a mi n ati o ns, 
f or 
s u bj e cts  < 1 8  y e ars  of  a g e  o n t h e  d at e  of i nf or m e d  c o ns e nt). 
1 1. 4. 1   
A d v er s e  E v e nt s  
All  A Es  will  b e  ass ess e d,  d o c u m e nt e d,  a n d r e p ort e d i n  a c c or d a n c e  wit h  c urr e nt I C H  E 6  G C P 
G ui d eli n es.  S e cti o n  1 3. 1  o utli n es t h e  d efi niti o ns,  c oll e cti o n  p eri o ds,  crit eri a,  a n d  pr o c e d ur es f or 
d o c u m e nti n g,  gr a di n g,  a n d r e p orti n g  A Es.  
1 1. 4. 2   
Cli ni c al  L a b or at or y  A s s e s s m e nt s  
As  d es cri b e d  b el o w,  uri n e  pr e g n a n c y t ests  will  eit h er  b e  a n al y z e d  b y t h e sit e  or  at  h o m e  usi n g  a 
h o m e  kit.  All  bl o o d s a m pl es  will  b e  c oll e ct e d  w hil e s u bj e cts  ar e i n  a s e at e d  or s u pi n e  p ositi o n. 
S p e cifi c i nstr u cti o ns f or t h e  c oll e cti o n,  pr o c essi n g,  a n d s hi p m e nt  of s a m pl es  will  b e  pr o vi d e d i n  a 
s e p ar at e  L a b or at or y  M a n u al.  
L a b or at or y t est r es ults t h at  ar e  a b n or m al  a n d  c o nsi d er e d  cli ni c all y si g nifi c a nt  will  b e r e p ort e d  as 
A Es (s e e  S e cti o n  1 3. 1 ). 
T h e s af et y l a b or at or y t est  p a n els  ar e s h o w n i n  T a bl e  1 1- 1 . 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  3 3  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
T a bl e  1 1- 1   
S af et y  L a b o r at o r y  T est  P a n els  
S e r u m  C h e mist r y  
H e m at ol o g y a 
Gl u c os e   
Bl o o d  ur e a  nitr o g e n b 
Cr e ati ni n e  
S o di u m  
P ot assi u m   
C al ci u m   
C hl ori d e   
M a g n esi u m   
Bi c ar b o n at e   
P h os p h at e   
T ot al  bilir u bi n,  dir e ct  bilir u bi n, i n dir e ct  bilir u bi n   
Al k ali n e  p h os p h at as e   
As p art at e tr a ns a mi n as e  
Al a ni n e tr a ns a mi n as e  
A m yl as e   
Li p as e   
G a m m a -gl ut a m yl tr a nsf er as e   
Pr ot ei n   
Al b u mi n   
Cr e ati n e  ki n as e c 
C h ol est er ol    
H e m o gl o bi n   
Er yt hr o c yt es  
M e a n  c or p us c ul ar  v ol u m e  
Pl at el ets   
R eti c ul o c yt es   
L e u k o c yt es   
Diff er e nti al ( a bs ol ut e  a n d  p er c e nt):  
E osi n o p hils  
B as o p hils   
N e utr o p hils  
L y m p h o c yt es  
M o n o c yt es   
  
a  
H e m at ol o g y  will  o nl y  b e  p erf or m e d  at s cr e e ni n g.  
b  
If  bl o o d  ur e a  nitr o g e n  c a n n ot  b e  c oll e ct e d,  ur e a  m a y  b e s u bstit ut e d. 
c  
Cr e ati n e  ki n as e  m e as ur e d  at s cr e e ni n g  o nl y.  
Pr e g n a n c y ( β -h u m a n  c h ori o ni c  g o n a d otr o pi n)  T ests f or  all  F e m al e  S u bj e cts:  All f e m al e s u bj e cts 
m ust  h a v e  a s er u m  pr e g n a n c y t est  at s cr e e ni n g.  S er u m  pr e g n a n c y t ests  will  b e  p erf or m e d  b y sit e 
m e di c al st aff  a n d  a n al y z e d  at t h e  c e ntr al l a b or at or y.  Uri n e  pr e g n a n c y t ests  will  eit h er  b e 
p erf or m e d  a n d  a n al y z e d  at t h e sit e  or  at  h o m e  b y  usi n g  a  h o m e  kit  pr o vi d e d  b y t h e sit e.  R es ults 
will  b e r e p ort e d t o t h e sit e  b y t el e m e di ci n e  c o nt a ct .  T h e  uri n e  pr e g n a n c y t est  o n  D a y  1  m ust  b e 
n e g ati v e  b ef or e t h e first  d os e  of st u d y  dr u g is  a d mi nist er e d t o t h e s u bj e ct.  A d diti o n al  pr e g n a n c y 
t ests  m a y  b e r e q uir e d  a c c or di n g t o l o c al r e g ul ati o ns  a n d/ or r e q uir e m e nts. 
F S H ( S cr e e ni n g  P eri o d  o nl y):  Bl o o d s a m pl es f or  F S H  will  b e  m e as ur e d f or  a n y s us p e ct e d 
p ost m e n o p a us al f e m al e  wit h  at l e ast  1 2  m o nt hs  of  c o nti n u o us s p o nt a n e o us  a m e n orr h e a 
( S e cti o n 1 1. 4. 6. 1 ).  S eru m  F S H  l e v els  m ust  b e i n t h e  p ost m e n o p a us al r a n g e  as  d et er mi n e d  b y t h e 
l a b or at or y  p erf or mi n g t h e t est. 
C F  g e n ot y p e ( S cr e e ni n g  P eri o d  o nl y):  A  v ali d  pr e vi o us  C F T R   g e n ot y p e l a b or at or y r e p ort  m a y  b e 
us e d t o  est a blis h  eli gi bilit y. If s u bj e cts  c a n n ot  pr o vi d e  a  v ali d  pr e vi o us  C F T R   g e n ot y p e 
l a b or at or y r e p ort  at s cr e e ni n g,  c e ntr al l a b or at or y  C F  g e n ot y pi n g  will  b e  p erf or m e d  o n  all s u bj e cts 
t o  c o nfir m t h e  g e n ot y p e  d o c u m e nt e d i n t h e s u bj e ct's  m e di c al r e c or d.  
A d diti o n al  E v al u ati o ns:  A d diti o n a l  cli ni c al l a b or at or y  e v alu ati o ns  will  b e  p erf or m e d  at  ot h er 
ti m es if j u d g e d t o  b e  cli ni c all y  a p pr o pri at e.  
F or  p ur p os es  of st u d y  c o n d u ct,  o nl y l a b or at or y t ests  d o n e i n t h e  c e ntr al l a b or at or y  m a y  b e  us e d. 
L o c al l a b or at ori es  m a y  b e  us e d  at t h e  dis cr eti o n  of t h e l o c al i n v esti g at or f or  m a n a g e m e nt  of 
ur g e nt  m e di c al iss u es. If  a l o c al l a b or at or y t est  v al u e is f o u n d t o  b e  a b n or m al  a n d  cli ni c all y 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  3 4  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
si g nifi c a nt, it  will  b e  v erifi e d  b y t h e  c e ntr al l a b or at or y  as s o o n  as  p ossi bl e  aft er t h e i n v esti g at or 
b e c o m es  a w ar e  of t h e  a b n or m al r es ult. If it  is  n ot  p ossi bl e t o s e n d  a ti m el y s p e ci m e n t o t h e 
c e ntr al l a b or at or y ( e. g.,  t h e s u bj e ct  w as  h os pit ali z e d  els e w h er e), t h e i n v esti g at or  m a y  b as e t h e 
ass ess m e nt  of  a n  A E  o n t h e l o c al l a b or at or y  v al u e . 
1 1. 4. 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 ys t e ms  a n d  vit al si g ns  ass ess m e nt  will  b e  p erf or m e d  at s cr e e ni n g  a n d s el e ct 
st u d y  visits.  At  ot h er  visits, s y m pt o m - dir e ct e d  P Es  a n d s y m pt o m-dir e ct e d  vit al si g ns  ass ess m e nts 
c a n  b e  p erf or m e d  at t h e  dis cr eti o n  of t h e i n v esti g at or  or  h e alt h c ar e  pr o vi d er . 
A  P E i n cl u d es  a r e vi e w  of t h e f oll o wi n g s yst e ms:  h e a d,  n e c k,  a n d t h yr oi d;  e y es,  e ars,  n os e,  a n d 
t hr o at ( E E N T); r es pir at or y;  c ar di o v as c ul ar; l y m p h  n o d es;  a b d o m e n; s ki n;  m us c ul os k el et al;  a n d 
n e ur ol o gi c al.  Br e ast,  a n or e ct al,  a n d  g e nit al  e x a mi n ati o ns  will  b e  p erf or m e d  w h e n  m e di c all y 
i n di c at e d.  Aft er s cr e e ni n g,  a n y  cli ni c all y si g nifi c a nt  a b n or m al fi n di n gs i n  P Es  will  b e r e p ort e d  as 
A Es.  

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  3 5  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
1 1. 4. 6   
C o ntr a c e p ti o n  a n d  Pr e g n a n c y 
T h e  eff e cts  of  E L X  m o n ot h er a p y  or i n  c o m bi n ati o n  wit h  T E Z/I V A  o n  c o n c e pti o n,  pr e g n a n c y, 
a n d l a ct ati o n i n  h u m a ns  ar e  n ot  k n o w n.  E L X,  T E Z,  a n d I V A  di d  n ot s h o w  g e n ot o xi c  p ot e n ti al i n 
a st a n d ar d  b att er y  of i n  vitr o ( A m es t est,  c hr o m os o m al  a b err ati o n,  or  mi cr o n u cl e us i n  c ult ur e d 
m a m m ali a n  c ells)  a n d i n  vi v o (r o d e nt  mi cr o n u cl e us)  st u di es.  R e pr o d u cti v e t o xi c ol o g y st u di es  of 
E L X,  T E Z,  a n d I V A  h a v e  n ot s h o w n t er at o g e ni cit y i n r ats  a n d r a b bits. 
1 1. 4. 6. 1   
C o ntr a c e pti o n  
C o nt r a c e pti o n  r e q ui r e m e nt f o r  a  c o u pl e is  w ai v e d f o r t h e f oll o wi n g:  
•   Tr u e  a bsti n e n c e f or t h e s u bj e ct,  w h e n t his is i n li n e  wit h t h e  pr ef err e d  a n d  us u al lif est yl e  of 
t h e s u bj e ct.  P eri o di c  a bsti n e n c e ( e. g.,  c al e n d ar,  o v ul ati o n, s y m pt ot h er m al,  p ost o v ul ati o n 
m et h o ds)  a n d  wit h dr a w al  ar e  n ot  a c c e pt a bl e  m et h o ds  of  c o ntr a c e pti o n.  Tr u e  a bsti n e n c e  m ust 
b e  pr a cti c e d fr o m t h e  S cr e e ni n g  Visit t hr o u g h  9 0  d a ys  aft er t h e l ast  d os e  of st u d y  dr u g.  
•   If t h e  m al e is i nf ertil e ( e. g.,  bil at er al  or c hi e ct o m y). If  a  m al e s u bj e ct is  ass u m e d t o  h a v e 
c o m pl et e  bil at er al  a bs e n c e  of t h e  v as  d ef er e ns, i nf ertilit y  m ust  b e  d o c u m e nt e d  b ef or e t h e first 
d os e  of st u d y  dr u g ( e. g.,  e x a mi n ati o n  of  a s e m e n s p e ci m e n  or  b y  d e m o nstr ati o n  of t h e 
a bs e n c e  of t h e  v as  d ef er e ns  b y  ultr a s o u n d). 
•   If t h e f e m al e is  of  n o n- c hil d b e ari n g  p ot e nti al.  T o  b e  c o nsi d er e d  of  n o n- c hil d b e ari n g  p ot e nti al, 
t h e f e m al e  m ust  m e et  at l e ast  1  of t h e f oll o wi n g  crit eri a: 
o   P ost m e n o p a us al:  A m e n orr h ei c f or  at l e ast  1 2  c o ns e c uti v e  m o nt hs  a n d  a s er u m  F S H 
l e v el  wit hi n th e l a b or at or y’s r ef er e n c e r a n g e f or  p ost m e n o p a us al f e m al es  
o   D o c u m e nt e d  h yst er e ct o m y  or  bil at er al  o o p h or e ct o m y/s al pi n g o- o o p h or e ct o m y 
N ot e:  All  ot h er f e m al es (i n cl u di n g f e m al es  wit h t u b al li g ati o ns)  will  b e  c o nsi d er e d t o  b e  of 
c hil d b e ari n g  p ot e nti al.  
•   S a m e -s e x r el ati o ns hi ps 
F o r s u bj e cts f o r  w h o m t h e  c o nt r a c e pti o n  r e q ui r e m e nt is  n ot  w ai v e d,  st u d y  p arti ci p ati o n 
r e q uir es  a  c o m mit m e nt fr o m t h e s u bj e ct t h at at l e ast  1  a c c e pt a bl e  m et h o d   of  c o ntr a c e pti o n is 
us e d  as  a  c o u pl e.  M et h o ds  of  c o ntr a c e pti o n  m ust  b e i n s u c c essf ul  us e fr o m si g ni n g  of  c o ns e nt 
a p pr o xi m at el y  2 8  d a ys  b ef or e t h e first  d os e  of st u d y  dr u g ( u nl ess  ot h er wis e  n ot e d),  a n d  u ntil 
9 0  d a ys f oll o wi n g t h e l ast  d os e  of st u d y  dr u g.  A d diti o n al  c o ntr a c e pti o n r e q uir e m e nts  m a y  n e e d 
t o  b e f oll o w e d  a c c or di n g t o l o c al r eg ul ati o ns  a n d/ or r e q uir e m e nts.  A c c e pt a bl e  m et h o ds  of 
c o ntr a c e pti o n  ar e list e d i n  T a bl e   1 1- 2. 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  3 6  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
T a bl e   1 1- 2    
Ac c e pt a bl e  M et h o ds  of  C o nt r a c e pti o n  
 
M al e  S u bj e cts  a n d  T h ei r 
F e m al e ( N o n -st u d y) 
P a rt n e rs  
F e m al e  S u bj e cts  a n d 
T h ei r  M al e ( N o n -st u d y) 
P a rt n e rs  
V as e ct o m y  p erf or m e d  at l e ast  6  m o nt hs  pr e vi o usl y, 
wit h  a  d o c u m e nt e d  n e g ati v e  p ost v as e ct o m y s e m e n 
a n al ysis f or  s p er m 
Y es  
Y es  
Bil at er al t u b al  o c cl usi o n ( e. g., li g ati o n)  p erf or m e d  at 
l e ast  6 m o nt hs  pr e vi o usl y  
Y es  
Y es  
M al e  or f e m al e  c o n d o m  wit h  or  wit h o ut s p er mi ci d e
a  
Y es  
Y es  
F e m al e  b arri er  c o ntr a c e pti o n (s u c h  as  di a p hr a g m, 
c er vi c al  c a p,  or s p o n g e)  wit h  s p er mi ci d e 
Y es  
Y es  
C o nti n u o us  us e  of  a n i ntr a ut eri n e  d e vi c e f or  at l e ast 
9 0  d a ys  b ef or e t h e first  d os e  of st u d y  dr u g  
Y es  
Y es  
Or al, i m pl a nt e d, i nj e ct e d,  or  v a gi n al  h or m o n al 
c o ntr a c e pti v es, if s u c c essf ull y  us e d f or  at l e ast 
6 0  d a ys  b ef or e t h e first  d os e  of st u d y  dr u g.  
Y es  
Y es  
a  
A f e m al e  c o n d o m  c a n n ot  b e  us e d  wit h  a  m al e  c o n d o m  d u e t o ris k  of t e ari n g.  
A d diti o n al  n ot es:  
•   If  o v er t h e  c o urs e  of t h e st u d y t h e s u bj e ct  m e ets t h e  crit eri a f or  w ai vi n g t h e  c o ntr a c e pti o n 
r e q uir e m e nts, t h e s u bj e ct  d o es  n ot  n e e d t o f oll o w t h e  c o ntr a c e pti v e  m et h o ds list e d i n 
T a bl e   1 1- 2.  
•   M al e s u bj e cts  m ust  n ot  d o n at e s p er m  d uri n g t h e  p eri o d st arti n g fr o m t h e first  d os e  of st u d y 
dr u g  u ntil  9 0   d a ys  aft er t h e l ast  d os e  of st u d y  dr u g. 
•   F e m al e s u bj e cts s h o ul d  n ot  n urs e  a  c hil d  d uri n g t h e  p eri o d st arti n g fr o m t h e first  d os e  of 
st u d y  dr u g  u ntil  9 0  d a ys  aft er t h e l ast  d os e  of st u d y  dr u g. 
•   F or  m al e s u bj e cts  wit h  a f e m al e  p art n er  of  c hil d b e a ri n g  p ot e nti al, t h e  c o u pl e s h o ul d  n ot  pl a n 
t o  b e c o m e  pr e g n a nt  d uri n g t h e st u d y  or  wit hi n  9 0  d a ys  aft er t h e l ast  d os e  of st u d y  dr u g, wit h 
t h e  e x c e pti o n  of  c o u pl es  w h o  pl a n t o  b e c o m e  pr e g n a nt  b y artifi ci al i ns e mi n ati o n  usi n g s p er m 
b a n k e d  b y t h e  m al e s u bj e ct  b ef or e t h e first  d os e  of st u d y  dr u g  or s p er m fr o m  a n ot h er s o ur c e. 
1 1. 4. 6. 2   
Pr e g n a n c y  
S u bj e cts  will  b e  c o u ns el e d t o i nf or m t h e i n v esti g at or  of  a n y  pr e g n a n c y t h at  o c c urs  d uri n g st u d y 
tr e at m e nt  a n d f or  9 0  d a ys  aft er t h e l ast  d os e  of st u d y  dr u g. 
If  a f e m al e s u bj e ct  b e c o m es  pr e g n a nt  d uri n g st u d y  p arti ci p ati o n, st u d y  dr u g  will  b e  p er m a n e ntl y 
dis c o nti n u e d i m m e di at el y.  T h e i n v esti g at or  will  n otif y t h e  m e di c al  m o nit or  a n d  V ert e x  Gl o b al 
P ati e nt  S af et y ( G P S )  wit hi n  2 4  h o urs  of t h e sit e’s  k n o wl e d g e  of t h e s u bj e ct’s ( or  p art n er’s) 
pr e g n a n c y  usi n g t h e  Pr e g n a n c y I nf or m ati o n  C oll e cti o n  F or m.  M al e s u bj e cts  wit h f e m al e  p art n ers 
w h o  b e c o m e  pr e g n a nt  d uri n g t h e st u d y  m ust  us e  a  m al e  c o n d o m t o  a v oi d  e x p os ur e  of  a  p ot e nti al 
e m br y o  or f et us t o st u d y  dr u g  vi a t h e s e mi n al fl ui d.  
T h e s u bj e ct  or  p art n er  will  b e f oll o w e d  u ntil t h e  e n d  of t h e  pr e g n a n c y  a n d t h e i nf a nt  will  b e 
f oll o w e d f or  1  y e ar  aft er t h e  birt h,  pr o vi d e d i nf or m e d  c o ns e nt is  o bt ai n e d.  A s e p ar at e I C F  will  b e 
pr o vi d e d t o  e x pl ai n t h es e f oll o w -u p  a cti viti es.  Pr e g n a n c y its elf  d o es  n ot  c o nstit ut e  a n  A E. 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  3 7  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
1 2   
S T A TI S TI C A L  A N A L Y SI S  
1 2. 1   
S a m pl e  Si z e  a n d  P o w er  
A p pr o xi m at el y  1 0 0 s u bj e cts  will  b e  e nr oll e d.  
T h e  pri m ar y  effi c a c y  e n d p oi nt is  p er c e nt r e d u cti o n fr o m  b as eli n e i n  c o u g h fr e q u e n c y ( c o u g h 
e v e nts  p er  d a y) t o t h e  a v er a g e  of  W e e k  8 t hr o u g h  W e e k  1 2.  Ass u mi n g  a st a n d ar d  d e vi ati o n  of 
1 f or t h e l o g r ati o  of  c o u g h fr e q u e n c y  p ost- b as eli n e  v ers us  b as eli n e,  a s a m pl e si z e  of 
a p pr o xi m at el y  1 0 0 s u bj e cts  will  pr o vi d e  9 5 %  c o nfi d e n c e i nt er v als  ( w hi c h r e pr es e nts t h e 
esti m ati o n  pr e cisi o n)  as  s h o w n i n T a bl e  1 2- 1  at  v ari o us  o bs er v e d  p er c e nt r e d u cti o ns i n  c o u g h 
fr e q u e n c y ( 3 0 %,  4 0 %,  a n d  5 0 %),  aft er  a c c o u nti n g f or  2 0 %  missi n g. N ot e  t h at p er c e nt r e d u cti o n 
e q u als  1 0 0 %  × ( 1-r ati o  of  c o u g h fr e q u e n c y  p ost- b as eli n e  v ers us  b as eli n e).  
T a bl e  1 2- 1  
9 5 %  C o nfi d e n c e I nt e r v als f o r  P e r c e nt  R e d u cti o n i n  C o u g h  F r e q u e n c y  p e r 
D a y  F r o m  B as eli n e  
P e r c e nt  r e d u cti o n i n  c o u g h f r e q u e n c y  
3 0 %  
4 0 %  
5 0 %  
9 5 %  C o nfi d e n c e I nt e r v als  
( 1 3 %,  4 4 %)  
( 2 5 %,  5 2 %)  
( 3 8 %,  6 0 %) 
N ot e:  3 0 %,  4 0 %,  a n d  5 0 %  p er c e nt  r e d u cti o n  c orr es p o n ds t o r ati o  of  0. 7,  0. 6, a n d  0. 5 i n  c o u g h fr e q u e n c y 
( p ost-b as eli n e  vs.  b as eli n e), r es p e cti v el y.  
 
1 2. 2   
A n al y si s  S et s  
T h e f oll o wi n g  a n al ysis s ets  ar e  d efi n e d:  All  S u bj e cts  S et,  F ull  A n al ysis  S et ( F A S),  a n d  S af et y 
S et.  
T h e  All  S u bj e cts  S et  will i n cl u d e  all s u bj e cts  w h o  w er e  e nr oll e d.  T his  a n al ysis s et  will  b e  us e d 
f or  all i n di vi d u al s u bj e ct  d at a listi n gs  a n d  dis p ositi o n s u m m ar y t a bl es,  u nl ess  ot h er wis e s p e cifi e d. 
T h e  F A S  is  d efi n e d  as  all  e nr oll e d s u bj e cts  w h o  c arr y t h e i nt e n d e d C F T R  all el e   m ut ati o n  a n d 
h a v e r e c ei v e d  at l e ast  1  d os e  of st u d y  dr u g.  T h e  F A S is t o  b e  us e d  i n  effi c a c y  a n al ys es. 
T h e  S af et y  S et  is  d efi n e d  as  all s u bj e cts  w h o  h a v e r e c ei v e d  at l e ast  1  d os e  of st u d y  dr u g.  T h e 
S af et y  S et is t o  b e  us e d f or  all s af et y  a n al ys es.  
1 2. 3   
St ati sti c al  A n al y si s  
T his s e cti o n  pr es e nts  a s u m m ar y  of t h e  pri n ci p al f e at ur es  of t h e  pl a n n e d st atisti c al  a n al ys es. 
St atisti c al  a n al ysis  d et ails  will  b e i n t h e st atisti c al  a n al ysis  pl a n ( S A P)  w hi c h  will  b e fi n ali z e d 
b ef or e  cli ni c al  d at a b as e l o c k.  
1 2. 3. 1   
G e n er al  C o n si d er a ti o n s 
C o nti n u o us  v a ri a bl es  will  b e s u m m ari z e d  usi n g t h e f oll o wi n g  d es cri pti v e s u m m ar y st atisti cs: 
t h e  n u m b er  of s u bj e cts ( n),  m e a n,  S D,  m e di a n,  mi ni m u m  v al u e ( mi n),  a n d  m a xi m u m  v al u e 
( m a x). 
C at e g o ri c al  v a ri a bl es  will  b e s u m m ari z e d  usi n g  c o u nts  a n d  p er c e nt a g es.  
B as eli n e  v al u e ,  u nl ess s p e cifi e d  ot h er wis e,  will  b e  d efi n e d  as t h e  m ost r e c e nt  n o n- missi n g 
m e as ur e m e nt (s c h e d ul e d  or  u ns c h e d ul e d)  c oll e ct e d  b ef or e t h e first  d os e  of st u d y  dr u g.  D et ails 
will  b e  pr o vi d e d i n t h e  S A P. 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  3 8  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
A bs ol ut e  c h a n g e f r o m  b as eli n e  will  b e  c al c ul at e d  as  p ost -b as eli n e  v al u e  −  b as eli n e  v al u e.  
R el ati v e  c h a n g e f r o m  b as eli n e  will  b e  c al c ul at e d  a n d  e x pr ess e d i n  p er c e nt a g e  as 
1 0 0 %  ×  ( p ost-b as eli n e  v al u e  - b as eli n e  v al u e)/ b as eli n e  v al u e.  
T r e at m e nt -e m e r g e nt ( T E)  P e ri o d  will i n cl u d e t h e ti m e fr o m t h e first  d os e  of st u d y  dr u g t o 
2 8  d a ys  aft er t h e l ast  d os e  of st u d y  dr u g  or t o t h e  c o m pl eti o n  of st u d y  p arti ci p ati o n ( as  d efi n e d i n 
S e cti o n  9. 1. 6 ),  w hi c h e v er  o c c urs first. 
I n c o m pl et e/ missi n g  d at a  will  n ot  b e i m p ut e d,  u nl ess s p e cifi e d  ot h er wis e.  
1 2. 3. 2   
B a c k gr o u n d  C h ar a ct eri sti c s  
S u bj e ct  dis p ositi o n ( e. g.,  e nr oll e d,  c o m pl et e d tr e at m e nt,  pr e m at ur el y  dis c o nti n u e d tr e at m e nt ,  a n d 
e nt er e d  a n  o p e n -l a b el  e xt e nsi o n)  will  b e s u m m ari z e d  b as e d  o n t h e  All  S u bj e cts  S et. 
D e m o gr a p hi cs  a n d  b as eli n e  c h ar a ct eristi cs  will  b e s u m m ari z e d.  Als o,  m e di c al  hist or y  a n d 
m e di c ati o n  us e  will  b e s u m m ari z e d  d es cri pti v el y  
E x p os ur e t o st u d y  dr u g i n (i. e.,  d ur ati o n  of tr e at m e nt)  a n d  d osi n g  c o m pli a n c e (i. e.,  p er c e nt a g e  of 
d a ys  b ei n g  c o m pli a nt t o tr e at m e nt)  will  b e s u m m ari z e d  d es cri pti v el y.  
I m p ort a nt  pr ot o c ol  d e vi ati o ns  will  b e  pr o vi d e d i n  a n i n di vi d u al s u bj e ct  d at a listi n g  a n d 
s u m m ari z e d,  as  a p pr o pri at e.  
A d diti o n al  d et ails  will  b e  pr o vi d e d i n t h e  S A P.  
1 2. 3. 3   
Effi c a c y  A n al y si s  
1 2. 3. 3. 1   
A n al y si s  of  Pri m ar y  E n d p oi nt  
T h e  pri m ar y  e n d p oi nt is  p er c e nt r e d u cti o n fr o m  b as eli n e i n  c o u g h fr e q u e n c y ( c o u g h  e v e nts  p er 
d a y) t o t h e  a v er a g e  of  W e e k  8 t hr o u g h  W e e k  1 2.  T h e  pri m ar y  a n al ysis  will  b e  b as e d  o n  a  mi x e d-
eff e c ts  m o d el f or r e p e at e d  m e as ur es ( M M R M)  wit h  c h a n g e fr o m  b as eli n e  at  e a c h  p ost-b as eli n e 
visit  o n t h e  n at ur al l o g s c al e  as t h e  d e p e n d e nt  v ari a bl e.  T h e  m o d el  will i n cl u d e  w e e k  as fi x e d 
eff e cts  a n d  b as eli n e  c o u g h fr e q u e n c y  as  c o v ari at e.  
T h e  pri m ar y r es ult  o bt ai n e d fr o m t h e  m o d el  will  b e t h e  esti m at e d  p er c e nt r e d u cti o n i n  c o u g h 
fr e q u e n c y fr o m  b as eli n e t o t h e  a v er a g e  of  W e e k  8 t hr o u g h  W e e k  1 2, i. e.,  1 0 0 %  × ( 1- e x p o n e nti al 
f or m  of  L S  m e a n  c h a n g e  esti m at e fr o m t h e  a b o v e  M M R M  m o d el).  T h e  2-si d e d  9 5 %  c o nfi d e n c e 
i nt er v als  will  b e  pr o vi d e d.  F urt h er m or e, t h e  esti m at e d  p er c e nt r e d u cti o n  at  e a c h  p ost‑ b as eli n e 
w e e k  will  als o  b e  pr o vi d e d.  
A d diti o n al  d et ails  will  b e  pr o vi d e d i n t h e  S A P. 
1 2. 3. 3. 2   
A n al y si s  of  S e c o n d ar y  E n d p oi nt  
T h e s e c o n d ar y  e n d p oi nt is  a bs ol ut e  c h a n g e fr o m  b as eli n e i n t ot al st e p  c o u nt  p er  d a y t o t h e 
a v er a g e  of  W e e k   8 t hr o u g h  W e e k  1 2. 
F or t ot al st e p  c o u nts  p er  d a y, t h e  b as eli n e  v al u e is  d efi n e d t h e  a v er a g e  of t ot al st e p  c o u nt  p er  d a y 
i n  a  7- d a y  p eri o d  pri or t o first  d os e  of st u d y  dr u g.  T h e tr e at m e nt  p eri o d  will  b e  di vi d e d i nt o 
1 2  w e e kl y i nt er v als ( W e e k  1,  W e e k  2, ...  W e e k  1 2),  a n d t h e  a v er a g e  of t ot al st e p  c o u nt  p er  d a y 
will  b e  c al c ul at e d f or  e a c h  w e e kl y i nt er v al.  T h e  a n al ysis  will  b e  b as e d  o n  a  M M R M  m o d el  wit h 
c h a n g e fr o m  b as eli n e  at  e a c h  p ost -b as eli n e  w e e kl y i nt er v al  as  t h e  d e p e n d e nt  v ari a bl e.  T h e  m o d el 
will i n cl u d e  w e e k  as fi x e d  eff e cts  a n d  b as eli n e t ot al st e p  c o u nt  p er  d a y  as  c o v ari at e.  

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  3 9  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
T h e  pri m ar y r es ult  o bt ai n e d fr o m t h e  m o d el  will  b e t h e  esti m at e d  m e a n  c h a n g e fr o m  b as eli n e t o 
t h e  a v er a g e  of  W e e k  8 t hr o u g h  W e e k  1 2.  T he  2 -si d e d  9 5 %  c o nfi d e n c e i nt er v als  will  b e  pr o vi d e d. 
F urt h er m or e, t h e  esti m at e d  m e a n  c h a n g e  at  e a c h  p ost‑ b as eli n e  w e e kl y i nt er v al  will  als o  b e 
pr o vi d e d.  
A d diti o n al  d et ails  will  b e  pr o vi d e d i n t h e  S A P. 
1 2. 3. 3. 3   
M ulti pli cit y  A dj u st m e nt  
N o  m ulti pli cit y  a dj ust m e nt is  pl a n n e d. 
1 2. 3. 3. 4   
Mi s si n g  D at a  H a n dli n g  
F or t h e  pri m ar y  a n al ysis  of t h e  pri m ar y  e n d p oi nt,  missi n g  d at a  will  b e  ass u m e d t o  b e  missi n g  at 
r a n d o m  c o n diti o n al  o n t h e  o bs er v e d  d at a  a n d  c o v ari at e;  c o ns e q u e ntl y,  n o i m p ut ati o n  of  missi n g 
d at a  will  b e  p erf or m e d.  
1 2. 3. 4   
S af et y  A n al y si s  
T h e  o v er all s af et y  pr ofil e  will  b e  ass ess e d i n t er ms  of t h e f oll o wi n g s af et y  e n d p oi nts:   
•   I n ci d e n c e  of tr e at m e nt  e m er g e nt  a d v ers e  e v e nts (T E A Es)   
•   Cli ni c al l a b or at or y  v al u es  
F or s af et y  a n al ys es,  n o st atisti c al  h y p ot h esis t esti n g  will  b e  c o n d u ct e d.  A d diti o n al  d et ails  will  b e 
pr o vi d e d i n t h e  S A P. 
1 2. 4   
I nt eri m A n al y si s  
N ot  a p pli c a bl e 
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 pli c a bl e 
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  d efi n e d  as  a n y  u nt o w ar d  m e di c al  o c c urr e n c e i n  a s u bj e ct  d uri n g t h e st u d y; t h e  e v e nt 
d o es  n ot  n e c ess aril y  h a v e  a  c a us al r el ati o ns hi p  wit h t h e tr e at m e nt.  T his i n cl u d es  a n y  n e wl y 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  4 0  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
o c c urri n g  e v e nt  or  w ors e ni n g  of  a  pr e- e x isti n g  c o n diti o n ( e. g., i n cr e as e i n its s e v erit y  or 
fr e q u e n c y)  aft er t h e I C F is si g n e d.  
A n  A E is  c o nsi d er e d s eri o us if it  m e ets t h e  d efi niti o n i n  S e cti 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  ass ess m e nts i n cl u di n g l a b or at or y t ests,  E C Gs,  a n d  vit al si g ns  will  b e  ass ess e d  a n d t h os e 
d e e m e d t o  h a v e  cli ni c all y si g nifi c a nt  w ors e ni n g fr o m  b as eli n e  will  b e  d o c u m e nt e d  as  a n  A E. 
W h e n  p ossi bl e,  a  cli ni c al  di a g n osis f or t h e st u d y  ass ess m e nt  will  b e  pr o vi d e d, r at h er t h a n t h e 
a b n or m al t est r es ult  al o n e ( e. g.,   uri n ar y tr a ct i nf e cti o n,  a n e mi a). I n t h e  a bs e n c e  of  a  di a g n osis, 
t h e  a b n or m al st u d y  ass ess m e nt its elf  will  b e list e d  as t h e  A E ( e. g., b a ct eri a  i n  uri n e  or  d e cr e as e d 
h e m o gl o bi n). 
A n  a b n or m al st u d y  ass ess m e nt is  c o nsi d er e d  cli ni c all y si g nifi c a nt if t h e s u bj e ct  h as  1  or  m or e  of 
t h e f oll o wi n g: 
•   C o n c o mit a nt si g ns  or s y m pt o ms r el at e d t o t h e  a b n or m al st u d y  ass ess m e nt  
•   F urt h er  di a g n osti c t esti n g  or  m e di c al /s ur gi c al i nt er v e nti o n 
•   A  c h a n g e i n t h e  d os e  of st u d y  dr u g  or  dis c o nti n u ati o n fr o m t h e st u d y 
R e p e at t esti n g t o  d et er mi n e  w h et h er t h e r es ult is  a b n or m al, i n t h e  a bs e n c e  of  a n y  of t h e  a b o v e 
crit eri a,  d o es  n ot  n e c ess aril y  m e et  cli ni c all y si g nifi c a nt  crit eri a.  T h e  d et er mi n ati o n  of  w h et h er t h e 
st u d y  ass ess m e nt r es ults  ar e  cli ni c all y si g nifi c a nt  will  b e  m a d e  b y t h e i n v esti g at or.  
A l a b or at or y  v al u e t h at is  Gr a d e  4  will  n ot  a ut o m ati c all y  b e  a n  S A E.  A  Gr a d e  4  l a b or at or y  v al u e 
will  b e  a n  S A E if t h e s u bj e ct’s  cli ni c al  st at us i n di c at es  a lif e-t hr e at e 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  b e  c oll e ct e d fr o m t h e ti m e t h e I C F is si g n e d  u ntil t h e s u bj e ct  c o m pl et es st u d y 
p arti ci p ati o n,  as  d efi n e d i n  S e cti o n  9. 1. 6 . 
All s u bj e cts ( or t h eir  p ar e nt/l e g al  g u ar di a n)  will  b e  q u eri e d,  usi n g  n o nl e a di n g  q u esti o ns,  a b o ut 
t h e  o c c urr e n c e  of  A Es  at  e a c h st u d y  visit. W h e n  p ossi bl e,  a  c o nst ell ati o n  of si g ns  a n d/ or 
s y m pt o ms  will  b e i d e ntifi e d  as  1  o v er all  e v e nt  or  di a g n osis. All  A Es f or  e nr oll e d s u bj e cts  will  b e 
r e c or d e d i n t h e  C R F  a n d s o ur c e  d o c u m e nt.  A Es f or s u bj e cts  w h o  ar e s cr e e n e d  b ut  n ot 
s u bs e q u e ntl y  e nr oll e d  will  b e r e c or d e d  o nl y i n t h e s u bj e ct’s s o ur c e  d o c u m e nts.  T h e f oll o wi n g 
d at a  will  b e  d o c u m e nt e d f or  e a c h  A E: 
•   D es cri pti o n  of t h e  e v e nt 
•   Cl assifi c ati o n  of  “s eri o us ”  or  “ n o ns eri o us ”  
•   D at e  of first  o c c urr e n c e  a n d  d at e  of r es ol uti o n (if  a p pli c a bl e)  
•   S e v erit y  
•   C a us al r el ati o ns hi p t o st u d y  dr u g(s)  
•   A cti o n t a k e n  
•   O ut c o m e  
•   C o n c o mit a nt  m e di c ati o n  or  ot h er tr e at m e nt  gi v e n  

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  4 1  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
1 3. 1. 1. 4   
A d v er s e  E v e nt  S e v erit y  
T h e i n v esti g at or  will  d et er mi n e  a n d r e c or d t h e s e v erit y  of  all s eri o us  a n d  n o ns eri o us  A Es.  T h e 
g ui d a n c e  a v ail a bl e  at t h e f oll o wi n g  w e bsit e  will  b e  c o ns ult e d:  C o m m o n  T er mi n ol o g y  Crit eri a  f or 
A d v ers e  E v e nts ( C T C A E),  V ersi o n   5. 0,  C a n c er  T h er a p y  E v al u ati o n  Pr o gr a m, 
htt p:// ct e p. c a n c er. g o v/ pr ot o c ol D e v el o p m e nt/ el e ctr o ni c _ a p pli c ati o ns/ ct c. ht m  ( A c c ess e d 
S e pt e m b er  2 0 1 9).  W h e n  c o nsi d eri n g t h e s e v erit y  of  a n  A E i n  a  p e di atri c s u bj e ct, t h e i n v esti g at or 
will  c o nsi d er t h at r ef er e n c e r a n g es f or  p e di atri c  cli ni c al l a b or at or y  p ar a m et ers  m a y  diff er fr o m 
t h os e i n t h e  C T C A E.  T h e s e v erit y  of  a n  A E  d es cri b e d  b y  a t er m t h at  d o es  n ot  a p p e ar i n t h e 
C T C A E  will  b e  d et er mi n e d  a c c or di n g t o t h e  d efi niti o ns i n  T a bl e   1 3- 1.  
T a bl e   1 3- 1    
G r a di n g  of  A E  S e v e rit y  
Cl assifi c ati o n  
D es c ri pti o n  
G r a d e  1 ( Mil d)  
Mil d;  as y m pt o m ati c  or  mil d s y m pt o ms;  cli ni c al  or  di a g n osti c  o bs er v ati o ns  o nl y; 
i nt er v e nti o n  n ot i n di c at e d 
G r a d e  2 ( M o d e r at e)  
M o d er at e;  mi ni m al, l o c al,  or  n o ni n v asi v e i nt er v e nti o n i n di c at e d; li miti n g  a g e -
a p pr o pri at e i nstr u m e nt al  A D L a 
G r a d e  3 ( S e v e r e)  
S e v er e  or  m e di c all y si g nifi c a nt  b ut  n ot i m m e di at el y lif e -t hr e at e ni n g; 
h os pit ali z ati o n  or  pr ol o n g ati o n  of  h os pit ali z ati o n i n di c at e d;  dis a bli n g; li miti n g 
s elf-c ar e  A D L b 
G r a d e  4 ( Lif e -
t h r e at e ni n g) 
Lif e -t hr e at e ni n g  c o ns e q u e n c es;  ur g e nt i nt er v e nti o n i n di c at e d  
G r a d e  5 ( D e at h)  
D e at h r el at e d t o  a d v ers e  e v e nt  
S o ur c e:  htt p:// ct e p. c a n c er. g o v/ pr ot o c ol D e v el o p m e nt/ el e ctr o ni c _ a p pli c ati o ns/ ct c. ht m  ( A c c ess e d  S e pt e m b er 2 0 1 9)  
A D L:  a cti viti es  of  d ail y li vi n g;  A E:  a d v ers e  e v e nt  
N ot e:  A s e mi -c ol o n i n di c at es ‘ or’  wit hi n t h e  d es cri pti o n  of t h e  gr a d e.  
a  
I nstr u m e nt al  A D L r ef er t o  pr e p ari n g  m e als, s h o p pi n g f or  gr o c eri es  or  cl ot h es,  usi n g t h e t el e p h o n e,  m a n a gi n g 
m o n e y,  et c.  
b  
S elf -c ar e  A D L r ef er t o  b at hi n g,  dr essi n g  a n d  u n dr essi n g, f e e di n g s elf,  usi n g t h e t oil et, t a ki n g  m e di c ati o ns, 
a n d  n ot  b e dri d d e n.  
1 3. 1. 1. 5   
A d v er s e  E v e nt  C a u s alit y  
E v er y  eff ort  will  b e  m a d e  b y t h e i n v esti g at or t o  ass ess t h e r el ati o ns hi p  of t h e  A E, if  a n y, t o t h e 
st u d y  dr u g(s).  C a us alit y  will  b e  cl assifi e d  usi n g t h e  c at e g ori es i n  T a bl e  1 3 - 2. 
T a bl e   1 3- 2  
Cl assifi c ati o ns f o r  A E  C a us alit y  
Cl assifi c ati o n  
D efi niti o n  
R el at e d  
T h er e is  a n  ass o ci ati o n  b et w e e n t h e  e v e nt  a n d t h e  a d mi nistr ati o n  of i n v esti g ati o n al 
st u d y  dr u g,  a  pl a usi bl e  m e c h a nis m f or t h e  e v e nt t o  b e r el at e d t o t h e i n v esti g ati o n al 
st u d y  dr u g  a n d  c a us es  ot h er t h a n t h e i n v esti g ati o n al st u d y  dr u g  h a v e  b e e n r ul e d  o ut, 
a n d/ or t h e  e v e nt r e a p p e ar e d  o n r e -e x p os ur e t o t h e i n v esti g ati o n al st u d y  dr u g.  
P ossi bl y  r el at e d  
T h er e is  a n  ass o ci ati o n  b et w e e n t h e  e v e nt  a n d t h e  a d mi nistr ati o n  of t h e 
i n v esti g ati o n al st u d y  dr u g  a n d t h er e is  a  pl a usi bl e  m e c h a nis m f or t h e  e v e nt t o  b e 
r el at e d t o i n v esti g ati o n al st u d y  dr u g,  b ut t h er e  m a y  als o  b e  alt er n ati v e  eti ol o g y, 
s u c h  as  c h ar a ct eristi cs  of t h e s u bj e ct’s  cli ni c al st at us  or  u n d erl yi n g  dis e as e.  
U nli k el y  r el at e d  
T h e  e v e nt is  u nli k el y t o  b e r el at e d t o t h e i n v esti g ati o n al st u d y  dr u g  a n d li k el y t o  b e 
r el at e d t o f a ct ors  ot h er t h a n i n v esti g ati o n al st u d y  dr u g.  
N ot  r el at e d  
T h e  e v e nt is r el at e d t o  a n  eti ol o g y  ot h er t h a n t h e i n v esti g ati o n al st u d y  dr u g (t h e 
alt er n ati v e  et i ol o g y  will  b e  d o c u m e nt e d i n t h e s u bj e ct’s  m e di c al r e c or d). 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  4 2  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
T a bl e   1 3- 2  
Cl assifi c ati o ns f o r  A E  C a us alit y  
Cl assifi c ati o n  
D efi niti o n  
A E:  a d v ers e  e v e nt  
1 3. 1. 1. 6   
St u d y  Dr u g  A cti o n  T a k e n  
T h e i n v esti g at or  will  cl assif y t h e st u d y  dr u g  a cti o n t a k e n  wit h r e g ar d t o t h e  A E.  T h e  a cti o n t a k e n 
will  b e  cl assifi e d  a c c or di n g t o t h e  c at e g ori es i n  T a bl e   1 3- 3.  
T a bl e   1 3- 3    
Cl assifi c ati o ns f o r  St u d y  D r u g  A cti o n  T a k e n  Wit h  R e g a r d t o  a n  A E 
Cl assifi c ati o n a 
D efi niti o n  
D os e  n ot  c h a n g e d   
St u d y  dr u g  d os e  n ot  c h a n g e d i n r es p o ns e t o  a n  A E  
D os e  r e d u c e d  
St u d y  dr u g  d os e r e d u c e d i n r es p o ns e t o  a n  A E  
D r u g i nt e r r u pt e d   
St u d y  dr u g  a d mi nistr ati o n i nt err u pt e d i n r es p o ns e t o  a n  A E   
D r u g  wit h d r a w n   
St u d y  dr u g  a d mi nistr ati o n  p er m a n e ntl y  dis c o nti n u e d i n r es p o ns e t o  a n  A E  
N ot  a p pli c a bl e  
A cti o n t a k e n r e g ar di n g st u d y  dr u g  a d mi nistr ati o n  d o es  n ot  a p pl y.   
“ N ot  a p pli c a bl e ”  will  b e  u s e d i n  cir c u mst a n c es s u c h  as  w h e n t h e i n v esti g ati o n al 
tr e at m e nt  h a d  b e e n  c o m pl et e d  b ef or e t h e  A E  b e g a n  a n d  n o  o p p ort u nit y t o  d e ci d e 
w h et h er t o  c o nti n u e, i nt err u pt,  or  wit h dr a w tr e at m e nt is  p ossi bl e.  
A E:  a d v ers e  e v e nt  
a  
R ef er t o  S e cti o ns  9. 7  a n d  9. 8  f or  dir e cti o ns r e g ar di n g  w h at  dr u g  a cti o ns  ar e  p er mitt e d  p er  pr ot o c 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  b e f oll o w e d  u ntil t h e i n v esti g at or  h as  d et er mi n e d  a n d  pr o vi d e d t h e fi n al  o ut c o m e. 
T h e  o ut c o m e  will  b e  cl assifi e d  a c c or di n g t o t h e  c at e g ori es i n  T a bl e   1 3- 4. 
T a bl e   1 3- 4    
Cl assifi c ati o ns f o r  O ut c o m e  of  a n  A E 
Cl assifi c ati o n  
D efi niti o n  
R e c o v e r e d/ r es ol v e d   
R es ol uti o n  of  a n  A E  wit h  n o r esi d u al si g ns  or s y m pt o ms  
R e c o v e r e d/ r es ol v e d  wit h 
s e q u el a e 
R es ol uti o n  of  a n  A E  wit h r esi d u al si g ns  or s y m pt o ms  
N ot  r e c o v e r e d/ n ot 
r es ol v e d ( c o nti n ui n g)  
Eit h er i n c o m pl et e i m pr o v e m e nt  or  n o i m pr o v e m e nt  of  a n  A E, s u c h t h at it r e m ai ns 
o n g oi n g  
F at al  
O ut c o m e  of  a n  A E is  d e at h.  “ F at al ”  will  b e  us e d  w h e n  d e at h is  at l e ast  p ossi bl y 
r el at e d to t h e  A E.  
U n k n o w n  
O ut c o m e  of  a n  A E is  n ot  k n o w n ( e. g.,  a s u bj e ct l ost t o f oll o w  u p)  
A E:  a d v ers e  e v e nt  
1 3. 1. 1. 8   
Tr e at m e nt  Gi v e n  
T h e i n v esti g at or  e ns ur es  a d e q u at e  m e di c al  c ar e is  pr o vi d e d t o s u bj e cts f or  a n y  A Es, i n cl u di n g 
cli ni c all y si g nifi c a nt  l a b or at or y  v al u es r el at e d t o st u d y  dr u g. I n  a d diti o n, t h e i n v esti g at or  will 
d es cri b e  w h et h er  a n y tr e at m e nt  w as  gi v e n f or t h e  A E.  “ Y es ” is  us e d if  a n y tr e at m e nt  w as  gi v e n 
i n r es p o ns e t o  a n  A E,  a n d  m a y i n cl u d e tr e at m e nts s u c h  as  ot h er  m e di c ati o ns, s ur g er y,  or  p h ysi c al 
t h er a p y.  “ N o ” i n di c at es t h e  a bs e n c e  of  a n y  ki n d  of tr e at m e nt f or  a n  A E. 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  4 3  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati 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 h at  m e ets  a n y  of t h e f oll o wi n g  o ut c o m es: 
•   F at al ( d e at h, r e g ar dl ess  of  c a us e, t h at  o c c urs  d uri n g  p arti ci p ati o n i n t h e st u d y  or  o c c urs  aft er 
p arti ci p ati o n  a n d is s us p e ct e d  of  b ei n g  a  d el a y e d t o xi cit y  d u e t o  a d mi nistr ati o n  of t h e st u d y 
dr u g) 
•   Lif e -t hr e at e ni n g, s u c h t h at t h e s u bj e ct  w as  at i m m e di at e ris k  of  d e at h fr o m t h e r e a cti o n  as it 
o c c urr e d  
•   I n p ati e nt  h os pit ali z ati o n  or  pr ol o n g ati o n  of  h os pit ali z ati o n 
•   P ersist e nt  or si g nifi c a nt  dis a bilit y/i n c a p a cit y ( dis a bilit y is  d efi n e d  as  a s u bst a nti al  disr u pti o n 
of  a  p ers o n’s  a bilit y t o  c o n d u ct  n or m al lif e f u n cti o ns) 
•   C o n g e nit al  a n o m al y  or  birt h  d ef e ct 
•   I m p ort a nt  m edi c al  e v e nt t h at,  b as e d  u p o n  a p pr o pri at e  m e di c al j u d g m e nt,  m a y j e o p ar di z e t h e 
s u bj e ct  or  m a y r e q uir e  m e di c al  or s ur gi c al i nt er v e nti o n t o  pr e v e nt  1  of t h e  o ut c o m es list e d 
a b o v e ( e. g.,  a n  all er gi c  br o n c h os p as m r e q uiri n g i nt e nsi v e tr e at m e nt i n  a n  e m er g e n c y r o o m  or 
at  h o m e)   
If  a s u bj e ct  h as  a  h os pit ali z ati o n  or  pr o c e d ur e ( e. g., s ur g er y) f or  a n  e v e nt  or  c o n diti o n t h at 
o c c urr e d  b ef or e t h e s u bj e ct si g n e d t h e I C F,  a n d t h e  h os pit ali z ati o n  or  pr o c e d ur e  w as  pl a n n e d 
b ef or e t h e s u bj e ct si g n e d t h e I C F, t h e  h os pit ali z ati o n  or  pr o c e d ur e  will  n ot  b e  c o nsi d er e d t o 
i n di c at e  a n  S A E,  u nl ess  a n  A E  c a us e d t h e  h os pit ali z ati o n  or  pr o c e d ur e t o  b e r es c h e d ul e d s o o n er 
or t o  b e  pr ol o n g e d r el ati v e t o  w h at  w as  pl a n n e d. I n  a d diti o n,  h os pit ali z ati o ns  cl e arl y  n ot 
ass o ci at e d  wit h  a n  A E ( e. g.,  s o ci al  h os pit ali z ati o n f or  p ur p os es  of r es pit e  c ar e)  will  n ot  b e 
c o nsi d er e d t o i n di c at e  a n  S A E. 
Cl arifi c ati o n  will  b e  m a d e  b et w e e n t h e t er ms  “s eri o us ”  a n d  “s e v er e ”  b e c a us e t h e y  ar e  n ot 
s y n o n y m o us.  T h e t er m  “s e v er e ” is  oft e n  us e d t o  d es cri b e t h e i nt e nsit y  (s e v erit y)  of  a s p e cifi c 
e v e nt,  as i n  mil d,  m o d er at e,  or s e v er e  m y o c ar di al i nf ar cti o n.  T h e  e v e nt its elf,  h o w e v er,  m a y  b e 
of r el ati v el y  mi n or  m e di c al si g nifi c a n c e, s u c h  as  a s e v er e  h e a d a c h e.  T his is  n ot t h e s a m e  as 
“s eri o us ”,  w hi c h is  b as e d  o n s u bj e ct/ e v e nt   o ut c o m e  or  a cti o n  d es cri b e d  a b o v e,  a n d is  us u all y 
ass o ci at e d  wit h  e v e nts t h at  p os e  a t hr e at t o  a s u bj e ct’s lif e  or f u n cti o ni n g.  S eri o us n ess,  n ot 
s e v erit y, s er v es  as  a  g ui d e f or  d efi ni n g  e x p e dit e d r e g ul at or y r e p orti n g  o bli g ati o ns.  
1 3. 1. 2. 2   
R e p orti n g  a n d  D o c u m e nt at i o n  of  S eri o u s  A d v er s e  E v e nt s 
All  S A Es t h at  o c c ur  aft er  o bt ai ni n g i nf or m e d  c o ns e nt  a n d  ass e nt ( w h er e  a p pli c a bl e) t hr o u g h t h e 
S af et y  F oll o w - u p  Visit, r e g ar dl ess  of  c a us alit y,  will  b e r e p ort e d  b y t h e i n v esti g at or t o  V ert e x 
G P S  wit hi n  2 4  h o u rs  of  i d e ntifi c ati o n. I n  a d diti o n,  all  S A Es t h at  o c c ur  aft er t h e  S af et y 
F oll o w- u p  Visit  a n d  ar e  c o nsi d er e d r el at e d t o st u d y  dr u g(s)  will  b e r e p ort e d t o  V ert e x  G P S 
wit hi n  2 4  h o u rs  of i d e ntifi c ati o n .  
F or  S A Es t h at  o c c ur  aft er  o bt ai ni n g i nf or m e d  c o ns e nt  a n d  ass e nt  ( w h er e  a p pli c a bl e) t hr o u g h t h e 
S af et y  F oll o w -u p  Visit, t h e  S A E  F or m  will  b e  c o m pl et e d f or  n e w/i niti al  e v e nts  as  w ell  as t o 
r e p ort f oll o w- u p i nf or m ati o n  o n  pr e vi o usl y r e p ort e d  e v e nts. I n v esti g at ors  ar e  as k e d t o r e p ort 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  4 4  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
f oll o w- u p i nf or m ati o n  as s o o n  as it  b ec o m es  a v ail a bl e t o  e ns ur e ti m el y r e p orti n g t o  h e alt h 
a ut h oriti es.  
Pl e as e s e n d  c o m pl et e d  S A E  F or ms t o  V ert e x  G P S  vi a:  
E m ail: 
 ( pr ef err e d  c h oi ce)  
F a x: 
  
F or t e c h ni c al iss u es r el at e d t o s u b mitti n g t h e f or m,  c o nt a ct t el e p h o n e: 
 
S A Es t h at  o c c ur  aft er t h e  S af et y  F oll o w - u p  Visit  a n d  ar e  c o nsi d er e d r el at e d t o st u d y  dr u g(s) will 
b e r e c or d e d  o n t h e  V ert e x  Cli ni c al  Tri al  S af et y I nf or m ati o n  C oll e cti o n  F or m ( h er e aft er r ef err e d 
t o  as t h e  “ S A E  F or m ”)  usi n g  a r e c o g ni z e d  m e di c al t er m  or  di a g n osis t h at  a c c ur at el y r efl e cts t h e 
e v e nt.  S A Es  will  b e  ass ess e d  b y t h e i n v esti g at or f or r el at i o ns hi p t o t h e i n v esti g ati o n al st u d y 
dr u g(s)  a n d  p ossi bl e  eti ol o gi es.  O n t h e  S A E  F or m, r el ati o ns hi p t o st u d y  dr u g(s)  will  b e  ass ess e d 
o nl y  as r el at e d (i n cl u d es  p ossi bl y r el at e d)  or  n ot r el at e d (i n cl u d es  u nli k el y r el at e d),  a n d s e v erit y 
ass ess m e nt  will  n ot  b e r e q uir e d.  F or t h e  p ur p os es  of st u d y  a n al ysis, if t h e  e v e nt  h as  n ot r es ol v e d 
at t h e  e n d  of t h e st u d y r e p orti n g  p eri o d, it  will  b e  d o c u m e nt e d  as  o n g oi n g.  F or  p ur p os es  of 
r e g ul at or y s af et y  m o nit ori n g, t h e i n v esti g at or is r e q uir e d t o f oll o w t h e  e v e nt t o r es ol uti o n  a n d 
r e p ort t h e  o ut c o m e t o  V ert e x  usi n g t h e  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  
V ert e x,  as st u d y s p o ns or, is r es p o nsi bl e f or r e p orti n g s us p e ct e d,  u n e x p e ct e d, s eri o us  a d v ers e 
r e a cti o ns ( S U S A Rs) i n v ol vi n g t h e st u d y  dr u g(s) t o  all r e g ul at or y  a ut h oriti es, I E C,  a n d 
p arti ci p ati n g i n v esti g at ors i n  a c c or d a n c e  wit h  c urr e nt I C H  E 2 A  G ui d eli n es  a n d/ or l o c al 
r e g ul at or y r e q uir e m e nts,  as  a p pli c a bl e. I n  a d diti o n,  V ert e x,  or  a ut h ori z e d  d esi g n e e,  will  b e 
r es p o nsi bl e f or t h e s u b missi o n  of s af ety l ett ers t o  c e ntr al I E Cs.   
It is t h e r es p o nsi bilit y  of t h e i n v esti g at or  or  d esi g n e e t o  pr o m ptl y  n otif y t h e l o c al I R B/I E C  of  all 
u n e x p e ct e d s eri o us  a d v ers e  dr u g r e a cti o ns i n v ol vi n g ris k t o  h u m a n s u bj e cts.  
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 u ct  c o m pl ai nt is  d efi n e d  as  a n y  v er b al  or  writt e n  c o m m u ni c ati o n  a d dr ess e d t o  V ert e x,  or 
d esi g n e e,  of i n q uir y  or  diss atisf a cti o n  wit h t h e i d e ntit y, str e n gt h,  q u alit y,  or  p urit y  of  a r el e as e d 
dr u g  pr o d u ct, I M P,  or  m e di c al  d e vi c e. I n  a d diti o n, s us p e ct e d  c o u nt erf eit/f alsifi e d  pr o d u ct is 
c o nsi d er e d  a  pr o d u ct  c o m pl ai nt.   
Pr o d u ct  c o m pl ai nts  ar e t o  b e r e p ort e d t o  V ert e x. 
1 3. 2. 2   
Et hi c al  C o n si d er ati o n s  
T h e st u d y  will  b e  c o n d u ct e d i n  a c c or d a n c e  wit h t h e  c urr e nt I C H  E 6  G C P  G ui d eli n es,  w hi c h  ar e 
c o nsist e nt  wit h t h e  et hi c al  pri n ci pl es f o u n d e d i n t h e  D e cl ar ati o n  of  H elsi n ki,  a n d i n  a c c or d a n c e 
wit h l o c al  a p pli c a bl e l a ws  a n d r e g ul ati o ns.  T h e I R B/I E C  will r e vi e w  all  a p pr o pri at e st u d y 
d o c u m e nt ati o n t o s af e g u ar d t h e ri g hts, s af et y,  a n d  w ell- b ei n g  of t h e s u bj e cts.  T h e st u d y  will  b e 
c o n d u ct e d  o nl y  at sit es  w h er e I R B/I E C  a p pr o v al  h as  b e e n  o bt ai n e d.  T h e  pr ot o c ol, I n v esti g at or’s 
Br o c h ur e, s a m pl e I C F,  a d v ertis e m e nts (if  a p pli c a bl e),  writt e n i nf or m ati o n  gi v e n t o t h e s u bj e cts 
(i n cl u di n g  di ar y  c ar ds), s af et y  u p d at es,  a n n u al  pr o gr ess r e p orts,  a n d  a n y r e visi o ns t o t h es e 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  4 5  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
d o c u m e nts  will  b e  pr o vi d e d t o t h e I R B/I E C  b y t h e i n v esti g at or  or  V ert e x,  as  all o w a bl e  b y l o c al 
a p pli c a bl e l a ws  a n d r e 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  
Aft er t h e st u d y  h as  b e e n f ull y  e x pl ai n e d, i nf or m e d  c o ns e nt  will  b e  o bt ai n e d fr o m t h e s u bj e ct  or 
l e g al r e pr es e nt ati v e  or  g u ar di a n (if  a p pli c a bl e),  a n d  ass e nt  will  b e  o bt ai n e d fr o m t h e s u bj e ct (if 
a p pli c a bl e),  b ef or e st u d y  p arti ci p ati o n.  T h e  m et h o d  of  o bt ai ni n g  a n d  d o c u m e nti n g t h e i nf or m e d 
c o ns e nt  a n d  ass e nt (if  a p p li c a bl e)  a n d t h e  c o nt e nts  of t h e  c o ns e nt  will  c o m pl y  wit h  c urr e nt 
I C H  E 6  G C P  G ui d eli n es  a n d  all  a p pli c a bl e l a ws  a n d r e g ul ati o ns  a n d  will  b e s u bj e ct t o  a p pr o v al 
b y  V ert e x  or its  d esi g n e e. 
1 3. 2. 4   
I n v e sti g at or  C o m pli a n c e 
N o  m o difi c ati o ns t o t h e  pr ot o c ol  will  b e  m a d e   wit h o ut t h e  a p pr o v al  of  b ot h t h e i n v esti g at or  a n d 
V ert e x.  C h a n g es t h at si g nifi c a ntl y  aff e ct t h e s af et y  of t h e s u bj e cts, t h e s c o p e  of t h e i n v esti g ati o n, 
or t h e s ci e ntifi c  q u alit y  of t h e st u d y (i. e.,  effi c a c y  ass ess m e nts)  will r e q uir e I R B/I E C  n otifi c ati o n 
b ef or e i m pl e m e nt ati o n,  e x c e pt  w h er e t h e  m o difi c ati o n is  n e c ess ar y t o  eli mi n at e  a n  a p p ar e nt 
i m m e di at e  h a z ar d t o  h u m a n s u bj e cts.  V ert e x  will s u b mit  all  pr ot o c ol  m o difi c ati o ns t o t h e 
r e q uir e d r e g ul at or y  a ut h oriti es. 
W h e n  cir c u mst a n c es r e q uir e  a n i m m e di at e  d e p a rt ur e fr o m  pr o c e d ur es s et f ort h i n t h e  pr ot o c ol, 
t h e i n v esti g at or  will  c o nt a ct  V ert e x t o  dis c uss t h e  pl a n n e d  c o urs e  of  a cti o n. If  p ossi bl e,  c o nt a ct 
will  b e  m a d e  b ef or e t h e i m pl e m e nt ati o n  of  a n y  c h a n g es.  A n y  d e p art ur es fr o m t h e  pr ot o c ol  will 
b e f ull y  d o c u m e nt e d i n t h e s o ur c e  d o c u m e nt ati o n  a n d i n  a  pr ot o c ol  d e vi ati o n l o g.  
1 3. 2. 5   
A c c e s s t o  R e c or d s  
T h e i n v esti g at or  will  m a k e t h e  offi c e  a n d/ or  h os pit al r e c or ds  of s u bj e cts  e nr oll e d i n t his st u d y 
a v ail a bl e f or i ns p e cti o n  b y  V ert e x  or its r e pr es e nt ati v e  at t h e ti m e  of  e a c h  m o nit ori n g  visit  a n d 
f or  a u dits.  T h e r e c or ds  will  als o  b e  a v ail a bl e f or  dir e ct i ns p e cti o n,  v erifi c ati o n,  a n d  c o p yi n g,  as 
r e q uir e d  b y  a p pli c a bl e l a ws  a n d r e g ul ati o ns,  b y  offi ci als  of t h e r e g ul at or y  h e alt h  a ut h oriti es 
( F D A  a n d  ot h ers).  T h e i n v esti g at or  will  c o m pl y  wit h  a p pli c a bl e  pri v a c y  a n d s e c urit y l a ws f or  us e 
a n d  dis cl os ur e  of i nf or m ati o n r el at e d t o t h e r es e ar c h s et f ort h i n t his  pr ot o c ol.   
1 3. 2. 6   
S u bj e ct  Pri v a c y  
T o  m ai nt ai n s u bj e ct  c o nfi d e nti alit y  a n d t o  c o m pl y  wit h  a p pli c a bl e  d at a  pr ot e cti o n  a n d  pri v a c y 
l a ws  a n d r e g ul ati o ns,  all  d at a  pr o vi d e d t o  V ert e x, st u d y r e p orts,  a n d  c o m m u ni c ati o ns r el ati n g t o 
t h e st u d y  will i d e ntif y s u bj e cts  b y  assi g n e d s u bj e ct  n u m b ers,  a n d  a c c ess t o s u bj e ct  n a m es li n k e d 
t o s u c h  n u m b ers  will  b e li mit e d t o t h e sit e  a n d t h e st u d y  p h ysi ci a n  a n d  will  n ot  b e  dis cl os e d t o 
V ert e x.  As r e q uir e d  b y  a p pli c a bl e l a ws  a n d r e g ul ati o ns i n t h e  c o u ntri es i n  w hi c h t h e st u d y is 
b ei n g  c o n d u ct e d, t h e i n v esti g at or  will  all o w  V ert e x  a n d/ or its r e pr es e nt ati v es  a c c ess t o  all 
p erti n e nt  m e di c al r e c or ds t o  all o w f or t h e  v erifi c ati o n  of  d at a  g at h er e d  a n d t h e r e vi e w  of t h e  d at a 
c oll e cti o n  pr o c ess.  T h e  F D A  a n d r e g ul at or y  a ut h oriti es i n  ot h er j uris di cti o ns, i n cl u di n g t h e 
I R B/I E C,  m a y  als o r e q u est  a c c ess t o  all st u d y r e c or ds, i n cl u di n g s o ur c e  d o c u m e nt ati o n, f or 
i ns p e cti on. 
1 3. 2. 7   
R e c or d  R et e nti o n  
T h e i n v esti g at or  will  m ai nt ai n  all st u d y r e c or ds  a c c or di n g t o  c urr e nt I C H   E 6  G C P  G ui d eli n es 
a n d/ or  a p pli c a bl e l o c al r e g ul at or y r e q uir e m e nt(s),  w hi c h e v er is l o n g est,  as  d es cri b e d i n t h e 
Cli ni c al  Tri al  A gr e e m e nt. If t h e i n v esti g at or  wit h d r a ws fr o m t h e r es p o nsi bilit y  of  k e e pi n g t h e 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  4 6  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
st u d y r e c or ds,  c ust o d y  will  b e tr a nsf err e d t o  a  p ers o n  willi n g t o  a c c e pt t h e r es p o nsi bilit y  a n d 
V ert e x  will  b e  n otifi e d.  
1 3. 2. 8   
St u d y  T er mi n ati o n  
At  a n y ti m e,  V ert e x  m a y t er mi n at e t his st u d y i n its  e ntir et y  or  m a y t er mi n at e t his st u d y  at  a n y 
p arti c ul ar sit e. I n  a d diti o n, f or r e as o n a bl e  c a us e,  eit h er t h e i n v esti g at ors  or t h eir I R Bs/I E Cs  m a y 
t er mi n at e t h e st u d y  at t h eir  c e nt er. 
C o n diti o ns t h at  m a y  l e a d t o r e as o n a bl e  c a us e  a n d w arr a nt t er mi n ati o n i n cl u d e,  b ut  ar e  n ot li mit e d 
t o: 
•   S u bj e ct  or i n v esti g at or  n o n c o m pli a n c e  
•   U ns atisf a ct or y s u bj e ct  e nr oll m e nt  
•   L a c k  of  a d h er e n c e t o  pr ot o c ol  pr o c e d ur es 
•   L a c k  of  e v al u a bl e  a n d/ or  c o m pl et e  d at a 
•   P ot e nti all y  u n a c c e pt a bl e ris k t o st u d y s u bj e cts 
•   D e cisi o n t o  m o dif y  dr u g  d e v el o p m e nt  pl a n 
•   D e cisi o n  b y t h e  F D A  or  ot h er r e g ul at or y  a ut h orit y 
Writt e n  n otifi c ati o n t h at i n cl u d es t h e r e as o n f or t h e  cli ni c al st u d y t er mi n ati o n is r e q uir e d.  
1 3. 2. 9   
E n d  of  St u d y  
T h e  e n d  of st u d y is  d efi n e d  as t h e l ast s c h e d ul e d  visit ( or s c h e d ul e d  c o nt a ct)  of t h e l ast s u bj e ct.  
1 3. 3   
D at a  Q u alit y  A s s ur a n c e  
V ert e x  or its  d esi g n at e d r e pr es e nt ati v e  will  c o n d u ct  a st u d y sit e  visit t o  v erif y t h e  q u alifi c ati o ns 
of  e a c h i n v esti g at or, i ns p e ct  cli ni c al st u d y sit e f a ciliti es,  a n d i nf or m t h e i n v esti g at or  of 
r es p o nsi biliti es  a n d  pr o c e d ur es f or  e ns uri n g  a d e q u at e  a n d  c orr e ct st u d y  d o c u m e nt ati o n  p er 
c urr e nt I C H  E 6  G C P  G ui d eli n es.  
T h e i n v esti g at or is r e q uir e d t o  pr e p ar e  a n d  m ai nt ai n  a d e q u at e  a n d  a c c ur at e  c as e  hist ori es 
d esi g n e d t o r e c or d  all  o bs er v ati o ns  a n d  ot h er  d at a  p erti n e nt t o t h e st u d y f or  e a c h s u bj e ct.  St u d y 
d at a f or  e a c h  e nr oll e d s u bj e ct  will  b e  e nt er e d i nt o  a  C R F  b y st u d y sit e  p ers o n n el  usi n g  a s e c ur e, 
v ali d at e d,  w e b- b as e d  el e ctr o ni c  d at a  c a pt ur e ( E D C)  a p pli c ati o n.  V ert e x  will  h a v e r e a d - o nl y 
a c c ess t o sit e -e nt er e d  cli ni c al  d at a i n t h e  E D C  a p pl i c ati o n.  
I nst a n c es  of  missi n g,  dis cr e p a nt,  or  u ni nt er pr et a bl e  d at a  will  b e  q u eri e d  wit h t h e i n v esti g at or f or 
r es ol uti o n.  A n y  c h a n g es t o st u d y  d at a  will  b e  m a d e t o t h e  C R F  a n d  d o c u m e nt e d i n  a n  a u dit tr ail, 
w hi c h  will  b e  m ai nt ai n e d  wit hi n t h e  cli ni c al  d at a b as e.  
1 3. 4   
M o nit ori n g  
M o nit ori n g  a n d  a u diti n g  pr o c e d ur es  d e v el o p e d  or  a p pr o v e d  b y  V ert e x  will  b e f oll o w e d t o 
c o m pl y  wit h  G C P  G ui d eli n es.  C h e c ki n g  of t h e  C R Fs/ S A E  F or ms f or  c o m pl et e n ess  a n d  cl arit y, 
cr oss - c h e c ki n g  wit h s o ur c e  d o c u m e nts,  a n d  cl arifi c ati o n  of  a d mi nistr ati v e  m att ers  will  b e 
p erf or m e d. 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  4 7  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
T h e st u d y  will  b e  m o nit or e d  b y  V ert e x  or its  d esi g n e e.  M o nit ori n g  will  b e  d o n e  b y  a 
r e pr es e nt ati v e  of  V ert e x  or  d esi g n e e (st u d y sit e  m o nit or),  w h o  will r e vi e w t h e  C R Fs/ S A E  F or ms 
a n d s o ur c e  d o c u m e nts  p er  c urr e nt I C H  E 6  G C P  G ui d eli n es.  T h e st u d y sit e  m o nit or  will  e ns ur e 
t h at t h e i n v esti g ati o n is  c o n d u ct e d  a c c or di n g t o t h e  pr ot o c ol  d esi g n  a n d r e g ul at or y r e q uir e m e nts. 
1 3. 5   
El e ctr o ni c  D at a  C a pt ur e  
V ert e x  will  pr o vi d e t h e st u d y sit es  wit h s e c ur e  a c c ess t o  a n d tr ai ni n g  o n t h e  E D C  a n d 
d e c e ntr ali z e d tri al  pl atf or m  a p pli c ati o ns s uffi ci e nt t o  p er mit st u d y sit e  p ers o n n el t o  e nt er  or 
c orr e ct i nf or m ati o n i n t h e  C R Fs  o n t h e s u bj e cts f or  w hi c h t h e y  ar e r es p o nsi bl e.  
A  C R F  will  b e  c o m pl et e d f or  e a c h  e nr oll e d st u d y s u bj e ct. It is t h e i n v esti g at or’s r es p o nsi bilit y t o 
e ns ur e t h e  a c c ur a c y,  c o m pl et e n ess,  cl arit y,  a n d ti m eli n ess  of t h e  d at a r e p ort e d i n t h e s u bj e ct’s 
C R F.  S o ur c e  d o c u m e nt ati o n s u p p orti n g t h e  C R F  d at a  will i n di c at e t h e s u bj e ct’s  p arti ci p ati o n i n 
t h e st u d y  a n d  will  d o c u m e nt t h e  d at es  a n d  d et ails  of st u d y  pr o c e d ur es,  A Es,  ot h er  o bs er v ati o ns, 
a n d s u bj e ct st at us.  
T h e i n v esti g at or,  or  d esi g n at e d r e pr es e nt ati v e,  will  c o m pl et e t h e  C R F  as s o o n  as  p ossi bl e  aft er 
i nf or m ati o n is  c oll e ct e d.  
T h e  a u dit tr ail  e ntr y  will s h o w t h e  us er’s i d e ntifi c ati o n  i nf or m ati o n  a n d t h e  d at e  a n d ti m e  of  a n y 
c orr e cti o n.  T h e i n v esti g at or  will  pr o vi d e f or m al  a p pr o v al  of  all t h e i nf or m ati o n i n t h e  C R Fs, 
i n cl u di n g  a n y  c h a n g es  m a d e t o t h e m, t o  e n d ors e t h e fi n al s u b mitt e d  d at a f or t h e s u bj e cts f or 
w h o m t h e i n v esti g at or is r es p o nsi bl e.  
V ert e x  will r et ai n t h e  C R F  d at a   a n d  c orr es p o n di n g  a u dit tr ails.  A  c o p y  of t h e fi n al  ar c hi v al  C R F 
i n t h e f or m  of  a  c o m p a ct  dis c ( C D)  or  ot h er  el e ctr o ni c  m e di a  will  b e  pl a c e d i n t h e i n v esti g at or’s 
st u d y fil e. 
Sit es  will  us e  a n  E D C t o ol t o  r e c or d  d at a f or  e a c h  e nr oll e d s u bj e ct.  A d diti o n all y, s u bj e cts  will 
us e t h e  d e c e ntr ali z e d tri al  pl atf or m t o r e c or d  el e ctr o ni c  a cti vit y  a n d  c o u g h  di ar y, 
 
  w hi c h  will  b e  c o nsi d er e d t h e s o ur c e f or t h at  d at a. 
It is t h e i n v estig at or’s r es p o nsi bilit y t o  e ns ur e t h e  a c c ur a c y,  c o m pl et e n ess,  cl arit y,  a n d ti m eli n ess 
of t h e  d at a r e p ort e d.  T h e i n v esti g at or is r e q uir e d t o  pr e p ar e  a n d  m ai nt ai n  a d e q u at e  a n d  a c c ur at e 
c as e  hist ori es  d esi g n e d t o r e c or d  all  o bs er v ati o ns  a n d  ot h er  d at a  p erti n e nt t o t h e st u d y f or  e a c h 
s u bj e ct, i n cl u di n g t h e  d at es  a n d  d et ails  of st u d y  pr o c e d ur es,  A Es,  ot h er  o bs er v ati o ns,  a n d s u bj e ct 
st at us.  
T h e  a u dit tr ail  e ntr y  will s h o w t h e  us er’s i d e ntifi c ati o n i nf or m ati o n  a n d t h e  d at e  a n d ti m e  of  a n y 
c orr e cti o n.  T h e i n v esti g a t or  will  pr o vi d e f or m al  a p pr o v al  of  all  d at a r e p ort e d t o  V ert e x, i n cl u di n g 
a n y  c h a n g es  m a d e, t o  e n d ors e t h e fi n al s u b mitt e d  d at a f or t h e s u bj e cts f or  w h o m t h e i n v esti g at or 
is r es p o nsi bl e.  
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 s ci e ntifi c,  c o m m er ci al,  a n d t e c h ni c al i nf or m ati o n  dis cl os e d  b y  V ert e x i n t his 
pr ot o c ol  or  els e w h er e  will  b e  c o nsi d er e d t h e  c o nfi d e nti al  a n d  pr o pri et ar y  pr o p ert y  of  V ert e x.  T h e 
i n v esti g at or s h all  h ol d s u c h i nf or m ati o n i n  c o nfi d e n c e  a n d s h all  n ot  dis cl os e t h e i nf or m ati o n t o 
a n y t hi r d  p art y  e x c e pt t o s u c h  of t h e i n v esti g at or’s  e m pl o y e es  a n d st aff  as  h a v e  b e e n  m a d e  a w ar e 
t h at t h e i nf or m ati o n is  c o nfi d e nti al  a n d  w h o  ar e  b o u n d t o tr e at it  as s u c h  a n d t o  w h o m  dis cl os ur e 
is  n e c ess ar y t o  e v al u at e t h at i nf or m ati o n.  T h e i n v esti g at or s h all  n ot  us e s u c h i nf or m ati o n f or  a n y 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  4 8  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
p ur p os e  ot h er t h a n  d et er mi ni n g  m ut u al i nt er est i n  p erf or mi n g t h e st u d y  a n d, if t h e  p arti es  d e ci d e 
t o  pr o c e e d  wit h t h e st u d y, f or t h e  p ur p os e  of  c o n d u cti n g t h e st u d y. 
T h e i n v esti g at or  u n d erst a n ds t h at t h e i nf or m ati o n  d e v el o p e d  fr o m t his  cli ni c al st u d y  will  b e  us e d 
b y  V ert e x i n  c o n n e cti o n  wit h t h e  d e v el o p m e nt  of t h e st u d y  dr u g  a n d  ot h er  dr u gs  a n d  di a g n osti cs, 
a n d t h er ef or e  m a y  b e  dis cl os e d  as r e q uir e d t o  ot h er  cli ni c al i n v esti g at ors,  b usi n ess  p art n ers  a n d 
ass o ci at es, t h e  F D A,  a n d  ot h er  g o v er n m e nt  a g e n ci es.  T h e i n v esti g at or  als o  u n d erst a n ds t h at, t o 
all o w f or t h e  us e  of t h e i nf or m ati o n  d eri v e d fr o m t h e  cli ni c al st u d y, t h e i n v esti g at or  h as t h e 
o bli g ati o n t o  pr o vi d e  V ert e x  wit h  c o m pl et e t est r es ults  a n d  all  d at a  d e v el o p e d i n t h e st u d y. 
1 3. 7   
P u bli c ati o n s  a n d  Cli ni c al  St u d y  R e p ort  

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  4 9  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
1 3. 7. 2   
Cli ni c al  St u d y  R e p ort   
A  cli ni c al st u d y r e p ort ( C S R),  writt e n i n  a c c or d a n c e  wit h t h e  c urr e nt I C H  E 3  G ui d eli n e,  will  b e 
s u b mitt e d i n  a c c or d a n c e  wit h l o c al r e g ul ati o ns. 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  5 0  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
1 4   
R E F E R E N C E S  
1    
C ysti c  Fi br osis  F o u n d ati o n.  2 0 1 9  P ati e nt  R e gistr y  A n n u al  D at a  R e p ort.  B et h es d a,  M D: 
2 0 2 0. 
2    
E ur o p e a n  C ysti c  Fi br osis  S o ci et y.  2 0 1 8  E C F S  P ati e nt  R e gistr y  A n n u al  D at a  R e p ort. 
K ar u p,  D e n m ar k:  2 0 2 0. 
3  
R us e c k ait e  R,  A h er n  S,  R a n g er  T,  D e a n J,  G ar d a m  M,  B ell  S,  et  al.  T h e  A ustr ali a n  C ysti c 
Fi br osis  D at a  R e gistr y  A n n u al  R e p ort,  2 0 1 7.  M o n as h  U ni v ersit y:  D e p art m e nt  of 
E pi d e mi ol o g y  a n d  Pr e v e nt ati v e  M e di ci n e;  M ar c h  2 0 1 9,  R e p ort  # 2 0. 
4    
C ysti c  Fi br osis  C a n a d a.  T h e  C a n a di a n  C ysti c  Fi br osis  R e gistr y  2 0 1 9  A n n u al  D at a 
R e p ort.  T or o nt o,  O nt ari o:  C ysti c  Fi br osis  C a n a d a;  2 0 2 0. 
5    
R o m m e ns J M, I a n n u z zi  M C,  K e r e m  B,  Dr u m m  M L,  M el m er  G,  D e a n  M,  et  al. 
I d e ntifi c ati o n  of t h e  c ysti c fi br osis  g e n e:  c hr o m os o m e  w al ki n g  a n d j u m pi n g.  S ci e n c e. 
1 9 8 9; 2 4 5( 4 9 2 2): 1 0 5 9- 6 5.  
6  
Kr ei n dl er J L.  C ysti c fi br osis:  e x pl oiti n g its  g e n eti c  b asis i n t h e  h u nt f or  n e w t h er a pi es. 
P h ar m a c ol  T h er.  2 0 1 0; 1 2 5( 2): 2 1 9 - 2 9. 
7  
K o nst a n  M W,  M c K o n e  E F,  M oss  R B,  M ari g o w d a  G,  Ti a n  S,  W alt z  D,  et  al.  Ass ess m e nt 
of s af et y  a n d  effi c a c y  of l o n g -t er m tr e at m e nt  wit h  c o m bi n ati o n l u m a c aft or  a n d i v a c aft or 
t h er a p y i n  p ati e nts  wit h  c ysti c fi br osis  h o m o z y g o us f or t h e  F 5 0 8 d el- C F T R  m ut ati o n 
( P R O G R E S S):  a  p h as e  3   e xt e nsi o n st u d y   L a n c et  R es pir  M e d   2 0 1 7; 5( 2): 1 0 7- 1 8  
1 1    
L e v e y  A S,  B os c h J P,  L e wis J B,  Gr e e n e  T,  R o g ers  N,  R ot h  D.  A  m or e  a c c ur at e  m et h o d t o 
esti m at e  gl o m er ul ar filtr ati o n r at e fr o m s er u m  cr e ati ni n e:  a  n e w  pr e di cti o n  e q u ati o n. 
M o difi c ati o n  of  Di et i n  R e n al  Dis e as e  St u d y  Gr o u p.  A n n I nt er n  M e d.  1 9 9 9; 1 3 0( 6): 4 6 1-
7 0. 
1 2    
L e v e y  A S,  C or es h J,  Gr e e n e  T,  St e v e ns  L A,  Z h a n g  Y L,  H e n dri ks e n  S,  et  al.  Usi n g 
st a n d ar di z e d s er u m  cr e ati ni n e  v al u es i n t h e  m o difi c ati o n  of  di et i n r e n al  dis e as e st u d y 
e q u ati o n f or  esti m ati n g  gl o m er ul ar filtr ati o n r at e.  A n n I nt er n  M e d.  2 0 0 6; 1 4 5( 4): 2 4 7- 5 4.  
1 3    
C o u n a h a n  R,  C h a ntl er  C,  G h a z ali  S,  Kir k w o o d  B,  R os e  F,  B arr att  T M.  Esti m ati o n  of 
gl o m er ul ar filtr ati o n r at e fr o m  pl as m a  cr e ati ni n e  c o n c e ntr ati o n i n  c hil dr e n.  Ar c h  Dis 
C hil d.  1 9 7 6; 5 1( 1 1): 8 7 5- 7 8. 
1 4  
G oss  C H,  Q uitt n er  A L.  P ati e nt -r e p ort e d  o ut c o m es i n  c ysti c fi br osis.  Pr o c  A m  T h or a c 
S o c   2 0 0 7; 4( 4): 3 7 8- 8 6  
1 6  
B attisti  W P,  W a g er  E,  B alt z er  L,  Bri d g es  D,  C air ns  A,  C ars w ell  CI,  et  al.  G o o d 
p u bli c ati o n  pr a cti c e f or  c o m m u ni c ati n g  c o m p a n y -s p o ns or e d  m e di c al r es e ar c h:  G P P 3. 
A n n I nt er n  M e d.  2 0 1 5; 1 6 3( 6): 4 6 1- 4. 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  5 1  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
1 7  
I nt er n ati o n al  C o m mitt e e  of  M e di c al J o ur n al  E dit ors (I C MJ E).  D e c e m b er  2 0 1 7. 
R e c o m m e n d ati o ns f or t h e  c o n d u ct, r e p orti n g,  e diti n g,  a n d  p u bli c ati o n  of s c h ol arl y  w or k 
i n  m e di c al j o ur n als.  A v ail a bl e  at: htt p:// w w w.i c mj e. or g/r e c o m m e n d ati o ns/ .  A c c ess e d  0 3 
A u g ust  2 0 1 8. 
 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  5 2  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
A P P E N DI X  A   
Eli gi bl e  M F  C F T R  M ut ati o n s  
“ M F ”  m ut ati o ns  ar e  a s u bs et  of  mi ni m al f u n cti o n  m ut ati o ns t h at  ar e  n o n -r es p o nsi v e t o I V A  a n d 
T E Z/I V A.  A  m ut ati o n is  c o nsi d er e d  a n  M F  m ut ati o n if it  m e ets  at l e ast  1  of t h e f oll o wi n g 
2  crit eri a:  
( 1) N o  bi ol o gi c al  pl a usi bil it y  of tr a nsl at e d  pr ot ei n ( g e n eti c s e q u e n c e  pr e di cts t h e  c o m pl et e 
a bs e n c e  of  C F T R  pr ot ei n),  or 
( 2) i n  vitr o t esti n g t h at s u p p orts l a c k  of r es p o nsi v e n ess t o I V A  a n d  T E Z/I V A. 
I n cl usi o n  of  M F  M ut ati o ns  B as e d  o n I n  Vit r o  T esti n g  
M ut ati o ns t h at  w er e  c o nsi d er e d t o  b e  M F  m ut ati o ns  b as e d  o n i n  vitr o t esti n g  m et t h e f oll o wi n g 
crit eri a i n i n  vitr o  e x p eri m e nts:  
•   b as eli n e  c hl ori d e tr a ns p ort t h at  w as  < 1 0 %  of  wil dt y p e  C F T R 
•   a n i n cr e as e i n  c hl ori d e tr a ns p ort  of  < 1 0 %  o v er  b as eli n e f oll o wi n g t h e  a d diti o n  of I V A  a n d 
T E Z/I V A i n t h e  ass a y  
Eli gi bl e  M F  M ut ati o ns  
T h e  m ut ati o ns  b el o w  ar e  d et e ct a bl e  b y  a n  F D A- cl e ar e d  g e n ot y pi n g  ass a y  or  ot h er  m et h o d 
( e. g., s e q u e n ci n g). 
T his list  d o es  n ot i n cl u d e  e v er y  eli gi bl e  m ut ati o n,  a n d i n v esti g at ors s h o ul d  c o nt a ct t h e  m e di c al 
m o nit or r e g ar di n g  ot h er  m ut ati o ns t h at  m a y  als o  m e et st u d y  eli gi bilit y  crit eri a.  

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  5 3  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
N o n -e x h a usti v e  List  of  Mi ni m al  F u n cti o n  C F T R  M ut ati o ns  Eli gi bl e f o r  V X 2 0 - 4 4 5- 1 2 6 
 
 
 
 
 
Q 2 X  
L 2 1 8 X  
Q 5 2 5 X  
R 7 9 2 X  
E 1 1 0 4 X  
S 4 X  
Q 2 2 0 X  
G 5 4 2 X  
E 8 2 2 X  
W 1 1 4 5 X  
W 1 9 X  
Y 2 7 5 X  
G 5 5 0 X  
W 8 8 2 X  
R 1 1 5 8 X  
G 2 7 X  
C 2 7 6 X  
Q 5 5 2 X  
W 8 4 6 X  
R 1 1 6 2 X  
Q 3 9 X  
Q 2 9 0 X  
R 5 5 3 X  
Y 8 4 9 X  
S 1 1 9 6 X  
W 5 7 X  
G 3 3 0 X  
E 5 8 5 X  
R 8 5 1 X  
W 1 2 0 4 X  
E 6 0 X  
W 4 0 1 X  
G 6 7 3 X  
Q 8 9 0 X  
L 1 2 5 4 X  
R 7 5 X  
Q 4 1 4 X  
Q 6 8 5 X  
S 9 1 2 X  
S 1 2 5 5 X  
L 8 8 X  
S 4 3 4 X  
R 7 0 9 X  
Y 9 1 3 X  
W 1 2 8 2 X  
E 9 2 X  
S 4 6 6 X  
K 7 1 0 X  
Q 1 0 4 2 X  
Q 1 3 1 3 X  
Q 9 8 X  
S 4 8 9 X  
Q 7 1 5 X  
W 1 0 8 9 X  
Q 1 3 3 0 X  
Y 1 2 2 X  
Q 4 9 3 X  
L 7 3 2 X  
Y 1 0 9 2 X  
E 1 3 7 1 X  
E 1 9 3 X  
W 4 9 6 X  
R 7 6 4 X  
W 1 0 9 8 X  
Q 1 3 8 2 X  
W 2 1 6 X  
C 5 2 4 X  
R 7 8 5 X  
R 1 1 0 2 X  
Q 1 4 1 1 X  
 
 
 
 
 
1 8 5 + 1 G > T  
7 1 1 + 5 G > A   
1 7 1 7 -8 G > A  
2 6 2 2 + 1 G > A   
3 1 2 1 -1 G > A  
2 9 6 + 1 G > A  
7 1 2 -1 G > T   
1 7 1 7 -1 G > A  
2 7 9 0 -1 G > C   
3 5 0 0 -2 A > G  
2 9 6 + 1 G > T  
1 2 4 8 + 1 G > A   
1 8 1 1 + 1 G > C  
3 0 4 0 G > C  ( G 9 7 0 R)  
3 6 0 0 + 2i ns T  
4 0 5 + 1 G > A  
1 2 4 9 -1 G > A   
1 8 1 1 + 1. 6 k b A > G  
3 8 5 0 -1 G > A  
4 0 5 + 3 A > C  
1 3 4 1 + 1 G > A   
1 8 1 1 + 1 6 4 3 G > T    
3 1 2 0 G > A  
4 0 0 5 + 1 G > A  
4 0 6 -1 G > A  
1 5 2 5 -2 A > G   
1 8 1 2 -1 G > A  
3 1 2 0 + 1 G > A   
4 3 7 4 + 1 G > T  
6 2 1 + 1 G > T  
1 5 2 5 -1 G > A   
1 8 9 8 + 1 G > A  
3 1 2 1 -2 A > G   
 
7 1 1 + 1 G > T  
 
1 8 9 8 + 1 G > C  
 
 
 
 
 
 
 
1 8 2 d el T  
1 1 1 9 d el A   
1 7 8 2 d el A  
2 7 3 2i ns A  
3 7 9 1 d el C  
3 0 6i ns A  
1 1 3 8i ns G   
1 8 2 4 d el A  
2 8 6 9i ns G  
3 8 2 1 d el T  
3 6 5 -3 6 6i ns T  
1 1 5 4i ns T C   
1 8 3 3 d el T  
2 8 9 6i ns A G   
3 8 7 6 d el A  
3 9 4 d el T T  
1 1 6 1 d el C   
2 0 4 3 d el G  
2 9 4 2i ns T  
3 8 7 8 d el G  
4 4 2 d el A  
1 2 1 3 d el T   
2 1 4 3 d el T  
2 9 5 7 d el T  
3 9 0 5i ns T  
4 4 4 d el A  
1 2 5 9i ns A   
2 1 8 3 A A > G  a 
3 0 0 7 d el G  
4 0 1 6i ns T  
4 5 7 T A T > G  
1 2 8 8i ns T A   
2 1 8 4 d el A  
3 0 2 8 d el A  
4 0 2 1 d u p T  
5 4 1 d el C  
1 3 4 3 d el G   
2 1 8 4i ns A  
3 1 7 1 d el C  
4 0 2 2i ns T  
5 7 4 d el A  
1 4 7 1 d el A   
2 3 0 7i ns A  
3 1 7 1i ns C  
4 0 4 0 d el A  
6 6 3 d el T  
1 4 9 7 d el G G   
2 3 4 7 d el G  
3 2 7 1 d el G G   
4 2 7 9i ns A  
8 4 9 d el G   
1 5 4 8 d el G   
2 5 8 5 d el T  
3 3 4 9i ns T  
4 3 2 6 d el T C  
9 3 5 d el A  
1 6 0 9 d el  C A   
2 5 9 4 d el G T  
3 6 5 9 d el C  
 
1 0 7 8 d el T  
1 6 7 7 d el T A   
2 7 1 1 d el T  
3 7 3 7 d el A  
 
 
 
 
 
 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  5 4  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati o n  
N o n -e x h a usti v e  List  of  Mi ni m al  F u n cti o n  C F T R  M ut ati o ns  Eli gi bl e f o r  V X 2 0 - 4 4 5- 1 2 6 
 
 
 
 
 
C F T R d el e 1  
C F T R d el e 1 6 -1 7 b  
9 9 1 d el 5  
C F T R d el e 2  
C F T R d el e 1 7 a, 1 7 b  
1 4 6 1i ns 4  
C F T R d el e 2, 3  
C F T R d el e 1 7 a -1 8  
1 9 2 4 d el 7  
C F T R d el e 2 -4  
C F T R d el e 1 9  
2 0 5 5 d el 9 > A  
C F T R d el e 3 -1 0, 1 4 b -1 6   
C F T R d el e 1 9 -2 1  
2 1 0 5 -2 1 1 7 d el 1 3i ns A G A A A  
C F T R d el e 4 -7  
C F T R d el e 2 1  
2 3 7 2 d el 8  
C F T R d el e 4 -1 1  
C F T R d el e 2 2 -2 4  
2 7 2 1 d el 1 1  
C F T R 5 0 k b d el  
C F T R d el e 2 2, 2 3  
2 9 9 1 d el 3 2  
C F T R d u p 6 b -1 0  
1 2 4 d el 2 3 b p  
3 1 2 1 -9 7 7 _ 3 4 9 9 + 2 4 8 d el 2 5 1 5  
C F T R d el e 1 1  
3 0 6 d el T A G A  
3 6 6 7i ns 4  
C F T R d el e 1 3, 1 4 a   
6 0 2 d el 1 4   
4 0 1 0 d el 4  
C F T R d el e 1 4 b -1 7 b   
8 5 2 d el 2 2  
4 2 0 9 T G T T > A A  
 
 
 
 
 
A 4 6 D  
V 5 2 0 F   
Y 5 6 9 D  
N 1 3 0 3 K  
  
G 8 5 E  
A 5 5 9 T   
L 1 0 6 5 P  
 
 
R 3 4 7 P  
R 5 6 0 T   
R 1 0 6 6 C  
 
 
L 4 6 7 P  
R 5 6 0 S   
L 1 0 7 7 P  
 
 
I 5 0 7 d el 
A 5 6 1 E   
M 1 1 0 1 K  
 
 
 
 
 
 
 
C F T R : c ysti c fi br osis tr a ns m e m br a n e  c o n d u ct a n c e r e g ul at or  g e n e  
S o ur c e:  C F T R 2. or g.  Cli ni c al  a n d f u n cti o n al tr a nsl ati o n  of  C F T R.  T h e  Cli ni c al  a n d  F u n cti o n al  Tr a nsl ati o n  of  C F T R ( C F T R 2), 
U S  C ysti c  Fi br osis  F o u n d ati o n, J o h ns  H o p ki ns  U ni v ersit y, t h e  H os pit al f or  Si c k  C hil dr e n.  A v ail a bl e  at: 
htt p :// w w w. cftr 2. or g.  A c c ess e d  1 5  F e br u ar y  2 0 1 6. 
a  
Als o  k n o w n  as  2 1 8 3 d el A A > G. 
 

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  5 5  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati 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 o c ol  #:   
V X 2 0 -4 4 5 -1 2 6   V ersi o n  #:   1. 0  
V ersi o n  D at e:   3 0  A pril  2 0 2 1  
St u d y  Titl e:  A  P h as e  3 b  O p e n -l a b el  St u d y  E v al u ati n g t h e  Eff e cts  of 
El e x a c aft or/ T e z a c aft or/I v a c aft or  o n  C o u g h  a n d  P h ysi c al  A cti vit y i n  C ysti c  Fi br osis  S u bj e cts 
1 2  Y e ars  of  A g e  a n d  Ol d er  W h o  Ar e  H et er o z y g o us f or t h e  F 5 0 8 d el   M ut ati o n  a n d  a  Mi ni m al 
F u n cti o n  M ut ati o n ( F/ M F) 
T his  cli ni c al st u d y  pr ot o c ol  h as  b e e n r e vi e w e d  a n d  a p pr o v e d  b y t h e s p o ns or. 
Pri nt e d  N a m e  
  
Titl e  
Si g n at ur e  
  
D at e  

Pr ot o c ol  V X 2 0 -4 4 5 -1 2 6 ,  V ersi o n 1. 0  
P a g e  5 6  of  5 6  
V ert e x  P h ar m a c e uti c als I n c or p or at e d  
C o nfi d e nti al I nf or m ati 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 o c ol  #:    V X 2 0 -4 4 5 -1 2 6   V ersi o n  #:   1. 0  
V ersi o n  D at e:   3 0  A pril  2 0 2 1  
St u d y  Titl e:  A  P h as e  3 b  O p e n -l a b el  St u d y  E v al u ati n g t h e  Eff e cts  of 
El e x a c aft or/ T e z a c aft or/I v a c aft or  o n  C o u g h  a n d  P h ysi c al  A cti vit y i n  C ysti c  Fi br osis  S u bj e cts 
1 2  Y e ars  of  A g e  a n d  Ol d er  W h o  Ar e  H et er o z y g o us f or t h e  F 5 0 8 d el   M ut ati o n  a n d  a  Mi ni m al 
F u n cti o n  M ut ati o n ( F/ M F) 
 
 
I  h a v e r e a d  Pr ot o c ol V X 2 0 - 4 4 5- 1 2 6,  V ersi o n  1. 0,  a n d  a gr e e t o  c o n d u ct t h e st u d y  a c c or di n g t o its 
t er ms. I  u n d erst a n d t h at  all i nf or m ati o n  c o n c er ni n g  el e x a c aft or/t e z a c aft or/i v a c aft or 
( E L X/ T E Z/I V A)  a n d t his  pr ot o c ol s u p pli e d t o  m e  b y  V ert e x  P h ar m a c e uti c als I n c or p or at e d 
( V ert e x) is  c o nfi d e nti al. 
 
 
Pri nt e d  N a m e  
  
 
Si g n at ur e  
  
D at e