Conditions: Cystic Fibrosis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 82
Healthy volunteers: no

Brief summary:
This study will evaluate the effects of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) on cough and physical activity using wearable technology in CF participants.

Detailed description:

Arms:
arm 1: Participants received ELX 200 milligram (mg) once daily (qd)/TEZ 100 mg qd/IVA 150 mg every 12 hours (q12h) in the treatment period approximately 13 weeks.

Interventions: intervention 1: ELX/TEZ/IVA intervention 2: IVA
Intervention descriptions: intervention 1: Fixed dose combination (FDC) tablet for oral administration. intervention 2: Tablet for oral administration.

Protocol document:
Prot_000.pdf: 


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  
 
 
 
 

SAP_001.pdf: 
Statistical Analysis Plan (Methods) 
Page 1 of 32 
Protocol Number: VX20-445-126 
 
 
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Confidential Information 
1 
TITLE PAGE 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan 
(Methods) 
Protocol Number VX20-445-126 Version 1.0 
(Final Analysis) 
 
 
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) 
 
Authors of SAP: 
 
 
Version: 1.0 
Version Date of SAP: August 24, 2022 
 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, Massachusetts 02210-1862 
 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written 
consent of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under 
applicable laws or regulations.  Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 


Statistical Analysis Plan (Methods) 
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Protocol Number: VX20-445-126 
 
 
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2 
TABLE OF CONTENTS 
 
1 
Title Page ................................................................................................................................ 1 
2 
Table of Contents ................................................................................................................... 2 
4 
Introduction ............................................................................................................................ 5 
5 
Study Objectives .................................................................................................................... 5 
6 
Study Endpoints ..................................................................................................................... 5 
6.1 
Primary Endpoint .............................................................................................................. 5 
6.2 
Secondary Endpoint .......................................................................................................... 5 
7 
Study Design ........................................................................................................................... 6 
7.1 
Overall Design .................................................................................................................. 6 
7.2 
Sample Size and Power .................................................................................................... 7 
8 
Analysis Sets ........................................................................................................................... 7 
8.1 
All Subjects Set ................................................................................................................ 7 
8.2 
Full Analysis Set ............................................................................................................... 8 
8.3 
Safety Set .......................................................................................................................... 8 
9 
Statistical Analysis ................................................................................................................. 8 
9.1 
General Considerations .................................................................................................... 8 
9.2 
Background Characteristics .............................................................................................. 8 
9.2.1 
Subject Disposition ................................................................................................... 8 
9.2.2 
Demographics and Baseline Characteristics ............................................................. 9 
9.2.3 
Medical History ...................................................................................................... 10 
9.2.4 
Prior and Concomitant Medications ....................................................................... 10 
9.2.5 
Study Drug Exposure .............................................................................................. 10 
9.2.6 
Study Drug Compliance ......................................................................................... 11 
9.2.7 
Important Protocol Deviations ................................................................................ 11 
9.3 
Efficacy Analysis ............................................................................................................ 11 
9.3.1 
Analysis of Primary Efficacy Variable ................................................................... 11 
9.3.2 
Analysis of Secondary Efficacy Variable ............................................................... 12 
9.4 
Safety Analysis ............................................................................................................... 16 
9.4.1 
Adverse Events ....................................................................................................... 16 
9.4.2 
Clinical Laboratory ................................................................................................. 18 
9.4.6 
Physical Examination ............................................................................................. 19 
9.4.8 
COVID-19 Impacted Visits .................................................................................... 19 


Statistical Analysis Plan (Methods) 
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10 Interim and DMC Analyses ................................................................................................ 19 
10.1 Interim Analysis ............................................................................................................. 19 
10.2 DMC analysis ................................................................................................................. 19 
11 References ............................................................................................................................. 20 
12 List of Appendices ................................................................................................................ 21 
Appendix A: Analysis Visit Windows for Safety and Efficacy Assessments ......................... 21 
Appendix B: Details of GLI Equations for Calculating ppFEV1 ............................................. 24 
Appendix C: Imputation Rules for Missing Prior/Concomitant Medication Dates ................. 25 
Appendix D: Imputation Rules for Missing AE dates ............................................................. 26 
Appendix E: Adverse Events of Special Interest ..................................................................... 27 
Appendix F: Criteria for Threshold Analysis .......................................................................... 28 
 
 


Statistical Analysis Plan (Methods) 
Page 4 of 32 
Protocol Number: VX20-445-126 
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Statistical Analysis Plan (Methods) 
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Protocol Number: VX20-445-126 
 
 
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4 
INTRODUCTION 
Study VX20-445-126 (Study 445-126) is a Phase 3b open-label study evaluating the efficacy of 
elexacaftor (ELX, VX-445) in triple combination (TC) with tezacaftor (TEZ) and ivacaftor 
(IVA) on cough and physical activity using wearable devices in subjects 12 years of age 
(inclusive) and older with cystic fibrosis (CF) who are heterozygous for F508del and a minimal 
function mutation (F/MF). 
This statistical analysis plan (SAP) is based on the most recent approved clinical study protocol 
(CSP), the most recent approved electronic case report form (eCRF), and the most recent 
approved eCRF completion guidelines.  
This SAP (Methods) documents the planned statistical analyses of efficacy and 
 
defined in the VX20-445-126 study protocol. It also documents analyses for additional efficacy 
and safety variables not specified in the protocol, which will provide supportive information for 
the scientific understanding of the drug entity.  
The Vertex Biometrics Department will perform the statistical analysis of efficacy and 
 
; SAS (Version 9.4 or higher) will be used to generate all statistical outputs (tables, figures, 
listings, and datasets). The SAP will be finalized and approved prior to the clinical database lock. 
Any revisions to the approved SAP will be documented and approved in an amendment to the 
SAP.  
5 
STUDY OBJECTIVES  
To evaluate the effects of ELX/TEZ/IVA on cough and physical activity using wearable 
technology 
6 
STUDY ENDPOINTS 
6.1 
Primary Endpoint 
• Percent reduction from baseline in cough frequency (cough events per day) to the average of 
Week 8 through Week 12 
6.2 
Secondary Endpoint 
• Absolute change from baseline in total step count per day to the average of Week 8 through 
Week 12 


Statistical Analysis Plan (Methods) 
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7 
STUDY DESIGN  
7.1 
Overall Design  
This is a Phase 3b, open-label study evaluating the effects of ELX/TEZ/IVA on cough and 
physical activity using wearable technology. A schematic of the study design is shown in Figure 
7-1. All subjects will receive ELX 200 mg once daily (qd)/TEZ 100 mg qd/IVA 150 mg every 12 
hours (q12h) for approximately 13 weeks. A treatment duration of approximately 13 weeks 
allows the efficacy endpoints to be collected with wearable devices through Week 12 (i.e. a 
complete, 24-hour cough assessment during Week 12 and at least 12 complete weeks of 
continuous actigraphy measures in the treatment period). The Week 13 clinic visit is for 
operational purposes, at which patients return the wearable devices and complete any in-clinic 
assessments. Approximately 100 subjects will be enrolled.  
 
 
 
 




Statistical Analysis Plan (Methods) 
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8.2 
Full Analysis Set  
The Full Analysis Set (FAS) is defined as all enrolled subjects who carry the intended CFTR 
allele mutation and have received at least 1 dose of study drug. The FAS is to be used in efficacy 
analyses. 
8.3 
Safety Set 
The Safety Set is defined as all subjects who have received at least 1 dose of study drug. The 
Safety Set is to be used for all safety analyses. 
9 
STATISTICAL ANALYSIS 
9.1 
General Considerations 
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, SD, median, minimum value (min), and maximum value 
(max). 
Categorical variables will be summarized using counts and percentages. 
Baseline value, unless specified otherwise, will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of study drug.  
Absolute change from baseline will be calculated as post-baseline value − baseline value. 
Relative change from baseline will be calculated and expressed in percentage as 100% × 
(post-baseline value - baseline value)/baseline value. 
Treatment-emergent (TE) Period will include the time from the first dose of study drug to 
28 days after the last dose of study drug or to the completion of study participation, whichever 
occurs first. 
Incomplete/missing data will not be imputed, unless specified otherwise. 
Unscheduled visits: Unscheduled visit measurements will be included in analysis as follows: 
1) In scheduled visit windows per specified visit windowing rules 
2) In the derivation of baseline and last on-treatment measurements 
3) In the derivation of maximum and minimum values during TE period, and maximum and 
minimum change from baseline values during TE period for safety analyses 
4) In individual subject data listings as appropriate 
Visit windowing rules: The analysis visit windows for protocol-defined visits are provided in 
Appendix A. 
Outliers: No formal statistical analyses will be performed to detect or remedy the presence of 
statistical outliers, unless specified otherwise. 
9.2 
Background Characteristics  
9.2.1 
Subject Disposition 
The number and percentage (based on All Subjects set) of subjects in each of the following 
disposition categories will be summarized: 
• Enrolled 


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• Completed study drug treatment 
• Prematurely discontinued treatment (i.e., discontinued all study drugs) and the reason for 
discontinuation  
• Completed study 
• Prematurely discontinued the study and the reason for discontinuation  
• Rollover to the open-label study 
A listing will be provided for subjects who discontinued treatment or who discontinued study 
with reasons for discontinuation.  
9.2.2 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized based on the FAS. 
Demographic data will include the following: 
• Age at baseline (in years) 
• Sex (female and male) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local regulations) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or Other Pacific Islander, Other, and not collected per local regulations) 
• Country 
Baseline characteristics will include the following: 
• Weight (kg) 
• Height (cm) 
• BMI (kg/m2) 
Disease characteristics will include the following: 
• ppFEV1 at baseline (<30, ≥30 to <40, ≥40 to <70, ≥70 to ≤90, and >90) 
• ppFEV1 at baseline (continuous)  
• Prior use of dornase alfa (Yes, No) 
• Prior use of azithromycin (Yes, No) 
• Prior use of inhaled antibiotic (Yes, No) 
• Prior use of bronchodilator (Yes, No) 
• Prior use of inhaled bronchodilator (Yes, No) 
• Prior use of inhaled hypertonic saline (Yes, No) 
• Prior use of inhaled corticosteroids (Yes, No) 
In addition, data listings will also be provided for: 


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• Informed consent; 
• Inclusion/Exclusion criteria violation for subjects with any such violations. 
The predicted FEV1 will be calculated using the Global Lung Function Initiative (GLI)1; details 
are provided in Appendix B.  
9.2.3 
Medical History 
Medical history will be coded by using the Medical Dictionary for Regulatory Activities 
(MedDRA). Medical history will be summarized descriptively by System Organ Class (SOC) 
and Preferred Term (PT) for the FAS. The corresponding data listing will also be provided. 
9.2.4 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization Drug Dictionary (WHO-DD) 
and categorized as follows: 
• Prior medication: any medication that administered during the 56 days before the first 
dose of study drug. 
• Concomitant medication: medication continued or newly received during the TE 
period. 
• Post-treatment medication: medication continued or newly received after the 
corresponding TE period. 
A given medication may be classified as a prior medication, a concomitant medication, or a post 
treatment medication; both prior and concomitant; both concomitant and post treatment; or prior, 
concomitant, and post treatment.  
If a medication has a missing or partially missing start/end date or time and if it cannot be 
determined whether it was taken before the first dose of study drug, concomitantly during the TE 
Period, or after the TE Period, it will be considered in all 3 categories of prior, concomitant, and 
post treatment medication. Details for imputing missing or partial start and/or stop dates of 
medication are described in Appendix C. 
Prior medications and concomitant medications during the Treatment Period will be summarized 
descriptively for the FAS using frequency tables by: 1) preferred name (PN); and 2) anatomic 
class (ATC) level 1, ATC level 2, and PN.  
The number of subjects who used hormonal therapy concomitantly during the Treatment Period 
will be summarized based on the Safety Set. 
9.2.5 
Study Drug Exposure  
Study drug exposure will be summarized based on the Safety Set. 
Duration of study drug exposure (in weeks) will be calculated as: (last dose date of study drug – 
first dose date of study drug + 1)/7, regardless of study drug interruption.  
Study drug exposure in weeks will be summarized descriptively by the number of subjects (n), 
mean, SD, median, min, and max. It will also be summarized by intervals using counts and 
percentages. 


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9.2.6 
Study Drug Compliance 
Study drug compliance will be summarized based on the FAS.   
Study drug compliance will be calculated as: 100 × [1 - (total number of days of study drug 
interruption) / (duration of study drug exposure in days)]. A study drug interruption on a given 
day is defined as an interruption of any study drugs on that day. A study drug interruption that 
continues through the end of the study participation (i.e., subject does not resume study drug 
before the end of the study participation) will not be included in the compliance calculation. 
Study drug compliance will be summarized descriptively by the number of subjects (n), mean, 
SD, median, min, and max.  It will also be summarized in categories: <80% and ≥80% using 
frequency tables. 
9.2.7 
Important Protocol Deviations  
An important protocol deviation (IPD) is a deviation that may significantly affect the 
completeness, accuracy, or reliability of the study data or that may significantly affect a subject’s 
rights, safety, or well-being. A protocol deviation review team will categorize IPDs according to 
the Protocol Deviation Plan during the study. 
IPDs will be summarized descriptively based on the FAS. Additionally, IPDs will be provided in 
an individual subject data listing.  
9.3 
Efficacy Analysis  
Unless otherwise defined, all efficacy analyses described in this section will be based on the 
FAS.  
9.3.1 
Analysis of Primary Efficacy Variable 
9.3.1.1 
Definition of Variable 
The primary endpoint is percent reduction from baseline in cough frequency (cough events per 
day) to the average of Week 8 through Week 12. Percent reduction from baseline will be 
calculated and expressed in percentage as 100% × (baseline value - post-baseline value)/baseline 
value (i.e., -relative change) 
Cough frequency per day will be measured by a non-invasive, semi-automated, ambulatory 
cough monitoring system. The device will be used for a single day (defined by 24 continuous 
hours) at visits specified in Table 3-2 in CSP. The 24-hour assessment is considered valid if there 
are at least 10 cumulative hours of recording duration while awake, excluding any duration 
where the recording is identified as muted, flagged, or device not attached, and excluding any 
duration where the recording ended early.2 For valid assessments, the cough frequency per day is 
the total number of cough events in the 24-hour period (excluding any duration where the 
recording is identified as muted, flagged, or device not attached, and excluding any duration 
where the recording ended early). 
The baseline value is defined as the geometric mean of valid cough measurements prior to the 
first dose of study drug (e.g., Day -14 and Day -7). If one value is missing or invalid, the non-
missing, valid value will be used. If the cough frequency is zero at a given visit, 0.5 will be 
added to ensure a non-zero number. 


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9.3.1.2 
Primary Analysis  
The primary endpoint is the percent reduction from baseline in cough frequency (cough events 
per day) to the average of Week 8 through Week 12. The primary analysis will be based on a 
mixed-effects model for repeated measures (MMRM) with change from baseline at each post-
baseline visit (Week 2 to Week 12) on the natural log scale (i.e., log(post-baseline) – log 
(baseline)) as the dependent variable. Note that if cough frequency is zero at any visit, 0.5 will be 
added in order to ensure a non-zero number for appropriate natural log calculations. The model 
will include visit as a fixed effect and log baseline cough frequency as a covariate. The model 
will be estimated using restricted maximum likelihood. Denominator degrees of freedom for the 
F-test for fixed effects will be estimated using the Kenward-Roger approximation.3 An 
unstructured covariance structure will be used to model the within-subject errors. If the model 
estimation does not converge, a compound symmetry covariance structure will be used instead. 
Conditional on the observed data and covariates, missing data will be assumed to be missing at 
random; no additional imputation of missing data will be performed. 
The primary result obtained from the model will be the estimated percent reduction in cough 
frequency from baseline to the average of Week 8 through Week 12 (defined as the average of 
Weeks 8, 9, 10, 11, 12). Percent reduction will be calculated as 100% × (1-exponential form of 
LS mean change at the average of Weeks 8 through 12 on the natural log scale from the above 
MMRM model). The 2-sided 95% confidence intervals will be provided. Furthermore, the 
estimated percent reduction at each post‑baseline week will also be provided. The estimated 
percent reduction at each post-baseline week up to Week 12 will be plotted.  
The geometric mean and geometric SD of the raw values at baseline and each post-baseline visit 
up to Week 12 will also be summarized. In addition, daytime and overnight cough frequency per 
hour will be summarized in a similar way. If the daytime or overnight cough frequency per hour 
is zero at a given visit, 0.5/24 will be added to ensure a non-zero number. 
 
9.3.2 
Analysis of Secondary Efficacy Variable 
9.3.2.1 
Definition of Variables 
The secondary endpoint is the absolute change from baseline in total step count per day to the 
average of Week 8 through Week 12. 
Total step count per day will be measured by the wrist-worn actigraphy sensor on each calendar 
day. The wrist-worn device will be worn 24 hours per day continuously from Day -14 throughout 
the Treatment Period. The daily assessment is considered as valid if there are at least 10 
cumulative hours of valid wear (excluding periods of non-wear, no data, and artifact [noise]) 
while awake on that day.4 The 2-week baseline period and 12-week treatment period will be 
divided into 14 weekly intervals (Day -14, Day -7, Week 1, Week 2, ..., Week 12), and the 
average of total step count per valid day will be calculated for each weekly interval, provided 
that there are valid daily assessments on at least 3 weekdays and 1 weekend day. 


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The baseline value will be defined as the average of valid weekly interval measurements prior to 
the first dose of study drug (e.g., average of Day -14 and Day -7). If one weekly interval 
measurement is missing or invalid, the non-missing, valid interval measurement will be used. 
9.3.2.2 
Analysis Method 
The analysis will be based on an MMRM model similar to the analysis of the primary efficacy 
variable (without any natural log transformation), with change from baseline at each post-
baseline weekly interval (Week 1 to Week 12) as the dependent variable. The model will include 
the weekly intervals as fixed effects and baseline total step count per day as a covariate. 
The primary result obtained from the model will be the estimated mean change from baseline to 
the average of Week 8 through Week 12. The estimated mean change and 2-sided 95% 
confidence interval will be provided. Furthermore, the estimated mean change at each 
post‑baseline weekly interval will also be provided. The estimated mean change at each post-
baseline weekly interval up to Week 12 will be plotted. 
In addition, the post-baseline raw values and the change from baseline at each post-baseline 
weekly interval up to Week 12 will be summarized descriptively (n, mean, SD, median, 
minimum, and maximum). 
9.3.2.3 
Multiplicity Adjustment 
Not applicable. 
9.3.2.4 
Sensitivity Analysis 
Not applicable. 


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9.4 
Safety Analysis 
All safety analyses will be based on data from the TE period in the Safety Set, unless otherwise 
specified.  
The overall safety profile of study drug will be assessed in terms of the following safety and 
tolerability endpoints:  
• Treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values 
Only descriptive analysis of safety will be performed. No statistical testing will be performed. 
Note that post-baseline safety measurements (except TEAEs) are only scheduled at Week 13. 
9.4.1 
Adverse Events  
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs during the Treatment 
Period, and post-treatment AEs, defined as follows:  
• Pretreatment AE: any AE that occurred before the first dose date of study drug.  
• TEAE during the Treatment Period: any AE that worsened (either in severity or 
seriousness) or that was newly developed at or after the first dose date of study drug 
through the end of the TE period  
• Post-treatment AE: any AE that worsened (either in severity or seriousness) or that was 
newly developed after the TE period. 
For AEs with completely missing or partially missing start dates, if there is no clear evidence 
that the AEs were pretreatment or post-treatment, the AEs will be classified as TEAEs.  
Details for imputing missing or partial start dates of adverse events are described in Appendix D. 
An overview of all TEAEs will be provided with the following categories: 
• Number of TEAEs  
• Subjects with any TEAEs  
• Subjects with TEAEs by strongest relationship 
• Subjects with TEAEs by maximum severity 
• Subjects with TEAEs leading to study drug discontinuation  
• Subjects with TEAEs leading to study drug interruption 
• Subjects with Grade 3/4/5 TEAEs 
• Subjects with related TEAEs 


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• Subjects with serious TEAEs 
• Subjects with related serious TEAEs 
• Subjects with TEAEs leading to death  
The following summary tables of TEAEs will be presented by MedDRA System Organ Class 
(SOC) and Preferred Term (PT) using frequency counts and percentages (i.e., number and 
percentage of subjects with an event):  
• All TEAEs 
• Grade 3/4/5 TEAEs 
• TEAEs by strongest relationship 
• TEAEs by maximum severity 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption 
• Related TEAEs 
• Serious TEAEs 
• Related serious TEAEs 
• TEAEs leading to death 
Summaries will be presented by MedDRA SOC and PT using frequency counts and percentages 
(i.e., number and percentage of subjects with an event). When summarizing the number and 
percentage of subjects, subjects with multiple occurrences of the same AE or a continuing AE 
will be counted once and only the maximum severity level will be presented in the severity 
summaries, and the strongest relationship level will be presented in the relationship summaries.  
All AEs, including pretreatment AEs, TEAEs, and post-treatment AEs, will be presented in an 
individual subject data listing based on the All Subjects Set. In addition, a listing containing 
individual subject adverse event data for TEAEs leading to treatment discontinuation, TEAEs 
leading to treatment interruption, Grade 3/4/5 TEAEs, SAEs and all deaths will be provided. 
Listings for SAEs and deaths will include a flag indicating the TEAE status. 
9.4.1.1 
Adverse Events of Special Interest 
For this study, elevated transaminase events and rash events, as determined by MedDRA 
preferred terms in Appendix E, are considered as adverse events of special interest. 
For treatment-emergent elevated transaminase events and rash events, the following categories 
will be summarized by treatment group: 
• Subjects with events 
• Subjects with events by maximum severity 
• Subjects with events leading to treatment discontinuation 
• Subjects with events leading to treatment interruption 


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• Subjects with serious events 
• Subjects with related serious events 
• Subjects with events leading to death 
• Duration of events 
• Time-to-onset of first event 
In addition, for treatment-emergent rash events, these categories will be summarized for the 
following subgroups: 
• Sex (male, female) 
• Female subjects with concomitant hormonal therapy (Yes, No) 
9.4.2 
Clinical Laboratory 
For the treatment-emergent laboratory measurements, the observed values and change from 
baseline values of the continuous serum chemistry results will be summarized in SI units at each 
clinic visit.  
The number and percentage of subjects meeting at least 1 threshold analysis criterion, during the 
TE period will be summarized. The threshold analysis of shift from baseline will also be 
summarized for liver function tests (LFTs) laboratory parameters. The threshold analysis criteria 
are provided in Appendix F. 
For selected LFTs, (alanine transaminase [ALT], aspartate transaminase [AST], alkaline 
phosphatase [ALP], and total bilirubin), a scatter plot of the maximum treatment-emergent value 
versus the baseline value corresponding to ×ULN (upper limit of normal) will be presented. 
Further, a scatter plot of the maximum treatment-emergent value of ALT and AST, separately, 
versus the maximum treatment-emergent value of total bilirubin corresponding to ×ULN will 
also be presented.  
Results of urinalysis and positive urine/serum pregnancy test will be listed in individual subject 
data listings only. For positive serum pregnancy listing, subjects with serum HCG which are 
above non-pregnant levels will be selected. 
In addition, a listing containing individual subject chemistry values will be provided. This listing 
will include data from both scheduled and unscheduled visits.  


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9.4.6 
Physical Examination  
Abnormal PE findings will be presented as an individual subject data listing only. 
9.4.8 
COVID-19 Impacted Visits 
A listing containing subjects’ visits impacted due to COVID-19 will be provided. 
10 
Interim and DMC Analyses 
10.1 
Interim Analysis 
Not applicable.  
10.2 
DMC analysis 
Not applicable.  


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11 
REFERENCES 
1 Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall G, Culver BH, et al. Multi-ethnic reference 
values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur 
Respir J. 2012;40(6):1324-43. 
2 Kerem E, Wilschanski M, Miller NL, Pugatsch T, Cohen T, Blau H, Rivlin J, Shoseyov D, 
Reha A, Constantine S, Ajayi T. Ambulatory quantitative waking and sleeping cough 
assessment in patients with cystic fibrosis. Journal of Cystic Fibrosis. 2011 May 1;10(3):193-
200. 
3  Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics. 1997;53:983-97. 
4 McLellan G, Arthur R, Donnelly S, Buchan DS. Segmented sedentary time and physical 
activity patterns throughout the week from wrist-worn ActiGraph GT3X+ accelerometers 
among children 7–12 years old. Journal of sport and health science. 2020 Mar 1;9(2):179-88.  
 
 
 




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Table 12-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Notes: 
1 Visit name for analysis purpose is used to report data in tables and figures. In this context, visit may not necessarily 
refer to a clinic visit and can include telemedicine contact or wearable device measurement. 
 
2 Step count and 
 are measured on a weekly basis, so this column denotes the first day of the 
7-day interval.    
3 The analysis visit windows will be applied using the following rules for both scheduled and unscheduled visits: 
a. 
If no numerical measurement is available within a visit window, the measurement will be considered missing 
for the visit. 
b. If there is more than 1 numerical measurement available within a visit window, use the following rules:  
i. The measurement closest to the target day will be used; or  
ii. If there are multiple measurements with the same distance from the target day, the latest measurement 
will be used. 
4 For lab, ECG and vital sign measurement collected on the date of first dose of study drug, if it cannot be 
determined whether the measurement is before or after the first dose:  
a. 
Scheduled measurement will be treated as pre-dose observation. 
b. Unscheduled measurement will be treated as post-dose observation. 
5 For safety assessments, the Safety Follow-up analysis visit will be based on the nominal Safety Follow-up visit. If 
a subject doesn’t have a nominal Safety Follow-up visit but has an ETT visit with study day > nominal Week 13 
visit, then the ETT visit will be mapped into Safety Follow-up analysis visit. 
6 For nutrition variables (BMI, Weight, Height and their Z-scores), if there are multiple assessments > nominal 
Week 13 visit, then the nominal Safety Follow-up visit will be mapped to the Safety Follow-up visit. If there is only 
ETT assessment > nominal Week 13 visit, the ETT visit will be mapped to the Safety Follow-up visit; else if there 
are multiple assessments with > nominal Week 13 visit then select the earliest record.   
Derived Variables: 
1. Age (in years) at first dose date and nominal visit (for demographics, listing and the calculation of [percent] 
predicted spirometry variables): 
Obtain the age at informed consent (in days) in “yy, mm” format (e.g., 24 years, 6 months) from the Vital Signs 
(VS) page at the Screening Visit, and add 0.5 month to convert to days. 
Obtain the informed consent date. 
Then age (in years) at first dose or nominal visit = [(first dose date or nominal visit date – informed consent 
date) in days + age at informed consent (in days)]/365.25. 
2. Age (in months) at nominal visit (for use in calculation of BMI and weight z-score): 
Obtain the age at informed consent (in months) in “yy, mm” format (e.g., 24 years, 6 months) from Vital Signs 
(VS) page at the Screening Visit. 
Obtain the informed consent date. 


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Table 12-1 
Analysis Visit Windows for Safety and Efficacy Assessments 
Assessment 
Visit1 
Target Study Day2 
Analysis Visit Window 
(in study days)3, 4, 5, 6 
Then age (in months) at nominal visit = integer part of {[(age at informed consent (in months) + 0.5 + diff(first 
dose date or nominal visit date, informed consent date) in months]} + 0.5. 
3. Missing first dose date or last dose date 
If the first dose date is missing, use Day 1 visit date to impute. 
If the last dose date is missing or partial date is reported, the last dose date will be imputed based on, in 
descending order priority, the Early Treatment Termination (ETT) visit date, last visit date before the Safety 
Follow-up, or the last study drug administration date from EX SDTM domain, as appropriate.  The imputation 
algorithm will ensure the imputed last dose date does not exceed the study participation end date. 
7 The baseline value is defined as the geometric mean of valid cough measurements prior to the first dose of study 
drug (e.g., Day -14 and Day -7). If one value is missing or invalid, the non-missing, valid value will be used. If the 
cough frequency is zero at a given visit, 0.5 will be added to ensure a non-zero number. 
8 The baseline value will be defined as the average of valid weekly interval measurements prior to the first dose of 
study drug (e.g., average of Day -14 and Day -7). If one weekly interval measurement is missing or invalid, the non-
missing, valid interval measurement will be used. 
9 The baseline value will be defined as the Day 1 assessment. 
 
 
 
 
 


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Appendix B: Details of GLI Equations for Calculating ppFEV1 
Percent predicted values will be calculated for parameters of FEV1, FVC, FEV1/FVC, and 
FEF25%-75% using the Quanjer GLI-2012 Regression Equations and Lookup Tables. 
The regression equations and lookup tables required to implement the Quanjer GLI-2012 
predicted values are available in: 
Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, Janet Stocks. Quanjer GLI-2012 Regression 
Equation and Lookup Tables (Version 7 April 2013). Global Lung Function Initiative. [online] 
Available at: http://www.ers-education.org/home/browse-all-content.aspx?idParent=138978 
[Accessed Mar 26, 2018]. 
The instructions and tools on how to implement the Quanjer GLI-2012 equations are:   
Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, Janet Stocks. Implementing GLI-2012 
regression equations (Version 19 July 2015). Global Lung Function Initiative. [online] Available 
at: http://www.ers-education.org/home/browse-all-content.aspx?idParent=138979 [Accessed Mar 
26, 2018].   
Sanja Stanojevic. GLI-2012 - SAS Macro (Version 2, 7 April 2013). Global Lung Function 
Initiative. [online] Available at: http://www.ers-education.org/home/browse-all-
content.aspx?idParent=138988 [Accessed  Mar 26, 2018]. 
Data handling rule for spirometry is as follows:  
• Input age with at least 2 decimal place 
• Use height at screening regardless if height is collected at other study visits for subjects 
whose age at informed consent is >21 years. For subjects with age <=21 years, height 
collected at the respective visit should be used; if the height at the respective visit is not 
available, the last non-missing record will be used. 
• For race, map the CRF reported Black or African American to Black, all other races in 
CRF (except White) are mapped to 'other'; multiple checks for race in CRF are also 
mapped to 'other'; white is a reference race in the equations and assumes 0 values for all 
race coefficients in the GLI  equations. 
 
 




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Appendix D: Imputation Rules for Missing AE dates  
Imputation rules for missing or partial AE start date are defined below.  If the imputed AE start 
date is before the study informed consent/assent date, the AE start date will be imputed using the 
study informed consent/assent date. 
• If only Day of AE start date is missing: 
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then  
 if AE start year and month are equal to the month and year of first dose date 
of the Treatment Period, then impute the AE start day as the day of first dose 
date of the Treatment Period;  
 else impute the AE start day as 1.  
o else impute the AE start day as 1.  
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE or post-treatment AE. 
• If Day and Month of AE start date are missing: 
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then  
 if AE start year is equal to the year of first dose date of the Treatment Period, 
then impute the AE start month and day as the month and day of first dose 
date of the Treatment Period;  
 else impute the AE start month as January and day as 1.  
o else impute the AE start month as January and day as 1.  
Compare the imputed AE start date with TE period to determine whether the AE is 
pretreatment AE, TEAE or post-treatment AE. 
• If Year of AE start date is missing: 
If the year of AE start is missing or AE start date is completely missing then query site and  
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then impute the AE start date as the first dose date 
of the Treatment Period;  
o else impute the AE start date as the informed consent/assent date. 
 
Imputation rules for partial AE end date are defined below:  
• Impute the AE end date as min (the last day of the month, end of study participation) if day is 
missing, or min (Dec, end of study participation) if month is missing. 
 
 


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Appendix E: Adverse Events of Special Interest  
Table 12-7 MedDRA Preferred Terms for Event of Special Interest 
Adverse event of special interest 
MedDRA preferred terms 
Elevated transaminase 
Alanine aminotransferase abnormal, Alanine aminotransferase 
increased, Aspartate aminotransferase abnormal, Aspartate 
aminotransferase increased, Transaminases abnormal, 
Transaminases increased, Liver function test abnormal, Liver 
function test increased, Hypertransaminasaemia, Hepatic 
enzyme abnormal, Hepatic enzyme increased 
Rash 
Rash, Rash erythematous, Rash macular, Rash maculo-papular, 
Rash maculovesicular, Rash vesicular, Rash pruritic, Rash 
follicular, Rash pustular, Nodular rash, Drug eruption, Fixed 
eruption, Urticaria, Urticaria papular, Urticaria vesiculosa, 
Urticarial dermatitis, Rash morbilliform, Rash papular, Rash 
papulosquamous, Rash rubelliform, Rash scarlatiniform , Drug 
hypersensitivity, Type IV hypersensitivity reaction, Dermatitis, 
Dermatitis atopic, Epidermolysis, Skin toxicity, Dermatitis 
allergic, Dermatitis exfoliative, Dermatitis exfoliative 
generalised, Erythema multiforme, Exfoliative rash, 
Mucocutaneous rash, Acute generalised exanthematous 
pustulosis, Cutaneous vasculitis, Urticarial vasculitis, Dermatitis 
bullous, Drug reaction with eosinophilia and systemic 
symptoms, Epidermal necrosis, Oculomucocutaneous syndrome, 
Skin exfoliation, Skin necrosis, Stevens-Johnson syndrome, 
Toxic epidermal necrolysis, Toxic skin eruption, Perioral 
dermatitis, Vasculitic rash, Immune-mediated dermatitis, Penile 
rash, SJS-TEN overlap, Erythrodermic atopic dermatitis, Scrotal 
dermatitis 
Note: the preferred terms listed in the table is based on the MedDRA version applicable at the time of 
finalization of the SAP.  If the MedDRA version is upgraded at the time of the analysis, the 
corresponding preferred terms based on the upgraded version will be used in the analysis of adverse 
events of special interest. 
 
 
 


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Appendix F: Criteria for Threshold Analysis 
Table 12-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry (LFT) 
ALT 
>ULN - ≤3xULN 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>8x - ≤ 20.0xULN 
>20.0xULN 
FDA DILI Guidance Jul 2009.  
AST 
>ULN - ≤3xULN 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>8x - ≤ 20.0xULN 
>20.0xULN 
FDA DILI Guidance Jul 2009. 
ALT or AST 
 (ALT>ULN - ≤  3xULN) or 
(AST>ULN - ≤  3xULN) 
(ALT>3x - ≤  5xULN) or  (AST>3x - ≤ 
5xULN) 
(ALT>5x- ≤  8xULN) or  (AST>5x - ≤  
8xULN) 
(ALT>8x - ≤  20xULN) or (AST>8x - 
≤ 20xULN) 
ALT>20xULN or AST> 20 xULN 
FDA DILI Guidance 
Alkaline Phosphatase 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2.5 xULN 
>2.5 – ≤ 5.0 x ULN 
>5.0 – ≤ 20.0 x ULN 
>20.0 x ULN 
FDA DILI Guidance Jul 2009.  
Total Bilirubin 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2xULN 
>2 – ≤ 3xULN  
>3 – ≤ 10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
Direct Bilirubin 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2xULN 
>2 – ≤ 3xULN  
>3 – ≤ 10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
Indirect Bilirubin 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2xULN 
>2 – ≤ 3xULN  
>3 – ≤ 10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
ALT and Total Bilirubin 
ALT>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
 


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Table 12-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
AST and Total Bilirubin 
AST>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
 
(ALT or AST) and Total Bilirubin (ALT>3xULN or AST>3xULN) and 
TBILI>2×ULN 
FDA DILI Guidance Jul 2009. 
GGT 
>ULN - ≤ 2.5xULN 
>2.5 –  ≤ 5.0xULN 
>5.0 –  ≤ 20.0xULN  
>20.0xULN 
CTCAE grade 1-4 
Clinical Chemistry (NON-LFT) 
 
Albumin 
<LLN - ≥ 30 g/L 
<30 – ≥ 20 g/L 
<20 g/L 
CTCAE grade 1-3 
Amylase 
>1x -  ≤  1.5xULN 
>1.5x -  ≤  2xULN 
>2x -  ≤  5xULN 
>5xULN 
Criteria based upon CTCAE 
Creatinine 
>ULN - ≤ 1.5xULN 
>1.5 - ≤ 3.0xULN 
>3.0 - ≤ 6.0xULN 
>6.0xULN 
CTCAE grades 1-4 
Lipase 
>ULN -  ≤  1.5xULN 
>1.5x -  ≤  2xULN 
>2x -  ≤  5xULN 
>5xULN 
Criteria based upon CTCAE 
Total protein 
 
<LLN  
>ULN 
No CTCAE 
Creatine kinase 
>ULN - ≤ 2.5 x ULN 
>2.5 - ≤ 5 x ULN 
>5 - ≤ 10x ULN  
>10 x ULN 
CTCAE grades 1-4 
 
  
Table 12-4 
Threshold Analysis Criteria for ECGs 
Parameter 
Threshold Analysis 
Comments 
HR 
Bradycardia 
<50 bpm  
<45 bpm 
Decrease from baseline ≥10 bpm 
Decrease from baseline ≥20 bpm 
<50 bpm and decrease from baseline ≥10 bpm 
<50 bpm and decrease from baseline ≥20 bpm 
Per HV grade 2, 3, plus shift change 
 
 


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Table 12-4 
Threshold Analysis Criteria for ECGs 
Parameter 
Threshold Analysis 
Comments 
 
Tachycardia 
>100 bpm 
>115 bpm  
>130 bpm  
Increase from baseline ≥10 bpm 
Increase from baseline ≥20 bpm  
>100 bpm and increase from baseline ≥10 bpm 
>100 bpm and increase from baseline ≥20 bpm 
Per HV grade 1, 2, 3, plus shift change 
 
 
PR 
≥240 ms 
≥300 ms 
≥200 ms and increase from baseline ≥40 ms 
≥200 ms and increase from baseline ≥100 ms 
 
QRS 
>110 ms 
>160 ms 
Increase from baseline ≥20 ms 
Increase from baseline ≥40 ms 
 
QTc 
 
>450 to <500ms (Male) or >470 to <500ms 
(Female) 
≥500 ms 
 
Increase from baseline 
Increase from baseline >10 ms 
Increase from baseline >20 ms 
Increase from baseline >40 ms 
Increase from baseline >60 ms 
To be applied to any kind of QT correction 
formula.  
 
 
 
 
 
Table 12-5 
Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
Pulse Rate 
Same as above in ECG category 
 
SBP increased 
 
>140 mmHg 
>160 mmHg 
>10 mmHg increase from baseline 
>20 mmHg increase from baseline 
 
>140 mmHg & >10 mmHg increase from 
baseline 
>140 mmHg & >20 mmHg increase from 
baseline 
>160 mmHg & >10 mmHg increase from 
baseline 
>160 mmHg & >20 mmHg increase from 
baseline 
809/770 analyses 


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Table 12-5 
Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
SBP decrease 
 
<90 mmHg 
<80 mmHg 
>10 mmHg decrease from baseline 
>20 mmHg decrease from baseline 
 
<90 mmHg and >10 mmHg decrease from 
baseline 
<90 mmHg and >20 mmHg decrease from 
baseline 
<80 mmHg and >10 mmHg decrease from 
baseline 
<80 mmHg and >20 mmHg decrease from 
baseline 
Per HV grade 1, 3, plus shift change 
DBP increased 
>90 mmHg 
>100 mmHg 
>5 mmHg increase from baseline 
>10 mmHg increase from baseline 
 
>90 mmHg and >5 mmHg increase from 
baseline 
>90 mmHg and >10 mmHg increase from 
baseline 
>100 mmHg and >5 mmHg increase from 
baseline 
>100 mmHg and >10 mmHg increase from 
baseline 
 
DBP decreased 
 
<60 mmHg 
<45 mmHg 
>5 mmHg decrease from baseline 
>10 mmHg decrease from baseline 
 
<60 mmHg and >5 mmHg decrease from 
baseline 
<60 mmHg and >10 mmHg decrease from 
baseline 
<45 mmHg and >5 mmHg decrease from 
baseline 
<45 mmHg and >10 mmHg decrease from 
baseline 
 
Weight   
Weight gain  
≥5 % increase from baseline   
≥10 % increase from baseline  
≥ 20% increase from baseline  
CTCAE grade 1-3 
 
 
Weight loss  
≥5 % decrease from baseline   
≥10 % decrease from baseline  
≥ 20% decrease from baseline  
CTCAE grade 1-3 
 
 


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Table 12-6 
Threshold Analysis Criteria for Laboratory Tests (for labeling purpose) 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry (LFT) 
ALT or AST 
>3xULN 
>5xULN 
>8xULN 
For labeling purpose