Clinical trial NCT04223635
Conditions: Moderate Hepatic Impairment
Keywords: Moderate hepatic impaired Healthy subjects Pexidartinib Clinical pharmacology study Tenosynovial giant cell tumor (TGCT)
Sponsor: Daiichi Sankyo
Start date: 2020-01-07; Completion date: 2020-10-02
Enrollment: 16 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The pharmacokinetics of a single dose of pexidartinib was investigated in participants with impaired hepatic function and compared with healthy control participants with normal hepatic function.

Detailed description:
Pexidartinib is an orally administered tyrosine kinase inhibitor, currently approved in the US for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery.

The primary objective of this study is to determine the plasma pharmacokinetics (PK) of pexidartinib after a single oral dose of 200 mg in participants with moderate hepatic impairment (HI) as defined by National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria compared to the healthy controls participants with normal hepatic function.

Arms: arm 1: Participants with moderate hepatic impairment who will receive a single oral dose of pexidartinib. arm 2: Sex-, age-, and weight-matched healthy participants who will receive a single oral dose of pexidartinib.
Interventions: intervention 1: Pexidartinib
Intervention descriptions: intervention 1: Single, 200-mg capsule will be administered orally on Day 1 with 240 mL of water, following an overnight fast of at least 10 hours.

Protocol documents:
Prot_SAP_000.pdf: 
Pr o pri et ar y  a n d  C o nfi d e nti al   
P a g e  1  
C  LI  NI  C  A  L  S  T  U  D  Y  P  R  O  T  O  C  O  L   
A  N   O P  E  N  -L  A  B  E  L,  SI  N  G  L  E  -D  O S  E  S  T  U  D  Y   T  O 
A S S  E S S   T  H  E  P  H  A  R  M  A  C  O  K  I  N  E  TI  C S   O F 
P  E  XI  D  A  R  TI  NI  B  I  N  S  U  B J  E  C  T S   WI  T  H  M  O  D  E  R  A  T  E 
H  E P  A  TI  C I  M P  AI  R  M  E  N  T   C  O  M P  A  R  E  D   T  O 
H  E  A  L  T  H  Y  S  U  B J  E  C  T S    
 
 
P  L 3 3 9 7 -A  -U 1 2  9  
 
I  N  D 1 0 5 5 2 1  
V  E  R SI  O  N  2. 0,  1  0  D  E  C  2 0 1 9  
 V  E  R SI  O  N   1. 0 , 2 3  O  C  T  2 0 1 9  
 
D  AII  C  HI  S  A  N  K  Y  O, I  N  C.   
2 1 1   M  T.   AI  R  Y   R  O  A  D   
B  A S  KI  N  G   RI  D  G  E,   N J  0 7  9 2 0  
 
 
C  O  N FI  D  E  N  TI  A  LI  T  Y  S  T  A  T  E  M  E  N  T   
I nf or  m ati o n  c o nt ai n e d i n t his  d o c u  m e nt is  pr o pri et ar y t o   D aii c hi  S a n k y o, I n c. (  D SI).   T h e 
i nf or  m ati o n is  pr o vi d e d t o  y o u i n  c o nfi d e n c e,   w hi c h is r e q u est e d  u n d er  a n  a gr e e d  u p o n 
a n d si g n e d   C o nfi d e nti alit y  a n d   Dis cl os ur e   A gr e e  m e nt.    D o  n ot  gi v e t his  d o c u  m e nt  or  a n y 
c o p y  of it  or r e v e al  a n y  pr o pri et ar y i nf or  m ati o n  c o nt ai n e d i n it t o  a n y t hir d  p art y ( ot h er 
t h a n t h os e i n  y o ur  or g a ni z ati o n   w h o  ar e  assisti n g  y o u i n t his   w or k  a n d  ar e  b o u n d  b y t h e 
C o nfi d e nti alit y  a n d   Dis cl os ur e   A gr e e  m e nt)   wit h o ut t h e  pri or   writt e n  p er  missi o n  of  a n 
a ut h ori z e d r e pr es e nt ati v e  of   D SI.  
 
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1








P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  4  
S  U  M  M  A  R  Y   O F   C  H  A  N  G  E S  
R ati o n al e  :  
C h a n g es   w er e   m a d e t o t h e  pr ot o c ol i n r es p o ns e t o   c o  m  m e nts  fr o  m t h e F o o d  a n d  D  r u g 
A d  mi n  istr ati o n ( F  D  A). 
C h a n g es t o t h e  Pr ot o c ol  : 
T h e s u  m  m ar y  of  c h a n g es  b el o  w is  a t o p -li n e s u  m  m ar y  a n d r ati o n al e  of si g nifi c a nt 
c h a n g es t o   V ersi o n  1 . 0  of t h e P L 3 3 9 7 -A  -U 1 2 9   cli ni c al st u d y  pr ot o c ol  b y s e cti o n.   
 
D  E S  C  RI P  TI  O  N   O F   E  A  C  H   HI  G  H  -L  E  V  E  L   C  H  A  N  G  E   
S e cti o ns    
C h a n g e   
S e cti o n  4. 1  
I n cl usi o n   Crit eri a 
As  a d vis e d  b y t h e   F  D  A , th e f oll o  wi n g  crit eri o n   w as  a d d e d t o t h e list  of 
i n cl usi o n  crit eri a: 
“ Cr e ati ni n e   Cl e ar a n c e  ≥  7 0   m L/  mi n  esti  m at e d  usi n g t h e   C o c k cr oft   G a ult 
f or  m ul a   wit h o ut  a n y   m ar k ers  of  c hr o ni c  ki d n e y  dis e as e  at S cr e e ni n g  a n d 
C  h e c k -i n. ” 
S e cti o n  4. 2  
E x cl usi o n   Crit eri a  
T h e f oll o  wi n g  crit eri o n  # 8  w as  d el et e d   fr o  m t h e list  of  e x cl usi o n  crit eri a: 
“ Esti  m at e d  gl o  m er ul ar filtr ati o n r at e  < 7 0   m L/  mi n  b y   C o c kr oft  -G a ult 
e q u ati o n  at  S cr e e ni n g  a n d   C h e c k -i n”  
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  5  
P  R  O  T  O  C  O  L  S  Y  N  O P SI S  
E u dr a  C T:  
N ot  a p pli c a bl e   
I  N  D   N u  m b er: 
1 0 5 5 2 1  
Pr ot o c ol   N u  m b er:  
P L 3 3 9 7 -A  -U 1 2 9   
I n v esti g ati o n al M e di ci n al 
Pr o d u ct:  
P e xi d arti ni b   H y dr o c hl ori d e (  H  Cl) ( P L  X 3 3 9 7   H  Cl)  c a ps ul es 
( 2 0 0   m g) 
 A cti v e I n gr e di e nt:     
P e xi d arti ni b ( P L  X 3 3 9 7)  
St u d y  Titl e:  
A n   O p e n  -l a b el,  Si n gl e-d os e  St u d y t o   Ass ess t h e 
P h ar  m a c o ki n eti cs  of  P e xi d arti ni b i n  S u bj e cts   wit h 
M o d er at e   H e p ati c I  m p air  m e nt   C o  m p ar e d t o   H e alt h y 
S u bj e cts  
St u d y  P h as e:  
P h as e  1  
I n di c ati o n   U n d er I n v esti g ati o n: N ot  a p pli c a bl e   
St u d y   R ati o n al e  
 
F oll o  wi n g  a  si n gl e  d os e  of  2 0 0   m g  p e xi d arti ni b,  e x p os ur e 
w a  s  n ot  aff e ct e d  b y   mil d  a n d   m o d er at e  h e p ati c i  m p air  m e nt 
(  HI) ( as  d efi n e d  b y   C hil d-P u g h  crit eri a) ( P L 3 3 9 7 -A  -U 1 2 3). 
H o  w e v er, f oll o  wi n g r e a n al ysis  of t h e  d at a  b y  c at e g ori zi n g 
t h e   HI s u bj e cts  usi n g N ati o n al   C a n c er   I nstit ut e Or g a n 
D ysf u n cti o n   W or ki n g   Gr o u p (  N  CI  -O  D  W  G  ) crit eri a f or 
h e p ati c  i  m p air  m e nt,  o nl y  1 s u bj e ct   w as i d e ntifi e d   wit h 
m o d er at e   HI.  T h er ef or e, t h e  c urr e nt st u d y  h as  b e e n 
d esi g n e d t o i n v esti g at e t h e  eff e ct  of   m o d er at e   HI  as  d efi n e d 
b y t h e   N  CI -O  D  W  G   crit eri a  o n  t h e p h ar  m a c o ki n eti cs ( P  K ) 
of  p e xi d arti ni b .  
I n t his st u d y,   HI   will  b e  ass ess e d  b y (  N  CI-O  D  W  G)   crit eri a 
w hi c h is  b as e d  o n t ot al  bilir u bi n ( T  B  I L)  a n d as p art at e 
a  mi n otr a nsf er as e ( A S T  ),  as  c o  m p ar e d t o   C hil d-P u g h   w hi c h 
us es  a  c o  m p osit e s c or e  of  T  B I L, pr ot hr o  m bi n ti  m e, 
pr es e n c e  of  as c it es,  a n d  h e p ati c  e n c ep h al o p at h y.  
St u d y   O bj e cti v es  
 
 
 
 
 
 
 
P ri  m a r y   O bj e cti v e  
T o  d et er  mi n e t h e  pl as  m a  p h ar  m a c o ki n eti cs ( P  K) 
of  p e xi d arti n i b  aft er  a si n gl e  or al  d os e  of  2 0 0   m g 
i n s u bj e cts   wit h   m o d er at e   HI  c o  m p ar e d t o t h at i n 
h e alt h y s u bj e cts   wit h  n or  m al  h e p ati c f u n cti o n .  
S e c o n d a r y   O bj e cti v es  
    T o  ass ess t h e s af et y  a n d t ol er a bilit y  of 
p e xi d arti n i b  aft er  a si n gl e  or al  d os e  of  20 0 
m g i n s u bj e cts   wit h  n or  m al  a n d   m o d er at el y 
i  m p air e d  h e p ati c f u n cti o n 
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  6  
    T o  d et er  mi n e t h e  P  K  of  Z  A  A  D -1 0 0 6 a i n 
s u bj e cts   wit h   m o d er at e   HI,  c o  m p ar e d t o t h at 
i n  h e alt h y s u bj e cts wit h  n or  m al  h e p ati c 
f u n cti o n 
    T o  ass ess  pr ot ei n  bi n di n g  of  p e xi d arti ni b  a n d  
Z  A  A  D -1 0 0 6 a  i n s u bj e cts   wit h   m o d er at e  HI, 
c o  m p ar e d t o t h at i n  h e alt h y s u bj e cts  wit h 
n or  m al  h e p ati c f u n cti o n.   
St u d y   D esi g n:  
T his is  a  P h as e  1,  o p e n -l a b el, si n gl e d os e  P  K st u d y i n   m al e 
a n d f e  m al e s u bj e cts   wit h  n or  m al  a n d  m o d er at el y   i  m p air e d 
h e p ati c f u n cti o n.   T h e st u d y   will  c o nsist  of  8  s u bj e cts   wit h 
m o d er at e   HI  a n d   m at c h e d  c o ntr ols ( 8   h e alt h y s u bj e cts   wit h 
n or  m al  h e p ati c f u n cti o n).  T h e s e v erit y  of   HI   will  b e 
ass ess e d  b y t h e  N  CI  -O  D  W  G  crit eri a   t o i d e ntif y s u bj e cts 
wit h   m o d er at e   HI f or  e nr oll  m e nt   i n t his st u d y.  T h e  c o h ort 
of s u bj e cts   wit h  n or  m al  h e p ati c f u n cti o n   will  b e  gr o u p 
m at c h e d t o s u bj e cts   wit h   m o d er at e   HI  a c c or di n g t o s e x,  a g e 
( ± 1 0  y e ars  [ y]),  a n d w ei g ht   (±  2 0  % ) b as e d  o n   m e a n  v al u es . 
S u bj e cts   wit h  m o d er at e   HI   will  b e r e cr uit e d first.   H e alt h y 
s u bj e cts wit h  n or  m al  h e p ati c f u n cti o n   will  b e  e nr oll e d  aft er 
all  m o d er at e   HI   s u bj e cts  h a v e r e c ei v e d st u d y  dr u g .  
S u bj e cts   will  b e s cr e e n e d   wit hi n  2 1  d a ys ( d)  pri or t o t h e 
a d  mi nistr ati o n  of st u d y  dr u g.   S u bj e cts   will  b e  a d  mitt e d t o 
t h e  cli ni c al  u nit  o n   D a y -2  a n d   will r e  m ai n  d o  mi cil e d  u ntil 
t h e  c o  m pl eti o n  of  all st u d y  pr o c e d ur es  a p pr o xi  m at el y 
1 6 8  h o urs ( h)  aft er  or al  a d  mi nistr ati o n  of  2 0 0   m g 
p e xi d arti ni b ( 1  ×  2 0 0 -m g  c a ps ul e).   St u d y  dr u g   will  b e 
a d  mi nist er e d  o n   D a y  1 i n t h e   m or ni n g f oll o  wi n g  a n 
o v er ni g ht f ast  of  1 0  h.    W at er  c o ns u  m pti o n   will  b e 
r estri ct e d fr o  m  1  h  pr e d os e t o  2  h  p ost d os e,  e x c e pt f or t h e 
s p e cifi e d  a  m o u nt t h at is t o  b e  a d  mi nist er e d   wit h st u d y  dr u g.  
F asti n g   will  c o nti n u e  u ntil  4  h  aft er st u d y  dr u g 
a d  mi nistr ati o n.  
S eri al  bl o o d s a  m pl es   will  b e  c oll e ct e d f or  P  K  a n al ysis  of 
p e xi d arti ni b  a n d  Z  A  A  D -1 0 0 6 a  at  pr e d os e (  wit hi n 
3 0  mi n ut es [  mi n]  pri or t o  d osi n g)  a n d  at  0. 5,  1,  1. 5,  2,  2. 5, 
3,  3. 5,  4,  4. 5,  5,  6,  8,  1 0,  1 2,  2 4,  3 6,  4 8,  7 2,  9 6,  1 2 0,  1 4 4, 
a n d  1 6 8  h  p ost  d os e.  
Pl as  m a   will  b e  h ar v est e d  a n d  a n al y z e d f or t h e 
q u a ntifi c ati o n  of  p e xi d arti ni b  usi n g  a  v ali d at e d li q ui d 
c hr o  m at o gr a p h y -t a n d e  m   m ass s p e ctr o  m etr y   m et h o d.  
Z  A  A  D -1 0 0 6 a   will  b e  a n al y z e d  usi n g  a  q u alifi e d li q ui d 
c hr o  m at o gr a p h y -t a n d e  m   m ass s p e ctr o  m etr y  ass a y.   
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  7  
A  c o  m pl et e  p  h ysi c al  e x a  mi n ati o n   will  b e  p erf or  m e d  at 
S cr e e ni n g,   C h e c k -i n,  a n d   C h e c k-o ut  or  E a rl y  T er  mi n ati o n 
( E T). 
Cli ni c al  c h e  mistr y  p a n el,  h e  m at ol o g y,  uri n al ysis,  a n d 
c o a g ul ati o n t ests   will  b e  p erf or  m e d  at  S cr e e ni n g,   C h e c k -i n, 
at  4 8  h  a n d  1 2 0  h  p ost  d os e , a n d  at   C h e c k -o ut  or  E T . 
Si n gl e  1 2 -l e a d  el e ctr o c ar di o gr a  ms ( E  C  Gs) a n d  vit al si g ns 
will  b e  p erf or  m e d  at  S cr e e ni n g,   C h e c k  -i n,   D a y 1  ( pr e d os e 
[ at l e ast  6 0 mi n  pri or t o  p e xi d arti ni b  d osi n g],   a n d  at  1,  2,  3 
a n d  4  h  p ost  d os e),  at   C h e c k -o ut  or  E T . 
A d v ers e  e v e nts   (  A Es) a n d  pri or/ c o n c o  mit a nt   m e di c ati o ns 
will  b e   m o nit or e d  a n d r e c  or d e d t hr o u g h o ut t h e st u d y.    
St u d y   D ur ati o n:  
S cr e e ni n g  will   o c c ur   wit hi n  2 1  d  of   C h e c k -i n (  D a y -2)  at 
t h e  cli ni c.  T h e  d ur ati o n  of t h e st u d y f or  e a c h i n di vi d u al 
s u bj e ct   will  b e  a p pr o xi  m at el y  5  w e e ks   (  w k) fr o  m t h e st art 
of  S cr e e ni n g (  wit hi n  2 1  d  of  d osi n g) t hr o u g h t h e  E n d -of -
St u d y .   
St u d y  Sit e s a n d  L o c ati o n s:   
T h e st u d y   will  b e  c o n d u ct e d  at  u p t o  3 sit es.   
S u bj e ct  Eli gi bilit y   Crit eri a:    
S cr e e ni n g:   M al e  a n d f e  m al e s u bj e cts,  1 8  y t o  7 5  y  of  a g e, 
i n cl usi v e,   wit h b o d y   m ass i n d e x (  B  MI)  1 8  k g/  m 2 t o  4 0 
k g/  m 2, i n cl usi v e at  S cr e e ni n g .   
S u bj e cts   wit h   HI  ar e r e q uir e d t o  h a v e:   
    D o c u  m e nt e d  hist or y  of  c hr o ni c li v er  dis e as e 
di a g n os e d  b y  ultr as o n o gr a p h y,  c o  m p ut e d 
t o  m o gr a p h y s c a n, li v er  bi o ps y,  or   m a g n eti c 
r es o n a n c e i  m a gi n g  or  hist or y  of  c hr o ni c 
( > 6 m o nt hs  )  h e p atitis   B  vir us  or  h e p atitis C 
vir us i nf e cti o n . 
    M  o d er at e   HI  as  ass ess e d  b y  t h e   N ati o n al   C a n c er 
I nstit ut e-Or g a n   D ysf u n cti o n   W or ki n g   Gr o u p 
(N  CI  -O  D  W  G  ) crit eri a  (t ot al  bilir u bi n [T  B I L] 
> 1. 5  t o 3 x  u p p er li  mit  of  n or  m al [ U L  N  ]) n ot  d u e 
t o   Gil b ert’s s y n dr o  m e.   
    N or  m al  or  n o n cli ni c all y   r el e v a nt fi n di n gs  at 
p h ysi c al  e x a  mi n ati o n  a n d  n or  m al li  mits  or 
n o n cli ni c all y  r el e v a nt d e vi ati o ns i n  cli ni c al 
l a b or at or y  e v al u ati o ns,   wit h  e x c e pti o n  of 
fi n di n gs t h at i n t h e  o pi ni o n  of in v esti g at or  ar e 
c o nsist e nt   wit h s u bj e ct’s   HI . 
    Cli ni c al st a bilit y i n t h e  o pi ni o n  of t h e 
in v esti g at or . 
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  8  
    F e  m al e s u bj e cts  (b ot h,  h e alt h y  a n d  HI   s u bj e cts) 
w h o  ar e  of  n o n  -c hil d b e ari n g  p ot e nti al   m ust  b e:  
    S ur gi c all y st eril e (i e,  bil at er al t u b al li g ati o n 
or r e  m o v al  of  b ot h  o v ari es  a n d/ or  ut er us  at 
l e ast  6   m o pri or t o  d osi n g,  or  Ess ur e ®  wit h 
h yst er os al pi n g o gr a  m [ d o c u  m e nt ati o n t o 
c o nfir  m t u b al  o c cl usi o n  1 2   w k  aft er 
pr o c e d ur e]).  
    N at ur all y  p ost  m e n o p a us al (s p o nt a n e o us 
c ess ati o n  of   m e ns es) f or  at l e ast 
1 2  c o ns e c uti v e   m o  pri or t o  d osi n g, 
c o nfir  m e d  b y f olli cl e sti  m ul a ti n g  h or  m o n e 
( F S  H) or  estr a di ol  t esti n g. 
    F e  m al e s u bj e cts  ( b ot h,  h e alt h y  a n d HI   s u bj e cts) 
w h o  ar e  of  c hil d b e ari n g  p ot e nti al   m ust  a gr e e t o 
b arri er   m et h o d  of  c o ntr a c e pti v e t h er a p y  or 
r efr ai n fr o  m s e x u al i nt er c o urs e t o  pr e v e nt 
pr e g n a n c y  u ntil  1   m o  p ost  d os e.   If t h e s u bj e ct is 
o n  or al  c o ntr a c e pti v e, t h e s u bj e ct  n e e ds t o  us e 
t h e  b arri er   m et h o d i n  a d diti o n t o  or al 
c o ntr a c e pti v e.  F e  m al e s u bj e cts   m ust r efr ai n 
fr o  m  br e astf e e di n g f or  at l e ast  2   w e e ks p ost 
d os e .   
    M al e s u bj e cts   ( b ot h,  h e alt h y  a n d HI   s u bj e cts) 
m ust s ur  gi c all y st eril e  or  a gr e e t o  us e  d o u bl e 
b arri er   m et h o ds  of  c o ntr a c e pti o n fr o  m   C h e c k -i n 
u ntil  1   m o  aft er t h e  d os e  of  p e xi d arti ni b.    Als o, 
m al e s u bj e cts   m ust  n ot  d o n  at e s p er  m fr o  m 
C h e c k  -i n  u ntil 1   m o  aft er  p e xi d arti ni b  
a d  mi nistr ati o n.    
D os a g e  F or  m,   D os e,   a n d   R o ut e 
of   A d  mi nistr ati o n:  
P e xi d arti ni b  1    2 0 0 -m g  c a ps ul e   will  b e  a d  mi nist er e d 
or all y  o n   D a y  1  wit h  2 4 0   m L  of   w at er, f oll o  wi n g  a n 
o v er ni g ht f ast  of  at l e ast  1 0  h.  
St u d y  E n d p oi nts:  
P h a r  m a c o ki n eti c   E n d p oi nt s   
    P e xi d arti ni b:  C  m a x  ,  T  m a x, A  U  Cl ast  , A  U  Ci nf,   
k el, t 1/ 2,   C L/ F,   V z/ F  a n d  d e gr e e  of  pl as  m a 
pr ot ei n  bi n di n g .  
    T h e f oll o  wi n g  P  K  p ar a  m et ers  of  Z  A  A  D -1 0 0 6 a 
will  b e  c al c ul at e d:   C  m a x,   T  m a x,  A  U  Cl ast, 
A  U  Ci nf,   t 1/ 2,  d e gr e e  of  pl as  m a  pr ot ei n  bi n di n g 
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  9  
a n d   m et a b olit e t o  p ar e nt r ati o (  M P  R) f or 
A  U  Cl ast  a n d   A  U  Ci nf.    
S af et y   E n d p oi nts  
P e xi d arti ni b s af et y  a n d t ol er a bilit y   will  b e  ass ess e d  b y:  
    A  E s 
    Vit al si g ns   
    1 2 -l e a d E  C  Gs  
    Cli ni c al l a b or at or y   t ests 
Pl a n n e d  S a  m pl e  Si z e:    
Si xt e e n  s u bj e cts   will  b e  e nr oll e d;  8  will  h a v e   m o d er at e   HI   
a n d  8  will  b e  h e alt h y s u bj e cts   wit h  n or  m al  h e p ati c f u n cti o n   
w h o  ar e  gr o u p   m at c h e d t o s u bj e cts i n t h e   HI  gr o u p   b y  a g e, 
s e x,  a n d b o d y   w ei g ht .   
St atisti c al   A n al ys es:  
P h a r  m a c o ki n eti cs : 
D es cri pti v e st atisti cs   b y  p o p ul ati o n (  m o d er at e   HI  a n d 
h e alt h y s u bj e cts   wit h  n or  m al  h e p ati c f u n cti o n)  wi  ll  b e 
pr es e nt e d f or  p e xi d arti ni b  a n d  Z  A A  D  -1 0 0 6 a  pl as  m a 
c o n c e ntr ati o ns  at  e a c h ti  m e  p oi nt  a n d f or  all  P  K  p ar a  m et ers 
of  p e xi d arti ni b  a n d  Z  A  A  D -1 0 0 6 a  f or  b ot h t ot al a n d 
u n b o u n d  pl as  m a  c o n c e ntr ati o ns .  
C  m a x,   A  U  Cl ast,  a n d   A  U  Ci nf  of   p e xi d arti ni b  ( b as e d  o n 
t ot al  a n d  u n b o u n d c o n c e ntr ati o ns)  will  b e  c o  m p ar e d 
b et  w e e n  s u bj e cts i n t h e HI   gr o u p  a n d  s u bj e cts i n t h e 
m at c h e d  c o ntr ol  gr o u p   wit h   n or  m al  h e p ati c f u n cti o n .  
T h es e  c o  m p aris o ns   will  b e   m a d e  usi n g  a n  a n al ysis  of 
v ari a n c e   m o d el.  T h e r es ulti n g  p oi nt  e sti  m at es ( g e o  m etri c 
l e ast s q u ar es   m e a ns), t h eir r ati os (  HI/ n or  m al  h e p ati c 
f u n cti o n),  a n d  90 %  c o nfi d e n c e i nt er v als   (  CIs) f or t h e r ati os 
will  b e  pr es e nt e d.   
S af et y:  
T h e  n u  m b er  a n d  p er c e nt a g e  of s u bj e cts r e p orti n g 
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) will  b e 
t a b ul at e d  b y   M e di c al   Di cti o n ar y f or   R e g ul at or y   A cti viti es 
(  M e d  D  R  A) s yst e  m  or g a n  cl ass  a n d  pr ef err e d t er  m , f or  e a c h 
gr o u p  a n d t h e  o v er all st u d y .  E  C  G  i nt er v al   m e as ur e  m e nts 
a n d  ot h er s af et y  e n d p oi nt s   will  b e s u  m  m ari z e d  usi n g 
d es cri pti v e st atisti cs   w h e n  a p pr o pri at e.    
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  1 0  
T  A  B  L  E   O F   C  O  N  T  E  N  T S   
I  N  V E S TI  G  A T  O  R   A  G  R E E  M EN T  ...................................................................................................2  
P  R  O T  O  C  O L  S  Y  N  O P SI S  ................................................................................................................5  
LI S T   O F  A  B  B  R E  VI  A TI  O  N S   ........................................................................................................1 7  
1.  
I  N T  R  O  D  U  C TI  O  N ...........................................................................................................2 0  
1. 1.  
B a c k gr o u n d   ......................................................................................................................2 0  
1. 2.  
D at a  S u  m  m ar y   .................................................................................................................2 1  
1. 2. 1.  
O v er vi e  w   of   Bi o p h ar  m a c e uti cs  .......................................................................................2 1  
1. 2. 2.  
O v er vi e  w  of   Cli ni c al  P h ar  m a c ol o g y   ...............................................................................2 1  
1. 2. 3.  
Cli ni c al  E x p eri e n c e   .........................................................................................................2 2  
1. 3.  
St u d y   R ati o n al e  ...............................................................................................................2 2  
1. 4.  
Ris ks  a  n d   B e n efits f or  St u d y  S u bj e cts  .............................................................................2 3  
2.  
S T  U  D  Y   O  BJ E  C TI  V E S   A  N  D  H  Y P  O T  H E SI S   ................................................................2 4  
2. 1.  
St u d y   O bj e cti v es  ..............................................................................................................2 4  
2. 1. 1.  
Pri  m a r y   O bj e cti v e ............................................................................................................2 4  
2. 1. 2.  
S e c o n d ar y   O bj e cti v es  ......................................................................................................2 4  
2. 2.  
St u d y   H y p ot h esis  .............................................................................................................2 4  
2. 3.  
St u d y  E n d p oi nts  ...............................................................................................................2 4  
2. 3. 1.  
Pri  m a r y  E n d p oi nts ...........................................................................................................2 4  
2. 3. 2.  
S e c o n d ar y  E n d p oi nts  .......................................................................................................2 5  
2. 3. 3.  
E x pl or at or y  E n d p oi nt  ......................................................................................................2 5  
3.  
S T  U D  Y   D E SI  G  N   ............................................................................................................2 6  
3. 1.  
O v er all   D esi g n   .................................................................................................................2 6  
3. 1. 1.  
O v er vi e  w   .........................................................................................................................2 6  
3. 1. 2.  
D os e  Es c al a  ti o n  Pr o c ess ..................................................................................................2 6  
3. 1. 3.  
St u d y  St o p pi n g   Crit eri a  ...................................................................................................2 7  
3. 2.  
Dis c ussi o n  of  St u d y   D esi g n   .............................................................................................2 7  
4.  
S T  U  D  Y  P  O P  U L  A TI  O  N  ..................................................................................................2 8  
4. 1.  
I n cl usi o n   Crit eri a .............................................................................................................2 8  
4. 2.  
E x cl usi o n   Crit eri a  ............................................................................................................2 9  
5.  
S T  U  D  Y  T  R E  A T  M E  N T S  ................................................................................................3 1  
5. 1.  
Assi g ni n g  S u bj e cts t o  Tr e at  m e nt   Gr o u ps/ S e q u e n c es  a n d   Bli n di n g   ................................3 1  
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  1 1  
5. 1. 1.  
Tr e at  m e nt   Gr o u ps/ S e q u e n c es  ..........................................................................................3 1  
5. 1. 2.  
M et h o d  of  Tr e  at  m e nt   All o c ati o n  .....................................................................................3 1  
5. 1. 3.  
Bli n di n g   ...........................................................................................................................3 1  
5. 1. 4.  
E  m er g e n c y   U n bli n di n g  Pr o c e d ur e  ..................................................................................3 1  
5. 2.  
St u d y   Dr u g  .......................................................................................................................3 1  
5. 2. 1.  
D es cri pti o n   ......................................................................................................................3 1  
5. 2. 2.  
L a b eli n g  a n d  P a c k a gi n g  ..................................................................................................3 1  
5. 2. 3.  
Pr e p ar ati o n  .......................................................................................................................3 1  
5. 2. 4.  
A d  mi nis  tr ati o n .................................................................................................................3 1  
5. 2. 5.  
St or a g e  .............................................................................................................................3 2  
5. 2. 6.  
Dr u g   A c c o u nt a bilit y   ........................................................................................................3 2  
5. 2. 7.  
R et e nti o n  S a  m pl es   ...........................................................................................................3 3  
5. 3.  
C o ntr ol  Tr e at  m e nt   ...........................................................................................................3 3  
5. 4.  
D os e I nt err u pti o ns  a n d   R e d u cti o ns   .................................................................................3 3  
5. 5.  
M et h o d  of   Ass essi n g  Tr e at  m e nt   C o  m pli a n c e   ..................................................................3 3  
5. 6.  
Pri or  a n d   C o n c o  mit a nt   M e di c ati o ns  ................................................................................3 3  
5. 6. 1.  
Di et ar y  a n d  Lif est yl e   R estri cti o ns   ...................................................................................3 4  
5. 7.  
S u bj e ct   Wit h dr a  w al/  Dis c o nti n u ati o n  ...............................................................................3 5  
5. 7. 1.  
R e as o ns f or   Wit h dr a  w al   ..................................................................................................3 5  
5. 7. 2.  
Wit h dr a  w al  Pr o c e d ur es   ...................................................................................................3 5  
5. 7. 3.  
S u bj e ct   R e pl a c e  m e nt  .......................................................................................................3 5  
5. 7. 4.  
S u bj e ct   R e -t esti n g  Pr o c e d ur es .........................................................................................3 5  
5. 8.  
Crit eri a f or  S us p e n di n g  St u d y  Tr e at  m e nt   ........................................................................3 5  
6.  
S T  U  D  Y  P  R  O  C E  D  U  R E S  .................................................................................................3 6  
6. 1.  
S cr e e ni n g  .........................................................................................................................3 6  
6. 2.  
S u bj e ct   M a n a g e  m e nt  .......................................................................................................3 6  
6. 3.  
R a n d o  mi z ati o n   .................................................................................................................3 7  
6. 4.  
Tr e at  m e nt  P eri o d  .............................................................................................................3 7  
6. 4. 1.  
C h e c k  -i n ..........................................................................................................................3 7  
6. 4. 2.  
Tr e at  m e nt  P h as e  ..............................................................................................................3 8  
6. 4. 2. 1.  D a y  1   D osi n g   ...................................................................................................................3 8  
6. 4. 2. 2.  D a y  2 t hr o u g h   D a y  4   .......................................................................................................3 8  
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  1 2  
6. 4. 2. 3.  D a y  5 t hr o u g h   D a y  7   .......................................................................................................3 8  
6. 5.  
W as h o ut   ...........................................................................................................................3 9  
6. 6.  
C h e c k  -o ut  or  E arl y  T er  mi n ati o n  ......................................................................................3 9  
6. 7.  
F oll o  w -u p  ........................................................................................................................3 9  
7.  
P  H  A  R  M  A  C  O  KI  N E TI  C / P  H  A  R  M  A  C  O  D  Y  N  A  MI  C   A S SE S S  M E  N T S  ...........................4 0  
7. 1.  
P h ar  m a c o ki n eti c   Ass ess  m e nts  .........................................................................................4 0  
7. 2.  
P h ar  m a c o d y n a  mi c   Ass ess  m e nts  ......................................................................................4 0  
7. 3.  
I  m  m u n o g e ni cit y ...............................................................................................................4 0  
8.  
S  A F E T  Y  E  V  A L  U  A TI  O  N   A  N D   R E P  O  R TI  N  G   ..............................................................4 1  
8. 1.  
Ass ess  m e nt  of  S af et y  E n d p oi nt  E v e nts   ...........................................................................4 1  
8. 2.  
A d v ers e  E v e nt   C oll e cti o n  a n d   R e p orti n g   ........................................................................4 1  
8. 3.  
A d v ers e  E v e nts  of  S p e ci al I nt er est   ..................................................................................4 2  
8. 4.  
A d v ers e  E v e nt   .................................................................................................................4 2  
8. 4. 1.  
D efi nit  i o n  of   A d v ers e  E v e nt ............................................................................................4 2  
8. 4. 2.  
S eri o us   A d v ers e  E v e nt  ....................................................................................................4 2  
8. 4. 3.  
S e v erit y   Ass ess  m e nt  ........................................................................................................4 3  
8. 4. 4.  
C a us alit y   Ass ess  m e nt   ......................................................................................................4 3  
8. 4. 5.  
A cti o n  T a k e n f or  E v e nt   ...................................................................................................4 4  
8. 4. 6.  
A d v ers e  E v e nt   O ut c o  m e   ..................................................................................................4 4  
8. 5.  
S eri o us   A d v ers e  E v e nts   R e p orti n g  –  Pr o c e d ur e  F or I n v esti g at ors  .................................4 4  
8. 6.  
N otif yi n g   R e g ul at or y   A ut h oriti es, I n v esti g at ors,  a n d I nstit uti o n al   R e vi e  w   B o ar d   .........4 5  
8. 7.  
E x p os ur e i n   Ut er o   D uri n g   Cli ni c al  St u di es  .....................................................................4 5  
8. 8.  
Cli ni c al  L a b or at or y  E v al u ati o ns   ......................................................................................4 6  
8. 9.  
Vit al  Si g ns   .......................................................................................................................4 6  
8. 1 0.  
El e ctr o c ar di o gr a  ms  ..........................................................................................................4 7  
8. 1 1.  
P h ysi c al  E x a  mi n ati o ns  .....................................................................................................4 7  
8. 1 2.  
Dr u g  a n d   Al c o h ol  S cr e e n   ................................................................................................4 7  
8. 1 3 . 
Pr e g n a n c y  T est  ................................................................................................................4 7  
8. 1 4.  
S er u  m  F S  H  ......................................................................................................................4 7  
8. 1 5.  
Ot h er  E x a  mi n ati o ns   .........................................................................................................4 7  
9.  
O T  H E  R   A S S E S S  M E  N T S   ...............................................................................................4 9  
1 0.  
S T  A TI S TI  C  A L   M E T  H  O  D S  ...........................................................................................5 0  
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  1 3  
1 0. 1.  
G e n er al  St atisti c al   C o nsi d er ati o ns   ...................................................................................5 0  
1 0. 2.  
A n al ysis  S ets   ...................................................................................................................5 0  
1 0. 2. 1.  P h ar  m a c o ki n eti c   A n al ysis  S et  .........................................................................................5 0  
1 0. 2. 2.  S af et y   A n al ysis  S et  ..........................................................................................................5 0  
1 0. 3.  
St u d y  P o p ul ati o n   D at a  .....................................................................................................5 0  
1 0. 4.  
St atisti c al   A n al ysis  ..........................................................................................................5 1  
1 0. 4. 1 . P h ar  m a c o ki n eti c   A n al ys es  ...............................................................................................5 1  
1 0. 4. 2.  P h ar  m a c o d y n a  mi c   A n al ys es  ............................................................................................5 1  
1 0. 4. 3.  P h ar  m a c o g e n o  mi c   A n al ys es  ............................................................................................5 1  
1 0. 4. 4.  S af et y   A n al ys es  ...............................................................................................................5 1  
1 0. 4. 4. 1.  A d v ers e  E v e nt   A n al ys es   ..................................................................................................5 1  
1 0. 4. 4. 2.  Cli ni c al  L a b or at or y  E v al u ati o n   A n al ys es   ........................................................................5 2  
1 0. 4. 4. 3.  Vit al  Si g n   A n al ys es   .........................................................................................................5 2  
1 0. 4 . 4. 4. El e ctr o c ar di o gr a  m   A n al ys es  ............................................................................................5 2  
1 0. 4. 4. 5.  P h ysi c al  E x a  mi n ati o n   A n al ys es  ......................................................................................5 2  
1 0. 4. 4. 6.  E x pl or at or y  S af et y   A n al ys es  ...........................................................................................5 3  
1 0. 4. 4. 7.  Ot h er  S af et y   A n al ys es   .....................................................................................................5 3  
1 0 . 5. 
S a  m pl e  Si z e   D et er  mi n ati o n  .............................................................................................5 3  
1 0. 6.  
St atisti c al   A n al ysis  Pr o c ess  .............................................................................................5 3  
1 1.  
D  A T  A I  N T E  G  RI T  Y   A  N  D   Q  U  A LI T  Y   A S S  U  R  A  N  C E   ..................................................5 4  
1 1. 1.  
M o nit ori n g  a n d I ns p e cti o ns   .............................................................................................5 4  
1 1. 2.  
D at a   C oll e cti o n   ................................................................................................................5 4  
1 1. 3.  
D at a   M a n a g e  m e nt   ............................................................................................................5 5  
1 1. 4.  
St u d y  D o c u  m e nt ati o n  a n d  St or a g e   ..................................................................................5 5  
1 1. 5.  
R e c or d   K e e pi n g   ...............................................................................................................5 6  
1 2.  
FI  N  A  N  CI  N  G   A  N  D I  N S  U  R  A N  C E   ..................................................................................5 7  
1 2. 1.  
Fi n a n c es  ...........................................................................................................................5 7  
1 2. 2.  
R ei  m b urs e  m e nt, I n d e  m nit y,  a n d I ns ur a n c e   .....................................................................5 7  
1 3.  
P  U  B LI  C  A TI  O  N  P  O LI  C  Y  ...............................................................................................5 8  
1 4.  
E T  HI C S  A  N  D  S T  U  D  Y   A  D  MI  NI S T  R  A TI  V E I  N F  O  R  M  A TI  O  N   ...................................5 9  
1 4. 1.  
C o  m pli a n c e  St at e  m e nt,  Et hi cs  a n d   R e g ul at or y   C o  m pli a n c e   ...........................................5 9  
1 4. 2.  
S u bj e ct   C o nfi d e nti alit y  ....................................................................................................5 9  
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  1 4  
1 4. 3 . 
I nf or  m e d   C o ns e nt ............................................................................................................5 9  
1 4. 4.  
R e g ul at or y   C o  m pli a n c e   ...................................................................................................6 0  
1 4. 5.  
Pr ot o c ol   D e vi ati o ns  .........................................................................................................6 1  
1 4. 6.  
S u p pl y  of   N e  w I nf or  m ati o n   Aff e cti n g t h e   C o n d u ct  of t h e  St u d y  ...................................6 1  
1 4. 7.  
Pr ot o c ol   A  m e n d  m e nts  .....................................................................................................6 2  
1 4. 8.  
St u d y  T er  mi n ati o n  ...........................................................................................................6 2  
1 4. 9.  
D at a   a n d  S af et y   M o nit ori n g   B o ar d  ..................................................................................6 2  
1 4. 1 0.  
A d dr ess  List   .....................................................................................................................6 2  
1 4. 1 0. 1.  S p o ns or’s   Cli ni c al  St u d y  L e a d er  .....................................................................................6 2  
1 4. 1 0. 2.  S p o ns or’s   Cli ni c al  St u d y  M a n a g er   ..................................................................................6 2  
1 4. 1 0. 3.  S p o ns or’s  P h ar  m a c o ki n eti cs   R e vi e  w er  ...........................................................................6 3  
1 4. 1 0. 4.  S p o ns or’s   M e di c al  M o nit or   .............................................................................................6 3  
1 4. 1 0. 5.  S p o ns or’s  S af et y   C o nt a cts  ...............................................................................................6 3  
1 4. 1 0. 6.  E  D  C   V e n d or  ....................................................................................................................6 3  
1 4. 1 0. 7.  Bi o a n al yti c al   V e n d or   .......................................................................................................6 3  
1 4. 1 0. 8.  C e ntr al  L a b or at or y   ...........................................................................................................6 4  
1 4. 1 0. 9.  S p o ns or’s   Bi ost atisti ci a n  .................................................................................................6 4  
1 4. 1 0. 1 0.  D at a  a n d  S af et y   M o nit ori n g   B o ar d   .............................................................................6 4  
1 4. 1 0. 1 1.  C  R  O   ............................................................................................................................6 4  
1 4. 1 0. 1 1. 1.  C  R  O I n v e  sti g at or  ........................................................................................................6 4  
1 4. 1 0. 1 1. 2.  C  R  O  Pr oj e ct   M a n a g er   .................................................................................................6 4  
1 5.  
R E F E  R E  N  C E S   ................................................................................................................6 6  
1 6.  
A P P E  N  DI C E S   .................................................................................................................6 7  
1 6. 1.  
L a b eli n g  a n d  P a c k a gi n g  ..................................................................................................6 7  
1 6. 2.  
Bl o o d   C oll e cti o n   V ol u  m e  b y   C at e g or y  a n d  T ot al   ...........................................................6 7  
1 6. 2. 1.  Bl o o d   C oll e cti o n   V ol u  m es   ..............................................................................................6 7  
1 6. 3.  
A d diti o n al I nf or  m ati o n (f or J a  p a n es e  St u d y  Sit es   O nl y)  ................................................6 7  
1 6. 3. 1.  G  C P  c o  m pli a n c e   ..............................................................................................................6 7  
1 6. 3. 2.  St u d y  P eri o d  ....................................................................................................................6 8  
1 6. 3. 3.  P a y  m e nt f or  P arti ci p ati o n,   C o  m p e ns ati o n f or  St u d y -R el at e d I nj uri es,  a n d 
I ns ur a n c e ..........................................................................................................................6 8  
1 6. 3. 4.  St u d y   A d  mi nistr ati v e  Str u ct ur e  .......................................................................................6 8  
1 6. 4.  
I nstr u cti o ns f or  S p e ci  m e n   C oll e cti o n,  St or a g e  a n d  S hi p  m e nt .........................................6 8  
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  1 5  
1 6. 4. 1.  Pl as  m a  P h ar  m a c o ki n eti c  S a  m pl e   C oll e cti o n,  St or a g e  a n d  S hi p  m e nt I nstr u cti o ns  ..........6 8  
1 6. 5.  
S c h e d ul e  of  E v e nts  ..........................................................................................................7 2  
1 6. 5. 1.  S c h e d ul e  of  E v e nts  ..........................................................................................................7 2  
1 6. 6.  
I n d u c ers  a n d I n hi bit ors  of   Dr u g   M et a b oli zi n g  E n z y  m es ................................................7 5  
 
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  1 6  
LI  S  T   O F  FI  G  U  R  E S  
Fi g ur e  3. 1:  O v er vi e  w  of st u d y  d esi g n   ...........................................................................................2 6  
 
 
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  1 7  
LI S  T   O F   A  B  B  R  E  VI  A  TI  O  N  S  
A  B  B  R  E  VI  A  TI  O  N     
D  E FI  NI  TI  O  N   
A E   
a d v ers e  e v e nt  
A L T   
al a ni n e  a  mi n otr a nsf er as e  
A S T   
as p art at e  a  mi n otr a nsf er as e  
A  U  C   
ar e a  u n d er t h e  c o n c e ntr ati o n -ti  m e  c ur v e 
A  U  Ci nf    
ar e a  u n d er t h e  c o n c e ntr ati o n -ti  m e  c ur v e  u p t o i nfi nit y 
A  U  Cl ast   
ar e a  u n d er t h e  c o n c e ntr ati o n -ti  m e  c ur v e  u p t o t h e l ast   m e as ur a bl e 
ti  m e  p oi nt 
B  MI   
b o d y   m ass i n d e x  
CI   
c o nfi d e n c e i nt er v al  
C L/ F   
t ot al  a p p ar e nt  cl e ar a n c e 
C  m a x    
m a xi  m u  m  c o n c e ntr ati o n   
C  R  O   
C o ntr a ct   R es e ar c h   Or g a ni z ati o n   
C S F  -1  
c ol o n y sti  m ul ati n g f a ct or -1  
C S F 1  R   
r e c e pt or  of   C S F-1  a n d i nt erl e u ki n  3 4  
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  
d  
d a y(s)  
D  B P   
di ast oli c  bl o o d  pr ess ur e  
D SI   
D aii c hi  S a n k y o, I n c.   
E  C  G  
el e ctr o c ar di o gr a  m  
e  C  R F  
e l e ctr o ni c   C as e   R e p ort  F or  m 
E  D  C  
el e ctr o ni c  d at a  c a pt ur e  
EI  U  
e x p os ur e i n  ut er o  
E o S  
E n d  of  St u d y  
E T  
E arl y  T er  mi n ati o n  
F  D  A  
F o o d  a n d   Dr u g   A d  mi nistr ati o n  
F S  H  
f olli cl e-sti  m ul ati n g  h or  m o n e  
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  
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  1 8  
A  B  B  R  E  VI  A  TI  O  N     
D  E FI  NI  TI  O  N   
h  
h o ur(s)  
H  A  V   
h e p atitis   A  vir us  
H  Bs  A g   
h e p atitis   B s urf a c e  a nti g e n    
H  B  V   
h e p atitis   B  vir us  
H  C  V   
h e p atitis   C  vir us    
HI   
h e p ati c i  m p air  m e nt  
HI  V   
h u  m a n i  m  m u n o d efi ci e n c y  vir us  
I  B 
I n v esti g at or’s   Br o c h ur e  
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 nis ati o n  of  T e c h ni c al   R e q uir e  m e nts 
f or  P h ar  m a c e uti c als f or   H u  m a n   Us e 
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  R 
I nt er n ati o n al   N or  m ali z e d   R ati o 
I  R  B 
I nstit uti o n al   R e vi e  w   B o ar d 
k el  
Eli  mi n ati o n r at e  c o nst a nt  
M e d  D  R  A   
M e di c al   Di cti o n ar y f or   R e g ul at or y   A cti viti es   
mi n   
mi n ut e(s)   
m o   
m o nt h(s)   
M P  R   
m et a b olit e t o  p ar e nt r ati o   aft er  a dj usti n g f or   m ol e c ul ar   w ei g ht  
ms   
millis e c o n d(s)   
N  CI  -O  D  W  G     
N ati o n al   C a n c er I nstit ut e   Or g a n   D ysf u n cti o n   W or ki n g   Gr o u p   
N  D  A   
N e  w   Dr u g   A p pli c ati o n   
O T  C   
o v er -t h e-c o u nt er  
P  K  
p h ar  m a c o ki n eti c  
P T  
pr ot hr o  m bi n ti  m e  
Q T c  B   
Q T i nt er v al  c orr e ct e d f or  h e art r at e  usi n g   B a z ett’s f or  m ul a   
Q T c F   
Q T i nt er v al  c orr e ct e d f or  h e art r at e  usi n g  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  A  V E  R  
S eri o us   A d v ers e  E v e nt   R e p ort  
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  1 9  
A  B  B  R  E  VI  A  TI  O  N     
D  E FI  NI  TI  O  N   
S  B P  
s yst oli c  bl o o d  pr ess ur e  
S  O  C  
s yst e  m  or g a n  cl ass  
S  U S  A  R  
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 n   
t 1/ 2 
t er  mi n al  eli  mi n ati o n  h alf-lif e 
T  BI L  
t ot al  bilir u bi n 
T E  A E  
tr e at  m e nt-e  m er g e nt  a d v ers e  e v e nt  
T  G  C T  
t e n os y n o vi al  gi a nt  c ell t u  m or 
U  G T   
uri di n e  5' -di p h os p h o -gl u c ur o n os yltr a nsf er as e  
U L  N   
U p p er li  mit  of  n or  m al   
U S   
U nit e d  St at es   
V z/ F   
v ol u  m e  of  distri b uti o n i n t h e t er  mi n al  p h as e  
W  H  O   
W orl d   H e alt h   Or g a ni z ati o n   
w k   
w e e k(s)   
y  
y e ar(s)  
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  2 0  
1.    
I  N  T  R  O  D  U  C  TI  O  N 
1. 1.    
B a c k g r o u n d   
P e xi d arti ni b is  a  n o v el,  or all y  a d  mi nist er e d, s  m all -m ol e c ul e   t yr osi n e  ki n as e i n hi bit or t h at t ar g ets 
t h e r e c e pt or f or  c ol o n y sti  m ul ati n g f a ct or-1 (  C S F -1)  a n d i nt erl e u ki n  3 4 (  C S F 1  R),   Kit (t h e 
r e c e pt or f or st e  m  c ell f a ct or),  a n d  o n c o g e ni c  Flt 3 (t h e r e c e pt or for  Flt 3 li g a n d),  b ut it r e  m ai ns 
hi g hl y s el e cti v e  c o  m p ar e d t o  ot h er t yr osi n e  ki n as e i n hi bit ors.   T h e  p ot e nt i n hi biti o n  of t h es e 
ki n as es  c a n  b e  e x pl oit e d t o  att a c k t u  m ors  vi a  diff er e nt   m e c h a nis  ms:  1)  dir e ctl y i n hi biti n g 
o n c o g e ni c  dri v ers, s u c h  as  o n c o g e ni c   K it  a n d  Flt 3   m ut a nt  pr ot ei ns,  2) i n hi biti n g  p ar a cri n e l o o ps 
b et  w e e n str o  m al  c ells  a n d t u  m ors,  3)  bl o c ki n g   mi gr ati o n  a n d  a n gi o g e n esis,  a n d  4)  disr u pti n g 
ost e ol yti c   m et ast as es. 1  C S F  -1  a n d its r e c e pt or   C S F 1  R  h a v e  b e e n s h o  w n t o  pl a y  a r ol e i n  a r ar e 
c o n n e cti v e tiss u e  n e o pl asi a  k n o  w n  as  pi g  m e nt e d  vill o n o d ul ar s y n o vitis,   m or e r e c e ntl y t er  m e d 
t e n os y n o vi al  gi a nt  c ell t u  m or ( T  G  C T).2  T his  dis e as e is  g e n er all y  c h ar a ct eri z e d  b y 
h y p ers e cr eti o n  of   C S F -1  as  a r es ult  of tr a nsl o c ati o ns   wit hi n s y n o vi al  c ells li n ki n g t h e   C S F -1  a n d 
t h e  c oll a g e n   C  O L 6  A 3  g e n es.   T h e r es ulti n g t u  m or  c ells  o v er e x pr ess   C S F-1,   w hi c h l e a ds t o t h e 
r e cr uit  m e nt  of   C S F 1  R-e x pr essi n g   m o n o c yt es  a n d   m a cr o p h a g es.  I n d e e d, t h e  pi g  m e nt t h at 
c h ar a ct eri z es t h e t u  m or   m ass is  d eri v e d  pri  m aril y fr o  m  h e  m osi d eri n -l a d e n   m a cr o p h a g es.   T h e 
str o n g  g e n eti c li n k  b et  w e e n  T  G  C T  a n d   C S F -1/  C S F 1  R  pr o vi d es  a s oli d s ci e ntifi c r ati o n al e f or t h e 
us e  of  p e xi d arti ni b i n t h e tr e at  m e nt  of  T  G  C T,  as  a t h er a p y t ar g eti n g t h e  u n d erl yi n g  g e n eti c 
d ef e ct.  
As  of  3 1 J ul   2 0 1 8 ,  p e xi d arti ni b  h as  b e e n  e v al u at e d i n 2 8  c o  m p a n y -s p o ns or e d cli ni c al st u di es  i n 
h e alt h y s u bj e cts  a n d i n  p ati e nt  p o p ul ati o ns ( c a n c er  a n d  T  G  C T).  
S e v e n st u di es i n  p ati e nt  p o p ul ati o ns  h a v e  b e e n  c o  m pl et e d:  St u d y  P L  X 1 0 8 -0 3 i n  s u bj e cts wit h 
r el a ps e d  or r efr a ct or y   H o d g ki n’s l y  m p h o  m a,  St u d y  P L  X 1 0 8-0 4 i n  s u bj e cts   wit h  r e c urr e nt 
gli o bl ast o  m a   m ultif or  m e (  G  B  M),  St u d y  P L  X 1 0 8 -0 5 i n s u bj e cts   wit h r el a ps e d  or r efr a ct or y 
F L T 3 -I T  D-p ositi v e  a c ut e   m y el oi d l e u k e  mi a  (  A  M L), St u d y  P L  X 1 0 8 -0 6 i n  s u bj e cts  wit h 
a d v a n c e d   m et ast ati c  pr ost at e  c a n c er,  St u d y  P L  X 1 0 8 -0 7 i n s u bj e cts   wit h  a d v a n c e d s oli d t u  m ors 
tr e at e d   wit h  P L  X 3 3 9 7  a n d  p a clit a x el,  St u d y P L  X 1 0 8 -0 8 i n s u bj e cts   wit h  n e  wl y  di a g n os e d 
gli o bl ast o  m a,  a n d  St u d y  P L  X 1 0 8 -0 9  p e xi d arti ni b i n  c o  m bi n ati o n   wit h  v e  m ur af e ni b i n  v -R af 
m uri n e s ar c o  m a  vir al  o n c o g e n e  h o  m ol o g   B (  B  R  A F)  -m ut at e d   u nr es e ct a bl e  or   m et ast ati c 
m el a n o  m a.   T h er e   w er e   6  o n g oi n g st u di es i n  p ati e nt  p o p ul ati o ns ,  of   w hi c h 5  w er e   P h as e  1  or 
P h as e  1/ 2  st u di es ( P L  X 1 0 8 -0 1,  P L  X 1 0 8 -1 3,  P L  X 1 0 8 -1 4,  P L 3 3 9 7 -A  -A 1 0 3,   a n d  P L  X 1 2 1 -0 1)  a n d 
1  w as  a  P h as e  3 st u d y ( P L  X 1 0 8  -1 0).   A cr oss t h es e st u di es,  6 4 5   s u bj e cts   wit h  c a n c er  or  T  G  C T 
w er e tr e at e d   wit h  p e xi d arti ni b  a n d   w er e  ass ess e d f or s af et y  a n d  eff  i c a c y.   
Fift e e n  cli ni c al  p h ar  m a c ol o g y st u di es   w er e  c o  m pl et e d  or  ar e  o n g oi n g.   F o urt e e n  si n gl e-d os e 
st u di es   w er e  c o  m pl et e d i n  h e alt h y s u bj e cts, i n cl u di n g  2 st u di es i n s u bj e cts   wit h r e n al  or  h e p ati c 
i  m p air  m e nt  al o n g   wit h  h e alt h y s u bj e cts ( P L 3 3 9 7-A  -U 1 2 4  a n d   P L 3 3 9 7 -A  -U 1 2 3, r es p e cti v el y).    
I n t h e  c o  m pl et e d  cli ni c al  p h ar  m a c ol o g y st u di es, a t ot al  of  3 3 8  s u bj e cts   w er e tr e at e d   wit h 
p e xi d arti ni b.   O n e   m ulti pl e  -d os e st u d y i n s u bj e cts is  c urr e ntl y  o n g oi n g ( P L 3 3 9 7 -A  -U 1 2 6); t h es e 
s u bj e cts   w er e  n ot i n cl u d e d i n t h e t ot al  n u  m b er  of s u bj e cts tr e at e d.    
I n  a d diti o n, 6  i n v esti g at or-i niti at e d st u di es  e v al u ati n g  p e xi d arti ni b  ar e  o n g oi n g. 
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  2 1  
1. 2.    
D at a  S u  m  m a r y   
D et ail e d  n o n cli ni c al  a n d  cli ni c al i nf or  m ati o n  c a n  b e f o u n d i n t h e I n v esti g at or’s   Br o c h ur e (I  B). 1  
T h e  c urr e nt  F  D  A  a p pr o v e d  Pr es cri bi n g I nf or  m ati o n f or  p e xi d arti ni b ( T ur ali o ™) is  att a c h e d. 3    
1. 2. 1.    
O v e r vi e  w  of   Bi o p h a r  m a c e uti cs   
P e xi d arti ni b is  a d  mi nist er e d  as  a  2 0 0   m g  c a ps ul e str e n gt h   wit h   m ulti pl e  c a ps ul es  b ei n g  gi v e n t o 
a c hi e v e t h e t ar g et  d ail y  d os e  of  8 0 0   m g ( 2  ×  2 0 0   m g  c a ps ul es  t  wi c e  d ail y).   F oll o  wi n g  or al 
a d  mi nistr ati o n,  p e xi d arti ni b  e x p os ur e i n cr e as e d  d os e  pr o p orti o n all y  o v er t h e  d os e  r a n g e  of 
2 0 0  m g t o   2 4 0 0   m g .  D  u e  t o t h e r el ati v el y l ar g e f o o d  eff e ct ( d o u bli n g  of  e x p os ur e   w h e n 
a d  mi nist er e d   wit h  a  hi g h f at   m e al) ,  p e xi d arti ni b is r e c o  m  m e nd e d t o  b e t a k e n  o n  a n  e  m pt y 
st o  m a c h  at l e ast  1  h o ur  b ef or e  or  2  h o urs  aft er  a   m e al.    
C o a d  mi nistr ati o n  of  p e xi d arti ni b   wit h  a s yst e  mi c  g astri c  p  H   m o difi er,  es o  m e pr a z ol e, r es ult e d i n 
a n  a p pr o xi  m at e  5 0  %  d e cr e as e d  e x p os ur e  of  p e xi d arti ni b irr es p e cti v e  of t h e  c a ps ul e  f or  m ul ati o n 
us e d  ( St u d y  P L  X 1 0 8-1 1  a n d  St u d y  P L 3 3 9 7 -A  -U 1 2 0),   pr es u  m a bl y  d u e t o  d e cr e as e d s ol u bilit y 
l e a di n g t o r e d u c e d a bs or pti o n  of  p e xi d arti ni b   wit h  a n i n cr e as e i n  g astri c  p  H .  C o nsist e nt   wit h t h e 
d e cr e as e d  e x p os ur e  of t h e  p ar e nt,  Z  A  A  D -1 0 0 6 a  e x p os ur e   w as  als o  d e cr e as e d  b y  a p pr o xi  m at el y 
5 0  % r es ulti n g i n  a si  mil ar  m et a b olit e   t o p ar e nt  m ol ar r ati o   (  M P  R) b et  w e e n t h e tr e at  m e nts 
c o nsist e nt   wit h t h e  c o n cl usi o n  of  a  d e cr e as e i n  p e xi d arti ni b  a bs or pti o n   wit h  a n i n cr e as e i n  g a stri c 
p  H.    
O v er all, t h e   bi o p h ar  m a c e uti cs  of  p e xi d arti ni b  h a v e  b e e n   w ell  c h ar a ct eri z e d.  
F or  a d diti o n al i nf or  m ati o n  r ef er t o t h e I n v esti g at or Br o c h ur e   V er  si o n 1 0 . 0, 1 9   D E  C  2 0 1 8 .  
1. 2. 2.    
O v e r vi e  w  of   Cli ni c al  P h a r  m a c ol o g y   
A  c o  m pr e h e nsi v e s eri es  of  cli ni c al (  N = 1 4) st u di es  a n d  a n al ys es  h a v e  b  e e n  c o n d u ct e d t o  el u ci d at e 
t h e  P  K  of  p e xi d arti ni b  a n d t h e i  m p a ct  of i ntri nsi c ( e. g. r e n al f u n cti o n,  g astri c  p  H)  a n d  e xtri nsi c 
f a ct ors ( e. g. f o o d,  c o n c o  mit a nt  a d  mi nistr ati o n   wit h str o n g   C  Y P 3  A 4 i n d u c ers/i n hi bit ors,   U  G T 
i n hi bit ors,  g astri c  a ci d l o  w eri n g  a g e nts)  o n t h e  e x p os ur e  of  p e xi d arti ni b. I n  all  c as es, t h e 
n o n cli ni c al st u d y r es ults   w er e  ali g n e d   wit h  a n d s u p p ort e d t h e  cli ni c al st u d y r es ults,  a n d t h e 
i nt e gr at e d  a n al ys es   w er e  c o nsist e nt   wit h t h e i n di vi d u al st u di es.  
I n  St u d y  P L 3 3 9 7-A  -U 1 2 3,  p e xi d arti ni b  P  K   w a  s  n ot  aff e ct e d  b y   mil d  a n d   m o d er at e  h e p ati c 
i  m p air  m e nt (HI  ),  as  d efi n e d  b y   C hil d-P u g h  crit eri a,  c o  m p ar e d t o s u bj e cts   wit h  n or  m al  h e p ati c 
f u n cti o n.  T h er e   w as  h o  w e v er,  a n i n cr e as e i n  Z  A  A  D-1 0 0 6 a   A  U  C ( u p t o  a p pr o xi  m at el y  5 0  %)  a n d 
M P  R   ( u p t o a b o ut  4 0  %).   
S u bs e q u e ntl y , a d diti o n al  a n al ysis   w as  c o n d u ct e d  b y r e c at e g ori zi n g t h e   HI s u bj e cts  usi n g   N  CI -
O  D  W  G  crit eri a 4.  B a  s e d  o n t his r e c at e g ori z ati o n  o nl y  1 s u bj e ct   wit h   m o d er at e  h e p ati c 
i  m p air  m e nt   w as i d e ntifi e d. T h e r ef or e, t h e  c urr e nt st u d y  h as  b e e n  d esi g n e d. T h e   U S PI  pr o vi d es 
d osi n g  r e c o  m  m e n d ati o ns f or  p ati e nts   wit h mil d  h e p ati c i  m p air  m e nt.   
 
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  2 2  
1. 2. 3.    
Cli ni c al   E x p e ri e n c e   
T h e  p e xi d a rti ni b  cli ni c al  d e v el o p  m e nt  pr o gr a  m,  u p t o t h e   N e  w   Dr u g   A p pli c ati o n (  N  D  A)  c ut off 
d at e  of  3 1 J a n  2 0 1 8,  c o  m pris e d  2 8  c o  m pl et e d  or  o n g oi n g st u di es s p o ns or e d  b y   D aii c hi  S a n k y o, 
I n c. (  D SI),  or its s u bsi di ar y  Pl e x xi k o n I n c.   
I n   m ost  cli ni c al  p h ar  m a c ol o g y st u di es,  a si n gl e  6 0 0  m g  d os e  of  p e xi d arti ni b   w as  a d  mi nist er e d i n 
t h e f ast e d st at e  a n d r es ult e d i n   m e a n   C  m a x  a n d   A  U  C  of a p pr o xi  m at el y  6 0 0 0  n g/  m L  a n d 
1 1 0 ,0 0 0  n g• h/  m L, r es p e cti v el y ( P L 3 3 9 7 -U 1 1 7).   T h e  hi g h est  e x p os ur e  of  p e xi d arti ni b   w as 
o bs er v e d  at  1 8 0 0   m g  a d  mi nis t er e d   wit h  a  hi g h-f at   m e al (  C  m a x: 2 0 ,8 0 0  n g/  m L 
A  U  C:   4 9 1 ,9 4 8  n g• h/  m L).  I n t h e f ast e d st at e,  p e xi d arti ni b  e x p os ur e i n cr e as es   wit h  d os e i n  a n 
a p pr o xi  m at e  d os e  pr o p orti o n al   m a n n er.  I n  g e n er al,  Z  A  A  D -1 0 0 6 a   w as  pr es e nt  at  a p pr o xi  m at el y 
1 1 0  %  of  p ar e nt  e x p os ur e ( C  m a x  a n d   A  U  C)  a n d   wit h  a n  eli  mi n ati o n   t 1/ 2 si  mil ar t o t h at  of 
p e xi d arti ni b.    B as e d  o n t h e  d osi n g i nt er v al  a n d  eli  mi n ati o n  t 1/ 2 of  p e xi d arti ni b,  a c c u  m ul ati o n  of 
p ar e nt   wit h r e p e at e d  a d  mi nistr ati o n is  e x p e ct e d t o  b e  a b o ut  2 -f ol d  c o  m p ar e d t o t h e first  d os e.  
Alt h o u g h t h e fi n di n gs fr o  m st u d y  P L 3 3 9 7  -A  -U 1 2 3  d e  m o nstr at e d   mil d  a n d   m o d er at e   HI,  as 
ass ess e d  b y t h e  C hil d  -P u g h  crit eri a,  d o es  n ot  aff e ct  p e xi d arti ni b  e x p os ur e,  c o  m p ar e d t o  h e alt h y 
s u bj e cts, t h e  v ast   m aj orit y  of s u bj e cts   wit h   m o d er at e   HI  di d  n ot   m e et t h e   N CI -O  D  W  G  crit eri a f or 
m o d er at e   HI,   w hi c h is  b as e d  o n   t ot al  bilir u bi n (T  BI L ).  I n  h e alt h y s u bj e cts, si n gl e  d os es  u p t o 
2 4 0 0   m g (  wit h  or   wit h o ut f o o d)   w er e   w ell -t ol er at e d.  Asi d e fr o  m   mi n or  g astr oi nt esti n al si d e 
eff e cts,  n o s af et y si g n als i n  vit al si g ns,  p h ys i c al  e x a  mi n ati o ns,  or  el e ctr o c ar di o gr a  ms ( E  C  Gs) 
w er e r e p ort e d f oll o  wi n g  u p t o   3  si n gl e  d os es  of  p e xi d arti ni b  a d  mi nist er e d   wit h  a s u bj e ct  a cr oss 
m ulti pl e st u di es.  1 , 5  
B as e d  o n  p o ol e d  d at a fr o  m t h e  cli ni c al st u di es i n  p ati e nts, t h e   m o  st fr e q u e nt a d v ers e  e v e nts 
(A Es  ) ( o c c urri n g i n  >1 0  %  of s u bj e cts)  p ot e nti all y r el at e d t o st u d y  dr u g   w er e f ati g u e,  n a us e a, 
d e cr e as e d  a p p etit e,  h air  c ol or  c h a n g es,  di arr h e a,  as p art at e  a  mi n otr a nsf er as e (  A S T) /  al a ni n e 
a  mi n otr a nsf er as e (  A L T) i n cr e as es,  v o  miti n g,  a n e  mi a,  d ys g e usi a , a n d r as h.    A  m o n g  all  c o  m  m o n 
tr e at  m e nt-r el at e d 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), f ati g u e, i n cr e a s e d   A S T/  A L T, 
a n e  mi a,  a n d r as h  o c c urr e d  at   Gr a d e  3  or  hi g h er s e v erit y  a n d  at  a fr e q u e n c y  gr e at er t h a n  1  %.    At 
d os a g e l e v els  ≥ 6 0 0   m g/ d, tr a nsi e nt i n cr e as es i n   A S T  a n d/ or   A L T  h a v e  b e e n  c o  m  m o nl y  o bs er v e d 
wit h r e p e at e d  d osi n g. 1  Mil d t o   m o d er at e (  G  r a d e  1 t o  2) i n cr e as es i n  a  mi n otr a nsf er as es  h a v e  b e e n 
f o u n d i n  a b o ut  5 0  %  of s u bj e cts tr e at e d   wit h  p e xi d arti ni b  al o n e  or i n  c o  m bi n ati o n.  T h es e fi n di n gs  
m a y  b e r e  l at e d t o t ar g et i n hi biti o n  of C S F 1  R i n t h e   K u pff er  c ells t h at  ar e r es p o nsi bl e f or  cl e ari n g 
tr a ns a  mi n as es t h at l e a k fr o  m h e p at o c yt es .  Si n gl e  d os es  u p t o  2 6 0 0   m g  h a v e  b e e n  a d  mi nist er e d t o 
s u bj e cts   wit h  c a n c er.    A  m o n g  c o  m  m o n  T E  A Es, f ati g u e, i n cr e as e d   A S T  a n d  A L T l e v els,  a n e  mi a, 
a n d r as h  o c c urr e d  at   Gr a d e  3  or  hi g h er s e v erit y  a n d  at  a fr e q u e n c y  gr e at er t h a n  1  %. 1 
El e v ati o ns  of li v er tr a ns a  mi n as es  a n d  bilir u bi n  h a v e  b e e n  o bs er v e d i n st u di es   wit h  p e xi d arti ni b, 
t o g et h er   wit h  c as es  of  dr u g i n d u c e d c h ol est ati c li v er i nj ur y f oll o  wi n g   m ulti pl e  d os es .  C as es  of 
c h ol est asis  h a v e  b e e n  o bs er v e d i n t h e first  8   w k,  h a v e  g e n er all y r es ol v e d   wit h tr e at  m e nt 
dis c o nti n u ati o n,  b ut i n s o  m e  c as es  h a v e  b e e n s e v er e, r e q uiri n g li v er  di al ysis  a n d  h a d  a  pr otr a ct e d 
c o urs e ( 8  m o nt hs   [  m o]).   
1. 3.    
St u d y   R ati o n al e  
Gi v e n t h e si g nifi c a nt  c o ntri b uti o n  of  h e p ati c   m et a b olis  m  a n d  bili ar y  e x cr eti o n  of  p e xi d arti ni b   i n 
h u  m a ns , fi n di n gs fr o  m  St u d y P L 3 3 9 7 -A  -U 1 2 3  d e  m o nstr at e d   mil d  a n d   m o d er at e   HI,  as  ass ess e d 
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  2 3  
b y t h e   C hil d -P u g h  crit eri a,  d o  n ot  aff e ct  p e xi d arti ni b  e x p os ur e,  c o  m p ar e d t o  h e alt h y s u bj e cts .  
B e c a us e t h e  v ast   m aj orit y  of s u bj e cts   wit h   m o d er at e   HI   as  d efi n e d  b y   C hil d -P u g h  i n t h e first 
st u d y  di d  not   m e et t h e   N  CI -O  D  W  G  crit eri a f or  h e p ati c  d ysf u n cti o n,   w hi c h is  b as e d  o n,   T  BI L 
a n ot h er st u d y  is b ei n g  c o n d u ct e d t o f urt h er  d efi n e t h e  eff e ct  of   m o d er at e   HI  o n t h e  P  K  of 
p e xi d arti ni b.   Fi n di n gs fr o  m t his st u d y   will  b e  us ef ul i n   m a ki n g  d os e r e c o  m  m e n d ati o ns i n 
p ati e nts   wit h  m o d er at e   HI   w h o   w o ul d  b e n efit fr o  m  p e xi d arti ni b.     
T h e  c urr e nt  (T ur ali o ™ U S PI  -T  U  R -0 8 9 1 9 -r 0 0 1)  F  D  A  pr o d u ct l a b eli n g st at es t h at  n o  d os a g e 
a dj ust  m e nt is r e c o  m  m e n d e d f or  p ati e nts   wit h   mil d  h e p ati c i  m p air  m e nt  ( T  BI L  ≤   U L  N wit h   A S T   > 
U L  N   or  T  BI L  >  1 t o  1. 5   X   U L  N   wit h  a n y   A S T.  Als o, t h e  c urr e nt  F  D  A  pr o d u ct l a b eli n g   st at es 
t h at t h e r e c o  m  m e n d e d  d os e  of T ur ali o ™ h as  n ot  b e e n  est a blis h e d f or  p ati e nts   wit h   m o d er at e  
( T  BI L  >  1. 5 t o  3 X   U L  N  a n d  a n y   A S T) t o s e v er e   ( T  BI L  > 3   X   U L  N  a n d  a n y   A S T) h e p ati c 
i  m p air  m e nt.   
1. 4.    
Ris ks  a n d   B e n efits f o r  St u d y  S u bj e cts   
T h er e is  n o  dir e ct  b e n efit f or s u bj e cts i n t h e  c urr e nt st u d y.  I n dir e ct  b e n efits t o t h e  h e alt h y 
s u bj e cts  e nr oll e d i n t his st u d y  ar e t h e fr e e   m e di c al t ests r e c ei v e d  d uri n g  S cr e e ni n g  a n d t h e s af et y 
m o nit ori n g  as   m a n d at e d  b y t h e st u d y.     
T h e  P  K, s af et y,  a n d t ol er a bilit y  of si n gl e  d os es  of  p e xi d arti ni b ( 2 0 0   m g t o  2 4 0 0   m g) i n 
a p pr o xi  m at el y  1 9 0  h e alt h y s u bj e cts  h as  b e e n  e v al u at e d i n  9  st u di es.  I n  g e n er al,  p e xi d arti ni b   w as 
w ell  -t ol er at e d  u p t o  a v er a g e  p e a k  e x p os ur e  of 2 0 ,8 0 0  n g/  m L  a n d  a t ot al  e x p os ur e ( b as e d  o n 
A  U  C)  of  4 9 1  ,9 4 8  n g• h/  m L ( 1 8 0 0   m g f e d st at e).    N o s af et y si g n als i n  vit al si g ns,  p h ysi c al 
e x a  mi n ati o ns,  or  E  C  G r e c or di n gs, i n cl u di n g   Q T  pr ol o n g ati o n,   w er e r e p ort e d. 1  A  ss u  mi n g  a 5 0  % 
d e cr e as e i n  h e p ati c   m et a b olis  m  a n d  bili ar y  e x cr eti o n  of  p e xi d arti ni b i n s u bj e cts   wit h   m o d er at e 
HI  , t he  e x p os ur e fr o  m  a  2 0 0 -m g  d os e   w o ul d  n ot  b e  e x p e ct e d t o  e x c e e d t h  at  o bs er v e d f oll o  wi n g 
a n  1 8 0 0 -m g  d os e  a d  mi nist er e d   wit h f o o d i n  h e alt h y s u bj e cts ( e g  , 4 - t o 6 -f ol d  diff er e n c e i n C  m a x 
a n d  A  U  C).    T h er ef or e, t h e ris k f or  u n c o v eri n g  a  n e  w  u nt o  w ar d  eff e ct  of  a s  i n gl e  d os e  of 
p e xi d arti ni b is r el ati v el y s  m all.  
B as e d  o n  p o ol e d  d at a fr o  m t h e  o n c ol o g y st u di es   wit h   m ulti pl e  d osi n g, t h e   m o  st fr e q u e nt   A Es 
( o c c urri n g i n  >1 0  %  of s u bj e cts)  p ot e nti all y r el at e d t o t h e st u d y  dr u g   w er e f ati g u e,  n a us e a, 
d e cr e as e d  a p p etit e,  h air  c ol or  c h a n g es,  di arr h e a, i n cr e as es i n   A S T  a n d   A L T l e v els,  v o  miti n g, 
a n e  mi a,  d ys g e usi a,  a n d r as h.    At  d os a g e l e v els    6 0 0   m g/ d, tr a nsi e nt i n cr e as es i n   A S T  a n d/ or 
A L T l e v els  h a v e  b e e n  c o  m  m o nl y  o bs er v e d   wit h   m ulti pl e  d osi n g.    A  m o n g  c o  m  m o n  T E  A Es, 
f ati g u e, i n cr e as e d   A S T  a n d   A L T l e v els,  a n e  mi a,  a n d r as h   w er e r at e d   Gr a d e  3  or  hi g h er   wit h  a 
fr e q u e n c y  >1  %. 1  
El e v ati o ns  of li v er tr a ns a  mi n as es  a n d  bilir u bi n  h a v e  b e e n  o bs er v e d i n st u di es   wit h  p e xi d arti ni b, 
t o g et h er   wit h  c as es  of  dr u g i n d u c e d c h ol est ati c li v er i nj ur y f oll o  wi n g   m ulti pl e  d os es .    C as es  of 
c h ol est asis  h a v e  b e e n  o bs er v e d i n t h e first  8   w k,  h a v e  g e n er all y r es ol v e d   wit h tr e at  m e nt 
dis c o nti n u ati o n,  b ut i n s o  m e  c as es  h a v e  b e e n s e v er e, r e q uiri n g li v er  di al ysis  a n d  h a d  a  pr otr a ct e d 
c o urs e ( 8  m o  ) (T ur ali o ™ F ull  Pr es cri bi n g I nf or  m ati o n ).3  
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  2 4  
2.  
S  T  U  D  Y   O  B J  E  C  TI  V  E S   A  N  D  H  Y P  O  T  H  E SI S
2. 1.    
St u d y   O bj e cti v es  
2. 1. 1.    
P ri  m a r y   O bj e cti v e  
T h e  pri  m ar y  o bj e cti v e  of t his st u d y is:   
  T o  d et er  mi n e t h e  pl as  m a  P  K  of  p e xi d arti ni b  aft er  a si n gl e   or al  d os e  of  2 0 0  m g i n
s u bj e cts   wit h   m o d er at e  HI   c o  m p ar e d t o  t h at i n h e alt h y  s u bj e cts   wit h  n or  m al  h e p ati c
f u n cti o n
2. 1. 2.    
S e c o n d a r y   O bj e cti v es  
T h e s e c o n d ar y  o bj e cti v es  of t his st u d y  ar e:  
  T o  ass ess t h e s af et y  a n d t ol er a bilit y  of  p e xi d arti ni b   aft er  a si n gl e  or al  d o s e  of 2 0 0   m g
i n s u bj e cts   wit h  n or  m al  a n d m o d er at el y   i  m p air e d  h e p ati c f u n cti o n
  T o  d et er  mi n e t h e  P  K  of  Z  A  A  D -1 0 0 6 a i n s u bj e cts   wit h   m o d er at e  HI  ,  c o  m p ar e d t o t h at
i n h e alt h y  s u bj e cts   wit h  n or  m al  h e p ati c f u n cti o n
  T o  ass ess  pr o t ei n  bi n di n g  of  p e xi d arti ni b a n d  Z  A A  D  -1 0 0 6 a  i n m o d er at e   HI  ,
c o  m p ar e d t o  t h at i n h e alt h y  s u bj e cts   wit h  n or  m al  h e p ati c f u n cti o n
2. 2.    
St u d y   H y p ot h esis
T his is  n ot  a  h y p ot h esis t esti n g st u d y.   T his  st u d y   will  esti  m at e t h e  eff e ct  of  m o d er at e   h e p ati c 
d ysf u n cti o n  o n t h e  P  K  of  p e xi d arti ni b  a n d  Z  A  A  D -1 0 0 6 a ,  c o  m p ar e d t o  a  gr o u p  of  h e alt h y 
s u bj e cts   wit h  n or  m al  h e p ati c f u n cti o n .  
2. 3.    
St u d y   E n d p oi nts  
2. 3. 1.    
P ri  m a r y   E n d p oi nts  
P h a r  m a c o ki n eti c   E n d p oi nts  
  P e xi d arti ni b:  Pl as  m a  C  m a x  , T  m a x , A  U  Cl ast  , A  U  Ci nf,   K el,   t 1/ 2, C L/ F,   V z/ F  , a n d
pr ot ei n  bi n di n g
  Z  A  A  D -1 0 0 6 a:  Pl as  m a  C  m a x  , T  m a x , A  U  Cl ast  , A  U  Ci nf  , t 1/ 2, M P  R  b as e d  o n   A  U  Cl ast
a n d   A  U  Ci nf ,  a n d  pr ot ei n  bi n din g
T h e f oll o  wi n g  u n b o u n d  P  K  p ar a  m et ers   will  b e  c al c ul at e d f or  b ot h  p e xi d arti ni b  a n d 
Z  A  A  D  1 0 0 6 a:  
  C  m a x
  T  m a x
  A  U  Cl ast
  A  U  Ci nf
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  2 5  
  t 1/ 2
A n d  als o f or  p e xi d arti ni b: 
  C L/ F
  V z/ F
2. 3. 2.    
S e c o n d a r y  E n d p oi nts   
S af et y   E n d p oi nts  
  A Es
  Vit al si g ns
  1 2 -l e a d  E  C  Gs
  Cli ni c al l a b or at or y t ests
2. 3. 3.    
E x pl o r at o r y   E n d p oi nt
N ot  a p pli c a bl e   
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  2 6  
3.  
S  T  U  D  Y   D  E SI  G  N
3. 1.    
O v e r all   D esi g n   
3. 1. 1.    
O v e r vi e  w   
T his is  a  P h as e  1,  o p e n -l a b el, 1 -tr e at  m e nt, 1 -p eri o d st u d y  c o n d u ct e d i n  h e alt h y s u bj e cts  wit h 
n or  m al  h e p ati c f u n cti o n  a n d i n s u bj e cts   wit h  m o d er at e   h e p ati c  i  m p air  m e nt. A n  o v er vi e  w  of t h e 
st u d y is  d e pi ct e d i n  Fi g ur e  3. 1  b el o  w:  
Fi g u r e  3. 1 :   O v e r vi e  w  of st u d y  d esi g n   
 
S cr e e ni n g  will   o c c ur   wit hi n  2 1  d  of   C h e c k -i n (  D a y -2)  at t h e  cli ni c ,  a n d  eli gi bl e i n di vi d u als   will 
b e  c o nfi n e d  at t h e  cli ni c st arti n g  o n   D a y  -2  f or  a p pr o xi  m at el y 8  d.   All s  u bj e cts   will  b e  gi v e n  a 
si n gl e  d os e  of p e xi d arti ni b  (1    2 0 0 -m g  c a ps ul e  ) or all y  o n   D a y  1  wit h  2 4 0   m L  of   w at er  .  
S u bj e cts   will f ast f or  at l e ast  1 0  h  b ef or e  p e xi d arti ni b  d osi n g  a n d   will  c o nti n u e t o f ast f or  at l e ast 
4  h  aft er  p e xi d arti ni b  a d  mi nistr ati o n.    W at er   will  b e  all o  w e d  a d li bit u  m  u p t o  1  h  pri or t o  d os i n g 
a n d r es u  mi n g  at  2  h  aft er  p e xi d arti ni b  a d  mi nistr ati o n.  
S u bj e cts   will  c h e c k  o ut fr o  m t h e  cli ni c  o n   D a y  8  of  t h e st u d y f oll o  wi n g  c o  m pl eti o n  of t h e fi n al 
bl o o d  c oll e cti o n  a n d  C  h e c k -o ut  pr o c e d ur es.   
D et ails f or  e a c h st u d y  visit  ar e  pr o vi d e d i n t h e st u d y  pr  o c e d ur es s e cti o n (s e e  S e cti o n  6 )  a n d t h e 
S c h e d ul e  of  E v e nts t a bl e (s e e  A p p e n di x   1 6. 5 ). 
3. 1. 2.    
D os e   Es c al ati o n  P r o c ess   
N ot   a p pli c a bl e  
n  =  8   m o d er at e  h e p ati c i  m p air  m e nt    
n  =  8  gr o u p   m at c h e d ( a g e,  g e n d er,   B  MI) 
   
 
S cr e e ni n g  
A d  missi o n   
D os e   
Dis c h ar g e   
Bl o o d   C oll e cti o n f or  P  K, 
E  C  Gs,   Cli n  L a bs,   A E,  P E  
D a ys               D   -2 2 t o   D  -2  
D   -2    
    D  1 t o   D  8      
      D  8   
  
A b br e vi ati o ns:   D  =   D a y;  P  K  =   p h ar  m a c o ki n eti cs  
 i 
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  2 7  
3. 1. 3.    
St u d y  St o p pi n g   C rit e ri a  
N ot  a p pli c a bl e   
3. 2.    
Dis c ussi o n  of  St u d y   D esi g n   
T h e  p ur p os e  of t his st u d y is t o  ass ess t h e  eff e ct  of  m o d er at e   HI   o n t h e  P  K  of  p e xi d arti ni b.   T h e 
st u d y   will  c o nsist  of  8  s u bj e cts   wit h   m o d er at e   HI  a n d  8  m at c h e d  c o ntr ols.   T h e s e v  erit y  of   HI 
will  b e  ass ess e d   b y t h e   N  CI -O  D  W  G  gr o u p   T  BI L  > 1. 5  t o 3 x   U L  N , n ot  d u e  to   Gil b ert’s s y n dr o  m e .  
S u bj e cts   wit h  n or  m al  h e p ati c f u n cti o n   will  b e   m at c h e d t o s u bj e cts   wit h   m o d er at e   HI  a c c or di n g t o 
s e x,  a g e ( ± 1 0  y e ars  [ y]),  a n d w ei g ht   ( ± 2 0  %)  b as e d  o n   m e a n  v al u es .  S u bj e cts   wit h   HI   will  b e 
r e cr uit e d first.  H e alt h y s u bj e cts   wit h  n or  m al li v er f u n cti o n   will  b e  e nr oll e d  aft er   all  s u bj e cts   wit h 
m o d er at e   HI   h a v e r e c ei v e d st u d y  dr u g . 
A si n gl e   2 0 0 -m g  d os e  of  p e xi d arti ni b (  1    2 0 0 -m g  c a ps ul e  ) w as  c h os  e n  b as e d  o n t h e s af et y 
pr ofil e  a n d   wit h  a n  ass u  m pti o n t h at   m o d er at e  h e p ati c i  m p air  m e nt   m a y  d o u bl e t h e  e x p os ur e .   T h e 
o p e n -l a b el, si n gl e  d os e st u d y  d esi g n is  a p pr o pri at e f or t his  P h as e  1 st u d y.    
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  2 8  
4.  
S  T  U  D  Y  P  O P  U  L  A  TI  O  N
All s u bj e cts   m ust si g n  a n I nf or  m e d   C o ns e nt  F  or  m (I C F)  pr o vi d e d  b y t h e sit e.  
4. 1.    
I n cl usi o n   C rit e ri a  
S u bj e cts   m ust s atisf y  all  of t h e f oll o  wi n g  crit eri a t o  b e i n cl u d e d i n t h e st u d y:  
1.  M al e  a n d f e  m al e s u bj e cts  1 8  y t o   7 5  y  of  a g e (i n cl usi v e),   wit h  a  b o d y   m ass i n d e x (  B  MI)
o f  1 8  k g/  m2 t o  4 0 k g/  m 2 (i n cl usi v e)  at  S cr e e ni n g.
2.  F e  m al e s u bj e cts   w h o  ar e  of  n o n -c hil d b e ari n g  p ot e nti al   m ust  b e:
a.  S ur gi c all y st eril e (i e,  bil at er al t u b al li g ati o n  or r e  m o v al  of  b ot h  o v ari es  a n d/ or  ut er us
at l e ast  6   m o  pri or t o  d osi n g,  or  Ess ur e ®  wit h  h yst er os al pi n g o gr a  m [ d o c u  m e n  t ati o n t o
c o nfir  m t u b al  o c cl usi o n  1 2   w k  aft er  pr o c e d ur e]).
b.  N at ur all y  p ost  m e n o p a us al (s p o nt a n e o us  c ess ati o n  of   m e ns es) f or  at l e ast
1 2  c o ns e c uti v e   m o  pri or t o  d osi n g,  c o nfir  m e d  b y f olli cl e sti  m ul ati n g  h or  m o n e ( F S  H)
t esti n g or  estr a di ol t esti n g .
3.  F e  m al e s u bj e cts   w h o  ar e  of  c hil d b e ari n g  p ot e nti al   m ust  a gr e e t o  n o n h or  m o n al  m et h o d  s of
c o ntr a c e pti v e t h er a p y  or r efr ai n fr o  m s e x u al i nt er c o urs e t o  pr e v e nt  pr e g n a n c y  u ntil  1   m o
p ost d os e.   If t h e s u bj e ct i s  o n  or al  c o ntr a c e pti v e, t h e s u bj e ct als o  n e e ds t o  us e  a
n o n h or  m o n al  m et h o d i n  a d diti o n t o  or al  c o ntr a c e pti v e.    F e  m al e s u bj e cts   m ust r efr ai n
fr o  m  br e astf e e di n g f or  at l e ast  2   w e e ks p ost  d os e .
4.  M al e s u bj e cts   m ust  a gr e e t o  us e  a  c o n d o  m  a n d s p er  mi ci d e  d uri n g s e x u al i nt er c o urs e  u ntil
1  m o  p ost  d os e  or   m ust  h a v e  h a d  a  v as e ct o  m y  a n d   m ust  b e   willi n g  n ot t o  d o n at e s p er  m
u ntil  1   m o  p ost  d os e.
5.  All s u bj e cts   m ust  a gr e e  n ot t o  d o n at e  bl o o d,  pl as  m a,  pl at el ets,  or  a n y  ot h er  bl o o d
c o  m p o n e nts fr o  m  S cr e e ni n g t o  4   w k  p ost  d os e.
6.  All s u bj e cts   m ust  b e   willi n g t o r efr ai n fr o  m  c o ns u  mi n g  gr a p efr ui  t/ gr a p efr uit j ui c e,  S e vill e
or a n g es,  a n d  p o  m e gr a n at es/ p o  m e gr a n at e j ui c e  1 0  d  b ef or e t h e  d os e  of st u d y  dr u g is  gi v e n
o n   D a y  1  u ntil  E n d -of -St u d y ( E o S).
7.  All s u bj e cts   m ust  pr o vi d e   writt e n i nf or  m e d  c o ns e nt  pri or t o  p arti ci p ati n g i n t h e st u d y.
8.  S u bj e cts   wit h   HI  ar e r e q uir e d t o  h a v e:
a.  D o c u  m e nt e d  hist or y  of  c hr o ni c li v er  dis e as e  di a g n os e d  b y  ultr as o n o gr a p h y,  c o  m p ut e d
t o  m o gr a p h y s c a n, li v er  bi o ps y,  or   m a g n eti c r es o n a n c e i  m a gi n g  or  hist or y  of  c hr o ni c
( > 6   m o)  h e p atitis   B  vir us (  H  B  V)  or h e p atitis   C  vir us ( H  C  V  ) i nf e cti o n
b.  M o d er at e   HI  as  ass ess e d  b y   N  CI  -O  D  W  G  crit eri a [t ot al  bilir u bi n ( T  BI L)  > 1. 5   t o 3 x
U L  N ( n ot  d u e t o   Gil b ert’s s y n dr o  m e)]  a n d   c o nfir  m e d  at  C h e c k   i n.
c.  N or  m al  or  cli ni c all y  n o n  r el e v a nt fi n di n gs  at  p h ysi c al  e x a  mi n ati o n  a n d  n or  m al li  mits
or  cli ni c all y  n o n r el e v a nt d e vi ati o ns i n  cli ni c al l a b or at or y  e v al u ati o ns,   wit h  e x c e pti o n
of fi n di n gs t h at i n t h e  o pi ni o n  of i n v esti g at or  ar e  c o nsist e nt   wit h s u bj e ct’s   HI .
9.  C  r e ati ni n e   Cl e ar a n c e ≥  7 0   m L/  mi n  esti  m at e d  usi n g t h e   C o c k cr oft   G a ult f or  m ul a   wit h o ut
a n y   m ar k ers  of  c hr o ni c  ki d n e y  dis e as e  at  S cr e e ni n g  a n d  C  h e c k -i n.
1 0.  Cli ni c al st a bilit y i n t h e  o pi ni o n  of t h e i n v esti g at or
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  2 9  
4. 2.    
E x cl usi o n   C rit e ri a   
S u bj e cts   w h o   m e et  a n y  of t h e f oll o  wi n g  crit eri a   will  b e  dis q u alifi e d fr o  m  e nt eri n g t h e st u d y:  
1.  Cli ni c all y r el e v a nt  a b n or  m al  hist or y,  p h ysi c al fi n di n gs,  E  C  G,  or l a b or at or y  v al u es  at t h e
S cr e e ni n g  ass ess  m e nt t h at  c o ul d i nt erf er e   wit h t h e  o bj e cti v es  of t h e st u d y  or t h e s af et y  of
t h e s u bj e ct
2.  S u bj e cts   wit h  pri  m ar y  bili ar y  cirr h osis  or  pri  m ar y s cl er osi n g  c h ol a n gitis
3.  C o n c o  mit a nt   m e di c ati o n (  m o d er at e  or str o n g i n hi bit or  or i n d u c er  of   C  Y P 3  A 4
[ e g, itr a c o n a z ol e, rif a  m pi n],   C  Y P 2  C 9 [ e g, fl u c o n a z ol e,  c ar b a  m a z e pi n e]  a n d
U  G T   [ e g, pr o b e n e ci d, rif a  m pi n])   wit hi n  2   w k  b ef or e  d os i n g  a n d t hr o u g h o ut st u d y
4.  Hist or y  of st o  m a c h  or i nt esti n al s ur g er y  or r es e cti o n t h at   w o ul d  p ot e nti all y  alt er
a bs or pti o n  a n d/ or  e x cr eti o n  of  or all y  a d  mi nist er e d  dr u gs (  wit h t h e  e x c e pti o n  of
a p p e n d e ct o  m y,  h er ni a r e p air,  a n d/ or  c h ol e c yst e ct o  m y)
5.  Pr es e n c e  or  hi st or y  of s e v er e  a d v ers e r e a cti o n t o  a n y  dr u g ( e x c e pt  p e ni cilli n)
6.  A  p ositi v e  dr u gs  of  a b us e s cr e e n ( u nl ess t h e  dr u g is   m e di c all y  pr es cri b e d  b y  a li c e ns e d
h e alt h  c ar e  pr o vi d er)  or  al c o h ol  br e at h t est  at  S cr e e ni n g  or  at   C h e c k -i n  o n   D a y -2  or  a
s u bj e ct   w h o   will  n ot  a gr e e t o s  m o k e  ≤ 1 0  ci g ar ett es  or  e q ui v al e nt  p er  d a y fr o  m  S cr e e ni n g
u p t o  E nr oll  m e nt,  a n d is  u n a bl e t o  b e r estri ct e d t o  ≤ 5  ci g ar ett es  p er  d a y  a n d f or  6  h  p ost
d os e  d uri n g t h eir  p eri o d  of r esi d e n c e i n t h e  cli ni c al  u nit
7.  C o n c o  mit a nt  us e  of   m e di c ati o ns  k  n o  w n t o  aff e ct t h e  eli  mi n ati o n  of s er u  m  cr e ati ni n e ( e g,
tri  m et h o pri  m  or  ci  m eti di n e)  a n d i n hi bit ors  of r e n al t u b ul ar s e cr eti o n ( e g,  pr o b e n e ci d)
wit hi n  6 0  d  of   D a y   -2
8.  Hist or y  or  pr es e n c e  of  a n  a b n or  m al  E  C  G,   w hi c h, i n t h e i n v esti g at or’s  o pi ni o n, is
cli ni c all y  si g nifi c a nt  a n d/ or  a   Q T i nt er v al  c orr e ct e d f or  h e art r at e  usi n g  Fr id eri ci a’s
f or  m ul a (  Q T c F)  ≥ 4 5 0   millis e c o n ds (  ms)  a n d  ≥ 4 7 0   ms f or  h e alt h y   m al e  a n d f e  m al e
s u bj e cts, r es p e cti v el y,  a n d  > 5 0 0   ms f or s u bj e cts   wit h   HI  at  S cr e e ni n g
9.  C o ns u  m pti o n  of  al c o h ol  -wit hi n   7 2  h  pri or t o   C h e c k -i n a n d  c aff ei n e -c o nt ai ni n g  b e v er a g es
wit hi n  4 8  h  pri or t o   C h e c k  -i n  a n d  d uri n g  c o nfi n e  m e nt
1 0.  C o ns u  m pti o n  of   m or e t h a n  2 8  u nits  of  al c o h ol  p er   w k f or   m al es  or  1 4  u nits  of  al c o h ol  p er
w k f or f e  m al es,   w h er e  1  u nit  of  al c o h ol  e q u als  o n e  -h alf  p i nt  of  b e er,  4  o u n c es ( o z)  of
wi n e,  or  1  o z  of s pirits,  or si g nifi c a nt  hist or y  of  al c o h olis  m  or  dr u g/ c h e  mi c al  a b us e   wit hi n
t h e l ast  2  y
1 1.  P ositi v e s er ol o g y f or   H  Bs  A g  a n d  a nti -H  C  V ( h e alt h y s u bj e cts),   H  A  V i  m  m u n o gl o b uli n   M,
or  a nti -HI  V  T y p e  1  a n d  T y p e  2 ( all s u  bj e cts)
1 2.  L oss  of   m or e t h a n  4 5 0   m L  bl o o d  d uri n g t h e  3   m o  b ef or e t h e tri al ( e g,  as  a  bl o o d  d o n or)
1 3.  C urr e nt  e nr oll  m e nt i n  or  h a v e  n ot  y et  c o  m pl et e d  at l e ast  3 0  d  or  5  eli  mi n ati o n  h alf  -li v es,
w hi c h e v er is l o n g er, si n c e r e c ei vi n g  a n i n v esti g ati o n al  d e vi c e  or  pr o d  u ct,  or r e c ei pt  of
ot h er i n v esti g ati o n al  a g e nts   wit hi n  3 0  d  of  p e xi d arti ni b
1 4.  Hist or y  of  a n y   m ali g n a n c y ( e x c e pt  b as al  c ell  c ar ci n o  m a) i n t h e  p ast  5  y
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  3 0  
1 5.  I n t h e  o pi ni o n  of t h e i n v esti g at or,  hist or y  of  a  cli ni c all y si g nifi c a nt ill n ess   wit hi n  4   w k
pri or t o  a d  mi nis tr ati o n  of st u d y  dr u g
1 6.  P arti ci p ati o n i n  a  pr e vi o us  p e xi d arti ni b st u d y
1 7.  E  m pl o y  m e nt  b y t h e  cli ni c  or t h e  S p o ns or
1 8.  A n y  ot h er r e as o n, i n t h e  o pi ni o n  of t h e i n v esti g at or,   w hi c h  pr e cl u d es s u bj e ct  p arti ci p ati o n
i n t h e st u d y
1 9.  F a  mili al r el ati o ns hi p   wit h  a n ot h er st u d y  p arti ci p a nt
A d diti o n al  E x cl usi o n   Crit eri a f or   M at c h e d   H e alt h y  S u bj e cts:   
1.  A n y  cli ni c all y r el e v a nt  a b n or  m alit y i d e ntifi e d  o n t h e  p h ysi c al  e x a  mi n ati o n,  E  C  G,  vit al
si g ns,  or l a b or at or y t ests  at  S cr e e ni n g.
2.  A n y  cli ni c all y  u nst a bl e,  u n c o ntr oll e d   m e di c al  c o n diti o n.
3.  Li v er f u n cti o n (  A S T,   A L T,  al k ali n e  p h os p h at as e  of li v er  ori gi n,  a n d  T  BI L ) t est r es ults
a b o v e t h e  u p p er li  mit  of  n or  m al  at  S cr e e ni n g  a n d  o n   D a y  -2 .
4.  Us e  of  a n y  pr es cri pti o n  or  o v er  -t h e-c o u nt er (  O T  C)   m e di c ati o ns (s yst e  mi c  or t o pi c al),
vit a  mi ns,  or  di et ar y/ h er b al s u p pl e  m e nts   wit hi n  1 4  d  pri or t o st u d y  dr u g  d osi n g,   wit h t h e
e x c e pti o n  of  a c et a  mi n o p h e n ( ≤ 2  g/ d), st o ol s oft e n ers,  a n d t o pi c al  h y dr o c ortis o n e  cr e a  m,
w hi c h  ar e  p er  mitt e d.
A d diti o n al  E x cl usi o n   Crit eri a f or  S u bj e cts   wit h   H e p ati c I  m p air  m e nt:   
1.  A n y  cli ni c al  l y  u nst a bl e,  u n c o ntr oll e d   m e di c al  c o n diti o ns  ot h er t h a n t h os e  ass o ci at e d   wit h
HI  .
2.  E vi d e n c e  of i nf e cti o n   wit h   H  B  V  a n d/ or  n e  w  or  a c ut e   H  C  V i nf e cti o n   wit hi n t h e  pr e c e di n g
6   m o .
3.  HI s u bj e cts   m ai nt ai n e d  o n  a  g astri c  p  H   m o difi er ( e g,  pr ot o n  p u  m p i n hi bit or),   m ust   b e
dis c o nti n u e d fr o  m t his   m e di c ati o n  7  d  pri or t o  a n d  2 4  h  aft er  p e xi d arti ni b  a d  mi nistr ati o n.
T h e s u bj e ct s h o ul d  b e s  wit c h e d t o   G el usil ( al u  mi n u  m  h y dr o xi d e,   m a g n esi u  m  h y dr o xi d e,
a n d si  m et hi c o n e)  as  n e e d e d f or  u p t o  4 8  h  pri or t o t h e  a d  mi nistr ati o n  of  p e xi d arti ni b.
G el usil  us e is  pr o hi bit e d fr o  m  4 8  h  pri or t o t h e  a d  mi nistr ati o n  of  p e xi d arti ni b t o  2 4  h  p ost
p e xi d arti ni b  d osi n g.    At  2 4  h  p ost  p e xi d arti ni b, tr e at  m e nt   wit h t h e  us u al  g astri c  p  H
m o difi er  c a n  b e r es u  m e d.
4.  HI s u bj e cts   m ai nt ai n e d  o n  or al  or tr a ns d e  r  m al  h or  m o n e r e pl a c e  m e nt t h er a p y f or
p ost  m e n o p a us al s y  m pt o  ms i n f e  m al es  or  h y p o g o n a dis  m i n   m e n  ar e  e x cl u d e d fr o  m
p arti ci p ati n g  u nl ess t h e y  h a v e  b e e n  dis c o nti n u e d f or  at l e ast  2 8  d  pri or t o  p e xi d arti ni b
a d  mi nistr ati o n  a n d f or  7  d  p ost  p e xi d arti ni b.    Ot h er  h or  m o n al r e pl a c e  m e nt t h er a p y f or
m ai nt e n a n c e  of  c hr o ni c  c o n diti o ns ( e g, i ns uli n, t h yr o xi n) is  p er  mitt e d.    Or al
c o ntr a c e pti v es  ar e  p er  mitt e d i n   w o  m e n  of  c hil d b e ari n g  p ot e nti al.
5.  S u bj e cts   wit h  a cti v e  S t a g e  3  or S t a g e  4  e n c e p h al o p at h y
6.  Fl u ct u ati n g  or r a pi dl y  d et eri or ati n g  h e p ati c f u n cti o n  as i n di c at e d  b y r e c e nt  hist or y  or
w ors e ni n g  of  cli ni c al  a n d/ or l a b or at or y si g ns  of   HI  as j u d g e d  b y t h e i n v esti g at or.
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  3 1  
5.  
S  T  U  D  Y   T  R  E  A  T  M  E  N  T S
5. 1.    
Assi g ni n g  S u bj e cts t o   T r e at  m e nt   G r o u ps/ S e q u e n c es  a n d   Bli n di n g   
5. 1. 1.    
T r e at  m e nt   G r o u ps/ S e q u e n c es   
T h is is  a n  o p e n-l a b el, 1 -tr e at  m e nt, 1 -p eri o d st u d y.  
P e xi d arti ni b ( 1  ×  2 0 0 -m g  c a ps ul e)   will  b e  a d  mi nist er e d  or all y t o  all s u bj e cts  o n   t h e   m or ni n g  of 
D a y   1   wit h  2 4 0   m L  of   w at er.   S u bj e cts   will f ast f or  at l e ast  1 0  h  b ef or e  p e xi d arti ni b  d osi n g  a n d 
will  c o nti n  u e t o f ast f or  at l e ast  4  h  aft er  p e xi d arti ni b  a d  mi nistr ati o n.    W at er i n g esti o n is 
r estri ct e d fr o  m  1  h  pri or t o  a n d  u p t o  2  h  p ost  p e xi d arti ni b  a d  mi nistr ati o n. 
D et ails f or  e a c h st u d y  visit  ar e  pr o vi d e d i n t h e st u d y  pr o c e d ur es (s e e   S e cti o n  6 )  a n d i n t h e 
S c h e d ul e  of  E v e nts (s e e  S e cti o n  1 6. 5 ). 
5. 1. 2.    
M et h o  d  of   T r e at  m e nt   All o c ati o n  
S u bj e cts   wi t h HI   will  b e r e cr uit e d first.    W h e n   all  m o d er at e   HI   s u bj e cts h a v e  r e c ei v e d st u d y 
dr u g , t h e  gr o u p  of  h e alt h y s u bj e cts wit h  n or  m al  h e p ati c f u n cti o n   c a n  b e  e nr oll e d.  T h er e is  n o 
r a n d o  mi z ati o n i n t his st u d y. 
5. 1. 3.    
Bli n di n g   
T his  is  a n  o p e n-l a b el st u d y.    N o  bli n di n g   will  b e r e q uir e d. 
5. 1. 4.    
E  m e r g e n c y   U n bli n di n g  P r o c e d u r e   
N ot  a p pli c a bl e   
5. 2.    
St u d y   D r u g  
5. 2. 1.    
D es c ri pti o n 
P e xi d arti ni b is f or  m ul at e d  as  o p a q u e,   w hit e,  2 0 0 -m g  c a ps ul es,   w hi c h   will  b e s u p pli e d  b y t h e 
S p o ns or.    
5. 2. 2.    
L a b eli n g  a n d  P a c k a gi n g   
A d e q u at e  a  m o u nts  of st u d y  dr u g   will  b e  pr o vi d e d i n  b ottl es,   wit h  c o nt e nts i d e ntifi e d  o n t h e l a b el.  
I n v esti g ati o n al  pr o d u ct l a b els   will i n cl u d e  all  of t h e i nf or  m ati o n r e q uir e d  b y f e d er al  a n d l o c al 
r e g ul ati o ns.    A p pli c a bl e s u p p orti n g  pr o d u ct i nf or  m ati o n  o n p e xi d arti ni b   will  b e  pr o vi d e d  b y t h e 
S p o ns or.  
5. 2. 3.    
P r e p a r ati o n  
T h e st u d y  dr u g  will  b e s u p pli e d  as  c a ps ul es t h at  n e e d  n o  pr e p ar ati o n  at t h e st u d y sit e.  
5. 2. 4.    
A d  mi nist r ati o n   
P e xi d arti ni b   will  b e  a d  mi nist er e d  or all y  as  a si n gl e  d os e  of  1    2 0 0 -m g  c a ps ul e  at t h e  cli ni c   wit h 
2 4 0   m L  of   w at er f oll o  wi n g  at l e ast  a  1 0 -h  o v er ni g ht f ast.   
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  3 2  
T h e st u d y  dr u g   will  b e  a d  mi nist er e d i n  a c c or d a n c e   wit h t h e  pr ot o c ol.    T h e s t u d y  dr u g   will  b e 
a d  mi nist er e d  o nl y t o s u bj e cts  p arti ci p ati n g i n t h e  cli ni c al st u d y.  It is  a  vi ol ati o n  of t h e 
r e g ulati o ns t o  us e  u n a p pr o v e d i n v esti g ati o n al   m e di ci n al  pr o d u cts (I  M Ps) f or  p ur p os es  ot h er t h a n 
t h os e st at e d i n t h e  pr ot o c ol.   T h e sit e   will  c o  m pl et e t h e r e q uir e d  d o c u  m e nt ati o n  as  pr o vi d e d  b y 
D aii c hi  S a n k y o, I n c. (  D SI  ),  or its r e pr es e nt ati v es, t o  d o c u  m e nt  dis p ensi n g  of I  M Ps.    All 
i nf or  m ati o n   will  b e r e c or d e d i  m  m e di at el y  o n  a  dr u g-dis p e nsi n g f or  m  e a c h ti  m e t h e I  M Ps  ar e 
dis p e ns e d t o  a s u bj e ct.  
5. 2. 5.    
St o r a g e  
Dr u g s u p pli es   m ust  b e st or e d i n  a s e c ur e, li  mit e d  a c c ess st or a g e  ar e a   wit hi n t h e r e c o  m  m e n d e d 
st or a g e  c o n diti o ns.   D SI   s h o ul d  b e  c o nt a ct e d  if st or a g e  c o n diti o ns f all o utsi d e t h e s p e cifi e d 
r a n g e.    All  dr u g s u p pli es s h o ul d  b e  q u ar a nti n e d  p e n di n g a  d e cisi o n fr o  m   D SI.  
5. 2. 6.    
D r u g   A c c o u nt a bilit y   
W h e n  a  dr u g s hi p  m e nt is r e c ei v e d, t h e   in v esti g at or  or  d esi g n e e   will  c h e c k t h e  a  m o u nt,  c o n diti o n, 
a n d t e  m p er at ur e r e c or di n g  of t h e st u d y  dr u g;  c h e c k f or  a p pr o pri at e l o c al l a n g u a g e  o n t h e l a b el 
a n d  dr u g  e x pir ati o n  d at e;  a n d si g n t h e r e c ei pt  of s hi p  m e nt f or  m  pr o vi d e d.   T h e r e c ei pt  of t h e 
s hi p  m e nt f or  m s h o ul d  b e f a x e d  as i nstr u ct e d  o n t h e f or  m.   T h e  ori gi n al   will  b e r et ai n e d  at t h e 
sit e.  I n  a d diti o n, t h e  in v esti g at or  or  d esi g n e e s h all  c o nt a ct t h e  S p o ns or  as s o o n  as  p ossi bl e if 
t h er e is  a  pr o bl e  m   wit h t h e s hi p  m e nt.  
A  dr u g  a c c o u nt a bilit y r e c or d   will  b e  pr o vi d e d f or t h e I  M Ps  or t h e sit e  c a n  us e t  h eir  o  w n 
D SI  -a p pr o v e d  dr u g  a c c o u nt a bilit y l o g.   T h e r e c or d   m ust  b e  k e pt  c urr e nt  a n d s h o ul d  c o nt ai n t h e 
d at es  a n d  q u a ntiti es  of t h e  dr u g r e c ei v e d, t h e s u bj e ct’s i d e ntifi c ati o n  n u  m b er  a n d/ or i niti als  or 
s u p pl y  n u  m b er,  as  a p pli c a bl e, t o   w h o  m t h e I  M P   w as  dis p e ns e d, t h e  d at e  a n d  q u a ntit y  of t h e I  M P 
dis p e ns e d  a n d r e  m ai ni n g (if fr o  m i n di vi d u al s u bj e ct  dr u g  u nits),  as   w ell  as t h e i niti als  of t h e 
dis p e ns er.   T h e  dis p e ns er’s i nf or  m ati o n   m ust  b e  n ot e d  o n t h e  d el e g ati o n  of  d uti es l o g.  
At t h e  e n d  of t h e st u d y,  or  as  dir  e ct e d,  all  p e xi d arti ni b  pr o d u cts, i n cl u di n g  u n us e d,  p arti all y  us e d, 
or  e  m pt y  c o nt ai n ers,   will  b e  d estr o y e d  aft er f ull  a c c o u nt a bilit y  p er  dr u g  u nit.  If t h e  p e xi d arti ni b 
pr o d u cts  ar e  d estr o y e d  at t h e st u d y  c e nt er,  a p pr o v al i n   writi n g fr o  m t h e  S p o ns or   m ust  b e 
r e c ei v e d,  a n d t h e  S p o ns or   m ust r e c ei v e  c o pi es  of t h e st u d y  c e nt er’s  dr u g  h a n dli n g  a n d 
dis p ositi o n st a n d ar d  o p er ati n g  pr o c e d ur es.    D os a g e f or  m (i e,  c a ps ul e) sit e -l e v el  a c c o u nt a bilit y 
d o c u  m e nt ati o n is r e q uir e d  as  p art  of t h e  dis p ositi o n r e c or ds  of t h e I  M P.   T h e  d os a g e f or  m 
sit e-l e v el  a c c o u nt a bilit y  d o c u  m e nt ati o n s h o ul d  b e  a p p e n d e d t o t h e   C ertifi c at e  of   D estr u cti o n  a n d 
pr o vi d e d t o   D SI.    
T h e I  M P  will  b e r et ur n e d t o  a  d esi g n e e,  as i nstr u ct e d  b y t h e  S p o ns or,   o nl y  if t h e st u d y  c e nt er is 
u n a bl e t o  p erf or  m t h e  d e str ucti o n  of t h e  pr o d u cts.   T h e I  M P  will  b e r et ur n e d  o nl y  aft er t h e st u d y 
m o nit or  h as  c o  m pl et e d  a fi n al i n v e nt or y t o  v erif y t h e  q u a ntit y t o  b e r et ur n e d.   T h e 
r et ur n/ d estr u cti o n  of I  M P s   m ust  b e  d o c u  m e nt e d,  a n d t h e  d o c u  m e nt ati o n   m ust  b e i n cl u d e d i n t h e 
s hi p  me nt.    At t h e  e n d  of t h e st u d y,  a fi n al I  M P r e c o n cili ati o n st at e  m e nt   m ust  b e  c o  m pl et e d  b y t h e 
in v esti g at or,  or  d esi g n e e,  a n d  pr o vi d e d t o t h e  S p o ns or.    
D os a g e f or  m (i e,  c a ps ul e) sit e  -l e v el  a c c o u nt a bilit y  d o c u  m e nt ati o n   m ust  b e i n cl u d e d   wit h  e a c h 
dr u g s u p pl y  r et ur n s hi p  m e nt  or  ot h er r et ur ni n g f a cilit y, s u c h  as  a n ot h er  d e p ot.   
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  3 3  
T h e  af or e  m e nti o n e d  d o c u  m e nt ati o n is r e q uir e d  as  p art  of t h e r e c ei vi n g r e c or ds f or r et ur n 
s hi p  m e nts.  
All I  M P i n v e nt or y f or  ms   m ust  b e   m a d e  a v ail a bl e f or i ns p e cti o n  b y  a  S p o ns or  -a ut h ori z e d  
r e pr es e nt ati v e  or  d esi g n e e  a n d r e g ul at or y  a g e n c y i ns p e ct ors.   T h e in v esti g at or is r es p o nsi bl e f or 
t h e  a c c o u nt a bilit y  of  all  us e d  a n d  u n us e d st u d y  dr u g  at t h e sit e.  
5. 2. 7.    
R et e nti o n  S a  m pl es   
N ot  a p pli c a bl e   
5. 3.    
C o nt r ol   T r e at  m e nt   
N ot  a p pli c a bl e   
5. 4.    
D os e I nt e r r u pti o ns  a n d   R  e d u cti o ns  
N ot  a p pli c a bl e   
5. 5.    
M et h o d  of   Ass essi n g   T r e at  m e nt   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,  all  d os es   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  cli ni c al 
st u d y  p ers o n n el.    A   m o ut h  a n d  h a n d  c h e c k   m ust  b e  c arri e d  o ut i n  all t h e s u bj e cts t o  e ns ur e t h at 
all t h e  c a ps ul es  h a v e  b e e n s  w all o  w e d.    
T h e  e x a ct ti  m es  of  I  M P d osi n g  a n d t h e  n u  m b er  of  u nits  a d  mi nist er e d   will  b e r e c or d e d i n t h e 
el e ctr o ni c   C as e   R e p ort  F or  m ( e  C  R F).  
5. 6.    
P ri o r  a n d   C o n c o  mit a nt   M e di c ati o ns  
M e di c ati o ns  us e d   wit hi n  3 0  d  pri or t o  S cr e e ni n g   will  b e r e c or d e d.    
All  pr es cri pti o n  or   O T  C   m e di c ati o ns (s yst e  mi c  a n d t  o pi c al),  vit a  mi ns,  g astri c  p  H   m o difi er s,  a n d 
di et ar y  or  h er b al s u p pl e  m e nts   will  b e  pr o hi bit e d  1 4  d  b ef or e  t h e  d os e  of p e xi d arti ni b  a n d f or t h e 
d ur ati o n  of t h e st u d y.   St J o h n’s   W ort ( h y p eri ci n) s h o ul d  n ot  h a v e  b e e n t a k e n   wit hi n  3 0  d  pri or t o 
t h e  d os e  of p e xi d arti ni b  (s e e S e cti o n  4. 2 ).  F or   HI s u bj e cts,  c o n c o  mit a nt   m e di c ati o ns r e q uir e d f or 
a   m e di c al  c o n diti o n  c a n  b e  c o nti n u e d  as l o n g  as t h e y  ar e  n ot  p r o hi bit e d  as  n ot e d  b el o  w  a n d  b y 
t h e s p e cifi c  e x cl usi o ns i n S e cti o n  4 . 2. 
H  I s u bj e cts   m ai nt ai n e d  o n  a  g astri c  p  H   m o difi er ( e g,  pr ot o n  p u  m p i n hi bit or),  m ust  b e 
dis c o nti n u e d fr o  m t his   m e di c ati o n  7  d  pri or t o  a n d  2 4  h  aft er  p e xi d arti ni b  a d  mi nistr ati o n.   T h e 
s u bj e ct s h o ul d  b e s  wit c h e d t o   G el usil ( al u  mi n u  m  h y dr o xi d e,   m a g n esi u  m  h y dr o xi d e,  a n d 
si  m et hi c o n e)  as  n e e d e d f or  u p t o  4 8  h  pri or t o  t h e a d  mi nistr ati o n  o f  p e xi d arti ni b.  G e  l usil  us e is 
pr o hi bit e d fr o  m  4 8  h  pri or t o t h e  a d  mi nistr ati o n  of  p e xi d arti ni b t o  2 4  h  p ost  p e xi d arti ni b  d osi n g.   
At  2 4  h  p ost  p e xi d arti ni b, tr e at  m e nt   wit h t h e  us u al  g astri c  p  H   m o difi er  c a n  b e r es u  m e d.    
H  I s u bj e cts   m ai nt ai n e d  o n  or al  or tr a ns d er  m al  h or  m o n e r e pl a c e  m e nt t h er a p y f or  p ost  m e n o p a us al  
s y  m pt o  ms i n f e  m al es  or  h y p o g o n a d is  m i n   m e n  ar e  e x cl u d e d fr o  m  p arti ci p ati n g  u nl ess t h e y  h a v e 
b e e n  dis c o nti n u e d f or  at l e ast  2 8  d  pri or t o  p e xi d arti ni b  a d  mi nistr ati o n  a n d f or  7  d  p ost 
p e xi d arti ni b.    Ot h er  h or  m o n al r e pl a c e  m e nt t h er a p y f or   m ai nt e n a n c e  of  c hr o ni c  c o n diti o ns ( e g, 
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  3 4  
i ns uli n, t h yr o xi n) is  p er  mitt e d.  Or al  c o ntr a c e pti v es  ar e  p er  mitt e d i n   w o  m e n  of  c hil d b e ari n g 
p ot e nti al.  
A c et a  mi n o p h e n (  ≤ 2  g/ d)  a n d t o pi c al  h y dr o c o rtis o n e f or  c o nt a ct  d er  m atitis  ar e  all o  w e d  d uri n g t h e 
i n p ati e nt st a y  at t h e  dis cr eti o n  of t h e in v esti g at or.    
A n y   m e di c ati o n ( ot h er t h a n s  t u d y  dr u g) t a k e n  b y s u bj e cts  d uri n g t h e  c o urs e  of t h e st u d y   will  b e 
r e c or d e d  a n d  c o d e d  usi n g t h e   W orl d   H e alt h   Or g a ni z ati o n (  W  H  O) dr u g  di cti o n ar y.  If  dr u g 
t h er a p y  ot h er t h a n t h at s p e cifi e d  b y t h e  pr ot o c ol is t a k e n,  a j oi nt  d e cisi o n   will  b e   m a d e  b y t h e 
in v esti g at or  a n d t h e  S p o ns or   w h et h er t o  c o nti n u e  or  dis c o nti n u e t h at s u bj e ct.   O n t h e  d a y 
p e xi d arti ni b is t a k e n,  a n y  c o n c o mit a nt  or al   m e di c ati o n t h at is r e q u  ir e d f or  a   m e di c al  c o n diti o n 
( e g,  di a b et es  or  h y p ert e nsi o n) is t o  b e t a k e n  at  8  h  p ost  d os e. 
5. 6. 1.    
Di et a r y  a n d   Lif est yl e   R est ri cti o ns   
S u bj e cts   will f ast ( n o f o o d  or  dri n k  ot h er t h a n   w at er)  o v er ni g ht ( at l e ast  1 0  h)  b ef or e t h e  c li ni c al 
l a b or at or y s af et y t ests  o n   D a y -2,  at  4 8  h  a n d  1 2 0  h  p ost  d os e,  a n d  at   C h e c k -o ut /  E arl y 
T er  mi n ati o n ( E T) .  Aft er  p e xi d arti ni b  a d  mi nistr ati o n, s u bj e cts   will  c o nti n u e t o f ast f or  4   h  p ost 
d os e.   S u bj e cts   will  n ot  b e  all o  w e d   w at er  d uri n g t h e  1 -h  p eri o d  b ef or e  a n d  2 -h  p eri o d  aft er  e a c h 
d os e  of  p e xi d arti ni b.    
A st a n d ar d   m e n u  a n d   m e al s c h e d ul e  b as e d  o n t h e   U nit e d  St at es   (  U S) R e c o  m  m e n d e d   D ail y 
All o  w a n c e   will  b e  e  m pl o y e d  u nif or  ml y t o  all s u bj e cts.    M e als  a n d/ or s n a c ks   will  b e s er v e d  at 
a p pr o pri at e ti  m es t h er e aft er.   T h e  c al ori e  c o nt e nt,  as   w ell  as t h e  p er c e nt  of  c al ori es fr o  m  pr ot ei n, 
c ar b o h y dr at e,  a n d f at,   will  b e  u nif or  m f or  e a c h   m e al  d uri n g t h e st u d y ( e g,  br e a kf ast  u nif or  m t o 
br e a kf ast, l u n c h  u nif or  m t o l u n c h).    
E x c e pt   w h e n  E  C  Gs  ar e  p erf or  m e d, s u bj e cts  will r e  m ai n s e at e d   wit h   mi ni  m al  a  m b ul ati o n (i e,  o nl y 
t o  a n d fr o  m t h e   w as hr o o  m  or f or st u d y  pr o c e d ur es) f or t h e first  4  h f oll o  wi n g  p e xi d arti ni b 
a d  mi nistr ati o n.    
S u bj e cts   m ust r efr ai n fr o  m  c o ns u  mi n g  gr a p efr uit/ gr a p efr uit j ui c e  a n d  S e vill e  or a n g es f or  7  d 
b ef or e  a d  mi nistr ati o n  o f st u d y  dr u g  o n   D a y  1  u ntil t h e E o S ,  a n d f o o d  or  b e v er a g es  c o nt ai ni n g 
c aff ei n e/ x a nt hi n e  f or  4 8  h  pri or t o   C h e c k-i n  o n   D a y -2  u ntil t h e  E o S  or  al c o h ol  f or 7 2  h  pri or t o 
C h e c k  -i n  o n   D a y -2  u ntil t h e  E o S .   S u bj e cts   m ust  n ot  e n g a g e i n  vig or o us  e x er cis e   w hil e r esi di n g 
i n t h e   Cli ni c al   U nit  or   wit hi n  7  d  of  e nt eri n g t h e   Cli ni c al   U nit.   
M al e s u bj e cts   m ust  us e  a  c o n d o  m  a n d s p er  mi ci d e,  a n d t h eir f e  m al e  p art n ers   m ust  us e  a n 
a d diti o n al   m et h o d  of  n o n h or  m o n al  c o ntr a c e pti o n (s u c h  as  a  c a p  or  di a p hr a g  m,  or i ntr a ut eri n e 
d e vi c e , if t h e y  ar e  o n a n  or al  c o ntr a c e pti v e,  t h e y  n e e d t o  us e a  n o n h or  m o n al   m et h o d i n  a d diti o n 
t o a n  or al  c o ntr a c e pti v e ) f or 1   m o  p ost -d os e ,  u nl ess t h e s u bj e ct’s  p art n er is  p ost  m e n o p a us al  or 
h as  h a d  a  h yst er e ct o  m y,  a  bil at er al s al pi n g e ct o  m y,  or  a  bil at er al  o o p h or e ct o  m y.   S u bj e cts   m ust 
us e  a  c o n d o  m  a n d s p er  mi ci d e if t h eir  p art n er  h as  h a d  a t u b al li g ati o n.   F or t h e  1 -m o   p eri o d  p ost 
d os e , m al e   s u bj e cts   m ust  n ot  h a v e s e x   wit h  a   w o  m a n   w h o is  pr e g n a nt  or  br e astf e e di n g,   wit h o ut 
usi n g  a  c o n d o  m.   T o  pr ot e ct  p art n ers fr o  m  p ossi bl e  e x p os ur e t o st u d y  dr u g i n s e  m e n,  m al e 
s u bj e cts   m ust  us e  a  c o n d o  m f or t h e  1 -m o   p eri o d  p ost  d os e ,  e v e n if t h e y  h a v e  h a d  a  v as e ct o  m y  or 
t h eir  p art n er is  n ot  of  c hil d b e ari n g  p ot e nti al.   P art n ers   w h o  ar e  n ot  of  c hil d b eari n g  p ot e nti al  ar e 
d efi n e d  as:   m e n;  p ost  m e n o p a us al   w o  m e n ( n o   m e nstr u al  p eri o ds f or  at l e ast  1 2  c o ns e c uti v e  m o); 
or   w o  m e n   w h o  h a v e  u n d er g o n e  a  h yst er e ct o  m y,  a  bil at er al  o o p h or e ct o  m y,  or  a  bil at er al 
s al pi n g e ct o  m y.    
S u bj e cts   m ust  n ot s u n b at h e  or  us e  a s u n b e d  d uri n g t h e st u d y.  
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  3 5  
5. 7.    
S u bj e ct   Wit h d r a  w al/  Dis c o nti n u ati o n  
5. 7. 1.    
R e as o ns f o r   Wit h d r a  w al   
A n y s u bj e ct   w h o  dis c o nti n u es   fr o  m t h e st u d y f or  a n y r e as o n   will  h a v e t h e  d at e  of dis c o nti n u ati o n 
a n d  r e as o n(s) r e c or d e d.    A s u bj e ct   will  b e  c o nsi d er e d  a  c o  m pl et er if  h e/s h e  pr ovi d es t h e l ast 
s c h e d ul e d  P  K s a  m pl e.  
S u bj e cts   m a y  b e   wit h dr a  w n fr o  m t h e st u d y  aft er si g ni n g i nf or  m e d  c o ns e nt f or t h e f oll o  wi n g 
r e as o ns:  
    A E   
    Wit h dr a  w al  of  c o ns e nt  b y s u bj e ct   
    P h ysi ci a n  d e cisi o n  
    Pr e g n a n c y  
    Pr ot o c ol  d e vi ati o n  
    St u d y t er  mi n at e d  b y  S p o ns or  
    Ot h er   
5. 7. 2.    
Wit h d r a  w al  P r o c e d u r es   
If  a s u bj e ct is   wit h dr a  w n fr o  m t h e st u d y, t h e in v esti g at or   will  c o  m pl et e  a n d r e p ort t h e 
o bs er v ati o ns  as t h or o u g hl y  as  p ossi bl e  u p t o t h e  d at e  of   wit h dr a  w al, i n cl u di n g t h e  d at e  of l ast 
tr e at  m e nt  a n d t h e r e as o n f or   wit h dr a  w al.   
If t h e s u bj e ct is   wit h dr a  w n  d u e t o  a n   A E, t h e  in v esti g at or   will f oll o  w t h e s u bj e ct  u ntil t h e   A E  h as 
r es ol v e d  or st a bili z e d.   
All s u bj e cts   w h o  ar e   wit h dr a  w n fr o  m t h e st u d y s h o ul d  c o  m pl et e  pr ot o c ol  -s p e cifi e d   wit h dr a  w al 
pr o c e d ur es.    
5. 7. 3.    
S u bj e ct   R e pl a c e  m e nt  
S u bj e cts   wi t h HI   m a y  b e r e pl a c e d   wit h  a p pr o v al fr o  m t h e  S p o ns or.   
5. 7. 4.    
S u bj e ct   R e -t esti n g P r o c e d u r es  
P ot e nti al  HI   s u bj e cts   w h o  h a v e  a  dis q u alif yi n g l a b or at or y r es ult   will  b e  all o  w e d t o r e -t est a n d , 
o nl y  u p o n  q u alif yi n g f or t h e st u d y , will r e c ei v e  a s u bj e ct  n u  m b er  . 
5. 8.    
C rit e ri a   f o r  S us p e n di n g  St u d y   T r e at  m e nt 
T h e s u bj e ct   will  b e  dis c o nti n u e d fr o  m t h e st u d y f or r e as o ns s u c h  as:   
1.    If  a n y  cli ni c al l a b or at or y  a b n or  m alit y is  d et e ct e d  a n d  c o nsi d er e d  cli ni c all y si g nifi c a nt,  at 
t h e  dis cr eti o n  of t h e in v esti g at or  a n d f oll o  wi n g  dis c ussi o n   wi t h t h e  S p o ns or. 
2.    If  a s u bj e ct  pr es e nts  a n y si g nifi c a nt tr e at  m e nt  e  m er g e nt A E,  as  d et er  mi n e d  b y t h e 
in v esti g at or.  
3.    If  a s u bj e ct  us es  c o n c urr e nt   m e di c ati o ns s p e cifi e d i n t h e  e x cl usi o n  crit eri a ( S e cti o n  4. 2 ). 
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  3 6  
6.    
S  T  U  D  Y  P  R  O  C  E  D  U  R  E S  
T his is  a  P h as e  1,  o p e n -l a b el, 1 -tr e at  m e nt, 1 -p eri o d st u d y.   A st u d y  visit s c h e d ul e i n t a b ul ar 
f or  m at is  pr o vi d e d i n A p p e n di x   1 6. 5 . 
6. 1.    
S c r e e ni n g  
S u bj e cts   will  b e  s cr e e n e d   D a y  -2 2 t hr o u g h   D a y  -2 .   
T h e f oll o  wi n g  a cti viti es  a n d/ or  ass ess  m e nts   will  b e  p erf or  m e d:   
D a y   -2 2 t o   D a y  -2  ( S cr e e ni n g)  
    I nf or  m e d  c o ns e nt.  
    M e di c al/s ur gi c al  hist or y,  d e  m o gr a p hi cs,  a n d i n cl usi o n/ e x cl usi o n  crit eri a.    
    C o  m pl et e  p  h ysi c al  e x a  mi n ati o n.   
    Uri n e  dr u g  s  of  a b us e s cr e e n ( o pi at es,  b e n z o di a z e pi n es,  a  m p h et a  mi n es,  c a n n a bi n oi ds, 
c o c ai n e,  b ar bit ur at es,  p h e n c y cli di n e),  c oti ni n e,  a n d  br e at h  al c o h o l t esti n g. 
    Bl o o d t est f or   HI  V  a nti b o d y,   H  Bs  A g,  a n d   H  C  V   or   H  A  V  a nti b o d y.   
    S er u  m  pr e g n a n c y t est f or f e  m al e s u bj e cts.   
    S er u  m  F S  H t est f or  p ost  m e n o p a us al f e  m al e s u bj e cts.   
    Cli ni c al l a b or at or y t ests f or s er u  m  c h e  mistr y,  h e  m at ol o g y,  c o a g ul ati o n   (i n cl u di n g  P T 
a n d  I nt er n ati o n al   N or  m ali z e d   R ati o [I  N  R]),  a n d  uri n al ysis f oll o  wi n g  at l e ast  a 1 0 -h 
o v er ni g ht f ast.  S u bj e cts s h o ul d  n ot  h a v e i n g est e d  al c o h ol f or  7 2  h  pri or t o t h e  visit.  
    Si n gl e  1 2 -l e a d  E  C  Gs  aft er  1 0 mi n  of r est i n t h e s u pi n e  p ositi o n.   
    Vit al si g ns ( di ast oli c   bl o o d  pr ess ur e [  D  B P], s yst oli c  bl o o d  pr ess ur e [ S  B P],  or al 
t e  m p er at ur e,  p uls e,  a n d r es pir at or y r at e)   m e as ur e d  aft er  at l e ast  1 0   mi n  of r est i n t h e 
s u pi n e  p ositi o n;  b o d y   w ei g ht,  h ei g ht,  a n d   B  MI   will  b e r e c or d e d.  
    R e c or d  e  G F  R    
    R e c or d   C hil d  -P u g h s c or e  f or s u bj ects   wit h   m o d er at e   HI .  T his   will  b e  coll e ct e d f or 
i nf or  m ati o n  p ur p os e  o nl y a n d   will  b e i n cl u d e d i n t h e  cli ni c al  d at a b as e . 
    R e c or d  h e p ati c i  m p air  m e nt st at us   b y   N  CI -O  D  W  G  crit eri a f or s u bj e cts   wit h   m o d er at e 
HI.  T his   will  b e  us e d f or i n cl usi o n/ e x cl usi o n  crit eri a   a n d   will  b e i n cl u d e d i n t h e 
cli ni c al  d at a b as e .  
    R e c or d  pri or/ c o n c o  mit a nt   m e di c ati o ns.    
    R e c or d   A Es   a n d  r el at e d n ess t o tr e at  m e nts ( dr u g  a n d  n o n dr u g)  gi v e n f or   A Es. 
6. 2.    
S u bj e ct   M a n a g e  m e nt  
N ot  a p pli c a bl e   
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  3 7  
6. 3.    
R a n d o  mi z ati o n   
N ot  a p pli c a bl e   
6. 4.    
T r e at  m e nt  P e ri o d   
6. 4. 1.    
C h e c k  -i n 
Eli gi bl e s u bj e cts   will  b e  a d  mitt e d t o t h e  cli ni c  d uri n g   C h e c k  -i n  o n   D a y -2 .  S u bj e cts   will r e  m ai n 
i n t h e  cli ni c  u ntil t h e  c o  m pl eti o n  of  all st u d y  pr o c e d ur es,  a p pr o xi  m at el y  1 6 8  h ( 7 d a ys)  aft er  or al 
a d  mi nistr ati o n  of  p e xi d arti ni b (s e e s c h e d ul e  of  ass ess  m e nt s).  T h e f oll o  wi n g  a cti viti es  a n d/ or 
ass ess  m e nts   will  b e  p erf or  m e d:   
D a y   -2  (  C h e c k-i n) 
  A d  missi o n
  M e di c al/s ur gi c al  hist or y  a n d i n cl usi o n/ e x cl usi o n  crit eri a.
  C o  m pl et e  p  h ysi c al  e x a  mi n ati o n.
  Uri n e  dr u g  s  of  a b us e s cr e e n ( o pi at es,  b e n z o di a z e pi n es,  a  m p h et a  mi n es,  c a n n a bi n oi ds,
c o c ai n e,  b ar bit ur at es,  p h e n c y cli di n e),  c oti ni n e,  a n d  br e at h  al c o h ol  t esti n g.
  S er u  m  pr e g n a n c y t est f or f e  m al e s u bj e cts.
  Cli ni c al l a b or at or y t ests f or s er u  m  c h e  mistr y,  h e  m at ol o g y,  c o a g ul ati o n   (in cl u di n g  P T
a n d I  N  R) ,  a n d  uri n al ysis f oll o  wi n g  at l e ast  a  1 0-h  o v er ni g ht f ast.  I n t h e   HI  gr o u p,
cli ni c al l a b t ests f or  T  B I L   m ust  b e  c o nfir  m e d.
  Si n gl e  1 2 -l e a d  E  C  Gs r e c or d e d  aft er  1 0 mi n  of r est i n t h e s u pi n e  p ositi o n.
  Vit al si g ns (  D  B P,  S  B P,  or al t e  m p er at ur  e,  p uls e,  a n d r es pir at or y r at e)   m e as ur e d  aft er
at l e ast  1 0   mi n  of r est i n t h e s u pi n e  p ositi o n.    B o d y   w ei g ht   will  b e r e c or d e d.
  R e c or d  e  G F  R
  R e c or d   pri or/ c o n c o  mit a nt   m e di c ati o ns.
  R e c or d   A Es  a n d tr e at  m e nts ( dr u g  a n d  n o n dr u g)  gi v e n f or   A Es.
  B e gi n   cli ni c  c o nfi n e  m e nt .
D a y   -1  
  R e c or d  pri or/ c o n c o  mit a nt   m e di c ati o ns  .
  R e c or d   A Es  a n d tr e at  m e nts ( dr u g  a n d  n o n  -dr u g)  gi v e n f or   A Es .
  If  d e e  m e d  n e c ess ar y  b y t h e  PI,  T  BI L l e v el   m a y  b e r e c o nfir  m e d i n s u bj e cts   wit h
m o d er at e   HI  .
  R e c or d   C hil d  -P u g h  cl assifi c ati o n s c or e f or i n f or  m ati o n  o nl y.
  Cli ni c  c o nfi n e  m e nt  .
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  3 8  
6. 4. 2.    
T r e at  m e nt  P h as e   
T h e f oll o  wi n g  a cti viti es  a n d/ or  ass ess  m e nts   will  b e  p erf or  m e d:   
6. 4. 2. 1.    D a y  1   D osi n g   
    Si n gl e  1 2 -l e a d  E  C  Gs   will  b e r e c or d e d at  pr e d os e ( at  6 0   mi n  pri or t o  p e xi d arti ni b 
d osi n g)  a n d  at  1,  2,  3 , a n d  4  h  p ost -p e xi d arti n i b  d os e. 
    Vit al si g ns (  D  B P,  S  B P,  or al t e  m p er at ur e,  p uls e,  a n d r es pir at or y r at e)   will  b e   m e as ur e d 
at  pr e d os e ( at  6 0   mi n  pri or t o  p e xi d arti ni b  d osi n g)  a n d  at  1,  2,  3 , a n d  4  h  
p ost -p e xi d arti ni b  d os e.  
    P e xi d arti ni b  d osi n g : s u bj e cts   will r e c ei v e  20 0  m g ( 1     2 0 0 -m g  c a ps ul e  )  of 
p e xi d arti ni b  or all y   wit h  2 4 0   m L  of   w at er f oll o  wi n g  at l e ast  a  1 0 -h  o v er ni g ht f ast; 
s u bj e cts   will  c o nti n u e t o f ast f or  a n  a d diti o n al  4  h  aft er  d osi n g.    
    Bl o o d s a  m pl es ( 1  ×  4  -m L t u b e  c o nt ai ni n g  Li   H e p ari n)   will  b e  c oll e ct e d f or  P  K 
a n al ysi s  of  p e xi d arti ni b  a n d  Z  A  A  D -1 0 0 6 a  at  pr e d os e (  wit hi n  3 0   mi n  pri or t o  d osi n g) 
a n d  at  0. 5,  1,  1. 5,  2,  2. 5,  3,  3. 5,  4,  4. 5,  5,  6,  8,  1 0,  a n d  1 2  h  p ost  d os e.    
    A   1 0 -m L   bl o o d s a m pl e   will  b e  o bt ai n e d  at   2. 5  h  p ost  d os e f or  pl as  m a  pr ot ei n  bi n di n g.  
    R e c or d   pri or/ c o n c o  mit a nt   m e di c ati o ns  b ef or e  a n d  aft er  p e xi d arti ni b  d osi n g .  
    R e c or d   A Es  a n d   r el at e d n ess t o tr e at  m e nts ( dr u g  a n d  n o n-dr u g)  gi v e n f or   A Es  b ef or e 
a n d  aft er  p e xi d arti ni b  d osi n g . 
    Cli ni c  c o nfi n e  m e nt  . 
6. 4. 2. 2.    D a y   2  t h r o u g h   D a y 4    
    Cli ni c al l a b or at or y t ests f or s er u  m  c h  e  mistr y,  h e  m at ol o g y,  c o a g ul ati o n  (i n cl u di n g  P T 
a n d I  N  R) ,  a n d  uri n al ysis f oll o  wi n g  at l e ast  a  1 0-h  o v er ni g ht f ast  at  4 8  h  p ost  d os e . 
    Bl o o d s a  m pl es ( 1  ×  4  -m L t u b e  c o nt ai ni n g  Li   H e p ari n)   will  b e  c oll e ct e d f or  P  K 
a n al ysis  of  p e xi d arti ni b  a n d  Z  A  A  D -1 0 0 6 a  at  2 4 , 3 6 , 4 8 , a n d  7 2  h  p ost  d os e.    
    A  1 0  -m L  bl  o o d s a  m pl e   will  b e  o bt ai n e d  at  2 4  h  p ost  d os e f or  pl as  m a  pr ot ei n  bi n di n g.  
    R e c or d  c o n c o  mit a nt   m e di c ati o ns  .  
    R e c or d   A Es  a n d   r el at e d n ess t o tr e at  m e nts ( dr u g  a n d  n o n-dr u g)  gi v e n f or   A Es .  
    Cli ni c  c o nfi n e  m e nt  . 
6. 4. 2. 3.    D a y   5  t h r o u gh   D a y  7  
    Cli ni c al l a b or at or y t ests f or s er u  m  c h e  mistr y,  h e  m at ol o g y,  c o a g ul ati o n   (i n cl u di n g  P T 
a n d I  N  R) ,  a n d  uri n al ysis f oll o  wi n g  at l e ast  a 1 0 -h  o v er ni g ht f ast  at  1 2 0  h  p ost  d os e . 
    Bl o o d s a  m pl es ( 1  ×  4  -m L t u b e  c o nt ai ni n g  Li   H e p ari n)   will  b e  c oll e ct e d f or  P  K 
a n al ysis  of  p e xi d arti ni b  a n d  Z  A  A  D -1 0 0 6 a  at  9 6,  1 2 0,  a n d  1 4 4  h  p ost  d os e.  
    R e c or d  c o n c o  mit a nt   m e di c ati o ns.    
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  3 9  
    R e c or d   A Es  a n d   r el at e d n ess t o tr e at  m e nts ( dr u g  a n d  n o n-dr u g)  gi v e n f or   A Es.  
    Cli ni c  c o nfi n e  m e nt  . 
6. 5.    
W as h o ut   
N ot  a p pli c a bl e   
6. 6.    
C h e c k  -o ut  o r   E a rl y   T e r  mi n ati o n  
S u bj e cts   will  b e  dis c h ar g e d  o n   D a y  8  aft er t h e y  u n d er g o t h e  ass ess  m e nts  d es cri b e d  b el o  w.  
S u bj e cts   w h o   wit h dr a  w fr o  m t h e st u d y  e arl y   will  u n d er g o t h e s a  m e  ass ess  m e nts  as t h os e 
a d  mi nist er e d  o n   D a y  8 :  
    C o  m pl et e  p  h ysi c al  e x a  mi n ati o n.    
    Uri n e   pr e g n a n c y t est f o r f e  m al e s u bj e cts.  
    Cli ni c al l a b or at or y t ests f or s er u  m  c h e  mistr y,  h e  m at ol o g y,  c o a g ul ati o n   (i n cl u di n g  P T 
a n d I  N  R) ,  a n d  uri n al ysis f oll o  wi n g  at l e ast  a 1 0 -h  o v er ni g ht f ast.  
    Si n gl e  1 2 -l e a d  E  C  G   will  b e r e c or d e d  b ef or e  br e a kf ast  a n d  aft er  1 0   mi n  of r est i n t h e 
s u pi n e  p ositi o n.   
    Vit al si g ns (  D  B P,  S  B P,  or al t e  m p er at ur e,  p uls e,  a n d r es pir at or y r at e)   will  b e   m e as ur e d 
b ef or e  br e a kf ast  a n d  aft er  at l e ast  1 0   mi n i n t h e s u pi n e  p ositi o n.    B o d y   w ei g ht   will  b e 
r e c or d e d. 
    Bl o o d s a  m pl e ( 1     4 -m L t u b e  c o nt ai ni n g  Li   H e p ari n)   f or  P  K  a n al ysis  of  p e xi d arti ni b 
a n d  Z  A  A  D -1 0 0 6 a  at  1 6 8  h  p ost  d os e . 
    R e c or d  c o n c o  mit a nt   m e di c ati o ns.   
    R e c or d   A Es  a n d   r el at e d n ess t o tr e at  m e nts ( dr u g  a n d  n o n-dr u g)  gi v e n f or   A Es.  
6. 7.    
F oll o  w -u p  
F oll o  w  u p   will  o c c ur f or  a n y  T E  A E  u ntil r es ol v e d  or st a bili z e d .  
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  4 0  
7.  
P  H  A  R  M  A  C  O  KI  N  E  TI  C/ P  H  A  R M  A  C  O  D  Y  N  A  MI  C   A S S  E S S  M  E  N  T S
7. 1.    
P h a r  m a c o ki n eti c   Ass ess  m e nts
B  l o o d s a  m pl es ( 1  ×  4-m L t u b e  c o nt ai ni n g  Li   H e p ari n)   will  b e  c oll e ct e d f or  P  K  a n al ysis  of 
p e xi d arti ni b  a n d  Z  A  A  D -1 0 0 6 a   m et a b olit e,  at  pr e d os e (  wit hi n  6 0  mi n  pri or t o  d osi n g)  a n d  at  0. 5, 
1,  1. 5,  2,  2. 5,  3,  3. 5,  4,  4. 5,  5,  6,  8,  1 0,  1 2,  2 4,  3 6,  4 8,  7 2,  9 6,  1 2 0,  1 4 4,  a n d  1 6 8  h  p ost  d os e.   
A  d diti o n al  1 0 -m L   s a  m pl es   will  b e  c oll e ct e d t o  d et er  mi n e  pr ot ei n  bi n di n g of  p e xi d arti ni b  a n d 
Z  A  A  D -1 0 0 6 a  at  2. 5  a n d  2 4  h  p os t d os e . 
Pl as  m a   will  b e  h ar v est e d  a n d  a n al y z e d f or t h e  q u a ntifi c ati o n  of  p e xi d arti ni b  usi n g  a  v ali d at e d 
li q ui d  c hr o  m at o gr a p h y-t a n d e  m   m ass s p e ctr o  m etr y   m et h o d.   T h e  Z  A  A  D-1 0 0 6 a   m et a b olit e   will  b e 
a n al y z e d  usi n g  a  q u alifi e d li q ui d  c hr o  m at o gr a p h y -t a n d e  m   m ass s pe ctr o  m etr y  ass a y.  A d diti o n al 
e x pl or at or y  m et a b olit e   a n al ysis   m a y  b e  c o n d u ct e d  usi n g t h e l eft o v er  pl as  m a s a  m pl es.   
F or t h e   wi n d o  ws f or  P  K  bl o o d s a  m pl e  c oll e cti o n  a n d  pr ot ei n  bi n di n g s a  m pl e  c oll e cti o n  will   
f oll o  w t h e D aii c hi  S a n k y o’s   N o n c o  m p art  m e nt al   A n al ysi  s   G ui d eli n es. 
P  K  bl o o d s a  m pl e  c oll e cti o n s h o ul d  h a v e  p ri o rit y  o v e r  ot h e r st u d y  ass ess  m e nts.   F or  ot h er 
st u d y  ass ess  m e nts, i n  c as e t h e  distri b uti o n  of   m e als  or ti  m e f or st u d y  ass ess  m e nts  c oi n ci d e   wit h 
t h e s a  m pl e  c oll e cti o n ti  m e, t h e s e q u e n c e  of  e v e nts s h o uld  b e  as f oll o  ws:  E  C  G,   m e as ur e  m e nt  of 
vit al si g ns,  bl o o d s a  m pli n g,  a n d  distri b uti o n  of   m e als,  u nl ess st at e d  diff er e ntl y.    D e vi ati o ns fr o  m 
t h e list e d  P  K   wi n d o  ws  ar e r e g ar d e d  as  pr ot o c ol  d e vi ati o ns.    All ot h er  ass ess  m e nts s h o ul d  b e 
c o  m pl et e d   wit hi n  3 0   mi n  of  t h e s c h e d ul e d ti  m e  p oi nt, t h e   wi n d o  w f or  pr e d os e  ass ess  m e nts  c a n 
o c c ur  u p t o  9 0  mi n  pri or t o  d osi n g.    D e vi ati o ns fr o  m t h e s c h e d ul e d ti  m e  of  all  ot h er  pr o c e d ur es 
o utsi d e  of  3 0   mi n   will  b e r e g ar d e d  as  pr ot o c ol  d e vi ati o ns.  
T h e f oll o  wi n g  P  K  p ar a  m et ers   will  b e  c al c ul at e d  b y  c o  m p art  m e nt -m o d el  -i n d e p e n d e nt  a n al ysis, 
b as e d  o n t h e  t ot al  a n d  u n b o u n d c o n c e ntr ati o n s of  p e xi d arti ni b  in t h e  pl as  m a;   C  m a x,  T  m a x, 
A  U  Cl ast,   A  U  Ci nf,   k el,  t 1/ 2,   C L/ F,  a n d   V z/ F.  T h e f oll o  wi n g  P  K  p ar a  m et ers   will  b e  c al c ul at e d 
f or  Z  A  A  D-1 0 0 6 a  b as e d  o n t h e  t ot al  a n d  u n b o u n d c o n c e ntr ati o n s of  Z  A  A  D -1 0 0 6 a  in t h e  pl as  m a : 
C  m a x,  T  m a x,   A  U  Cl ast,   A  U  Ci nf,  a n d t 1/ 2  .  T h e   M P  R   will  b e  d et er  mi n e d  b as e d  o n t ot al 
c o n c e ntr ati o ns  of  p e xi d arti ni b  a n d  Z  A  A D  -1 0 0 6 a.  
P  K  a n al ysis   will  b e  c o n d u ct e d i n  c o  m pli a n c e   wit h   D ai i c hi  S a n k y o’s   N o n c o  m p art  m e nt al   A n al ysis 
G ui d eli n es  .6  
7. 2.    
P h a r  m a c o d y n a  mi c   Ass ess  m e nts  
N ot  a p pli c a bl e   
7. 3.    
I  m  m u n o g e ni cit y  
N ot  a p pli c a bl e   
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  4 1  
8.    
S  A F  E  T  Y   E  V  A  L  U  A  TI  O  N   A  N D   R  E P  O  R  TI  N  G   
8. 1.    
Ass ess  m e nt  of  S af et y   E n d p oi nt   E v e nt  s 
T h e s af et y  e n d p oi nts i n cl u d e  p h ysi c al  e x a  mi n ati o n fi n di n gs,  vit al si g n   m e as ur e  m e nts, i n ci d e n c e 
of   A Es,  cli ni c al l a b or at or y t est r es ults (i n cl u di n g   A S T/  A L T),  a n d  E  C  G r e c or di n gs.   
8. 2.    
A d v e rs e   E v e nt   C oll e cti o n  a n d   R e p o rti n g   
All  cli ni c al   A Es (s e e   S e cti o n  8. 4. 1  f or  d efi niti o ns)  o c c urri n g  aft er t h e s u bj e ct si g ns t h e I  C F  a n d 
u p t o  3 0  d  aft er t h e  fi n al d os e  of  p e xi d arti ni b,   w h et h er  o bs er v e d  b y t h e  in v esti g at or  or r e p ort e d 
b y t h e s u bj e ct,   will  b e r e c or d e d  o n t h e   A E  e  C  R F  p a g e.    M e di c al  c o n diti o ns (i n cl u di n g  cli ni c al 
l a b or at or y  v al u es/ vit al si g ns t h at  ar e  o ut  of r a n g e) t h at   w er e  di a g n os e d  or  k n o  w n t o  e xist  pri or t o 
inf o r  m e d c o ns e nt   will  b e r e c or d e d  as  p art  of   m e di c al  hist or y.    
All   A Es, i n cl u di n g s eri o us  a d v ers e  e v e nts ( S  A Es),  ar e t o  b e r e p ort e d  a c c or di n g t o t h e  pr o c e d ur es 
i n S e cti o n  8. 5 .   
All  cli ni c al l a b or at or y r es ults,  vit al si g ns,  a n d  E  C  G r es ults  or fi n di n gs s h o ul d  b e  a p pr ais e d  b y t h e 
in v esti g at or t o  d et er  mi n e t h eir  cli ni c al si g nifi c a n c e.  Is ol at e d  a b n or  m al  cli ni c al l a b or at or y t est 
r es ults,  vit al si g n fi n di n gs,  or  E  C  G fi n di n gs (i e,  n ot  p art  of  a r e p ort e d  di a g n osis) s h o ul d  b e 
r e p ort e d  as   A Es if t h e y  ar e s y  m pt o  m ati c, l e a d t o st u d y  dr u g  disc o nti n u ati o n,  d os e r e d u cti o n, 
r e q uir e  c orr e cti v e tr e at  m e nt,  or  c o nstit ut e  a n   A E i n t h e in v esti g at or’s  cli ni c al j u d g  m e nt.  
At  e a c h   ti  m e  p oi nt, t h e in v esti g at or   will  d et er  mi n e   w h et h er  a n y   A Es  h a v e  o c c urr e d  b y  e v al u ati n g 
t h e s u bj e ct.    AE s   m a y  b e  dir e ctl y  o bs er v e d, r e p ort e d s p o nt a n e o usl y  b y t h e s u bj e ct  or  b y 
q u esti o ni n g t h e s u bj e ct  at  e a c h  ti  m e  p oi nt.   S u bj e cts s h o ul d  b e  q u esti o n e d i n  a  g e n er al   w a y, 
wit h o ut  as ki n g  a b o ut t h e  o c c urr e n c e  of  a n y s p e cifi c s y  m pt o  ms.   T h e   in v esti g at or   m ust  ass ess  all 
A Es t o  d et er  mi n e s  eri o us n ess, s e v erit y,  a n d  c a us alit y, i n  a c c or d a n c e   wit h t h e  d efi niti o ns i n 
S e cti o n  8. 4 .   T h e in v esti g at or’s  ass ess  m e nt   m ust  b e  cl e arl y  d o c u  m e nt e d i n  t h e st u d y sit e’s s o ur c e 
d o c u  m e nt ati o n   wit h t h e  in v esti g at or’s si g n at ur e.    
Al  w a ys r e p ort t h e  di a g n osis  as t h e   A E  or  S  A E t er  m.    W h e n  a  di a g n osis is  u n a v ail a bl e, r e p ort t h e 
pri  m ar y si g n  or s y  m pt o  m  as t h e   A E  or  S  A E t er  m   wit h  a d diti o n al  d et ails i n cl u d e d i n t h e  n arr ati v e 
u ntil t h e  di a g n osis  b e c o  m es  a v ail a bl e.  If t h e si g ns  a n d s y  m pt o  m s  ar e  disti n ct  a n d  d o  n ot s u g g est 
a  c o  m  m o n  di a g n osis, r e p ort t h e  m  as i n di vi d u al  e ntri es  of   A E  or  S  A E.    
F or  e v e nts t h at  ar e s eri o us  d u e t o  h os pit ali z ati o n, t h e r e as o n f or  h os pit ali z ati o n   m ust  b e r e p ort e d 
as t h e  S  A E  ( di a g n osis  or s y  m pt o  m r e q uiri n g  h os pit aliz ati o n).    A  pr o c e d ur e is  n ot  a n   A E  or  S  A E, 
b ut t h e r e as o n f or t h e  pr o c e d ur e   m a y  b e  a n   A E  or  S  A E.   Pr e -pl a n n e d ( pri or t o si g ni n g t h e  I C F) 
pr o c e d ur e s or tr e at  m e nt s r e q uiri n g  h os pit ali z ati o n f or  pr e-e xisti n g  c o n diti o ns  t h at d o  n ot   w ors e n 
i n s e v erit y s h o ul d  n ot  b e r e p ort e d  as  S  A Es (s e e S e cti o n  8. 4. 2  f or  d efi niti o ns).   
F or  d e at hs, t h e  u n d erl yi n g  or i  m  m e di at e  c a us e  of  d e at h s h o ul d  al  w a ys  b e r e p ort e d  as  a n  S  A E.  
A n y s eri o us,  u nt o  w ar d  e v e nt t h at   m a y  o c c ur s u bs e q u e nt t o t h e r e p orti n g  p eri o d t h at t h e 
in v esti g at or  ass ess es  as r el at e d t o st u d y  dr u g s h o ul d  als o  b e r e p ort e d  a n d   m a n a g e d  as  a n  S  A E.  
T h e  in v esti g at or s h o ul d f oll o  w s u bj e cts   wit h   A Es  u ntil t h e  e v e nt  h as r es ol v e d  or t h e  c o n diti o n 
h as st a bili z e d.  I n  c as e  of  u nr es ol v e d   A Es, i n cl u di n g si g nifi c a nt  a b n or  m al  cli ni c al l a b or at or y 
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  4 2  
v al u es  at t h e  e n d  of st u d y  ass ess  m e nt, t h es e  e v e nts   will  b e f oll o  w e d  u ntil r es ol uti o n  or  u ntil t h e y 
b e c o  m e  cli ni c all y  n ot r el e v a nt.   
8. 3.    
A d v  e rs e   E v e nts  of  S p e ci al I nt e r est  
A d v e rs e   E v e nts  of  S p e ci al I nt e r est   
C o  m bi n e d  el e v ati o ns  of  a  mi n otr a nsf er as es  a n d  bilir u bi n,  eit h er s eri o us  or  n o ns eri o us  a n d 
w h et h er  or  n ot  c a us all y r el at e d,   m e eti n g t h e  crit eri a  of  a  p ot e nti al   H y’s  L a  w  c as e (t ot al  bilir u bi n 
l e v el  ≥ 2  ×   U L  N   wit h si  m ult a n e o usl y   A L T  or   A S T  ≥ 3  ×   U L  N) s h o ul d  al  w a ys  b e r e p ort e d t o t h e 
S p o ns or  as s o o n  as  p ossi bl e f oll o  wi n g t h e  pr o c e d ur es  o utli n e d i n  S e cti o n  8. 5  f or  S  A E r e p orti n g, 
wit h t h e i n v esti g at or’s  ass ess  m e nt  of s eri o us n ess,  c a us alit y,  a n d  a  d et ail e d  n arr ati v e.   
8. 4.    
A d v e rs e   E v e nt   
8. 4. 1.    
D efi niti o n  of   A d v e rs e   E v e nt   
A n   A E is  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  a d  mi nist er e d  a  p h ar  m a c e uti c al  pr o d u c  t 
a n d t h at  d o es  n ot  n e c ess aril y  h a v e t o  h a v e  a  c a us al r el ati o ns hi p   wit h t his tr e at  m e nt.    A n   A E  c a n 
t h er ef or e  b e  a n y  u nf a v or a bl e  a n d  u ni nt e n d e d si g n (i n cl u di n g  a n  a b n or  m al  cli ni c al l a b or at or y 
fi n di n g, f or  e x a  m pl e), s y  m pt o  m,  or  dis e as e t e  m p or all y  ass o ci at e d wit h t h e  us e  of  a   m e di ci n al 
pr o d u ct,   w h et h er  or  n ot  c o nsi d er e d r el at e d t o t h e   m e di ci n al  pr o d u ct (I  C  H  E 2  A   G ui d eli n e.  
Cli ni c al  S af et y   D at a   M a n a g e  m e nt:   D efi niti o ns  a n d  St a n d ar ds f or  E x p e dit e d   R e p orti n g, 
O ct  o b er 1 9 9 4).  
It is t h e r es p o nsi bilit y  of in v esti g at ors ,  b as e d  o n t h eir  k n o  wl e d g e  a n d  e x p eri e n c e, t o  d et er  mi n e 
t h os e  cir c u  mst a n c es  or  a b n or  m al  cli ni c al l a b or at or y fi n di n gs   w hi c h s h o ul d  b e  c o nsi d er e d   A Es. 
8. 4. 2.    
S e ri o us   A d v e rs e   E v e nt  
A n  S  A E is  a n y  u nt o  w ar d   m e di c al  o c c urr e n c e t h at  at  a n y  d os e:   
    R es ults i n  d e at h   
    Is lif e-t hr e at e ni n g 
    R e q uir es i n p ati e nt  h os pit ali z ati o n  or  pr ol o n g ati o n  of  e xisti n g  h os pit ali z ati o n   
    R es ults i n  p ersist e nt  or si g nifi c a nt  dis a bilit y/i n c a p a cit y   
    Is  a  c o n g e nit al  a n o  m al y/ birt h  d ef e ct  or 
    Is  a n i  m p ort a nt   m e di c al  e v e nt 
N ot e:  T h e t er  m  “lif e  -t hr e at e ni n g ” i n t h e  d efi niti o n  of  “s eri o us ” r ef ers t o  a n  e v e nt i n   w hi c h t h e 
s u bj e ct   w as  at ris k  of  d e at h  at t h e ti  m e  of t h e  e v e nt; it  d o es  n ot r ef er t o  a n  e v e nt   w hi c h 
h y p ot h eti c all y   mi g ht  h a v e  c a us e d  d e at h if it   w er e   m or e s e v er e (I  C  H  E 2  A   G ui d eli n e.    Cli ni c al 
S af et y   D at a  M a n a g e  m e nt:   D efi niti o ns  a n d  St a n d ar ds f or  E x p e dit e d   R e p orti n g,   O ct o b er  1 9 9 4).   
M e di c al  a n d s ci e ntifi c j u d g  m e nt s h o ul d  b e  e x er cis e d i n  d e ci di n g   w h et h er  e x p e dit e d r e p orti n g is 
a p pr o pri at e i n  ot h er sit u ati o ns, s u c h  as i  m p ort a nt   m e di c al  e v e nts t h at   m a y  n ot  b e i m  m e di at el y 
lif e-t hr e at e ni n g  or r es ult i n  d e at h  or  h os pit ali z ati o n  b ut   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 
i nt er v e nti o n t o  pr e v e nt  o n e  of t h e  ot h er  o ut c o  m es list e d i n t h e  d efi niti o n  a b o v e.   E x a  m pl es 
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  4 3  
i n cl u d e  all er gi c  br o n c h os p as  m,  c o n v ulsi o ns,  a n d  bl o od  d ys cr asi as  or  d e v el o p  m e nt  of  dr u g 
d e p e n d e n c y  or  dr u g  a b us e.  
N ot e:    
Pr o c e d ur es  ar e  n ot   A Es  or  S  A Es,  b ut t h e r e as o n f or t h e  pr o c e d ur e   m a y  b e  a n   A E  or  S  A E.    
Pr e -pl a n n e d ( pri or t o si g ni n g t h e I  C F)  pr o c e d ur es  or tr e at  m e nts r e q uiri n g  h os pit ali z ati o ns f or 
pr e -e xisti n g  c o n diti o ns t h at  d o  n ot   w ors e n i n s e v erit y  ar e  n ot  S  A Es.  
8. 4. 3.    
S e v e rit y   Ass ess  m e nt  
T h e f oll o  wi n g  d efi niti o ns s h o ul d  b e  us e d t o  ass ess i nt e nsit y  of   A Es ( b as e d  o n t h e   N ati o n al 
C a n c er I nstit ut 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 T  C  A E],  v er  si o n 5 . 0): 
    Gr a d e  1:   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  
    Gr a d e  2:   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 cti viti es  of  d ail y li vi n g ( e g,  pr e p ari n g f or   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)  
    Gr a d e  3:  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 cti viti es  of  d ail y li vi n g (i e,  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) 
    Gr a d e  4:  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 
    Gr a d e  5:   D e at h r el at e d   t o   A E 
8. 4. 4.    
C a us alit y   Ass ess  m e nt   
T h e  in v esti g at or s h o ul d  ass ess  c a us al r el ati o ns hi p  b et  w e e n  a n   A E  a n d t h e st u d y  dr u g  o n t h e  b asis 
of  his/ h er  cli ni c al j u d g  m e nt  a n d t h e f oll o  wi n g  d efi niti o ns.   T h e  c a us alit y  ass ess  m e nt   m ust  b e 
m a d e  b as e d  o n t h e  a v ail a bl e i nf or  m ati  o n  a n d  c a n  b e  u p d at e d  as  n e  w i nf or  m ati o n  b e c o  m es 
a v ail a bl e.  
    R el at e d:   
    T h e   A E f oll o  ws  a r e as o n a bl e t e  m p or al s e q u e n c e fr o  m st u d y  dr u g  a d  mi nistr ati o n, 
a n d  c a n n ot  b e r e as o n a bl y  e x pl ai n e d  b y t h e s u bj e ct’s  cli ni c al st at e  or  ot h er f a ct ors 
( e g,  dis e as e  u n d er st u d y, c o n c urr e nt  dis e as es,  a n d  c o n c o  mit a nt   m e di c ati o ns).  
O  R   
    T h e   A E f oll o  ws  a r e as o n a bl e t e  m p or al s e q u e n c e fr o  m st u d y  dr u g  a d  mi nistr ati o n, 
a n d it is  a  k n o  w n r e a cti o n t o t h e  dr u g  u n d er st u d y  or its  c h e  mi c al  gr o u p,  or it is 
pr e di ct e d  b y  k n o  w n  p h ar  m a c ol o g y.  
    U n r el at  e d:  
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
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Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  4 4  
    T h e   A E  d o es  n ot f oll o  w  a r e as o n a bl e s e q u e n c e fr o  m st u d y  dr u g  a d  mi nistr ati o n,  or 
c a n  b e r e as o n a bl y  e x pl ai n e d  b y t h e s u bj e ct’s  cli ni c al st at e  or  ot h er f a ct ors ( e g, 
dis e as e  u n d er st u d y,  c o n c urr e nt  dis e as es,  c o n c o  mit a nt   m e di c ati o ns).  
8. 4. 5.    
A cti o n   T a k e n f o r   E v e nt   
    N o n e   
    N o tr e at  m e nt   w as r e q uir e d.   
    M e di c ati o n r e q uir e d.   
    Pr es cri pti o n  a n d/ or   O T  C   m e di c ati o n   w as r e q uir e d t o tr e at t h e   A E.  
    Ot h er.   
8. 4. 6.    
A d v e rs e   E v e nt   O ut c o  m e   
    R e c o v er e d/  R es ol v e d   
    T h e s u bj e ct f ull y r e c o v er e d fr o  m t h e   A E   wit h  n o r esi d u al  eff e ct  o bs er v e d.   
    R e c o v eri n g/  R es ol vi n g   
    T h e   A E i  m pr o v e d  b ut  h as  n ot f ull y r es ol v e d.   
    N ot r e c o v er e d /   N ot r es ol v e d   
    T h e   A E its elf is still  pr es e nt  a n d  o bs er v a bl e.   
    R e c o v er e d /   R es ol v e d   wit h  S e q u el a e   
    T h e r esi d u al  eff e cts  of t h e   A E  ar e still  pr es e nt  a n d  o bs er v a bl e.   
    I n cl u d e s e q u el ae/r esi d u al  eff e cts.  
    F at al  
    F at al s h o ul d  b e  us e d   w h e n  d e at h is  a  dir e ct  o ut c o  m e  of t h e   A E.  
    U n k n o  w n   
8. 5.    
S e ri o us   A d v e rs e   E v e nts   R e p o rti n g  –  P r o c e d u r e  F o r I n v esti g at o rs  
All   A Es  ,   A E SIs a n d  S  A Es   will  b e r e p ort e d i n t h e  e  C  R F.  
T h e f oll o  wi n g t y p es  of  e v e nts s h o ul d  b e r e p ort e d  b y t h e i n v esti g at or  o n  a  S  A  V E  R ( S eri o us 
A d v ers e  E v e nt   R e p ort) f or  m   wit hi n  2 4  h  of  a  w ar e n ess:   
    S  A Es  a n d  S  A  V E  Rs  (s e e S e cti o n  8. 4. 2  f or  d efi niti on)  
    S A E  s a n d   A E SIs  s h o ul d  b e r e p ort e d  b y t h e  in v esti g at or  o n  a  S eri o us   A d v ers e  E v e nt 
R e p ort ( S  A  V E  R) f or  m   wit hi n  2 4  h  of  a  w ar e n ess   (s e e S e cti o n  8. 4. 2  f or t h e  d efi niti o n 
of  a n  S  A E).  
All  e v e nts (s eri o us  a n d  n o n  -s eri o us)   m ust  b e r e p ort e d   wit h t h e  in v esti g at or’s  ass ess  m e nt  of t h e 
e v e nt’s s eri o us n ess, s e v erit y,  a n d  c a us alit y t o t h e st u d y  dr u g.   A  d et ail e d  n arr ati v e s u  m  m ari zi n g 
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  4 5  
t h e  c o urs e  of t h e  e v e nt, i n cl u di n g its  e v al u ati o n, tr e at  m e nt,  a n d  o ut c o  m e s h o ul d  b e  pr o vi d e d.  
S p e cifi c  or  esti  m at e d  d at es  of  e v e nt  o ns et, tr e at  m e nt,  a n d r es ol uti o n s h o ul d  b e i n cl u d e d   w h e n 
a v ail a bl e.    M e di c al  hist or y,  c o n c o  mit a nt   m e di c ati o ns,  a n d  cli ni c al l a b or at or y  d at a t h at  ar e 
r el e v a nt t o t h e  e v e nt s h o ul d  als o  b e s u  m  m ari z e d i n t h e  n arr ati v e.   F or f at al  e v e nts, t h e  n arr ati v e 
s h o ul d st at e   w h et h er  a n  a ut o ps y   w as  or   will  b e  p erf or  m e d,  a n d i n cl u d e t h e r es ults if  a v ail a bl e.  
S o ur c e  d o c u  m e nts (i n cl u di n g   m e di c al r e p orts)   will  b e r et ai n e d  at t h e sit e  a n d s h o ul d  n ot  b e 
s u b  mitt e d t o t h e  S p o ns or f or  S  A E r e p orti n g  p ur p os es.  
Ur g e nt s af et y  q u eri es   m ust  b e f oll o  w e d  u p  a n d  a d dr ess e d  pr o  m ptl y.   F oll o  w  -u p i nf or  m ati o n  a n d 
r es p o ns e t o  n o n-ur g e nt s af et y  q u eri es s h o ul d  b e  c o  m bi n e d f or r e p orti n g t o  pr o vi d e t h e   m ost 
c o  m pl et e  d at a  p ossi bl e   wit hi n  e a c h f oll o  w -u p.   
All  c o  m pl et e d  S  A  V E  R f or  ms   m ust  b e si g n e d  b y t h e   in v esti g at or  a n d  e -m ail e d   t o D SI   at t h e 
f oll o  wi n g  e-m ail  a d dr ess:   
.  S e e  S e cti o n  1 4. 1 0. 5  f or  c o nt a ct i nf or  m ati o n 
f or  S  A E r e p orti n g.  Pl e as e  c all  t h e  S p o ns or’s   m e di c al   m o nit or f or  a n y  q u esti o ns  o n  S  A E 
r e p orti n g (S e cti o n  1 4. 1 0. 4 ). 
Pl a c e t h e i niti al  v ersi o n  of  S  A  V E  R i n t h e s u bj e ct’s fil e.  
8. 6.    
N otif yi n g   R e g ul at o r y   A ut h o riti es, I n v esti g at o rs,  a n d I nstit uti o n al 
R e vi e  w   B o a r d   
D SI  a n d/ or   W orl d  wi d e   Cli ni c al  Tri als  E arl y  P h as e  S er  vi c es,  L L  C  will i nf or  m   in v esti g at ors, 
I nstit uti o n al   R e vi e  w   B o ar d (I  R  B) a n d r e g ul at or y  a ut h oriti es  of  all  S  A Es r e p ort e d fr o  m t his st u d y, 
a n d  a n y  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 n  ( S  U S  A  R) o c c urri n g i n  ot h er st u di es  of 
t h e i n v esti g ati o n al dr u g ,  as a p pr o pri at e  p er l o c al r e p orti n g r e q uir e  m e nts.  D SI  a n d/ or   W orl d  wi d e 
Cli ni c al  Tri als  E arl y  P h as e  S er vi c es,  L L  C   will  c o  m pl y   wit h  a n y  a d diti o n al l o c al s af et y r e p orti n g 
r e q uir e  m e nts.  
I n t h e   U S,  u p o n r e c ei pt  of t h e  S p o ns or’s  n otifi c ati o n  of S  U S  A  Rs  t h at  o c c urr ed   wit h t h e st u d y 
dr u g,  u nl ess  d el e g at e d t o t h e  S p o ns or, it is t h e  in v esti g at or’s r es p o nsi bilit y t o i nf or  m t h e I R  B  p er 
S p o ns or’s i nstr u cti o n.  
8. 7.    
E x p os u r e i n   Ut e r o   D u ri n g   Cli ni c al  St u di es   
D SI   m ust  b e  n otifi e d  of  a n y s u bj e ct   w h o  b e c o  m es  pr e g n a nt   w hil e r e c ei vi n g  or   wit hi n  9 0  d  of 
dis c o nti n ui n g t h e  st u d y  dr u g.   
D SI   m ust  b e  n otifi e d  of  a n y   m al e s u bj e ct   w h os e f e  m al e  p art n er  b e c o  m es  pr e g n a nt   w hil e t h e 
s u bj e ct is r e c ei vi n g  or   wit hi n  9 0  d  of  dis c o nti n ui n g t h e  st u d y  dr u g.  R e p orti n g  aft er   E T  is  d o n e 
v ol u nt aril y  b y t h e  in v esti g at or.  
Alt h o u g h  pr e g n a n c y is  n ot t e c h ni c all y  a n   A E,  all  pr e g n a n ci es   m ust  b e f oll o  w e d t o  c o n cl usi o n t o 
d et er  mi n e t h eir  o ut c o  m e.   T his i nf or  m ati o n is i  m p ort a nt  b ot h f or  dr u g s af et y  a n d  p u bli c  h e alt h 
c o n c er ns.  It is t h e r es p o nsi bilit y  of t h e  in v esti g at or,  or  d esi g n e e, t o r e p ort  a n y  pr e g n a n c y i n  a 
f e  m al e s u bj e ct,  or  a   m al e s u bj e ct’s f e  m al e  p art n er,  usi n g t h e  e x p os ur e i n  ut er o ( EI  U) r e p orti n g 
f or  m.   Pl e as e  c o nt a ct  y o ur st u d y   m o nit or t o re c ei v e t h e  EI  U r e p orti n g f or  m  u p o n l e ar ni n g  of  a 
pr e g n a n c y.   T h e  in v esti g at or s h o ul d   m a k e  e v er y  eff ort t o f oll o  w t h e s u bj e ct  u ntil  c o  m pl eti o n  of 
t h e  pr e g n a n c y  a n d  c o  m pl et e t h e  EI  U   R e p orti n g for  m   wit h  c o  m pl et e  pr e g n a n c y  o ut c o  m e 
i nf or  m ati o n, i n cl u di n g  n or  m al d eli v er y  a n d i n d u c e d  a b orti o n.   T h e  a d v ers e  pr e g n a n c y  o ut c o  m e, 
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1
P P D


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  4 6  
eit h er s eri o us  or  n o n -s eri o us, s h o ul d  b e r e p ort e d i n  a c c or d a n c e   wit h st u d y  pr o c e d ur es.   If t h e 
o ut c o  m e  of t h e  pr e g n a n c y   m e ets t h e  crit eri a f or i  m  m e di at e  cl assifi c ati o n  as  a n  S  A E (i e,  p ost -
p art u  m  c o  m pli c ati o ns, s p o nt a n e o us  or i n d u c e d  a b orti o n, still birt h,  n e o n at al  d e at h,  or  c o n g e nit al 
a n o  m al y, i n cl u di n g t h at i n  a n  a b ort e d f et us), t h e  in v esti g at or s h o ul d f oll o  w t h e  pr o c e d ur es f or 
r e p orti n g  S  A Es  o utli n e d i n S e cti o n  8. 5 .  
F or r e p orts  of  pr e g n a n c y i n t h e f e  m al e  p art n er  of  a   m al e s u bj e ct, t h e  EI  U f or  m ( or  S  A E f or  m if 
ass o ci at e d   wit h  a n  a d v ers e  o ut c o  m e) s h o ul d  b e  c o  m pl et e d   wit h  t h e s u bj e ct’s r a n d o  mi z ati o n 
n u  m b er, i niti als,  a n d  d at e  of  birt h,  a n d  d et ails r e g ar di n g t h e f e  m al e  p art n er s h o ul d  b e  e nt er e d i n 
t h e  n arr ati v e s e cti o n. 
8. 8.    
Cli ni c al   L a b o r at o r y   E v al u ati o ns   
Bl o o d s a  m pl es f or t h e f oll o  wi n g s er u  m  c h e  mistr y,  h e  m at ol o g y,  a n d  c o a g ul at  i o n  p a n els   will  b e 
p erf or  m e d  aft er  at l e ast  a  1 0 -h  o v er ni g ht f ast  at t h e ti  m e  p oi nts i n di c at e d i n  A p p e n di x   1 6. 5 .   F or 
cli ni c al l a b or at or y  p ar a  m et ers,  t h e r ef er e n c e r a n g e  at t h e i nstit uti o n t h at  p erf or  ms t h e 
m e as ur e  m e nts   will  b e  us e d.   
T h e s er u  m  c h e  mistr y  pr ofil es   m ust  b e  o bt ai n e d  u n d er f asti n g  c o n diti o ns ( a p pr o xi  m at el y  1 0  h).  
R es ults  of  all l a b or at or y t ests   will  b e i n cl u d e d i n t h e s u bj e ct’s  e  C  R F.   
T h e f oll o  wi n g  cli ni c al l a b or at or y  p ar a  m et ers   will  b e  e v al u at e d:  
    S er u  m  c h e  mistr y ( a p pr o xi  m at el y  8. 5   m L): s o di u  m,  p ot assi u  m,   m a g n esi u  m, 
bi c ar b o n at e,  c hl ori d e,  c al ci u  m, i n or g a ni c  p h os p h or us,   A S T,   A L T,  G  G T,   al k ali n e 
p h os p h at as e,  dir e ct  bilir u bi n,  t ot al  bilir u bi n, gl u c os e,  cr e ati ni n e,  bl o o d  ur e a  nitr o g e n, 
t ot al  pr ot ei n,  al b u  mi n,  uri c  a ci d,  cr e ati n e  ki n as e, t ot al  c h ol est er ol,  a n d tri gl y c eri d es. 
    H e  m at ol o g y ( a p pr o xi  m at el y  4   m L):  h e  m o gl o bi n,  h e  m at o crit, r e d  bl o o d  c ell (  R  B  C) 
c o u nt (  wit h i n di c es), r eti c ul o c yt e  c o u nt,   w hit e  bl o o d  c ell (  W  B  C)  c o u nt (  wit h 
diff er e nti al),  a n d  pl at el et  c o u nt.  
    Uri n al ysis: st a n d ar d  uri n al ysis, i n cl u di n g  a   mi cr os c o pi c  e x a  mi n ati o n  a n d s p e cifi c 
gr a vit y,  p  H,  pr ot ei n,  gl u c os e,  k et o n es,  bl o o d,   R  B  C,   W  B  C,  bilir u bi n,  a n d 
ur o bili n o g e n.  
C al c ul ati o n  of  e  G F  R ( u  si n g t h e   C o c k cr oft -G a ult  e q u ati o n)   will  b e  p erf or  m e d  at  S cr e e ni n g.   
T ests f or  vir ol o g y (  HI  V  a nti b o d y,   H  Bs  A g,  a n d   H  C  V  a nti b o d y)   will  b e  p erf or  m e d  at  S cr e e ni n g 
o nl y.    
C o a g ul ati o n t ests ( P T/I  N  R  a n d  a P T T)  . 
C hil d  -P u g h  S c or e   will  b e  c al c ul at e d  at s cr e e ni n g  o nl y  f or t h e s u bj e cts   wit h   m o d er at e  h e p ati c 
i  m p air  m e nt f or i nf or  m ati o n  p ur p os e  o nl y.  
8. 9.    
Vit al  Si g ns   
S  B P,  D  B P  , a n d  p uls e   will  b e   m e as ur e d  aft er t h e s u bj e ct  h as r est e d i n  a s u pi n e  p ositi o n f or  1 0   mi n 
or   m or e.  
R esti n g  vit al si g ns ( bl o o d  pr ess ur e,  h e art r at e,  or al t e  m p er at ur e,  a n d r es pir at or y r at e)   will  b e 
p erf or  m e d  at  S cr e e ni n g,  pr e d os e  a n d  at  2,  2 4,  a n d  1 4 4  h  p ost  d os e,  or  E arl y  T er  mi n ati o n.  
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  4 7  
W h e n  vit al si g ns   m e as ur e  m e nts  a n d  a  bl o o d  dr a  w  ar e s c h e d ul e d f or t h e s a  m e ti  m e  p oi nt, t h e  vit al 
si g ns s h o ul d  b e t a k e n   wit hi n  a p pr o xi  m at el y  5   mi n  pri or t o t h e  bl o o d  dr a  w.   Pr e d os e  vit al si g ns 
m e as ur e  m e nts   will  b e t a k e n   at  1  h  pri or t o t h e  d os e.  
B o d y   w ei g ht  a n d  h ei g ht   will  b e r e c or d e d  at  S cr e e ni n g.    B o d y   w ei g ht   will  als o  b e r e c or d e d  at 
C h e c k  -i n  a n d  at   C h e c k-o ut , or  E arl y  T er  mi n ati o n.    B  MI   will  b e  c al c ul at e d  at  S cr e e ni n g.  
I nf or  m ati o n   will  b e  e nt er e d i n t h e  e  C  R F  o n   w h et h er  or  n ot   m e as ur e d,  d at e  of   m e as ur e  m e nt,  a n d 
m e as ur e  m e nt r es ults f or t h e f oll o  wi n g it e  ms:  S  B P,   D  B P,  p uls e, r es pir at or y r at e,  or al t e  m p er at ur e, 
h ei g ht,  b o d y   w ei g ht,  a n d  B  MI  . 
8. 1 0.    
El e ct r o c a r di o g r a  ms   
T h e  E  C  Gs   will  b e r e a d  o n sit e  as  p art  of t h e s af et y  ass ess  m e nts.   W h et h er   m e as ur e  m  e nt is 
p erf or  m e d,  d at e  p erf or  m e d, r es ults,  a n d fi n di n gs   will  b e r e c or d e d i n t h e  e C  R F.   
T h e  si n gl e 1 2 -l e a d  E  C  Gs s h o ul d  b e  p erf or  m e d  aft er  at l e ast  1 0   mi n  of  q ui et r est i n t h e s u pi n e 
p ositi o n (s e e ti  m e  p oi nts i n di c at e d i n  A p p e n di x   1 6. 5 ).    B ef or e  el ectr o d es  ar e r e  m o v e d, t h e 
el e ctr o d e  p ositi o n is t o  b e   m ar k e d  o n t h e s ki n   wit h i n d eli bl e i n k  a n d t h e s a  m e  el e ctr o d e  p ositi o n 
us e d f or  all s u bs e q u e nt  E  C  Gs  d uri n g  c o nfi n e  m e nt f or  e a c h s u bj e ct.   W h e n  a  bl o o d  dr a  w is 
s c h e d ul e d  c o n c o  mit a ntl y   wit h  a n  E  C  G, t h e  E  C  G  s h o ul d  b e t a k e n   wit hi n  1 0   mi n  pri or t o t h e 
bl o o d  dr a  w.   Pr e d os e  E  C  Gs   will  b e t a k e n  at  1  h  pri or t o t h e  d os e.  
8. 1 1.    
P h ysi c al   E x a  mi n ati o ns  
A  c o  m pl et e  p h ysi c al  e x a  mi n ati o n   will  b e  p erf or  m e d  b y  a   m e di c all y  q u alifi e d  p ers o n  at t h e ti  m e 
p oi nts i n di c at e d i n  A p p e n di x   1 6. 5 .  A   m e di c all y  q u alifi e d  p ers o n   will  p erf or  m t h e  p h ysi c al  e x a  m.    
T h e  p h ysi c al  e x a  mi n ati o n   will i n cl u d e  a n  e v al u ati o n  of t h e r es pir at or y,   c ar di o v as c ul ar, 
g astr oi nt esti n al,  d er  m at ol o gi c al,   m us c ul os k el et al,  ps y c hi atri c,  a n d  n e ur ol o gi c s yst e  ms,  as   w ell  as 
t h e  h e a d,  e y es,  e ars,  n os e,  a n d t hr o at. 
8. 1 2.    
D r u g  a n d   Al c o h ol  S c r e e n   
A  uri n e s cr e e n f or  al c o h ol,  c oti ni n e,  a n d  dr u gs  of  a b us e   will  b e  p erf or  m e d f o  r  all s u bj e cts  at 
S cr e e ni n g  a n d  at   C h e c k -i n.    Al c o h ol,  c oti ni n e,  a  m p h et a  mi n es,  b ar bit ur at es,  b e n z o di a z e pi n es, 
c o c ai n e,  o pi at es,  p h e n c y cli di n e  a n d  c a n n a bi n oi ds   will  b e i n cl u d e d i n t h e  ass a y.   
8. 1 3.    
P r e g n a n c y   T est  
F or  all f e  m al e s u bj e cts, s er u  m  pr e g n a n c y t ests   wil l  b e  p erf or  m e d  at  S cr e e ni n g, C h e c k  -i n  a n d 
C h e c k  -o ut  or  E arl y  T er  mi n ati o n .    D osi n g  o n   D a y 1   will  b e  c o nti n g e nt  u p o n  a  n e g ati v e r es ult.  
8. 1 4.    
S e r u  m  F S  H  
At  S cr e e ni n g, s h o ul d  a f e  m al e s u bj e ct r e p ort  p ost  m e n o p a us al st at us  n ot i n d u c e d  b y s ur gi c al 
st erili z ati o n,  a s er um  F S  H   m e as ur e  m e nt   will  b e  o bt ai n e d.   
8. 1 5.    
Ot h e r   E x a  mi n ati o ns   
A  uri n e s cr e e n f or  c oti ni n e  a n d  dr u gs  of  a b us e ( a  m p h et a  mi n es,  b ar bit ur at es,  b e n z o di a z e pi n es, 
c o c ai n e,  o pi at es,  p h e n c y cli di n e,  a n d  c a n n a bi n oi ds)   will  b e  p erf or  m e d f or  all s u bj e cts  at t h e ti  m e 
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  4 8  
p oi nts i n d i c at e d i n A p p e n di x   1 6. 5 .    Br e at h  al c o h ol t esti n g   will  als o  b e  p erf or  m e d  at t h e ti  m e 
p oi nts i n di c at e d i n  A p p e n di x   1 6. 5 .   F or f e  m al e s u bj e cts  of  c hil d b e ari n g  p ot e nti al,  a  q u alit ati v e 
s er u  m or  uri n e  pr e g n a n c y t est   will  b e  p erf or  m e d  at t h e ti  m e  p oi nts i n di c at e d i n  A p p e n di x   1 6. 5 .  
F or  all  p ost  m e n o p a us al f e  m al e s u bj e cts,  a n  F S  H t est   will  b e  p erf or  m e d  at  S cr e e ni n g.    
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  4 9  
9.    
O  T  H  E  R   A S S  E S S  M  E  N  T S   
N ot  a p pli c a bl e    
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  5 0  
1 0.    
S  T  A  TI S  TI  C  A  L   M  E  T  H  O  D S  
1 0. 1.    
G e n e r al  St atisti c al   C o nsi d e r ati o ns   
All  P  K  a n d s af et y  d at a  o bt ai n e d i n t his st u d y   will  b e  dis pl a y e d i n  d at a listi n gs  a n d, if  a p pr o pri at e, 
s u  m  m ari z e d  usi n g  d es cri pti v e st atisti cs.    A  d et ail e d  St atisti c al   A n al ysis  Pl a n ( S  A P)  d es cri bi n g 
t h e   m et h o d ol o g y t o  b e  us e d i n t h e fi n al  a n al ysis   will  b e  pr e p ar e d  a n d fi n ali z e d  pri or t o t h e 
d at a b as e l o c k.    C h a n g es t o t h e st atisti c al  a n al ys es   will r e q uir e  a  pr ot o c ol  a  m e n d  m e nt  o nl y if 
pri n ci p al f e at ur es  of t h e  pr ot o c ol  ar e  c h a n g e d.    A n y  d e vi ati o ns fr o  m t h e  pl a n n e d st atisti c al 
a n al ys es i n t h e  pr o t o c ol   will  b e f ull y  d es cri b e d i n t h e  S  A P  a n d t h e  cli ni c al st u d y r e p ort.   
C at e g ori c al  d at a   will  b e  pr es e nt e d i n  c o nti n g e n c y t a bl es   wit h  c ell fr e q u e n ci es  a n d  p er c e nt a g es 
f or t h e s u bj e ct  p o p ul ati o n.  
I n  g e n er al,  d at a   will  b e s u  m  m ari z e d f or t h e m o d er at e   h e p at i c i  m p air  m e nt gr o u p  a n d  t h e s u bj e cts 
wit h   n or  m al  h e p ati c f u n cti o n . F or  p oi nt  esti  m ati o ns  of  k e y  P  K  p ar a  m et ers,  9 0  %  c o nfi d e n c e 
i nt er v als (C  Is) f or   HI/ n or  m al  h e p ati c f u n cti o n   will  b e  c al c ul at e d (s e e S e cti o n  1 0. 4. 1 ). 
F or t h e  d at a  a n al ysis,   missi n g  d at a   will  n ot  b e i  m p ut e d;  a n al ys es   will  b e  p erf or  m e d  o n  o bs er v e d 
d at a  o nl y,  u nl ess  ot h er  wis e  n ot e d.   
R a  w  d at a   will  b e  pr es e nt e d   wit h t h e  e x a ct  pr e cisi o n   wit h   w h  i c h t h e y   w er e  c oll e ct e d. 
1 0. 2.    
A n al ysis  S ets   
1 0. 2. 1.    
P h a r  m a c o ki n eti c   A n al ysis  S et   
T h e  P  K  A  n al ysis  S et   will i n cl u d e  all s u bj e cts   w h o r e c ei v e d  a  d os e  of  p e xi d arti ni b  a n d  h a v e 
s uffi ci e nt  pl as  m a  c o n c e ntr ati o n  d at a t o  c h ar a ct eri z e t h e  P  K  p ar a  m et ers.   T h e i  m p a ct  of  cli ni c all y 
r el e v a nt e v e nts t h at   m a y  aff e ct t h e  esti  m at e  of  P  K  p ar a  m et ers   will  b e  ass ess e d   w hil e  a n al y zi n g 
d at a  a n d  h a n dl e d  a p pr o pri at el y.    A n y  e x cl usi o n   will  b e  cl e arl y  d eli n e at e d i n t h e r e p ort.    
I n di vi d u al  pl as  m a  c o n c e ntr ati o ns of  p e xi d arti ni b  a n d  Z A  A  D  -1 0 0 6 a  will   b e r e p ort e d f or  all 
s u bj e cts. 
1 0. 2. 2.    
S af et y   A n al ysis  S et   
T h e  S af et y  A  n al ysis  S et   will i n cl u d e  all s u bj e cts   w h o r e c ei v e d  a  d os e  of  p e xi d arti ni b.  
1 0. 3.    
St u d y  P o p ul ati o n   D at a  
T h e s af et y s u bj e ct  p o p ul ati o n   will  b e s u  m  m ari z e d f or  d e  m o gr a p hi c  c h ar a ct eristi cs.    C o nti n u o us 
d e  m o gr a p hi c  v ari a bl es ( a g e [ c al c ul at e d fr o  m t h e  d at e  of  birt h t o t h e  d at e   w h e n t h e I  C F   w as 
si g n e d],  b o d y   w ei g ht,  h ei g ht,  a n d   B  MI) f or  all s u bj e cts   will  b e s u  m  m ari z e d   wit h  d es cri pti v e 
st atisti cs f or b ot h  gr o u p s.    C at e g ori c al  d e  m o gr a p hi c  v ari a bl es (s e x, r a c e,  a n d  et h ni cit y)   will  b e 
s u  m  m ari z e d   wit h fr e q u e n c y  c o u nts  a n d  c orr es p o n di n g  p er c e nt a g es.   
M e di c al  hist or y  d at a,  p h ysi c al  e x a  mi n ati o n  d at a,  a n d  pri or/ c o n c o  mit a nt   m e di c ati o ns   will  b e 
list e d. 
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  5 1  
1 0. 4.    
St atisti c al   A n al ysis  
1 0. 4. 1.    
P h a r  m a c o ki n eti c   A n al ys es  
T h e  P  K   A n al ysis  S et   w ill  b e  us e d f or  all  P  K  a n al ys es.  D es cri pti v e st atisti cs   will  b e  pr es e nt e d f or 
p e xi d arti ni b  a n d  Z  A A  D  -1 0 0 6 a  pl as  m a  c o n c e ntr ati o ns  at  e a c h  e v al u ati o n ti  m e  p oi nt  a n d f or  all 
q u a ntit ati v e  P  K  p ar a  m et ers  of  p e xi d arti ni b  a n d  Z  A A  D  -1 0 0 6 a .  
Pl as  m a  c o n c e ntr ati o n -ti  m e d at a   will  b e  a n al y z e d  usi n g  n o n c o  m p art  m e nt al   m et h o ds.   T h e 
f oll o  wi n g  P  K  p ar a  m et ers  of  p e xi d arti ni b   will  b e  c al c ul at e d usi n g  b ot h t ot al  a n d  u n b o u n d  pl as  m a 
c o n c e ntr ati o n s:   C  m a x,  T  m a x,   A  U  Cl ast, A  U  Ci nf  , k el,  t 1/ 2,   C L/ F, a n d  V z/ F  .  Pl as  m a  P  K 
p ar a  m et ers (  C  m a x,  T  m a x,   A  U  Cl ast ,   A  U  Ci nf, t 1/ 2)   will  b e  c al c ul at e d b as e d  o n  b ot h t ot al  a n d 
u n b o u n d  pl as  m a  c o n c e ntr ati o n s of  Z  A  A  D -1 0 0 6 a . 
P  K  p ar a  m et ers f or  p e xi d arti ni b  a n d  Z  A  A  D -1 0 0 6 a  will  b e  ass ess e d  b y  d es cri pti v e st atisti cs   f or 
t h e HI  gr o u p  a n d   m at c hi n g   c o ntr ol  gr o u p .  T h e  m et a b olit e  -t o-p ar e nt r ati o f or   A  U  Cl ast  a n d 
A  U  Ci nf   f or t ot al  c o n c e ntr ati o ns,  a dj ust e d f or   m ol e c ul ar   w ei g ht,   will  b e  d et er  mi n e d f or t h e HI 
a n d  n or  m al  h e p ati c f u n cti o n  gr o u ps . 
C  m a x,   A  U  Cl ast  , a n d   A  U  Ci nf  of  p e xi d arti ni b  (b as e d  o n t ot al  a n d  u n b o u n d  pl as  m a 
c o n c e n tr ati o ns) will  b e  c o  m p ar e d   f or t h e HI   gr o u p  a n d  t h os e of  n or  m al  h e p ati c f u n cti o n .  T h es e 
c o  m p aris o ns  b et  w e e n  t h e HI  gr o u p   wit h t h e   m at c h e d  c o ntr ol  gr o u p   will  b e   m a d e  usi n g  a  n 
a n al ysis  of  v ari a n c e   m o d el.   T h e r es ulti n g  p oi nt  esti  m at es ( g e o  m etri c l e ast s q u ar  es   m e a ns ), t h eir 
r ati os (  HI/ n or  m al  h e p ati c f u n cti o n),  a n d  90 %  c o nfi d e n c e i nt er v als   (  CIs) f or t h e r ati os   will  b e 
pr es e nt e d.  
1 0. 4. 2.    
P h a r  m a c o d y n a  mi c   A n al ys es  
N ot  a p pli c a bl e   
1 0. 4. 3.    
P h a r  m a c o g e n o  mi c   A n al ys es  
N ot  a p pli c a bl e   
1 0. 4. 4.    
S af et y   A n al ys es  
All s af et y  a n al ys es   will  b e  p erf or  m e d   usi n g t h e  S af et y   A n al ysis  S et.   T h e  n u  m b er  a n d  p er c e nt a g e 
of s u bj e cts r e p orti n g  T E  A Es  will  b e t a b ul at e d  b y   t h e   M e di c al   Di cti o n ar y f or   R e g ul at or y 
A cti viti es   (M e d  D  R  A  ) s yst e  m  or g a n  cl ass  ( S  O  C) a n d  pr ef err e d t er  m   wit h  a  br e a k d o  w n  b y  d e gr e e 
of   HI (i e,   m o d er at e  HI  a n d  n or  m al  h e p ati c f u n cti o n)   a n d  o v er all .   EC  G   i nt er v al   m e as ur e  m e nts 
a n d  ot h er s af et y  e n d p oi nt s   will  b e s u  m  m ari z e d  usi n g  d es cri pti v e st atisti cs  b y  d e gr e e  of   HI   w h e n 
a p pr o pri at e.  
1 0. 4. 4. 1.    A d v e rs e   E v e nt   A n al ys es   
A  E s   will  b e  c o d e d  b y t h e   M e d  D  R  A.    All   A Es, i n cl u di n g  S  A Es,   will  b e   m a p p e d t o  S  O  C  a n d 
pr ef err e d t er  m  a n d   will  b e list e d i n t h e  d at a listi n g.  
A  T E  A E is  d efi n e d  as  a n   A E t h at  e  m er g es  d uri n g tr e at  m e nt,  h a vi n g  b e e n  a bs e nt  pr e  -tr e at  m e nt,  or 
w ors e ns r el ati v e t o t h e  pr e  -tr e at  m e nt st at e.   T h e  n u  m b er  a n d  p er c e nt a g e of s u bj e cts r e p orti n g 
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  5 2  
T E  A Es   will  b e  c al c ul at e d  o v er all,  b y  S  O  C ,  b y  pr ef err e d t er  m,  a n d  b y h e p ati c f u n cti o n  gr o u p .  
T E  A E s   will  b e f urt h er s u  m  m ari z e d  b y  C T  C  A E  gr a d e   a n d r el ati o ns hi p t o st u d y  dr u g.    
A n y   A E   t h at st arts  pri or t o  d osi n g   wit h  a n y st u d y  dr u g is  co nsi d er e d  a  pr etr e at  m e nt  A E  . 
A n y   A E   t h at st arts  aft er  a s p e cifi e d   m o nit ori n g  p eri o d is  c o nsi d er e d  a  p ost-tr e at  m e nt A E  . 
A  b y  -s u bj e ct   A E (i n cl u di n g tr e at  m e nt -e  m er g e nt)  d at a listi n g i n cl u di n g  b ut  n ot li  mit e d t o 
v er b ati  m t er  m,  pr ef err e d t er  m,  S  O  C ,   C T  C  A E  gr a d e, a n d r el ati o ns hi p t o st u d y tr e at  m e nt   will  b e 
pr o vi d e d.    D e at hs,  ot h er  S  A Es,  a n d  ot h er si g nifi c a nt   A Es   will  b e list e d.   
1 0. 4. 4. 2.    Cli ni c al   L a b o r at o r y   E v al u ati o n   A n al ys es   
D es cri pti v e st atisti cs   will  b e  pr o vi d e d f or t h e  cli ni c al l a b or at or y r es ults  b y s c h e d ul e d ti  m e  of 
e v al u ati o n  a n d  b y  h e p ati c f u n cti o n  gr o u p  f or t h e  S af et y   A n al ysis  S et,  as   w ell  as f or t h e  c h a n g e 
fr o  m  b as eli n e.   T h e  b as eli n e  v al u e is  d efi n e d  as t h e l ast  n o n-missi n g  v al u e  b ef or e t h e i niti al 
a d  mi nistr ati o n  of st u d y tr e at  m e nt.  I n  a d diti o n,   m e a n  c h a n g e s fr om  b as eli n e   will  b e  pr es e nt e d  b y 
f or s u bj e cts   wit h   m o d er at e   HI  a n d h e alt h y s u bj e cts   wit h  n or  m al  h e p ati c f u n cti o n  f or t h e 
m a xi  m u  m  a n d   mi ni  m u  m  p ost  -tr e at  m e nt  v al u es  a n d t h e  v al u es  at   C h e c k-o ut.  
A b n or  m al  cli ni c al l a b or at or y r es ults   will  b e  gr a d e d  a c c or di n g t o   N ati o n al   C a n c er I nstit ut e 
C T  C  A E  v ersi o n   5 . 0, if  a p pli c a bl e,  a n d t h e  gr a d e   will  b e  pr es e nt e d i n  a  b y-s u bj e ct  d at a listi n g.    A 
s hift t a bl e,  pr es e nti n g t h e  2 -w a y fr e q u e n c y t a b ul ati o n f or  b as eli n e  a n d t h e   w orst  p ost  -tr e at  m e nt 
v al u e  a c c or di n g t o t h e   C T  C  A E  gr a d e , b y  h e p ati c f u n cti o n  gr o u p , will  b e  pr o vi d e d f or  cli ni c al 
l a b or at or y t ests.    A b n or  m al  cli ni c al l a b or at or y r es ults  d e e  m e d  of  cli ni c al si g nifi c a n c e  or  of 
Gr a d e   3  or  4   will  b e list e d.   
1 0. 4. 4. 3.    Vit al  Si g n   A n al ys es   
V  it al si g ns   m e as ur e  m e nts will  b e list e d   b y s c h e d ul e d ti  m e  of  e v al u ati o n  a n d  b y  h e p ati c f u n cti o n 
gr o u p  f or t h e S af et y  A n al ysis  S et  ,  as   w ell  as f or t h e  c h a n g e fr o  m  b as eli n e.  T h e  b as eli n e  v al u e is 
d efi n e d  as t h e l ast  n o n -missi n g  v al u e  b ef or e t h e  a d  mi nistr ati o n  of st u d y   dr u g .  
1 0. 4. 4. 4.    E  l e ct r o c a r di o g r a  m   A n al ys es 
D es cri pti v e st atisti cs   will  b e  pr o vi d e d f or t h e  E  C  G   m e as ur e  m e nts ( P  R,   R  R,   Q  R S,  a n d   Q T 
i nt er v als,  a n d   Q T i nt er v al  c orr e ct e d f or  h e art r at e  usi n g   B a z ett’s f or  m ul a (  Q T c  B)  a n d   Q T c F 
i nt er v als   w h er e t h e   Q T i nt er v als  c orr e ct e d f or  h e art r at e  b y t h e   B a z ett’s a n d  Fri d eri ci a’s f or  m ul as 
[  Q T c  B  =   Q T/(  R  R)½  a n d   Q T c F  =   Q T/(  R  R) ⅓ r es p e cti v el y])  b y s c h e d ul e d ti  m e  of  e v al u ati o n  a n d 
b y  h e p ati c f u n cti o n  gr o u p  f or t h e S af et y  A n al ysis  S et  ,  as   w ell  as f or t h e  c h a n g e fr o  m  b as eli n e.   
T h e l ast  n o n -missi n g  v al u e  b ef or e  p e xi d arti  ni b  a d  mi nistr ati o n   will s er v e  as  b as eli n e .   
T h e  n u  m b er  a n d  p er c e nt a g e  of s u bj e cts   wit h  a bs ol ut e   Q T,   Q T c F,  a n d   Q T c  B i nt er v als i n   t h e 
pr e -s p e cifi e d  c at e g ori es ( > 4 5 0,  > 4 8 0,  a n d  > 5 0 0   ms),  a n d t h e  c h a n g e fr o  m  b as eli n e i n   Q T,   Q T c F, 
a n d   Q T c  B i nt er v als ( > 3 0  a n d  > 6 0 ms)   will  b e s u  m  m ari z e d  b y   h e p ati c f u n cti o n  gr o u p  a n d  o v er all.    
1 0. 4. 4. 5.    P h ysi c al   E x a  mi n ati o n   A n al ys es  
R es ults  of  p  h ysi c al  e x a  mi n ati o n s will  b e   dis pl a y e d i n  a listi n g.    
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  5 3  
1 0. 4. 4. 6.    E x pl o r at o r y  S af et y   A n al ys es   
N ot  a p pli c a bl e   
1 0. 4. 4. 7.    Ot h e r  S af et y   A n al ys es   
N ot  a p pli c a bl e   
1 0. 5.    
S a  m pl e  Si z e   D et e r  mi n ati o n  
Si xt e e n  s u bj e cts   will  b e  e nr oll e d.   H alf   of t h es e s u bj e cts  will   b e  m o d er at e   HI   a n d t h e  ot h er  h alf 
will  b e  h e alt h y s u bj e cts   wit h  n or  m al  h e p ati c f u n cti o n   m at c h e d  b y  a g e,  g e n d er  , a n d  b o d y  w ei g ht  . 
T h e s a  m pl e si z es  ar e  n ot  b as e d  o n st atisti c al  c o nsi d er ati o ns.   T h e  n u  m b er  of s u bj e cts is 
c o nsi d er e d s uffi ci e nt t o  a c hi e v e t h e st u d y  o bj e cti v es  (s e e  F  D  A G ui d a n c e  2 0 0 3)  . 7  S u bj e cts   w h o 
dis c o nti n u e  aft er r e c ei vi n g st u d y  dr u g  will  n ot  b e r e pl a c e d   u nl ess  a p pr o v e d  b y t h e s p o ns or . 
1 0. 6.    
St atisti c al   A n al ysis  P r o c e ss 
T o  pr es er v e t h e i nt e grit y  of t h e st atisti c al  a n al ys es  a n d  cli ni c al st u d y  c o n cl usi o ns, t h e  S  A P   will 
b e fi n ali z e d  pri or t o  d at a b as e l o c k.  
All st atisti c al  a n al ys es   will  b e  p erf or  m e d  usi n g  S  A S ® V ersi o n   1 0. 6  or  hi g h er ( S  A S I nstit ut e, 
C ar y,   N  C  2 7 5 1 3).   
 
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  5 4  
1 1.    
D  A  T  A I  N  T  E  G  RI  T  Y   A  N  D   Q  U  A  LI  T  Y   A S S  U  R  A  N  C  E   
T h e i n v esti g ati o n al sit e   will  p er  mit st u d y -r el at e d   m o nit ori n g,  a u dits, I R  B r e vi e  w,  a n d r e g ul at or y 
i ns p e cti o ns  b y  pr o vi di n g  dir e ct  a c c ess t o s o ur c e  d at a/ d o c u  m e nts.    Dir e ct  a c c ess i n cl u d es 
p er  missi o n t o  e x a  mi n e,  a n al y z e,  v erif y ,  a n d r e pr o d u c e  a n y r e c or ds  a n d r e p orts t h at  ar e i  m p ort a nt 
t o t h e  e v al u ati o n  of  a  cli ni c al st u d y. 
1 1. 1.    
M o nit o ri n g  a n d I ns p e cti o ns   
T h e   D SI/  C  R  O   m o nit or  a n d r e g ul at or y  a ut h orit y i ns p e ct ors  ar e r es p o nsi bl e f or  c o nt a cti n g  a n d 
visiti n g t h e  in v esti g at or f or t h e  p ur p os e  of i ns p e cti n g t h e f a ciliti es  a n d,  u p o n r e q u est, i ns p e cti n g 
t h e  v ari o us r e c or ds  of t h e st u d y ( e g, e C  R Fs, s o ur c e  d at a,  a n d  ot h er  p erti n e nt  d o c u  m e nts).   
T h e  v erifi c ati o n  of  a d h er e n c e t o t h e  pr ot o c ol;  c o  m pl et e n ess,  a c c ur a c y,  a n d  c o nsist e n c y  of t h e 
d at a;  a n d  a d h er e n c e t o I  C  H  G o o d   Cli ni c al  Pr a cti c e (  G  C P)  a n d l o c al r e g ul ati o ns  o n t h e  c o n d u ct  of 
cli ni c al r es e ar c h  will  b e  a c c o  m plis h e d t hr o u g h  a  c o  m bi n ati o n  of  o nsit e  visits  b y t h e   m o nit or  a n d 
r e vi e  w  of st u d y  d at a r e  m ot el y.  T h e fr e q u e n c y  of t h e   m o nit ori n g  visit   wil l  v ar y  b as e d  o n t h e 
a cti vit y  at  e a c h  sit e.   T h e   m o nit or is r es p o nsi bl e f or i ns p e cti n g t h e e C  R Fs  a n d  e ns uri n g 
c o  m pl et e n ess  of t h e st u d y  ess e nti al  d o c u  m e nts.   T h e   m o nit or s h o ul d  h a v e  a c c ess t o s u bj e ct 
m e di c al r e c or ds  a n d  ot h er st u d y  -r el at e d r e c or ds  n e e d e d t o v erif y t h e  e ntri es  o n t h e  e C  R Fs.    
D et ail e d i nf or  m ati o n is  pr o vi d e d i n t h e   m o nit ori n g  pl a n.   
T h e   m o nit or   will  c o  m  m u ni c at e  d e vi ati o ns fr o  m t h e  pr ot o c ol,   St a n d ar d   O p er ati n g  Pr o c e d ur e s, 
G  C P  , a n d  a p pli c a bl e r e g ul ati o ns t o t h e  in v esti g at or  a n d   will  e ns ur e t h at  a p pr o pri at e  a cti o n (s) 
d esi g n e d t o  pr e v e nt r e c urr e n c e  of t h e  d et e ct e d  d e vi ati o ns is t a k e n  a n d  d o c u  m e nt e d.  
T h e  in v esti g at or  a gr e es t o  c o o p er at e   wit h t h e   m o nit or t o  e ns ur e t h at  a n y  pr o bl e  ms  d et e ct e d i n t h e 
c o urs e  of t h es e   m o nit ori n g  visits  ar e  a d dr ess e d  t o t h e s atisf a cti o n  of t h e  S p o ns or  a n d 
d o c u  m e nt e d.  
I n  a c c or d a n c e   wit h I  C  H   G  C P  a n d t h e  S p o ns or’s  a u dit  pl a ns, t his st u d y sit e  m a y  b e s el e ct e d f or 
a u dit  b y r e pr es e nt ati v es fr o  m  t h e S p o ns or.   A u dit   of  sit e f a ciliti es ( e g,  p h ar  m a c y,  dr u g st or a g e 
ar e as, l a b or at ori es)  a n d r e vi e  w  of st u d y r el at e d r e c or ds   will  o c c ur i n  or d er t o  e v al u at e t h e st u d y 
c o n d u ct  a n d  c o  m pli a n c e   wit h t h e  pr ot o c ol, I C  H   G  C P,  a n d  a p pli c a bl e r e g ul at or y r e q uir e  m e nts.   
T h e  in v esti g at or  s h o ul d r es p o n d t o a u dit fi n di n gs .  I n t h e  e v e nt t h at  a r e g ul at or y  a ut h orit y 
i nf or  ms t h e in v esti g at or t h at it i nt e n ds t o  c o n d u ct  a n i ns p e cti o n, t h e  S p o ns or s h all  b e  n otifi e d 
i  m  m e di at el y. 
1 1. 2.    
D at a   C oll e cti o n   
D SI  or  a  d esi g n e e   will s u p pl y  e  C  R Fs.    A n  e  C  R F   m ust  b e  c o  m pl et e d f or  e a c h s u bj e ct   w h o si g ns 
a n I C F  a n d r e c ei v es  a  d os e  of  p e xi d arti ni b.    All  d at a  c oll e ct e d  d uri n g t h e st u d y   will  b e r e c or d e d 
i n t his i n di vi d u al, s u bj e ct-s p e cifi c  e  C  R F.  I nstr u cti o ns   will  b e  pr o vi d e d f or t h e  c o  m pl eti o n  of t h e 
e  C  R F  a n d  a n y  c orr e cti o ns   m a d e   will  b e  a ut o  m ati c all y  d o c u  m e nt e d  vi a t h e  el e ctr o n i c  d at a  c a pt ur e 
( E  D  C) s oft  w ar e’s  “ a u dit tr ail. ” 
C o  m pl eti o n  of t h e  e  C  R F s h o ul d  b e  k e pt  c urr e nt t o  e n a bl e t h e   m o nit or t o r e vi e  w t h e s u bj e ct’s 
st at us t hr o u g h o ut t h e  c o urs e  of t h e st u d y.    All i nf or  m ati o n  a n d  ot h er   m at eri al t o  b e  us e d  b y 
s u bj e cts  a n d i n v esti g at i v e st aff   m ust  us e  v o c a b ul ar y  a n d l a n g u a g e t h at  ar e  cl e arl y  u n d erst o o d.  
T h e  e  C  R F   will  b e  c o  m pl et e d, r e vi e  w e d,  a n d si g n e d  off  or  e  -si g n e d  b y t h e i n v esti g at or.   T h e 
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  5 5  
in v esti g at or   will si g n  a n d  d at e t h e i n di c at e d  pl a c es  o n t h e  e  C  R F  vi a t h e  E  D  C s yst e  m’s  el e ctr o ni c 
si g n at ur e.   T h es e si g n at ur es   will i n di c at e t h at t h e  in v esti g at or i ns p e ct e d  or r e vi e  w e d t h e  d at a  o n 
t h e  e  C  R F, t h e  d at a  q u eri es,  a n d t h e st u d y sit e  n otifi c ati o ns,  a n d  a gr e es   wit h t h e  c o nt e nt.  S cr e e n 
f ail ur e i nf or  m ati o n   will  b e  c oll e ct e d  at t h e sit e  a n d will  n ot  b e r e p ort e d i n t h e  E  D  C.   
1 1. 3.    
D at a   M a n a g e  m e nt   
E a c h s u bj e ct   will  b e i d e ntifi e d i n t h e  d at a b as e  b y  a  u ni q u e s u bj e ct i d e ntifi er  as  d efi n e d  b y t h e 
S p o ns or.  
T o  e ns ur e t h e  q u alit y  of  cli ni c al  d at a  a cr oss  all s u bj e cts  a n d   st u d y sit es,  a   Cli ni c al   D at a 
M a n a g e  m e  nt r e vi e  w   will  b e  p erf or  m e d  o n s u bj e ct  d at a  a c c or di n g t o s p e cifi c ati o ns  gi v e n t o   D SI.  
D at a   will  b e  v ett e d  b ot h  el e ctr o ni c all y  a n d   m a n u all y f or   e C  R Fs   a n d  t h e  d at a   will  b e 
el e ctr o ni c all y  v ett e d  b y  pr o gr a  m  m e d  d at a r ul es   wit hi n t h e  a p pli c ati o n.    Q u eri es  g e n er at e d  b y 
r ul es  a n d r ais e d  b y r e vi e  w ers   will  b e  g e n er at e d   wit hi n t h e  E  D  C  a p pli c ati o n.    D uri n g t his r e vi e  w, 
s u bj e ct  d at a   will  b e  c h e c k e d f or  c o nsist e n c y,  c o  m pl et e n ess,  a n d  a n y  a p p ar e nt  dis cr e p a n ci es.    
D at a r e c ei v e d fr o  m  e xt er n al s o ur c es s u c h  as  c e ntr al l a b  or at ori e s   will  b e r e c o n cil e d t o t h e  cli ni c al 
d at a b as e.  
S  A E s i n t h e  cli ni c al  d at a b as e   will  b e r e c o n cil e d   wit h t h e s af et y  d at a b as e.  
All   A Es   will  b e  c o d e d  usi n g   M e d  D  R  A.   Pri or  a n d  c o n c o  mit a nt   m e di c ati o n  e nt er e d i nt o t h e 
d at a b as e   will  b e  c o d e d  usi n g t h e  W  H  O   dr u g  di cti o n ar y (  V ersi o n  1 8. 1  or  hi g h er).    
1 1. 4.    
St u d y   D o c u  m e nt ati o n  a n d  St o r a g e  
T h e  in v esti g at or   will   m ai nt ai n  a  Si g n at ur e  List  of  a p pr o pri at el y  q u alifi e d  p ers o ns t o   w h o  m 
h e/s h e  h as  d el e g at e d st u d y  d uti es.    All  p ers o ns  a ut h ori z e d t o   m a k e  e ntri es  a n d/ or  c orr e cti o ns  o n 
e  C  R Fs   will  b e i n cl u d e d  o n t h e  Si g n at ur e  List.  
I n v esti g at ors   will   m ai nt ai n  a  c o nfi d e nti al s cr e e ni n g l o g  of  all  p ot e nti al st u d y  c a n di d at es t h at 
i n cl u d es li  mit e d i nf or  m ati o n  of t h e s u bj e cts,  d at es,  a n d  o ut c o  m es  of s cr e e ni n g  pr o c ess. 
I n v esti g at ors   will  b e e x p e ct e d t o   m ai nt ai n  a n  E nr oll  m e nt  L o g  of  all s u bj e cts  e nr oll e d i n t h e st u d y 
i n di c ati n g t h eir  assi g n e d st u d y  n u  m b er. 
I n v esti g at ors   will   m ai nt ai n  a  c o nfi d e nti al s u bj e ct i d e ntifi c ati o n  c o d e list.   T his  c o nfi d e nti al list  of 
n a  m es  of  all s u bj e cts  all o c at e d t o  st u d y  n u  m b ers  o n  e nr olli n g i n t h e st u d y  all o  ws t h e  in v esti g at or 
t o r e v e al t h e i d e ntit y  of  a n y s u bj e ct   w h e n  n e c ess ar y. 
S o ur c e  d o c u  m e nts  ar e  ori gi n al  d o c u  m e nts,  d at a,  a n d r e c or ds fr o  m   w hi c h t h e s u bj e ct’s  e  C  R F  d at a 
ar e  o bt ai n e d.   T h es e i n cl u d e  b ut  ar e  n ot li  m it e d t o  h os pit al r e c or ds,  cli ni c al  a n d  offi c e  c h arts, 
l a b or at or y  a n d  p h ar  m a c y r e c or ds,  di ari es,   mi cr ofi c h es,   X-r a ys,  a n d  c orr es p o n d e n c e.   
R e c or ds  of s u bj e cts, s o ur c e  d o c u  m e nts,   m o nit ori n g  visit l o gs,  d at a  c orr e cti o n f or  ms,  e  C  R Fs, 
i n v e nt or y  of st u d y  dr u g, r e g ul at or y  d o c u  m e nts ( e g,  pr ot o c ol  a n d  a  m e n d  m e nts, I R  B 
c orr es p o n d e n c e  a n d  a p pr o v als,  a p pr o v e d  a n d si g n e d I C Fs,  in v esti g at or’s  a gr e e  m e nt,  cli ni c al 
s u p pli es r e c ei pts,  distri b uti o n  a n d r et ur n r e c or ds),  a n d  ot h er  S p o ns or  c orr es p o n d e n c e  p ert ai ni n g 
t o t h e st u d y m ust  b e  k e pt i n  a p pr o pri at e st u d y fil es  at t h e st u d y sit e ( Tri al   M ast er  Fil e).   S o ur c e 
d o c u  m e nts i n cl u d e  all r e c or di n gs  a n d  o bs er v ati o ns  or  n ot ati o ns  of  cli ni c al  a cti viti es  a n d  all 
r e p orts  a n d r e c or ds  n e c ess ar y f or t h e  e v al u ati o n  a n d r e c o nstr u cti o n  of t h e  cli ni c al st u d y.   T h es e 
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  5 6  
r e c or ds   will  b e r et ai n e d i n  a s e c ur e fil e f or t h e  p eri o d r e q uir e d  b y t h e i nstit uti o n  or st u d y sit e 
p oli c y.   Pri or t o tr a nsf er  or  d estr u cti o n  of t h es e r e c or ds, t h e  S p o ns or   m ust  b e  n otifi e d i n   writi n g 
a n d  b e  gi v e n t h e  o p p ort u nit y t o f u rt h er st or e s u c h r e c or ds. 
1 1. 5.    
R e c o r d   K e e pi n g   
T h e  in v esti g at or  a n d st u d y st aff  ar e r es p o nsi bl e f or   m ai nt ai ni n g  a  c o  m pr e h e nsi v e  a n d  c e ntr ali z e d 
fili n g s yst e  m ( Tri al   M ast er  Fil e)  of  all st u d y-r el at e d  d o c u  m e nt ati o n, s uit a bl e f or i ns p e cti o n  at  a n y 
ti  m e  b y r e pr es e ntati v es fr o  m t h e  S p o ns or  a n d/ or  a p pli c a bl e r e g ul at or y  a ut h oriti es.   T h e  Tri al 
M ast er  Fil e i n cl u d es:   
    S u bj e ct fil es  c o nt ai ni n g  c o  m pl et e d  e  C  R Fs, I C Fs,  a n d s u p p orti n g  c o pi es  of s o ur c e 
d o c u  m e nt ati o n (if  k e pt).  
    St u d y fil es  c o nt ai ni n g t h e  pr ot o c ol   wit h  all  a  m e n d  m e nts, I  B,  c o pi es  of r el e v a nt 
ess e nti al  d o c u  m e nts r e q uir e d  pri or t o  c o  m  m e n ci n g  a  cli ni c al st u d y,  a n d  all 
c orr es p o n d e n c e t o  a n d fr o  m t h e I R  B  a n d t h e  S p o ns or.  
    R e  c or ds r el at e d t o t h e st u d y  dr u g  i n cl u di n g  a c k n o  wl e d g  m e nt  of r e c ei pt  at sit e, 
a c c o u nt a bilit y r e c or ds , fi n al r e c o n cili ati o n,  a n d  a p pli c a bl e  c orr es p o n d e n c e. 
I n  a d diti o n,  all  ori gi n al s o ur c e  d o c u  m e nts s u p p orti n g  e ntri es i n t h e  e  C  R Fs   m ust  b e   m ai nt ai n e d 
a n d  b e r e a dil y  a v ail a bl e.  
T h e  Tri al   M ast er  Fil e   will  b e r et ai n e d  b y t h e  in v esti g at or  u ntil  at l e ast  3  y  aft er t h e l ast  a p pr o v al 
of  a   m ar k eti n g  a p pli c ati o n i n  a n I C  H r e gi o n  a n d  u ntil t h er e  ar e  n o  p e n di n g  or  c o nt e  m pl at e d 
m ar k eti n g  a p pli c ati o ns i n  a n I C  H r e gi o n  or  at l e ast  3  y  h a v e l a ps e d si n c e t h e f or  m al 
dis c o nti n u ati o n  of  cli ni c al  d e v el o p  m e nt  of t h e i n v esti g ati o n al  dr u g.   T h es e  d o c u  m e nts s h o ul d  b e 
r et ai n e d f or  a l o n g er  p eri o d,  h o  w e v er, if r e q uir e d  b y t h e  a p pli c a bl e r e g ul at or y r e q uir e  m e nts  or  b y 
a n  a gr e e  m e nt   wit h t h e  S p o ns or.  It is t h e r es p o nsi bilit y  of t h e  S p o ns or t o i nf or  m t h e 
in v esti g at or/i nstit uti o n  as t o   w h e n t h es e  d o c u  m e nts  n o l o n g er  n e e d t o  b e r et ai n e d.  
T h e s u bj e ct’s   m e di c al fil es s h o ul d  b e r et ai n e d i n  a c c or d a n c e   wit h  a p pli c a bl e l e gisl ati o n  a n d i n 
a c c or d a n c e   wit h t h e   m a xi  m u  m  p eri o d  of ti  m e  p er  mitt e d  b y t h e  h os pit al, i nstit uti o n,  or  pri v at e 
pr a cti c e.   
N o st u  d y  d o c u  m e nt s h o ul d  b e  d estr o y e d   wit h o ut  pri or   writt e n  a gr e e  m e nt  b et  w e e n t h e  S p o ns or 
a n d t h e  in v esti g at or.   S h o ul d t h e  in v esti g at or   wis h t o  assi g n t h e st u d y r e c or ds t o  a n ot h er  p art y  or 
m o v e t h e  m t o  a n ot h er l o c ati o n,  h e/s h e   m ust  n otif y t h e  S p o ns or i n   writi n g   of t h e  n e  w r es p o nsi bl e 
p ers o n  a n d/ or t h e  n e  w l o c ati o n.  
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  5 7  
1 2.    
FI  N  A  N  CI  N  G   A  N  D I  N S  U  R  A N  C  E   
1 2. 1.    
Fi n a n c es  
Pri or t o st arti n g t h e st u d y, t h e  in v esti g at or  a n d/ or i nstit uti o n   will si g n  a  cli ni c al st u d y  a gr e e  m e nt 
wit h   D SI.   T his  a gr e e  m e nt   will i n cl u d e t h e fi n a n ci al i nf or  m ati o n   a gr e e d  u p o n  b y t h e  p arti es.  
1 2. 2.    
R ei  m b u rs e  m e nt, I n d e  m nit y,  a n d I ns u r a n c e   
T h e  S p o ns or  pr o vi d es i ns ur a n c e f or st u d y s u bj e cts t o   m a k e  a v ail a bl e  c o  m p e ns ati o n i n  c as e  of 
st u d y-r el at e d i nj ur y. 
R ei  m b urs e  m e nt, i n d e  m nit y,  a n d i ns ur a n c e s h all  b e  a d dr ess e d i n  a s e p ar at e   a gr e e  m e nt  o n t er  ms 
a gr e e d  u p o n  b y t h e  p arti es.  
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  5 8  
1 3.    
P  U  B  LI  C  A  TI  O  N  P  O  LI  C  Y  
A st u d y sit e   m a y  n ot  p u blis h r es ults  of  a st u d y  u ntil  aft er  a  c o or di n at e d   m ulti c e nt er  p u bli c ati o n 
h as  b e e n s u b  mitt e d f or  p u bli c ati o n  or  u ntil  1  y  aft er t h e st u d y  h as  e n d e d,   w hi c h e v er  o c c urs  first.  
T h er ef or e, t h e st u d y sit e   will  h a v e t h e  o p p ort u nit y t o  p u blis h t h e r es ults  of t h e st u d y,  pr o vi d e d 
t h at   D SI  h as  h a d t h e  o p p ort u nit y t o r e vi e  w  a n d  c o  m  m e nt  o n t h e st u d y sit e’s  pr o p os e d  p u bli c ati o n 
pri or t o its  b ei n g s u b  mitt e d f or  p u bli c ati o n   wit h t h e  pri or  a d vi c e  of   D SI  L e g al   Aff airs 
(i nt ell e ct u al  pr o p ert y  c o u n cil)  a n d   wit h  pr o p er r e g ar d t o t h e  pr ot e cti o n  of s u bj e cts’ i d e ntiti es.   
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  5 9  
1 4.    
E  T  HI  C S   A  N  D  S  T  U  D  Y   A  D  M  I  NI S  T  R  A  TI  V  E I  N F  O  R  M  A  T I  O  N 
1 4. 1.    
C o  m pli a n c e  St at e  m e nt,   Et hi cs  a n d   R e g ul at o r y   C o  m pli a n c e   
T his st u d y   will  b e  c o n d u ct e d i n  c o  m pli a n c e   wit h t h e  pr ot o c ol, t h e  et hi c al  pri n ci pl es t h at  h a v e 
t h eir  ori gi n i n t h e   D e cl ar ati o n  of   H elsi n ki, t h e I C  H  c o ns oli d at e d   G ui d eli n e  E 6 f or   G  C P 
(  C o  m  mitt e e f or M  e di ci n al  P r o d u cts f or H  u  m a n  U  s e/I C  H/ 1 3 5/ 9 5),  a n d  a p pli c a bl e r e g ul at or y 
r e q uir e  m e nts i n cl u di n g t h e f oll o  wi n g:  
    E ur o p e a n   C o  m  missi o n   Dir e cti v e ( 2 0 0 1/ 2 0/ E  C   A pr  il 2 0 0 1)  
    E ur o p e a n   C o  m  missi o n   Dir e cti v e ( 2 0 0 5/ 2 8/ E  C   A pr  il 2 0 0 5)  
    U S   F  D  A  G  C P   R e g ul ati o ns:   C o d e  of  F e d er al   R e g ul ati o ns   Titl e  2 1,  p arts  1 1,  5 0,  5 4, 
5 6,  a n d  3 1 2  as  a p pr o pri at e   
    J a p a n es e   Mi ni str y  of   H e alt h,  L a b or  a n d   W elf ar e   Or di n a n c e   N o.  2 8  of  2 7   M ar c h  1 9 9 7   
    T h e   A ct  o n  S e c uri n g   Q u alit y,  Effi c a c y  a n d  S af et y  of  P h ar  m a c e uti c als,   M e di c al 
D e vi c es,   R e g e n er ati v e  a n d   C ell ul ar  T h er a p y  Pr o d u cts,   G e n e  T h er a p y  Pr o d u cts,  a n d 
C os  m eti cs   N o.  1  of  2 5   N o v e  m b er   2 0 1 4  a n d/ or  
    Ot h er  a p pli c a bl e l o c al r e g ul ati o ns   
1 4. 2.    
S u bj e ct   C o nfi d e nti alit y  
T h e  in v esti g at ors  a n d t h e  S p o ns or   will  pr es er v e t h e  c o nfi d e nti alit y  of  all s u bj e cts t a ki n g  p art i n 
t h e st u d y, i n  a c c or d a n c e   wit h   G  C P  a n d l o c al r e g ul ati o ns. 
T h e  in v esti g at or   m ust  e ns ur e  t h at t h e s u bj e ct’s  a n o n y  mit y is   m ai nt ai n e d.    O n t h e  e  C  R Fs  or  ot h er 
d o c u  m e nts s u b  mitt e d t o t h e  S p o ns or  or t h e   C  R  O, s u bj e cts s h o ul d  b e i d e ntifi e d  b y  a  u ni q u e 
s u bj e ct i d e ntifi er  as  d esi g n at e d  b y t h e  S p o ns or.    D o c u  m e nts t h at  ar e  n ot f or s u b  missi o n t o t h e 
S p o n s or  or t h e   C  R  O ( e g, si g n e d I  C F) s h o ul d  b e  k e pt i n stri ct  c o nfi d e n c e  b y t h e  in v esti g at or.  
I n  c o  m pli a n c e   wit h I  C  H   G  C P   G ui d eli n es, it is r e q uir e d t h at t h e in v esti g at or  a n d i nstit uti o n 
p er  mit  a ut h ori z e d r e pr es e nt ati v es  of t h e  c o  m p a n y,  of t h e r e g ul at or y  a g e n c y( i es),  a n d t h e I  R  B 
dir e ct  a c c ess t o r e vi e  w t h e s u bj e ct’s  ori gi n al   m e di c al r e c or ds f or  v erifi c ati o n  of st u d y -r el at e d 
pr o c e d ur es  a n d  d at a.   T h e  in v esti g at or is  o bli g at e d t o i nf or  m t h e s u bj e ct t h at  his/ h er st u d y -r el at e d 
r e c or ds   will  b e r e vi e  w e d  b y t h e  a b o v e-n a m e d r e pr es e nt ati v es   wit h o ut  vi ol ati n g t h e 
c o nfi d e nti alit y  of t h e s u bj e ct.  
1 4. 3.    
I nf o r  m e d   C o ns e nt  
B ef or e  a s u bj e ct’s  p arti ci p ati o n i n t h e st u d y, it is t h e   in v esti g at or’s r es p o nsi bilit y t o  o bt ai n fr e el y 
gi v e n  c o ns e nt, i n   writi n g, fr o  m t h e s u bj e ct  aft er  a d e q u at e  e x pl a n ati o n  of t h e  ai  ms,   m et h o ds, 
a nti ci p at e d  b e n efits,  a n d  p ot e nti al  h a z ar ds  of t h e st u d y  a n d  b ef or e  a n y  pr ot o c ol -s p e cifi c 
pr o c e d ur es  or  a n y st u d y  dr u g is  a d  mi nist er e d.   S u bj e cts s h o ul d  b e  gi v e n t h e  o p p ort u nit y t o  as k 
q u esti o ns  a n d r e c ei v e s atisf a ct or y  a ns  w ers t o t h eir i n q uiri es  a n d s h o ul d  h a v e  a d e q u at e ti  m e t o 
d e ci d e   w h et h er  or  n ot t o  p arti ci p at e i n t h e st u d y.   T h e   writt e n I  C F s h o ul d  b e  pr e p ar e d i n t h e l o c al 
l a n g u a g e(s)  of t h e  p ot e nti al s u bj e ct  p o p ul ati o n. 
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  6 0  
I n  o bt ai ni n g  a n d  d o c u  m e nti n g i nf or  m e d  c o ns e nt, t h e in v esti g at or s h o ul d  c o  m pl y   wit h t h e 
a p pli c a bl e r e g ul at or y r e q uir e  m e nts,  a n d s h o ul d  a d h er e t o   G  C P  a n d t o t h e  et hi c al  pri n ci pl es t h at 
h a v e t h eir  ori gi n i n t h e   D e cl ar ati o n  of   H elsi n ki.   T h e  c o ns e nt f or  m  a n d  a n y r e visi o n(s) s h o ul d  b e 
a p pr o v e d  b y t h e I R  B  pri or  t o  b ei n g  pr o vi d e d t o  p ot e nti al s u bj e cts. 
T h e s u bj e ct’s   writt e n i nf or  m e d  c o ns e nt s h o ul d  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 ds.  
T h e I C F s h o ul d  b e si g n e d  a n d  p ers o n all y  d at e d  b y t h e s u bj e ct  a n d  b y t h e  p ers o n   w h o  c o n d u ct e d 
t h e i nf or  m e d  c o ns e nt  dis c ussi o n ( n ot  n e c ess aril y t h e  in v esti g at or).   T h e  ori gi n al si g n e d I  C F 
s h o ul d  b e r et ai n e d i n  a c c or d a n c e   wit h i nstit uti o n al  p oli c y,  a n d  a  c o p y  of t h e si g n e d  c o ns e nt f or  m 
s h o ul d  b e  pr o vi d e d t o t h e s u bj e ct.   T h e  d at e  a n d ti  m e (if  a p pli c a bl e) t h at i nf or  m e d  c o ns e nt  w as 
gi v e n s h o ul d  b e r e c or d e d  o n t h e  e  C  R F.  
If t h e s u bj e ct  c a n n ot r e a d, t h e n  a c c or di n g t o I C  H   G  C P   G ui d eli n e  S e cti o n  4. 8. 9,  a n i  m p arti al 
wit n ess s h o ul d  b e  pr es e nt  d uri n g t h e  e ntir e i nf or  m e d  c o ns e nt  dis c ussi o n.   T his   wit n ess s h o ul d 
si g n t h e I  C F  aft er t h e s u bj e ct  h as  c o ns e nt e d t o t h e s u bj e ct’s  p arti ci p ati o n  a n d, if  p ossi bl e, si g n e d 
t h e I C F.    B y si g ni n g t h e I  C F, t h e   wit n ess  att ests t h at t h e i nf or  m ati o n i n t h e I C F  a n d  a n y  ot h er 
writt e n i nf or  m ati o n   w as  a d e q u at el y  e x pl ai n e d t o  a n d  a p p ar e ntl y  u n d erst o o d  b y t h e s u bj e c  t  a n d 
t h at i nf or  m e d  c o ns e nt   w as fr e el y  gi v e n  b y t h e s u bj e ct. 
S u g g est e d   m o d el t e xt f or t h e I C F f or t h e st u d y  a n d  a n y  a p pli c a bl e s u b p arts ( P  K,  et c)  ar e 
pr o vi d e d i n t h e  S p o ns or’s I C F t e  m pl at e f or t h e i n v esti g at or t o  pr e p ar e t h e  d o c u  m e nts t o  b e  us e d 
at  his  or  h er  st u d y sit e.    U p d at es t o  a p pli c a bl e f or  ms   will  b e  c o  m  m u ni c at e d  vi a l ett er fr o  m t h e 
S p o ns or . 
A d diti o n al  c o ns e nt is r e q uir e d f or   H e alt h I ns ur a n c e  P ort a bilit y  a n d   A c c o u nt a bilit y   A ct  . S u bj e cts 
will  c o ns e nt t o  vir ol o g y t esti n g (  HI  V  a nti b o d y,   H  Bs  A g  a n d   H  C  V  a nti b o d y)  as  p art  of t h eir i niti al 
i nf or  m e d  c o ns e nt.   T his t esti n g   will  b e  d es cri b e d i n t h e I C F. 
1 4. 4.    
R e g ul at o r y   C o  m pli a n c e   
T h e st u d y  pr ot o c ol, s u bj e ct i nf or  m ati o n  a n d  c o ns e nt f or  m, t h e I  B,   a n y s u bj e ct   writt e n 
i nstr u cti o ns t o  b e  gi v e n t o t h e s u bj e ct,  a v ail a bl e s af et y i nf or  m ati o n, s u bj e ct r e cr uit  m e nt 
pr o c e d ur es ( e g,  a d v ertis e  m e nts), i nf or  m ati o n  a b o ut  p a y  m e nts  a n d  c o  m p e ns ati o n  a v ail a bl e t o t h e 
s u bj e cts,  a n d  d o c u  m e nt ati o n  e vi d e n ci n g t h e  in v esti g at or’s  q u alifi c ati o ns s h o ul d  b e s u b  mitt e d t o 
t h e I R  B f or  et hi c al r e vi e  w  a n d  a p pr o v al  a c c or di n g t o l o c al r e g ul ati o ns,  pri or t o t h e st u d y 
i niti ati o n.   T h e   writt e n  a p pr o v al s h o ul d i d e ntif y  all  d o c u  m e nts r e vi e  w e d  b y  n a  m e  a n d  v ersi o n. 
C h a n g es i n t h e  c o n d u ct  of   t h e st u d y  or  pl a n n e d  a n al ysis   will  b e  d o c u  m e nt e d i n  a  pr ot o c ol 
a  m e n d  m e nt  a n d/ or t h e  S  A P.  
T h e  in v esti g at or  a n d/ or  S p o ns or   m ust s u b  mit  a n d,   w h er e  n e c ess ar y,  o bt ai n  a p pr o v al fr o  m t h e 
I  R  B f or  all s u bs e q u e nt  pr ot o c ol  a  m e n d  m e nts  a n d  c h a n g es t o t h e I  C F.   T h e in v esti g at or s h o ul d 
n otif y t h e I  R  B  of  d e vi ati o ns fr o  m t h e  pr ot o c ol  or  S  A Es  o c c urri n g  at t h e st u d y sit e  a n d  ot h er   A E 
r e p orts r e c ei v e d fr o  m t h e  S p o ns or/  C  R  O, i n  a c c or d a n c e   wit h l o c al  pr o c e d ur es.  
As r e q uir e d  b y l o c al r e g ul ati o ns, t h e  S p o ns or’s l o c al   R e g ul at or y   Af  f airs  gr o u p  or r e pr es e nt ati v e 
t o   w h o  m t his r es p o nsi bilit y  h as  b e e n  d el e g at e d   will  e ns ur e  all l e g al  as p e cts  ar e  c o v er e d,  a n d 
a p pr o v al fr o  m t h e  a p pr o pri at e r e g ul at or y  b o di es  o bt ai n e d,  pri or t o st u d y i niti ati o n.  If  c h a n g es t o 
t h e i niti al  pr ot o c ol  a n d  ot h er rel e v a nt st u d y  d o c u  m e nts  ar e   m a d e, t his r e pr es e nt ati v e   will  als o 
e ns ur e t h at  a n y r e vis e d  d o c u  m e nts r e q uir e d f or s u b  missi o n  ar e s u b  mitt e d t o r e g ul at or y 
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  6 1  
a ut h oriti es  a n d i  m pl e  m e nt ati o n  of t h es e  c h a n g es  h a p p e n  o nl y  aft er  a p pr o v al  b y t h e r el e v a nt 
r e g ul at or y  b o dies,  as r e q uir e d.  
I n t h e  e v e nt  of  a n y  pr o hi biti o n  or r estri cti o n i  m p os e d ( e g,  cli ni c al  h ol d)  b y  a n  a p pli c a bl e 
R e g ul at or y   A ut h orit y i n  a n y  ar e a  of t h e   w orl d,  or if t h e   in v esti g at or is  a  w ar e  of  a n y  n e  w 
i nf or  m ati o n   w hi c h   mi g ht i nfl u e n c e t h e  e v al u ati o n  of t h e  be n efits  a n d ris ks  of t h e i n v esti g ati o n al 
dr u g, t h e  S p o ns or s h o ul d  b e i nf or  m e d i  m  m e di at el y.    
I n  a d diti o n, t h e in v esti g at or   will i nf or  m t h e  S p o ns or i  m  m e di at el y  of  a n y  ur g e nt s af et y   m e as ur es 
t a k e n  b y t h e in v esti g at or t o  pr ot e ct t h e st u d y s u bj e cts  a g ai nst  a n y  i  m  m e di at e  h a z ar d,  a n d  of  a n y 
s us p e ct e d/ a ct u al s eri o us   G  C P  n o n -c o  m pli a n c e t h at t h e  in v esti g at or  b e c o  m es  a  w ar e  of.  
1 4. 5.    
P r ot o c ol   D e vi ati o ns  
T h e  in v esti g at or s h o ul d  c o n d u ct t h e st u d y i n  c o  m pli a n c e   wit h t h e  pr ot o c ol  a gr e e d t o  b y t h e 
S p o ns or  a n d, if r e q uir e d,  b y t h e r e g ul at or y  a ut h orit y,  a n d   w hi c h   w as  gi v e n  a p pr o v al/f a v or a bl e 
o pi ni o n  b y t h e I  R  B.  
A  d e vi ati o n t o  a n y  pr ot o c ol  pr o c e d ur e  or   w ai v er t o  a n y st at e d  crit eri a   will  n ot  b e  all o  w e d i n t his 
st u d y  e x c e pt   w h er e  n e c ess ar y t o  eli  mi n at e i  m  m e di at e  h a z ar d(s) t o t h e s u bj e ct.   T h e  S p o ns or   m ust 
b e  n otifi e d  of  all i nt e n d e d  or  u ni nt e n d e d  d e vi ati o ns t o t h e  pr ot o c ol ( e g, i n cl usi o n/ e x cl usi o n 
crit eri a,  d osi n g,   miss e d st u d y  visits)  o n  a n  e x p e dit e d  b asis.  
T h e  in v esti g at or,  or  p ers o n  d esi g n at e d  b y t h e  in v esti g at or, s h o ul d  d o c u  m e nt  a n d  e x pl ai n  a n y 
d e vi ati o n fr o  m t h e  a p pr o v e d  pr ot o c ol.  
If  a s u bj e ct   w as i n eli gi bl e  or r e c ei v e d t h e i n c orr e ct  d os e  or st u d y tr e at  m e nt,  a n d  h a d  at l e ast 
1  a d  mi nistr ati o n  of st u d y  dr u g,  d at a s h o ul d  b e  c oll e ct e d f or s af et y  p ur p os es.  
If  a p pli c a bl e, t h e in v esti g at o r s h o ul d  n otif y t h e I R  B  of  d e vi ati o ns fr o  m t h e  pr ot o c ol i n 
a c c or d a n c e   wit h l o c al  pr o c e d ur es.  
1 4. 6.    
S u p pl y  of   N e  w I nf o r  m ati o n   Aff e cti n g t h e   C o n d u ct  of t h e  St u d y  
W h e n  n e  w i nf or  m ati o n  b e c o  m es  a v ail a bl e t h at   m a y  a d v ers el y  aff e ct t h e s af et y  of s u bj e cts  or t h e 
c o n d u ct  of t h e st u d y, t h e  S p o ns or   will i nf or  m  all  in v esti g at ors i n v ol v e d i n t h e  cli ni c al st u d y, 
I  R  B,  a n d r e g ul at or y  a ut h oriti es  of s u c h i nf or  m ati o n,  a n d   w h e n  n e e d e d,   will  a  m e n d t h e  pr ot o c ol 
a n d/ or s u bj e ct i nf or  m ati o n.  
T h e  in v esti g at or s h o ul d i  m  m e di at el y i nf or  m t h e s u bj e ct   w h e n e v er  n e  w i nf or  m ati o n  b e c o  m es 
a v ail a bl e t h at   m a y  b e r el e v a nt t o t h e s u bj e ct’s  c o ns e nt  or   m a y i nfl u e n c e t h e s u bj e ct’s   willi n g n ess 
t o  c o nti n u e  p arti ci p ati o n i n t h e st u d y.   T h e  c o  m  m u ni c ati o n s h o ul d  b e  d o c u  m e nt e d  o n   m e di c al 
r e c or ds, f or  e x a  m pl e,  an d it s h o ul d  b e  c o nfir  m e d   w h et h er t h e s u bj e ct is   willi n g t o r e  m ai n i n t h e 
st u d y.   
If t h e s u bj e ct i nf or  m ati o n is r e vis e d, it   m ust  b e r e-a p pr o v e d  b y t h e I R  B.   T h e  in v esti g at or s h o ul d 
o bt ai n   writt e n i nf or  m e d  c o ns e nt t o  c o nti n u e  p arti ci p ati o n   wit h t h e r e vis e d  writt e n i nf or  m ati o n 
e v e n if s u bj e cts   w er e  alr e a d y i nf or  m e d  of t h e r el e v a nt i nf or  m ati o n.   T h e  in v esti g at or  or  ot h er 
r es p o nsi bl e  p ers o n n el   w h o  pr o vi d e d  e x pl a n ati o ns  a n d t h e s u bj e ct s h o ul d si g n  a n d  d at e t h e 
r e vis e d I  C F. 
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1










P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  6 6  
1 5.    
R  E F  E  R  E  N  C  E S   
1.    P L  X 3 3 9 7 I n v esti g at or’s   Br o c h ur e,   V ersi o n  1 0. 0  1 9   D E  C  2 0 1 8 . 
2.    P L  X 1 0 8 -1 1   C S  R.  
3.    T ur ali o  ™   U S PI (  U S PI -T  U  R -0 8 9 1 9 -r 0 0 1) 
4.    P at el   H,  E g ori n   MJ,   R e  mi c k  S  C,   M ul k eri n   D,  T a ki  m ot o   C  H  M,   D or os h o  w J  H,  et  al. 
C o  m p aris o n  of   C hil d  -P u g h (  C P)  crit eri a  a n d   N  CI  or g a n  d ysf u n cti o n   w or ki n g  gr o u p 
(  N  CI-O  D  W  G)  crit eri a f or  h e p ati c  d ysf u n cti o n (  H  D): I  m pli c ati o ns f or  c h e  m ot h er a p y 
d osi n g. J   Cli n   O n c ol . J ul. 2 0 0 4  2 2( 1 4 _s u p pl): 6 0 5 1. 
5.    P L 3 3 9 7 -A  -U 1 1 4   C S  R   
6.    D aii c hi  S a n k y o   N o n c o  m p art  m e nt al   A n al ysis   G ui d eli n es    2 0 1 9 . 
7.    F  D  A   H e p ati c   G ui d a n c e  2 0 0 3.  
 
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  6 7  
1 6.    
A P P  E  N  DI  C  E S   
1 6. 1.    
L a b eli n g  a n d  P a c k a gi n g   
N ot  a p pli c a bl e   
1 6. 2.    
Bl o o d   C oll e cti o n   V ol u  m e  b y   C at e g o r y  a n d   T ot al   
1 6. 2. 1.    
Bl o o d   C oll e cti o n   V ol u  m es   
Ti  m e  P oi nt   
T est It e  m     
C oll e cti o n 
V ol u  m e 
(  m  L) 
F r e q u e n c y a   
T ot al   V ol u  m e 
(  m  L)a   
S cr e e ni n g    
H e  m at ol o g y t est   
4 . 0 
1  
 
2 5. 2  
 
Bl o o d  c o a g ul ati o n 
s yst e  m t est  
2. 7  
Bl o o d  c h e  mistr y t est     
8. 5  
T est f or i nf e cti o ns  
1 0. 0  
C h e c k  -i n 
(  D a y -2 ) 
 
H e  m at ol o g y t est   
4. 0  
1  
1 5. 2  
 
Bl o o d  c o a g ul ati o n 
s yst e  m t est   
2. 7  
Bl o o d  c h e  mistr y t est      
8. 5  
Tr e at  m e nt     
H e  m at ol o g y t est   
4. 0  
3  
4 5. 6  
Bl o o d  c o a g ul ati o n 
s yst e  m t est  
2. 7  
Bl o o d  c h e  mistr y t est     
8. 5  
 
 
 
 
 
Tr e at  m e nt    
P e xi d arti ni b  P  K  
4. 0  
2 3  
9 2  
Pr ot ei n  bi n di n g  
1 0. 0  
2  
2 0  
C h e c k  -o ut/ E T    
H e  m at ol o g y t est   
4. 0  
1  
1 5. 2  
 
Bl o o d  c o a g ul ati o n 
s yst e  m t est  
2. 7  
 
 
 
Bl o o d  c h e  mistr y t est     
8. 5  
 
 
T ot al    
3 1   
2 1 3 .2  
a  Bl o o d  c oll e cti o n i n s u bj e cts   wit h   A Es s h o ul d  b e  c o nti n u e d  u ntil r es ol uti o n  of t h e  e v e nts ( e v e n  aft er t h e s c h e d ul e d  o bs er v ati o  n  p eri o d).  
   Bl o o d t o  b e  us e d f or s e v er al  diff er e nt t ests  b ut t a k e n  a  t  1 ti  m e   will  b e  c o u nt e d  as  1  c oll e cti o n ( e g,   F S  H). 
N ot e:  F or f e  m al es,  a n  a d diti o n al  4   m L  of  bl o o d   m a y  b e t a k e n f or s er u  m  pr e g n a n c y t esti n g  at  S cr e e ni n g  a n d  o n   D a y   -2.  
A b br e vi ati o ns:   A E  =  a d v ers e  e v e nt;   E T  =  E arl y  T er  mi n ati o n;  F S  H  =  f olli cl e sti  m ul ati n g  hor  m o n e;  P  K  =  p h ar  m a c o ki n eti cs  
1 6. 3.    
A d diti o n al I nf o r  m ati o n (f o r  J a p a n es e   St u d y  Sit es   O nl y)  
N ot  a p pli c a bl e  . 
1 6. 3. 1.    
G  C P  c o  m pli a n c e   
N ot  a p pli c a bl e.   
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  6 8  
1 6. 3. 2.    
St u d y  P e ri o d  
N ot  a p pli c a bl e.   
1 6. 3. 3.    
P a y  m e nt  f o r P a rti ci p ati o n ,   Co  m p e ns ati o n  f o r S t u d y-R  el at e d  Inj u ri es , a n d  
Ins u r a n c e  
N ot   a p pli c a bl e.  
1 6. 3. 4.    
St u d y   A d  mi nist r ati v e  St r u ct u r e  
N ot  a p pli c a bl e.   
1 6. 4.    
I nst r u cti o ns f o r  S p e ci  m e n   C oll e cti o n,  St o r a g e  a n d  S hi p  m e nt  
1 6. 4. 1.    
Pl as  m a  P h a r  m a c o ki n eti c  S a  m pl e   C oll e cti o n,  St o r a g e  a n d  S hi p  m e nt I nst r u cti o ns   
A  2   m L  bl o o d s a  m pl e   will  b e t a k e n  b y  v e ni p u n ct ur e  of f or e ar  m  v  ei n(s)  at ti  m e  p oi nts  d et ail e d i n 
t h e  S c h e d ul es  of  E v e nts ( S e cti o n 1 6. 5 ). 
Bl o o d s a  m pl es   will  b e  c oll e ct e d i nt o  pr e  -c hill e d  2   m L   V a c ut ai n er ®  t u b es  c o nt ai ni n g lit hi u  m 
h e p ari n  as  a nti c o a g ul a nt f or t h e  pr e p ar ati o n  of  pl as  m a.  It is i  m p ort a nt t o fill t h e   V a c ut ai n er ®  
t u b es t o t h e s p e cifi e d  c oll e cti o n  v ol u  m e. 
T h e t u b e  c o nt ai ni n g  bl o o d f or  pl as  m a  pr e p ar ati o n   will  b e  g e ntl y i n v ert e d   m ulti pl e ( > 8) ti  m es t o 
e ns ur e t h or o u g h   mi xi n g  of  a nti c o a g ul a nt  a n d  bl o o d, t h e n i  m  m e di at el y  pl a c e d i n  a  c o ol  b o x 
c o nt ai ni n g i c e   w at er.   T h e s a  m pl es s h o ul d  b e  c e ntrif u g e d   wit hi n  3 0   mi n  aft er  c oll e cti o n,  at 
a p pr o xi  m at el y  1 5 0 0  g f or  a p pr o xi  m at el y  1 0   mi n  at  a p pr o xi  m at el y  + 4°  C.  I  m  m e di at el y f oll o  wi n g 
c e ntrif u g ati o n, t h e s e p ar at e d  pl as  m a f or  e a c h s a  m pl e   will  b e  di vi d e d i nt o  2  ali q u ots  at t h e 
f oll o  wi n g  v ol u  m es: 
    Ali q u ot  1 (f or   p e xi d arti ni b  ass a y):  0. 5   m L  
    Ali q u ot  2 ( b a c k  -u p f or  p e xi d arti ni b  ass a y): r e  m ai ni n g  pl as  m a  
T h e  2  ali q u ots  of  pl as  m a  s h o ul d  e a c h  b e  pi p ett e d i nt o  p ol y pr o p yl e n e  cr y o g e ni c s a  m pl e st or a g e 
vi als ( at l e ast  2 t o  3   m L si z e,   wit h s cr e  w -c a p),  d esi g n at e d  S et  1  a n d  S et  2,  a n d l a b el e d   wit h 
a p pr o pri at e i nf or  m ati o n ( b ar c o d e  a n d/ or s u bj e ct I  D, ti  m e  p oi nts,  a n d  ali q u ot  n u  m b er).   T h e 
ali q u ots   m ust  b e  k e pt  c hill e d f or t h e  e ntir e ti  m e  b ef or e t h e y  ar e tr a nsf err e d t o t h e fr e e z er.   E a c h 
s et  of  ali q u ots   m ust  b e st or e d i n s e p ar at e  b o x es.    Wit hi n  6 0   mi n  aft er  bl o o d  dr a  w, t h e s a  m pl e 
st or a g e  vi als   will  b e st or e d i n t h e  d ar k i n  a  -2 0°  C ( -1 5°  C t o  -3 0 °  C) fr e e z er.  
A n y s a  m pl e  a n o  m ali es s h o ul d  b e r e c or d e d  o n t h e s a  m pli n g f or  ms.   
S et  1 s a  m pl es   will  b e s e nt t o t h e  bi o a n al yti c al l a b or at or y  at   C el eri o n f or t h e  d et er  mi n ati o n  of 
p e xi d arti ni b  pl as  m a  c o n c e ntr ati o ns.   S et  1 s a  m pl es s h o ul d  b e s hi p p e d  aft er t h e  e n d  o f  e a c h  p eri o d 
t o  arri v e  at t h e  bi o a n al yti c al l a b or at or y  at   C el eri o n t h e  n e xt  d a y.   S et  2 s a  m pl es  c a n  b e s hi p p e d t o 
t h e  bi o a n al yti c al l a b or at or y  at   C el eri o n  o n c e t h e sit e  c o nfir  ms r e c ei pt  of  S et  1 s a  m pl es fr o  m  a 
p eri o d.  
S hi p pi n g   G ui d e  
    Bi ol o gi c al s a  m pl es ( e g  ,  pl as  m a) s h o ul d  b e s hi p p e d  o n  dr y i c e. 
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  6 9  
    S a  m pl es s h o ul d  b e s hi p p e d  o nl y  o n  a   M o n d a y,  T u es d a y,   W e d n es d a y,  or  T h urs d a y t o 
mi ni  mi z e t h e  p ossi bilit y  of t h e  m  b ei n g i n tr a nsit  o v er  a   w e e k e n d.   
    If  d u pli c at e s a  m pl es  ar e  b ei n g s hi p p e d,  1 s et  of s a  m pl es s h o ul d  b e s e nt.   T h e s e c o n d 
s et s h o ul d  b e s hi p p e d  aft er r e c ei vi n g  c o nfir  m ati o n  of  arri v al  of t h e first s et  at 
C el eri o n.   
S a  m pl e  P a c ki n g  
    Arr a n g e t h e s a  m pl e  c oll e cti o n,   wit h  c o uri er.   
    Us e  a  St yr of o a  m  b o x, f or  e x a  m pl e  1 9 ”  ×  1 9 ”  ×  1 2 ”.    Us e  a l ar g er  o n e if s hi p pi n g 
m a n y   s a  m pl es.  
    O bt ai n  2 0 l bs  of  dr y i c e  p ell ets.    Us e  as   m u c h  dr y i c e  as  p ossi bl e, t o  h el p s af e g u ar d 
a g ai nst  a n y  p ossi bl e  d el a ys.  
    Pl a c e  a  4 ” l a y er  of  dr y i c e i n t h e  b ott o  m  of t h e  St yr of o a  m  b o x.  
    S a  m pl es s h o ul d  b e i d e ntifi e d  usi n g s elf -a d h esi v e l a b els,   w hi c h s h o ul d  b e  a p pli e d 
pri or t o fr e e zi n g t h e s a  m pl es.  
    Pl a c e t h e s a  m pl es i n  b o x es  p er st a n d ar d sit e  pr o c e d ur e.   Pl a c e t h e  b o x es i n t h e 
St yr of o a  m  c o ol er  a n d fill t h e  e x c ess s p a c e   wit h t h e r e  m ai ni n g  dr y i c e  p ell ets.  
    R e c or d t h e  esti  m at e d   w ei g ht  of t h e  dr y i c e  us e d  p er  b  o x.  
    Pl a c e t h e li d  o n t h e  St yr of o a  m  b o x  a n d s e al  c o  m pl et el y   wit h t a p e.  
    T a p e  a list  of t h e s a  m pl es  c o nt ai n e d i nsi d e t h e  b o x, t o t h e li d ( e g,  pl as  m a, s u bj e cts  1   - 
2 4,  pr e d os e,  3 0   mi n,  1 h).  I n  or d er t o  pr ot e ct t his  p a p er  w or k i ns ert it i nt o  a  pl asti c 
b a g.  
    Pl a c e t h e  St yr of o a  m  b o x i n  a  c ar d b o ar d s hi p pi n g  c art o n, s e al s e c ur el y   wit h t a p e.  
L a b eli n g   
L a b el t h e  c ar d b o ar d  b o x  as f oll o  ws:  
    M ar k t h e  o utsi d e  of t h e  c art o ns   wit h t all y  n u  m b er  e g,  1  of  3,  2  of  3,  a n d  3  of  3.   
    Affi x  a n  a d dr ess l a b el,   wit h t h e i nf or  m ati o n  b el o  w,   t o t h e  o utsi d e  of  e a c h  b o x: 
C el e ri o n   
Att n:  S a  m pl e   R e c ei pt,   C el eri o n   
6 2 4  P e a c h  Str e et  Li n c ol n,   N E  6 8 5 0 2  
 
 
Affi x t h e f oll o  wi n g l a b els  o n  e a c h  b o x:   
    1  c ar b o n  di o xi d e l a b el   wit h t h e   w ei g ht i n cl u d e d.  
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1
P P D


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  7 0  
    2 l a b els   wit h i nt er n ati o n all y r e c o g ni z e d  dr y i c e s y  m b ols (  Cl ass  9)  - 1  o n  eit h er si d e  of 
t h e  b o x. 
 
  
    1   K E E P  F  R  O Z E  N l a b el  
 
    1  P E  RI S  H  A  B L E   G  O  O  D S l a b el  
    I n di c at e r et ur n  a d dr ess  a n d  c o nt a ct  p ers o n  o n  e a c h  c art o n. 
P a p e r  w o r k t o   A c c o  m p a n y  S hi p  m e nt   
    T h es e  h u  m a n  bi ol o gi c al s a  m pl es  ar e  n ot  k n o  w n t o  b e   i nf e cti o us  or  h a z ar d o us. 
    F or l a b or at or y  us e  o nl y.  
    $ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ f or  c ust o  ms ( a  n o  mi n al  v al u e,  e g,  $ 5. 0 0)  
    N o  c o  m  m er ci al  v al u e.   
B e gi n ni n g   wit h t h e first s hi p  m e nt, i n cl u d e  all  of t h e f oll o  wi n g i nf or  m ati o n:   
    S u bj e ct i d e ntifi c ati o n  
    Ti  m e  p oi nt i d e ntifi c ati o n  
    Pr ot o c ol  n u  m b er  
    S p o ns or  n a  m e  
A n y   missi n g i nf or  m ati o n   m a y  c a us e  a  d el a y i n  a n al ysis.   
N otif y   C el eri o n  b y  e  m ail  or f a x i  m  m e di at el y  aft er t h e s a  m pl es  h a v e  b e e n  c oll e ct e d  b y t h e 
c o uri er.   Pl e as e  pr o vi d e t h e f oll o  wi n g i nf or  m ati o n:  
    N a  m e  of  c o uri er  or tr a ns p ort  c o  m p a n y   
    D at e  a n d ti  m e t h e s hi p  m e nt l eft  y o ur  pr e  mis es   
    T h e  air  w a y  bill  n u  m b er  
T h e  c o nt a ct  or s a  m pl e r e c ei pt is:  
 
C el eri o n   
6 2 1   R os e  Str e et  
Li n c ol n,   N E  6 8 5 0 2  
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1




P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  7 2  
1 6. 5.    
S c h e d ul e  of   E v e nts  
1 6. 5. 1.    
S c h e d ul e  of   E v e nts   
St u d y  P e ri o d  →   
S c r e e ni n g a  C h e c k
-i n 
T r e at  m e nt   
St u d y   D a y →   
-2 2 t o  -2    
-2    
-1  
1  
 
 
   
 
H o u r  P ost   D os e   
St u d y   E v e nt  ↓   
St u d y   H o u r  →   
 
   
   
P r e d os e    0. 5    
1    
1. 5    
2    
2. 5    
3    
3. 5    
4    
4. 5    
5    
6    
8    
1 0    
1 2  
I nf or  m e d   C o ns e nt 
X     
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 
A d  missi o n   
   
X     
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 
I n cl usi o n/ E x cl usi o n   Crit eri a   
X     
X     
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 
D e  m o gr a p hi c I nf or  m ati o n     
X     
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 
M e di c al/ S ur gi c al   Hist or y     
X     
X     
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 
C o  m pl et e  P h ysi c al 
E x a  mi n ati o n  
X     
X     
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 
B o d y   W ei g ht  ,  h eig ht b,  a n d 
B  MI b 
X     
X     
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 
Uri n e   Dr u g  s  of   A b us e, 
C oti ni n e,   Al c o h ol  S cr e e n c 
X     
X     
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 
Vir ol o g y 
(  H  Bs  A g/  HI  V/  H  A  V/  H  C  V) 
X     
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 
S er u  m  Pr e g n a n c y  T est d 
X     
X     
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 
F S  H e 
X     
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 
H e  m at ol o g y,  S er u  m 
C h e  mistr y,   Uri n al ysis f 
X     
X     
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 
H e p ati c  F u n cti o n   St at us  
(N  CI  -O  D  W  G  crit eri a)   
X     
X     
X     
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 
C hil d  -P u g h s c or e  
(i nf or  m ati o n  o nl y) 
 
X     
   
X     
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 
C o a g ul ati o n ( P T, I  N  R   a n d 
a P T T ) 
X     
X     
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  7 3  
St u d y  P e ri o d  →   
S c r e e ni n g a  C h e c k
-i n 
T r e at  m e nt   
St u d y   D a y →   
-2 2 t o  -2    
-2    
-1  
1  
 
 
   
 
H o u r  P ost   D os e   
St u d y   E v e nt  ↓   
St u d y   H o u r  →   
 
   
   
P r e d os e    0. 5    
1    
1. 5    
2    
2. 5    
3    
3. 5    
4    
4. 5    
5    
6    
8    
1 0    
1 2  
1 2 -l e a d  E  C  Gsg 
X     
X     
 
X h 
   
X  
   
X     
   
X     
   
X     
   
   
   
   
   
 
Vit al  Si g ns (  B P,  p uls e, 
r es pir at or y r at e,  or al 
t e  m p er at ur e)i 
X     
X     
   
X  
   
X     
   
X     
   
X     
   
X     
   
   
   
   
   
 
P e xi d arti ni b   A d  mi nistr ati o n
j 
   
   
   
X  
   
   
   
   
   
   
   
   
   
   
   
   
   
 
P  K   Bl o o d  S a  m pl es  
   
   
   
X     
X     
X     
X     
X     
X     
X     
X     
X     
X     
X     
X     
X     
X     
X   
Pr ot ei n   Bi n di n g  S a  m pl e s   
   
   
   
   
   
   
   
   
X     
   
   
   
   
   
   
   
   
 
R e c or d  e  G F  R   
X     
X     
 
A E   M o nit ori n g   
X     
X     
  ---------------------------------------------------------------------------- c o nti n u o us  -------------------------------------------------   
Pri or/  C o n c o  mit a nt 
M e di c ati o ns   
  ----------------------------------------------------------------------------- -----------------------------c o nti n u o us  ------------------------------------------------   
Cli ni c   C o nfi n e  m e nt     
 
  ------------------------------------------------------------------------------------------- c o nti n u o us  ----------------------------------------------   
A b br e vi ati o ns:   A E  =  a d v ers e  e v e nt;   B  MI  =  b o d y   m ass i n d e x;   B P  =  bl o o d  pr ess ur e;  d  =  d a y(s);  E  C  G  =  el e ctr o c  ar di o gr a  m;  e  G F R  =  esti  m at e d  gl o  m er ul ar filtr ati o n r at e;  E T  =  E arl y  T er  mi n ati o n;  F S  H  = 
f olli cl e sti  m ul ati n g  h or  m o n e;   H  A  V  =  h e p atitis   A  vir us;   H  C  V  =  h e p atitis   C  vir us;   H Bs  A g  =  h e p atitis   B s urf a c e  a nti g e n;   HI  V  =  h u  m a n i  m  m u n o d efi ci e n c y  vir us;  h  =  h o ur(s); I  N  R  = I nt er n ati o n al 
N or  m ali z e d   R ati o;  P  K   =  p h ar  m a c o ki n eti c;  P T  =  pr ot hr o  m bi n ti  m e  
a T o  b e  c o n d u ct e d   wit hi n  2 1  d  pri or t o  d osi n g.  
b H ei g ht   a n d  B  MI  at  S cr e e ni n g  o nl y.  
c A  br e at h t est is  als o  a c c e pt a bl e f or  al c o h ol s cr e e ni n g.  
d F e  m al e s u bj e cts  o nl y.  
e N at ur all y  p ost  m e n o p a us al f e  m al e s u bj e cts  o nl y.  
f S a  m pl es f or s er u  m  c h e  mistr y   will  b e  c oll e ct e d  aft er  a  1 0 -h f ast.    
g Si n gl e  E  C  G  aft er  at l e ast  1 0   mi n  of  q ui et r est i n t h e s u pi n e  p ositi o n.    W h e n  a  bl o o d  c oll e cti o n is s c h e d ul e d  c o n c o  mit a ntl y   wit h  a n  E  C  G, t h e  E  C  G s h o ul d  b e t a k e n   wit hi n  1 0   mi n  pri or t o t h e  bl o o d 
c oll e cti o n. 
h At  6 0   mi n  pri or t o  p e xi d arti ni b  d osi n g.   
i Vit al si g ns   will  b e t a k e n  aft er  at l e ast  a  1 0  -mi n s u pi n e r est.  
j P e xi d arti ni b   will  b e  a d  mi nist er e d f oll o  wi n g  a n  o v er ni g ht f ast  of  1 0  h.    W at er  c o ns u  m pti o n   will  b e r estri ct e d fr o  m  1  h  pr e d os e   t o  2  h  p ost  d os e,  e x c e pt f or t h e s p e cifi e d  a  m o u nt t h at is t o  b e  a d  mi nist er e d 
wit h st u d y  dr u g.   S  u bj e cts   will  c o nti n u e t o f ast f or  4  h  p ost  d os e.  
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1


P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  7 4  
 
St u d y  P e ri o d  →   
T r e at  m e nt   
 
St u d y   D a y →   
2 t h r o u g h  7  
E  T/  C h e c k  -o ut a 
 
H o u r  P ost   D os e   
St u d y   E v e nt  ↓   
St u d y   H o u r  →   
2 4  
3 6  
4 8  
7 2  
9 6    
1 2 0    
1 4 4    
1 6 8  
M e di c al/ S ur gi c al   Hist or y   
 
 
 
 
 
 
 
 
C o  m pl et e  P h ysi c al  E x a  mi n ati o n   
 
 
 
 
 
 
 
X   
B o d y   W ei g ht  a n d   B  MI b 
 
 
 
 
 
 
 
X   
Dr u g,   C oti ni n e,   Al c o h ol  S cr e e n   
 
 
 
 
 
 
 
 
Uri n e  Pr e g n a n c y  T est c 
 
 
 
 
 
 
 
X   
H e  m at ol o g y,  S er u  m   C h e  mistr y,   Uri n al ysis d 
 
 
X   
 
 
X   
 
X   
C o a g ul ati o n ( P T, I  N  R  ,  a n d a P T T ) 
 
 
X   
 
 
X   
 
X   
1 2 -l e a d  E  C  Gse 
 
 
 
 
 
 
 
X   
Vit al  Si g ns (  B P,  p uls e, r es pir at or y r at e,  or al 
t e  m p er at ur e)f 
 
 
 
 
 
 
 
X   
P  K   Bl o o d  S a  m pl es  
X   
X   
X   
X   
X   
X   
X   
X g 
Pr ot ei n   Bi n di n g  S a  m pl e  
X   
 
 
 
 
 
 
 
A E   M o nit ori n g   
  -------------------------------------------------- ------------------c o nti n u o us ----------------------------------------------------------------   
C o n c o  mit a nt   M e di c ati o ns   
  -------------------------------------------------- ------------------c o nti n u o us  ------------------------------------------------- --------------   
Cli ni c   C o nfi n e  m e nt   
  ---------------------------------------------------- ----------------c o nti n u o us  ---------------------------------------------------------------    
 A b br e vi ati o ns:   A E  =  a d v ers e  e v e nt;   B  MI  =  b o d y   m ass i n d e x;   B P  =  bl o o d  pr ess ur e;  d  =  d a y(s);  E  C  G  =   el e ctr o c ar di o gr a  m;  e  G F R  =  esti  m at e d  gl o  m er ul ar filtr ati o n r at e;  E T  =  E arl y  T er  mi n ati o n;  F S  H  = 
f olli cl e sti  m ul ati n g  h or  m o n e;   H  A  V  =  h e p atitis   A  vir us;   H  C  V  =  h e p atitis   C  vir us;   H Bs  A g  =  h e p atitis   B s urf a c e  a nti g e n;   HI  V  =  h u  m a n i  m  m u n o d efi ci e n c y  vir us;  h  =  h o ur( s); I  N  R  = I nt er n ati o n al 
N or  m ali z e d   R ati o;  P  K   =  p h ar  m a c o ki n eti c;  P T  =  pr ot hr o  m bi n ti  m e  
a F oll o  wi n g fi n al  bl o o d  c oll e cti o ns; s a  m e  pr o c e d ur es t o  b e  p erf or  m e d  at  E T  as  at   C h e c k -o ut . 
b B  MI  at  S cr e e ni n g  o nl y.   
c F e  m al e s u bj e cts  o nl y.  
d S a  m pl es f or s er u  m  c h e  m istr y   will  b e  c oll e ct e d  aft er  a  1 0-h f ast.    
e Si n gl e  E  C  G  aft er  at l e ast  1 0   mi n  of  q ui et r est i n t h e s u pi n e  p ositi o n.    W h e n  a  bl o o d  c oll e cti o n is s c h e d ul e d  c o n c o  mit a ntl y   wit h  a n  E  C  G, t h e  E  C  G   s h o ul d  b e t a k e n   wit hi n  1 0   mi n  pri or t o t h e  bl o o d 
c oll e cti o n.  
f Vit al si g ns   will  b e t a k e n  aft er  at l e ast  a  1 0  -mi n s u pi n e r est.   
g P  K  bl o o d s a  m pl e t o  b e  c oll e ct e d  pri or t o   C h e c k -o ut  pr o c e d ur es.  
Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1




P L 3 3 9 7 -A  -U 1 2  9  Pr ot o c ol  
V ersi o n   2 . 0, 1 0  D E  C   2 0 1 9  
 
Pr o pri et ar y  a n d   C o nfi d e nti a l 
P a g e  7 6  
v ori c o n a z ol e  
z afirl u k a st  
o x c ar b a z e pi n e  
pr o b e ni ci d  
ti cl o pi di n e2  
t o pir a  m at e 
v ori c o n a z ol e  
c o c ai n e  
di p h e n h y dr a  mi n e  
d o x e pi n  
d o x or u bi ci n  
es cit al o pr a  m  
h al of a ntri n e  
h al o p eri d ol  
hist a  mi n e   H 1 
r e c e pt or  a nt a g o nists 
h y dr o x y zi n e  
l e v o  m e pr o  m a zi n e 
m et h a d o n e   
m et o cl o pr a  mi d e   
mi b efr a dil   
mi d o dri n e   
m o cl o b e  mi d e   
p er p h e n a zi n e  
pr o  m et h a zi n e  
ra niti di n e  
r e d u c e d-h al o p eri d ol  
rit o n a vir 
ti cl o pi di n e 
tri p el e n n a  mi n e 
 
ci  m eti di n e  
 
a  mi o d ar o n e  
a zit hr o  m y ci n  
c hl or a  m p h e ni c ol  
b o c e pr e vir  
ci pr ofl o x a ci n  
d el a viri di n e  
di et h yl -
dit hi o c ar b a  m at e  
fl u v o x a  mi n e 
g est o d e n e  
i  m ati ni b 
mi b efr a dil   
mif e prist o n e   
n orfl o x a ci n  
n orfl u o x eti n e  
st arfr uit  
t el a pr e vir 
v ori c o n a z ol e  
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Cli nical St u d y Re p ort P L 3 3 9 7- A- U 1 2 9 
Versi o n 1. 0, 1 7 Fe b 2 0 2 1