A Phase 1, Open-Label, Randomized, 3-Period Crossover Study to Assess the Effect of Low-Fat Food on Pexidartinib Pharmacokinetics in Healthy Subjects
Phase: PHASE1
Conditions: Healthy Volunteers
Sponsor: Daiichi Sankyo

Pr o prietar y a n d C o nfi de ntial 
Pa ge 1 
 
C LI NI C A L S T U D Y P R O T O C O L 
A P H A S E 1, O P E N- L A B E L, R A N D O MI Z E D, 3- P E RI O D 
C R O S S O V E R S T U D Y T O A S S E S S T H E E F F E C T O F 
L O W- F A T F O O D O N P E XI D A R TI NI B 
P H A R M A C O KI N E TI C S I N 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 8 
 
I N D N U M B E R 1 0 5, 5 2 1 
 
V E R SI O N 1. 0 , 2 0  M A R 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 mati o n c o ntai ne d i n t his d oc u me nt is pr o prietar y t o Daiic hi Sa n k y o, I n c.  T he i nf or mati o n is 
pr o vi de d t o y o u i n c o nfi d e nce w hi c h is re q ueste d u n der a n a gree d u p o n a n d si g ne d 
C o nfi de ntialit y a n d Discl os ure A gree me nt.  D o n ot gi ve t his d oc u me nt or a n y c o p y of it or re v eal 
a n y pr o prietar y i nf or mati o n c o ntai ne d i n it t o a n y t hir d part y ( ot her t h a n t h ose i n y o ur 
or ga niz ati o n w h o are assisti n g y o u i n t his w or k a n d are b o u n d b y t he C o nfi de ntialit y a n d 
Discl os ure A gree me nt) wit h o ut t he pri or writte n per missi o n of a n a ut h orize d re prese ntati ve of 
Daiic hi Sa n k y o, I nc. 

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P R O T O C O L S Y N O P SI S 
E u dra C T:  
N ot a p plica ble  
I N D N u m ber: 
1 0 5, 5 2 1  
Pr ot oc ol N u m ber:  
P L 3 3 9 7 -A -U 1 2 8  
I n vesti gati o nal Pr o d uct:  
Pe xi darti ni b h y dr oc hl ori de ( H Cl) ca ps ules 2 0 0 m g  
Acti ve I n gre die nt /I N N: 
Pe xi darti ni b  
St u d y Title:  
A P hase 1, O pe n -La bel, Ra n d o mize d, 3 -Peri o d Cr oss o ver St u d y t o 
Assess t he Effect of L o w -F at F o o d o n Pe xi darti ni b P har mac o ki netics 
i n Healt h y S u bjec ts 
St u d y P hase:  
P hase 1  
I n dicati o n U n der I n vesti gati o n: 
N ot A p plica ble.  
St u d y O bj ecti ves:  
P ri m ar y O bjecti ves  
T he pri mar y o bjecti ves of t his st u d y are : 
 
T o assess t he effect of l o w-fat f o o d o n t he p har mac o ki netics 
( P K) of pe xi darti ni b f oll o wi n g a si n gle oral d ose of 4 0 0 m g 
a d mi nistere d i n healt h y s u bjects  
 
T o assess t he P K of pe xi darti ni b f oll o wi n g a si n gle oral d ose 
of 2 0 0 m g a d mi nistere d wit h l o w -fat f o o d i n healt h y s u bj ects 
Sec o n d ar y O bjecti ve  
T he sec o n dar y o bj ecti ve of t his st u d y is : 
 
T o c haracterize t he safet y a n d t olera bilit y of pe xi darti ni b i n 
healt h y s u bjects f oll o wi n g a d mi nistrati o n of a si n gle oral d ose 
of pe xi darti ni b wit h l o w fat f o o d a n d wit h o ut f o o d  
St u d y Desi g n:  
T his is a n o pe n -label, ra n d o mize d, 3 -treat me nt, 3-peri o d cr os s o ver 
st u dy i n healt h y s u bjects.  I n t he first peri o d, su bjects will c hec k i n o n 
Da y -1 a n d recei ve treat me nt o n Da y 1, as per t he ra n d o mizati o n 
sc he d ule.  T he s u bjects will c o nti n ue t o sta y i n t he cli nic a n d recei ve 
pe xi darti ni b o n Da y 1 of eac h peri o d as  per t he ra n d o mizati o n 
sc he d ule.    
S u bj ects will be ra n d o mize d t o 1 of 6 se q ue nces: A B C , A C B, B A C, 
B C A, C A B, a n d C B A. Treat me nts are as f oll o ws:  
Treat me nt A: Si n gle oral 4 0 0 m g ( 2 × 2 0 0 m g ca ps ules) d ose of 
pe xi darti ni b  i n t he m or ni n g u n der fasti n g c o n diti o ns 
wit h 2 4 0 m L of water  
Treat me nt B: Si n gle oral 4 0 0 m g ( 2 × 2 0 0 m g ca ps ules) d ose of 
pe xi darti ni b i n t he m or ni n g wit hi n 3 0  mi n utes ( mi n) 
after  a l o w-fat sta n dar d brea kfast meal  
Treat me nt C: Si n gle oral 2 0 0 m g ( 1 × 2 0 0  m g ca ps ule ) d ose of 
pe xi darti ni b i n t he m or ni n g wit hi n 3 0  mi n after  a l o w-
fat sta n dar d brea kfast meal  

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S u bj ects i n Treat me nt  A will fast o ver ni g ht f or at least 1 0  h o urs  ( h) 
pri or t o  d osi n g.  S u bjects i n Treat me nts B a n d C will fast o ver ni g ht f or 
at least 1 0  h u ntil 3 0  mi n pri or t o d osi n g, at w hic h ti me t he y will be 
a d mi nistere d a l o w -fat sta n dar d brea kfast w hic h m ust be e ntirel y 
c o ns u me d wit hi n 3 0 mi n.  S u bj ects i n all treat me nts will fast f or at 
least 4 h f oll o wi n g d osi n g.  Water will be all o we d a d li bit u m u p t o 1  h 
pri or t o d osi n g a n d starti n g at 2  h after d osi n g.  
T here w ill be a was h o ut of at least 6  da ys ( d) bet wee n eac h d ose of 
pe xi dar ti ni b.  S u bj ects will be c o nfi ne d at t he cli nic fr o m C hec k -i n t o 
at least 1 4 4 h after  t he Peri o d 3 d ose.  
I n eac h peri od, bl o o d sa m ples ( 1 × 2  m L) will be c ollecte d f or P K  
a nal ysis at pre d ose ( wit hi n 3 0 mi n pri or t o d osi n g) a n d 0. 5, 1, 1. 5, 2, 
2. 5, 3, 3. 5, 4, 4. 5, 5, 6, 8, 1 0, 1 2, 1 4, 2 2, 2 4, 2 8, 3 2, 3 6, 4 8, 5 4, 6 0, 7 2, 
8 4, 9 6, 1 0 8, 1 2 0, 1 3 2, a n d 1 4 4  h p ost d ose.  
Plas ma wil l be har veste d a n d a nal yze d f or pe xi darti ni b usi n g a 
vali date d li q ui d c hr o mat o gra p h y -ta n de m mass s pectr o metr y ( L C-
M S/ M S) met h o d.  
1 2 -lea d electr ocar di o grams ( E C Gs) will be perf or me d at S cree ni n g, 
pre d ose a n d at 2 , 2 4 a n d 1 4 4 h p ost d ose i n eac h st u d y peri o d , at 
C hec k -o ut of Peri o d 3  or Earl y T er mi nati o n . 
Vital si g ns ( bl o o d press ure, heart rate, oral te m perat ure, a n d 
res pirat or y rate) will be perf or me d at S cree ni n g, pre d ose a n d at 2, 2 4, 
a n d 1 4 4 h p ost d ose i n eac h st u d y peri o d, at C hec k-o ut of Peri o d 3 or 
Earl y T er mi nati o n . 
Cli nical la b orat or y tests ( he mat ol o g y, ser u m c he mistr y, a n d 
uri nal ysis) will be perf or me d at S cree ni n g, C hec k -in t o Peri o d  1, Da y 
7 of eac h peri o d a n d  at Chec k -o ut of Peri o d 3 or Earl y T er mi nati o n . 
A p h ysical e x a mi nati o n will be perf or me d at Scree ni n g, C hec k -i n t o 
Peri o d 1  a n d c hec k -o ut of Peri o d 3 or Earl y Ter mi nati o n . 
A d verse e ve nts a n d c o nc o mita nt me dicati o n will be c ollecte d 
t hr o u g h o ut t he st u d y. 
St u d y D urati o n:  
S u bj ects will be  scree ne d n o m ore t ha n 2 1 d pri or t o d osi n g o n Da y 1 
of Peri o d 1.  
T he d ur ati o n of t he st u d y (fr o m C hec k -i n t o Chec k o u t) will be 
a p pr o xi matel y 2 1 d.  
St u d y Site s a n d L ocati o n: 
T he st u d y will be c o n d ucte d i n 1 cli nical site, at W orl d wi de Cli nical 
Trials i n Sa n A nt o ni o, Te xas, U S A  
S u bj ect Eli gi bilit y Criteria:  
S u bj ects will be healt h y males or n o n -c hil d beari n g p ote ntial fe males, 
1 8 t o 6 0 years ( y) of a ge, i ncl usi ve a n d b o d y mass i n de x of 1 8 t o 3 0 
k g/ m 2, i ncl usi ve. 
D osa ge F or m, D ose a n d R o ute of 
A d mi nistrati o n:  
Treat me nt A: Si n gle o ral 4 0 0 m g ( 2 × 2 0 0 m g ca ps ules) of 
pe xi darti ni b i n t he m or ni n g u n der fasti n g c o n diti o ns wit h 2 4 0  m L of 
water  
Treat me nt B: Si n gle oral 4 0 0 m g ( 2 × 2 0 0 m g ca ps ules) of 
pe xi darti ni b wit h 2 4 0 m L of water i n t he m or ni n g wit hi n 3 0 mi n  of a 
l o w-fat sta n dar d breakfast  

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Treat me nt C: Si n gle oral 2 0 0 m g ( 1 × 2 0 0 m g ca ps ule ) of pe xi darti ni b 
wit h 2 4 0 m L of water i n t he m or ni n g wit hi n 3 0 mi n  of a l o w -fat 
sta n dar d brea kfast  
St u d y E n d p oi nts:  
P har mac o ki netics : 
Plas ma c o nce ntrati o n ti me data f or pe xi darti ni b  will be a nal yze d usi n g 
n o nc o m part me ntal met h o ds.  T he f oll o wi n g P K para meters will be 
re p orte d: ma xi m u m o bser ve d c o nce ntrati o n i n plas ma ( C ma x), ti me t o 
ma xi m u m o bser ve d c o nce ntrati o n ( T ma x), a n d area u n der t he 
c o nce ntrati o n -ti me c ur ve fr o m ti me of d osi n g t o last meas ura ble 
c o nce ntrati o n ( A U Clast)  a n d area u n der t he c o nce ntrati o n -ti me c ur ve 
fr o m ti me of d osi n g t o i nfi nit y ( A U Ci nf).  T er mi nal half -life (t 1/ 2), 
a p pare nt t otal b o d y cleara nce ( C L/ F), a n d a p p are nt v ol u me of 
distri b uti o n ( Vz / F) will als o be re p orte d. 
Safet y : 
Safet y e n d p oi nts i ncl u de E C G assess me nts ( Q T, P R, Q R S, R R, a n d 
Q T c [ Q Tc B, Q T c F] i nter vals), vital si g n meas ure me nts, cli nical 
la b orat or y tests, a d verse e ve nts, a n d fi n di n gs fr o m p h ysical 
e xa mi nati o ns . 
Pla n ne d Sa m ple Size:  
T we nt y -f o ur s u bjects will be ra n d o mize d, wit h t he e x pectati o n t hat at 
least 2 1 will c o m plete all 3 peri o ds of t he st u d y.  T he sa m ple size is 
n ot deter mi ne d base d o n statistical c o nsi derati o ns, b ut t o o btai n 
a de q uate precisi o n f or t he esti mati o n.   Disc o nti n ue d s u bj ects will n ot 
be re place d.  
Statistical A nal yses:  
P har mac o ki netics:  
I n di vi d ual a n d arit h metic mea n (sta n dar d de viati o n [ S D]) plas ma 
c o nce ntrati o n o ver ti me will be prese nte d gra p hicall y f or all 
treat me nts usi n g li near a n d se mil o g scales. 
Descri pti ve statistics will be prese nte d f or eac h e val uati o n ti me p oi nt 
f or plas ma c o nce ntrati o ns a n d f or all q ua ntitati ve P K para meters of 
pe xi darti ni b.  
T he pea k ( C ma x) a n d t otal e x p os ures ( A U Clast, A U Ci nf) of 
pe xi darti ni b will be c o m pare d bet wee n Treat m e nts B a n d A usi n g a n 
a p pr o priate a nal ysis of varia nce ( A N O V A) f or t he l o garit h m-
tra nsf or me d val ues of C ma x, A U Clast, a n d A U Ci nf.  Wit hi n t he 
fra me w or k of t he A N O V A, t he 2-si de d 9 0 % c o nfi de nce i nter vals 
( CIs) f or rati os of treat me nt ce ntral val ues will be calc ulate d b y 
e x p o ne ntiati o n of t he c orres p o n di n g 9 0 % CIs f or t he treat me nt 
differe nce bet wee n t he least s q uares mea ns calc ulate d f or t he 
l o garit h m-tra nsf or me d val ues. 
Safet y:  
Vital si g n meas ure me nts a n d ot her safet y e n d p oi nts will be 
s u m marize d wit h descri pti ve statistics b y treat me nt w he n a p pr o priate.  
T a b ulati o ns will be pr o vi de d f or cate g orical data.  
E C Gs will be rea d o n site as part of t he safet y assess me nts.  E C G 
e n d p oi nts will be s u m marize d wit h descri pti ve statistics b y treat me nt .  
Descri pti ve stati stics will als o be calc ulate d at eac h ti me p oi nt f or t he 
c ha n ges fr o m baseli ne b y treat me nt. 

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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 ................................................................................................................ 3  
T A B L E O F  C O N T E N T S ................................................................................................................. 6 
LI S T O F T A B L E S ......................................................................................................................... 1 2  
LI S T O F FI G U R E S ....................................................................................................................... 1 3  
LI S T O F A B B R E VI A TI O N S ........................................................................................................ 1 4  
1.  
IN T R O D U C TI O N ........................................................................................................ 1 6  
1. 1.  
B ac k gr o u n d ................................................................................................................... 1 6  
1. 2.  
Da ta S u m mar y ............................................................................................................... 1 6 
1. 2. 1.  
N o nc li nical St u dies ....................................................................................................... 1 6 
1. 2. 1. 1.  
Sa fet y P h ar mac ol o g y .................................................................................................... 1 6 
1. 2. 1. 2.  
N o ncli nical P har mac o ki n etics a n d Dr u g M eta b olis m................................................... 1 7  
1. 2. 1. 3.  
T o xic ol o g y  .................................................................................................................... 1 8 
1. 2. 1. 4.  
Cli nical E x perie nce ....................................................................................................... 1 8  
1. 3.  
S t u d y R ati o nale ............................................................................................................. 1 9 
1. 4.  
R is ks a n d Be nefits f or St u d y S u bjects .......................................................................... 1 9 
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 0  
2. 1.  
S t u d y O bjecti ves ........................................................................................................... 2 0 
2. 1. 1.  
P ri mar y O bj ecti ves ........................................................................................................ 2 0 
2. 1. 2.  
S ec o n dar y O bj ecti ve ..................................................................................................... 2 0  
2. 2.  
S t u d y H y p ot hesis .......................................................................................................... 2 0 
2. 3.  
S t u d y E n d p oi nts ............................................................................................................ 2 0 
2. 3. 1.  
Pri mar y E n d p oi nt .......................................................................................................... 2 0  
2. 3. 2.  
Sec o n dar y E n d p oi nt(s) .................................................................................................. 2 0  
2. 3. 3.  
E x pl orat or y E n d p oi nt .................................................................................................... 2 0  
3.  
S T U D Y D E SI G N .......................................................................................................... 2 1  
3. 1.  
O ve rall Desi g n .............................................................................................................. 2 1 
3. 1. 1.  
O ver vie w ....................................................................................................................... 2 1  
3. 1. 2.  
D ose  Escalati o n Pr ocess ................................................................................................ 2 1 
3. 1. 3.  
St u d y St o p pi n g Criteria ................................................................................................. 2 1  
3. 2.  
Disc ussi o n of St u d y Desi g n .......................................................................................... 2 1  

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4.  
S T U D Y P O P U L A TI O N ............................................................................................... 2 2  
4. 1.  
In cl usi o n Criteria ........................................................................................................... 2 2  
4. 2.  
E x cl usi o n Criteria.......................................................................................................... 2 3  
5.  
S T U D Y T R E A T M E N T( S) ........................................................................................... 2 5  
5. 1.  
Assi g ni n g S u bjects t o Treat me nt Gr o u p(s) / Se q ue nces a n d Bli n di n g .......................... 2 5  
5. 1. 1.  
Tr eat me nt Gr o u p(s) / Se q ue nces .................................................................................... 2 5  
5. 1. 2.  
Met h o d of  Treat me nt Gr o u p(s) / Se q ue nces All ocati o n ................................................ 2 5 
5. 1. 3.  
B li n di n g ......................................................................................................................... 2 5 
5. 1. 4.  
E mer ge nc y U n bli n di n g Pr oce d ure ................................................................................ 2 5  
5. 2.  
S t u d y Dr u g .................................................................................................................... 2 5 
5. 2. 1.  
De scri pti o n .................................................................................................................... 2 5 
5. 2. 2.  
L a b eli n g a n d Pac k a gi n g ................................................................................................ 2 5  
5. 2. 3.  
P re parati o n .................................................................................................................... 2 5 
5. 2. 4.  
A d mi ni strati o n .............................................................................................................. 2 6 
5. 2. 5.  
S t ora ge........................................................................................................................... 2 6 
5. 2. 6.  
Dr u g Acc o u nta bili t y ...................................................................................................... 2 6 
5. 2. 7.  
R ete nti o n Sa m ples ......................................................................................................... 2 7  
5. 3.  
C o ntr ol Treat me nt ......................................................................................................... 2 7  
5. 4.  
D ose  I nterr u pti o ns a n d Re d ucti o ns ............................................................................... 2 7 
5. 5.  
Met h o d of  Assessi n g Treat me nt C o m plia nce ............................................................... 2 7 
5. 6.  
P ri or a n d C o nc o mita nt Me dicati o ns.............................................................................. 2 7 
5. 6. 1.  
Die tar y a n d Lif est yl e Restricti o ns ................................................................................. 2 7 
5. 7.  
S u bject Wit h dra wal/ Disc o nti n uati o n ............................................................................ 2 8  
5. 7. 1.  
Reas o ns f or Wit h dra wal ................................................................................................ 2 8  
5. 7. 2.  
Wit h dra wal Pr oce d ures ................................................................................................. 2 9  
5. 7. 3.  
S u bject Re place me nt ..................................................................................................... 2 9  
5. 7. 1.  
S u bject Re-scree ni n g Pr oce d ures .................................................................................. 2 9  
5. 8.  
C riteria f or S us pe n di n g St u d y Treat me nt ..................................................................... 2 9 
6.  
S T U D Y P R O C E D U R E S .............................................................................................. 3 0  
6. 1.  
S cree ni n g ....................................................................................................................... 3 0  
6. 2.  
S u bject Ma na ge me nt ..................................................................................................... 3 0  
6. 3.  
Ra n d o mizati o n .............................................................................................................. 3 1  

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6. 4.  
Tr eat me nt Peri o d ........................................................................................................... 3 1  
6. 4. 1.  
Da y - 1 of Peri o d 1 C hec k- i n ......................................................................................... 3 1 
6. 4. 2.  
Da y 1 ............................................................................................................................. 3 1  
6. 4. 3.  
Da y 2 ............................................................................................................................. 3 2  
6. 4. 4.  
Da y 3 ............................................................................................................................. 3 2  
6. 4. 5.  
Da y 4 ............................................................................................................................. 3 2  
6. 4. 6.  
Da y 5 ............................................................................................................................. 3 2  
6. 4. 7.  
Da y 6 ............................................................................................................................. 3 2  
6. 4. 8.  
Da y 7 ............................................................................................................................. 3 3  
6. 5.  
W as h o ut......................................................................................................................... 3 3  
6. 6.  
C hec k- o ut or Earl y Ter mi nati o n ................................................................................... 3 3  
6. 7.  
F oll o w- u p ...................................................................................................................... 3 3  
7.  
P H A R M A C O KI N E TI C A S S E S S M E N T S ................................................................... 3 4  
7. 1.  
P har mac o ki netic Assess me nt(s) .................................................................................... 3 4  
7. 2.  
P har mac o d y na mic ( P D) Assess me nt (s) ....................................................................... 3 4  
7. 3.  
Im m u n o ge nicit y ............................................................................................................ 3 4  
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 ........................................................... 3 5  
8. 1.  
Asse ss me nt of Safet y E n d p oi nt E ve nt(s) ...................................................................... 3 5 
8. 2.  
A d ve rse E v e nt C ollecti o n a n d Re p orti n g ...................................................................... 3 5 
8. 3.  
A d ve rse E v e nts of S peci al I nt erest ............................................................................... 3 6 
8. 4.  
A d ve rse E v e nt ............................................................................................................... 3 6 
8. 4. 1.  
De fi niti o n of A d vers e E v e nt ......................................................................................... 3 6 
8. 4. 2.  
S eri o us A d verse E v e nt .................................................................................................. 3 6  
8. 4. 3.  
Se verit y Assess me nt ..................................................................................................... 3 7  
8. 4. 4.  
Ca usalit y Assess me nt .................................................................................................... 3 7  
8. 4. 5.  
Acti o n Ta ke n Re gar di n g St u d y Dr u g(s) ....................................................................... 3 8  
8. 4. 6.  
Ot her Acti o n Ta k e n f or E ve nt ....................................................................................... 3 8  
8. 4. 7.  
A d ve rse E v e nt O utc o me ............................................................................................... 3 8 
8. 5.  
Seri o us A d verse E v e nts Re p orti n g – Pr oce d ure f or I n v esti gat ors .................................. 3 9  
8. 6.  
N otif yi n g Re g ulat or y A ut h orities, I n vesti gat ors, a n d I nstit uti o nal Re vie w 
B oar d / Et hics C o m mittee ............................................................................................... 3 9 
8. 7.  
E x p os ure i n Uter o D uri n g Cli nical St u dies ................................................................... 4 0  
8. 8.  
Cli nical La b orat or y E val uati o ns ................................................................................... 4 0  

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8. 9.  
Vital S i g ns ..................................................................................................................... 4 1 
8. 1 0.  
Elec tr ocar di o gra ms ....................................................................................................... 4 1 
8. 1 1.  
P h ysical E x a mi nati o ns .................................................................................................. 4 1  
8. 1 2.  
Dr u g a n d Alc o h ol Scree n .............................................................................................. 4 2  
8. 1 3.  
P re g n a nc y T est .............................................................................................................. 4 2 
8. 1 4.  
S er u m F S H .................................................................................................................... 4 2  
8. 1 5.  
Ot he r E x a mi nati o ns ....................................................................................................... 4 2 
9.  
O T H E R A S S E S S M E N T S ............................................................................................. 4 3  
1 0.  
S T A TI S TI C A L M E T H O D S ......................................................................................... 4 4  
1 0. 1.  
Ge neral Statistical C o nsi derati o ns ................................................................................ 4 4  
1 0. 2.  
A na l ysis Sets ................................................................................................................. 4 4 
1 0. 2. 1.  
P ha r mac o ki netic A n al ysis Set ....................................................................................... 4 4 
1 0. 2. 2.  
Sa fet y A nal ysis Set ....................................................................................................... 4 4 
1 0. 3.  
S t u d y P o p ulati o n Dat a .................................................................................................. 4 4 
1 0. 4.  
S tatistical A nal ysis ........................................................................................................ 4 4 
1 0. 4. 1.  
P ha r mac o ki netic A n al ys es ............................................................................................ 4 4 
1 0. 4. 2.  
P ha r mac o d y na mic A n al yses ......................................................................................... 4 5 
1 0. 4. 3.  
Sa fet y A nal yses ............................................................................................................. 4 5 
1 0. 4. 3. 1.  A d verse  E v e nt A nal yses ............................................................................................... 4 5 
1 0. 4. 3. 2.  Cli nical La b orat or y E val uati o n A nal ys es ..................................................................... 4 5  
1 0. 4. 3. 3.  Vital Si g n A nal yses ....................................................................................................... 4 5  
1 0. 4. 3. 4.  Electr oc ar di o gra m A n al yses ......................................................................................... 4 6  
1 0 . 4. 3. 5. P h ysical Fi n di n g A n al ys es ............................................................................................ 4 6  
1 0. 4. 3. 6.  Ot her Safet y A n al yses ................................................................................................... 4 6  
1 0. 5.  
S a m ple Siz e Deter mi nati o n ........................................................................................... 4 6  
1 0. 6.  
Statistical A nal ysis Pr ocess ........................................................................................... 4 6  
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 ................................................ 4 7  
1 1. 1.  
M o ni t ori n g a n d I ns p ecti o ns .......................................................................................... 4 7 
1 1. 2.  
Data C ollecti o n.............................................................................................................. 4 7  
1 1. 3.  
Da ta Ma na ge me nt ......................................................................................................... 4 8 
1 1. 4.  
St u d y D oc u me ntati o n a n d St ora ge ................................................................................ 4 8  
1 1. 5.  
Rec or d Kee pi n g ............................................................................................................. 4 9  

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1 2.  
FI N A N CI N G A N D I N S U R A N C E ............................................................................... 5 0  
1 2. 1.  
F i na nces......................................................................................................................... 5 0 
1 2. 2.  
R ei m b urse me nt, I n de m nit y, a n d I ns ura n ce ................................................................... 5 0  
1 3.  
P U B LI C A TI O N P O LI C Y ............................................................................................. 5 1  
1 4.  
E T H I 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 2 
1 4. 1.  
C o m plia nce State me nt, Et hics a n d Re g ul at or y C o m plia nce......................................... 5 2  
1 4. 2.  
S u bject C o nfi de ntialit y.................................................................................................. 5 2  
1 4. 3.  
I nf orme d C o nse nt .......................................................................................................... 5 2  
1 4. 4.  
R e g ulat or y C o m plia nce ................................................................................................. 5 3  
1 4. 5.  
P r ot oc ol De viati o ns ....................................................................................................... 5 4 
1 4. 6.  
S u p pl y of Ne w I nf or m ati o n Affecti n g t he C o n d uct of t he St u d y ................................. 5 4  
1 4. 7.  
P r ot oc ol A me n d me nts ................................................................................................... 5 5 
1 4. 8.  
S t u d y Ter mi nati o n ......................................................................................................... 5 5 
1 4. 9.  
Da ta a n d Safet y M o nit ori n g B oar d ............................................................................... 5 5 
1 4. 1 0.  
A d dre ss List .................................................................................................................. 5 5 
1 4. 1 0. 1.  S p o ns or’s Cli nical St u d y Lea der ................................................................................... 5 5  
1 4. 1 0. 2.  S p o ns or’ s Cli nical St u d y Ma na ger................................................................................ 5 5 
1 4. 1 0. 3.  S p o ns or’ s P har mac o ki netics Re vie wer ......................................................................... 5 6 
1 4. 1 0. 4.  S p o ns or’ s Me dical M o nit or........................................................................................... 5 6 
1 4. 1 0. 5.  S p o ns or’ s Safet y C o ntacts ............................................................................................ 5 6 
1 4. 1 0. 6.  E D C Ve n d or  .................................................................................................................. 5 6 
1 4. 1 0. 7.  Bi oa na l ytical V e n d or .................................................................................................... 5 6 
1 4. 1 0. 8.  Ce ntral La b orat or y ........................................................................................................ 5 7  
1 4. 1 0. 9.  S p o ns or’ s Bi ostatisticia n ............................................................................................... 5 7 
1 4. 1 0. 1 0.  Da ta a n d Safet y M o nit ori n g B oar d ............................................................................... 5 7 
1 4. 1 0. 1 1.  C R O  .............................................................................................................................. 5 7 
1 4. 1 0. 1 1. 1.  C R O I n vesti gat or...................................................................................................... 5 7  
1 4. 1 0. 1 1. 2.  C R O Pr oject Ma na ger .............................................................................................. 5 8  
1 5.  
R E F E R E N C E S .............................................................................................................. 5 9  
1 6.  
A P P E N DI C E S .............................................................................................................. 6 0  
1 6. 1.  
La b eli n g a n d Pac k a gi n g ................................................................................................ 6 0  
1 6. 2.  
Bl o o d C ollecti o n V ol u me b y Cat e g or y a n d T ot al......................................................... 6 0  

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1 6. 3.  
A d diti o nal I nf or mati o n (f or J a pa nese St u d y Sites O nl y) .............................................. 6 1  
1 6. 3. 1.  
G C P c o m plia nce............................................................................................................ 6 1  
1 6. 3. 2.  
St u d y Peri o d .................................................................................................................. 6 1  
1 6. 3. 3.  
Pa y me nt f or Partici pati o n, C o m pe nsati o n f or St u d y- Rel ate d I nj uries, a n d 
I ns ura nce ....................................................................................................................... 6 1 
1 6. 3. 4.  
St u d y A d mi nistrati ve Str uct ure ..................................................................................... 6 1  
1 6. 4.  
Instr u cti o ns f or S peci me n C ollecti o n, St ora ge a n d S hi p me nt ...................................... 6 1  
1 6. 4. 1.  
Plas ma  P har mac o ki netic Sa m ple C ollecti o n, St ora ge a n d S hi p me nt 
I nstr u cti o ns .................................................................................................................... 6 1 
1 6. 5.  
C yt o c hr o me P 4 5 0 Cli nicall y Si g nifi ca nt Dr u g I nteracti o n T a ble ................................. 6 5  
1 6. 6.  
S c he d ule of E ve nts ........................................................................................................ 6 7  
 

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LI S T O F T A B L E S 
Ta ble 7. 1:  Plas ma P har mac o ki netic Varia bles ............................................................................. 3 4  
Ta ble 1 6. 1:  B l o o d C ollecti o n V ol u mes ......................................................................................... 6 0 
Ta ble 1 6. 2:  S c he d ule of E ve nts ( Scree ni n g t hr o u g h Da y 1) ........................................................... 6 7  
Ta ble 1 6. 3:  S c he d ule of E ve nts ( Da ys 2 t o C hec k of Peri o d 3 or Earl y Ter mi nati o n) .................. 6 9  
 

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LI S T O F FI G U R E S 
Fi g ure 3. 1:  Sc he matic C hart of St u d y Desi g n ............................................................................... 2 1  
 
 

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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 verse e ve nt 
A E SI  
a d verse e ve nt of s pecial i nterest  
A L P  
ser u m al kali ne p h os p hatase 
A L T  
ser u m ala ni ne a mi n otra nsferase  
A S T  
ser u m as partate a mi n otra nsferase 
A U C  
area u n der t he c o nce ntrati o n -ti me c ur ve 
A U Ci nf  
area u n der t he co nce ntrati o n -ti me cur ve u p t o infi nit y  
A U C last 
area u n der t he c o nce ntrati o n -ti me c ur ve u p t o ti me u p t o t he ti me of t he last 
q ua ntifia ble c o nce ntrati o n  
C C G  
C ase R e p ort F or m  C o m pleti o n G ui deli ne  
C DI S C  
Cli nical Data I nterc ha n ge Sta n dar ds C o ns orti u m  
C F R  
C o de of Fe deral Re g ulati o ns  
C L/ F  
ap pare nt total b o d y cleara nce 
C ma x  
m a xi m u m co nce ntrati o n  
C R F  
Case Re p ort F or m  
C R O  
C o ntract  Researc h Or ga nizati o n  
C S P V  
Cli nical Safet y a n d P har mac o vi gila nce  
C T C A E  
C o m m o n T er mi n ol o g y  Criteria  f or A d verse E ve nts 
d  
da y(s)  
D M C  
Data M o nit ori n g C o m mittee  
E C  
Et hics C o m mittee  
e C C G 
Electr o nic C ase R e p ort F or m  C o m pleti o n G ui deli ne  
E C G  
electr ocar di o gra m  
e C R F 
Electr o nic Case Re p ort F or m  
E D C  
Electr o nic Data Ca pt ure  
F A S  
F ull A nal ysis Set  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
G C P  
G o o d Cli nical Practice  
HI P A A  
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act  
h  
h o ur(s)  

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A B B R E VI A TI O N  
D E FI NI TI O N  
I B 
I n vesti gat or’s Br oc h ure  
I C F 
I nf or me d C o nse nt F or m 
I C H 
I nter nati o nal C o u ncil f or Har m o nis ati o n of T ec h nical Re q uire me nts f or 
P har mace uticals f or H u ma n Use  
I M P 
i n vesti gati o nal me dici nal pr o d uct 
I N N 
I nter nati o nal N o n-pr o prietar y Na me  
I R B 
I nstit uti o nal Re vie w B oar d 
I R T 
I nteracti ve Res p o nse T ec h n ol o g y 
IX R S  
I nteracti ve We b/ V oice Res p o nse S yste m 
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
mi n  
mi n ute(s)  
m o  
m o nt h(s)  
ms  
millisec o n d(s)  
N CI  
Nati o nal Ca ncer I nstit ute  
O T C  
o ver -t he-c o u nter 
P D  
p har mac o d y na mic  
P G x  
p har mac o ge n o mics  
P K  
p har mac o ki netic  
P P S  
per -pr ot oc ol set  
S A E  
seri o us a d verse e ve nt 
S A P  
Statistical A nal ysis Pla n  
S A V E R  
Seri o us A d verse E ve nt Re p ort  
S U S A R  
s us pecte d u ne x pecte d seri o us a d verse reacti o n 
T B iL  
t otal bilir u bi n  
T E A E  
treat me nt-e mer ge nt a d verse e ve nt  
T 1/ 2  
ter mi nal eli mi nati o n half-life 
T ma x  
ti me t o reac h ma xi m u m c o nce ntrati o n 
U G T  
U D P -gl uc ur o n os yltra nsferase  
Vz/ F  
a p pare nt v ol u me of distri b uti o n  
w k  
wee k(s)  
y  
year(s)  

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1.  
I N T R O D U C TI O N 
1. 1.  
B ac k gr o u n d 
Pe xi darti ni b is a n o vel, orall y acti ve, s mall m olec ule i n hi bit or t hat tar gets 3 ki nases: C S F 1 R (als o 
k n o w n as F M S), t he rece pt or f or C S F- 1 (als o k n o w n as M- C S F) as well as t he li ga n d I L- 3 4, KI T, 
t he rece pt or f or S C F, a n d o nc o ge nic F L T 3-I T D m uta nt, b ut re mai ns hi g hl y s electi ve vers us ot her 
ki nases.  T he  p ote nt i n hi biti o n of t hese t hree ki nases ca n be e x pl oite d t o attac k t u m ors via 
differe nt mec ha nis ms: 1) directl y i n hi biti n g o n c o ge nic dri vers s u c h as o nc o ge ni c Kit a n d Flt 3 
m uta nt pr otei ns, 2) i n hi biti n g paracri n e l o o ps bet w ee n str o mal cells a n d t u m ors, 3) bl oc ki n g 
mi grati o n a n d a n gi o ge nesis, 4) re pr o gra m mi n g t u m or i m m u ne micr oe n vir o n me nt, a n d 
4) disr u pti n g oste ol ytic metastases. 1   
T he r ole of C S F- 1 a n d its rece pt or F ms has b ee n el uci date d i n t he rare c o n n ecti ve tiss ue 
ne o plasia k n o w n as pi g m e nte d vill o n o d ular s y n o vitis ( P V N S). 2  T his disease is ge n erall y 
characteriz e d b y h y persecreti o n of C S F- 1 as a res ult of a tra nsl ocati o n wit hi n s y n o vial cells of 
t he C S F- 1 ge ne b e hi n d t he c olla ge n C O L 6 A 3 pr o m oter.  T he res ulti n g t u m or occasi o n all y 
i n v ol ves e x pressi o n of F ms o n t he t u m or cells a n d lea ds t o t he recr uit me nt of F ms-e x pressi n g 
m o n oc ytes a n d macr o p ha ges.  I n dee d, t h e pi g m e nt t hat c haracterizes t he t u m or mass is deri ve d 
pri maril y fr o m he m osi deri n-la de n ma cr o p ha ges.  T he str o n g ge netic li n k b et wee n P V N S a n d 
C S F- 1/ F ms pr o vi des s oli d scie ntific rati o nale t o tr eat P V N S patie nts wit h pe xi darti ni b as a 
t hera p y tar geti n g t h e u n d erl yi n g ge netic defect. 
A brief s u m mar y of data relate d t o pe xi darti ni b precli nical a n d cli nical e x perie nce t h us far is 
prese nte d b el o w a n d det ails ca n be f o u n d i n t he I n vesti gat or’s Br oc h ure. 1 
1. 2.  
D at a S u m m ar y 
1. 2. 1.  
N o ncli n ic al St u dies 
1. 2. 1. 1.  
S afet y P h ar m ac ol o g y 
T w o i n vitr o st u dies, c o n d ucte d u n der q ualifie d G o o d La b orat or y Practice ( G L P) c o n diti o ns, 
e x a mi ne d t he effects of p e xi darti ni b o n se veral electr o p h ysi ol o gical para m eters, wit h partic ular 
attenti o n t o p ote ntial f or pe xi darti ni b t o pr ol o n g car diac re p olarizati o n, w hic h has bee n 
ass ociate d wit h t he ris k of t orsa des de p oi ntes, a p ote ntiall y let hal car diac arr h yt h mia.  W he n 
e val uate d i n h u ma n e m br y o nic ki d ne y ( H E K) cells i nt o w hic h t he ge n e c o di n g f or t h e h u ma n 
et her a g o- g o ( h E R G) c h a n nel, w hic h is ass ociat e d wit h a n o ut war d p otassi u m c urre nt, a n 
i n hi bit or y c o nce ntrati o n of 5 0 % (I C 5 0) of 0. 7 μ M was o btai ne d.  T his I C 5 0 val ue is c o nsi dera bl y 
less p ote nt t ha n t hat f or refere nce c o ntr ol a ge nts, s uc h as E- 4 0 3 1 or t erfe na di ne, w hic h t y pi call y 
ha ve I C 5 0 val ues i n t he n a n o m olar ra n ge.  M ore i m p orta ntl y, i n e x peri me nts t o e val uate 
pe xi darti ni b’s p ote ntial effects o n t his car diac re p olarizi n g c urre nt, al b u mi n or ot her pr otei ns 
were a bse nt i n t he assa y b uffer.  T h us, all test article was free, u n b o u n d a ge nt.  Usi n g 
e q uili bri u m dial ysis, pe xi darti ni b was o bser v e d t o bi n d plas ma pr otei ns e xte nsi vel y ( > 9 9 %).  
T h us, t hi s s h o ul d be ta ke n i nt o acc o u nt i n i nter preti n g t he res ults of t hes e st u dies.  T he hi g h 

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pr otei n bi n di n g has t he effect of raisi n g t h e f u ncti o nal I C 5 0 v ers us h E R G c h a n nel i n hi biti o n f or 
pe xi darti ni b b y a fact or of 1 0 0, t hat is, 7 0 μ M. 
A d diti o nal f oll o w- u p st u dies e val uate d t he electr o p h ysi ol o gical effects of p e xi darti ni b o n ra b bit 
car diac P ur ki nje fi bers i n vitr o.  I n t his assa y, n o mea ni n gf ul test article-relate d effects o n acti o n 
p ote ntial d urati o n, acti o n p ote ntial a m plit u de or s pee d of car diac de p olarizati o n (as j u d ge d b y 
d V/ dt ma x) were o bser ve d.  Beca use pe xi darti ni b bi n ds t o t he h E R G c ha n nel yet n o Q T 
pr ol o n gati o n has b ee n i d e ntifie d n o ncli nicall y, a n i n vesti gati ve safet y p har mac ol o g y st u d y was 
c o n d ucte d t o e x a mi ne p ote ntial bi n di n g t o t he L t y pe calci u m c ha n nel ( h Ca v 1. 2) w h ose 
i n hi biti o n has bee n ne gati vel y c orrel ate d wit h ris k f or Q T pr ol o n gati o n.  I C 5 0 f or t he i n hi bit or y 
effect of pe xi darti ni b o n h Ca v 1. 2 calci u m c urre nt was deter mi ne d t o b e 0. 2 μ M. 
I n a d diti o n t o t he a b o ve i n vitr o st u dies, t he he m o d y na mic a n d electr ocar di o gra p hic effects of 
pe xi darti ni b were e val u ate d i n c o nsci o us, tele metr y-e q ui p pe d male Bea gle d o gs at d oses of 5 0, 
3 0 0, a n d 1 0 0 0 m g/ k g.  P e xi darti ni b plas ma e x p os ures were 6 2 9 6 9 n g· h/ m L a n d 3 3 5 6 3 3 n g· h/ m L 
i n a ni mals gi ve n 5 0 an d 1 0 0 0 m g/ k g pe xi darti ni b, res pecti vel y.  I m p orta ntl y n o Q T i nter val 
c orrecte d f or heart rate ( Q Tc) pr ol o n gati o n was s ee n.  N o test article-relat e d effects were n ote d 
f or t he Q Tc i nter val u p t o t he ma xi m u m d ose teste d ( 1 0 0 0 m g/ k g).  All electr ocar di o gra p hic 
para meters were q ualitati vel y a n d q ua ntitati vel y wit hi n n or mal li mits.  Left ve ntric ular 
c o ntractilit y ( L V d P/ dt ma x) val ues were si g nifica ntl y l o wer b y 8 3 3 a n d 8 1 5 m m H g/sec 
c o m pare d t o ve hi cle c o ntr ols i n d o gs t hat recei ve d 3 0 0 a n d 1 0 0 0 m g/ k g, res pecti vel y.  
A d diti o nall y, pe xi darti ni b d ose- de pe n d e ntl y l o w ere d t he arterial p ulse press ure.  Base d o n t hes e 
res ults, oral a d mi nistrati o n of pe xi darti ni b c o ul d ha ve p har m ac o d y na mic effects o n art erial p ulse 
press ure a n d L V d P/ dt ma x t hat c o ul d tra nslate i nt o re d uce d c o ntractilit y.  T heref ore, o n t he basis 
of t his i n vi v o st u d y, it is n ot a ntici pate d t hat pe xi darti ni b will pr o d uce Q T pr ol o n gati o n, b ut 
pe xi darti ni b d oes ha ve t he p ote ntial t o affect he m o d y na mics a n d car diac c o ntractilit y.  
T he ce ntr al ner v o us s yste m ( C N S) a n d res pirat or y safet y p har m ac ol o g y of pe xi darti ni b were 
e val uate d i n f e male rats at d oses of 2 0, 6 0, a n d 2 0 0 m g/ k g.  N o test articl e-relate d a d v erse effects 
were o bs er ve d i n eit her of t hese st u dies.  O n t he b asis of t h ose st u dies, a n o- o bser ve d-effect-l e vel 
( N O E L) was deter mi ne d t o be 2 0 0 m g/ k g. 
1. 2. 1. 2.  
N o ncli nic al  P h ar m ac o ki netics a n d Dr u g Met a b olis m 
Pe x i darti ni b is orall y bi o a vaila ble i n all precli nical s pecies ( m o use, rat, d o g a n d m o n ke y).  
Pe xi darti ni b is e xte nsi vel y b o u n d t o plas ma pr ot ei n irres pecti ve of t he s pecies ( m o use, rat, d o g, 
h u ma n).  After i ntra ve n o us a d mi nistrati o n i n n o ncli nical st u dies, t he ter mi nal eli mi nati o n 
half- life (t 1/ 2) v al ues were 3. 5 h i n mice, 5. 1 h i n rats, 1. 9 h i n d o gs, a n d 3. 7 h i n m o n ke ys. 
A n i n vitr o st u d y usi n g rec o m bi na nt h u ma n c yt oc hr o me P 4 5 0 ( C Y P) i n dicate d t h at C Y P 3 A 4 a n d 
C Y P 3 A 5 were t he maj or is of or ms res p o nsi ble f or pe xi darti ni b meta b olis m.  A d diti o nall y, 
C Y P 2 D 6, C Y P 2 C 8, C Y P 2 C 9, a n d C Y P 2 C 1 9 mi g ht pla y mi n or r oles.  Di- o x y ge n ate d, 
h y dr o ge nate d, a n d N- d eal k ylate d p e xi darti ni b were f or me d as t he maj or C Y P- me diate d 
meta b olites.  T he N- gl uc ur o ni de of pe xi darti ni b, Z A A D- 1 0 0 6a, was mai nl y pr o d u ce d b y 
U G T 1 A 4. 

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1. 2. 1. 3.  
T o xic ol o g y 
Ni ne i n vi v o t o xic ol o g y st u dies were c o m plete d i n rats a n d d o gs, wit h 3 st u dies i n eac h of t h ese 
2 s pecies perf or me d u n d er G L P c o n diti o ns. 
T he i nitial 2 G L P t o xic ol o g y st u dies i n v ol ve d o nce dail y ( Q D) i n rats a n d t wice dail y i n d o gs via 
or al ( ga v a ge) a d mi nistrati o n of pe xi darti ni b f or 4 wee ks ( w k), wit h 1 6- da y ( d) (rat) or 1 4- d ( d o g) 
reco veries.  Neit her a N O E L n or a n o- a d verse-effect-le vel ( N O A E L) of p e xi darti ni b c o ul d be 
deter mi ne d i n eit her s p ecies i n t hese st u dies d ue t o t o xicit y see n at t he l o west d ose.  T he 
si g nifica nt a d vers e, test article-rel ate d o bser vati o ns see n i n t hese 2 hi g h- d ose G L P st u dies a p pear 
t o be relate d t o t he me c h a nis m of pe xi darti ni b- me diate d i n hi biti o n of F ms a n d Kit ki nase.  
pe xi darti ni b-relate d hist o pat h ol o gic o bser vati o ns i ncl u de d testic ular s per mat o g o nia re d ucti o n, 
b o ne marr o w  h y p o cell ularit y, t h y mi c l y m p h oi d re d ucti o n, b o ne h y p er ost osis a n d h y p ertr o p h y, 
o varia n f ollic ular d e ge n erati o n a n d li ver he p at ocell ular h y p ertr o p h y.  All a d verse fi n di n gs were 
partiall y or f ull y re v ersi ble.  T w o a d diti o nal G L P t o xic ol o g y st u dies at l o wer d ose le vels 
i n v ol ve d dail y ( Q D i n rats a n d d o gs) oral ( ga va ge) a d mi nistrati o n of pe xi darti ni b f or 4 weeks, 
wit h 8 -w k  rec o v eries at d oses of 0. 5, 2, a n d 1 0 m g/ k g/ d i n rats, a n d 1, 6, a n d 3 0 m g/ k g/ d i n d o gs.  
N O A E L s of pe xi darti ni b we re d eter mi ne d t o be 1 0 m g/ k g/ d i n rats a n d 6 m g/ k g/ d i n d o gs i n 
t hese a d diti o nal st u dies.  All a d verse fi n di n gs w ere f ull y re versi ble, i ncl u di n g testic ular 
s per mat o g o nia re d u cti o n.  T w o 1 3-w k  G L P t o xic ol o g y st u dies i n v ol ve d dail y ( Q D i n rats a n d 
d o g s) oral ( ga v a ge) a d mi nistrati o n of pe xi darti ni b f or 1 3 weeks, wit h 8- w k rec o veries at d oses of 
0. 5, 4, a n d 2 0 m g/ k g/ d i n rats, a n d 1, 6, a n d 3 0 m g/ k g/ d i n d o gs.  N O A E Ls of pe xi darti ni b were 
deter mi ne d t o be 4 m g/ k g/ d i n rats a n d 6 m g/ k g/ d i n d o gs i n t hese a d diti o n al st u dies.  N o ne w 
tar get orga n t o xicities were defi n e d i n eit her st u d y; re pr o d ucti ve t o xicit y fi n di n gs 
(s per mat o g o nial re d ucti o n) a n d i ncrease d i nci d e nce of e mesis esta blis he d i n t he d o g at 3 0 m g/ k g 
were d e m o nstrate d t o be re versi ble.  A ne mia a n d b o ne marr o w d e pleti o n, a n d he pat ocell ular 
vac u olati o n ass ociat e d wit h i ncrease d li ver e nz y m es were see n i n t he rat. 
P ote ntial effects of p e xi darti ni b o n e m br y ofetal d e vel o p me nt i n rats were ass esse d at 4, 1 0, a n d 
4 0 m g/ k g / d i n a defi niti ve st u d y.  Bas e d o n c ha n ges i n he mat ol o g y p ara m eters at 4 0 m g/ k g/ d i n 
t he da ms a n d fet al e xter nal a n d visceral malf or mati o ns a n d s keletal de vel o p me ntal variati o ns 
(fi n di n gs pri maril y relate d t o decreases i n ossificati o n) i n t he fet uses at 4 0 m g/ k g/ d, a d ose le vel 
of 1 0 m g/ k g/ d was c o nsi dere d t o be t he N O A E L. 
Pe x i darti ni b s h o we d n o p ote ntial t o ca use p h ot ot o xicit y i n vitr o i n t he NI H 3 T 3 fi br o blast assa y.    
I n t hr ee ge n ot o xicit y st u dies, pe xi darti ni b di d e x ert a n y m uta ge nic or clast o ge ni c effects. 
1. 2. 1. 4.  
Cli n ic al E x perie nce 
A c o m pre he nsi v e series of n o ncli nical a n d cli nical ( N = 1 4) st u dies a n d a nal ys es el uci date d t he 
P K a n d P D a n d t he i nfl u e nce of i ntri nsic a n d e xtri nsic fact ors o n t he P K of pe xi darti ni b h u ma n 
e x p os ure has bee n e val uate d i n 6 cli nical st u dies. 
Pe xi darti ni b is a n orall y bi oa vaila ble dr u g wit h a t er mi nal eli mi nati o n half-life of 2 7 h o urs ( h).  
Pe xi darti ni b is meta b olize d mai nl y b y U D P- gl uc ur o n os yltra nsferase ( U G T) 1 A 4 a n d c yt o c hr o me 
P 4 5 0 ( C Y P) 3 A a n d u n der g o es mi ni mal uri nar y eli mi nati o n as u nc ha n ge d dr u g.  Str o n g i n hi bit ors 
of t hese meta b olic p at h w a ys i ncrease pe xi darti ni b e x p os ures.  C Y P 3 A i n d ucers, li ke rif a m pi n 
dece ases pe xi darti ni b e x p os ure.  C o nc urre nt a d mi nistrati o n of s yste mic p H m o difiers (e g, 
es o me praz ole) re d uces pe xi darti ni b e x p os ure b y a p pr o xi matel y 4 0 t o 5 0 %.  N o d ose a dj ust me nt 

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is nee de d f or s u bj ects wit h re nal i m pair me nt i ncl u di n g patie nts o n r o uti ne h e m o dial ysis.  
A d mi nistrati o n of pe xi darti ni b wit h f o o d ( hi g h fat meal) i ncrease d e x p os ure a p pr o xi matel y 
2-f ol d.  T heref ore, it is rec o m me n de d t o d ose pe xi darti ni b t wice dail y at least 1 h bef ore or 2 h 
after a meal.  Pe xi darti ni b d oes n ot pr ol o n g t he Q Tc i nter val. 
1. 3.  
St u d y R ati o n ale 
W he n a d mi nistere d wit h t he F D A hi g h-fat meal, p e xi darti ni b e x p os ure d o u bles. C urre ntl y i n 
o ut patie nt- base d st u dies pe xi darti ni b is rec o m me n de d t o be ta ke n t wice a d a y o n a n e m pt y 
st o mac h, at least 1 h bef ore or 2 h after a meal. T h e i nf or mati o n deri ve d fr o m t his st u d y c o ul d 
hel p wit h pr o vi di n g fle xi bilit y i n d osi n g, ti mi n g of f o o d i nta ke, a n d t y p es of meals f or s u bjects 
wit h te n os y n o vial gia nt cell t u m or ( T G C T). 
1. 4.  
Ris ks a n d Be nefits f or St u d y S u bjects 
T here is n o direct be nefit f or st u d y s u bjects i n t he c urre nt st u d y. I n dir ect be nefits t o t he healt h y 
s u bjects e nr olle d i n t his st u d y are t he free m e dical tests recei ve d d uri n g Scree ni n g a n d t he safet y 
m o nit ori n g as ma n dat e d b y t he st u d y. 
T he P K, safet y, a n d t olera bilit y of si n gle d oses of pe xi darti ni b ( 2 0 0 m g t o 2 4 0 0 m g) i n 
a p pr o xi matel y 1 9 0 healt h y s u bjects h a ve bee n e v al uate d i n 9 st u dies. I n ge n eral, pe xi darti ni b 
was well-t olerate d u p t o a vera ge pea k e x p os ure of 2 0, 8 0 0 n g/ m L a n d a t otal e x p os ure ( A U C) of 
4 9 1, 9 4 8 n g• h/ m L  ( 1 8 0 0 m g fe d st ate) n g• h/ m L. N o safet y si g nals i n vital si g ns, p h ysical 
e x a mi nati o ns, or E C G rec or di n gs, i n cl u di n g Q T pr ol o n gati o n, were re p ort e d. 1  T heref ore, t he 
ris k for u nc o veri n g a ne w u nt o war d effect of a si n gle d ose of pe xi darti ni b is relati vel y s mall. 
Base d o n p o ol e d data fr o m t he o nc ol o g y st u dies wit h m ulti ple d osi n g, t he m ost fre q ue nt A Es 
( occ urri n g i n > 1 0 % of s u bjects) p ote ntiall y relate d t o t he st u d y dr u g were fati g ue, na us ea, 
decrease d a p petite, hair c ol or c ha n ges, diarr hea, i n creas es i n A S T a n d A L T le vels, v o miti n g, 
a ne mia, d ys ge usia, a n d ras h. At d osa ge le vels ≥6 0 0 m g/ d, tra nsie nt i ncreases i n A S T a n d/ or A L T 
le vels ha ve bee n c o m m o nl y o bser ve d wit h m ulti ple d osi n g. A m o n g c o m m o n T E A Es, fati g ue, 
i ncreas e d A S T a n d A L T le vels, a ne mia, a n d ras h were rate d Gra de 3 or hi g her wit h a fre q ue n c y 
greater t ha n 1 % 1. 
Ele va ti o ns of li ver tra ns a mi nases a n d bilir u bi n ha ve bee n o bser ve d i n st u dies wit h pe xi darti ni b, 
t o get her wit h cas es of dr u g i n d uc e d c h olestatic li ver i nj ur y f oll o wi n g m ulti ple d oses. Cases of 
c h olestasis ha ve bee n o bser ve d i n t he first 8 w eeks, ha ve ge nerall y res ol v e d wit h treat me nt 
disc o nti n uati o n, b ut i n rare cas es ha ve b ee n s e vere, re q uiri n g li ver dial ysis a n d ha d a pr otract e d 
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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 bjecti ves 
2. 1. 1.  
P ri m ar y O bjecti ves 
T he pri mar y o bje cti ves of t his st u d y are: 
 T o assess t he effect of l o w-fat f o o d o n t h e p har mac o ki netics ( P K) of pe xi darti ni b 
f oll o wi n g a si n gle oral d ose of 4 0 0 m g a d mi nistere d i n healt h y s u bjects 
 T o a ssess t he P K of pe xi darti ni b f oll o wi n g a si n gl e oral d ose of 2 0 0 m g a d mi nistere d 
wit h l o w-fat f o o d i n healt h y s u bjects 
2. 1. 2.  
S ec o n d ar y O bjecti ve 
T he sec o n d ar y o bjecti ve of t his st u d y is: 
 T o c haracteriz e t he safet y a n d t olera bilit y of pe xi darti ni b i n healt h y s u bjects 
f oll o wi n g a d mi nistrati o n of a si n gl e oral d ose of pe xi darti ni b wit h l o w fat f o o d a n d 
wit h o ut f o o d 
2. 2.  
St u d y H y p ot hesis 
T here is n o h y p ot hesis f or t his st u d y.  T his st u d y is bei n g c o n d ucte d t o esti mate t he effect of 
l o w-fat f o o d o n p e xi darti ni b P K. 
2 . 3. 
St u d y E n d p oi nts 
2. 3. 1.  
Pri m ar y E n d p oi nt 
Plas ma c o nce ntr ati o n ti me data f or pe xi darti ni b will be a nal yze d usi n g n o nc o m part me ntal 
met h o ds.  T he f oll o wi n g P K para meters will be re p orte d: ma xi m u m o bser ve d c o nce ntrati o n i n 
plas ma ( C ma x), ti me t o ma xi m u m o bser ve d c o nce ntrati o n ( T ma x), a n d area u n der t he 
c o nce ntr ati o n-ti me c ur ve fr o m ti me of d osi n g t o last meas ura ble c o n ce ntr ati o n ( A U Clast) a n d 
area u n d er t he c o nce ntrati o n-ti me c ur ve fr o m ti me of d osi n g t o i nfi nit y ( A U Ci nf).  Ter mi nal 
half-life (t 1/ 2), a p pare nt t otal b o d y cl eara nce ( C L/ F), a n d a p pare nt v ol u me of distri b uti o n ( V z/ F) 
will als o be re p orte d. 
2. 3. 2.  
S ec o n d ar y E n d p oi nt(s) 
Safet y e n d p oi nts i n cl u de E C G assess me nts ( Q T, P R, Q R S, R R, a n d Q Tc [ Q Tc B, Q Tc F] 
i nter vals), vital si g n me as ure me nts, cli nical la b orat or y t ests, a d verse e ve nts, a n d fi n di n gs fr o m 
p h ysical e x a mi nati o ns 
2. 3. 3.  
E x pl or at or y E n d p oi nt 
N ot a p plica ble 

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3.  
S T U D Y D E SI G N 
3. 1.  
O ver all Desi g n 
3. 1. 1.  
O ver vie w 
Fi g ure 3. 1: 
Sc he m atic C h art of St u d y Desi g n 
 
 
3. 1. 2.  
D ose  Esc al ati o n Pr ocess 
N ot a p plica ble. 
3. 1. 3.  
S t u d y St o p pi n g Criteri a 
N ot a p plica ble 
3. 2.  
Disc ussi o n of St u d y Desi g n 

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4.  
S T U D Y P O P U L A TI O N 
4. 1.  
I ncl usi o n Criteri a 
S u bjects m ust satisf y all of t he f oll o wi n g criteri a t o be i ncl u de d i n t he st u d y: 
1.  He alt h y male a n d fe male s u bjects bet wee n 1 8 a n d 6 0 years ( y) of a ge, i ncl usi ve. 
2.  B MI of 1 8 t o 3 0 k g/ m
2, i ncl usi ve. 
3.  G o o d he alt h as deter mi ne d at Scree ni n g a n d C hec k-i n b y e x a mi ni n g me di cal hist or y 
( Screeni n g o nl y) a n d perf or mi n g p h ysic al e xa mi nati o ns, vital si g ns, E C Gs, ser u m 
c he mistr y, h e mat ol o g y, c oa g ul ati o n tests ( Scree ni n g o nl y), vir ol o g y ( S cree ni n g o nl y), 
a n d uri nal ysis. 
4.  Ne gati ve ser u m pre g na n c y test at Scree ni n g a n d d uri n g C hec k-i n f or fe mal e s u bjects. 
5.  F e male s u bjects m ust be: 
 S ur gicall y sterile ( d oc u m e nte d h yst erect o m y, bilat eral t u bal li gati o n, or bilateral 
sal pi n g o- o o p h orect o m y, Ess ure ® wit h h yster osal pi n g o gra m [ d oc u me ntati o n t o 
c o nfir m t u bal occl usi o n 1 2 w k after pr oce d ure]) 
O R  
 Na t urall y p ost me n o pa usal (s p o nta ne o us cess ati o n of me nses) f or at least 1 2 
c o nsec uti ve m o pri or t o d osi n g, wit h a f ollicle sti m ulati n g h or m o ne ( F S H) l e vel at 
Scree ni n g of ≥4 0 mI U/ m L 
A N D 
 N o nla ctati n g 
6.  Male  s u bjects m ust be: 
 S ur gicall y sterile (c o nfir me d b y d o c u me nte d az o os per mia 9 0 d after t he pr oce d ure) 
O R  
 A gr ee t o use d o u bl e barrier met h o ds of c o ntr ace pti o n fr o m C hec k-i n u ntil 9 0 d after 
t he fi nal d ose of pe xi darti ni b. A de q uate met h o ds of c o ntrace pti o n f or s u bj ects or 
part ners i nc l u de: c o n d o m wit h s per mici dal gel, dia p hra g m wit h s per mici dal gel, a n d 
a bsti ne nce. If a s u bject is n ot se x uall y acti ve b ut b ec o mes acti ve, he a n d his part ner 
m ust use t he a b o ve liste d d o u ble barrier met h o ds of c o ntrace pti o n. Male s u bjects 
m ust n ot d o nate s per m d uri n g t he st u d y a n d f or u p t o 9 0 d after t he fi n al d ose. 
7.  Ne gati ve uri ne t est f or dr u gs of a b use ( o piat es, be nz o diaze pi nes, a m p heta mi nes, 
ca n na bi n oi ds, c ocai ne, b ar bit urates, a n d p h e nc ycli di ne), c oti ni ne, a n d alc o h ol at 
Scre e ni n g a n d C hec k-i n.  
8.  Ne gati ve test r es ult f or h u ma n i m m u n o deficie nc y vir us ( HI V) a nti b o d y, h e patitis B 
s urface a nti ge n ( H Bs A g), a n d he patitis C vir us ( H C V) a nti b o d y at Scree ni n g. 

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9.  Willi n g ness t o refrai n fr o m c o ns u mi n g f o o d or b e vera ges c o ntai ni n g caffei ne/ x a nt hi ne or 
alc o h ol f or 4 8 h pri or t o C hec k-i n o n Da y - 1 u ntil t he e n d of t he st u d y. 
1 0.  Willi n g ness t o refrai n fr o m c o ns u mi n g gra p efr uit/ gra pefr uit j uice a n d Se ville ora n ges 7 d 
bef ore t h e first d ose of st u d y dr u g o n Da y 1 u ntil t he e n d of t he st u d y. 
4. 2.  
E xcl usi o n Criteri a 
S u bjects w h o meet a n y of t he f oll o wi n g criteri a will be dis q ualifie d fr o m e nteri n g t he st u d y: 
1.  Hist or y of a n y cli nicall y si g nifica nt dis or der, i ncl u di n g car di o vasc ul ar, he mat ol o gic, 
p ul m o nar y, h e patic, re nal, gastr oi ntesti nal, c o n n ecti ve tiss ue disease, u nc o ntr olle d 
e n d ocri ne/ meta b olic, o n c ol o gic ( wit hi n t he last 5 y), n e ur ol o gic, a n d ps yc hiatric diseases, 
or a n y dis or der t h at ma y pre ve nt t he s uccessf ul c o m pleti o n of t he st u d y. 
2.  Hist or y of st o ma c h or i ntesti nal s ur ger y or resecti o n t hat w o ul d p ote ntiall y alter 
a bs or pti o n a n d/ or e x creti o n of orall y a d mi nistere d dr u gs ( wit h t he e x ce pti o n of 
a p pe n dect o m y, h er nia re pair, a n d/ or c h ol ec ystect o m y). 
3.  Hist or y of cli nicall y si g nifica nt ne utr o pe ni a. 
4.  Use  of a n y prescri pti o n me dicati o ns/ pr o d ucts a n d a n y m e dicati o ns k n o w n t o i n d uce or 
i n hi bit C Y P a n d U G T e nz y m es wit hi n 2 8 d fr o m t he first d ose a n d d uri n g t he st u d y (s ee 
Sec ti o n 1 6. 5 f or a list of dr u g pr o d ucts t hat i n hi bit/i n d uce C Y P a n d U G T e nz y m es). 
5.  Use  of f o o d or b e vera ges c o ntai ni n g gra pefr uit 7 d pri or t o d osi n g a n d d uri n g t he st u d y. 
6.  Use  of o ver t he c o u nter ( O T C), n o n prescri pti o n me dicati o n (i ncl u di n g vita mi n D 
pre parati o ns a n d cal ci u m) wit hi n 1 4 d fr o m t he first d ose a n d d uri n g t he st u d y (e x cl u di n g 
aceta mi n o p he n ( ≤ 2 g/ d ). 
7.  Use  of s u p ple me nts (i ncl u di n g p h yt ot hera p e utic/ h er bal/ pla nt- deri ve d pre parati o ns a n d 
m ost vita mi ns a n d mi nerals) wit hi n 1 4 d fr o m t he first d ose a n d d uri n g t he st u d y. 
8.  Use  of or caffei ne- c o ntai ni n g f o o ds or be vera ges wit hi n 4 8 h pri or t o C hec k-i n a n d 
d uri n g c o nfi ne me nt. 
9.  C o ns u m pti o n of alc o h ol wit hi n 4 8 h pri or t o C hec k-i n a n d d uri n g c o nfi ne m e nt. 
1 0.  La b orat or y res ults (ser u m c he mistr y, h e mat ol o g y, a n d uri nal ysis) o utsi de t he n or mal 
ra n ge, if c o nsi dere d cli nicall y si g nifica nt b y t he i n vesti gat or.  Li v er f u n cti o n test res ults 
( A L T, A S T, t otal bilir u bi n) great er t ha n t he u p per li mit of n or mal.  He m o gl o bi n le vels 
m ust be ≥ 1 1. 5 g / d L f or fe male s u bjects a n d ≥ 1 2. 5 g/ d L f or male s u bjects. 
1 1.  Esti mate d gl o mer ular filtrati o n rate (e G F R) ( usi n g t he C oc kcr oft- Ga ult e q u ati o n) 
< 9 0  m L/ mi n at S cree ni n g. 
1 2.  Hist or y or prese n ce of a n a b n or mal E C G, w hic h, i n t he i n vesti gat or’s o pi ni o n, is 
cli nicall y si g nifica nt a n d/ or a c orrect e d Q T i nter val usi n g Fri d ericia’s f or m ula ( Q Tc F) 
≥ 4 5 0 msec f or males a n d ≥ 4 7 0 msec f or fe males at S cree ni n g. 
1 3.  Bl o o d d o nati o n of 5 0 0 m L or m ore or a si g nifi ca nt l oss of bl o o d wit hi n 5 6 da ys pri or t o 
t he first d ose. 
1 4.  Recei pt of a tr a nsf usi o n or a n y bl o o d pr o d ucts wit hi n 3 0 da ys pri or t o t he first d ose. 

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1 5.  C urre nt partici pati o n i n a n ot her i n vesti gati o nal st u d y or w h o ha ve p artici pat e d i n a n 
i n vesti gati o nal st u d y wit hi n t he past 3 0 d a ys pri or t o t he first d ose. 
1 6.  C o ns u m pti o n of m ore t ha n 2 8 u nits of alc o h ol per w k ( males) or 1 4 u nits of alc o h ol per 
w k (fe mal es), w here 1 u nit of alc o h ol e q uals 1/ 2 pi nt of beer, 4 o u n ces of wi ne, or 
1 o u nce of s pirits, or si g nifica nt hist or y of alc o h olis m or dr u g/ c he mic al a b use wit hi n t he 
last 2 y. 
1 7.  Use of t o bacc o pr o d u cts or nic oti ne-c o ntai ni n g pr o d ucts (i ncl u di n g s m o ki n g cessati o n 
ai ds, s uc h as g u ms or pat c hes) wit hi n 6 m o pri or t o t he first d ose. 
1 8.  P ositi ve res ults o n tests f or dr u gs of a b us e, c oti ni ne or alc o h ol at Scree ni n g or C hec k-i n. 
1 9.  P osit i ve test res ult f or H Bs A g, H C V a nti b o d y, or HI V a nti b o d y. 
2 0.  E m pl o y m e nt b y t he cli ni c. 
2 1.  U na ble t o c o ns u me or aller gic t o t he brea kfast meal 
2 2.  A n y ot her reas o n, i n t he o pi ni o n of t he i n vesti gat or, t hat precl u d es s u bject partici pati o n i n 
t he st u d y. 
2 3.  Fa milial relati o ns hi p wit h a n ot her st u d y partici pa nt. 
S u bjects m ust be c o m plia nt wit h all i ncl usi o n a n d n o ne of t he e x cl usi o n criteria 

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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 bjects t o Tre at me nt Gr o u p(s) / Se q ue nces a n d Bli n di n g 
5. 1. 1.  
T re at me nt Gr o u p(s) / Se q ue nces 
S u bjects wi ll be ra n d o mize d t o 1 of 6 se q ue nces: A B C, A C B, B A C, B C A, C A B, a n d C B A. 
T he st u d y tr eat me nts i ncl u de: 
 Tr eat me nt A: Si n gl e oral 4 0 0 m g ( 2 × 2 0 0 m g ca ps ules) of pe xi darti ni b i n t he 
m or ni n g wit h 2 4 0 m L of water after a n o ver ni g ht f ast of 1 0 h 
 Treat me nt B: Si n gle oral 4 0 0 m g ( 2 × 2 0 0 m g ca ps ules) of pe xi darti ni b i n t he 
m or ni n g wit hi n 3 0 mi n of a l o w-fat sta n dar d brea kfast meal 
 Tr eat me nt C: Si n gle oral 2 0 0 m g ( 1 × 2 0 0 m g ca ps ule) of pe xi darti ni b i n t he m or ni n g 
wit hi n 3 0 mi n of a l o w-fat sta n dar d brea kfast meal 
5. 1. 2.  
M et h o d of Tre at me nt Gr o u p(s) / Se q ue nces All oc ati o n 
T his is a n o pe n-la bel r a n d o mize d st u d y.  T h e ra n d o mizati o n sc he d ule will be pr o d uce d b y a 
statisticia n fr o m W orl d wi de Cli nical Trials, u n der t he s pecificati o n a p pr o ve d b y t h e s p o ns or 
statisticia n.  A d u m m y sc he d ule will first be pr o d uce d a n d will be c hec k e d b y t he s p o ns or 
statisticia n.  Pri or t o t he start of t he st u d y, a c o p y of t he ra n d o mizati o n sc he d ule will be s u p plie d 
b y t he W orl d wi de Cli nical Trials statisticia n t o t he cli nical site p har macist a n d at a n a p pr o priate 
ti me t o t he bi oa nal ytical di visi o n at Celeri o n. 
5. 1. 3.  
B li n di n g 
N ot a p plica ble. T his is a n o pe n-la bel st u d y. 
5. 1. 4.  
E mer ge nc y U n bli n di n g Pr o ce d ure 
N ot a p plica ble. 
5. 2.  
St u d y Dr u g 
5. 2. 1.  
De scri pti o n  
Pe xi darti ni b 2 0 0 m g ca ps ules will be pr o vi de d b y t he s p o ns or i n o pe n-la bele d b ottles. 
5. 2. 2.  
L a beli n g a n d P ac k a gi n g 
Pe xi darti ni b 2 0 0 m g b ottles will be la bele d i n c o m plia nce wit h re g ulat or y re q uire me nts.  T h e 
pac ka gi n g will cle arl y dis pla y t he n a me of t he st u d y dr u g, t h e l ot n u m ber, st ora ge c o n diti o n, a n d 
ot her re q uir e d i nf or mati o n i n acc or d a nce wit h l ocal re g ul ati o ns. 
5. 2. 3.  
P re p ar ati o n 
T he st u d y dr u g will be s u p plie d as ca ps ules t hat nee d n o f urt her pre p arati o n at t he st u d y site. 

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5. 2. 4.  
A d mi nistr ati o n 
Pe xi darti ni b will be a d mi nistere d orall y i n t he cli nic wit h a p pr o xi matel y 2 4 0 m L of water. 
T he st u d y pr o d uct will be a d mi nistere d i n acc or d a nce wit h t he pr ot o c ol.  St u d y pr o d u ct will be 
a d mi nistere d o nl y t o s u bj ects partici pati n g i n t he cli nical st u d y.  It is a vi olati o n of t he 
re g ulati o ns t o use u na p pr o ve d st u d y pr o d u ct f or p ur p oses ot her t ha n t he pr ot oc ol. 
T he site will c o m plete t he re q uir e d d oc u me ntati o n as pr o vi de d b y Daiic hi S a n k y o, I nc. ( D SI) or 
its re prese ntati ves t o d oc u me nt dis pe nsi n g of t he st u d y pr o d u cts.  All i nf or mati o n will be 
rec or d e d i m me diatel y o n a dr u g dis pe nsi n g f or m eac h ti me t he st u d y pr o d ucts are dis pe ns e d t o a 
s u bject 
5. 2. 5.  
S t or a ge 
Dr u g s u p plies m ust be st ore d i n a sec ure, li mite d access st ora ge area u n der t he rec o m me n d e d 
st ora ge c o n diti o ns. 
Pe xi darti ni b 2 0 0 m g ca ps ules s h o ul d be st ore d at 2 0º C t o 2 5º C ( 6 8 º F t o 7 7º F).  E x c ursi o ns are 
per mitte d t o 1 5º C t o 3 0º C ( 5 9º F t o 8 6º F).  Ca ps ul es s h o ul d n ot be fr oze n. 
5. 2. 6.  
Dr u g Acc o u nt a bilit y 
W he n a dr u g s hi p me nt is recei v e d, t he i n vesti gat or or desi g nee will c hec k t he a m o u nt a n d 
c o n diti o n of t he st u d y dr u g, c h ec k f or a p pr o priate l ocal la n g ua ge i n t he la bel a n d s u p p orti n g 
d oc u me ntati o n, a n d si g n t he Recei pt of S hi p me nt F or m pr o vi de d.  T h e Recei pt of S hi p me nt 
F or m s h o ul d be fa x e d as i nstr ucte d o n t he f or m.  T he ori gi n al will be retai n e d at t he site.   
I n a d diti o n, t he i n vesti gat or or desi g nee s hall c o ntact D SI as s o o n as p ossi ble if t here is a 
pr o ble m wit h t he s hi p me nt. 
A Dr u g Acc o u nta bilit y R ec or d will be pr o vi d e d f or t he pe xi darti ni b st u d y pr o d uct.  T he rec or d 
m ust be ke pt c urre nt a n d s h o ul d c o ntai n t he dates a n d q ua ntities of dr u g recei ve d, eac h s u bject’s 
i de ntificati o n n u m ber a n d/ or i nitials or s u p pl y n u m ber as a p plica ble, t o w h o m t he i n vesti gati o nal 
me dici nal pr o d uct were dis pe nse d, t he date a n d q u a ntit y of i n vesti gati o nal me dici nal pr o d uct 
dis pe nse d a n d r e mai ni n g, if fr o m i n di vi d ual s u bject dr u g u nits as well as t he i nitials of t he 
dis pe nser. 
At t he e n d of t he st u d y, or as direct e d, t he i n vesti gat or will arra n ge f or t h e destr ucti o n of u n use d, 
partiall y us e d, or e m pt y c o ntai ners of pe xi darti ni b st u d y pr o d uct.  D uri n g t he site a p pr o val 
pr ocess, a p pr o priate a n d acce pta ble destr u cti o n pr oce d ures will be verifie d.  If a bs ol utel y 
necessar y a n d after D SI a p pr o val, dr u g ( use d/ u n us e d) ma y be ret ur ne d t o D SI or a desi g nee as 
i nstr ucte d by D SI. 
If i n t he e ve nt t he i n v esti gati o nal me di ci nal pr o d u cts are ret ur ne d f or s o me pre-a p pr o ve d reas o n, 
t he i n vestigati o nal me dici nal pr o d uct will be ret ur ne d o nl y after t h e st u d y m o nit or has c o m plete d 
a fi nal i n ve nt or y t o verif y t he q u a ntit y t o be ret ur ne d.  T he ret ur n of i n vesti gati o nal me dici nal 
pr o d uct m ust be d oc u me nte d, a n d t he d oc u me nt ati o n i ncl u de d i n t he s hi p me nt.  At t he e n d of t he 
st u d y, a fi n al i n vesti gati o nal me dici nal pr o d uct r ec o nciliati o n state me nt m ust be c o m plete d b y 
t he i n vestigat or or desi g n ee a n d pr o vi d e d t o t he s p o ns or. 

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All i n vesti gati o nal me dici nal pr o d uct i n ve nt or y f or ms m ust be ma de a vaila ble f or i ns pecti o n b y a 
s p o ns or a ut h orize d re prese ntati ve or desi g nee a n d re g ulat or y a ge nc y i ns pe ct ors.  T he i n vesti gat or 
is res p o nsi ble for t he acc o u nta bilit y of all use d a n d u n use d st u d y s u p plies at t he site. 
5. 2. 7.  
Re te nti o n S a m ples 
N ot a p plica ble. 
5. 3.  
C o ntr ol Tre at me nt 
N ot a p plica ble. 
5. 4.  
D ose I nterr u pti o ns a n d Re d ucti o ns 
N ot a p plica ble 
5 . 5. 
Met h o d of Assessi n g Tre at me nt C o m pli a nce 
I n or der t o e ns ure tr eat m e nt c o m plia nce, all d oses will be a d mi nistere d u n d er t he s u per visi o n of 
cli nical st u d y pers o n nel.  A m o ut h a n d ha n d c hec k of all s u bjects s h o ul d be carrie d o ut t o e ns ure 
t hat all ca ps ules ha ve bee n s wall o we d. 
5. 6.  
Pri or a n d C o nc o mit a nt Me dic ati o ns 
Me dicati o ns use d 3 0 d pri or t o Scree ni n g will be rec or de d. 
T he f oll o wi n g m e dicati o ns a n d pr o d ucts will be pr o hi bite d: 
 A n y prescri pti o n me dicati o ns/ pr o d ucts a n d a n y me dicati o ns k n o w n t o i n d uce or 
i n hi bit CY P a n d U G T e nz y m es wit hi n 2 8 d fr o m t he first d ose a n d d uri n g t he st u d y 
(see Secti o n 1 6. 5 f or a list of dr u g pr o d ucts t hat i n hi bit/i n d uce C Y P a n d U G T 
enz y mes). 
 A n y O T C, n o n prescri pti o n me dicati o ns (i ncl u di n g vita mi n D pre p arati o ns a n d 
calci u m) wit hi n 1 4 d fr o m t he first d ose a n d d uri n g t he st u d y.  H o we ver, t o pical 
h y dr o c ortis o ne will be all o we d f or c o nt act der m atitis, a n d pr u ne j uice will be all o we d 
f or c o nsti pati o n. 
 Use  of s u p ple me nts (i ncl u di n g p h yt ot hera p e utic/ h er bal/ pla nt- deri ve d pre parati o ns a n d 
m ost vita mi ns a n d mi nerals) wit hi n 1 4 d fr o m t he first d ose a n d d uri n g t he st u d y. 
Aceta mi n o p he n ( ≤ 2 g/ d) is all o we d d uri n g c o nfi n e me nt at t he discreti o n of t he i n vesti gat or. 
A n y me di cati o n ( ot her t h a n st u d y dr u gs) ta ke n b y s u bjects d uri n g t he c o urse of t he st u d y will be 
rec or d e d a n d c o de d usi n g t he W orl d Healt h Or ga nizati o n ( W H O) dicti o nar y.  If dr u g t hera p y 
ot her t ha n t hat s pecifi e d b y t he pr ot oc ol is ta ke n, a j oi nt decisi o n will be ma de b y t he i n vesti gat or 
a n d s p o ns or w het her t o c o nti n ue or disc o nti n ue t he s u bject. 
5. 6. 1.  
Die t ar y a n d Lif est yle Restricti o ns 
At Scree ni n g, s u bjects will be i nf or me d t hat if acce pte d f or t he st u d y, n o f o o ds or be vera ges 
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p r o hi bite d f or 4 8 h pri or t o C hec k-i n a n d d uri n g c o nfi ne me nt.  S u bjects m ust als o a gree t o 
a bstai n fr o m ca ffei n e-c o ntai ni n g f o o ds or be vera ges fr o m 4 8 h pri or t o C h ec k-i n a n d d uri n g 
c o nfi ne me nt. 
Tre at me nt A: 
S u bjects will be re q uire d t o fast o ver ni g ht f or at least 1 0 h pri or t o d osi n g. 
Tre at me nt B a n d Tre at me nt C: 
S u bjects will be re q uire d t o fast o ver ni g ht f or at least 1 0 h u ntil 3 0 mi n pri or t o d osi n g, w he n 
t he y will be gi ve n a sta n dar d l o w-fat brea kfast w hic h will be e ntirel y c o ns u me d wit hi n 3 0 mi n.  
T he brea kfast will c o nsist of 8 o u nces of 1 perce nt fat mil k, 1 b oile d e g g, a n d o ne pac k et of 
i nsta nt fla v ore d oat meal ma de wit h water. 
S u bjects s h o ul d be d ose d wit hi n 5 mi n utes of c o m pleti n g t he meal. 
F or all  tre at me nts: 
F oll o wi n g d osi n g, s u bjects will be re q uire d t o fast f or at least 4 h.  A sta n dar d me n u a n d meal 
sc he d ule ( b ase d o n U nite d States Rec o m me n de d Dail y All o w a nce) will be a d mi nistere d 
u nif or ml y t o all s u bjects.  Meals a n d/ or s nac ks will be ser ve d at a p pr o pri ate ti mes f oll o wi n g 
d osi n g.  I de ntical meals will be ser ve d f or eac h tr eat me nt (e x ce pt f or t h e test brea kfast).  T he 
cal orie c o nt e nt, as well as t he perce nt of cal ories fr o m pr otei n, car b o h y drat e, a n d fat, will be 
u nif or m f or eac h me al d uri n g t he st u d y (ie, brea kfast u nif or m t o brea kfast, l u nc h u nif or m t o 
l u nc h). 
Water will n ot be per mitte d fr o m 1 h bef ore u ntil 2 h after d osi n g ( wit h t he e x ce pti o n of 2 4 0 m L 
of water a d mi nistere d wit h d osi n g a n d t he li q ui d gi ve n wit h brea kfast), b ut will be all o we d at all 
ot her ti mes. 
E x ce pt w he n E C Gs m ust be ta ke n i n s u pi ne p ositi o n, s u bjects will re mai n seate d i n a n u pri g ht 
p ositi o n wit h mi ni mal a m b ulati o n (ie, o nl y t o a n d fr o m t he was hr o o m or f or st u d y pr oce d ures) 
f or t he first 4 h f oll o wi n g d osi n g. W he n E C Gs ass ess me nt a n d P K sa m ples are sc he d ule d at t he 
sa me ti me, E C G will be d o ne first f oll o we d b y P K sa m pli n g. 
5. 7.  
S u bject Wit h dr a w al/ Disc o nti n u ati o n 
5. 7. 1.  
Re as o ns f or Wit h dr a w al 
A n y s u bject w h o disc o nti n ues fr o m t he st u d y treat me nt f or a n y reas o n will ha ve t heir st u d y 
treat me nt disc o nti n uati o n rec or d e d. 
F oll o wi n g ra n d o mizati o n, s u bjects ma y b e wit h dra w n bef ore c o m pleti n g t he st u d y p er pr ot oc ol 
f or a n y of t he f oll o wi n g reas o ns: 
 A E  
 Wit h dra wal of c o nse nt b y s u bject 
 P h ysicia n decisi o n 
 P re g n a nc y 

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 Pr ot oc ol de viati o n 
 S t u d y t er mi nate d b y s p o ns or 
 Ot he r 
All s u bjects w h o are wit h dra w n fr o m t he st u d y s h o ul d c o m plete pr ot oc ol s p ecifie d wit h dr a wal 
pr oce d ures ( Secti o n 6. 6 ). 
5. 7. 2.  
Wit h dr a w al Pr oce d ures 
I n acc or da n ce wit h t he D eclarati o n of Helsi n ki a n d ot her a p plica ble re g ulati o ns, a s u bject has t he 
ri g ht t o wit h dra w fr o m t h e st u d y at a n y ti me a n d f or a n y reas o n wit h o ut prej u dice t o his or her 
f ut ure me dical care b y t h e st u d y p h ysicia n or at t h e st u d y site. 
If a s u bject wit h dra ws fr o m t he st u d y, s/ he will be re q uir e d t o ha ve E arl y Ter mi nati o n st u d y 
pr oce d ures perf or me d (refer t o Secti o n 6. 6 ).   
If a s u bject is wit h dra w n fr o m t he st u d y, t he i n v esti gat or will c o m plete a n d re p ort t he 
o bser vati o ns as t h or o u g hl y as p ossi ble u p t o t he d ate of wit h dra wal, i ncl u di n g t he dat e of last 
treat me nt a n d t he reas o n f or wit h dra w al. 
If t he s u bject is wit h dra w n d ue t o a n A E , t he i n vesti gat or will f oll o w t he s u bject u ntil t he A E  has 
res ol ve d or sta biliz e d. 
All s u bjects w h o are wit h dra w n fr o m t he st u d y s h o ul d c o m plete pr ot oc ol-s p ecifie d wit h dr a wal 
pr oce d ures. 
5. 7. 3.  
S u bject Re pl ace me nt 
T here is n o pla n f or s u bject re pla ce me nt. 
5. 7. 1.  
S u bject Re-scree ni n g Pr oce d ures 
N ot a p plica ble. 
5. 8.  
Criteri a f or S us pe n di n g St u d y Tre at me nt 
N ot a p plica ble. 

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6.  
S T U D Y P R O C E D U R E S 
6. 1.  
Scree ni n g  
Scree ni n g will be c o n d u cte d a n yti me wit hi n 2 1 d pri or t o d osi n g.  I nf or me d c o nse nts ( ge n eral 
st u d y pr oce d ures/ ge n ot y pi n g a n d t he Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act 
[ HI P A A]4) will be o btai ne d fr o m t he s u bject pri or t o perf or mi n g a n y of t h e S cree ni n g 
assess me nts. 
T he f oll o wi n g acti vities a n d/ or assess me nts will be perf or me d at Scree ni n g: 
 Inf or me d c o ns e nt 
 In cl usi o n/e x cl usi o n criteria 
 Me dic al hist or y 
 P ri or a n d c o nc o mita nt m e dicati o n hist or y 
 C o m plete p h ysical e x a m 
 He i g ht a n d b o d y wei g ht ( a n d B MI calc ulati o n) 
 1 2 -lea d E C G 
 Vital si g ns ( bl o o d press ure, heart rate, oral te m perat ure, a n d res pirat or y rat e) 
 B l o o d sa m ples f or: 
 HI V a nti b o d y 
 H Bs A g a n d H C V a nti b o dies 
 Cli nical la b orat or y tests ( he mat ol o g y a n d fasti n g s er u m c he mistr y); s u bjects will 
fast f or a p pr o xi matel y 1 0 h pri or t o S cree ni n g f or t he ser u m c he mistr y tests 
 C oa g ulati o n tests ( pr ot hr o m bi n ti me [ P T] / I N R a n d acti vate d partial 
t hr o m b o plasti n ti me [a P T T]) 
 Ser u m pre g na n c y test f or all fe males 
 F S H test f or nat ur all y p ost me n o pa usal fe male s u bjects 
 Ur i ne sa m ples f or: 
 Uri ne dr u g scree n ( o piates, be nz o diaze pi nes, a m p heta mi nes, ca n n a bi n oi ds, 
c ocai ne, b ar bit urates, p h e nc ycli di ne), c oti ni ne, a n d alc o h ol 
 Cli nical la b orat or y tests ( uri nal ysis) 
 Calc ulati o n of e G F R ( usi n g t he C oc k cr oft- Ga ult e q uati o n) 
6. 2.  
S u bject M a n a ge me nt 
N ot a p plica ble. 

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6. 3.  
R a n d o miz ati o n 
O n Da y - 1 of Peri o d 1, f oll o wi n g t he re vi e w of t h e safet y la b orat or y assess me nts a n d 1 2-lea d 
E C G meas ure me nts, r a n d o mizati o n n u m bers will be assi g n e d t o s u bjects wit h o ut re gar d t o t he 
ra n d o mizati o n sc he d ule.  A s u bject is c o nsi dere d ra n d o mize d o nce he/s he recei ves t he first d ose. 
N o s u bject will be re pla ce d. 
M ore i nf or mati o n o n t he met h o d of assi g ni n g s u bj ects is f o u n d i n Secti o n 5. 1. 2 . 
6 . 4. 
Tre at me nt Peri o d 
6. 4. 1.  
D a y - 1 of Peri o d 1 C hec k-i n 
A s uf ficie nt n u m ber of alter nate s u bjects will be br o u g ht i nt o t he cli nic at C hec k-i n ( Da y - 1) of 
Peri o d 1.  A lter nate s u bjects will u n der g o all baseli ne assess me nts.  I n t he e ve nt t hat a s u bject 
sc he d ule d t o be ra n d o mize d ca n n ot be d ose d, a n alter nate s u bject will be assi g ne d t he s a me 
ra n d o mizati o n n u m ber a n d se q ue nce of treat me nts. 
T he f oll o wi n g pr oce d ures will be carrie d o ut at C hec k-i n: 
 A d mis si o n t o cli nic 
 In cl usi o n/e x cl usi o n criteria 
 A b bre viate d me di cal hist or y (a p plica bl e t o Peri o d 1 o nl y, si nce Scree ni n g) a n d 
c o nc o mita nt me dicati o n hist or y  
 C o m plete p h ysical e x a m 
 B o d y wei g ht 
 B l o o d sa m ples f or: 
 Cli nical la b orat or y tests ( he mat ol o g y a n d fasti n g s er u m c he mistr y); s u bjects will 
fast f or a p pr o xi matel y 1 0 h pri or t o C hec k-i n f or t he ser u m c h e mistr y tests 
 S er u m pre g na n c y test f or all fe males 
 Ur i ne sa m ples f or: 
 Dr u g scree n ( o piat es, be nz o diaze pi nes, a m p heta mi nes, ca n na bi n oi ds, c ocai n e, 
bar bit urates, p he n c ycli di ne), c oti ni ne, a n d alc o h ol 
 Cli nical la b orat or y uri nal ysis tests 
6. 4. 2.  
D a y 1  
T he f oll o wi n g pr oce d ures will be perf or me d o n Da y 1 of eac h peri o d: 
 A d mi ni strati o n of pe xi darti ni b acc or di n g t o t he ra n d o mizati o n sc he me at Ti me 0; f or 
Tre at me nt A, s u bjects will fast f or a p pr o xi matel y 1 0 h pri or t o d osi n g; f or 
Treat me nt B a n d Treat m e nt C, s u bjects will fast f or a p pr o xi matel y 1 0 h t h e n c o ns u me 
a sta n dar d l o w-fat meal starti n g 3 0 mi n bef ore d osi n g. 

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 Vital si g ns ( bl o o d press ure, heart rate, oral te m perat ure, a n d res pirat or y rat e) pri or t o 
d osi n g a n d at a p pr o xi matel y 2 h p ost d ose 
 1 2 -lea d E C Gs pri or t o d osi n g a n d at a p pr o xi matel y 2 h p ost d ose 
 B l o o d sa m ples f or: 
 P K a nal ysis 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, 
1 4, a n d 2 2 h p ost d ose 
 C o nti n u o us m o nit ori n g of A Es, starti n g fr o m d osi n g, a n d c o nc urre nt me dicati o n 
6. 4. 3.  
D a y 2  
T he f oll o wi n g pr oce d ures will be perf or me d o n Da y 2 of eac h peri o d: 
 Vital si g ns ( bl o o d press ure, heart rate, oral te m perat ure, a n d res pirat or y rat e) at 
a p pr o xi matel y 2 4 h p ost d ose 
 1 2 -lea d E C Gs at a p pr o xi matel y 2 4 h p ost d ose 
 B l o o d sa m ples f or P K a n al ysis at 2 4, 2 8, 3 2, a n d 3 6 h p ost d ose 
 C o nti n u o us m o nit ori n g of A Es a n d c o n c urre nt me dicati o n 
6. 4. 4.  
D a y 3 
T he f oll o wi n g pr oce d ures will be perf or me d o n Da y 3 of eac h peri o d: 
 Bl o o d sa m ples f or P K a n al ysis at 4 8, 5 4, a n d 6 0 h p ost d ose 
 C o nti n u o us m o nit ori n g of A Es a n d c o n c urre nt me dicati o n 
6. 4. 5.  
D a y 4  
T he f oll o wi n g pr oce d ures will be perf or me d o n Da y 4 of eac h peri o d: 
 Bl o o d sa m ples f or P K a n al ysis at 7 2 a n d 8 4 h p ost d ose 
 C o nti n u o us m o nit ori n g of A Es a n d c o n c urre nt me dicati o n 
6. 4. 6.  
D a y 5  
T he f oll o wi n g pr oce d ures will be perf or me d o n Da y 5 of eac h peri o d: 
 Bl o o d sa m ples f or P K a n al ysis at 9 6 a n d 1 0 8 h p ost d ose 
 C o nti n u o us m o nit ori n g of A Es a n d c o n c urre nt me dicati o n 
6. 4. 7.  
D a y 6 
T he f oll o wi n g pr oce d ures will be perf or me d o n Da y 6 of eac h peri o d: 
 Bl o o d sa m ples f or P K a n al ysis at 1 2 0 a n d 1 3 2 h p ost d os e 
 C o nti n u o us m o nit ori n g of A Es a n d c o n c urre nt me dicati o n 

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6. 4. 8.  
D a y 7 
T he f oll o wi n g pr oce d ures will be perf or me d o n Da y 7 of eac h peri o d: 
 Vital si g ns ( bl o o d press ure, heart rate, oral te m perat ure a n d res pirat or y rate) at 
a p pr o xi matel y 1 4 4 h p ost d ose 
 1 2 -lea d E C Gs at a p pr o xi matel y 1 4 4 h p ost d ose 
 B l o o d sa m ple f or P K a nal ysis at 1 4 4 h p ost d ose 
 C o nti n u o us m o nit ori n g of A Es a n d c o n c urre nt me dicati o n 
6. 5.  
W as h o ut 
T here will be a was h o ut of at least 6 d bet w ee n eac h d ose of pe xi darti ni b. 
6 . 6. 
C hec k- o ut or E arl y Ter mi n ati o n 
T he f oll o wi n g pr oce d ures will be perf or me d at c hec k- o ut of Peri o d 3 ( Da y 7) or u p o n Earl y 
Ter mi nati o n: 
 C o m plete p h ysical e x a m 
 B o d y wei g ht 
 Vital si g ns ( bl o o d press ure, heart rate, oral te m perat ure, a n d res pirat or y rat e), if n ot 
alrea d y ta k e n 
 1 2 -lea d E C Gs, if n ot alr ea d y t a ke n 
 B l o o d sa m ples f or: 
 Cli nical la b orat or y tests ( he mat ol o g y a n d fasti n g s er u m c he mistr y); s u bjects will 
fast f or a p pr o xi matel y 1 0 h pri or t o c hec k- o ut f or t he ser u m c he mistr y tests 
 Ser u m pre g na n c y test f or all fe males 
 Ur i ne sa m ples f or cli nical la b orat or y uri nal ysis tests 
 C o nti n u o us m o nit ori n g of A Es a n d c o n c urre nt me dicati o n 
6. 7.  
F oll o w- u p  
If a s u bject is wit h dra w n fr o m t he st u d y d u e t o a n A E, t he s u bject will be as ke d t o c o m plete, at a 
mi ni m u m, assess me nts of t he earl y wit h dra wal visit. If t he A E has still n ot res ol ve d, a d diti o nal 
f oll o w- u p will be c o n d ucte d, as a p pr o priate, bas e d o n t he i n vesti gat or’s j u d g me nt, a n d 
d oc u me nte d i n t he s u bject’s me dical rec or ds. At a mi ni m u m, seri o us a d verse e ve nts ( S A Es) 
s h o ul d be f oll o we d f or 3 0 d after t he s u bject’s last d ose of st u d y dr u g. 

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7.  
P H A R M A C O KI N E TI C A S S E S S M E N T S 
7. 1.  
P h ar m ac o ki netic Assess me nt(s) 
P har mac o ki netic a n al ysis will be c o n d ucte d i n c o m plia nce wit h D SI’s n o n c o m part me ntal 
a nal ysis g ui deli nes. 
T he plas ma c o n ce ntrati o n-ti me data will be a nal yze d usi n g act ual d osi n g a n d sa m pli n g ti me 
p oi nts usi n g n o nc o m part me ntal met h o ds.  T he P K para meters liste d i n Ta ble 7. 1  will be 
calc ulate d f or pe xi darti ni b fr o m t he i n di vi d ual plas ma c o nce ntr ati o ns usi n g a n o nc o m part me ntal 
a p pr oac h.  P h ar mac o ki n etic varia bles will be c o m p ute d usi n g Wi n N o nli n Pr ofessi o nal or ot her 
a p pr o priate s oft ware. 
T a ble 7. 1:  
Pl as m a P h ar m ac o ki netic V ari a bles 
P ar a meter  
U nits  
Descri pti o n  
C ma x  
n g/ m L  
Ma xi m u m o bser ve d plas ma dr u g c o nce ntrati o n  
T ma x  
h  
Ti me of ma xi m u m o bser ve d c o nce ntrati o n  
A U Clast  
n g h/ m L  
Area u n der t he plas ma c o nce ntrati o n -ti me c ur ve, fr o m ti me 0 t o t he 
last meas ura ble c o nce ntrati o n ( Clast), as calc ulate d b y t he l o g-li near 
tra pez oi dal met h o d 
A U Ci nf  
n g h/ m L  
A U C fr o m t he ti me of d osi n g e xtra p olate d t o i nfi nit y, calc ulate d as: 
A U Ci nf = A U Cla st + Clast/λ Z , w here λ Z  is t he a p pare nt ter mi nal 
eli mi nati o n rate c o nsta nt calc ulate d b y li near re gressi o n of t he 
ter mi nal li near p orti o n of t he l o g c o nce ntrati o n vers us ti me c ur ve 
A U Ce xtr %  
%  
Perce nta ge of A U C i nf t hat is e xtra p olate d fr o m tlast t o i nfi nit y, 
calc ulate d as: 1 0 0 ×[ 1 -( A U Clast/ A U Ci nf)], w here tlast is t he ti me of 
t he last meas ura ble plas ma dr u g c o nce ntrati o n 
t 1/ 2 
h  
T er mi nal eli mi nati o n half -life, calc ulate d as: l n( 2)/ λZ  
C L/ F  
L/ h  
A p pare nt t otal b o d y cleara nce, calc ulate d as: D ose/ A U C  
V z/F  
L  
A p pare nt v ol u me of distri b uti o n, calc ulate d as:  
D ose/ A U Ci nf × λ Z  
A m ore detaile d d escri pti o n of t he p har mac o ki neti c assess me nts will be pr o vi de d se paratel y i n 
t he S A P. 
7. 2.  
P h ar m ac o d y n a mic ( P D) Assess me nt (s) 
N ot a p plica ble. 
7. 3.  
I m m u n o ge nicit y 
N ot a p plica ble. 

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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.  
Assess me nt of S afet y E n d p oi nt E ve nt(s) 
T he safet y e n d p oi nts i ncl u de A Es, p h ysical e xa mi nati o n, vital si g ns, 1 2-lea d E C Gs, a n d cli nical 
la b orat or y tests (sta n d ar d he mat ol o g y, ser u m c he mistr y i ncl u di n g A S T/ A L T, c oa g ulati o n, a n d 
uri nal ysis). 
8. 2.  
A d verse E ve nt C ollecti o n a n d Re p orti n g 
All cli nical A Es (see Secti o n 8. 4. 1  f or defi niti o ns) occ urri n g after t h e s u bject si g ns t he I C F a n d 
u p t o 3 0 d afte r t he last d ose of st u d y dr u g (ie, Peri o d 3 d osi n g), w het h er o bser ve d b y t he 
i n vestigat or or re p ort e d b y t he s u bj ect, will be rec or de d o n t he A d v erse E v e nt C R F pa ge.  
Me dical c o n diti o ns (i ncl u di n g cli nical la b orat or y val ues/ vital si g ns t hat are o ut of ra n ge) t h at 
were dia g n os e d or k n o w n t o e xist pri or t o I nf or m e d C o nse nt will be rec or de d as part of m e dical 
hist or y.   
All A Es, seri o us a d vers e e ve nts ( S A Es), are t o be re p orte d acc or di n g t o t he pr oce d ures i n 
Sec ti o n 8. 5 .   
All cli nical la b orat or y res ults, vital si g ns, a n d E C G res ults or fi n di n gs s h o ul d be a p praise d b y t h e 
i n vestigat or t o det er mi ne t heir cli nical si g nifi ca nce.  Is olate d a b n or mal cli nical la b orat or y res ults, 
vita l si g n fi n di n gs, or E C G fi n di n gs (i e, n ot part of a re p ort e d dia g n osis) s h o ul d be re p orte d as 
A Es if t he y are s y m pt o m atic, lea d t o st u d y dr u g disc o nti n uati o n, d ose re d ucti o n, re q uire 
c orre cti ve treat me nt, or c o nstit ute a n A E i n t he i n vesti gat or’s cli nical j u d g me nt. 
At e ach ti me p oi nt, t he i n vesti gat or will deter mi ne w het her a n y A Es ha v e o cc urre d b y e v al uati n g 
t he s u bject.  A d vers e e ve nts ma y be dir ectl y o bser ve d, re p ort e d s p o nta ne o usl y b y t he s u bject or 
b y q uesti o ni n g t he s u bject at eac h ti me p oi nt.  S u bjects s h o ul d be q uesti o ne d i n a ge neral wa y, 
wit h o ut as ki n g  a b o ut t he occ urre nce of a n y s p ecifi c s y m pt o ms.  T he i n vesti gat or m ust ass ess all 
A Es t o deter mi ne seri o us ness, se verit y, a n d ca usalit y, i n acc or da n ce wit h t h e defi niti o ns i n 
Secti o n 8. 4 .  T he i n vesti gat or’s assess me nt m ust b e clearl y d o c u me nte d i n t he st u d y site’s s o urce 
d oc u me ntati o n wit h t he i n vesti gat or’s si g n at ure.   
Al wa ys re p ort t he dia g n osis as t he A E or S A E ter m.  W he n a dia g n osis is u na vaila ble, re p ort t he 
pri mar y si g n or s y m pt o m as t he A E or S A E ter m wit h a d diti o nal details i ncl u de d i n t he narrati ve 
u ntil t he dia g n osis bec o mes a vaila ble.  If t he si g ns a n d s y m pt o ms are disti nct a n d d o n ot s u g gest 
a c o m m o n dia g n osis, re p ort t he m as i n di vi d ual e ntries of A E or S A E.   
F or e v e nts t hat are s eri o us d ue t o h os pitalizati o n, t he reas o n f or h os pitalizati o n m ust be re p orte d 
as t he S A E ( dia g n osis or s y m pt o m re q uiri n g h os pitali zati o n).  A pr oce d ure is n ot a n A E or S A E, 
b ut t he r eas o n f or t he pr oce d ure m a y be a n A E or S A E.  Pre- pla n ne d ( pri or t o si g ni n g t he I C F ) 
pr oce d ures or treat me nts re q uiri n g h os pitalizati o n f or pre-e xisti n g c o n diti o ns t hat d o n ot w orse n 
i n se verity s h o ul d n ot be re p orte d as S A Es (see Secti o n 8. 4. 2  f or Defi niti o ns).   
F or deat hs, t he u n derl yi n g or i m me diate ca us e of deat h s h o ul d al wa ys be re p orte d as a n S A E. 
A n y s eri o us, u nt o war d e ve nt t hat ma y o cc ur s u bs e q ue nt t o t he re p orti n g p eri o d t hat t he 
i n vestigat or assesses as relate d t o st u d y dr u g s h o ul d als o be re p orte d a n d m a na ge d as a n S A E. 

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T he i n vesti gat or s h o ul d f oll o w s u bjects wit h A E s u ntil t he e ve nt has res ol v e d or t he c o n diti o n 
has sta biliz e d.  I n case of u nres ol ve d A E s, i ncl u di n g si g nifica nt a b n or mal cli nical la b orat or y 
val ues at t he e n d of st u d y assess me nt, t hese e v e nts will be f oll o we d u ntil res ol uti o n or u ntil t he y 
bec o me cli nicall y n ot r ele va nt. 
8. 3.  
A d verse E ve nts of S peci al I nterest 
C o m bi ne d ele vati o ns of a mi n otra nsferases a n d bilir u bi n, eit her seri o us or n o nseri o us a n d 
w het her or n ot ca usall y relate d, meeti n g t he criteri a of a p ote ntial H y’s La w case (t otal bilir u bi n 
le vel ≥2 × U L N wit h si m ulta ne o usl y A L T or A S T ≥3 × U L N) s h o ul d al w a ys be re p orte d t o t he 
S p o ns or as s o o n as p ossi ble f oll o wi n g t he pr oce d ures o utli ne d i n Secti o n 8. 5  f or S A E re p orti n g, 
wit h t he i n vesti gat or’s assess me nt of seri o us ness, ca usalit y, a n d a d etaile d narrati ve. 
Base d o n p o ol e d data fr o m 4 2 4 s u bjects w h o recei ve d pe xi darti ni b, ele vati o ns of li ver 
tra nsa mi nases ( u p t o Gra de 3) a n d bilir u bi n ha ve bee n o bser ve d i n st u dies wit h pe xi darti ni b, 
t o get her wit h cas es of dr u g-i n d uc e d c h olest asis. All t hese e ve nts oc c urre d i n s u bjects treate d 
wit h pe xi darti ni b i n a c o nti n u o us, m ulti ple d ose re gi me n.  Cas es of c h ol estasis ha ve bee n 
o bser ve d i n t he first 8 w k, ha ve ge n erall y res ol ve d wit h treat me nt disc o nti n uati o n, b ut i n rare 
cases ha ve bee n se vere, re q uiri n g li ver dial ysis a n d ha d a pr otracte d c o urse ( 8 m o). 
8. 4.  
A d verse E ve nt 
8. 4. 1.  
De fi niti o n of A d verse E ve nt 
A n A E  is a n y u nt o war d me dical occ urre n ce i n a s u bject a d mi nistere d a p h ar mace utical pr o d uct 
an d t hat d oes n ot necessaril y ha v e t o ha ve a ca us al relati o ns hi p wit h t his treat me nt.  A n A E ca n 
t heref or e be a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal cli nical la b orat or y 
fi n di n g, f or e x a m ple), s y m pt o m, or disease t e m p orall y ass ociate d wit h t he use of a me dici n al 
pr o d uct, w het her or n ot c o nsi dere d rel ate d t o t he me dici nal pr o d uct (I C H E 2 A G ui deli ne.  
Cli nical Safet y D ata Ma n a ge me nt: Defi niti o ns a n d Sta n dar ds f or E x pe dite d Re p orti n g, 
Oct 1 9 9 4). 
It is t he res p o nsi bilit y of i n vesti gat ors, bas e d o n t h eir k n o wle d ge a n d e x peri e nce, t o det er mi ne 
t h ose circ u msta nces or a b n or mal cli nical la b orat or y fi n di n gs w hi c h s h o ul d be c o nsi dere d A E s. 
8. 4. 2.  
S eri o us A d verse E ve nt 
A S A E is a n y u nt o w ar d me dical occ urre n ce t hat at a n y d ose: 
 Res ults i n deat h, 
 Is life-t hreate ni n g, 
 Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n, 
 Res ults i n persiste nt or si g nifica nt disa bilit y/i n ca p acit y, 
 Is a c o n ge nital a n o mal y/ birt h defect, or 
 Is a n i m p orta nt me dical e ve nt. 

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N ote: T he ter m “lif e-t hreate ni n g” i n t he defi niti o n of “seri o us” refers t o a n e ve nt i n w hic h t he 
s u bject was at ris k of d eat h at t he ti me of t he e ve nt; it d oes n ot refer t o a n e ve nt w hic h 
h y p ot hetic all y mi g ht ha v e ca use d d eat h if it were m ore se vere (I C H E 2 A G ui deli ne.  Cli nical 
Safet y Data M a na ge m e nt: Defi niti o ns a n d Sta n dar ds f or E x pe dite d Re p orti n g, Oct 1 9 9 4). 
Me dical a n d sci e ntific j u d g me nt s h o ul d be e x ercise d i n deci di n g w het her e x pe dite d re p orti n g is 
a p pr o priate i n ot her sit uati o ns, s uc h as i m p orta nt me dical e ve nts t hat ma y n ot be i m me diatel y 
life-t hreat e ni n g or res ult i n deat h or h os pitalizati o n b ut ma y je o par dize t he s u bject or ma y re q uire 
i nter ve nti o n t o pre ve nt o ne of t he ot her o ut c o mes liste d i n t he defi niti o n a b o ve.  E x a m ples 
i ncl u de aller gic br o nc h os pas m, c o n v ulsi o ns, a n d bl o o d d yscrasias or d e vel o p me nt of dr u g 
de pe n de n c y or dr u g a b us e. 
N ote:  
 P r oce d ures are n ot A Es or S A Es, b ut t he reas o n f or t he pr oce d ure ma y b e a n A E or 
S A E.   
 P re- pla n ne d ( pri or t o si g ni n g t he I C F) pr o ce d ures or treat me nts re q uiri n g 
h os pitaliz a ti o ns f or pre-e xisti n g c o n diti o ns t hat d o n ot w orse n i n se verit y are n ot 
S A Es. 
8. 4. 3.  
S e verit y Assess me nt 
T he f oll o wi n g d efi niti o ns s h o ul d be use d t o assess i nte nsit y of A Es ( base d o n t he Nati o nal 
Ca ncer I nstit ute ( N CI) C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts [ C T C A E], versi o n 
5. 0): 
 Gr a de 1: Mil d; as y m pt o matic or mil d s y m pt o ms; cli nical or dia g n ostic o bs er vati o ns 
o nl y; i nter ve nti o n n ot i n dicate d 
 Gra de 2: M o derate; mi ni mal, l ocal, or n o ni n vasi v e i nter ve nti o n i n dicate d; li miti n g 
a ge-a p pr o priate i nstr u me ntal acti vities of dail y li vi n g (e g, pre p ari n g f or meals, 
s h o p pi n g f or gr oceries or cl ot hes, usi n g t he tel e p h o ne, ma na gi n g m o ne y) 
 Gra de 3: Se vere or me dic all y si g nifica nt, b ut n ot i m me diatel y life-t hr eate ni n g; 
h os pitaliz ati o n or pr ol o n gati o n of h os pitalizati o n i n dicate d; disa bli n g; li miti n g 
 self-care acti vities of dail y li vi n g (ie, bat hi n g, dressi n g a n d u n dressi n g, fee di n g self, 
usi n g t he t oilet, ta ki n g m e dicati o ns, a n d n ot be dri d de n) 
 Gr a de 4: Lif e-t hreate ni n g c o nse q ue nces; ur ge nt i nt er ve nti o n i ndicate d 
 Gr a de 5: D eat h r elate d t o A E 
8. 4. 4.  
C a us alit y Assess me nt 
T he i n vesti gat or s h o ul d assess ca usal relati o ns hi p bet wee n a n A E  a n d t he st u d y dr u g o n t h e basis 
of  his/ her cli nical j u d g me nt a n d t he f oll o wi n g defi niti o ns.  T he ca usalit y assess me nt m ust be 
ma de  based o n t he a vaila ble i nf or mati o n a n d ca n be u p date d as n e w i nf or mati o n bec o mes 
a vaila ble. 

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 Relate d: 
 T he A E f oll o ws a reas o n a ble te m p oral se q u e nce fr o m st u d y dr u g a d mi nistrati o n 
a n d ca n n ot be reas o n a bl y e x plai ne d b y t he s u bject’s cli nical state or ot her fact ors 
(e g, disease u n der st u d y, c o nc urre nt diseases, a n d c o nc o mita nt me dicati o ns). 
or 
 T he A E f oll o ws a reas o n a ble te m p oral se q u e nce fr o m st u d y dr u g a d mi nistrati o n 
a n d is a k n o w n reacti o n t o t he dr u g u n der st u d y or its c he mical gr o u p or is 
pre dicte d b y k n o w n p h ar mac ol o g y. 
 U nr elate d: 
 T he A E d oes n ot f oll o w a reas o n a ble se q u e nce fr o m st u d y dr u g a d mi nistrati o n or 
ca n be reas o n a bl y e x plai ne d b y t h e s u bject’s cli ni cal state or ot her fact ors (e g, 
disease u n der st u d y, c o nc urre nt diseas es, a n d c o n c o mita nt me dicati o ns).  
8. 4. 5.  
Ac ti o n T a ke n Re g ar di n g St u d y Dr u g(s) 
 D ose  N ot C ha n ge d: N o c ha n ge i n st u d y dr u g d osa ge was ma de. 
 Dr u g Wit h dra w n: T he st u d y dr u g was per ma ne ntl y st o p pe d. 
 N ot A p plica ble: S u bject die d, st u d y treat me nt ha d bee n c o m plete d pri or t o 
reacti o n/e v e nt, or reacti o n/e ve nt occ urre d pri or t o start of treat me nt. 
8. 4. 6.  
Ot her  Acti o n T a ke n f or E ve nt 
 N o ne  
 N o treat me nt was re q uir e d 
 Me dicati o n re q uir e d 
 Prescri pti o n a n d/ or O T C me dicati o n was re q uire d t o treat t he A E  
 Ot he r 
8. 4. 7.  
A d ver se E ve nt O utc o me 
 R ec o vere d/ Res ol ve d 
 T he s u bject f ull y rec o vere d fr o m t he A E  wit h n o resi d ual effect o bser v e d. 
 R ec o veri n g/ Res ol vi n g 
 T he A E  i m pr o ve d b ut has n ot f ull y res ol ve d. 
 N ot Rec o vere d/ N ot Res ol ve d 
 T he A E  itself is still prese nt a n d o bser va ble. 
 Rec o vere d/ Res ol ve d wit h Se q uelae 
 T he resi d ual effects of t h e A E  are still prese nt a n d o bser va ble. 

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 I n cl u de se q u elae/r esi d ual effects. 
 F atal 
 Fatal s h o ul d be use d w he n deat h is a direct o utc o me of t he A E . 
 U n k n o w n  
8. 5.  
Seri o us A d verse E ve nts Re p orti n g – Pr oce d ure f or I n vesti g at ors 
All A Es, S A Es will be re p orte d i n t he C R F. 
T he f oll o wi n g t y p es of e ve nts s h o ul d be re p orte d b y t he i n vesti gat or o n a S A V E R ( Seri o us 
A d verse E v e nt Re p ort) f or m wit hi n 2 4 h of a ware ness: 
 S A Es (see Secti o n 8. 4. 2  f or defi niti o n) 
All A Es, A E S I, a n d S A Es will be re p orte d i n t he e C R F. 
S A Es a n d A E SIs ( Secti o n 8. 3 ) s h o ul d be re p ort e d b y t he i n vesti gat or o n a Seri o us A d verse E v e nt 
Re p ort ( S A V E R) f or m wit hi n 2 4 h of a ware n ess (see Secti o n 8. 4. 2  f or t he defi niti o n of a n S A E). 
All e ve nts (seri o us a n d n o n-seri o us) m ust be re p orte d wit h i n vesti gat or’s assess me nt of t he 
e ve nt’s seri o us n ess, se verit y, a n d ca usalit y t o t he st u d y dr u g.  A detaile d narrati ve s u m marizi n g 
t he c o urse of t h e e ve nt, i ncl u di n g its e val uati o n, treat me nt, a n d o utc o me s h o ul d be pr o vi de d.  
S pec ific or esti mate d d ates of e ve nt o ns et, treat me nt, a n d res ol uti o n s h o ul d be i ncl u de d w he n 
a vaila ble.  Me dic al hist or y, c o n c o mita nt me dicati o ns, a n d cli nical la b orat or y dat a t hat are 
rele va nt t o t he e v e nt s h o ul d als o be s u m marize d i n t he narrati ve.  F or fatal e ve nts, t he narrati ve 
s h o ul d state w het her a n a ut o ps y was or will be perf or me d a n d i ncl u d e t he res ults if a vaila ble.  
S o urce d oc u me nts (i ncl u di n g me dical re p orts) will be retai ne d at t he site a n d s h o ul d n ot be 
s u b mitte d t o t he S p o nsor f or S A E re p orti n g p ur p os es. 
Ur ge nt safet y q ueries m ust be f oll o we d u p a n d a d dresse d pr o m ptl y.  F oll o w- u p i nf or mati o n a n d 
res p o nse t o n o n- ur ge nt safet y q ueries s h o ul d be c o m bi ne d f or re p orti n g t o pr o vi de t he m ost 
c o m plete data p ossi ble wit hi n eac h f oll o w- u p.  
All c o m plete d S A V E R f or ms m ust be si g ne d b y t he i n vesti gat or a n d e- maile d t o 
C S P V- Cli nical @ dsi.c o m.  See Secti o n  1 4. 1 0. 5 f or c o ntact i nf or mati o n f or S A E re p orti n g.  
P lease call t he l ocal S A E H otli ne or y o ur st u d y m o nit or f or a n y q uesti o ns o n S A E re p orti n g.   
8. 6.  
N otif yi n g Re g ul at or y A ut h orities, I n vesti g at ors, a n d I nstit uti o n al 
Re vie w B o ar d / Et hics C o m mittee 
D SI  a n d/ or W orl d wi de Cli nical Trials Earl y P hase Ser vices, L L C will i nf or m i n vesti gat ors, 
I nstit uti o nal Re vie w B oar ds/ Et hics C o m mittees (I R Bs/ E Cs), a n d re g ulat or y a ut h orities of a n y 
S us pecte d U ne x pecte d S eri o us A d vers e Reacti o ns ( S U S A Rs) occ urri n g i n ot her st u dies of t he 
i n vesti gati o nal dr u g, as a p pr o priate per l ocal r e p orti n g re q uir e me nts.  DSI  a n d/ or C R O will 
co m pl y wit h a n y a d diti o nal l ocal safet y re p orti n g re q uire me nts. 
I n t he U S, u p o n recei pt of t he S p o ns or’s n otificati o n of S U S A Rs t hat occ urre d wit h t he st u d y 
dr u g, u nl ess dele gate d t o t he S p o ns or, it is t he i n vesti gat or’s res p o nsi bilit y t o i nf or m t he I R B per 
S p o ns or’s i nstr ucti o n. 

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8. 7.  
E x p os ure i n Uter o D uri n g Cli nic al St u dies 
D SI  m ust be n otifie d of a n y s u bject w h o bec o mes pre g na nt w hile recei vi n g or wit hi n 9 0 d of 
disc o nti n ui n g  t he st u d y dr u g.   
D SI  m ust be n otifie d of a n y male s u bject w h ose fe male part ner bec o mes pre g n a nt w hile t he 
s u bject is recei vi n g or wit hi n 9 0 d of disc o nti n ui n g t he st u d y dr u g.  Re p orti n g after E arl y 
Te r mi nati o n is d o ne v ol u ntaril y b y t he i n vesti gat or. 
Alt h o u g h pre g na nc y is n ot tec h nicall y a n A E , all pre g na nci es m ust be f oll o we d t o c o ncl usi o n t o 
deter mi ne t heir o utc o me.  T his i nf or mati o n is i m p orta nt f or b ot h dr u g safet y a n d p u blic h ealt h 
c o ncer ns.  It is t he res p o nsi bilit y of t he i n v esti gat or, or desi g nee, t o re p ort a n y pre g na nc y i n a 
fe male s u bject usi n g t he E x p os ure I n Uter o ( EI U) Re p orti n g f or m.  Please c o ntact y o ur st u d y 
m o nit or t o recei ve t he EI U Re p orti n g f or m u p o n lear ni n g of a pre g n a nc y.  T he i n vesti gat or 
s h o ul d ma ke e ver y eff ort t o f oll o w t he s u bject u ntil c o m pleti o n of t he pre g na nc y a n d c o m plete 
t he EI U Re p orti n g f or m wit h c o m plete pre g na n c y o utc o me i nf or mati o n, i ncl u di n g n or mal 
deli ver y a n d i n d uc e d a b orti o n.  T he a d verse pre g n a nc y o utc o me, eit her seri o us or n o n-seri o us, 
s h o ul d be re p orte d i n a cc or da nce wit h st u d y pr oce d ures.  If t he o ut c o me of t he pre g na n c y meets 
t he criteria f or i m me diate classificati o n as a S A E (ie, p ost- part u m c o m plicati o ns, s p o nta ne o us or 
i n d uce d a b orti o n, still birt h, ne o natal deat h, or c o n ge nital a n o mal y, i ncl u di n g t hat i n a n a b orte d 
fet us), t he i n vesti gat or s h o ul d f oll o w t he pr oce d ures f or re p orti n g S A Es o utli ne d i n Secti o n 8. 5 .  
F or re p orts of pre g na nc y i n t he fe male part ner of a male s u bject, t he EI U f or m ( or S A E f or m if 
ass ociate d wit h a n a d vers e o utc o me) s h o ul d be c o m plete d wit h t he s u bje ct’s ra n d o mizati o n 
n u m ber, i nitials, a n d date of birt h, a n d details re gar di n g t he fe male p art ner s h o ul d be e ntere d i n 
t he narrati ve secti o n. 
8. 8.  
Cli nic al L a b or at or y E v al u ati o ns 
Cli nical la b orat or y tests ( he mat ol o g y, ser u m c he mistr y, a n d uri nal ysis) will be perf or me d at 
Scre e ni n g, C hec k-i n of Peri o d 1 a n d at C hec k- o ut of Peri o d 3 or Earl y T er mi nati o n. 
T he ser u m c h e mistr y pr ofiles m ust be o btai ne d u n der fasti n g c o n diti o ns (a p pr o xi matel y 1 0 h).  
Res ults of all la b orat or y t ests will be i ncl u de d i n t he s u bject’s e C R F. 
T he f oll o wi n g cli nical la b orat or y para meters will be e val uat e d: 
 S er u m c he mistr y (a p pr o xi matel y 8. 5 m L): s o di u m, p otassi u m, ma g nesi u m, 
bicar b o nate, c hl ori de, cal ci u m, i n or ga ni c p h os p h or us, A S T, A L T, al kali ne 
p h os p hatase, t otal bilir u bi n, gl uc ose, creati ni ne, bl o o d urea nitr o ge n, t otal pr otei n, 
al b u mi n, uric aci d, creati ne ki nase, t otal c h olester ol, a n d tri gl yceri des. 
 He mat ol o g y (a p pr o xi matel y 4 m L): h e m o gl o bi n, he mat ocrit, re d bl o o d cell ( R B C) 
c o u nt ( wit h i n dices), retic ul oc yt e c o u nt, w hite bl o o d cell ( W B C) c o u nt ( wit h 
differe ntial), a n d platelet c o u nt. 
 Ur i nal ysis: sta n dar d uri n al ysis, i ncl u di n g a micr osc o pic e x a mi nati o n a n d s pecific 
gra vit y, p H, pr otei n, gl uc ose, ket o nes, bl o o d, R B C, W B C, bilir u bi n, a n d ur o bili n o ge n. 
Calc ulati o n of e G F R ( usi n g t he C oc k cr oft- Ga ult e q uati o n) will be perf or me d at S cree ni n g. 

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Tests 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 be perf or me d at S cree ni n g 
o nl y.   
C oa g ulati o n tests ( P T/I N R a n d a P T T) will be perf or me d at S cree ni n g o nl y.  A p pr o xi matel y 
2. 7  m L of bl o o d will be wit h dra w n f or t h ese tests. 
8. 9.  
Vit al Si g ns 
Resti n g vital si g ns will b e ta ke n after at least 1 0 mi n i n a s u pi ne p ositi o n. 
Resti n g vital si g ns ( bl o o d press ure, h eart rate, oral te m perat ure, a n d res pir at or y rate) will be 
perf or me d at Scree ni n g, pre d ose a n d at 2, 2 4, a n d 1 4 4 h p ost d ose i n eac h st u d y peri o d, or Earl y 
Ter mi nati o n. 
W he n vit al si g ns meas ur e me nts a n d a bl o o d dr a w are sc he d ule d f or t he sa me ti me p oi nt, t he vital 
si g ns s h o ul d be ta ke n wit hi n a p pr o xi matel y 5 mi n pri or t o t he bl o o d dra w.  Pre d ose vital si g ns 
meas ure me nts wil l be ta k e n wit hi n 2 h pri or t o t he d ose. 
B o d y wei g ht a n d h ei g ht will be rec or d e d at S cree ni n g.  B o d y wei g ht will als o be rec or d e d at 
C hec k-i n t o Peri o d 1 a n d at C hec k- o ut of Peri o d 3 or Earl y Ter mi nati o n.  B MI will be calc ulat e d 
at Scree ni n g. 
I nf or mati o n will be e ntere d i n t he C R F  o n w het her or n ot meas ure d, date of meas ure m e nt, a n d 
mea s ure me nt res ults f or t he f oll o wi n g ite ms: s yst olic bl o o d press ure, diast olic bl o o d press ure, 
p ulse, res pirat or y rate, b o d y te m perat ur e, hei g ht, b o d y wei g ht, a n d B MI. 
8. 1 0 . 
Electr oc ar di o gr a ms 
E C Gs will be rea d o n site as part of t h e safet y ass ess me nts. 
1 2-lea d E C Gs will be perf or me d at S cree ni n g, pre d ose, a n d at 2, 2 4 a n d 1 4 4 h p ost d ose, or Earl y 
Te r mi nati o n. 
S u bjects s h o ul d be l yi n g q uietl y i n a f ull y s u pi ne p ositi o n f or at least 1 0 mi n pri or t o eac h 
1 2 lea d E C G rec or di n g.   
W he n a  bl o o d dra w is sc he d ule d c o nc o mita ntl y wit h a n E C G, t he E C G s h o ul d be ta ke n wit hi n 
1 0 mi n pri or t o t he bl o o d dra w.  Pre d os e E C Gs will be ta ke n wit hi n 2 h pri or t o t he d ose. 
8. 1 1.  
P h ysic al E x a mi n ati o ns 
A c o m plete p h ysical e x a mi nati o n will be perf or m e d at S cree ni n g.  A c o m plete p h ysic al 
e x a mi nati o n will be perf or me d at C hec k-i n t o Peri o d 1 a n d at c hec k- o ut of Peri o d 3 or Earl y 
Ter mi na ti o n.  A me dicall y q ualifie d p ers o n will perf or m t he p h ysical e x a m.  T he p h ysi cal 
e x a mi nati o n will i ncl u de t he e x a mi nati o n of t he f oll o wi n g b o d y s yst e ms: res pirat or y, 
car di o vas c ular, gastr oi nt esti nal, der mat ol o gical, m usc ul os keletal, ps yc hiatric, ne ur ol o gic, a n d 
hea d, e yes, ears, n ose, a n d t hr oat. 

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8. 1 2.  
Dr u g a n d Alc o h ol Scree n 
A uri ne scree n f or alc o h ol, c oti ni ne, a n d dr u gs of a b use will be perf or me d f or all s u bjects at 
Scree ni n g a n d at C hec k- i n.  Alc o h ol, c oti ni ne, a m p heta mi nes, bar bit urat es, be nz o diaze pi nes, 
c ocai ne, o pi ates, p he nc ycli di ne a n d ca n na bi n oi ds will be i ncl u de d i n t he assa y.  
8. 1 3.  
Pre g n a nc y Test 
F or all fe male s u bjects, s er u m pre g n a nc y tests will be perf or m e d at S cree ni n g, C hec k-i n t o 
Peri o d 1 a n d C hec k- o ut of Peri o d 3 or Earl y T er mi nati o n.  D osi n g o n Da y 1 of Peri o d 1 will be 
c o ntin ge nt u p o n a ne gati ve res ult. 
8. 1 4.  
Ser u m F S H 
At Scree ni n g, s h o ul d a fe male s u bject re p ort p ost me n o pa usal stat us n ot i n d uce d b y s ur gical 
steriliz ati o n, a ser u m F S H meas ure m e nt will be o btai ne d. 
8. 1 5 . 
Ot her E x a mi n ati o ns 
N ot a p plica ble. 

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9.  
O T H E R A S S E S S M E N T S 
N ot a p plica ble 

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1 0.  
S T A TI S TI C A L M E T H O D S  
1 0. 1.  
Ge ner al St atistic al C o nsi der ati o ns 
All P K a n d safet y data o btai ne d i n t his st u d y will be dis pla ye d i n data listi n gs a n d s u m marize d 
usi n g descri pti ve statistics. 
Cate g orical data will be prese nte d i n c o nti n ge n c y ta bles wit h cell fre q u e ncies a n d perce nta ges 
f or t he s u bject p o p ulati o n. 
E xtra meas ure me nts (s uc h as u nsc he d ule d or re p eat safet y ass ess me nts) will n ot be i ncl u de d i n 
t he descri pti ve statistics, b ut will be i ncl u de d i n s u bject listi n gs. 
1 0. 2.  
A n al ysis Sets 
1 0. 2. 1.  
P h ar m a c o ki netic A n al ysis Set 
T he P K a nal ysis set i ncl u des all s u bjects w h o recei ve at least 1 d ose of pe xi darti ni b a n d ha ve 
s ufficie nt sa m ples t o a de q uatel y assess t he P K para meters.  T he i m pact of cli nicall y si g nifica nt 
e ve nts t hat ma y affect t h e esti mati o n of P K para m eters will be assess e d w hile a nal yzi n g data a n d 
ha n dle d a p pr o priatel y.  A n y e x cl usi o n will be clearl y deli neate d i n t he re p ort.  I n di vi d ual plas ma 
c o nce ntr ati o ns f or all s u bjects will b e re p orte d. 
1 0. 2. 2.  
S afet y A n al ysis Set 
T he safet y a nal ysis set i ncl u des all s u bjects w h o recei ve at least 1 d ose of pe xi darti ni b. 
1 0. 3.  
St u d y P o p ul ati o n D at a 
T he safet y a nal ysis set will be s u m marize d f or de m o gra p hi c c haracteristics.  C o nti n u o us 
de m o gra p hic varia bles ( a ge [cal c ulate d fr o m date of birt h t o t he date of w he n t he I C F was 
si g ne d], wei g ht, hei g ht, a n d B MI) f or all s u bjects will be s u m marize d wit h descri pti ve statistics.  
Cate g orical de m o gra p hic varia bles (s e x, race, a n d et h nicit y) will be s u m marize d wit h fre q ue nc y 
c o u nts a n d c orres p o n di n g perce nt a ges. 
Me dical hist or y d ata will als o be s u m marize d. 
1 0. 4.  
St atistic al A n al ysis 
1 0. 4. 1.  
P h ar m a c o ki netic A n al yses 
All P K a nal ys es will be base d o n t he P K a n al ysis s et. 
I n di vi d ual plas ma c o nce ntrati o n-ti me data will be prese nte d gra p hicall y b y treat me nt a n d act ual 
ti me p oi nts usi n g li near a n d se mil o g scal es.  Mea n ( S D) plas ma c o n ce ntrati o n-ti me data will be 
prese nte d gra p hicall y f or pe xi darti ni b b y n o mi nal ti me p oi nts usi n g li near a n d se mi-l o g scales. 
If a s u bject v o mits wit hi n a peri o d of ti me e q u al t o t w o ti mes t he me dia n T ma x of pe xi darti ni b, 
statistical a nal ysis will be perf or me d wit h a n d wit h o ut data fr o m t he peri o d s u bject v o mite d i n. 

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L o g-tr a nsf or m e d C ma x, A U Clast, a n d A U Ci nf of pe xi darti ni b will be a nal yz e d usi n g a mi x e d 
effe ct a nal ysis of varia nce ( A N O V A) m o del wit h treat me nt, peri o d, a n d se q ue nce as fi x e d 
effects a n d s u bject n este d wit hi n se q ue nce as a ra n d o m effect.  T he p oi nt esti mates of rati os of 
ce ntral val u es f or Treat m e nts B vers us A, will be calc ulate d b y e x p o ne ntiati o n of t he differe nces 
i n t he least s q uares me a ns (l o garit h m-tra nsf or m e d data) bet w ee n t he treat m e nts, Treat me nt B 
( 4 0 0 m g p e xi darti ni b a d mi nistere d wit h a l o w-fat meal) vers us Treat me nt A ( Refere nce, 4 0 0 m g 
pe xi darti ni b i n t he faste d state). T he 2-si de d 9 0 % c o nfi de nce i nter vals ( CIs) will be calc ulate d 
si milarl y b y e x p o ne ntiati o n of t he c orres p o n di n g 2 si de d 9 0 % f or t he differe nce b et wee n t he 
least s q uares me a ns cal c ulate d f or t he l n tra nsf or me d v al ues. 
A m ore detaile d d escri pti o n of t he pla n ne d p har mac o ki netic a nal ysis will be pr o vi de d se paratel y 
i n t he S A P. 
1 0. 4. 2.  
P h ar m a c o d y n a mi c A n al yses 
N ot a p plica ble. 
1 0. 4. 3.  
S afet y A n al yses 
All safet y a nal yses will be base d o n t he s afet y a n al ysis set. 
1 0. 4. 3. 1.  A d verse E ve nt A n al yses 
A d verse e ve nts will be c o de d usi n g t he M e dical Dicti o nar y f or Re g ul at or y Acti vities ( Me d D R A) 
c o di n g dicti o nar y.  All A Es i ncl u di n g seri o us A Es will be ma p pe d t o s yste m or ga n class a n d 
preferre d t er m a n d will b e liste d i n t he data listi n g. 
A T E A E is defi ne d as a n A E t hat e mer ges d uri n g treat me nt, ha vi n g bee n a bse nt pre-tr eat me nt, or 
w orse ns rel ati ve t o t he pre-treat me nt state.  T he n u m ber a n d perce nt a ge of s u bjects re p orti n g 
T E A E will be ta b ulate d f or t he safet y s et b y M e d D R A s yste m or ga n class a n d pr eferre d ter m 
wit h a brea k d o w n b y treat me nt, a n d f urt her b y relati o ns hi p (relate d / n ot rel ate d) t o st u d y dr u g 
a d mi nistere d a n d b y C o m m o n Ter mi n ol o g y Criteria ( C T C) A E  gra de.5  A n A E t hat e mer ges or 
w or se ns i n se verit y d uri n g a was h o ut peri o d will b e c o u nte d as a T E A E t o w ar d t he treat me nt i n 
t he prece di n g p eri o d.  Listi n gs of deat hs, S A Es, a n d A Es t hat lea d t o disc o nti n uati o n of a s u bject 
will be prese nte d. 
1 0. 4. 3. 2.  Cli nic al L a b or at or y E v al u ati o n A n al yses 
He mat ol o g y, s er u m c h e mistr y, a n d uri nal ysis, at eac h pla n ne d assess me nt will be s u m marize d 
f or t he safet y a nal ysis set b y treat me nt.  S hift ta bles ( C T C A E gra de of t h e w orst val ue) will als o 
be pr o vi de d b y treat me nt.  S u bjects wit h a b n or mal val ues will be n ote d i n t he data listi n gs. 
1 0. 4. 3. 3.  Vit al Si g n A n al yses 
Vital si g n e val u ati o ns at eac h pla n n e d assess me nt a n d c ha n ge i n vital si g n val ues fr o m bas eli ne 
at eac h pl a n ne d p ost- bas eli ne assess me nt will be s u m marize d f or t he safet y a n al ysis s et b y 
treat me nt. 
Oral te m perat ure a n d res pirat or y rate will n ot be statisticall y a nal yze d.  Data listi n gs f or oral 
te m perat ur e a n d res pirat or y rate will be descri be d as a p pr o priat e b y s u bject a n d treat me nt. 

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1 0. 4. 3. 4.  Electr oc a r di o gr a m A n al yses 
T he E C G para meters ( P R, R R, Q R S, a n d Q T i nter vals, a n d Q T c B, a n d Q Tc F i nter vals w here t he 
Q T i nter vals c orrect f or h eart rate b y t he Bazett’s a n d Fri deri cia’s f or m ula ( Q Tc B = Q T/[ R R] 1/ 2 
a n d Q Tc F = Q T/[ R R] 1/ 3 res pecti vel y) will be s u m marize d b y tr eat me nt. 
T he n u m ber a n d p erce nta ge of s u bjects wit h a bs ol ute Q T, Q Tc F a n d Q Tc B i nter vals i n t he pre-
s pecifie d cate g ories ( > 4 5 0, > 4 8 0, a n d > 5 0 0 msec), a n d t he c ha n ge fr o m b aseli ne i n Q T, Q Tc F 
a n d Q Tc B i nter vals ( > 3 0 a n d > 6 0 msec) will be s u m marize d b y treat me nt. 
1 0. 4. 3. 5.  P h ysic al Fi n di n g A n al yses 
P h ysical e x a mi nati o n data at eac h e v al uati o n will be liste d. 
1 0. 4. 3. 6.  Ot her S afet y A n al yses 
N ot a p plica ble. 
1 0. 5.  
S a m ple Size Deter mi n ati o n 
T we nt y-f o ur s u bj ects will be ra n d o mize d, wit h t he e x pectati o n t hat at least 2 1 will c o m plete all 
3 peri o ds of t he st u d y.  Disc o nti n ue d s u bjects will n ot be re place d. T he s a m ple siz e is n ot 
de ter mi ne d bas e d o n statistical c o nsi derati o ns, b ut t o o btai n a de q uate precisi o n f or t he 
esti mati o n. Base d o n t he res ults fr o m St u d y P L 3 3 9 7- A- U 1 1 4, t he i ntra-i n di vi d ual varia bilit y 
(i ntra-i n di vi d ual C V %) i n t his st u d y is ass u me d t o be ar o u n d 3 0 %. Wit h a sa m ple size of 2 1 a n d 
ass u me d c oefficie nt of v ariati o n ( C V) of 3 0 %, a 3 0 % or hi g h er i ncreas e i n ge o m etric mea n rati o 
of e x p os ures bet wee n Treat me nt A a n d B ca n be deter mi ne d wit h a n i mprecisi o n of 1 5 % 
( dista nce bet w ee n t he m ea n rati o a n d t he l o wer b o u n d of CI) w he n t he 9 0 % CIs are ge n erat e d. 
1 0. 6.  
St atistic al A n al ysis Pr ocess 
T o preser ve t he i nte grit y of t he statistical a nal ysis a n d cli nical st u d y c o ncl usi o ns, t he S A P will be 
fi nalize d pri or t o data bas e l oc k. 
All statistical a nal yses will be perf or me d usi n g S A S ®  Versi o n 1 0. 6 or hi g her ( S A S I nstit ute, 
C ar y, N C 2 7 5 1 3). 

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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 he i n vesti gat or/i n vesti gati o nal site will per mit st u d y-relate d m o nit ori n g, a u dits, I R B re vie w, 
a n d re g ulat or y i ns pe cti o ns b y pr o vi di n g direct access t o s o urce dat a/ d oc u m e nts.  Direct access 
i ncl u des per missi o n t o e xa mi ne, a nal yz e, verif y, a n d re pr o d uce a n y rec or ds a n d re p orts t hat are 
i m p orta nt t o t he e val uati o n of a cli nical st u d y. 
1 1. 1.  
M o nit ori n g a n d I ns pecti o ns 
T he W C T m o nit or a n d re g ulat or y a ut h orit y i ns pe ct ors are res p o nsi ble f or c o ntacti n g a n d visiti n g 
t he i n vesti gat or f or t he p ur p ose of i ns pecti n g t he facilities a n d, u p o n re q u est, i ns pecti n g t he 
va ri o us rec or ds of t he st u d y (e g, C R Fs, s o urce dat a, a n d ot her p erti ne nt d oc u me nts). 
T he verific ati o n of a d h ere nce t o t he pr ot o c ol; c o m plete ness, acc urac y, a n d c o nsiste nc y of t he 
da ta; a n d ad h ere n ce t o I C H G C P a n d l ocal re g ulati o ns o n t he c o n d uct of cli nical researc h will be 
acco m plis he d t hr o u g h a c o m bi nati o n of o nsite visits b y t he m o nit or a n d re vie w of st u d y d ata 
re m otel y.  T he fre q ue n c y of t he m o nit ori n g visit will var y bas e d o n t he acti vit y at eac h site.  T he 
m o nit or is res p o nsi ble f or i ns pecti n g t h e C R Fs a n d e ns uri n g c o m plete ness of t he st u d y esse ntial 
d oc u me nts.  T he m o nit or s h o ul d ha ve access t o s u bject me dical r ec or ds a n d ot her st u d y-relat e d 
rec or ds n ee de d t o v erif y t he e ntries o n t he C R Fs.  Detaile d i nf or mati o n is pr o vi de d i n t he 
m o nit ori n g pla n. 
T he m o nit or will c o m m u nicate de viati o ns fr o m t h e pr ot oc ol, S O Ps, G C P, a n d a p plica ble 
reg ulati o ns t o t he i n vesti gat or a n d will e ns ure t h at a p pr o priate acti o n (s) d esi g ne d t o pr e ve nt 
rec urre nce of t he d etecte d de viati o ns is ta ke n a n d d oc u me nte d. 
T he i n vesti gat or a grees t o c o o perat e wit h t he m o nit or t o e ns ure t hat a n y pr o ble ms detecte d i n t he 
c o urse of t hes e m o nit ori n g visits are a d dress e d t o t he satisfacti o n of t he S p o ns or a n d 
d oc u me nte d.  
I n acc or da n ce wit h I C H G C P a n d t he S p o ns or’s a u dit pla ns, t his st u d y site ma y b e select e d f or 
a u dit b y re pres e ntati ves fr o m t he S p o ns or.  A u dit of site facilities (e g, p h ar mac y, dr u g st ora ge 
areas, l a b orat ori es) a n d re vie w of st u d y relate d rec or ds will occ ur i n or d er t o e val uate t he st u d y 
c o n d uct a n d c o m plia n ce wit h t he pr ot oc ol, I C H G C P, a n d a p plica ble re g ul at or y re q uir e me nts.  
T he i n vesti gat or s h o ul d res p o n d t o a u dit fi n di n gs.   I n t he e ve nt t hat a re g ulat or y a ut h orit y 
i nf orms t he  i n vesti gat or t hat it i nte n ds t o c o n d uct a n i ns pecti o n, t he S p o ns or s hall be n otifie d 
i m me diatel y. 
1 1. 2.  
D at a C ollecti o n 
D SI  or a desi g nee will s u p pl y e C R Fs.  A n e C R F m ust be c o m plete d f or all s u bjects w h o recei ve d 
at least o ne d ose of st u d y me dicati o n.  All data c ollecte d d uri n g t he st u d y will be rec or d e d i n t his 
i n di vi d ual, s u bject-s pecific e C R F.  I nstr ucti o ns will be pr o vi de d f or t he c o m pleti o n of t he e C R F 
a n d a n y c orrecti o ns ma de will be a ut o maticall y d oc u me nte d via t he E D C s oft ware’ s “a u dit trail.” 
C o m pleti o n of t he e C R F s h o ul d be ke pt c urre nt t o e na ble t he m o nit or t o re vie w t he s u bject’ s 
stat us t hr o u gh o ut t he c o urse of t he st u d y.  All i nf or mati o n a n d ot her material t o be use d b y 
s u bjects a n d i n vesti gati ve staff m ust use v oca b ular y a n d la n g ua ge t hat are clearl y u n derst o o d.  
T he e C R F will be c o m pl ete d, re vie we d, a n d si g n e d off or e-si g n e d b y t he i n vesti gat or.  T h e 

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i n vesti gat or will si g n a n d date t he i n dicate d places o n t he e C R F via t he E D C s yste m’s electr o nic 
si g nat ur e.  T hese si g nat ures will i n dicate t hat t he i n vesti gat or i ns pe cte d or re vie we d t he data o n 
t he e C RF, t he data q u eries, a n d t he st u d y site n otificati o ns, a n d a grees wit h t he c o nte nt. 
1 1. 3.  
D at a M a n a ge me nt 
Eac h s u bject will be i de ntifie d i n t he data base b y a u ni q ue s u bject i de ntifier as defi ne d b y t h e 
S p o ns or. 
T o e ns ure t he q u alit y of cli nical data acr oss all s u bjects a n d st u d y sites, a Cli nical Data 
Ma na ge me nt re vie w will be perf or me d o n s u bject data acc or di n g t o s pecifi cati o ns gi ve n t o 
W orl d wi de Cli nical Trials.  Data will be vette d b ot h electr o nicall y a n d m a n uall y f or C R Fs a n d 
t he data will be ele ctr o ni call y v ette d b y pr o gra m me d data r ules wit hi n t he a p plicati o n.  Q ueries 
ge n erat e d b y r ules a n d raise d b y re vie wers will be ge n erat e d wit hi n t he E D C a p plicati o n.  D uri n g 
t his re vie w, s u bject data will be c hec k e d f or c o nsiste nc y, c o m plete ness, a n d a n y a p pare nt 
discre pa n cies. 
Data recei ve d fr o m e xter nal s o urces s uc h as ce ntr al la b orat ories will be rec o ncile d t o t he cli nical 
data base. 
S A Es i n t he cli nical data base will be rec o ncile d wit h t he safet y data base. 
All A d verse E v e nts will be c o de d usi n g Me d D R A (latest versi o n).  Pri or a n d c o nc o mita nt 
me dica ti o n e ntere d i nt o t he data bas e will be c o de d usi n g t he W H O Dr u g Dicti o nar y (latest 
versi o n). 
1 1. 4.  
St u d y D oc u me nt ati o n a n d St or a ge 
T he i n vesti gat or will mai ntai n a Si g nat ur e List of a p pr o priatel y q u alifie d p ers o ns t o w h o m 
he/s he has dele gate d st u d y d uties.  All pers o ns a ut h orize d t o ma ke e ntries a n d/ or c orrecti o ns o n 
C R Fs will be i ncl u de d o n t he Si g nat ure List. 
I n v esti gat ors will mai ntai n a c o nfi de ntial S cree ni n g l o g of all p ote ntial st u d y ca n di dates t hat 
i ncl u des li mite d i nf or mati o n of t he s u bjects, date a n d o utc o me of Scree ni n g pr ocess. 
I n v esti gat ors will be e x pecte d t o mai ntai n a n E nr oll me nt L o g of all s u bjects e nr olle d i n t he st u d y 
i n dicati n g t heir assi g n e d st u d y n u m ber. 
I n v esti gat ors will mai ntai n a c o nfi de ntial s u bject i de ntificati o n c o de list.  T his c o nfi de ntial list of 
na mes of all s u bjects all o cate d t o st u d y n u m b ers o n e nr olli n g i n t he st u d y all o ws t he i n vesti gat or 
t o re veal t he i de ntit y of a n y s u bject w he n necessar y. 
S o urce d oc u me nts are ori gi nal d oc u m e nts, data, a n d rec or ds fr o m w hic h t he s u bject’s C R F data 
are o btai ne d.  T hese i ncl u de b ut are n ot li mite d t o h os pital rec or ds, cli nical a n d office c harts, 
la b orat or y a n d p h ar mac y rec or ds, diaries, micr ofi c hes, X-ra ys, a n d c orres p o n de nce.  
Rec or ds of s u bjects, s o urce d oc u me nts, m o nit ori n g visit l o gs, dat a c orrecti o n f or ms, C R Fs, 
i n ve nt or y of st u d y dr u g, re g ulat or y d oc u m e nts (e g, pr ot oc ol a n d a me n d me nts, I R B/ E C 
c orres p o n d e nce a n d a p pr o vals, a p pr o ve d a n d si g n e d I C Fs, I n v esti gat or’s A gree me nt, cli nical 
s u p plies recei pts, distri b uti o n a n d ret ur n rec or ds), a n d ot her S p o ns or c orres p o n de nce p ertai ni n g 
t o t he st u d y m ust be ke pt i n a p pr o priate st u d y files at t he st u d y site ( Trial M aster File).  S o urce 
d oc u me nts i nc l u de all rec or di n gs a n d o bser vati o ns or n otati o ns of cli nical acti vities a n d all 

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re p orts a n d rec or ds n ecessar y f or t he e val uati o n a n d rec o nstr ucti o n of t h e cli nical st u d y.  T hes e 
rec or ds will be retai ne d i n a sec ure file f or t he peri o d re q uire d b y t he i nstit uti o n or st u d y site 
p olic y.  Pri or t o tra nsf er or destr ucti o n of t hese rec or ds, t he S p o ns or m ust be n otifie d i n writi n g 
a n d be gi ve n t he o p p ort u nit y t o f urt her st or e s uc h rec or ds. 
1 1. 5.  
Rec or d Kee pi n g 
T he i n vesti gat or a n d st u d y staff are res p o nsi ble f or mai ntai ni n g a c o m pre he nsi ve a n d ce ntr alize d 
fili n g s yste m ( Trial Mast er File) of all st u d y-relate d d oc u me ntati o n, s uita ble f or i ns pecti o n at a n y 
ti me b y re prese nt ati ves fr o m t he S p o ns or a n d/ or a p plica ble re g ulat or y a ut h orities.  Trial Master 
File  i ncl u des: 
 S u bject files c o ntai ni n g c o m plete d C R Fs, I C Fs, a n d s u p p orti n g c o pies of s o urce 
d oc u me ntati o n (if ke pt). 
 S t u d y files c o ntai ni n g t h e pr ot oc ol wit h all a me n d me nts, I n v esti gat or’s Br oc h ure, 
c o pies of rel e va nt esse nti al d oc u me nts re q uir e d pri or t o c o m me nci n g a cli nical st u d y, 
a n d all c orres p o n de nce t o a n d fr o m t he I R B/ E C a n d t he S p o ns or. 
 Rec or ds rel ate d t o t he st u d y dr u g(s) i ncl u di n g ac k n o wle d g m e nt of recei pt at site, 
acc o u nta bilit y rec or ds, fi nal rec o n ciliati o n, a n d a p plica ble c orres p o n de n ce. 
I n a d diti o n, all ori gi nal s o urce d oc u m e nts s u p p orti n g e ntries i n t he C R Fs m ust be mai ntai ne d a n d 
be rea dil y a v aila ble. 
Trial Master File will be retai ne d b y t he i n vesti gat or u ntil at least 3 y after t he last a p pr o val of a 
mar keti n g a p plicati o n i n a n I C H re gi o n a n d u ntil t here are n o p e n di n g or c o nte m plate d mar keti n g 
a p plicati o ns i n a n I C H re gi o n or at least 3 y ha ve l a pse d si nce t he f or mal disc o nti n uati o n of 
clinical de vel o p me nt of t he i n vesti gati o nal dr u g.  T hese d oc u me nts s h o ul d be retai ne d f or a 
l o n ger p eri o d, h o we ver, if re q uire d b y t h e a p plica ble re g ulat or y re q uire m e nts or b y a n a gree me nt 
wit h t he S p o ns or.  It is t he res p o nsi bilit y of t he S p o ns or t o i nf or m t he i n vesti gat or/i nstit uti o n as 
t o w he n t hese d oc u me nts n o l o n ger nee d t o be retai ne d. 
S u bject’ s me dical files s h o ul d be retai ne d i n acc or da nce wit h a p plica ble le gislati o n a n d i n 
acc or d a nce wit h t he ma xi m u m peri o d of ti me per mitte d b y t he h os pital, i nstit uti o n, or pri vate 
pra ctice.  
N o st u d y d oc u m e nt s h o ul d be destr o ye d wit h o ut pri or writte n a gr ee me nt b et wee n S p o ns or a n d 
t he i n vesti gat or.  S h o ul d t he i n vesti gat or wis h t o assi g n t he st u d y rec or ds t o a n ot her part y or 
m o ve t he m t o a n ot her l oc ati o n, he/s he m ust n otif y S p o ns or i n writi n g of t he ne w res p o nsi ble 
pers o n a n d/ or t he n e w l o cati o n. 

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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 nces 
Pr i or t o starti n g t he st u d y, t he i n vesti gat or a n d/ or i nstit uti o n will si g n a cli nical st u d y a gree me nt 
wit h t he s p o ns or.  T his a gree me nt will i ncl u de t he fi na ncial i nf or mati o n a gree d u p o n b y t he 
pa rties. 
1 2. 2.  
Rei m b urse me nt, I n de m nit y, a n d I ns ur a nce 
T he S p o ns or pr o vi des i ns ura nce f or st u d y s u bjects t o ma ke a vaila ble c o m pe nsati o n i n case of 
st u d y-relate d i nj ur y. 
Rei m b urse me nt, i n de m nit y a n d i ns ura nce s h all be a d dresse d i n a se parate a gree me nt o n ter ms 
a gree d u p o n b y t h e parties. 

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1 3.  
P U B LI C A TI O N P O LI C Y 
A st u d y site ma y n ot p u blis h res ults of a st u d y u ntil after a c o or di nate d m ultice nter p u blicati o n 
has bee n s u b m itte d f or p u blicati o n or u ntil 1 y aft er t he st u d y has e n de d, w hic he ver occ urs first.  
T heref o re, t he st u d y site will ha ve t he o p p ort u nit y t o p u blis h t he res ults of t he st u d y, pr o vi d e d 
t hat D SI h as ha d t he o p p ort u nit y t o re vie w a n d c o m me nt o n t he st u d y site’s pro p ose d p u blicati o n 
pri or t o its bei n g s u b mitte d f or p u blicati o n wit h t h e pri or a d vice of D SI Le gal Affairs 
(i ntellect ual pr o pert y c o u ncil) a n d wit h pr o per re gar d t o t he pr otecti o n of s u bjects’ i de ntities. 

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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 
1 4. 1.  
C o m pli a nce St ate me nt, Et hics a n d Re g ul at or y C o m pli a nce 
T his st u d y will be c o n d u cte d i n c o m plia nce wit h t he pr ot oc ol, t he et hical pri nci ples t hat ha ve 
t heir ori gi n i n t he Declarati o n of Helsi n ki, t he I nter nati o nal C o u ncil f or Har m o nizati o n of 
Tec h nica l Re q uir e me nts f or P har mace uticals f or H u ma n Use (I C H) c o ns oli date d G ui deli ne E 6 
f or G o o d Cli nical Practice ( G C P) ( C P M P/I C H/ 1 3 5/ 9 5), a n d a p plica ble re g ulat or y re q uire m e nt(s) 
i ncl u di n g t he f oll o wi n g: 
 E ur o pea n C o m missi o n Directi ve ( 2 0 0 1/ 2 0/ E C A pr 2 0 0 1) a n d/ or; 
 E ur o pea n C o m missi o n Directi ve ( 2 0 0 5/ 2 8/ E C A pr 2 0 0 5) a n d/ or; 
 U S F o o d a n d Dr u g A d mi nistrati o n ( F D A) G C P Re g ul ati o ns: C o de of Fe d eral 
Re g ulati o ns ( C F R) Title 2 1, parts 1 1, 5 0, 5 4, 5 6, a n d 3 1 2 3 as a p pr o priate a n d/ or; 
 Ja pa nese Mi nistr y of H ealt h, La b or a n d Welfare Or di na nce N o. 2 8 of 2 7 M arc h, 
1 9 9 7; a n d/ or 
 T he  Act o n Sec uri n g Q ualit y, Efficac y a n d Safet y of P har mace uticals, Me dical 
De vices, Re ge nerati ve a n d Cell ular T hera p y Pr o d ucts, Ge ne T h era p y Pr o d ucts, a n d 
C os metics N o. 1 of 2 5 N o ve m ber, 2 0 1 4; a n d/ or 
 Ot he r a p plica bl e l ocal r e g ulati o ns. 
1 4. 2.  
S u bject C o nfi de nti alit y 
T he i n vesti gat ors a n d t he S p o ns or will preser ve t h e c o nfi de ntialit y of all s u bjects ta ki n g p art i n 
t he st u d y, i n acc or d a nce wit h G C P a n d l ocal re g ul ati o ns. 
T he i n vesti gat or m ust e ns ure t hat t he s u bject’s a n o n y mit y is mai ntai ne d.  O n t he C R Fs or ot her 
d oc u me nts s u b mit te d t o t he S p o ns or or t he C R O, s u bjects s h o ul d be i de ntifie d b y a u ni q ue 
s u bject i de ntifier as d esi g nate d b y t he S p o ns or.  D oc u me nts t hat are n ot f or s u b missi o n t o t h e 
S p o ns or or t he C R O (e g, si g ne d I C F) s h o ul d be k e pt i n strict c o nfi de nce b y t he i n vesti gat or. 
I n c o m plia nce wit h I C H G C P G ui deli nes, it is re q uire d t hat t he i n vesti gat or a n d i nstit uti o n 
per mit a ut h orize d re prese ntati ves of t he c o m pa n y, of t he re g ulat or y a ge n c y(s), a n d t he I R B/ E C 
direct access t o re vie w t h e s u bject’s ori gi nal me di cal rec or ds f or v erificati o n of st u d y-relate d 
pr oce d ures a n d dat a.  T h e i n vesti gat or is o bli gate d t o i nf or m t he s u bject t hat his/ her st u d y-relate d 
rec or ds will be re vie we d b y t he a b o ve- n a me d re prese ntati ves wit h o ut vi olati n g t he 
c o nfi de ntialit y of t he s u bject. 
1 4. 3.  
I nf or me d C o nse nt 
Bef ore a s u bj ect’s partici pati o n i n t he st u d y, it is t he i n vesti gat or’s res p o nsi bilit y t o o btai n freel y 
gi ve n c o nse nt, i n writi n g, fr o m t he s u bject after a d e q uate e x pla nati o n of t he ai ms, met h o ds, 
a ntici pate d be nefits, a n d p ote ntial hazar ds of t he st u d y a n d b ef ore a n y pr ot oc ol-s pecific 
pr oce d ures or a n y st u d y dr u gs are a d mi nistere d.  S u bjects s h o ul d be gi ve n t he o p p ort u nit y t o as k 
q uesti o ns a n d recei ve satisfact or y a ns w ers t o t heir i n q uiries, a n d s h o ul d ha ve a de q u ate ti me t o 

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deci de w h et her or n ot t o partici pate i n t he st u d y.  T he writte n I C F s h o ul d b e pre pare d i n t he l ocal 
la n g u a ge(s) of t he p ote ntial s u bject p o p ulati o n. 
I n o btai ni n g a n d d o c u me nti n g i nf or me d c o nse nt, t he i n vesti gat or s h o ul d c o m pl y wit h t he 
a p plica ble re g ulat or y re q uire me nts, a n d s h o ul d a d here t o G C P a n d t o t he et hical pri nci ples t hat 
ha ve t heir ori gi n i n t he Declarati o n of Helsi n ki.  T he c o nse nt f or m a n d a n y re visi o n(s) s h o ul d be 
a p pr o ve d b y t he I R B or E C  pri or t o bei n g pr o vi d e d t o p ote ntial s u bjects. 
T he  s u bject’s writte n i nf or me d c o nse nt s h o ul d be d oc u me nte d i n t he s u bj ect’s me dical rec or ds.  
T he I C F s h o ul d be si g ne d a n d pers o nall y dat e d b y t he s u bject a n d b y t he pers o n w h o c o n d u cte d 
t he i nf or me d co nse nt dis c ussi o n ( n ot necess aril y t he i n vesti gat or).  T he ori gi nal si g ne d I C F 
s h o ul d be retai ne d i n a cc or da nce wit h i nstit uti o nal p olic y, a n d a c o p y of t h e si g ne d c o nse nt f or m 
s h o ul d be pr o vi de d t o t he s u bject.  T he date a n d ti me (if a p plica ble) t hat i nf or me d c o nse nt w as 
gi ve n s h o ul d be rec or de d o n t he C R F. 
If t he s u bject c a n n ot rea d, t he n acc or di n g t o I C H G C P G ui deli ne, Secti o n 4. 8. 9, a n i m partial 
wit ness s h o ul d be prese nt d uri n g t he e ntire i nf or m e d c o nse nt disc ussi o n.  T his wit ness s h o ul d 
si g n t he I C F after t he s u bject has c o nse nt e d t o t he s u bject’s partici pati o n a n d, if p ossi ble, si g ne d 
t he I C F.  B y si g ni n g t he I C F, t he wit ness attests t hat t he i nf or mati o n i n t he I C F a n d a n y ot h er 
writte n i nf or mati o n was a de q uatel y e x plai ne d t o a n d a p pare ntl y u n derst o o d b y t he s u bject a n d 
t hat i nf or me d c o nse nt w as freel y gi ve n b y t he s u bj ect. 
S u g geste d m o del te xt f or t he I C F f or t h e st u d y a n d a n y a p plica ble s u b p arts ( ge n o mic, P K, etc) 
are pr o vi d e d i n t he S p o ns or’s I C F te m plate f or t he i n vesti gat or t o pre pare t h e d oc u me nts t o be 
use d at his or her st u d y site.  U p dates t o a p plica bl e f or ms will be c o m m u nicate d via letter fr o m 
t he S p o ns or. 
A d diti o nal c o nse nt is re q uire d f or HI P A A. 4  S u bjects will c o nse nt t o vir ol o g y testi n g ( HI V 
anti b o d y, H Bs A g a n d H C V a nti b o d y) as part of t heir i nitial i nf or me d c o ns e nt.  T his testi n g will 
be desc ri b e d i n t he I C F. 
1 4. 4.  
Re g ul at or y C o m pli a nce 
T he st u d y pr ot oc ol, s u bje ct i nf or mati o n a n d c o nse nt f or m, t he I n vesti gat or ’s Br oc h ure, a n y 
s u bject writte n i nstr ucti o ns t o be gi ve n t o t he s u bj ect, a vaila ble s afet y i nf or mati o n, s u bject 
recr uit me nt pr o ce d ures ( e g, a d vertise m e nts), i nf or mati o n a b o ut pa y m e nts a n d c o m p e nsati o n 
a vaila ble t o t he s u bjects, a nd d oc u me ntati o n e vi de nci n g t he i n v esti gat or’s q ualificati o ns s h o ul d 
be s u b m itte d t o t he I R B or E C  f or et hical re vie w a n d a p pr o val acc or di n g t o l ocal re g ulati o ns, 
pri or t o t he st u d y i nitiati o n.  T he writte n a p pr o val s h o ul d i de ntif y all d oc u me nts re vie we d b y 
na me a n d versi o n. 
C ha n ges i n t he c o n d uct of t he st u d y or pla n ne d a n al ysis will be d oc u me nt e d i n a pr ot oc ol 
a me n d me nt a n d/ or t he S A P. 
T he I n vesti gat or m ust s u b mit a n d, w here necessar y, o btai n a p pr o val fr o m t he I R B or E C f or all 
s u bse q ue nt pr ot oc ol a me n d me nts a n d c ha n ges t o t he I C F.  T h e i n vesti gat or s h o ul d n otif y t he 
I R B or E C  of d e viati o ns fr o m t he pr ot oc ol or S A Es occ urri n g at t he st u d y site a n d ot her A E 
re p orts recei ve d fr o m t he S p o ns or/ C R O, i n acc or d a nce wit h l ocal pr oce d ures. 
As re q uire d b y l o cal re g ulati o ns, t he S p o ns or’s l ocal Re g ulat or y Affairs gr o u p or re prese ntati ve 
t o w h o m t his res p o nsi bilit y has bee n dele gate d will e ns ure all le gal as p ects are c o v ere d, a n d 

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a p pr o val fr o m t he a p pr o priate re g ul at or y b o dies o btai ne d, pri or t o st u d y i nitiati o n. If c ha n ges t o 
t he i nitial pr ot oc ol an d ot her rel e va nt st u d y d o c u m e nts are ma de, t his re pres e ntati ve will als o 
e ns ure t hat a n y re vise d d oc u me nts re q uire d f or s u b missi o n are s u b mitte d t o re g ulat or y 
a ut h orities a n d i m ple me ntati o n of t hese c ha n ges h a p pe n o nl y after a p pr o val b y t he rele va nt 
re g ulat ory b o dies, as re q uire d. 
I n t he e ve nt of a n y pr o hi biti o n or restricti o n i m p ose d (e g, cli nical h ol d) b y a n a p plica ble 
Re g ulat or y A ut h orit y(i es) i n a n y area of t he w orl d, or if t he i n vesti gat or is a ware of a n y n e w 
i nf or mati o n w hic h mi g ht i nfl ue nce t he e val uati o n of t he be nefits a n d ris ks of t he i n vesti gati o nal 
dr u g, t he S p o ns or s h o ul d be i nf or me d i m me diatel y.   
In a d diti o n, t he i n vesti gat or will i nf or m t he S p o ns or i m me diatel y of a n y ur ge nt safet y meas ures 
ta ke n b y t he i n vesti gat or t o pr otect t he st u d y s u bjects a gai nst a n y i m me diate hazar d, a n d of a n y 
s us pecte d/act u al seri o us G C P n o n-c o m plia nce t hat t he i n vesti gat or b ec o mes a ware of. 
1 4. 5.  
Pr ot oc ol De vi ati o ns 
T he i n vesti gat or s h o ul d c o n d uct t he st u d y i n c o m plia nce wit h t he pr ot oc ol a gree d t o b y S p o ns or 
a n d, if re q uir e d, b y t he re g ulat or y a ut h orit y(i es), a n d w hic h was gi ve n a p pr o val/fa v ora bl e 
o pi ni o n b y t he I R Bs/ E Cs. 
A de viati o n t o a n y pr ot oc ol pr oce d ure or wai ver t o a n y stat e d criteria will n ot be all o we d i n t his 
st u d y e x ce pt w here necessar y t o eli mi nate i m me diate hazar d(s) t o t he s u bject.  S p o ns or m ust be 
n otifie d of all i nte n de d or u ni nte n de d de viati o ns t o t he pr ot oc ol (e g, i ncl usi o n/e xcl usi o n criteria, 
d osi n g, misse d st u d y visits) o n a n e x pe dite d basis. 
T he i n vesti gat or, or pers o n desi g n ate d b y t he i n vesti gat or, s h o ul d d oc u me nt a n d e x plai n a n y 
de viati o n fr o m t he a p pr o ve d pr ot oc ol. 
If a s u bject w as i neli gi ble or recei ve d t h e i nc orrect d ose or st u d y tr eat me nt, a n d ha d at least 1 
a d mi nist rati o n of st u d y dr u g, d ata s h o ul d be c ollecte d f or safet y p ur p os es. 
If a p plica bl e, t he i n vesti gat or s h o ul d n otif y t he I R B of de vi ati o ns fr o m t he pr ot oc ol i n 
accor d a nce wit h l ocal pr oce d ures. 
1 4. 6.  
S u p pl y of Ne w I nf or m ati o n Affecti n g t he C o n d uct of t he St u d y 
W he n ne w i nf or mati o n b ec o mes a v aila ble t hat ma y a d v ersel y affect t he safet y of s u bj ects or t he 
c o n d uct of t he st u d y, t he S p o ns or will i nf or m all i n vesti gat ors i n v ol ve d i n t he cli nical st u d y, 
I R Bs/ E Cs, a n d re g ulat or y a ut h orities of s u c h i nf or mati o n, a n d w he n nee de d, will a me n d t he 
pr ot oc ol a n d/ or s u bject i nf or mati o n. 
T he i n vesti gat or s h o ul d i m me diatel y i nf or m t he s u bject w he ne v er ne w i nf or mati o n bec o mes 
a vaila ble t hat ma y be rel e va nt t o t he s u bject’s c o nse nt or ma y i nfl ue nce t he s u bject’s willi n g ness 
t o c o nti n ue partici pati o n i n t he st u d y.  T he c o m m u nicati o n s h o ul d be d oc u me nte d o n me dical 
rec or ds, f or e x a m ple, a n d it s h o ul d be c o nfir me d w het her t he s u bject is willi n g t o re mai n i n t he 
st u d y.  
If t he s u bject i nf or m ati o n is re vise d, it m ust be re-a p pr o ve d b y t he I R B/ E C.  T he i n vesti gat or 
s h o ul d o btai n writte n i nf or me d c o nse nt t o c o nti n u e partici pati o n wit h t he re vise d writte n 
i nf or mati o n e ve n if s u bje cts were alrea d y i nf or me d of t he rele va nt i nf or mati o n.  T he i n vesti gat or 

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or ot her res p o nsi ble p ers o n nel w h o pr o vi de d e x pla nati o ns a n d t he s u bject s h o ul d si g n a n d date 
t he re vise d IC F. 
1 4. 7.  
Pr ot oc ol A me n d me nts 
A n y a me n d me nts t o t he st u d y pr ot oc ol t hat se e m t o be a p pr o pri ate as t he st u d y pr o gress es will 
be c o m m u nicate d t o t he i n vesti gat or b y D SI  or t he C R O.  Als o, t he S p o ns or will e ns ure t he 
ti mel y s u b missi o n of a me n d me nts t o re g ulat or y a ut h orities. 
C ha n ges ma de b y pr ot oc ol a me n d me nts will be d oc u me nte d i n a S u m mar y of C ha n ges d oc u me nt.  
T hese pr ot oc ol a m e n d me nts will u n der g o t he sa m e re vie w a n d a p pr o val pr ocess as t he ori gi nal 
pr ot oc ol. 
A pr ot oc ol a me n d me nt ma y b e i m ple me nte d aft er it has bee n a p pr o ve d b y t he I R B/ E C a n d b y 
re g ulat or y a ut h orities w h ere a p pr o priate, u nl ess i m me diate i m ple me ntati o n of t he c ha n ge is 
necessa r y f or s u bject safet y. 
1 4. 8.  
St u d y Ter mi n ati o n 
T he S p o ns or has t he ri g ht t o ter mi nate t he st u d y at a n y ti me a n d st u d y ter mi nati o n ma y als o be 
re q ueste d b y a c o m pete nt a ut h orit y. 
1 4. 9.  
D at a a n d S afet y M o nit ori n g B o ar d 
N ot a p plica ble. 
1 4. 1 0.  
A d dress List 
1 4. 1 0. 1.  
S p o ns or’s Cli nic al St u d y Le a der 
 
C o ns ulta nt, Cli nical P har mac ol o g y 
Q ua ntitati ve Cli nical P har mac ol o g y 
Daiic hi S a n k y o, I nc. 
2 1 1 M o u nt Air y R oa d 
Bas ki n g Ri d ge, NJ 0 7 9 2 0 
  
 
 
1 4. 1 0. 2.  
S p o ns or’s Cli nic al St u d y M a n a ger 
 
Ass ociate Direct or 
Cli nical O perati o ns Earl y De vel o p me nt 
Daiic hi S a n k y o, I nc. 
2 1 1 M o u nt Air y R oa d 
Bas ki n g Ri d ge, NJ 0 7 9 2 0 
 
 

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1 4. 1 0. 3.  
S p o ns or’s P h ar m ac o ki netics Re vie wer 
 
Direct or, Cli nical P har m ac ol o g y 
Q ua ntitati ve Cli nical P har mac ol o g y 
Daiic hi Sa n k y o, I nc. 
2 1 1 M o u nt Air y R oa d 
Bas ki n g Ri d ge, NJ 0 7 9 2 0 
 
 
 
1 4. 1 0. 4.  
S p o ns or’s Me dic al M o nit or 
 
Se ni or Direct or 
Cli nical De vel o p me nt, O nc ol o g y 
Daiic hi Sa n k y o, I nc. 
2 1 1 M o u nt Air y R oa d 
Bas ki n g Ri d ge, NJ 0 7 9 2 0 
 
 
 
1 4. 1 0. 5.  
S p o ns or’s S afet y C o nt acts 
Da iic hi Sa n k y o P har ma De vel o p me nt 
Cli nical Safet y a n d P har mac o vi gila n ce 
E mail t o: C S P V- Cli nical @ dsi.c o m 
1 4. 1 0. 6.  
E D C Ve n d or 
W orl d wi de Cli ni cal Trials, Lt d 
1st Fl o or, Waterfr o nt H o use 
Beest o n B usi ness Par k 
Beest o n, N otti n g ha m  
N G 9 1 L A, U K 
 
 
1 4. 1 0. 7.  
Bi o a n al ytic al Ve n d or 
 
Bi oa nal ytical Pri nci pal I n vesti gat or 
Celeri o n 
6 2 1 R ose Street 
L i nc ol n, N E 6 8 5 0 2 
 

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w w w.ce l eri o n.c o m 
1 4. 1 0. 8.  
Ce ntr al L a b or at or y 
W orl d wi de Cli nical Trials Earl y P h ase Ser vices, L L C 
2 4 5 5 N. E. L o o p 4 1 0, S uite 1 5 0 
Sa n A nt o ni o, T X 7 8 2 1 7 
1 4. 1 0. 9.  
S p o n s or’s Bi ost atistici a n 
 
Bi ostatistics a n d Data M a na ge me nt 
Daiic hi S a n k y o, I nc. 
2 1 1 M o u nt Air y R oa d 
Bas ki n g Ri d ge, NJ 0 7 9 2 0 
 
 
1 4. 1 0. 1 0.  D at a a n d S afet y M o nit ori n g B o ar d 
N ot a p plica ble. 
1 4. 1 0. 1 1.  C R O  
W orl d wi de Cli nical Trials Earl y P h ase Ser vices, L L C 
2 4 5 5 N. E. L o o p 4 1 0, S uite 1 5 0 
Sa n A nt o ni o, T X 7 8 2 1 7 
 
1 4. 1 0. 1 1. 1. C R O I n vesti g at or 
 
W orl d wi de Cli nical Trials 
2 4 5 5 N. E. L o o p 4 1 0, S uite 1 5 0 
Sa n A nt o ni o, T X 7 8 2 1 7 
 
 
 

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P r o prietar y a n d C o nfi de ntial 
Pa ge 5 8 
1 4. 1 0. 1 1. 2. C R O Pr oject M a n a g er 
 
W orl d wi de Cli nical Trials 
2 4 5 5 N. E. L o o p 4 1 0, S uite 1 5 0 
Sa n A nt o ni o, T X 7 8 2 1 7 
 
 
 
 

P L 3 3 9 7- A- U 1 2 8 Pr ot oc ol 
Versi o n 1. 0, 2 0 Mar 2 0 1 9 
 
P r o prietar y a n d C o nfi de ntial 
Pa ge 5 9 
1 5.  
R E F E R E N C E S 
1.  P e xi darti ni b I nv esti gat or’s Br oc h ure, Versi o n 1 0 . 0, 1 9 Dec 2 0 1 8.  
2.  W est R B, R u bi n B P, Miller M A, et al. A la n ds ca p e effect i n te n os y n o vial gia nt-cell 
t u m or fr o m acti vati o n of C S F 1 e x pressi o n b y a tr a nsl ocati o n i n a mi n orit y of t u m or cells. 
Pr oc Natl Aca d Sci U S A. 2 0 0 6; 1 0 3( 3): 6 9 0- 6 9 5. 
3.  F o o d a n d Dr u g A d mi nistrati o n: C o de of Fe d eral Re g ul ati o ns ( C F R).  A vail a ble at 
htt p:// w w w. g p oaccess. g o v/cfr 
4.  U S He alt h I ns ura n ce P orta bilit y a n d Acc o u nta bilit y Act ( HI P A A). 2 1 A u g 1 9 9 6. 
htt p://as pe. h hs. g o v/a d m nsi m p/ pl 1 0 4 1 9 1. ht m 
5.  N ati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or A Es, versi o n 5. 0, p u blis he d 
2 7 N o v 2 0 1 7. A vaila ble at: 
htt ps://cte p.ca ncer. g o v/ pr ot oc ol de vel o p me nt/electr o nic _a p plicati o ns/ctc. ht m #ctc _ 5 0 
 
 

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P r o prietar y a n d C o nfi de ntial 
Pa ge 6 0 
1 6.  
A P P E N DI C E S 
1 6. 1.  
L a beli n g a n d P ac k a gi n g 
N ot a p plica ble 
1 6. 2.  
Bl o o d C ollecti o n V ol u me b y C ate g or y a n d T ot al 
T a ble 1 6. 1: 
Bl o o d C ollecti o n V ol u mes 
Test  
V ol u me per Test ( m L)  
N o. of Ti me P oi nts per 
S u bject  
T ot al V ol u me per 
Test ( m L)  
Scree ni n g  
Ser u m c he mistr y, 
HI V  a nti b o d y, 
H Bs A g, H C V  
a nti b o d y, F S H if 
a p plica ble, ser u m 
pre g na nc y  
8. 5  
1  
8. 5  
He mat ol o g y  
4. 0  
1  
4. 0  
C oa g ulati o n 
( P T/I N R a n d 
a P T T) 
2. 7  
1  
2. 7  
Ser u m c he mistr y , ser u m 
pre g na nc y, if a p plica ble  
8. 5  
2  
1 7 . 0 
He mat ol o g y  
4. 0  
2  
8 . 0 
P K pe xi darti ni b  
2. 0  
9 1  
1 8 2 . 0 
T ot al:  
- 
9 5  
2 2 2 . 2 
A b bre viati o ns: a P T T = acti vate d partial t hr o m b o plasti n ti me; F S H = f ollicle sti m ulati n g h or m o ne; H Bs A g = 
he p atitis B s urface a nti ge n; H C V = he p atitis C vir us; HI V = h u ma n i m m u n o deficie nc y vir us; I N R = i nter nati o nal 
n or malize d rati o; P K = p har mac o ki netic; P T = pr ot hr o m bi n ti me 
N otes: Bl o o d c ollecti o n i n s u bj ects wit h a d verse e ve nts s h o ul d be c o nti n ue d u ntil res ol uti o n of t he e ve nts (e ve n after 
t he sc he d ule d o bser vati o n peri o d). Bl o o d c ollecti o n t o be use d f or se veral differe nt tests b ut ta ke n at o ne ti me is 
c o u nte d as o ne c ollecti o n. 

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1 6. 3.  
A d diti o n al I nf or m ati o n (f or J a p a nese St u d y Sites O nl y) 
N ot a p plica ble. 
1 6. 3. 1.  
G C P c o m pli a nce 
N ot a p plica ble. 
1 6. 3. 2.  
St u d y Peri o d 
N ot a p plica ble. 
1 6. 3. 3.  
P a y me nt f or P artici p ati o n, C o m pe ns ati o n f or St u d y- Rel ate d I nj uries, a n d 
I ns ur a nce 
N ot a p plica ble. 
1 6. 3. 4.  
St u d y A d mi nistr ati ve Str uct ure 
N ot a p plica ble. 
1 6. 4.  
I nstr ucti o ns f or S peci me n C ollecti o n, St or a ge a n d S hi p me nt 
1 6. 4. 1.  
Pl as m a P h ar m ac o ki netic S a m ple C ollecti o n, St or a ge a n d S hi p me nt I nstr ucti o ns 
A 2 m L bl o o d sa m ple will be ta ke n b y ve ni p u nct ure of f orear m vei n(s) at ti me p oi nts detaile d i n 
t he Sc he d ules of E ve nts ( Secti o n 1 6. 6 ). 
Bl o o d s a m ples will be c ollecte d i nt o pre-c hille d 2 m L Vac utai ner ®  t u bes c o ntai ni n g lit hi u m 
he pari n as a ntic oa g ula nt f or t he pre p arati o n of plas ma.  It is i m p orta nt t o fill t he Vac utai ner ®  
t u bes t o t he s pecifie d c oll ecti o n v ol u me. 
T he t u be c o ntai ni n g bl o o d f or plas ma pre parati o n will be ge ntl y i n vert e d m ulti ple ( > 8) ti mes t o 
e ns ure t h or o u g h mi xi n g of a ntic oa g ula nt a n d bl o o d, t he n i m me diatel y place d i n a c o ol b o x 
c o ntai ni n g ic e wat er.  T h e sa m ples s h o ul d be ce ntrif u ge d wit hi n 3 0 mi n after c ollecti o n, at 
a p pr o xi matel y 1 5 0 0 g f or a p pr o xi matel y 1 0 mi n at a p pr o xi matel y + 4° C.  I m me diatel y f oll o wi n g 
ce ntrif u gati o n, t he se p arate d plas ma f or eac h s a m ple will be di vi de d i nt o 2 ali q u ots at t he 
f oll o wi n g v ol u mes: 
 Ali q u ot  1 (f or pe xi darti ni b assa y): 0. 5 m L 
 Ali q u ot 2 ( bac k- u p f or pe xi darti ni b assa y): re mai ni n g plas ma 
T he 2 ali q u ots of plas ma s h o ul d eac h be pi pette d i nt o p ol y pr o p yle ne cr y o ge nic sa m ple st ora ge 
vials (at least 2 t o 3 m L siz e, wit h scre w-ca p), desi g nat e d Set 1 a n d Set 2, a n d la bele d wit h 
a p pr o priate i nf or mati o n ( barc o de a n d/ or s u bject I D, ti me p oi nts, a n d ali q u ot n u m ber).  T he 
ali q u ots m ust be ke pt c hille d f or t he e ntire ti me bef ore t he y are tr a nsferre d t o t he freezer.  Eac h 
set of ali q u ots m ust be st ore d i n se parate b o xes.  Wit hi n 6 0 mi n after bl o o d dra w, t he sa m ple 
st ora ge vials will be st ore d i n t he dar k i n a - 2 0° C (- 1 5° C t o - 3 0° C) freezer. 
A n y s a m ple a n o malies s h o ul d be rec or de d o n t he sa m pli n g f or ms. 

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Set 1 sa m ples will be se nt t o t he bi oa nal ytical la b orat or y at Celeri o n f or t he deter mi nati o n of 
pe xi darti ni b plas ma c o nce ntrati o ns.  Set 1 sa m ples s h o ul d be s hi p pe d after t he e n d of eac h p eri o d 
t o arri ve at t he bi o a nal yti cal la b orat or y at Celeri o n t he ne xt da y.  Set 2 sa m ples ca n be s hi p pe d t o 
t he bi oa nal yti cal la b orat or y at Celeri o n o nce t he site c o nfir ms recei pt of Set 1 sa m ples fr o m a 
peri o d. 
S hi p pi n g G ui de 
 B i ol o gic al sa m ples ( e g, plas ma) s h o ul d be s hi p pe d o n dr y ice. 
 S a m ples s h o ul d be s hi p pe d o nl y o n a M o n da y, T u es da y, We d nes da y, or T h urs da y t o 
mi ni mize t he p ossi bilit y of t he m bei n g i n tra nsit o ver a wee ke n d. 
 If d u plicate sa m ples are bei n g s hi p pe d, 1 s et of sa m ples s h o ul d be se nt.  T he sec o n d 
set s h o ul d be s hi p pe d aft er recei vi n g c o nfir mati o n of arri val of t he first set at 
Celeri o n. 
S a m ple P ac ki n g 
 Ar ra n ge t he sa m ple c ollecti o n, wit h c o urier. 
 Use  a St yr of oa m b o x, f or e x a m ple 1 9” × 1 9” × 1 2 ”.  Use a lar ger o ne if s hi p pi n g 
ma n y sa m ples. 
 O bta i n 2 0 l bs of dr y ice p ellets.  Use as m uc h dr y i ce as p ossi ble, t o hel p safe g u ar d 
a gai nst a n y p ossi ble dela ys. 
 P lace a 4” l a yer of dr y ic e i n t he b ott o m of t he St yr of oa m b o x. 
 S a m ples s h o ul d be i de ntifie d usi n g s elf a d hesi ve l a bels, w hic h s h o ul d be a p plie d pri or 
t o freezi n g t h e sa m ples. 
 P lace t he sa m ples i n b o x es per sta n dar d site pr oce d ure.  Place t he b o xes i n t he 
St yr of oa m c o oler a n d fill t he e x cess s pace wit h t he re mai ni n g dr y ice pellets. 
 R ec or d t he esti mate d w ei g ht of t he dr y ice use d p er b o x. 
 P lace t he li d o n t he St yr of oa m b o x a n d seal c o m pletel y wit h ta pe. 
 Ta pe a list of t he sa m ples c o ntai ne d i nsi de t he b o x, t o t he li d (e g, plas m a, s u bjects 1 - 
2 4, pre d ose, 3 0 mi n, 1 h).  I n or der t o pr ot ect t his pa per w or k i nsert it i nt o a plastic 
ba g. 
 Place t he St yr of oa m b o x i n a car d b oar d s hi p pi n g cart o n, seal se c urel y wit h ta pe. 
L a beli n g 
La b el t he car d b oar d b o x as f oll o ws: 
 Mar k t he o utsi de of t he cart o ns wit h tall y n u m ber e g, 1 of 3, 2 of 3, a n d 3 of 3. 
 Af fi x a n a d dress la b el, wit h t he i nf or mati o n bel o w, t o t he o utsi de of eac h b o x: 

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Celeri o n 
Att n: Sa m ple Recei pt, Celeri o n 
6 2 4 Peac h Street Li nc ol n, N E 6 8 5 0 2 
P h o ne: ( 4 0 2) 4 3 7- 4 8 4 9 
 
Affi x t he f oll o wi n g la bels o n eac h b o x: 
 1 c ar b o n di o xi de la bel wit h t he wei g ht i ncl u d e d. 
 2 la be ls wit h i nter nati o nall y rec o g nize d dr y ice s y m b ols ( Class 9) - 1 o n eit her si de of 
t he b o x.  E xa m ple:  
 
  
 1 K E E P F R O Z E N la b el 
 
 
 1 P E RI S H A B L E G O O D S la bel 
 In dic ate ret ur n a d dress a n d c o ntact pers o n o n eac h cart o n. 
P a per w or k t o A cc o m p a n y S hi p me nt 
 T hese h u ma n bi ol o gical sa m ples are n ot k n o w n t o be i nfecti o us or hazar d o us. 
 F or la b orat or y use o nl y. 
 $ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ f or c ust o ms (a n o mi nal val ue, e g, $ 5. 0 0) 
 N o c o m mercial v al ue. 
Be gi n ni n g wit h t he first s hi p me nt, i ncl u de all of t he f oll o wi n g i nf or mati o n: 
 S u bject i de ntificati o n 
 Ti me p oi nt i de ntificati o n 
 Pr ot oc ol n u m ber 
 S p o ns or na me 

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A n y missi n g i nf or mati o n ma y ca use a dela y i n a nal ysis. 
N otif y Celeri o n b y e mail or fa x i m me diatel y after t he sa m ples ha ve b ee n c ollecte d b y t he 
c o urier.  Pleas e pr o vi de t he f oll o wi n g i nf or mati o n: 
 Na me of c o urier or tra ns p ort c o m pa n y 
 Da te a n d ti me t he s hi p me nt left y o ur pre mises 
 T he  air wa y bill n u m ber 
T he c o ntact f or sa m ple recei pt is: 
 
Celeri o n  
6 2 1 R ose Street 
Li nc ol n, N E 6 8 5 0 2 
 
 
If t he s hi p me nt l a beli n g a n d d oc u me nt ati o n are n ot c o m plete d c o rrectl y, t he s hi p me nt m a y 
be del a ye d. 
U p o n arri val at Celeri o n, t he s hi p me nt will be u n pac ke d, t he c o nte nts will be d oc u me nte d, a n d 
t he se n der will be a d vise d of its safe arri val. 

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1 6. 5.  
C yt oc hr o me P 4 5 0 Cli nic all y Si g nific a nt Dr u g I nter acti o n T a ble 
List o btai ne d fr o m P 4 5 0 Dr u g I nteracti o n Ta ble: A b bre viate d “ Cli nicall y Rele va nt” Ta ble, 
Versi o n 5. 0 rel ease d o n J a n uar y 1 2, 2 0 0 9, last u p d ate d o n 1 2 J ul 2 0 1 3.  A vaila ble at:  
htt p:// me dici ne.i u p ui.e d u/cli n p har m/ D DIs/ Cli nical Ta ble.as p x. 
I N HI BI T O R S 
1 A 2  
2 B 6  
2 C 8  
2 C 1 9  
a mi o dar o ne 
ci meti di n e 
efa vire nz  
fl u or o q ui n ol o nes 
fl u v o xa mi n e  
ticl o pi di ne 
cl o pi d o grel 
t hi ote pa 
ticl o pi di ne 
v oric o naz ole  
ge mfi br ozil  
m o ntel u kast  
ci meti di n e 
es o me praz ole  
fel b a mate 
fl u o xeti ne 
fl u v o xa mi n e 
is o niazi d 
ket o c o naz ole  
la ns o praz ole 
o me praz ole  
oral c o ntrace pti ves  
pa nt o praz ole  
ticl o pi di ne 
v oric o naz ole  
I N HI BI T O R S 
2 C 9  
2 D 6  
2 E 1  
3 A 4, 5, 7  
a mi o dar o ne 
efa vire nz 
fl u c o naz ole 
is o niazi d 
metr o ni d az ole  
par o xeti ne  
s ulfa met h o xaz ole 
v oric o naz ole  
b u pr o pi o n  
fl u o xeti ne 
 par o xeti ne  
 q ui ni di n e 1  
d ul o xeti ne  
a mi o dar o ne 
ci meti di n e 
ari pi praz ole 
di p he n h y dra mi n e  
c hl or p he nira mi n e  
cl o mi pra mi n e  
d o xe pi n  
hal o peri d ol  
met h a d o ne  
rit o na vir 
ter bi n afi n e 
dis ulfira m  
HI V a nti virals:  
i n di na vir 
nelfi n a vir  
rit o na vir 
 
clarit hr o m yci n  
itrac o naz ole 
ket o c o naz ole  
 nefaz o d o ne  
er yt hr o m yci n  
gra pefr uit j uice  
vera pa mil 2  
s u b o x o ne 
diltiaze m  
 ci meti di n e 
a mi o dar o ne 
N O T azit hr o m yci n  
fl u v o xa mi n e 
tr olea n d o m yci n 
v oric o naz ole  

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U G T I N HI BI T O R S  
v al pr oic aci d     p r o be neci d 
I N D U C E R S 
1 A 2  
2 B 6  
2 C 8  
2 C 1 9  
car ba maz e pi n e  
c har grille d me at  
rifa m pi n 
t o bacc o 
arte misi ni n 
car ba maz e pi n e  
efa vire nz  
ne vira pi n e  
p he n o bar bital  
p he n yt oi n  
rifa m pi n 
N/ A  
efa vire nz  
rifa m pi n 
rit o na vir 
St. J o h n's W ort  
I N D U C E R S 
2 C 9  
2 D 6  
2 E 1  
3 A 4, 5, 7  
car ba maz e pi n e  
ne vira pi n e  
p he n o bar bital  
rifa m pi n 
St. J o h n's W ort  
N/ A  
is o niazi d 
car ba maz e pi n e  
efa vire nz  
ne vira pi n e  
p he n o bar bital  
p he n yt oi n  
pi o glitaz o ne  
rifa b uti n 
rifa m pi n 
St. J o h n's W ort  
tr o glitaz o ne 
 

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1 6. 6.  
Sc he d ule of E ve nts 
T a ble 1 6. 2: 
Sc he d ule of E ve nts ( Scree ni n g t hr o u g h D a y 1) 
St u d y Peri o d → 
Scree ni n g a 
Peri o d 1  
Peri o ds 1, 2, a n d 3 b  
St u d y D a y c → 
-2 1 t o -2  
C hec k -i nd  
-1  
1  
St u d y E ve nt ↓  St u d y H o ur → 
 
 
pre -
d ose  
0  0. 5  1  1. 5  2  2. 5  3  3. 5  4  4. 5  5  6  8  1 0  1 2  1 4  
2 2  
I nf or me d c onse nt  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I ncl usi o n/e xcl usi o n criteria 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Me dical/ me dicati o ns hist or y  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C o m plete p h ysical e xa m  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
B o d y wei g ht  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hei g ht a n d B MI  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ra n d o mizati o n e 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dr u g, c oti ni ne, alc o h ol scree n  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vir ol o g y  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ser u m pre g na nc y test  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
F S H le vel f 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
He mat ol o g y, ser u m c he mistr y, 
uri nal ysis h 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C oa g ulati o n  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 2 -lea d E C Gs 
X  
 
X  
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
Vitals ( B P, H R, te m p, R R)  
X  
 
X  
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
A b bre viati o ns: A E = a d verse e ve nt; B MI = b o d y mass i n de x; B P = bl o o d press ure; d = da y; E C G = electr ocar di o gra m; F S H = f ollicle sti m ulati n g h or m o ne; h = 
h o ur; H R = heart rate; P K = p har mac o ki netic; R R = res pirat or y rate; te m p = oral te m perat ure 
a T o be c o n d ucte d wit hi n 2 1 d pri or t o first d osi n g. 

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b T here will be at least a 6- d was h o ut b et wee n t he d ose a d mi nistere d i n P eri o d 1 a n d t hat i n P eri o d 2, a n d t he d ose a d mi nistere d i n P eri o d 2 a n d t hat i n P eri o d 3. 
P eri o ds 2 a n d 3 will start after t he last P K sa m ple of t he pre vi o us d ose fr o m P eri o d 2 a n d 3, res pecti vel y. 
c St u d y da ys ar e re prese ntati o n of da ys i n eac h peri o d. 
d S u bj ects will c hec k i n o n Da y - 1 of P eri o d 1 a n d re mai n c o nfi ne d u ntil t he e n d of P eri o d 3 or Earl y T er mi nati o n.  
e O n Da y - 1 of P eri o d 1 o nl y, f oll o wi n g t he re vie w of safet y la b orat or y res ults a n d E C Gs, ra n d o mizati o n n u m bers will be assi g ne d t o s u bj ects.  A s u bj ect is 
c o nsi dere d ra n d o mize d o nce he/s he recei ves t he d ose. 
f F S H will be meas ure d f or nat urall y p ost me n o pa usal fe male s u bj ects. 
g A ge n ot y pi n g bl o o d sa m ple will be c ollecte d o n Da y 1 of P eri o d 1 o nl y, after ra n d o mizati o n (i.e. d osi n g). 
h Ti me wi n d o ws f or bl o o d dra ws are:  
 
-2 h f or sa m ples c ollecte d as pre- d ose 
 
± 5 mi ns f or sa m ples c ollecte d ≤ 4 h p ost d ose  
 
± 1 0 mi ns f or sa m ples c ollecte d > 4 h a n d ≤ 1 2 h p ost d ose  
 
± 3 0 mi ns f or sa m ples c ollecte d > 1 2 h a n d ≤ 7 2 h p ost d ose  
 
± 4 h o urs f or sa m ples c ollecte d > 7 2 h a n d < 7 da ys p ost d ose  
 
± 1 da y f or sa m ples c ollecte d ≥7 da ys p ost d ose  
 

P L 3 3 9 7- A- U 1 2 8 Pr ot oc ol 
Versi o n 1. 0, 2 0 Mar 2 0 1 9 
 
P r o prietar y a n d C o nfi de ntial 
Pa ge 6 9 
T a ble 1 6. 3: 
Sc he d ule of E ve nts ( D a ys 2 t o C hec k of Peri o d 3 or E arl y Ter mi n ati o n) 
St u d y Peri o d → 
Peri o ds 1, 2, a n d 3 a 
C hec k -o ut of Peri o d 3 
or E arl y Ter mi n ati o n  
St u d y D a y b  → 
2  
3  
4  
5  
6  
7  
St u d y E ve nt ↓  St u d y H o ur → 
2 4  
2 8  
3 2  
3 6  
4 8  
5 4  
6 0  
7 2  
8 4  
9 6  
1 0 8  
1 2 0  
1 3 2  
1 4 4  
C o m plete p h ysical e xa m  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
B o d y wei g ht  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
Ser u m pre g na nc y test  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
He mat ol o g y, ser u m c he mistr y, uri nal ysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
1 2 -lea d E C Gs 
X  
 
 
 
 
 
 
 
 
 
 
 
 
X  
X c 
Vitals ( B P, H R, te m p, R R)  
X  
 
 
 
 
 
 
 
 
 
 
 
 
X  
X c 
P K bl o o d c oll ecti o ns 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
A E  m o nit ori n g  
< ----------------------------------------------------------------- X ----------------------------------------------------------------->  
Rec or d of c o nc o mita nt me dic ati o n  
< ------------------------------------------------------------------ X ------------------------------------------------------------------>  
C o nfi ne me nt  
< ------------------------------------------------------------------ X ------------------------------------------------------------------>  
A b bre viati o ns: A E = a d verse e ve nt; B P = bl o o d press ure; E C G = electr ocar di o gra m; d = da y; h = h o ur; H R = heart rate; P K = p har mac o ki netic; 
R R  = res pirat or y rate; te m p = oral te m perat ure 
a T here will be at least a 6- d was h o ut b et wee n t he d ose a d mi nistere d i n P eri o d 1 a n d t hat i n P eri o d 2, a n d t he d ose a d mi nistere d i n P eri o d 2 a n d t hat i n 
P eri o d 3. P eri o ds 2 a n d 3 will start after t he last P K sa m ple of t he pre vi o us d ose fr o m peri o d 2 a n d 3, res pecti vel y. 
b St u d y da ys ar e re prese ntati o n of da ys i n eac h peri o d. 
c If n ot alrea d y ta ke n.