Clinical trial NCT03901313
Conditions: Healthy Volunteers
Keywords: Pharmacokinetics
Sponsor: Daiichi Sankyo
Start date: 2019-04-01; Completion date: 2019-05-22
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
All participants in this study are healthy volunteers.

Throughout the study, healthy volunteers will have physical exams, electrocardiograms and clinical laboratory tests. The study staff will keep track of symptoms, diet, and what medications they are taking.

Each participant will get all three treatments (A, B and C). Only the order in which they receive them will be different.

There are six groups based on the order: ABC, ACB, BAC, BCA, CAB, or CBA. Participants have an equal chance of being assigned to any of these groups.

For each treatment period, participants will:

* fast overnight
* receive the assigned treatment with or without food
* have a small tube of blood drawn prior to treatment
* after dosing, additional blood samples will be drawn at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 14, 22, 24, 28, 32, 36, 48, 54, 60, 72, 84, 96, 108, 120, 132, and 144 hours
* have a break from treatment for 6 days between each treatment period

All participants must reside in the clinic for a total of 20 days.

Detailed description:
The primary objectives of this study are:

* To assess the effect of low-fat food on the pharmacokinetics (PK) of pexidartinib following a single oral dose of 400 mg administered in healthy subjects
* To assess the PK of pexidartinib following a single oral dose of 200 mg administered with low-fat food in healthy subjects

The secondary objective of this study is:

* To characterize the safety and tolerability of pexidartinib in healthy subjects following administration of a single oral dose of pexidartinib with low fat food and without food

Arms: arm 1: Healthy volunteers will receive Treatments A, then B, and then C, with a 6-day washout between treatments, during a stay at the clinic of 20 days arm 2: Healthy volunteers will receive Treatments A, then C, and then B, with a 6-day washout between treatments, during a stay at the clinic of 20 days arm 3: Healthy volunteers will receive Treatments B, then A, and then C, with a 6-day washout between treatments, during a stay at the clinic of 20 days arm 4: Healthy volunteers will receive Treatments B, then C, and then A, with a 6-day washout between treatments, during a stay at the clinic of 20 days arm 5: Healthy volunteers will receive Treatments C, then A, and then B, with a 6-day washout between treatments, during a stay at the clinic of 20 days arm 6: Healthy volunteers will receive Treatments C, then B, and then A, with a 6-day washout between treatments, during a stay at the clinic of 20 days
Interventions: intervention 1: Treatment A - 400 mg Fasting intervention 2: Treatment B - 400 mg Fed intervention 3: Treatment C - 200 mg Fed
Intervention descriptions: intervention 1: Single oral 400 mg (2 × 200 mg capsules) dose of pexidartinib in the morning under fasting conditions intervention 2: Single oral 400 mg (2 × 200 mg capsules) dose of pexidartinib in the morning within 30 minutes (min) after a low-fat standard breakfast meal intervention 3: Single oral 200 mg (1 × 200 mg capsule) dose of pexidartinib in the morning within 30 min after a low-fat standard breakfast meal

Protocol documents:
Prot_SAP_000.pdf: 
Pr o prietar y a n d C o nfi de ntial 
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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 
c o urse ( 8 m o). 


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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 
c o ntai ni n g gra pefr uit is all o we d f or 7 d pri or t o d osi n g a n d t hr o u g h o ut t he st u d y, a n d alc o h ol is 


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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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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 6 
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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P r o prietar y a n d C o nfi de ntial 
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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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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 
 
 
 
 


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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. 


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 8 
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.