An Open-Label, 2-Part Study to Investigate the Effect of Lasmiditan on the Pharmacokinetics of Dabigatran and Rosuvastatin in Healthy Volunteers
Phase: PHASE1
Conditions: Healthy
Sponsor: Eli Lilly and Company

 
 
 
Pr ot oc ol H 8 H- M C- L AI O ( b)   
 
 
A n O pe n- La bel, 2- Part St u d y t o I n vesti gate t he E ffect of Las mi dita n o n t he P har mac o ki netics of 
Da bi gatra n a n d R os u vastati n  i n Healt h y V ol u nteers 
 
  
N C T 0 4 7 4 9 9 1 4 
 
A p pr o val Date: 0 6- N o v- 2 0 2 0 
 
 

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
1
Title p a ge
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt i s c o nfi d e nti al a n d i s i nt e n d e d f or t h e u s e of cli ni c al i n v e sti g at or s. It i s t h e pr o p ert y of 
Eli Lill y a n d C o m p a n y or it s s u b si di ari e s a n d s h o ul d n ot b e c o pi e d b y or di stri b ut e d t o p er s o n s n ot i n v ol v e d i n t h e cli ni c al 
i n v e sti g ati o n of l as mi dit a n ( L Y 5 7 3 1 4 4) , u nl e s s s u c h p er s o n s ar e b o u n d b y a c o nfi d e nti alit y a gr e e m e nt wit h Eli Lill y a n d C o m p a n y 
or it s s u b si di ari e s.
N ot e t o R e g ul at or y A ut h oriti e s: T hi s d o c u m e nt m a y c o nt ai n pr ot e ct e d p er s o n al d at a a n d/ or c o m m er ci all y c o nfi d e nti al i nf or m ati o n 
e x e m pt fr o m p u bli c di s cl o s ur e. Eli Lill y a n d C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r e l e a s e/r e d a cti o n pri or t o a n y p u bli c r el e a s e.
I n t h e U nit e d St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m ati o n A ct ( F OI A) E x e m pti o n 4 a n d m a y n ot b e r e pr o d u c e d or 
ot h er wi s e di s s e mi n at e d wit h o ut t h e writt e n a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s.
Pr ot oc ol Title:
A n O p e n - La bel, 2-Part S t u d y t o In vest i gate t he E ffect of L as mi dita n o n t he P har mac o ki net ics of 
D a bi gatra n a n d R os u vastati n i n H ealt hy V ol u nteers
Pr ot oc ol N u m ber: H 8 H -M C -L AI O
A me n d me nt N u m ber: H 8 H -M C -L AI O( b)
C o m p o u n d : L as mi dita n ( L Y 5 7 3 1 4 4)
St u d y P h ase: P hase 1
S h ort Title: A D DI St u d y  of Las mi dit a n wi t h Da bi gatra n ete xilate a n d R os u vastati n i n Healt h y 
V ol u nteers
S p o ns or N a me: El i Lill y  a n d C o mpa n y
Le g al Re gistere d A d dress: El i Lill y a n d C o m pa n y
I n dia na p olis, I n dia na U S A 4 6 2 8 5
Re g ul at or y A ge nc y I de ntifier N u m ber(s)
I N D: 1 0 3 4 2 0
A p pr o v al D ate: Pr ot oc ol Electr o nicall y Si g ne d a n d A p pr o ve d b y Lill y o n 1 1 Se pte m ber 2 0 2 0.
A me n d me nt (a) Electr o nicall y Si g ne d a n d A p pr o ve d b y Lill y o n 1 6 Se pte m ber 2 0 2 0 . 
A me n d me nt ( b) Electr o nicall y  Si g ne d a n d A p pr o ve d b y Lill y o n date pr o vide d bel o w.
A p pr o v al D at e: 0 6- N o v- 2 0 2 0 G M T

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
2
Me dical M o nit or Na me a n d C o ntact I nf or mat i on will be pr o vi de d s e paratel y.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
3
Pr ot oc ol A me n d me nt S u m m ar y of C h a n ges T a ble
D O C U M E N T HI S T O R Y
D oc u me nt
D ate
A m e n d m e nt ( a)
1 6 -S e p -2 0 2 0
Ori gi n al Pr ot o c ol
1 1- S e p -2 0 2 0
A me n d me nt [ b] 
O ver all R ati o n ale f or t he A me n d me nt:
Secti o n # a n d 
N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
5. 1. I ncl usi o n 
Cri teria
Cri t erio n # 4 has bee n u p date d t o 
s pecif y re nal a n d li ver f u nct i on 
c ut -off val ues.
T his a d dit i on was ma d e t o pr o vide 
a d ditio nal  clarit y.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
4
T a ble of C o nte nts
1.
Pr ot oc ol S u m m ar y ......................................................................................................7
1. 1.
S y n o psis .......................................................................................................................7
1. 2.
Sc he ma .........................................................................................................................9
1. 3.
Sc he d ule of Act i vities ( S o A) ......................................................................................1 0
2.
I ntr o d ucti o n ..............................................................................................................1 8
2. 1.
St u d y  Rati o nale ..........................................................................................................1 8
2. 2.
Bac k gr o u n d ................................................................................................................1 8
2. 3.
Be nefit/ Ris k Assess me nt ............................................................................................1 9
3.
O bjecti ves a n d E n d p oi nts .........................................................................................2 0
4.
St u d y Desi g n .............................................................................................................2 1
4. 1.
O verall Desi g n ............................................................................................................2 1
4. 1. 1.
N u m ber of Partici pa nts ...............................................................................................2 1
4. 2.
S ci e nt ific Rati o nale f or St u d y Desi g n.........................................................................2 1
4. 2. 1.
P arti cipa nt I n p ut i nt o Desi g n ......................................................................................2 2
4. 3.
J ustificati o n f or D ose..................................................................................................2 2
4. 4.
E n d of St u d y  Defi niti on ..............................................................................................2 3
5.
St u d y P o p ul ati o n ......................................................................................................2 4
5. 1.
I ncl usi on Cri t eria ........................................................................................................2 4
5. 2.
E xcl u sio n  Crit eria .......................................................................................................2 5
5. 3.
Lifest yle C o nsi derat i ons .............................................................................................2 8
5. 3. 1.
Meals a n d Dietar y  Restrict i ons ...................................................................................2 8
5. 3. 2.
Caffei ne, Alc o h o l, a n d T o bacc o..................................................................................2 8
5. 3. 3.
Act i vity ......................................................................................................................2 8
5. 4.
Scree n Fail ures ...........................................................................................................2 8
6.
St u d y I nter ve nti o n ....................................................................................................2 9
6. 1.
St u d y  I nter ve nti on(s) A d mi nistere d ............................................................................2 9
6. 1. 1.
A d mi nistrati o n Details ................................................................................................2 9
6. 2.
Pre parati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y .............................................................3 0
6. 3.
Meas ures t o Mi ni mize Bias: Ra n d o mizat i on a n d Bli n di n g ..........................................3 0
6. 3. 1.
Pac ka gi n g a n d La beli n g ..............................................................................................3 0
6. 4.
St u d y  I nter ve nti on C o m plia nce ...................................................................................3 0
6. 5.
C o nc o mita nt T hera p y ................................................................................................. 3 0
6. 6.
D ose M o dificat i on ......................................................................................................3 1
6. 7.
I nterve nti o n after t he E n d of t he St u d y ........................................................................3 1
7.
Disc o nti n u ati o n of St u d y I nter ve nti o n a n d P artici p a nt 
Disc o nti n u ati o n/ Wit h dr a w al ....................................................................................3 2
7. 1.
Di sc o nti n uatio n of  St u d y I nter ve nti on ........................................................................3 2
7. 2.
P arti cipa nt Disc o nti n uati o n/ Wit h dra wal fr o m t he St u d y .............................................3 2
7. 2. 1.
Di sc o nti n uatio n of  I na d verte ntl y Enr olle d Partici pa nts ...............................................3 3
7. 3.
L ost t o F oll o w u p .......................................................................................................3 3
8.
St u d y Assess me nts a n d Pr oce d ures .........................................................................3 4
8. 1.
Efficac y Assess me nts ................................................................................................. 3 4

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
5
8. 2.
S af et y Assess me nts ....................................................................................................3 4
8. 2. 1.
P h ysical E xa mi nat i ons ................................................................................................3 4
8. 2. 2.
Vi t al Sig ns.................................................................................................................. 3 5
8. 2. 3.
Electr ocar di o gra ms .....................................................................................................3 5
8. 2. 4.
Cli nical Safet y  La b orat or y Assess me nts .....................................................................3 5
8. 2. 5.
S af et y M o ni t ori n g.......................................................................................................3 6
8. 3.
A d verse E ve nts a n d Seri o us A d verse E ve nts ..............................................................3 9
8. 3. 1.
Ti me Peri o d a n d Fre q ue nc y  for C ollect i n g A E a n d S A E 
I nf or mat i on .................................................................................................................3 9
8. 3. 2.
Met h o d of Detecti n g A Es a n d S A Es ...........................................................................4 0
8. 3. 3.
F o ll ow- u p of  A Es a n d S A Es.......................................................................................4 0
8. 3. 4.
Re g ulat or y  Re p orti n g Re q uire me nts f or S A Es............................................................4 0
8. 3. 5.
Pre g na nc y ...................................................................................................................4 0
8. 3. 6.
Pr o d uct C o m plai nt s ....................................................................................................4 1
8. 4.
Treat me nt of O ver d ose ...............................................................................................4 2
8. 5.
P har mac o ki net ics........................................................................................................4 2
8. 5. 1.
Bi oa nal ysis .................................................................................................................4 2
8. 6.
P har mac o d y na mics .....................................................................................................4 2
8. 7.
Ge net ics .....................................................................................................................4 2
8. 8.
Bi o m ar kers .................................................................................................................4 3
8. 9.
I mm u n o ge nicit y Assess me nts .....................................................................................4 3
8. 1 0.
Heal t h Ec o n o mics.......................................................................................................4 3
9.
St atist ic al C o nsi der ati o ns.........................................................................................4 4
9. 1.
Stati stical H y p ot heses................................................................................................. 4 4
9. 2.
S a m ple Si ze Deter mi nat i on .........................................................................................4 4
9. 3.
P o p ul at i ons f or A nal yses ............................................................................................4 4
9. 3. 1.
St u d y  P artici pa nt Dis p osit i on ......................................................................................4 5
9. 3. 2.
St u d y  P artici pa nt C haracterist ics.................................................................................4 5
9. 3. 3.
Treat me nt C o m plia nce ................................................................................................4 5
9. 4.
Stati stical A nal yses .....................................................................................................4 5
9. 4. 1.
S af et y A nal yses ..........................................................................................................4 5
9. 4. 2.
P har mac o ki net ic A nal yses ..........................................................................................4 6
9. 4. 3.
P har mac o d y na mic A nal yses .......................................................................................4 6
9. 4. 4.
P har mac o ki net ic/ P har mac o d y na mic A nal yses ............................................................4 6
9. 4. 5.
Ot her A nal yses ...........................................................................................................4 6
9. 5.
I nteri m A nal yses.........................................................................................................4 6
9. 6.
Data M o nit ori n g C o m mittee .......................................................................................4 7
1 0.
S u p p orti n g D oc u me nt ati o n a n d O per ati o n al C o nsi der ati o n s ................................4 8
1 0. 1.
A p pe n di x 1: Re g ulat or y , Et hical, a n d St u d y O versi g ht 
C o nsi derati o ns ............................................................................................................4 8
1 0. 1. 1.
Re g ulat or y  a n d Et hical C o nsi derati ons ........................................................................4 8
1 0. 1. 2.
Fi na ncial Discl o s ure ...................................................................................................4 8
1 0. 1. 3.
I nf or me d C o nse nt Pr ocess ..........................................................................................4 9
1 0. 1. 4.
Data Pr otecti o n ...........................................................................................................4 9
1 0. 1. 5.
Di sse mi nati on of Cli nical St u d y  Data .........................................................................4 9
1 0. 1. 6.
Data Q ualit y Ass ura nce ..............................................................................................5 0

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
6
1 0. 1. 7.
S o urce D oc u me nts ......................................................................................................5 2
1 0. 1. 8.
St u d y  a n d Site Start a n d Clos ure .................................................................................5 2
1 0. 1. 9.
P u blicat i on P olic y .......................................................................................................5 2
1 0. 1. 1 0. L o n g -Ter m  Sa m ple Rete nti on .....................................................................................5 3
1 0. 2.
A p pe n di x 2: Cli nical La b orat or y  Tests........................................................................5 4
1 0. 2. 1.
Bl o o d S a m pli n g S u m mar y ..........................................................................................5 6
1 0. 3.
A p pe n di x 3: A d verse E ve nts: Defi nit i ons a n d Pr oce d ures f or 
Rec or di n g, E val uat i n g, F oll o w-u p, a n d Re p orti n g .......................................................5 7
1 0. 3. 1.
Defi nit i on o f A E .........................................................................................................5 7
1 0. 3. 2.
Defi nit i on o f S A E .......................................................................................................5 8
1 0. 3. 3.
Rec or di n g a n d F o ll ow- U p of A E a n d/ or S A E .............................................................5 9
1 0. 3. 4.
Re p orti n g of S A Es ......................................................................................................6 1
1 0. 4.
A p pe n di x 4: C o ntrace pti ve G ui da nce a n d C o llecti o n of 
Pre g na nc y I nf or mati o n ...............................................................................................6 2
1 0. 5.
A p pe n di x 5: Ge netics ................................................................................................. 6 5
1 0. 6.
A p pe n di x 6: Li ver Safet y:  S u g geste d Acti o ns a n d F oll o w- u p 
Assess me nts ...............................................................................................................6 6
1 0. 7.
A p pe n di x 7: A b bre v iati ons .........................................................................................7 1
1 1.
Refere nces .................................................................................................................7 4

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
7
1.
Pr ot oc ol S u m m ar y
1. 1.
S y n o psis
Pr ot oc ol Title: A n O pe n -La bel , 2-Part St u d y  t o I n vesti gate t he Effect of Las mi dita n o n t he 
P har mac o ki net ics of Da bi gatra n a n d R os u vastati n i n Healt h y V o l unt eers.
S h ort Title: A D DI St u d y  of Las mi dita n wi t h Da bi gatra n ete xilate a n d R os u vas tati n i n Health y 
V ol u nteers
R ati o n ale :
Las mi dita n ( L Y 5 7 3 1 4 4) is a hi g hl y selecti ve a n d p ote nt a g o nist at t he 5 -h y dr o x ytr y pta mi ne
1 F rece pt or. Las mi dita n has bee n de vel o pe d b y Eli Lill y a n d C o m pa n y, a n d a p pr o ve d b y t he U S 
F o o d a n d Dr u g A d mi nistrati o n ( F D A), f or t he ac ute treat me nt of mi grai ne attac ks, wit h or 
wi t ho ut a ura, i n a d ults .
P- gl yc o pr otei n ( P -g p) a n d breast ca ncer resista nce pr otei n ( B C R P) are me m bra ne -b o u n d, effl u x 
tra ns p orters l ocate d i n t he s mall i ntesti ne, c ol on, a n d li ver (a m o n g ot her tiss ues), ser vi n g t o li mit 
t he a bs or ptio n of  dr u gs fr o m t he gastr oi ntesti nal tract a n d t o i ncrease biliar y s e cr etio n of  dr u gs 
a n d t heir meta b o lites ( Malie paar d et al. 2 0 0 1, I nter nati onal Tra ns p orter C o ns orti u m et al. 2 0 1 0 ).
Certai n s u bstrates of B C R P or P - g p ha ve bee n s h o w n t o ha ve cli nicall y si g nifica nt dr u g 
i nteract i ons w he n a d mi nistere d wit h i n hi bit ors of B C R P or P -g p, res pecti vel y (I nter nat i onal 
Tra ns p orter C o ns orti u m et al. 2 0 1 0).
T he p ote ntial f or las mi dita n a n d its meta b olites t o i n hi bit effl u x tra ns p orters P -g p a n d B C R P was 
assesse d i n vitr o. T he i ntesti nal dr u g -dr u g i nteracti o n ( D DI) i n de x ( d ose / 2 5 0 m L 
[I 2]/c o nce ntrati o n of dr u g ca usi n g half -ma xi mal i n hi bit or y  effect [I C 5 0]) was deter mi ne d f or 
b o t h P-g p a n d B C R P i n hi bit i on i n c o nte xt of a 2 0 0-m g d ose, t he ma xi m u m a p pr o ve d d ose f or 
las mi dita n ( F D A 2 02 0a ). T he calc ulate d D DI i n de x was 1 6 f or B C R P a n d 2 5 f or P -g p. B ot h 
t hese val ues e xcee d t he F D A c ut off val ue of 1 0, i n dicat i n g t hat las mi dita n has t he p ote ntial t o 
i n hi bit P-g p a n d B C R P i n t he cli nic.
T his st u d y  ai ms t o e valuate t he safet y , t olera bilit y, a n d p har mac o ki net ics of  r os u vastatin a n d 
da bi gatra n i n t he prese nce of las mi dita n. D a bi gatra n ete xilate a n d r os u vastati n are se nsit i ve 
s u bstrates of effl u x tra ns p orters, P-g p a n d B C R P, res pect i vel y ( F D A 2 02 0 b ).
O b jecti ves a n d E n d p oi nts
O bject i ves
E n d p oi nts
Pri mar y

T o e val uate t he effect of las mi dita n o n 
P- gl yc o pr otei n ( P- g p) a n d breast 
ca ncer resista nce pr otei n ( B C R P )
acti vit y i n health y p arti ci pa nts

C ma x a n d A U C ( 0-∞) of  da bi gatra n t o 
assess P - g p acti vit y a n d r os u vastati n 
t o assess B C R P act i vity

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
8
Sec o n dar y

T o e val uate t he safet y a n d t olera bilit y 
of  da bi gatra n ete xilate or r os u vastati n 
i n c o m bi nat i on wi t h las mi dita n i n 
healt h y parti ci pa nts

T o e val uate t he p har mac o ki net ics of 
las mi dita n a n d M 8

A s u m mar y  of t he n u m ber of 
treat me nt -e mer ge nt a d verse e ve nts 
a n d seri o us a d verse e ve nts

C ma x , tma x , a n d A U C ( 0-∞) of  
las mi dita n a n d M 8
A b bre viati o ns: A U C ( 0-∞) = area u n der t he c o nce ntrati o n vers us ti me c ur ve fr o m zer o t o i nfi nit y; B C R P = breast 
ca ncer resista nce pr ot ei n; C ma x = ma xi m u m o bser ve d dr u g c o nce ntrati o n ; P- g p = p -gl y c o pr otei n; tma x = ti me 
of ma xi m u m o bser ve d dr u g c o nce ntrati o n.
O ver all Desi g n
T his is a P hase 1, t w o- part, t w o -peri o d, o pe n -la bel st u d y i n healt h y partici pa nts. Part 1 will st u d y 
da bi gatra n P - g p D DI wit h las mi dita n. Part 2 will st u d y  r os u vastati n B C R P D DI wit h las mi dita n.
Parts 1 a n d 2 will ha ve a si milar desi g n, i.e. , da bi gatra n et e xilate or r os u vastati n a d mi nistrati o n 
alo ne i n P eri o d 1 (D a y  1) f oll owe d b y a bri ef was h o ut, t he n las mi dita n o n Da y s 8, 9, a n d 1 0
(Peri o d 2 ) wit h c oa d mi nistrati o n of da bi gatra n ete xilate or r os u vastati n wit h las mi dita n o n Da y  
1 0. Eac h part will c o nsist of differe nt partici pa nts a n d t he 2 parts ma y r u n i n parallel.
Discl os ure St ate me nt : T hi s is an o pe n -lab el , parallel-gr o u p D DI stu d y wi t h 2 parts .
N u m ber of P artici p a nt s:
A p pr o xi matel y  7 2 parti ci pa nts will be e nr olle d t o P art 1 of t he st u d y t o e ns ure t hat at least 6 2
e val ua ble part ici pa nts c o mplete t hat part. A p pr o xi matel y 3 2 parti ci pa nts will be e nr olle d t o P art 
2 t o e n s ure t hat at least 2 8 e val ua ble parti ci pa nts c o mplete t hat part.
I nter ve nti o n Gr o u ps a n d D ur ati o n :
T his st u d y c o nsists of 2- parts a n d 2 -p eri o ds . Part 1 will c o nsist of si n gle oral d oses of da bi gatra n
ete xilate ( Perio d 1) , fol l owe d b y 3 dail y d oses of las mi dita n wi t h c oa d mi nistrati o n of a si n gle 
or al  d ose of da bi gatra n ete xilate gi ve n at t he sa me ti me as t he t hir d d ose of las mi dita n ( Perio d 2).
Part 2 will c o nsist of si n gle oral d oses of r os u vastati n ( Peri o d 1) f oll owe d b y 3 dail y d oses of 
las mi dita n wi t h c oa d mi nistrati o n of a si n gle d ose of r os u vastati n gi ve n at t he sa me ti me as t he 
t hir d d ose of las mi dita n ( P erio d 2).
Part 1: Da bi gatra n ete xilate/ Las mi dita n 
Part 2: R os u vastati n/ Las mi dita n 
P eri o d 1 
( Da y 1)
Peri o d 2
P eri o d 1
( Da y 1)
Peri o d 2
( Da ys 8- 9)
( Da y 1 0)
( Da ys 8- 9)
( Da y 1 0)
Da bi gatra n 
ete xilate
( 1 5 0 m g)
Las mi dita n
( 2 0 0 m g 1 x 
per da y )
Da bi gatra n ete xilate 
( 1 5 0 m g) 
+
Las mi dita n ( 2 0 0 m g)
R os u vastati n 
( 1 0 m g)
Las mi dita n
( 2 0 0 m g 1 x 
per da y )
R os u vastati n ( 1 0 m g)
+
Las mi dita n ( 2 0 0 m g)
D at a M o nit ori n g C o m mittee: N o

C O N FI D E N TI A L
H 8 H- M C -L AI O ( b)
9
1. 2.
Sc he m a

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
1 0
1. 3.
Sc he d ule of Acti vities ( S o A)
P art 1 – D a bi g atr a n ete xil ate/ L as mi dit a n
Scree
ni n g
D a ys
E D/
F oll o w
-U p
C o m me nts
Pr oce d ure
-4 5 t o 
- 2 
da y s 
pri or 
t o 
Da y 1
- 1
1
2
3
4
5
6
7
8
9
1 0
1 1
1 2
1 3
D a y 1 6 
+/ - 1
d a y
I nf or me d c o nse nt
X
I ncl usi o n a n d e xcl usi o n 
criteria
X
De m o gra p h y
X
Partici pa nt a d missi o n t o 
C R U
X
X
Partici pa nt d isc har ge fr o m 
C R U
X
X
At t he i n vesti gat or’s discreti o n, 
partici pa nts ma y re mai n i n patie nt 
after Da y 3 or 1 2.
Past a n d c urre nt m e dical 
h ist or y (i ncl u des s u bsta nce 
usa ge [a n d fa mil y hist or y of 
pre mat ure car di o vasc ular 
disease])
X
F ull p h ysical e xa mi nati o n 
i ncl u di n g hei g ht a n d wei g ht
X
A s ym pt o m -directe d p h ysical 
e xa mi nati o n ma y be perf or me d at 
ot her ti mes at t he discreti o n of 
t he i n vesti gat or.
Ser u m or uri ne pre g na nc y 
test (w o me n of c hil d beari n g 
p ote ntial o nl y)
X  
X
X
X
Ser u m pre g na nc y test will be 
perf or me d at scree ni n g. Uri ne 
pre g na nc y test will be perf or me d 
at e ver y a d missi on p e ri o d a n d at 
p ostst u d y, if a p plica ble.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
1 1
Scree
ni n g
D a ys
E D/
F oll o w
-U p
C o m me nts
Pr oce d ure
- 4 5 t o 
- 2 
da y s 
pri or 
t o 
Da y 1
- 1
1
2
3
4
5
6
7
8
9
1 0
1 1
1 2
1 3
D a y 1 6 
+/ - 1
d a y
H u ma n i m m u n o deficie nc y 
vir us, he patitis B a n d C 
scree ni n g
X
1 2 -lea d electr ocar di o gra m
( E C G)
X 
P  
X
P  
X
Vital si g ns (s u pi ne)
X
P, 1, 
2 h
2 4
h
P
P, 1, 
2 h
2 4 h
X
Ti me p oi nts ma y be a d de d f or 
eac h st u d y peri o d, if warra nte d 
a n d a gree d u p o n bet wee n Lill y 
a n d t he i n vesti gat or.
Cli nical la b orat or y 
assess me nts (i ncl u di n g li ver 
c he mistries)
X
P 
2 4
h
P
2 4
h
X
See A p pe n di x 1 0. 2 , Cli nical 
La b orat o r y Tests, f or details.
Ur i nal ysis perf or me d at 
scree ni n g, f oll o w- u p a n d E D
o nl y .
C- S S R S a n d Self -Har m
S u p ple me nt
X
X
X
“ Baseli ne” q uesti o n naire t o be 
use d at scree ni n g, all ot her ti me
p oi nts use “ Si nce Last Visit” 
q uesti o n naire . T he Self -Har m 
S u p ple me nt s h o ul d be c o m plete d 
e ver y ti me t he C-S S R S is 
a d mi nistere d. If, base d o n 
a d mi nistrati o n of t he C-S S R S, it 
is deter mi ne d t hat s uici de-relate d 
be ha vi ors ha ve occ urre d, t he n t he 
Self -Har m F oll o w -U p f or m will 
be use d t o c ollect a d diti o nal 
i nf or mati o n. T he Da y 7 
assess me nt ca n be perf or me d u p 
t o pre-d ose o n Da y 8.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
1 2
Scree
ni n g
D a ys
E D/
F oll o w
-U p
C o m me nts
Pr oce d ure
- 4 5 t o 
- 2 
da y s 
pri or 
t o 
Da y 1
- 1
1
2
3
4
5
6
7
8
9
1 0
1 1
1 2
1 3
D a y 1 6 
+/ - 1
d a y
Ge netic sa m ple
X
P K sa m ples - da bi gatra n 
( plas ma)
P , 
0. 5, 
1, 2, 
3, 4, 
6, 8, 
1 0, 
1 2 h
2 4,
3 6 
h
4
8
h
7 2
h
P, 
0. 5, 
1, 2, 
3, 4, 
6, 8, 
1 0, 
1 2 h 
2 4, 
3 6 
h
4 8
h
7 2
h
7 2- h o ur bl o o d dra w t o be 
perf or me d at o ut patie nt visit.
P K sa m ples - las mi dita n/ M 8 
( plas ma)
P, 
0. 5, 
1, 
1. 5, 
2, 4, 
8, 1 2
h
2 4, 
3 6 
h
4 8
h
7 2
h
7 2 -h o ur bl o o d dra w t o be 
perf or me d at o ut patie nt visit.
St u d y i nter ve nti o n 
a d mi nistrati o n
X
X  
X  
X
D a bi gatra n ete xilate t o be gi ve n 
o n Da y  1 ( Peri o d 1). Las mi dita n 
t o be gi ve n o n Da ys 8, 9, a n d 1 0
wit h a si n gle d ose of d a bi gatra n 
ete xilate c o-a d mi nistere d wit h 
las mi dita n o n Da y  1 0 ( Peri o d 2).
A d verse e ve nt/ seri o us 
a d verse e ve nt re vie w
X
= = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = 
X
C o nc o mita nt me dicati o n 
re vie w
X
= = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = 
X

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
1 3
Scree
ni n g
D a ys
E D/
F oll o w
-U p
C o m me nts
Pr oce d ure
- 4 5 t o 
- 2 
da y s 
pri or 
t o 
Da y 1
- 1
1
2
3
4
5
6
7
8
9
1 0
1 1
1 2
1 3
D a y 1 6 
+/ - 1
d a y
A b bre viati o ns: C R U = cli nical researc h u nit; C- S S R S = C ol u m bia -S uici de Se verit y Rati n g Scale; E C G = electr ocar di o gra m; E D = 
earl y disc o nti n uati o n; P = pre d ose; P K = p har mac o ki netics.
N ote: if m ulti ple pr oce d ures ta ke place at t he sa me ti me p oi nt, t he f oll o wi n g or der of t he pr oce d ure s h o ul d be use d: E C G, vit al si g ns, 
a n d ve ni p u nct ure. W here ve ni p u nct ure a n d ot her pr oce d ures ta ke place at t he sa me ti me p oi nt, t he f oll o w i n g ti me wi n d o ws f or 
o btai ni n g bl o o d sa m ples s h o ul d be mai ntai ne d: > 0 t o 2 h o urs p ost d ose: ± 5 mi n utes; 2. 5 t o 6 h o urs p ost d ose: ± 1 0 mi n utes; 7 t o 1 2 
h o urs p ost d ose: ± 2 0 mi n utes; 2 4 t o 4 8 h o urs p ost d ose: ± 3 0 mi n utes ; ≥7 2 h o urs p ost d ose: ± 1 2 0 mi n utes. W here re peats of s u pi ne 
vital si g n meas ure me nts are re q uire d, re peats s h o ul d be perf or me d after ve ni p u nct ure.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
1 4
P art 2 – R os u v ast ati n / L as mi dit a n
Scree n
i n g
D a ys
E D
F oll o w -
U p
C o m me nts
Pr oce d ure
- 4 5 t o -
2 da y s 
pri or 
t o 
Da y 1
- 1
1
2
3
4
5
6
7
8
9
1 0
1 1
1 2
1 3
D a y 1 6 
+/ - 1 da y
I nf or me d c o nse nt  
X
I ncl usi o n a n d e xcl usi o n 
criteria
X
De m o gra p h y
X
Partici pa nt a d missi o n t o 
C R U
X
X
Partici pa nt d isc har ge 
fr o m C R U
X
X
At t he i n vesti gat or’s 
discreti o n, partici pa nts 
m a y  re mai n i n patie nt after 
Da y  3 or 1 2.
Past a n d c urre nt 
m e dical h ist or y 
(i ncl u des s u bsta nce 
usa ge [a n d fa mil y 
hist or y  of pre mat ure 
car di o vasc ular disease])
X
F ull p h ysical 
e xa mi nati o n i ncl u di n g 
hei g ht a n d wei g ht
X
A s ym pt o m -directe d 
p h y sical e xa mi nati o n ma y 
be perf or me d at ot her 
ti mes at t he discreti o n of 
t he i n vesti gat or.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
1 5
Scree n
i n g
D a ys
E D
F oll o w -
U p
C o m me nts
Pr oce d ure
- 4 5 t o -
2 da y s 
pri or 
t o 
Da y 1
- 1
1
2
3
4
5
6
7
8
9
1 0
1 1
1 2
1 3
D a y 1 6 
+/ - 1 da y
Ser u m or uri ne 
pre g na nc y test ( w o me n 
of c hil d beari n g 
p ote ntial o nl y)
X  
X
X
X
Ser u m pre g na nc y test will 
be perf or me d at scree ni n g.
Ur i ne pr e g na nc y test will 
be perf or me d at e ver y 
a d missi o n peri o d a n d at 
p ostst u d y, if a p plica ble.
H u ma n 
i m m u n o deficie nc y 
vir us, he patitis B a n d C 
scree ni n g
X
1 2 -lea d 
electr ocar di o gra m 
( E C G)
X
P  
X
P  
X
Vital si g ns (s u pi ne)
X
P, 1, 
2 h
2 4
h
P
P, 1, 
2 h
2 4
h
X
Ti me p oi nts ma y be a d de d 
f or eac h st u d y peri o d, if 
warra nte d a n d a gree d u p o n 
bet wee n Lill y a n d t he 
i n vesti gat or.
Cli nical la b orat or y 
assess me nts (i ncl u di n g
li ver c he mistries)
X
P  
X
P
X
X
See A p pe n di x 1 0. 2 , 
Cli nical La b orat or y Tests, 
f or details. Uri nal ysis 
perf or me d at scree ni n g ,
f oll o w- u p a n d E D o nl y.
C- S S R S a n d Self-Har m 
S u p ple me nt
X
X
X
“ Baseli ne” q uesti o n naire t o 
be use d at scree ni n g, all 
ot her ti me p oi nts use 
“ Si nce Last Visit” 
q uesti o n naire . T he Self -
Har m S u p ple me nt s h o ul d 
be c o m plete d e ver y ti me 
t he C-S S R S is 

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
1 6
Scree n
i n g
D a ys
E D
F oll o w -
U p
C o m me nts
Pr oce d ure
- 4 5 t o -
2 da y s 
pri or 
t o 
Da y 1
- 1
1
2
3
4
5
6
7
8
9
1 0
1 1
1 2
1 3
D a y 1 6 
+/ - 1 da y
a d mi nistere d. If, base d o n 
a d mi nistrati o n of t he C -
S S R S, it is deter mi ne d t hat 
s uici de-relate d be ha vi ors 
ha ve occ urre d, t he n t he 
Self -Har m F oll o w -U p 
f or m will be use d t o c ollect 
a d diti o nal i nf or mati o n . T he 
Da y  7 assess me nt ca n be 
perf or me d u p t o pre -d ose 
o n Da y  8.
Ge netic sa m ple
X
Tra ns p o rt er ge n ot y pi n g
X
P K sa m ples -
ros u vastati n ( plas ma)
P , 
0. 5, 1, 
1. 5, 2, 
2. 5, 3, 
4, 5, 
6, 8, 
1 2 h
2 4 
h
4 8 
h
7 2 
h
P , 
0. 5, 1, 
1. 5, 2, 
2. 5, 3, 
4, 5, 
6, 8, 
1 2 h
2 4 
h
4 8 
h
7 2 
h
Bl o o d dr a w at 7 2 h o urs
will be perf or me d at a n
o ut patie nt visit .
P K sa m ples -
las mi dita n/ M 8 ( plas ma)
P,
0. 5, 1, 
1. 5, 2, 
4, 8, 
1 2 h
2 4
, 
3 6 
h
4 8 
h
7 2 
h
Bl o o d dra w at 7 2 h o urs 
will be perf or me d at 
o ut patie nt visit.
St u d y i nter ve nti o n
a d mi nistrati o n
X
X  
X  
X
R os u vastati n t o be gi ve n 
o n Da y  1 ( Peri o d 1). 

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
1 7
Scree n
i n g
D a ys
E D
F oll o w -
U p
C o m me nts
Pr oce d ure
- 4 5 t o -
2 da y s 
pri or 
t o 
Da y 1
- 1
1
2
3
4
5
6
7
8
9
1 0
1 1
1 2
1 3
D a y 1 6 
+/ - 1 da y
Las mi dita n t o be gi ve n o n 
Da ys 8, 9 , a n d 1 0 wit h a 
si n gle d ose of r os u vastati n
c o-a d mi nistere d wit h 
las mi dita n o n Da y 1 0 
( Peri o d 2).
A d verse e ve nt/ seri o us 
a d verse e ve nt re vie w
X
= = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = 
X
C o nc o mita nt 
me dicati o n re vie w
X
= = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = 
X
A b bre viati o ns: C R U = cli nical researc h u nit; C- S S R S = C ol u m bia -S uici de Se verit y Rati n g Scale; E C G = electr ocar di o gra m; E D = earl y 
disc o nti n uati o n; P = pre d ose ; P K = p har mac o ki netics.
N ote: if m ulti ple pr oce d ures ta ke place at t he sa me ti me p oi nt, t he f oll o wi n g or der of t he pr oce d ure s h o ul d be use d: E C G, vit al si g ns, a n d 
ve ni p u nct ure. W here ve ni p u nct ure a n d ot her pr oce d ures ta ke place at t he sa me ti me p oi nt, t he f oll o wi n g ti me wi n d o ws f or o btai ni n g bl o o d 
sa m ples s h o ul d be mai ntai ne d: > 0 t o 2 h o urs p ost d ose: ± 5 mi n utes; 2. 5 t o 6 h o urs p ost d ose: ± 1 0 mi n utes; 7 t o 1 2 h o urs p ost d ose: ± 2 0 mi n utes; 2 4 
t o 4 8 h o urs p ost d ose: ± 3 0 mi n utes ; ≥7 2 h o urs p ost d ose: ± 1 2 0 mi n utes . Wh er e  re peats of s u pi ne vital si g n meas ure me nts are re q uire d, re peats 
s h o ul d be perf or me d after ve ni p u nct ure.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
1 8
2.
I ntr o d ucti o n
Las mi dita n ( L Y 5 7 3 1 4 4) is a hi g hl y selecti ve a n d p ote nt a g o nist at t he 5 -h y dr o x ytr y pta mi ne 1 F 
( 5-H T 1 F) rece pt or. Las mi dita n has bee n d e vel o pe d b y Eli Lill y a n d C o m pa n y ( Lill y), a n d 
a p pr o ve d b y t he U S F o o d a n d Dr u g A d mi nistrati o n ( F D A), f or t he ac ute treat me nt of mi grai ne 
attac ks, wit h or wit h o ut a ura, i n a d ults. F ull details of t he precli nical a n d cli nical safet y a n d 
t olera bilit y data are c o ntai ne d i n t he I n vesti gat or’s Br oc h ure (I B). 
2. 1.
St u d y R ati o n ale
P- gl yc o pr otei n ( P -g p) a n d breast ca n cer resista nce pr otei n ( B C R P) are me m bra ne -b o u n d, effl u x 
tra ns p orters l ocate d i n t he s mall i ntesti ne, c ol on, a n d li ver (a m o n g ot her tiss ues), ser vi n g t o li mit 
t he a bs or ptio n of  dr u gs fr o m t he gastr oi ntesti nal tract a n d t o i ncrease biliar y s e cr etio n of  dr u gs 
a n d t heir meta b o lites. Certai n s u bstrates of B C R P or P -g p ha ve bee n s h o w n t o ha ve cli nicall y 
sig nifica nt dr u g i nteracti o ns w he n a d mi nistere d wit h i n hi bit ors of B C R P or P -g p, res pecti vel y 
(I nter nati o nal Tra ns p orter C o ns orti u m et al. 2 0 1 0).
T he p ote ntial f or las mi dita n a n d its meta b o lites t o i n hi bit effl u x tra ns p orters P- g p a n d B C R P was
assesse d i n vitr o. T he i ntesti nal dr u g -dr u g i nteracti o n ( D DI ) i n de x ( d ose/ 2 5 0 m L
[I 2]/c o nce ntrati o n of dr u g ca usi n g half -ma xi mal i n hi bit or y  effect [I C5 0]) was deter mi ne d f or b ot h 
P- g p a n d B C R P i n hi bit i on i n t he c o nte xt of a 2 0 0- m g d ose, t he ma xi m u m a p pr o ve d d ose ( F D A 
2 0 2 0a). T he calc ulate d D DI i n de x was 1 6 f or B C R P a n d 2 5 f or P -g p. B ot h t hese val ues e xcee d 
t he F D A c ut off val ue of 1 0, i n dicat i n g t hat las mi dita n has t he p ote ntial t o i n hi bit P-g p a n d B C R P 
i n t he cli nic.
T his st u d y  ai ms t o e valuate t he safet y , t olera bilit y, a n d p har mac o ki net ics (P K ) of  r os u vastati n 
a n d da bi gatra n i n t he prese nce of las mi dita n. R os u vastati n a n d da bi gatra n ete xilate are se nsit i ve 
s u bstrates of effl u x tra ns p orters, B C R P a n d P-g p , res pecti vel y ( FD A 2 0 2 0 b ).
2. 2.
B ac k gr o u n d
I n pre vi o us st u dies, f oll owi n g si n gle oral  d ose a d mi nistratio n of  las mi dit a n t o a d ult partici pa nts , 
las mi dita n was a bs or be d wit h a me dia n ti me of ma xi m u m o bser ve d dr u g c o nce ntrati o n ( tma x ) of  
1. 8 h o urs, a n d ra pi dl y eli mi nate d wit h a mea n half -life ass ociate d wit h t he ter mi nal eli mi nati on 
p hase ( t1/ 2) of  a p pr o xi matel y 5. 7 h o urs. Las mi dita n u n der g oes e xte nsi ve he pat ic a n d e xtra he patic 
meta b o lis m with ket o ne re d ucti o n t o i nact i ve met a b o lite M 8 as t he major bi otra nsf or mati o n 
pat h wa y . N o acc u m ulat i on of las mi dita n was o bser ve d wit h dail y d osi n g. M ore detaile d 
i nf or mat i on a b o ut t he P K a n d a bs or ptio n, di stri b uti o n, meta b olis m, a n d e xcret i on pr o perti es of 
las mi dita n ma y b e fo u n d i n t he I B.
Da bi gatra n ete xilate, a c o m p et iti ve, direct t hr o m bi n i n hi bit or, is a P-g p s u bstrate. F oll o wi n g 
a bs or ptio n, da bi gatra n ete xilate is h y dr ol yze d t o f or m da bi gatra n, t he acti ve m oiet y.  Da bigatra n 
c o nce ntrati o ns reac h tma x wi t hi n 2 h o urs of a d mi nistrati o n, a n d t he n c o nce ntrati o ns decli ne i n a 
bi p hasic ma n ner, wit h a ter mi nal t1/ 2 of  1 2 t o 1 7 h o urs. Da bi gatra n is pri maril y eli mi nate d 
t hr o u g h re nal e xcreti o n a n d d oes n ot a p pear t o be a s u bstrate f or re nal tra ns p orters base d o n t he 
re p orte d re nal cleara nce of  8 9 m L/ mi n (Sta n gi er 2 0 0 8) . Da bi gatra n itself is n ot a s u bstrate f or t he 
c yt o c hr o me P 4 5 0 ( C Y P ) famil y of meta b o lizi n g e nz y me n or a s u bstrate f or P-g p, mea ni n g t hat 

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
1 9
c ha n ges i n da bi gatra n e x p os ure f o ll owi n g a d mi nistrati o n of a P -g p i n hi bit or w o ul d be a nt ici pate d 
t o o nl y reflect t he acti vity of  t h e in hi bit i on of da bi gatra n ete xilate tra ns p ort at t he i ntest i nal wall
( Sta n gier 2 0 0 8). Pre vi o us st u dies ha ve i n vesti gate d t he effec t of P-g p i n hi bit ors o n da bi gatra n
P K. Da bi gatra n area u n der t he c o nce ntrati o n vers us ti me c ur ve ( A U C ) i ncrease d b y 5 8 % a n d 
5 3 % w he n c o -a d mi nistere d wit h a mi o dar o ne a n d q ui ni di ne , res pecti vel y ( Pra da xa® Prescri bi n g 
I nf or mat i on , 2 0 1 0). Ket oc o naz ole, a str o n g P-g p i n hi bit or, i ncrease d da bi gatra n A U C a n d C ma x
val ues b y 1 3 8 % a n d 1 3 5 %, res pecti vel y , after a si n gle d ose of 4 0 0 m g, a n d 1 5 3 % a n d 1 4 9 %, 
res pecti vel y, aft er mul tiple dail y  4 0 0-m g d oses ( Pra da xa Prescri bi n g I nf or mat i on , 2 0 1 0).
R os u vastati n , a 3-h y dr o x y - 3-met h yl gl utar yl -c oe nz y me A re d uctase i n hi bit or i n dicate d f or 
pati e nts wit h pri mar y h y perli pi de mia, is a B C R P s u bstrate. After d ose a d mi nistrati o n, 
r os u vastati n c o nce ntrati o ns reac h tma x a p pr o xi matel y 3 t o 5 h o urs p ost d ose a n d t he n 
c o nce ntrati o ns decli ne wit h t 1/ 2 of  a p pr o xi matel y 1 9 h o urs. A p pr o xi matel y 7 2 % of t otal 
r os u vastati n cleara nce is he patic, wit h t he maj ority of t his cleara nce occ urri n g t hr o u g h biliar y 
e xcret i on; a p pr o xi matel y 1 0 % of a n a d mi nistere d d ose of r os u vastati n is meta b o lize d, pri maril y 
via C Y P 2 C 9. U nli ke ma n y  ot her B C R P s u bstrates, h o we ver, r os u vastati n is neit her meta b olize d 
b y C Y P 3 A t o a cli nicall y si g nifica nt e xte nt, n or is it a s u bstrate f or P -g p ( Crest or ® Prescri bi n g 
I nf or mat i on , 2 0 2 0 ). Pre vi o us st u dies ha ve i n vesti gate d t he effect of B C R P i n hi bit ors o n 
r os u vastati n P K. R os u vastati n A U C i ncrease d b y 6 0 % a n d 6 1 0 % w he n c o -a d mi nistere d wit h 
B C R P i n hi bit ors, eltr o m b o pa g a n d c yclos p ori ne (Crest or Prescri bi n g I nf or mat i on , 2 0 2 0 ).
2. 3.
Be nefit/ Ris k Assess me nt
T he d ose of  las mi dita n t o be gi ve n i n t his st u d y is 2 0 0 m g. I n pre vi o us healt h y v ol unt eer st u dies, 
d oses of las mi dita n u p t o 4 0 0 m g ha ve bee n gi ve n as si n gle or m ult i ple d oses u p t o 7 da ys.
Las mi dita n has bee n ass ociate d wit h a mea n decrease i n heart rate of 5 t o 1 0 b p m c o m pare d t o 2 
t o 5 b p m for pl ace b o. A d dit i onall y, i n n o nel derl y healt h y v o l unt eers a sli g ht mea n i ncrease i n 
bl o o d press ure of 2 t o 3 m m H g was o bser ve d 1 h o ur after d osi n g. N o a d dit io nal fi n di n gs o n vital 
sig ns were n ote d f oll owi n g o nce -dail y d osi n g f or 7 da y s (H 8 H -M C -L A H E). Ner v o us s yst e m 
di s or ders, i ncl u di n g dizzi ness, fati g ue, a n d parest hesia a n d se dat i on were c o m m o nl y re p orte d as 
a d verse e ve nts (A Es ) (≥5 % a n d > place b o) i n t he P hase 2/ 3 p o ol, es peciall y at hi g her d ose 
le vels; t he y were ge nerall y mil d or m o derate i n i nt e nsit y. O verall, i n pre vi o us healt h y v o l unt eer 
st u dies t hese c ha n ges were well t olerate d. F urt her i nf or mat i on a b o ut a d verse dr u g reacti o ns ca n 
be f ou n d i n t he U S P rescri bi n g Inf or m at i on ( Re y v o w Prescri bi n g I nf or mat i on , 2 0 2 0).
Dri vi n g s h o ul d be a v o i de d f or at least 8 h o urs, a n d partici pa nts will re mai n i n t he cli nical 
researc h u nit ( C R U) f or 4 8 h o urs p ost d ose.
Da bi gatra n ete xilate a n d r os u vastati n d oses t o be a d mi nistere d i n t his st u d y ( 1 5 0 mg a n d 1 0 m g, 
res pecti vel y) are wit hi n t he t hera pe utic ra n ge (see Secti o n 4. 3 ), a n d ha ve pre vi o usl y bee n 
a d mi nistere d t o healt h y v o l unt eers wit h n o t ol era bilit y c o ncer ns i n ot her D DI st u dies (St u d y  I 8 D-
M C -A Z E E [ A Z E E]; N C T0 2 5 6 8 3 9 7 a n d St u d y I 8 D-M C -A Z E B [ A Z E B]; N C T0 3 0 1 9 5 4 9)].
T here i s n o a nticipate d t hera pe uti c be nefit for t he parti ci pa nts i n t his trial. H o we ver, partici pa nts 
ma y be nefit fr o m t he scree nin g pr oce d ures (t hr o u g h detecti o n of u n k n o w n healt h iss ues) e ve n if 
t he y recei ve n o t hera pe utic be nefit fr o m t he trial.
M ore detaile d i nf or mat i on a b o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks a n d reas o na bl y 
e x pecte d A E s of  las mi dita n ma y be f ou n d i n t he I B.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
2 0
3.
O bjecti ves a n d E n d p oi nts
O bject i ves
E n d p oi nts
Pri mar y

T o e val uate t he effect of las mi dita n o n 
P- g p a n d B C R P acti vit y i n health y 
parti ci pa nts

C ma x a n d A U C ( 0-∞) of  da bi gatra n t o 
assess P- g p acti vit y a n d r os u vastati n 
t o assess B C R P act i vity
Sec o n dar y

T o e val uate t he safet y a n d t olera bilit y 
of  da bi gatra n ete xilate or r os u vastati n 
i n c o m bi nat i on wi t h las mi dita n i n 
healt h y parti ci pa nts

T o e val uate t he p har mac o ki net ics of 
las mi dita n a n d M 8

A s u m mar y  of t he n u m ber of 
treat me nt -e mer ge nt a d verse e ve nts 
a n d serio us a d verse e ve nts

C ma x , tma x , a n d A U C ( 0-∞) of  
las mi dita n a n d M 8
A b bre viati o ns: A U C ( 0-∞) = area u n der t he c o nce ntrati o n vers us ti me c ur ve fr o m zer o t o i nfi nit y; B C R P = breast 
ca ncer resista nce pr otei n; C ma x = ma xi m u m o bser ve d dr u g c o nce ntrati o n ; P- g p = p -gl y c o pr otei n; tma x = ti me 
of ma xi m u m o bser ve d dr u g c o nce ntrati o n.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
2 1
4.
St u d y Desi g n
4. 1.
O ver all Desi g n
T his is a P hase 1, t w o-part, t w o -peri o d, o pe n -la bel st u d y i n healt h y partici pa nts. Part 1 will st u d y 
da bi gatra n P -g p D DI wi t h las mi dita n. Part 2 will st u d y r os u vastati n B C R P D DI wit h las mi dita n.
Parts 1 a n d 2 will ha ve a si milar desi g n, i.e. , da bi gatra n et e xilate or r os u vastati n a d mi nistrati o n 
alo ne i n P eri o d 1 (D a y  1) f oll owe d b y a bri ef was h o ut, t he n las mi dita n o n Da y s 8, 9, a n d 1 0
(Peri o d 2 ) wit h c o ad mi nistrati o n of da bi gatra n ete xilate or r os u vastati n wit h las mi dita n o n Da y  
1 0. Eac h part will c o nsist of differe nt partici pa nts a n d t he 2 parts ma y r u n i n parallel. Parti ci pa nts 
f or b ot h P art 1 a n d P art 2 will be c o nse nte d wit h a si n gle c o nse nt f or m, a n d b ot h ge n ot y pi n g a n d 
c oa g ulat i on tests will be perf or me d f or b ot h parts d uri n g scree ni n g. Part 2 will be pri orit ize d t o 
c o mplete first d ue t o a n a ntici pate d scree n fail rate of ~ 5 0 % sec o n dar y  t o ge n ot ype cri t eria. O nce 
Part 2 has ac hie ve d last pa rtici pa nt d ose d, n o f urt her ge n ot y pi n g will be nee de d f or L AI O 
scree ni n g. Partici pa nts w h o faile d P art 2 scree ni n g d ue t o ge n ot ypi n g o nl y  a nd ha ve a n or mal 
c oa g ulat i on pr ofile will a ut o mat icall y be eli gi ble f or P art 1.
4. 1. 1.
N u m ber of P artici p a nts
A p pr o xi matel y  7 2 parti cip a nts will be e nr olle d t o P art 1 of t he st u d y t o e ns ure t hat at least 6 2
e val ua ble part ici pa nts c o mplete t hat part. A p pr o xi matel y 3 2 parti ci pa nts will be e nr olle d t o P art 
2 t o e ns ure t hat at least 2 8 e val ua ble parti ci pa nts c o mplete t hat part. F or t he p ur p o ses of t his 
st u d y, a parti ci pa nt c o m p letes t he st u d y w he n all sc he d ule d pr oce d ures s h o w n i n t he Sc he d ule of 
Act i vities ( Secti o n 1. 3 ) ha ve bee n fi nis he d.
4. 2.
Scie ntific R ati o n ale f or St u d y Desi g n
T he st u d y  has a n o pe n-la bel, fi xe d-se q ue nce, 2- part desi g n i n w hic h eac h s u bject recei ves eit her 
da bi gatra n ete xilate or r os u vastati n al o ne ( Parts 1 a n d 2, res pecti vel y) , a n d las mi dita n alo ne f or 2
c o nsec ut i ve da ys f o ll owe d b y  las mi dit a n c o -a d mi nist ere d wi t h eit her da bi g atr a n ete xilate or 
r os u vastati n, allo wi n g eac h s u bject t o act as his/ her o w n c o ntr ol f or safet y a n d P K c o m par is o ns.
T he was h o ut peri o d bet wee n da bi gatra n ete xilate or r os u vastati n d oses of 7 days is c o nsi dere d 
s ufficie nt base d o n t he half-life of da bi gatra n of 1 2 t o 1 7 h o urs , a n d t he half-life of r os u vastati n 
of  a p pr o xi matel y 1 9 h o urs. A 2 0 0-m g d ose of las mi dita n was selecte d as it is t he hi g hest 
p ote nti al rec o m me n de d d ose f or las mi dit a n. Data fr o m  mul tiple d oses of l as mi dita n 
d e m o nstrate d t hat stea d y  state was ac hie ve d b y 4 8 h o urs aft er d ose wi t h n o acc u mulat i on wi t h 
o nce -dail y  d osi n g. Gi ve n t hat patie nts ma y ta ke las mi dita n o n c o nsec ut i ve da ys, 3 -d a y  d osi n g 
wi t h las mi dit a n is dee me d t o be a p pr o priate.
H u m a n B C R P (e nc o de d b y t he ge ne A B C G 2) is p ol y m or p hic. Parti ci pa nts wi t h t he c. 4 2 1 C > A 
a n d c. 3 4 G > A p ol y m or p his ms, s pecificall y t he c. 3 4 A A, c. 4 2 1 A A, a n d c. 3 4 G A/ 4 2 1 C A 
ge n ot y pes, will be e xcl u de d beca use t hese ge net ic p ol y m or p his ms are ass ociate d wit h i m paire d 
B C R P acti vit y ( F ur u ka wa et al. 2 0 0 9 ; Kes kital o et al. 2 0 0 9 ; Wa n et
al. 2 0 1 5). Beca use t he 
acti vit y of  B C R P is i m paire d wit h t hese parti cipa nts , it w o uld be a nt ici pate d t hat e ve n c o m plete 
i n hi biti on o f B C R P w o ul d n ot res ult i n a s u bsta nt ial c ha n ge i n r os u vastati n e x p os ure. 
Acc or di n gl y , e xcl u di n g parti ci pa nts wi t h t hese p ol y mor p his ms will e ns ure t hat t he “ w orst -case” 
i nteract i on bet wee n las midi t a n a n d r os u vastati n will be e val uate d i n t his st u d y.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
2 2
T he h u ma n o r ga nic a ni on- tra ns p ortin g p o l y pe pti de 1 B 1(O A T P 1 B 1 ) tra ns p orter (als o k n o w n as 
S L C O 1 B 1) is als o p ol y m or p hic. T o e val uate w orst -case i nteracti o ns bet wee n las mi dita n a n d 
r os u vastati n, partici pa nts wi t h t he c. 5 2 1 T C or c. 5 2 1 C C p ol y m or p his m s will  be e xcl u de d fr o m 
t his st u d y beca use t hese ge net ic p ol y m or p his ms ar e ass ociate d wit h decrease d tra ns p orti n g 
acti vit y of  O A T P 1 B 1 ( Nie mi et al. 2 0 1 1) a n d hi g her plas ma r os u vastati n c o nce ntrati o ns ( Crest or 
Prescri bi n g I nf or mat i on , 2 02 0 ).
4. 2. 1.
P artici p a nt I n p ut i nt o Desi g n
T hr o u g h o ut t his pr ot oc ol, t he ter m “partici pa nt ” is use d t o i n dicate a n i n di vi d ual w h o partici pates 
i n a cli nical trial, eit her as a reci pie nt of a n i n vesti gati o nal i nter ve nti on or as a c o ntr ol. T his 
usa ge reflects prefere nces i n dicate d b y  patient  a d v ocates t o m ore acc uratel y reflect t he r ole of 
pe o pl e w h o ta ke part i n cli nical trials.
4. 3.
J u stific ati o n f or D ose
Da bi gatra n ete xilate is c urre nt l y a p pr o ve d i n t he U S t o re d uce t he ris k of str o ke a n d s yste mic 
e m b o lis m i n patient s wit h n o n val v ular atrial fi brillati o n, f or t he treat me nt of dee p ve n o us 
t hr o mb osis a n d p ul m o nar y  e mb o lism,  a n d t o re d uce t he ris k of rec urre nce of dee p ve n o us 
t hr o mb osis a n d p ul m o nar y  e mb o lism ( Pra da xa Prescri bi n g I nf or mati o n, 2 0 1 0). T he 
rec o m me n de d d ose f or da bi gatra n ete xilate is 1 5 0 m g t wice dail y f or patie nts wit h creati ni ne 
cleara nc e > 3 0 mL/ mi n ( Pra da xa Prescri bi n g I nf or mat i on , 2 0 1 0). Si n gle oral d oses of 1 0 t o 4 0 0 
m g da bi gatra n ete xilate ha ve bee n a d mi nistere d t o healt h y parti ci pa nts an d were well t olerate d 
( Sta n gier et al. 2 0 0 8 ). C o a d mi nistrati o n of da bi gatra n ete xilate wit h las mi dita n ma y i ncrease 
da bi gatra n e x p os ure. T he selecte d 1 5 0 -m g d ose f or t his st u d y  s h o uld pr o vi de a de q uate pl as ma 
da bi gatra n c o nce ntrati o ns t o a d dress t he st u d y  o bjecti ves wit h mi ni mal ris k o f A Es ( Härtter et al. 
2 0 1 3 ).
R os u vastati n is c urre n tly a p pr o ve d i n t he U S as a n a dj u nct t o diet f or t he treat me nt of a d ult 
pati e nts wit h pri mar y h y perli pi de mia, mi xe d d ysli pi de mia, h y pertri gl yceri de mia or pri mar y 
d y s betalip o pr otei ne mia ( T y pe III h y perli p o pr otei ne mia), a n d f or t he slo wi n g t he pr o gressi o n of
at her oscler osis, ris k re d uctio n of  m y ocar dial  inf ar cti o n , str o ke, a n d arterial re vasc ularizati on 
pr oce d ures i n patie nts wit h o ut cli nicall y e vi de nt c hr o nic heart disease, b ut wit h mul tiple ris k 
fact ors ( Crest or Prescri bi n g I nf or mat i on , 2 0 2 0 ). R o s u vastati n is c o m m onl y a d mi nistere d t o 
a d ults at a n oral d ose of 5 t o 4 0 m g o nce -dail y , wit h t h e majori t y of t he cli nical D DI or 
p har mac o ge net ic st u dies c o n d ucte d usi n g a 1 0- or 2 0- m g d ose ( Lee et al. 2 0 1 5; Crest or 
Prescri bi n g I nf or mat i on , 2 0 2 0). R o s u vastati n a d mi nistere d orall y at a d ose of 1 0 m g is s u g geste d 
as a g o o d cli nical pr o be f or b ot h he pat ic a n d i ntesti nal B C R P f u ncti on ( Lee et al. 2 0 1 5).
C oa d mi nistrati o n of r os u vastat i n with las mi dita n ma y i ncrease r os u vastati n e x p os ure. T he 1 0- m g 
r os u vastati n d ose selecte d f or t his st u d y s h o uld pr o vi de a de q uate pl as ma r os u vastatin 
c o nce ntrati o ns t o a d dress t he st u d y o bject i ves wit h mi ni mal ris k o f A Es.
T he d ose le vel o f 2 0 0 m g i s t he hi g hest a p pr o ve d f or las mi dita n. D oses u p t o 4 0 0 m g ha ve bee n 
well t olerate d i n pre vi o us st u dies i n healt h y partici pa nts.
T he d oses will be a d mi nistere d at a p pr o xi matel y t he sa me t i me o n eac h treat me nt da y . T he act ual  
ti me of all d ose a d mi nistrati o ns will be rec or de d i n t he partici pa nt’s electr o nic case re p ort f or m
( C R F).

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
2 3
4. 4.
E n d of St u d y Defi niti o n
A partici pa nt is c o nsi dere d t o ha ve c o m p lete d t he st u d y if he/s he has c o m p lete d all re q uire d 
p hases of t he st u d y  s h o w n i n t he Sc he d ule of Acti vities ( S o A) wit h s ufficie nt P K f or a nal ysis .
T he e n d o f t he st u d y is defi ne d as t he date of t he last visit of t h e last partici pa nt i n t he st u d y or 
last sc he d ule d pr oce d ure sh o w n i n t he S o A f or t he last partici pa nt i n t he trial gl oball y .

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
2 4
5.
St u d y P o p ul ati o n
Eli gi bilit y of  p artici pa nts f or e nr oll me nt i n t he st u d y will be base d o n t he res ults of scree ni n g 
me dical hist or y , p h ysical e xa mi nati on, vital si g ns, cli nical la b orat or y  t ests, a n d 
electr ocar dio gr a m  ( E C G).
T he i ncl usi o n a n d e xcl usi o n cri t eria use d t o deter mi ne eli gi bilit y s h o uld be a p plie d at scree ni n g 
o nl y , a n d n ot c o nti n u o usl y t hr o u g h o ut t he trial.
Scree ni n g ma y occ ur u p t o 4 5 da ys pri or t o e nr oll me nt. Parti cipa nts w h o are n ot e nr olle d wit hi n 
4 5 d a y s of scree ni n g ma y u n der g o a n a d ditio nal me di cal assess me nt a n d/ or cli nical 
meas ure me nts t o c o nfir m t heir eli gi bilit y. I n s uc h i nsta nces, re peat t he f o ll owi n g scree ni n g tests 
a n d pr oce d ures: c li nical la b orat ory assess me nts a n d vital si g ns .
Pr os pecti ve a p pr o val o f pr ot oc ol  de viatio ns t o recr ui t me nt a n d e nr o ll me nt criteria, als o k n o w n as 
pr ot oc ol  wai vers or e xe m pti ons, is n ot per mitte d.
5. 1.
I ncl usi o n Criteri a
P arti cipa nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if all of t he fol l owi n g criteria a p pl y at 
scree ni n g. C o nti n ue d eli gi bilit y will be assesse d t hr o u g h ser u m pre g na nc y  (fe males o nl y) o n t he 
d a y  of a d missio n  t o t he C R U .
T y pe of P artici p a nt a n d Dise ase C h ar acteristics
1.
m ust be a ge d 2 1 t o 7 0 years , i ncl usi ve, at t he ti me of si g ni n g t he i nf or me d c o nse nt
2.
ha ve a b o d y  mass i n de x of 1 8. 5 t o 3 5. 0 k g/ m 2, i ncl usi ve, at t he ti me of scree ni n g
3.
w h o are o vertl y  he alt h y as deter mi ne d t hr o u g h me di cal e val uat i on i ncl u di n g me dical 
hist or y , p h ysical e xa mi nati on, a n d vit al sig ns
4.
ha ve cli nical la b orat or y  test res ults wit hi n n or mal refere nce ra n ge f or t he p o p ulati o n or 
C R U or res ul ts wit h acce pta ble de viati ons t hat are j u d ge d t o be n ot cli nicall y si g nifica nt 
b y t he i n vesti gat or (f or e xa m ple, est i mate d gl omer ul ar filtr atio n rate > 6 0 ml/ mi n/ 1. 7 3 m 2
a n d li ver f u ncti o n tests < 2 x U L N)
5.
ha ve a he m o gl o bi n le vel of ≥1 2. 5 g/ d L f or m ales or ≥1 1. 4 g/ d L f or fe males at t he ti me 
of  scree ni n g
6.
ha ve ve n o us access s ufficie nt t o all o w f or bl o o d sa m pli n g as per t he pr ot oc ol
7.
are relia ble a n d willi n g t o m a ke t he msel ves a vaila ble f or t he d urati o n of t he st u d y a n d are 
willi n g t o f oll o w st u d y  pr oce d ures
Se x
8.
m ale or f e male
C o ntrace pti ve use b y me n or w o me n s h o ul d be c o nsiste nt wit h l ocal re g ulat i ons re gar di n g 
t he met h o ds of c o ntrace pti o n f or t h ose partici pat i n g i n cli nical st u dies.
Male parti ci pa nts:
o
are n ot re q uire d t o a d here t o c o ntrace ptive re q ui re me nts

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
2 5
Fe male partici pa nts:
o
Fe male partici pa nts of c hil d beari n g p ote ntial (see A p pe n di x 1 0. 4 ) w h o are 
a bsti ne nt (if t his is c o m plete a bsti ne nce, as t heir preferre d a n d us ual lifest yle) or 
i n a sa me se x relat i ons hi p (as part of t hei r preferre d a n d us ual lifestyle) m ust 
a gree t o eit her re mai n a bst i ne nt or sta y i n a sa me se x relati o ns hi p wit h o ut se x ual 
r elat i ons hi ps wit h ma les. Peri o dic a bsti ne nce (e. g., cale n dar, o v ulat i on, 
s y m pt ot her mal, p ost-o v ul at i on met h o ds), decl arati o n of a bst i ne nce j ust f or t he 
d urati o n of  a trial, a n d wit hdra wal  are n ot acce pta ble met h o ds of c o ntrace pti o n.
o
Fe male parti ci pa nts of  c hil d beari n g p ote ntial, w h o are n ot a bsti ne nt as descri be d 
earlier , must a gree t o use a hi g hl y effect i ve met h o d of c o ntrace pti o n (i.e. , o ne 
wi t h less t ha n 1 % fail ure rate) s uc h as c o m bi nat i on or oral c o ntrace pti ves, 
i m pla nte d/i njecte d c o ntrace pti ves, i ntra uteri ne de vices, or sterile part ner u ntil 3 0 
da ys after t he last d ose of st u d y  me dicat i on.
o
Fe male parti ci pa nts n ot of c hil d beari n g p ot e ntial are n ot re q uire d t o use 
c o ntrace pti o n. T his i ncl u des fe males w h o are:

infertile d ue t o s ur gical sterilizati on ( h ysterect o m y, bilateral 
o o p h orect o m y , or t u bal li gati on) or c o n ge nital a n o mal y ( e. g. ,
M ülleria n a ge nesis)

p os t me n o pa usal as defi ne d i n A p p e n di x 1 0. 4 .
I nf or me d C o nse nt
9.
ca pa ble of gi vi n g si g ne d i nf or me d c o nse nt as descri be d i n A p pe n di x 1 0. 1 w hic h i ncl u des 
c o mplia nce wi t h t he re q uir e me nts a n d restrict i ons liste d i n t he i nf or me d c o nse nt f or m 
(I C F) a n d i n t his pr ot oc ol
5. 2.
E xcl usi o n Criteri a
P arti cipa nts are e xcl u de d fr o m  t he st u d y if a n y of t he f o ll owi n g cri t eria a p pl y:
Me dic al C o n diti o ns
1.
ha ve a p osit i ve pre g na nc y test at scree ni n g or Da y - 1 of  eac h perio d
2.
are pla n ni n g t o bec o me pre g na nt d uri n g t he st u d y  or wit hi n 1 mo n t h of st u d y c o mplet i on
3.
a re w o me n w h o are lactati n g
4.
h a ve k n o w n aller gies t o las mi dita n, da bi gatra n, r os u vastati n -relate d c o mp o u n ds or a n y  
c o mp o ne nts of t he f or m ulat i on of  las mi dit a n, da bi gatra n, r os u vastati n, or a hist or y  of 
sig nifica nt at o p y
5.
a hist or y of si g nifica nt aller gic reacti o ns t o me dicati o ns or f o o d pr o d ucts
6.
h a ve a n a b n or mal blo o d press ure a n d/ or p ulse rate as deter mi ne d b y  t he i n vesti gat or
7.
c li nicall y si g nifica nt a b n or malit ies o n E C G as deter mi ne d b y i n vesti gat or
8.
h a ve a hist or y or prese nce of car di o vasc ular, res pirat or y, re nal, gastr oi ntesti nal, 
e n d ocri ne, he mat ol o gical, or ne ur ol o gical dis or ders ca pa ble of si g nifica nt l y alteri n g t he 
a bs or ptio n, m eta b o lis m, or eli mi nati on of dr u gs; of c o nstit uti n g a ris k w he n ta ki n g t he 

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
2 6
st u d y int er ve ntio n s; or of i nterferi n g with t he i nter pretati o n of data . A p pe n dect o m y, 
s ple nect o m y, a n d c h olec ystect o m y are c o nsi dere d as acce pta ble
9.
s h o w a hist or y of ce ntral ner v o us s yst e m c o n ditio ns s uc h as str o kes, tra nsie nt isc he mic 
attac ks, si g nif ica nt hea d tra u ma, seiz ures, ce ntral ner v o us s yste m i nfecti ons, mi grai ne, 
brai n s ur ger y , or a n y ot her ne ur olo gi cal c o n ditio ns t hat, i n t he o pi ni o n of t he i n vest i gat or, 
i ncrease t he ris k of partici pati n g i n t he st u d y
1 0. ha ve a hist or y  or prese nce of ne ur o ps y c hiatric disease (e. g., ma nic de pressi ve ill ness, 
sc hiz o p hre nia, de pressi o n) c o nsi dere d as cli nicall y si g nifica nt b y t he i n vestig at or
1 1. are, i n t he j u d g me nt of t he i n vesti gat or, acti vel y s uici dal a n d t heref ore dee me d t o be at 
sig nifica nt ris k o f s uici de
1 2. ha ve a ns were d “ yes” t o eit her Q uest i on 4 or Q uesti o n 5 o n t he “ S uici dal I deat i on” 
p orti o n of  t he C olu m bia -S ui ci de Se verit y Rati n g Scale ( C-S S R S) or ha ve a ns were d “ yes” 
t o a n y of t he s uici de-relate d be ha vi ors o n t he “S uici dal B e ha vior ” p orti o n of  t he C-S S R S , 
a n d t he ideat i on or be ha vi or occ urre d wit hi n t he past m o nt h
1 3. re g ularl y use k n o w n dr u gs of a b use
1 4. s h o w e vi de nce of h u ma n i m m u n o deficie nc y vir us i nfecti on a n d/ or p osit i ve h u ma n 
i m m u n o deficie nc y vir us a nt i b o dies
1 5. prese nce of he pat itis B s urface a nti ge n at scree ni n g or wi t hi n 6 m o nt hs pri or t o fi rst d ose 
of  st u d y int er ve nt i on
1 6. p osi tive he pat itis C a nti b o d y test res ult at scree ni n g or wit hi n 6 m o nt hs pri or t o first d ose 
of  st u d y int er ve nt i on . N O T E: Partici pa nts wit h p ositive h e pat itis C a nti b o d y d ue t o prior 
res ol ve d disease ca n be e nr olle d if a c o nfir mat or y ne gati ve h e pat itis C R N A test is 
o btai ne d
1 7. p osi tive he pat itis C R N A test res ult at scree ni n g or wit hi n 6 m o nt hs pri or t o first d ose of 
st u d y int er ve ntio n . N O T E: Test is o ptio nal a n d parti ci pa nts wit h ne gati ve h e pat itis C 
a nt i b o d y test are n ot re q uire d t o als o u n der g o h e patitis C R N A testi n g
1 8. b l oo d d o nati o n of  4 5 0 m L or more, or partici pat i on i n a cli nical st u d y t hat re q uire d a 
bl o o d v ol u me of 4 0 0 m L or m ore si nce t he last st u d y  visit wit hi n t he past 3 cale n dar 
m o nt hs. 
1 9. ha ve a n y me dical c o n dit i ons, me dical hist or y , or are ta ki n g a n y me dicati ons t hat are 
c o ntrai n dicate d i n t he da bi gatra n ete xilate or r os u vastati n la bel
Pri or/ C o nc o mit a nt T her a p y
2 0. ha ve partici pate d, wit hi n t he p ast 3 0 da ys of a d missi o n, i n a cli nical st u d y i n v ol vi n g a ny
st u d y int er ve ntio n . If t he pre vio us st u d y int er ve nt i o n has a l o n g half -life, 5 half-li ves or 
3 0 d a y s ( w hic he ver is lo n ger) s h o ul d ha ve passe d
2 1. ha ve pre vi o usl y c o m plete d or wit h dra w n fr o m t his st u d y or a n y ot her st u d y in vest i gati n g 
las mi dita n, a n d ha ve pre vi o usl y recei ve d t he i n vesti gati onal pr o d uct 
2 2. use of m o n oa mi ne o xi dase -A i n hi bit ors a n d ot her dr u gs ass ociate d wit h ser ot o ni n 
s y n dr ome (i.e. , select i ve ser ot o ni n re u pta ke i n hi bit ors, selecti ve ser ot o ni n-n ore pi ne p hri ne 
re u pta ke in hi bit ors, tri c yclic a ntide pressa nts, a n d 5 -H T 1 a g o nists) wit hi n t he 3 m o nt hs 
pri or t o t he first d osi n g occasi o n

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
2 7
2 3. are i nte n di n g t o use o ver -t he- c o u nter or prescri pt i on me dicat i on, i ncl u di n g dietar y  
s u p ple me nts, tra ditio n al  me dici nes, a n d her bal s u p ple me nts , wit hi n 1 4 da ys pri or t o 
d osi n g a n d u nt il st u d y disc har ge (a part fr o m occasi o nal aceta mi n o p he n, h or m o nal 
c o ntrace pti o n, or h or m o ne re pl ace me nt t hera p y)
Pri or/ C o nc urre nt Cli nic al St u d y E x perie nce
2 4. are c urre ntl y e nr olle d i n a n y ot her cli nical st u d y in v o l vi n g a n i n vesti gati onal pr o d uct or 
a n y ot her t ype of me dical researc h j u d ge d n ot t o be scie nt ificall y or me dicall y c om pat i ble 
wi t h t his st u d y
Ot her E xcl usi o ns
2 5. ha ve a n a vera ge wee kl y  alc o h ol int a ke t hat e xcee ds 2 1 u nits per wee k ( males a ge d ≤6 5 
years) a n d 1 4 u nits per wee k (fe males [a n d males a ge d > 6 5 years ); 1 u nit = 1 2 oz or 3 6 0 
m L o f beer; 5 oz or 1 5 0 m L of wi ne; 1. 5 oz or 4 5 m L o f di stille d s pirit(s), or ha ve a 
p osi tive et ha n o l test at scree ni n g or a d missi o n
2 6. are u n willi n g t o st o p alc o h o l c o ns u m pt i on 4 8 h o urs pr i or t o a d missi on i n Peri o ds 1 a n d 2, 
a n d w hile resi de nt at t he C R U. At all ot her ti mes, parti ci pa nts m ust a gree t o c o ns u me n o 
m o re t ha n 2 u nits per da y
2 7. are s mo kers of m ore t ha n 1 0 ci garettes or e -ci garettes, or 3 ci gars or 3 pi pes per da y, a n d 
are u na ble t o refrai n fr o m s mo ki n g w hile resi de nt at t he C R U
2 8. c o ns u me e xcessi ve a m o u nts of c offee, tea, c ola, or ot her caffei nate d be vera ges per da y.
E xcessi ve a m o u nt is defi ne d as greater t ha n 6 ser vi n gs ( 1 ser vi n g is a p pr o xi matel y 
e q ui vale nt t o 1 2 0 m g of caffei ne)
2 9. c urre ntl y use or s h o w e vi de nce of s u bsta nce a b use (i ncl u di n g alc o h o l a b use) or 
de pe n de nce wit hi n t he past 6 m o nt hs base d o n hist or y  at scree ni n g visit
3 0. i na bility t o co m pl y wit h t he di et ar y re gi me n of t he cli nical researc h ce nter
3 1. are Lill y e m plo y ees or are a n e m pl o yee of a n y t hir d -part y  in v o l ve d i n t he st u d y w h o 
re q uire e xcl usi on of t heir e m pl o yees.
3 2. are i n vest i gat or site pers o n nel directl y affiliate d wit h t his st u d y a n d/ or t heir i m me diate 
fa milies. I mme diate fa mil y is defi ne d as a s p o use, pare nt, c hil d, or si bli n g, w het her 
bi o l ogical  or le gall y a d o pte d
3 3. i n t he o pi ni on of t he i n vest i gat or or s p o ns or, are u ns uita ble f or i ncl usi on i n t he st u d y
P art 1 O nl y ( D a bi g atr a n ete xil ate ar m)
3 4. ha ve k n o w n blee di n g dis or der i ncl u di n g pri or pers o nal or fa milial hist or y  of a b n or mal 
blee di n g, here ditar y  or a c q uire d c oa g ulat i on or pl at elet dis or der or a b n or mal c oa g ulat i on 
test ( pr ot hr o m bi n ti me/i nter nati o nal n or malize d rati o [I N R] or partial t hr o m b o plasti n 
ti me/acti vate d partial t hr o m b o plasti n ti me greater t ha n u p per li mit of n or mal [ U L N]) 
res ult at scree ni n g
P art 2 O nl y ( R os u v ast ati n ar m)
3 5. ha ve c. 3 4 A A, c. 4 2 1 A A, or c. 3 4 G A/ 4 2 1 C A ge n ot y pes of  A B C G 2 as deter mi ne d t hr o u g h
ge n ot y pi n g

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
2 8
3 6. ha ve c. 5 2 1 T C or c. 5 2 1 C C ge n ot y pes as deter mi ne d t hr o u g h ge n ot y pi n g 
5. 3.
Lifest yle C o nsi der ati o ns
1.
T hr o u g h o ut t he st u d y , parti ci pa nts ma y u n der g o me dical assess me nts a n d re vie w of 
c o mplia nce wi t h r e q uire me nts bef ore c o nti n ui n g i n t he st u d y
5. 3. 1.  
Me als a n d Diet ar y Restricti o ns
1.
D uri n g eac h c o nfi ne me nt peri o d, partici pa nts will c o ns u me o nl y f o o d a n d be vera ges t hat 
are pr o vi de d t o t he m b y t he C R U staff . Sta n dar d meals (e. g., brea kfast, l u nc h, di n ner, a n d 
s nac k) will be pr o vi de d t o t he partici pa nts w hile resi de nt at t he C R U.
2.
Da bi gatra n, r os u vastati n, a n d las mi dita n will be a d mi nistere d after a n o ver ni g ht fast of at 
least 8 h o urs. I n t he m or ni n g of  eac h treat me nt da y, partici pa nts will a bstai n fr o m water 1 
h o ur bef ore a n d after d osi n g (e xce pt f or water gi ve n wit h t he d ose). Partici pa nts will 
r e mai n fasti n g f or a p pr o xi matel y 3 h o urs p ost d ose, at w hic h t i me a meal will be ser ve d.
5. 3. 2.
C affei ne, Alc o h ol, a n d T o b acc o
1.
D uri n g eac h d osi n g sessi o n, parti ci pa nt s will a bstai n fr o m i n gesti n g caffei ne- or 
xa nt hi ne -c o ntai ni n g pr o d ucts ( e. g., c o ffee, tea, c ola dri n ks, a n d c h oc olate) f or 4 8 h o urs 
bef ore t he start of d osi n g u nt il aft er c ollect i on o f t he fi nal P K a n d/or p har m ac o d y na mic 
sa m ple.
2.
D uri n g eac h d osi n g sessi o n, parti ci pa nt s will a bstai n fr om alc o h o l f or 4 8 h o urs pri or t o 
a d missi o n u nt il aft er c ollect i on o f t he fi nal P K a n d/or p har m ac o d y na mic sa m ple .
3.
P arti cipa nt s w h o use t o bacc o pr o d ucts will be i nstr ucte d t hat use of nic oti ne-c o ntai ni n g 
pr o d ucts (i ncl u di n g nic oti ne patc hes) will n ot be per mitte d w hile t he y  are i n t he C R U .
5. 3. 3.
Acti vit y
1.
P arti cipa nt s will a bstai n fr om stre n u o us e xercise f or 4 8 h o urs bef ore eac h bl o o d 
c ollect i on f or cli nical la b orat or y tests. Partici pa nt s ma y partici pate i n li g ht recreati o nal 
acti vit ies d uri n g st u dies (e. g., watc h i n g t ele visio n , rea di n g).
5. 4.
Scree n F ail ures
Scree n fail ures are defi ne d as part ici pa nts w h o c o nse nt t o partici pate i n t he cli nical st u d y b ut are 
n ot s u bse q ue ntl y assi g ne d t o stu d y i nter ve ntio n .
I n di vi d uals w h o d o n ot meet t he criteria f or partici pati o n i n t his st u d y (scree n fail ure) ma y be 
r escree ne d. Rescree ne d partici pa nts s h o ul d be assi g ne d a ne w partici pa nt n u m ber. W h ile 
rescree ni n g, all scree ni n g tests a n d pr oce d ures s h o ul d be re peate d: I n di vi d uals ma y be 
rescree ne d u p t o 1 ti me. T he i nter val bet wee n scree ni n g a n d rescree ni n g s h o uld be at l east 
1 wee k . Eac h ti me rescree ni n g is perf or me d, t he i n di vi d ual m ust si g n a ne w I C F. Re peat i n g 
la b orat or y tests d uri n g t he scree ni n g peri o d or re peati n g scree ni n g tests t o c o m pl y with t he 
pr ot oc ol -desi g nate d scree ni n g peri o d d oes n ot c o nstit ute rescree ni n g . Parti ci pa nts w h o are 
dee m e d a scree n fail ure f or Part 1 ma y st ill be c o nsi dere d eli gi ble f or Part 2 ( or vice versa) if all 
eli gi bilit y crit eria are met (e. g. if a part ici pa nt is e xcl u de d fr om Part 2 d ue t o e xcl usi o n cri teria 
3 5 or 3 6, t he y  ma y st ill be e nr o lle d i n Part 1).

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
2 9
6.
St u d y I nter ve nti o n
St u d y  i nter ve nt i on is defi ne d as a ny i n vesti gati onal i nter ve nt i on (s), mar kete d pr o d uct(s), 
pl ace b o , or m e dical de vice(s) i nte n de d t o be a d mi nistere d t o a st u d y partici pa nt acc or di n g t o t he 
st u d y pr ot oc ol .
6. 1.
St u d y I nter ve nti o n(s) A d mi nistere d
T his st u d y  in v o l ves a c o m paris o n of da bi gatra n ete xilate a d mi nistere d o nce orall y with 
da bi gatra n ete xilate a n d las mi dita n a d mi nistere d o nce orall y. T his st u d y  als o i n v ol ves a 
c o mparis o n of r os u vastati n a d mi nistere d o nce orall y  wit h r os u vastatin a n d las mi dita n
a d mi nistere d o nce orall y. Ta ble L AI O. 1 s h o ws t he treat me nt re gi me ns.
T a ble L AI O. 1.
St u d y I nter ve nti o ns A d mi nistere d
St u d y I nter ve nti o n 
Las mi dita n
Da bi gatra n ete xilate
R os u vastati n
D os a ge F or m ul ati o n
Ta blet
Ca ps ule
Ta blet
U nit d ose 
stre n gt h(s)/ D os a ge 
Le vel(s)
( 2 1 0 0- m g) ta blet/
2 0 0- m g las mi dita n
1 5 0- m g ca ps ule
1 0- m g ta blet
R o ute of 
A d mi nistr ati o n
Oral
Oral
Oral
D osi n g i nstr ucti o ns
2 ta blets ta ke n 
o n Da y s 8, 9, a n d 1 0
1 ca ps ule ta ke n o n Da y 1
a n d 
1 ca ps ule ta ke n o n Da y 1 0
1 ta blet ta ke n o n Da y 1
an d 
1 ta blet ta ke n o n Da y 1 0
6. 1. 1.
A d mi nistr ati o n Det ails
F or t he d a bi gatr a n ete xilate c o h ort, a si n gle or al d ose of da bi gatra n ete xilate 1 5 0 m g will be 
a d mi nistere d i n t he m or ni n g of Peri o d 1 ( St u d y Da y 1 ). O n t he m or ni n g of St u d y  Da ys 8 a n d 9 
( Perio d 2), a d ose of las mi dita n 2 0 0 mg will  be a d mi nistere d. O n t he m or ni n g of St u d y  D a y 1 0 
( Perio d 2), a si n gle d ose of da bi gatra n ete xilate 1 5 0 m g a n d las mi ditan 2 0 0 m g will  b e 
a d mi nistere d. All treat me nts s h o ul d be a d mi nistere d orall y wi t h a p pr o xi matel y 2 4 0 m L of r o o m 
t e mperat ure water i n t he m or ni n g t o t he partici pa nts i n a sitti n g p ositi on. Parti ci pa nts will n ot be 
all o we d t o lie s u pi ne f or 2 h o urs after d osi n g, u nless cli nicall y i n dicate d or f or st u d y pr oce d ures.
F or t he r os u vastati n c o h ort, a si n gle oral d ose of r os u vastati n 1 0 m g will be a d mi nistere d i n t he 
m o r ni n g of P eri o d 1 ( St u d y D a y  1). O n t he m or ni n g of St u d y  Da ys 8 a n d 9 ( Perio d 2), a d ose of 
las mi dita n 2 0 0 m g will be a d mi nistere d. O n t he m or ni n g of St u d y  Da y  1 0 ( P erio d 2 ), a si n gle 
d ose of r os u vastati n 1 0 m g a n d las mi dita n 2 0 0 m g will be a d mi nistere d . All treat me nts s h o ul d be 
a d mi nistere d orall y wit h a p pr o xi matel y 2 4 0 m L of r o o m te m perat ure water i n t he m or ni n g t o t he 
parti ci pa nts i n a sitti n g p ositi o n. Pa rtici pa nts will n ot be all o we d t o lie s u pi ne f or 2 h o urs after 
d osi n g, u nless cli nicall y  in dicate d or f or st u d y  pr oce d ures.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
3 0
6. 2.
Pre p ar ati o n/ H a n dli n g/ St or a ge/ Acc o u nt a bilit y
1.
T he i n vest i gat or or desi g nee m ust c o nfir m a p pr o priate te m perat ure c o n diti ons ha ve bee n 
mai ntai ne d d uri n g tra nsit f or all st u d y  i nter ve nt i ons recei ve d a n d a n y discre pa ncies are 
re p orte d a n d res ol ve d bef ore use of t he st u d y int er ve nt i on.
2.
O nl y partici pa nts e nr o lle d i n t he st u d y ma y recei ve st u d y int er ve nt i on a n d o nl y 
a ut h orize d C R U staff ma y s u p pl y  or a d mi nister st u d y int er ve nt i on. All st u d y  
i nter ve nt i on s m u st be st ore d in a sec ure, e n vir o n me ntall y c o ntr olle d, a n d m o nit ore d 
( ma n ual or a ut o mate d) area in acc or da nce wit h t he la bele d st ora ge c o n dit i ons wit h access 
li mite d t o t he i n vesti gat or a n d a ut h orize d C R U staff.
3.
T he i n vest i gat or, i nstit uti o n, or t he hea d of t he me dical i nstituti o n ( w here a p plica ble) is 
res p o nsi ble f or st u d y int er ve ntio n acc o u nta bilit y, rec o nciliat i on, a n d rec or d mai nte na nce 
(i. e., receipt, rec o nciliat i on, a n d fi nal dis p o sitio n rec or ds).
4.
T he i n vest i gat or or desi g nee will ret ur n all u n use d st u d y i nter ve nti o ns t o Lill y or its 
desi g nee at t he e n d of t he st u d y .
5.
N ote: I n s o me cases, sit es ma y destr o y  t h e mat erial if, d uri n g t he C R U selecti on, t he 
e val uat or has verifie d a n d d oc u me nt e d t hat t he site has a p pr o priate facilit ies a n d writte n 
pr oce d ures t o dis p ose of cli nical materials.
6. 3.
Me as ures t o Mi ni mize Bi as: R a n d o miz ati o n a n d Bli n di n g
T his is a n o pe n -la bel st u d y. T here i s n o bias as t he pri mar y e n d p oi nt is P K a n d o bjecti ve i n 
meas ure.
6. 3. 1.
P ac k a gi n g a n d L a beli n g
Eac h ta blet of  las mi dita n c o ntai ns 1 0 0 m g of act i ve i n gre die nt a n d is pr o vi de d as b ul k s u p pl y i n 
b ottl es. Da bi g atr a n ete xilate ca ps ules ( 1 5 0 mg) a n d r os u vastati n ta blets ( 1 0 m g) ma y be pr o vi de d
b y t he C R U or s p o ns or .
6. 4.
St u d y I nter ve nti o n C o m pli a nce
W he n partici pa nts are d ose d at t he site, t he y  will recei ve st u d y int er ve nt i on di rectl y fr o m t he 
i n vesti gat or or desi g nee, u n der me dical s u per visi on. T he date a n d ti me of eac h d ose a d m i nistere d 
i n t he cli nic will be rec or de d i n t he s o urce d oc u me nts a n d rec or de d i n t he C R F. T he d ose of 
st u d y int er ve ntio n a n d st u d y  p artici p a nt ide nt ificati o n will be c o nfir me d at t he ti me of d osi n g b y  
a me m ber of t he C R U staff ot her t ha n t he pers o n a d mi nisteri n g t he st u d y int er ve nt i on . C R U 
pers o n nel will  e xa mi ne eac h partici pa nt’s mo ut h t o e ns ure t hat t he st u d y  int er ve nt i on was 
i n geste d.
6. 5.
C o nc o mit a nt T her a p y
A n y me dicat i on or vacci ne (i ncl u di n g o ver -t he- c o u nter or prescri pt i on me dici nes, vita mi ns, 
tra ditio n al  me dici nes, a n d/ or dietar y  or her bal s u p ple me nts or ot her s pecific cate g ories of 
i nterest) t hat t he partici pa nt is recei vi n g at t he ti me of e nr oll me nt or recei ves d uri n g t he st u d y  
m ust be rec or de d al o n g wit h:

Reas o n f or use

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
3 1

Dates of a d mi nistrati o n i ncl u di n g start a n d e n d dates

D osa ge i nf or mati o n i ncl u di n g d ose a n d fre q ue nc y f or c o nc o mita nt t hera p y of s pecial 
i nterest
T he me d ical mo ni t or s h o ul d be c o ntacte d if t here are a n y q uesti o ns re gar di n g c o nc o mit a nt or 
pri or t hera p y .
P arti cipa nts m ust a bstai n fr om ta ki n g prescri pti on or n o n prescri pt i on dr u gs (i ncl u di n g vita mi ns ,
di et ar y or her bal s u p ple me nts, a n d tra ditio nal  me dici nes ) wit hi n 7 da ys ( or 1 4 da ys if t he dr u g is 
a p ote ntial e nz y me i n d ucer) or 5 half-li ves ( w hic he ver is l o n ger) bef ore t he start of st u d y 
i nter ve nt i on u nt il c om p leti on of t he f o ll ow- u p visit , u nless, i n t he o pi ni o n of t he i n vest i gat or a n d 
s p o ns or, t he me dicat i on wil l n ot i nterfere wit h t he st u d y .
Aceta mi n o p he n at d oses of 3 g/ 2 4 h o urs , ma y be a d mi nistere d at t he discret i on of t he 
i n vesti gat or f or t he treat me nt of hea dac he, etc. C o ntrace pti ve me dicat i on is per mitte d as per t he 
i ncl usi on cri t eria. H or m o ne re place me nt t hera p y  is als o allo we d. Use of stati ns is n ot all o we d
ot her t ha n r os u vastati n a d mi nistrati o n as descri be d i n Sect i on 1. 3 .
If t he nee d f or c o nc o mita nt me dicati on ( ot her t ha n aceta mi n o p he n, h or m o nal c o ntrace pti o n, or 
h or m o ne re pl ace me nt t hera p y) arises, i ncl usi on or c o nti n uat i on of t he s u bject ma y be at t he 
di scretio n of  t he i n vesti gat or after c o ns ultati o n with a Lill y cli nical p har mac ol o gist ( C P), cli nical 
researc h p h ysicia n (C R P ), or desig nee. A n y me dicati o n use d d uri n g t he c o urse of t he st u d y  must 
be d oc u m e nte d.
6. 6.
D ose M o dific ati o n
D ose m o dificat i on will n ot be all o we d d uri n g t he st u d y .
6. 7.
I nter ve nti o n after t he E n d of t he St u d y
N ot a p plica ble.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
3 2
7.
Disc o nti n u ati o n of St u d y I nter ve nti o n a n d P artici p a nt 
Disc o nti n u ati o n/ Wit h dr a w al
P arti cipa nts disc o nt i n ui n g fr o m t he st u d y pr e mat urel y f or a n y reas o n must c o m plete A E a n d 
f oll ow- u p pr oce d ures per Secti o n 1. 3 of  t his pr ot oc ol.
7. 1.
Disc o nti n u ati o n of St u d y I nter ve nti o n
I n rare i nsta nces, it ma y be necessar y for a partici pa nt t o per ma ne nt l y disc o nti n ue ( defi niti ve 
di sc o nti n uati on) st u d y i nter ve nt i on . If st u d y i nter ve nt i on is defi nit i vel y disc o nt i n ue d, t he 
parti ci pa nt will r e mai n i n t he st u d y t o be e val uate d f or safety . See t he S o A f or data t o be 
c ollecte d at t he ti me of disc o nt i n uati on of st u d y  i nter ve nt i on a n d f o ll ow- u p a n d f or a n y  furt her 
e val uat i ons t hat nee d t o be c o mplete d.
Di sc o nti n uatio n of  t he st u d y int er ve nt i on f or a b n or mal liver test res ults s h o ul d be c o nsi dere d b y 
t he i n vest i gat or w he n a partici pa nt meets 1 of t he f oll o wi n g c o n diti ons after c o ns ultati o n wit h t he 
Lill y -desi g nate d m e dical mo ni t or:

ala ni ne a mi n otra nsferase ( A L T ), as partate a mi n otra nsferase (A S T ) >5 X U L N

A L T or A S T > 3 X U L N s ustai ne d f or m ore t ha n 2 wee ks or

A L T or A S T > 3 X U L N a n d t otal bilir u bi n le vel ( T B L) > 2 X U L N or I N R > 1. 5 or

A L T or A S T > 3 X U L N wit h t he a p peara nce of fat i g ue, na usea, v omit i n g, ri g ht u p per-
q ua dra nt pai n or te n der ness, fe ver, ras h, a n d/ or e osi n o p hilia ( > 5 %)

alkali ne p h os p hatase ( A L P) > 3 X U L N

A L P > 2. 5 X U L N a n d T B L > 2 X U L N

A L P > 2. 5 U L N wit h t he a p peara nce of fati g ue, na usea, v o mit i n g, ri g ht q ua dra nt pai n or 
te n der ness, fe ver, ras h, a n d/ or e osi n o p hilia ( > 5 %).
P arti cipa nts w h o di sc o nti n ue fr o m st u d y i nter ve nt i o n d ue t o t he a b n or mal li ver test res ults will 
u n der g o m o nit ori n g as descri be d i n A p pe n di x 1 0. 6 .
I n a d diti on, st u d y  dr u g ma y be disc o nti n ue d if partici pa nts

a ns were d “ yes” t o Q uesti o n 4 or Q uesti o n 5 o n t he “ S uici dal I deat i on” p orti o n of t he C -
S S R S, or

a ns were d “ yes” t o a n y of t he s uici de-relate d be ha vi ors o n t he S uici dal Be ha vi or p orti o n 
of  t he C-S S R S.
A ps yc hiatrist or a p pr o priatel y trai ne d pr ofessi o nal ma y  assist i n t he decisi o n t o disc o nti n ue t he 
parti ci pa nt fr o m t he st u d y.
P arti cipa nts disc o nt i n ui n g fr o m t he st u d y pr e mat urel y f or a n y reas o n must c o m plete A E a n d 
f oll ow- u p pr oce d ures per Secti o n 1. 3 of  t his pr ot oc ol.
7. 2.
P ar tici p a nt Disc o nti n u ati o n/Wit h dr a w al fr o m t he St u d y
A parti ci pa nt ma y wi t hdra w fr o m  t he st u d y:

at a n y ti me at his/ her o w n re q uest 

at t he re q uest of his/ her desi g nee ( e. g., pare nts or le gal g uar dia n)

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
3 3

at t he discreti o n of t he i n vest i gat or f or safety,  be ha vi or al , c o mplia nce, or a d mi nistrati ve 
reas o ns

if t he partici pa nt bec ome s pre g na nt d uri n g t he st u d y

if e nr oll me nt i n a n y ot her cli nical st u d y i n v ol vi n g a ny st u d y int er ve nt i on or e nr oll me nt 
i n a n y ot her t ype of me dical researc h j u d ge d n ot t o be scie nt ificall y or me dicall y 
c o mpat i ble wit h t his st u d y

if t he parti ci pa nt , for a n y  reas o n, re q uires treat me nt wit h a n ot her t hera pe utic a ge nt t hat 
has bee n de m o nstrate d t o be effect i ve f or treat me nt of t he st u d y in dicat i on, 
di sc o nti n uati on fr om t he st u d y occ urs prior t o i ntr o d ucti o n of  t he ne w a ge nt
Di sc o nti n uatio n is e x pecte d t o be u nc o m m o n. At  t he ti me of disc o nti n ui n g fr o m t he st u d y, if 
p ossi ble, a n earl y disc o nt i n uati on visit s h o ul d be c o n d ucte d, as s h o w n i n t he S o A. See S o A f or 
data t o be c ollecte d at t he ti me of  st u d y disc o nti n uati o n a n d f oll ow- u p a n d f or a n y  furt her 
e val uat i ons t hat nee d t o be c o m plete d . T he parti ci pa nt will be per ma ne ntl y disc o nt i n ue d fr om t he 
st u d y i nter ve ntio n a n d fr o m t he st u d y at t hat ti me. E nr olle d partici pa nts w h o disc o nt i n ue fr om 
t he st u d y wi t ho ut s t u d y int er ve nt i on will n ot be re q uire d t o atte n d t he earl y  disc o nt i n uati o n visit .
If t he parti ci pa nt wi t hdra ws c o nse nt f or discl osur e of  fut ure i nf or m at i on, t he s p o ns or m a y retai n 
a n d c o nt i n ue t o use a n y data c ollecte d bef ore s uc h a wit h dra wal of c o nse nt. If a partici pa nt
wi t hdra ws fr o m t he st u d y, he/s he ma y re q uest destr uctio n of  a n y sa mples ta ke n a n d n ot teste d ,
a n d t he i n vest i gat or m ust d oc u me nt t his i n t he site st u d y rec or ds.
7. 2. 1.
Disc o nti n u a ti o n of I n a d verte ntl y E nr olle d P artici p a nts
If t he sp o ns or or i n vest i gat or i de ntif y a partici pa nt w h o di d n ot meet e nr oll me nt criteria a n d was 
i na d verte ntl y e nr olle d, t he n t he parti ci pa nt s h o uld be disc o nt i n ue d fr om recei vi n g st u d y 
i nter ve nt i on u nless t here are e xte n uat i n g circ u msta nces t hat ma ke it me dicall y necessar y f or t he 
parti ci pa nt t o c o nti n ue o n st u d y int er ve nt i on. If t he i n vesti gat or a n d t he s p o ns or C P a gree it is 
me dicall y a p pr o priate t o c o nti n ue, t he i n vest i gat or m ust o btai n d oc u me nted a p pr o val  fr o m t he 
s p o ns or C P t o all o w t he i na d verte ntl y e nr olle d partici pa nt t o c o nti n ue i n t he st u d y wit h or 
wi t ho ut treat m e nt wit h st u d y int er ve ntio n .
T he d oc u me nte d a p pr o val m ust c o ntai n t he be nefit -ris k assess me nt a n d a r o b ust cli nical 
j ustificati on t hat c o nti n ui n g i n t he st u d y will not j e o par dize t he partici pa nt’s safet y.
All i na d verte ntl y e nr olle d partici pa nts will c om p lete safety f oll ow u p as o utli ne d i n Sect i on 1. 3
( Sc he d ule of Acti vities), Sectio n 8. 2 ( Safety Assess me nts), a n d Secti o n 8. 3 ( A d verse E ve nts a n d 
S eri o us A d verse E ve nts) of t he pr ot oc ol.
7. 3.
L ost t o F oll o w u p
A partici pa nt will be c o nsi dere d l ost t o f oll o w -u p if  he or s he re peate dl y fails t o ret ur n f or 
sc he d ule d visits a n d is u na ble t o be c o ntacte d b y t he C R U . Si te pers o n nel are e x pecte d t o ma ke 
dili ge nt atte m pts t o c o ntact partici pa nts w h o fail t o ret ur n f or a sc he d ule d visit or were ot her wise 
u na ble t o be f o ll owe d u p b y  t he sit e.
Di sc o nti n uatio n of  s pecific sites or of t he st u d y as a w h ole are ha n dle d as part of A p pe n di x 1 0. 1 .

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
3 4
8.
St u d y Assess me nts a n d Pr oce d ures

St u d y  pr oce d ures a n d t heir ti mi n g are s u m marize d i n t he S o A. P r ot oc ol wai ver s or 
e xe m pt i ons are n ot all o we d.

I mme diate safety c o ncer ns s h o uld be disc usse d wit h t he s p o ns or i m me diatel y  u p o n 
occ urre nce or a ware ness t o deter mi ne if t he partici pa nt s h o ul d c o nti n ue or disc o nti n ue 
st u d y i nter ve ntio n .

A d here nce t o t he st u d y  desi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he S o A, is 
esse nt ial a n d re q uire d f or st u d y c o n d uct.

All scree ni n g e val uati ons m u st be c o mplete d a n d re vie we d t o c o nfir m t hat p ote nti al 
parti ci pa nt s meet all eli gi bilit y cri t eria. T he i n vesti gat or will mai ntai n a scree ni n g l o g t o 
rec or d details of all partici pa nt s scree ne d a n d t o c o nfir m eli gi bilit y or rec or d reas o ns f or 
scree ni n g fail ure, as a p plica ble.

Secti o n 1. 3 lists t he S o A , detaili n g t he st u d y pr oce d ures a n d t heir ti mi n g (i ncl u di n g 
t olera nce li mit s for ti mi n g).

T he s pecificat i ons i n t his pr ot oc ol f or t he ti mi n gs of safety a n d sa m ple c o llecti on are 
gi ve n as tar gets t o be ac hie ve d wit hi n reas o na ble li mits. M o dificat i ons m a y be ma de t o 
t he ti me p o i nts base d u p o n e mer gi n g cli nical i nf or mat i on. T he sc he d ule d ti me p o i nts 
ma y be s u bject t o mi n or alterati o ns; h o we ver, t he act ual ti me has t o be c orrectl y 
rec or de d i n t he C R F. Fail u re or bei n g late (i.e., o utsi d e sti p ulate d ti me all o wa nces) t o 
perf or m  pr oce d ures or o btai n sa m ples d ue t o le giti mate cli nical iss ues (e. g., e q ui p me nt 
tec h nical pr o ble ms, ve n o us access diffic ulty,  or s u bject defa ulti n g or t ur ni n g u p late o n 
a n a gree d sc he d ule d pr oce d ure) will n ot be c o nsi dere d as pr ot oc ol de viat i ons b ut t he 
C R U will st ill be re q uire d t o n otif y  t he s p o ns or i n writi n g via a file n ote.

A p pe n di x 1 0. 2 lists t he la b orat or y tests t hat will be perf or me d f or t his st u d y.

A p pe n di x 1 0. 2. 1 pr o vi des a s u m mar y o f t he ma xi m u m nu m ber a n d v ol u me of i n vasi ve 
sa m ples, f or all sa m pli n g, d uri n g t he st u d y.

U nless ot her wise state d i n s u bsect i ons bel o w, all sa m ples c ollecte d f or s pecifie d 
la b orat or y tests will be destr o ye d wit hi n 6 0 da ys of recei pt of c o nfir me d test res ults.
Certai n sa m ples ma y be retai ne d f or a l o n ger peri o d, if necessar y , t o c o mpl y  wit h 
a p plica ble la ws, re g ulat i ons, or l a b orat or y certificatio n sta n dar ds.
8. 1.
Effic ac y Assess me nts
N ot a p plica ble.
8. 2.
S afet y Assess me nts
Pl a n ne d ti me p o i nts f or all safety assess me nts are pr o vi de d i n t he S o A.
8. 2. 1.
P h ysic al E x a mi n ati o ns

A c o m p lete p h ysical e xa mi nati on will i ncl u de, at a mi ni m u m, assess me nts of t he 
car dio vasc ular, res pi rat or y, gastr oi ntesti nal a n d neur ol o gical  s yste ms. Heig ht a n d 
w ei g ht will als o be meas ure d a n d rec or de d.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
3 5

A br ief p h ysical e xa mi nat i on will i ncl u de, at a mi ni m u m, assess me nts of t he s ki n, 
l u n gs, car di o vasc ular s yste m, a n d a b d ome n (li ver a n d s plee n).

I n vesti gat ors s h o ul d pa y s pecial atte ntio n t o cli nical si g ns relate d t o pre vi o us seri o us 
ill nesses.
8. 2. 2.
Vit al Si g ns

F or eac h parti ci pa nt , vit al si gn meas ure me nts s h o ul d be c o n d ucte d acc or di n g t o t he 
S o A ( Secti o n 1. 3 ) 

Bl o o d press ure a n d p ulse rate s h o ul d be meas ure d si n gl y after at least 5 mi n utes 
s u pi ne. F or eac h i n di vi d ual s u bject, t he sa me c uff size s h o ul d be use d t hr o u g h o ut t he 
st u d y for t he m eas ure me nts of bl o o d press ure . T he c uff s h o ul d , w he n p ossi ble, be 
attac he d t o t he s u bject’s d o mi na nt ar m.

U nsc he d ule d ort h ostatic vital si g ns s h o ul d be assesse d, if p ossi ble, d uri n g a n y A E of 
di zzi ness or p ost ure -i n d uce d s y m pt o ms. W here ort h ostatic meas ure me nts are re q uire d, 
parti ci pa nts s h o uld be s u pi ne f or at l east 5 mi n utes a n d t he n partici p a nts will sta n d,
a n d sta n di n g bl o o d press ure will be meas ure d after 2 mi n utes; n o l o n ger t ha n 3 
mi n utes. If t he s u bject feels u na ble t o sta n d, s u pi ne vital si g ns o nl y will be c ollecte d.
A d dit i onal vit al si g ns ma y be meas ure d d uri n g eac h st u d y p erio d if warra nte d. 
8. 2. 3.
Electr oc ar di o gr a ms

F or eac h partici pa nt, a si n gle 1 2- lea d di gital E C G will be c ollecte d acc or di n g t o t he 
S o A . Electr ocar di o gra ms m us t be rec or de d bef ore c ollecti n g a n y bl o o d sa m ples.
P arti cipa nts m ust be s u pi ne f or a p pr o xi matel y 5 t o 1 0 mi n utes bef ore E C G c ollect i on 
a n d re mai n s u pi ne b ut a wa ke d uri n g E C G c ollect i on. Electr ocar di o gra ms ma y be 
o btai ne d at a d dit i onal ti mes, w he n dee me d cl i nicall y necessar y. All E C Gs rec or de d 
s h o uld be st ore d at t he i n vest i gati onal sit e.

Electr ocar di o gra ms will be i nter prete d b y  a q ualifie d p h ysicia n (t he i n vesti gat or or 
q ualifie d desi g nee) at t he site as s o o n after t he ti me of E C G c ollecti o n as p ossi ble, a n d 
i deall y w hile t he partici pa nt is still prese nt, t o deter mi ne w het her t he partici pa nt meets 
e ntr y crit eria at t he rele va nt visit(s) a n d f or i m me diate partici pa nt ma na ge me nt, s h o ul d 
a n y cli nicall y rele va nt fi n di n gs be i de ntifie d.

If a cli nicall y si g nifica nt fi n di n g is i de nt ifie d (i ncl u di n g, b ut n ot li mite d t o, c ha n ges i n 
Q T/ c orrecte d Q T i nter val fr o m baseli ne) after e nr oll me nt, t he i n vest i gat or will 
deter mi ne if t he part ici pa nt ca n c o nti n ue i n t he st u d y. T he i n vest i gat or, or q ualifie d 
desi g nee, is res p o nsi ble f or deter mi ni n g if a n y c ha n ge i n partici pa nt ma na ge me nt is 
nee de d, a n d m ust d oc u me nt his/ her re vie w of t he E C G pri nte d at t he ti me of 
c ollect i on. A n y ne w cli nicall y rele va nt fi n di n g s h o ul d be re p orte d as a n A E .
8. 2. 4.
Cli nic al S afet y L a b or at or y Assess me nts

See A p pe n di x 1 0. 2 f or t he list of cli nical la b orat or y tests t o be perf or me d a n d t o t he 
S o A f or t he ti mi n g a n d fre q ue nc y.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
3 6

T he i n vest i gat or m ust re vie w t he la b orat or y re p ort, d oc u me nt t his re vie w, a n d rec or d 
a n y cli nicall y rele va nt c ha n ges occ urri n g d uri n g t he st u d y in t he A E secti o n of t he 
C R F. T he la b orat or y  re p orts must be file d wit h t he s o urce d oc u me nts. Cli nicall y 
sig nifica nt a b n or m al la b orat or y fi n di n gs are t h ose w hic h are n ot ass ociate d wit h t he 
u n derl yi n g disease, u nless j u d ge d b y t he i n vest i gat or t o be m ore se vere t ha n e x pecte d 
f or t he partici pa nt ’s c o n ditio n .

All la b orat or y tests wit h val ues c o nsi dere d cli nicall y si g nifica ntl y a b n or mal d uri n g 
parti ci pat i on i n t he st u d y s h o ul d be re peate d u ntil t he val ues ret ur n t o n or mal or 
baseli ne or are n o l o n ger c o nsi dere d cli nicall y si g nifica nt b y  t he i n vesti gat or or 
me dical m o nit or.
o
If s uc h val ues d o n ot ret ur n t o n or mal/ baseli ne withi n a perio d of ti me j u d ge d 
reas o na ble b y t he i n vesti gat or, t he eti ol og y  s h o uld be i de nt ifie d a n d t he s p o ns or 
n otifie d.
o
All pr ot oc ol -re q uire d la b orat or y assess me nts, as defi ne d i n A p pe n di x 1 0. 2 , must 
be c o n d ucte d i n acc or da nce wit h t he lab orat or y  ma n ual a n d t he S o A.
o
If la b orat or y val ues fr o m n o n pr ot oc ol -s pecifie d la b orat or y assess me nts perf or me d 
at t he i nst ituti o n’s l o c al  la b orat or y re q uire a c ha n ge i n partici pa nt mana ge me nt or 
are c o nsi dere d cli nicall y sig nifica nt b y  t he i n vesti gat or (e. g., seri o us a d verse 
e ve nt [ S A E ] or A E or d ose m o dificat i on), t he n t he res ul ts must be rec or de d i n t he 
C R F.

If a ce ntral ve n d or is use d f or t he st u d y, Lill y or its desig nee will  pr o vi de t he 
i n vesti gat or wit h t he res ults of la b orat or y tests a nal yze d b y a ce ntral ve n d or, u nless t he 
safety la b orat or y test res ults ma y u n bli n d t he st u d y.
8. 2. 5.
S afet y M o nit ori n g
T he Lill y C P or C R P/sci e nt ist will m onit or safet y data t hr o u g h o ut t he c o urse of t he st u d y .
Lill y will re vie w S A Es wit hi n t i me fra mes ma n date d b y c om pa n y pr oce d ures. T he Lill y C P or 
C R P will peri o dicall y re vie w t he f o ll owi n g data:

tre n ds i n safet y d at a

la b orat or y a nal ytes i ncl u di n g he mat ol o g y  a n d c he mistr y
W he n a p pr o priate, t he Lill y C P or C R P will c o ns ult wit h t he f u nct i onall y  in de pe n de nt Gl o bal 
P ati e nt Safet y t hera pe utic area p h ysicia n or cli nical researc h scie nt ist.
8. 2. 5. 1.
He p atic S afet y
Cl ose he pat ic m o nit ori n g
La b orat or y tests ( A p pe n di x 1 0. 6 ), i ncl u di n g A L T, A S T, A L P, T B L, a n d di rect bilir u bi n, s h o uld 
be re peate d wit hi n 4 8 t o 7 2 h o urs t o c o nfir m t he a b n or malit y a n d t o deter mi ne if it is i ncreasi n g 
or decreasi n g, if 1 or m ore of t hese c o n dit i ons occ ur:

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
3 7
If a partici pa nt wit h baseli ne res ults 
of  ... 
de vel o ps t he f o ll owi n g ele vat i ons:
A L T or A S T < 1. 5 x U L N
A L T or A S T ≥3 x U L N
A L P < 1. 5 x U L N
A L P ≥2 x U L N
T B L < 1. 5 x U L N
T B L ≥2 x U L N (e xce pt f or patie nts wit h Gil bert’s 
s y n dr ome)
A L T or A S T ≥1. 5 x U L N
A L T or A S T ≥2 x baseli ne
A L P ≥1. 5 x U L N
A L P ≥2 x baseli ne
T B L ≥1. 5 x U L N
T B L ≥2 x baseli ne (e xce pt f or patie nts wit h Gil bert’s 
s y n dr ome)
If t he a b n or mality persists or w orse ns, cli nical a n d la b orat or y  mo ni t ori n g, a n d e val uati on f or 
p ossi ble ca uses of a b n or mal li ver tests s h o ul d be i nit iate d b y t he i n vesti gat or i n c o ns ultati on wi t h 
t he Lill y-desi g nate d m e dical m o nit or. At a mi ni m u m, t his e va l uati on s h o ul d i ncl u de p h ysical 
e xa mi nat i on a n d a t h or o u g h me dical hist or y , i ncl u di n g s y m pt o ms, rece nt ill nesses (e. g. , heart 
fail ure, s yste mic i nfecti on, h y p ote nsi o n, or sei z ures), rece nt tra vel, hist or y of c o nc o mita nt 
me dicat i ons (i ncl u di n g o ver -t he- c o u nter), her bal a n d dietar y s u p ple me nts, hist or y of alc o h o l 
dri n ki n g a n d ot her s u bsta nce a b use. 
I nitiall y, mo ni t ori n g of s y m pt o ms a n d he patic bi oc he mical tests s h o ul d be d o ne at a fre q ue nc y o f 
1 t o 3 ti mes wee kl y , base d o n t he partici pa nt’s cli nical c o n dit i on a n d he pat ic bi oc he mical tests. 
S u bse q ue ntl y, t he fre q ue nc y  of mo ni t orin g m a y be lo were d t o o nce e ver y  1 t o 2 wee ks, if t he 
parti ci pa nt’s cli nical c o n dit i on a n d l a borat or y res ults sta bilize. M o nit ori n g of A L T, A S T, A L P, 
a n d T B L s h o ul d c o nti n ue u nt il le vels n or malize or ret ur n t o a p pr o xi mate baseli ne le vels.
C o m pre he nsi ve he patic e val uati o n
A c o m pre he nsi ve e val uat i on s h o ul d be perf or m e d t o searc h f or p ossi ble ca uses of li ver i nj ur y if 1
or m ore of t hese c o n dit i ons occ ur:
If a partici pa nt wit h baseli ne 
res ults of... 
de vel o ps t he f o ll owi n g ele vat i ons:
A L T or A S T < 1. 5 x U L N
A L T or A S T ≥3 x U L N wit h he patic si g ns/s y m pt o ms *, or
A L T or A S T ≥5 x U L N
A L P < 1. 5 x U L N
A L P ≥3 x U L N
T B L < 1. 5 x U L N
T B L ≥2 x U L N (e xce pt f or patie nts wit h Gil bert’s s y n dr o me)
A L T or A S T ≥1. 5 x U L N
A L T or A S T ≥2 x baseli ne wit h he pat ic si g ns/s y m pt o ms *, or
A L T or A S T ≥3 x baseli ne
A L P ≥1. 5 x U L N
A L P ≥2 x baseli ne
T B L ≥1. 5 x U L N
T B L ≥1. 5 x baseli ne (e xce pt f or patie nts wit h Gil bert’s 
s y n dr ome) 
* He p atic si g ns/s y m pt o ms are se vere f ati g ue, n a use a, v o miti n g, ri g ht u p per q u a dr a nt 
a b d o mi n al p ai n, fe ver, ras h, a n d/ or  e osi n o p hili a > 5 %.
At  a mi ni m u m, t his e val uati on s h o ul d i ncl u de p h ysical e xa mi nat i on a n d a t h or o u g h me dical 
hist or y, as o utli ne d earlier, as well as tests f or pr ot hr o m bi n t i me-I N R; tests f or viral he patitis A, 

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
3 8
B, C, or E; tests f or a ut oi m m u ne he patit is; a n d a n a b d omi nal i ma gi n g st u d y ( e. g. , ult ras o u n d or 
c o mp ute d t o m o gra p h y sca n). 
Base d o n t he patie nt ’s hist or y a n d i nitial res ults, furt her testi n g s h o ul d be c o nsi dere d i n 
c o ns ultati o n wit h t he Lill y -desi g nate d m e dical mo ni t or, i ncl u di n g tests f or he patitis D vir us, 
c yt o me galo vir us, E pstei n -Barr vir us, aceta mi n o p he n le vels, aceta mi n o p he n pr otei n a d d ucts, 
uri ne t o xic o l og y  scree n, Wils on’ s disease, bl o o d alc o h ol le vels, uri nar y et h yl gl uc ur o nide, a n d 
ser u m p h os p hati dylet ha n o l. Base d o n t he circ u msta nces a n d t he i n vesti gat or’s assess me nt of t he 
parti ci pa nt ’s cli nical c o n diti on, t he i n vest i gat or s h o ul d c o nsi der referri n g t he partici pa nt f or a 
he pat ol o gi st or gastr oe nter ol o gist c o ns ultati o n, ma g netic res o na nce c h olan gi o pa ncreat o gra p h y, 
e n d osc o pic retr o gra de c h ola n gi o pa ncreat o gra p h y, car diac ec h ocar dio gr a m , or a li ver bi o ps y.
A d diti o n al he p a tic d at a c ollecti o n ( he p atic s afet y C R F) i n st u d y p artici p a nts w h o h a ve 
a b n or m al li ver test res ult s d uri n g t he st u d y 
A d dit i onal he patic safet y data c ollect i on i n he pat ic safety C R F s s h o uld be perf or me d i n st u d y  
parti ci pa nts w h o meet 1 or m ore of t he f o ll owi n g 5 c o n di tio ns:
1.
Ele vat i on of ser u m A LT t o ≥5 x U L N o n 2 or m ore c o nsec uti ve bl o o d tests (if baseli ne 
A L T < 1. 5 x U L N)

I n partici pa nts wit h baseli ne A L T ≥1. 5 x U L N, t he t hres h o l d is A L T ≥3 x baseli ne 
o n 2 or m ore c o nsec uti ve tests
2.
Ele vat i on of T B L  t o ≥2 x U L N (if baseli ne T B L < 1. 5 x U L N) (e xce pt f or cases of k n o w n 
Gil bert ’s s y n dr o me)

I n partici pa nts wit h baseli ne T B L ≥1. 5 x U L N, t he t hres h o l d s h o ul d be T B L ≥2 x 
baseli ne
3.
Ele vat i on of ser u m A L P t o ≥2 x U L N o n 2 or m ore c o nsec uti ve bl o o d tests (if baseli ne 
A L P < 1. 5 x U L N)

I n partici pa nts wit h baseli ne A L P ≥1. 5 x U L N, t he t hres h o l d is A L P ≥2 x baseli ne 
o n 2 or m ore c o nsec uti ve bl o o d tests
4.
He pati c e ve nt c o nsidere d t o be a n S A E
5.
Di sc o nti n uatio n of  st u d y int er ve nt i on d ue t o a he pati c e ve nt 
N ote: t he i nter val bet wee n t he 2 c o nsec uti ve bl o o d tests s h o ul d be at least 2 da ys.
8. 2. 5. 2.
S uici d al I de ati o n a n d Be h a vi or Ris k M o nit ori n g
Las mi dita n is c o nsi dere d t o be a ce ntral ner v o us s yste m -act i ve dr u g.
P arti cipa nt s bei n g treate d wit h las mi dita n s h o uld b e m o ni t ore d a p pr o priatel y a n d o bser ve d 
clos el y  for s ui ci dal i deat i on a n d be ha vi or or a n y  ot her u n us ual c ha n ges i n be ha vi or, es peciall y at 
t he be gi n ni n g a n d e n d of t he c o urse of treat me nt, or at t he ti me of d ose c ha n g es, eit her i ncreases 
or decreases. C o nsi derati o n s h o ul d be gi ve n t o disc o nti n ui n g t he st u d y me dicat i on i n partici p a nts
w h o e x perie nce si g ns of s uici dal i deat i on or be ha vi or, f o ll owi n g a ri s k assess me nt.
C- S S R S 
C- S S R S is a scale t hat ca pt ures t he occ urre nc e, se verit y, a n d fre q ue nc y of s uici dal i deati on a n d 
be ha vi or d uri n g t he assess me nt peri o d via a q uest i o n naire. T he scale was de vel o pe d b y t he 
Nati o nal I nst itut e of Me ntal Healt h trial gr o u p (Treat me nt of A d o lesce nt S uici de Atte m pters) for 

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
3 9
t he p ur p ose of be i n g a c o u nter part t o t he C ol u m bia Classificati o n Al g orit h m of S uici de 
Assess me nt cate g orizat i on of s uici dal e ve nts.
8. 3.
A d verse E ve nts a n d Seri o us A d verse E ve nts
Pr o d uct co m plai nts are c o vere d i n Secti o n 8. 3. 6 .
A d verse e ve nt s will be re p orte d b y  t he partici pa nt ( or, w he n a p pr o priate, b y a care gi ver, 
s urr o gate, or t he partici pa nt’s le gall y a ut h orize d re prese ntati ve).
T he i n vest i gat or a n d a n y q ualified desi g nees are res p o nsi ble f or detecti n g, d oc u me nti n g, a n d 
rec or di n g e ve nts t hat meet t he defi niti on of a n A E or S A E a n d re mai n res p o nsi ble f or f o ll owi n g 
u p A Es t hat are seri o us, c o nsi dere d relate d t o t he st u d y  int er ve nt i on or st u d y  pr oce d ures, or t hat 
cause d t he parti ci pa nt t o disc o nti n ue t he st u d y int er ve nt i on or st u d y (see Secti o n 7 ).
8. 3. 1.
Ti me Peri o d a n d Fre q ue nc y f or C ollecti n g A E a n d S A E I nf or m ati o n
All S A Es will be c o llecte d fr om t he sig ni n g of t he I C F u nt il t h e fol l ow -u p visit at t he ti me p o i nts 
s pecifie d i n t he S o A ( Sectio n 1. 3 ).
All A Es will be c o llecte d fr om t he start of i nter ve nti o n u nt il t h e fol l ow- u p visit .
Me dical occ urre nces t hat be gi n bef ore t he start of st u d y  int er ve ntio n b ut after si g ni n g of t he I C F 
will b e rec or de d o n t he A d verse E ve nt C R F.
Alt h o u g h all A Es after si g ni n g t he I C F are rec or de d b y t he site i n t he C R F/electr o nic data e ntr y, 
S A E re p orti n g t o s p o ns or be gi ns after t he patie nt has si g ne d t he I C F a n d has recei ve d st u d y 
i nter ve nt i on. H o we ver, if a n S A E occ urs after si g ni n g t he I C F, b ut pri or t o recei vi n g st u d y 
i nter ve nt i on, it nee ds t o be re p orte d O N L Y if it is c o nsi dere d reas o na bl y p ossi bl y relate d t o st u d y 
pr oce d ures.
All S A Es will be rec or de d a n d re p orte d t o t he s p o ns or or desi g nee i m me diatel y a n d u n der n o 
circ u msta nce s h o uld t hi s e xcee d 2 4 h o urs, as i n dicate d i n A p pe n di x 1 0. 3 . T he i n vesti gat or will 
s u b mit a n y u p date d S A E data t o t he s p o ns or wit hi n 2 4 h o urs of i t bei n g a vaila ble.
I n vesti gat ors are n ot o bli gate d t o acti vel y see k A E or S A E aft er c o ncl usi o n of t he st u d y  
parti ci pat i on . H o we ver, if t he i n vesti gat or lear ns of a n y S A E, i ncl u di n g a deat h, at a n y ti me after 
a partici pa nt has bee n disc har ge d fr o m t he st u d y, a n d he/s he c o nsi ders t he e ve nt t o be reas o na bl y 
r elate d t o t he st u d y int er ve nt i on or st u d y  partici patio n , t he i n vesti gat or m ust pr o m ptl y n otif y  t he 
s p o ns or.
8. 3. 1. 1.
A d verse E ve nt M o nit ori n g wit h a S yste m atic Q uesti o n n aire
N o nl ea di n g A E c ollect i on s h o ul d occ ur pri or t o t he c ollect i on of t he C -S S R S. 
If a s uici de-relate d e ve nt is disc o vere d d uri n g t he C-S S R S b ut was n ot ca pt ure d d uri n g t he 
n o nlea di n g A E c ollect i on, si tes s h o uld n ot c ha n ge t he A E f or m. 
If a n A E is serio us or l ea ds t o disc o nti n uati on, it nee ds t o be i ncl u de d o n t he A E f or m a n d t he 
pr ocess f or re p orti n g S A Es is f o ll owe d.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
4 0
8. 3. 2.
Met h o d of Detecti n g A Es a n d S A Es
T he m et h o d of rec or di n g, e val uat i n g, a n d assessi n g ca usality of A E a n d S A E a n d t he pr oce d ures 
f or c o mplet i n g a n d tra ns mitti n g S A E re p orts are pr o vi de d i n A p pe n di x 1 0. 3 .
Care will be ta ke n n ot t o i ntr o d uce bias w he n detecti n g A Es a n d/ or S A Es. O pe n -e n de d a n d 
n o nlea di n g ver bal q uesti o ni n g of t he partici pa nt is t he preferre d met h o d t o i n q uire a b o ut 
A E occ urre nc es.
8. 3. 3.
F oll o w -u p of A Es a n d S A Es
After t he i nit ial A E/ S A E re p ort, t he i n vesti gat or is re q uire d t o pr oacti vel y f oll ow eac h partici pa nt 
at s u bse q ue nt visits/c o ntacts. All S A Es will be f o ll o we d u p u ntil res o l uti on, sta bilizat i on, t he 
e ve nt is ot her wise e x plai ne d, or t he partici pa nt is l ost t o f oll ow- u p (as defi ne d i n Secti o n 7. 3 ). 
F urt her i nf or mat i on o n f o ll ow- u p pr oce d ures i s pr o vi de d i n A p pe n di x 1 0. 3 .
8. 3. 4.
Re g ul at or y Re p orti n g Re q uire me nts f or S A Es

Pr o m pt n otificat i on b y t he i n vest i gat or t o t he s p o ns or of an S A E is esse nt ial s o t hat 
le gal o bli gati o ns a n d et hical res p o nsi bilities t o war d t he safet y of partici pa nts a n d t he 
safety of  a st u d y int er ve nt i on u n der cli nical i n vest i gati o n are met.

T he s p o ns or has a le gal res p o nsi bilit y t o n otif y b ot h t he lo c al  re g ulat or y a ut h orit y a n d 
ot her re g ulat or y  a ge ncies a b o ut t he safety of  a st u d y int er ve nt i on u n der cli nical 
i n vesti gati on. T he s p o ns or will c o m p l y wit h c o u ntr y-s pecific re g ulat or y re q uire me nts 
r elat i n g t o safety re p orti n g t o t he re g ulat or y a ut h ority,  I nstitut i onal Re vie w B oar ds 
(I R Bs)/I n de pe n de nt Et hics C o m mittees (I E Cs), a n d i n vesti gat ors.

A n i n vesti gat or w h o recei ves a n i n vesti gat or safet y re p ort descri bi n g an S A E or ot her 
s pecific safety i nf or mati on ( e. g., s u m mar y or listi n g of S A Es) fr om t he s p o ns or will 
re vie w a n d t he n file it al o n g wit h t he I B a n d will n otif y t he I R B/I E C, if a p pr o priate 
acc or di n g t o l ocal re q uire me nts.
8. 3. 5.
Pre g n a nc y

Details o f all pre g na ncies i n fe male partici pa nts a n d, if i n dicate d, fe male part ners of 
male partici pa nts will be c ollecte d after t he start of st u d y  int er ve nt i on a n d u nt il 
f oll ow- u p visit.

If a pre g na nc y is re p orte d, t he i n vesti gat or s h o ul d i nf or m t he s p o ns or wit hi n 2 4 h o urs of  
lear ni n g of t he pre g na nc y a n d s h o ul d f oll ow t he pr oce d ures o utli ne d i n A p pe n di x 1 0. 4 .

A b n or m al pre g na nc y o utc o mes (e. g., s p o nta ne o us a b orti o n, fetal deat h, still birt h, 
c o n ge nital a n o ma lies, ect o pic pre g na nc y) are c o nsi dere d S A Es.

Pre g na nc y ( mater nal or pater nal e x p os ure t o st u d y i nter ve nti on ) d oes n ot meet t he 
defi nit i on o f a n A E . H o we ver, t o f ul fill re g ulat or y re q uire me nts, a n y pre g na nc y s ho ul d 
be re p orte d f oll o wi n g t he S A E pr ocess descri be d i n A p pe n di x 1 0. 4 t o c ollect data o n 
t he o utc o me for b ot h m ot h er a n d fet us.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
4 1
8. 3. 6.
Pr o d uct C o m pl ai nts
A pr o d uct c o m plai nt is a n y writte n, electr o nic, or oral c o m m u nicat i on t hat alle ges deficie ncies 
r elate d t o t he i de ntit y, q ualit y, d ura bilit y, relia bilit y, s afet y,  effecti ve ness, or perf or ma nce of a 
trial int er ve nt i on.
S p o ns or c ollects pr o d uct c o m plai nts o n st u d y int er ve nt i on s a n d dr u g deli ver y s yste ms use d i n 
cli nical st u dies t o e ns ure t he safet y of  st u d y partici pant s, mo ni t or q ualit y, a n d t o facilitate 
pr ocess a n d pr o d uct i m pr o ve me nts.
P arti cip a nts will be i nstr ucte d t o c o ntact t he i n vest i gat or as s o o n as p ossi ble if he or s he has a 
c o mplai nt or pr o bl e m wit h t he st u d y int er ve nt i on s o t hat t he sit u atio n ca n be asses se d.
N O T E: A E s/ S A Es t hat are ass ociate d wit h a pr o d uct c o m plai nt will als o f o ll ow t he pr ocesses 
o utli ne d i n Sect i on 8. 3. 3 a n d A p pe n di x 1 0. 3 of  t he pr ot oc ol.
8. 3. 6. 1.
Ti me Peri o d f or Detecti n g Pr o d uct C o m pl ai nts
●
Pr o d uct c o m plai nt s t hat res ult i n a n A E will be detecte d, d oc u me nte d, a n d 
re p orte d t o t he s p o ns or d uri n g all peri o ds of t he st u d y i n w hic h t he dr u g/ de vice is 
use d.
●
If t he i n vestigat or l ear ns of a n y pr o d uct c o m plai nt at a n y ti me after a partici pa nt 
has bee n disc har ge d fr o m t he st u d y , a n d s uc h i nci de nt is c o nsi dere d reas o na bl y 
r elate d t o a dr u g/ de vice pr o vi de d f or t he st u d y, t he i n vest i gat or will pr om pt l y 
n otif y t he s p o ns or.
8. 3. 6. 2. Pr o m pt Re p orti n g of Pr o d uct C o m pl ai nts t o S p ons or
●
Pr o d uct c o m plai nts will  be re p orte d t o t he s p o ns or wit hi n 2 4 h o urs aft er t he 
i n vesti gat or bec o mes a ware of t he c o m p lai nt.
●
T he Pr o d uct C o m plai nt F or m  will be se nt t o t he s p o ns or t hr o u g h e mail. If e mail is 
u na vaila ble, t he n fa x s h o uld be ut ilize d.
8. 3. 6. 3.
F oll o w -u p of Pr o d uct C o m pl ai nts
●
F o ll ow- u p a p plies t o all partici pa nts, i ncl u di n g t h ose w h o disc o nt i n ue st u d y 
i nter ve nt i on.
●
T he i n vest i gat or is res p o nsi ble f or e ns uri n g t hat f oll o w-u p i ncl u des a n y 
s u p ple me ntal in vesti gati o ns as i n dicate d t o el uci date t he nat ure a n d/ or ca usalit y of  
t he pr o d uct c o m plai nt .
●
Ne w or u p date d i nf or mat i on will be rec or de d o n t he ori gi nall y c o m p lete d f or m 
wi t h all c ha n ges si g ne d a n d date d b y t he i n vest i gat or a n d s u b mitte d t o t he 
s p o ns or.
8. 3. 6. 4. Re g ul at or y Re p orti n g Re q uire me nts f or Pr o d uct C o m pl ai nts
●
T he i n vest i gat or will pr om pt l y re p ort all de vice -relate d pr o d uct c o m plai nts t o t he 
s p o ns or t o facilitate ti mel y re g ulat or y re p orti n g.
●
As re q ui re d b y lo c al  re g ulati ons, t he i n vest i gat or will re p ort t o t heir I R B/I E C a n y 
u na nt ici pate d a d verse de vice effect ( u na ntici pate d pr o ble m t hat res ulte d i n a n 

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
4 2
S A E), or a n y  pr o d uct c o mplai nt t hat c o ul d ha ve le d t o a n S A E ha d preca uti o ns 
n ot bee n ta ke n. 
8. 4.
Tre at me nt of O ver d ose
F or t he p ur p oses of t his st u dy, a n d over d ose of l as mi dit a n, d a bi g atr a n etexil ate , or r os uv ast ati n 
is c o nsi dere d a ny d ose hi g her t h a n t he d ose assi g ne d. T here is n o s pecific a nti d ote f or 
l as mi dit a n, or r os uv ast ati n.
I n t he e ve nt of  a n o ver d ose, t he i n vesti gat or/treati n g p h ysicia n s h o uld:
1.
c o ntact t he me d ical mo ni t or i m me diatel y.
2.
c l osel y mo ni t or t he partici pa nt f or a n y AE/ S A E a n d la b orat or y  a b n or malities u nt il st u d y 
i nter ve nt i on ca n n o l o n ger be detecte d s yste micall y ( at least 2 d a y s).
3.
d oc u m e nt t he q ua ntit y of t he e xcess d ose as well as t he d urati o n of t he o ver d ose i n t he 
C R F.
4.
in t he case of e mer ge nc y  u nc o ntr olle d blee di n g as a direct c o nse q ue nce of da bi gatra n, 
ur ge nt referral f or treat me nt wit h i dar uciz u ma b s h o ul d be c o nsi dere d .
Decisi o ns re gar di n g d ose i nterr u pti o ns or m o dificati o ns will be ma de b y t he i n vest i gat or i n 
c o ns ultati o n wit h t he me d ical m o nit or base d o n t he cli nical e val uati o n of t he partici pa nt.
8. 5.
P h ar m ac o ki netics
At  t he visits a n d ti mes s pecifie d i n t he S o A , ve n o us bl oo d sa m ples of  a p pr o xi matel y 2 m L eac h 
will be c o llecte d t o deter mi ne t he plas ma c o nce ntrati o ns of las mi dita n, met a b o lite M 8, 
r os u vastati n, a n d da bi gatra n. A ma xi m u m o f 3 sa m ples ma y be c ollecte d at a d dit i onal t i me 
p oi nts d uri n g t he st u d y  if warra nte d a n d a gree d u p o n bet wee n b ot h t he i n vest i gat or a n d s p o ns or.
I nstr uctio ns f or t he c ollect i on a n d ha n dli n g of bl o o d sa m ples will be pr o vi de d b y t he s p o ns or.
T he act ual  date a n d ti me ( 2 4- h o ur cl oc k ti me) of eac h sa m pli n g will be rec or de d.
8. 5. 1.
Bi o a n al ysis
S a m ples will  be a nal yze d at a la b orat or y a p pr o ve d b y t he s p o ns or a n d st ore d at a facility 
desi g nate d b y  t he s p o ns or.
C o nce ntrati o ns of  las mi dit a n, meta b o lite M 8, r os u vastatin, a n d da bi gatra n will be assa ye d usi n g 
a vali date d li q ui d c hr o mat o gra p h y wit h ta n de m mass s pectr o metr y met h o d.
Bi oa nal y tic al sa m ples c ollecte d t o meas ure st u d y i nter ve nti on c o nce ntrati o ns will be retai ne d f or 
a ma xi m u m of 2 year s f oll owi n g last parti ci pa nt visit f or t he st u d y.
8. 6.
P h ar m ac o d y n a mics
P har mac o d y na mic para meters a re n ot e val uate d i n t his st u d y.
8. 7.
Ge netics
A bl o o d or sali va sa m ple f or D N A is olati on will be c ollecte d fr o m parti ci pa nts. 
See A p pe n di x 1 0. 5 f or inf or m at i on re gar di n g ge netic researc h a n d A p pe n di x 1 0. 1. 1 0 f or details 
a b o ut sa m ple rete nti o n a n d cust o d y . 

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
4 3
8. 8.
Bi o m ar kers
Bi o m ar kers are n ot e valuate d i n t hi s st u d y.
8. 9.
I m m u n o ge nicit y Assess me nts
N ot a p plica ble f or t his st u d y.
8. 1 0.
He alt h Ec o n o mic s
T his sect i on is n ot a p plica ble f or t his st u d y.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
4 4
9.
St atistic al C o nsi der ati o ns
9. 1.
St atistic al H y p ot heses
T here i s n o direct c o ntr ol for m ul tiplici t y but b ot h pri mar y  o bjecti ve varia bles will be teste d as 
c o -c o nfir mat or y  varia bles. All ot her tests a n d/ or esti mat i on stati stics will n ot be c o nfir mat or y b ut 
will c o ntri b ute t o a b o d y  of e vi de nce t o s u p p ort fi nal c o ncl usi ons.
N o si g nifica nt D DI f or da bi gatra n or r os u vastati n will be c o ncl u de d if t he res pect i ve 9 0 % 
c o nfi de nce i nt er v al f or A U C fr om ti me zer o t o i nfi nity (A U C [ 0- ∞]) a n d C ma x is c om p letel y 
c o ntai ne d wit hi n t he n o -effect b o u n daries ( 0. 8 0, 1. 2 5). A descri pti o n o f eac h test is pr o vi de d i n 
Secti o n 9. 4 .
9. 2.
S a m ple Size Deter mi n ati o n
A p pr o xi matel y  7 2 parti ci pa nts will be e nr olle d t o P art 1 of t he st u d y t o e ns ure t hat at least 6 2
e val ua ble part ici pa nts c o mplete t hat part. Wit h 6 2 parti ci pa nts, we e x pect t he t w o 1- si de d t-tests 
( T O S Ts) f or e q ui vale nce a p plie d t o t he l o g n or mal mea n rati o t o ha ve a p o wer of at least 8 0 % f or 
t he A U C( 0 -∞) a n d C ma x tests i n P art 1. T his ass u mes a n o mi nal e x pecte d mea n rat i o of 1. 0 5, a 
c oefficie nt of  v ari at i on ( C V) of 3 9. 3 %, a n d a sig nifica nce le vel o f 0. 0 5 of eac h 1- si ded test w he n 
testi n g a gai nst a n u p per li mit of 1. 2 5 a n d a l ower li mit of 0. 8 0. T he tests will be dis pla ye d i n t he 
f or m of 9 0 % c o nfi de nce i nter vals, w hic h are e q ui vale nt t o t he acc or di n g T O S T. T he s o urce of 
t he C V is B oe hri n ger I n gle hei m bi oe q ui vale nce st u d y  ( E u dra C T n u m ber 2 0 0 7- 0 0 5 7 6 5- 3 5), a n d 
t he hi g her i nt ras u bject C V o bser ve d i n t he sec o n d -ge nerat i on da bi gatra n ar m was c h ose n.
A p pr o xi matel y  3 2 parti ci pa nts will be e nr olle d t o P art 2 t o e ns ure t hat at least 2 8 e val ua ble 
parti ci pa nts c o mplete t hat part. Wit h 2 8 partici pa nts , we e x pect the t w o 1- si de d t-tests f or 
e q ui vale nce a p plie d t o t he l o g n or mal mea n rati o t o ha ve a p o wer of at least 8 0 % f or t he A U C( 0 -
∞) a n d C ma x tests i n P art 2. T hi s ass u mes a n o mi nal e x pecte d mea n rati o of 1. 0 5, a C V of 
2 5. 1 %, a n d si g nifica nce le vel o f 0. 0 5 of eac h 1- si ded test w he n testi n g a gai nst a n u p per li mit of 
1. 2 5 a n d a l ower li mit of 0. 8 0. T he tests will be dis pla ye d i n t he f or m of 9 0 % c o nfi de nce 
i nter vals w hic h are e q ui vale nt t o t he acc or di n g T O S T. T he s o urce of t he C V is S t u d y A Z E B, a n d 
t he hi g her of t he r os u vastati n A U C( 0 -∞) a n d C ma x i ntras u bject C Vs was c h ose n.
9. 3.
P o p ul ati o ns f or A n al yses
T he f oll owi n g p o p ul at i ons are defi ne d:
P o p ul ati o n
Descri pti o n
E ntere d
All partici pa nts w h o si g n t he I C F
E nr olle d
All partici pa nts assi g ne d t o treat me nt, re gar dless of w het her t he y  
ta ke a n y d oses of st u d y int er ve nt i on , or if t he y t o o k t he c orrect 
treat me nt.
S af et y
All partici pa nts assi g ne d t o da bi gatra n ete xilate or r os u vastati n
a n d w h o ta ke at least 1 d ose of 1 of  t h ose pr o d ucts. Partici pa nts 
will be a nal yze d acc or di n g t o t he pr o d uct t he y act uall y recei ve d.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
4 5
P har mac o ki net ic A nal ysis
All partici pa nts w h o rece i ve at least 1 d ose of da bi gatra n 
ete xilate or r os u vastati n a n d ha ve e val ua ble P K.
9. 3. 1.
St u d y P artici p a nt Dis p ositi o n
A detaile d descri pti o n of  p artici pa nt dis p ositio n will be pr o vi de d at t he e n d of t he st u d y .
9. 3. 2.
St u d y P artici p a nt C h ar acteristics
T he s u bject’s a ge, se x, a n d ot her de m o gra p hic c haracterist ics will be rec or de d a n d s u m marize d.
D e m o gra p hic c haracteri stics ma y be c o nsi dere d i n t he i nter pretatio n of  P K a n d safety a nal yses.
9. 3. 3.
Tre at me nt C o m pli a nce
T he d ate a n d ti me of d osi n g will be rec or de d a n d liste d.
9. 4.
St atistic al A n al yses
Stati stical a nal ysis of t his st u d y will be t he res p o nsi bilit y of  t he sp o ns or or i ts desig nee.
P har mac o ki net ic a nal yses will be c o n d ucte d o n data fr om all partici pa nts w h o recei ve at least 1
d ose of las mi dit a n a n d ha ve e val ua ble P K. Statistical i nfere nce of P K para meters will ut ilize 
parti ci pa nts i n t he P K a nal ysis p o p ulati o n w hic h ha ve e val ua ble P K , b ot h bef ore a n d after t he 
i ntr o d uctio n of  las mi dit a n.
S af et y a nal yses will be c o n d ucte d f or all e nr o lle d partici pa nts w h o recei ve d at least 1 d ose of 
da bi gatra n ete xilate or r os u vastati n , w het her or n ot t he y c o mplete d all  pr ot oc ol re q uire me nts.
A d dit i onal e x plor at or y  a nal yses of t he data will be c o n d ucte d as dee me d a p pr o priate.
9. 4. 1.
S afet y A n al yses
9. 4. 1. 1.
Cli nic al E v al u ati o n of S afet y
A ll st u d y int er ve nt i on a n d pr ot oc ol pr oce d ure A Es will be liste d, a n d if t he fre q ue nc y of e ve nts 
all o ws, safet y data will be s u m marize d usi n g descri pt i ve met h o d ol o g y .
T he i nci de nce of A Es f or eac h treat me nt will be prese nte d b y  se verit y a n d b y ass ociat i on wi t h 
st u d y int er ve ntio n as percei ve d b y t he i n vesti gat or. A d verse e ve nts re p orte d t o occ ur pri or t o
e nr o ll me nt will be di sti n g uis he d fr o m t h ose re p orte d as ne w or i ncrease d i n se verit y d uri n g t he 
st u d y. Eac h A E will be classifie d b y t he m ost s uita ble ter m fr o m t he M e dical D icti onar y f or 
R e g ulat or y Act i vities.
T he n u m ber of st u d y int er ve nt i on- relate d S A Es will be re p orte d.
9. 4. 1. 2.
St atistic al E v al u ati o n of S afet y
S af et y para m eters t hat will be assesse d i ncl u de safet y la b orat or y para meters, vit al sig ns, a n d 
E C G para meters. T he para meters will be liste d, a n d s u m marize d usi n g sta n dar d descri pt i ve 
statistics. A d dit i onal a nal ysis will be perf or me d if warra nte d u p o n re vie w of t he data.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
4 6
9. 4. 2.
P h ar m ac o ki netic A n al yses
9. 4. 2. 1.
P K P ar a meter Esti m ati o n
P har mac o ki net ic para meter esti mates will be calc ulate d usi n g sta n dar d n o nc o m part me ntal 
met h o ds. T he pri mar y P K para meters f or a nal ysis of da bi gatra n a n d r os u vastati n will be C ma x
a n d A U C( 0 -∞). Ot he r n o nc o m partme nt al para meters, s uc h as t1/ 2, a p pare nt t otal b o d y cleara nce 
of  dr u g calc ulate d after e xtra vasc ular a d mi nistrati o n, a n d a p pare nt v ol u me of distri b uti o n d uri n g 
t he ter mi nal p hase after e xtra vasc ular a d mi nistrati o n, ma y be re p orte d as a p pr o pria t e.
N o nc o m part me nt al P K para meters will als o be calc ulate d f or las mi dita n a n d M 8.
9. 4. 2. 2.
P K St atistic al I nfere nce
P har mac o ki net ic para meters will be e val uate d t o esti mate dr u g i nteracti o n f or da bigatra n a n d 
r os u vastati n wi t h las mi dit a n. L o g -tra nsf or me d Cma x a n d AU C ( 0-∞) para m eters f or da bi gatra n 
a n d r os u vastati n will  be e val uate d se paratel y. T he treat m e nt differe nces will be bac k tra nsf or me d 
t o prese nt t he rati os of ge omet ric mea ns a n d t he c orres p o n din g 9 0 % c o nfi de nce i nter val.
T he tma x will be a nal yze d usi n g a Wilc o x o n si g ne d ra n k test. Esti mates of t he me dia n differe nce 
base d o n t he o bser ve d me dia ns, 9 0 % c o nfi de nce i nter val s a n d p-val ues fr o m t he Wilc o x o n test 
will be calc ulate d.
T he effect of p ol y m or p his ms i n ge nes c o di n g f or certai n tra ns p orters (e. g., A B C G 2, A B C B 1, 
A B C C 2, S L C O 1 B 3, N T C P, a n d S L C O 2 B 1) o n t he ma g nit u de of t he i nteracti o n bet wee n 
r os u vastati n a n d las mi dita n ma y be e x pl ore d. F or eac h s u bject, t he rati o of r os u vastati n 
e x p os ures wit h a n d wit h o ut c o nc o mita nt las mi dit a n e x p os ures will be calc ulate d. A gra p hical 
a nal ysis of t hese rat i os bet wee n parti ci pa nts wi t h a n d wit ho ut S N Ps of i nterest is i nte n de d.
A d dit i onal a nal yses ma y be c o n d ucte d as warra nte d .
9. 4. 3.
P h ar m ac o d y n a mic A n al yses
N ot a p plica ble f or t his st u d y .
9. 4. 4.
P h ar m ac o ki net ic/ P h ar m ac o d y n a mic A n al yses
N ot a p plica ble f or t his st u d y .
9. 4. 5.
Ot her A n al yses
A n al ysis of C -S S R S D at a
S ui ci de-relate d t h o u g hts a n d be ha vi ors occ urri n g d uri n g treat me nt will be s u m marize d base d o n 
res p o nses t o t he C-S S R S c o nsiste nt wit h t he C -S S R S Sc ori n g a n d D ata A nal ysis G ui de ( C S S R S 
[W W W ]).
9. 5.
I nteri m A n al yses 
N o i nt eri m a nal yses are pla n ne d f or t his st u d y. If a n u n pla n ne d i nteri m a nal ysis is dee me d 
necessar y  for reas o ns ot her t ha n a safet y c o ncer n, t he pr ot oc ol m ust be a me n de d.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
4 7
9. 6.
D at a M o nit ori n g C o m mittee
N o data m o nit ori n g c o m mittee is re q uire d f or t his st u d y.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
4 8
1 0.
S u p p orti n g D oc u me nt ati o n a n d O per ati o n al C o nsi der ati o ns
1 0. 1.
A p pe n di x 1: Re g ul at or y, Et hic al, a n d St u d y O versi g ht 
C o nsi der ati o ns
1 0. 1. 1.
Re g ul at or y a n d Et hic al C o nsi der ati o ns
T his st u d y  will be c o n d ucte d i n acc or da nce wit h t he pr ot oc ol a n d wit h t he f oll owi n g:
○C o nse ns us et hical pri nci ples deri ve d fr o m i nter natio nal g ui deli nes i ncl u di n g t he 
Declarati o n of Helsi n ki a n d C o u ncil f or I nter nati o nal Or ga nizat i ons of 
Me dical Scie nces I nter nat i onal Et hi cal G ui deli nes
○A p pli ca ble I nter nati onal C o u ncil f or Har m o nisati o n ( I C H) G o o d Cli nical 
Practi ce ( G C P) G uideli nes
○A p plica ble la ws a n d re g ulat i ons
●
T he pr ot oc ol, pr ot oc ol a me n d me nts, I C F, I B, rele va nt c urric ul u m vitae, a n d ot her 
r ele va nt d oc u me nts (e. g., a d vertise me nts) m ust be s u b mitte d t o a n I R B/I E C b y  t he 
i n vesti gat or a n d re vie we d a n d a p pr o ve d b y t he I R B/I E C bef ore t he st u d y is 
i nitiate d.
●
A n y a me n d me nts t o t he pr ot oc ol will re q uire I R B/I E C a p pr o val bef ore 
i m ple me ntati o n of c ha n ges ma de t o t he st u d y desi g n, e xce pt f or c ha nges 
necessar y  t o eli mi nate a n i m me diate hazar d t o st u d y p artici pa nts.
●
T he i n vest i gat or will be res p o nsi ble f or t he f oll owi n g:
○
Pr o vi di n g wri tte n s u m maries of t he stat us of t he st u d y t o t he I R B/I E C 
a n n uall y or m ore fre q ue ntl y i n acc or da nce wit h t he re q uire me nts, p olicies, a n d 
pr oce d ures esta blis he d b y t he I R B/I E C
○
N otif yi n g t he I R B/I E C of S A Es or ot her si g nifica nt safet y fi n di n gs as re q uire d 
b y I R B/I E C pr oce d ures
○
Pr o vi di n g o versi g ht of t he c o n d uct of t he st u d y at t he site a n d a d here nce t o 
re q uire me nts of  2 1 C o de of Fe deral Re g ulat i ons , I C H g uideli nes, t he 
I R B/I E C, E ur o pea n re g ulati o n 5 3 6/ 2 0 1 4 f or cli nical st u dies (if a p plica ble), 
a n d all ot her a p plica ble l ocal re g ulat i ons
●
I n vesti gat or sites are c o m pe nsate d f or partici pat i on i n t he st u d y  as detaile d i n t he 
cli nical trial a gree me nt.

S o m e of t he o bli gati ons of t he s p o ns or will be assi g ne d t o a t hir d -part y  
or ga ni zat i on.
1 0. 1. 2.
Fi n a nci al Discl os ure
I n vesti gat ors a n d s u bi n vesti gat ors will pr o vi de t he s p o ns or wit h s ufficie nt, acc urate fi na ncial 
i nf or mat i on as re q ueste d t o all o w t he s p o ns or t o s u b mit c o m plete a n d acc urate fi na ncial 
certificati o n or discl os ure state me nts t o t he a p pr o priate re g ulat or y  a ut h orities. I n vestigat ors are 

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
4 9
res p o nsi ble f or pr o vi di n g i nf or mati on o n fi na ncial i nterests d uri n g t he c o urse of t he st u d y  a n d f or 
1 year after c o m plet i on of t he st u d y .
1 0. 1. 3.
I nf or me d C o nse nt Pr ocess

T he i n vest i gat or or his/ her re prese ntati ve will e x plai n t he nat ure of t he st u d y, i ncl u di n g 
t he ris ks a n d be nefits, t o t he partici pa nt or his/ her le gall y a ut h orize d re prese ntati ve a n d 
a ns wer all q uest i ons re gar di n g t he st u d y .

P arti cipa nts m ust be i nf or m e d t hat t heir partici pat i o n is v ol unt ar y. Participa nts or t hei r 
le gall y a ut h orize d re prese ntati ve will be re q uire d t o sig n a state m e nt of i nf or me d 
c o nse nt t hat meets t he re q uire me nts of 2 1 C o de of Fe deral Re g ulat i ons 5 0, l o c al  
re g ulat i ons, I C H g ui deli nes, Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act 
re q uire me nts, w here a p plica ble, a n d t he IR B/I E C or s t u d y ce nter.

T he m e dical rec or d must i ncl u de a state m e nt t hat writte n i nf or me d c o nse nt was 
o btai ne d bef ore t he partici pa nt was e nter e d i n t he st u d y a n d t he date t he writte n c o nse nt 
was o btai ne d. T he a ut h orize d pers o n o btai ni n g t he i nf or me d c o nse nt m ust als o si g n t he 
I C F.

P arti cipa nts m ust be re -c o nse nte d t o t he m ost c urre nt versi o n of t he I C F(s) d uri n g t h eir 
parti ci pat i on i n t he st u d y.

A c o p y  of t he I C F(s) must be pr o vi de d t o t he partici pa nt or t he partici pa nt’s le gall y  
a ut h orize d re prese ntative a n d is ke pt o n file .
P arti cipa nts w h o are rescree ne d are re q uire d t o si g n a ne w I C F.
1 0. 1. 4.
D at a Pr otecti o n

P arti cipa nts will be assi g ne d a u ni q ue i de nt ifier b y t he s p o ns or. A n y partici pa nt rec or ds,
datasets , or tiss ue sa m ples t hat are tra nsferre d t o t he s p o ns or will c o ntai n t he i de nt ifier 
o nl y; part ici pa nt na mes or a n y inf or mat i on t hat w o ul d ma ke t he partici pa nt i de nt ifia ble 
will n ot be tra nsferre d.

T he parti ci pa nt m ust be i nf or me d t hat his/ her pers o nal st u d y-r elate d data will be use d 
b y t he s p o ns or i n acc or da nce wit h l ocal data pr otectio n la w. T he l e vel of discl o s ure 
m ust al s o be e x plai ne d t o t he partici pa nt w h o will be re q uire d t o gi ve c o nse nt f or t heir
data t o be use d as descri be d i n t he i nf or me d c o nse nt .

T he parti ci pa nt m ust be i nf or me d t hat his/ h er me dical rec or ds ma y be e xa mi ne d b y 
Cli nical Q ualit y Ass ura nce a u dit ors or ot her a ut h orize d pers o n nel a p p o i nte d b y t he 
s p o ns or, b y a p pr o priate I R B/I E C me m bers, a n d b y i ns pect ors fr o m re g ulat or y 
a ut h orities.

T he sp o ns or has pr ocesses i n place t o e ns ure data pr otecti o n, i nf or mat i on sec urit y, a n d 
data i nte grit y. T hese pr ocesses i ncl u de a p pr o priate c o nti n ge nc y pla n(s) f or a p pr o priate 
a n d ti mel y res p o nse i n t he eve nt of a data sec urit y breac h.
1 0. 1. 5.
Disse mi n ati o n of Cli nic al St u d y D at a
C o m m u nic ati o n of S us pe n de d or Ter mi n ate d D osi n g

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
5 0
If a decisi on is ta ke n t o s us pe n d or ter mi nate d osi n g i n t he trial d ue t o safety fi n di n gs, t his 
decisi o n will be c o m m u nicate d b y Lill y t o a ll i n vesti gat ors (e. g., t hr o u g h p h o ne a n d/ or e mail) as 
s o o n as p ossi ble. It will be a re q uire me nt t hat i n vesti gat ors res p o n d u p o n recei pt t o c o nfir m t hat 
t he y u n dersta n d t he c o m m u nicati on a n d ha ve ta ke n t he a p pr o priate acti o n pri or t o f urt her d osi n g 
a n y partici pa nts wit h st u d y int er ve nt i on. A n y i n vesti gat or n ot res p o n di n g will be f o ll owe d u p b y  
Lill y pers o n nel pri or t o a n y  furt her pl a n ne d d osi n g. If a d ose is pla n ne d i m mi ne nt l y, Lill y 
pers o n nel will i m me diatel y, a n d c o nt i n uall y, use all eff orts t o reac h i n vest i gat ors u ntil c o ntact is 
ma de a n d i nstr ucti o ns are verifie d.
Re p orts
T he s p o ns or will discl ose a s u m mar y o f st u d y inf o r mat i on, i ncl u di n g ta b ular st u d y res ults, o n 
p u bli cl y a vaila ble we bsites w here re q uire d b y lo c al  la w or re g ulat i on.
D at a 
T he s p o ns or d oes n ot pr oacti vel y s hare data fr o m P hase 1 cli nical trials. Re q uests f or access t o 
P hase 1 cli nical trial data are e val uate d o n a case -b y -case basis ta ki n g i nt o c o nsi derat i on t he 
a bilit y t o a n o n y mize t he data a n d t he nat ure of t he data c ollecte d.
1 0. 1. 6.
D at a Q u alit y Ass ur a nce
All p artici pa nt data relat i n g t o t he st u d y will be rec or de d o n pri nte d or electr o nic C R F u nless 
tra ns mitte d t o t he s p o ns or or desi g nee electr o nicall y (e. g., la bor at or y  data). T he i n vesti gat or is 
res p o nsi ble f or verif yi n g t hat data e ntries are acc urate a n d c orrect b y p h ysicall y or electr o nicall y 
sig ni n g t he C R F.
●
T he i n vest i gat or m ust mai ntai n acc urate d oc u me ntati o n (s o urce data) t hat 
s u p p orts t he i nf or mati on e nt ere d i n t he C R F.
●
T he i n vest i gat or m ust per mit st u d y-r elat e d mo ni t ori n g, a u dits, I R B/I E C re vie w, 
a n d re g ulat or y a ge nc y i ns pecti ons a n d pr o vi de direct access t o s o urce data 
d oc u m e nts.
●
M o ni t ori n g details descri bi n g strate g y ( e.g. , ris k-base d i nit iati ves i n o perati o ns 
a n d q ualit y s uc h as Ris k Ma na ge me nt a n d Mit i gati o n Strate gies a n d A nal ytical 
Ris k -Base d M o nit ori n g), met h o ds, res p o nsi bilit ies, a n d re q uire me nts, i ncl u di n g 
ha n dli n g of n o nc o m p lia nce iss ues a n d m o nit ori n g tec h ni q ues are pr o vi de d i n t he 
M o ni t ori n g Pla n.
●
T he s p o ns or or desi g nee is res p o nsi ble f or t he data ma na ge me nt of t his st u d y  
i ncl u di n g q uality c hec ki n g of t he data.
●
T he s p o ns or ass u mes acc o u nta bilit y f or actio ns dele gate d t o ot her i n di vi d uals 
( e.g. , c o nt ract researc h or ga nizati ons ).

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
5 1
●
St u d y m o nit ors will perf or m  o n g oi n g s o urce data verificati o n t o c o nfir m t hat data 
e ntere d i nt o t he C R F b y a ut h orize d C R U pers o n nel are acc urate, c o m plete, a n d 
verifia ble fr o m s o urce d oc u me nts; t hat t he safet y a n d rig hts of  partici pa nts are 
bei n g pr otecte d; a n d t hat t he st u d y is bei n g c o n d ucte d i n acc or da nce wit h t he 
c urre ntl y a p pr o ve d pr ot oc ol a n d a n y ot her st u d y a gree me nts, I C H G C P, a n d all 
a p plica ble re g ulat or y r e q uire me nts.
●
Rec or ds a n d d oc u me nts, i ncl u di n g si g ne d I C Fs, pertai ni n g t o t he c o n d uct of t his 
st ud y m ust be retai ne d b y t he i n vest i gat or f or t he time peri o d o utli ne d i n t he 
Cli nical Trial A gree me nt u nless l ocal re g ulat i ons or i nst ituti o nal  p olicies re q uire a 
l on ger rete nti o n peri o d. N o rec or ds ma y be destr o ye d d uri n g t he rete nti o n peri o d 
wi t ho ut t he w ritte n a p pr o val of t he s p o ns or. N o rec or ds ma y be tra nsferre d t o 
a n ot her l ocati o n or part y wit ho ut wri tte n n otificati o n t o t he s p o ns or.
●
I n a d diti on, t he sp o ns or or i ts re prese ntati ves will peri o dicall y c hec k a sa m ple of 
t he partici pa nt data rec or de d a gai nst s o urce d oc u me nts at t he C R U . T he st u d y  
ma y be a u dite d b y t he sp o ns or or i ts re prese ntati ves, a n d/ or re g ulat or y a ge ncies at 
a n y ti me. I n vesti gat ors will be gi ve n n otice bef ore a n a u dit occ urs.

T o e ns ure acc urate, c o m plete, a n d relia ble data, Lill y or it s re prese ntati ves will d o t he 
f oll owi n g:

pr o vi de i nstr ucti o nal materi al t o t he C R Us , as a p pr o priate.

pr o vi de trai ni n g t o i nstr uct t he i n vest i gat ors a n d st u d y c o or di nat ors. T hi s trai ni n g 
will gi ve i nstr ucti o n o n t he pr ot oc ol, t he c o m pleti o n of t he C R Fs, a n d st u d y 
pr oce d ures.

ma ke peri o dic visit s t o t he C R U .

be a vaila ble f or c o ns ultati o n a n d sta y  in c o ntact wit h t he C R U pers o n nel t hr o u g h
mail, tel e p h o ne, or fa x.
D at a C a pt ure S yste m
T he i n vest i gat or is res p o nsi ble f or e ns uri n g t he acc urac y, c o m plete ness, le gi bility,  a n d ti meli ness 
of  t he data re p orte d t o t he s p o ns or. 
A n electr o nic data ca pt ure s y st e m will be use d i n t his st u d y for t he c ollect i on of C R F data. T he 
i n vesti gat or mai ntai ns a se parate s o urce f or t he data e ntere d b y t he i n vesti gat or or desi g nee i nt o 
t he s p o ns or -pr o vi de d electr o nic data ca pt ure s yste m. T he i n vesti g at or is res p o nsi ble f or t he 
i de ntificati on of a n y data t o be c o nsi dere d s o urce a n d f or t he c o nfir mat i on t hat data re p orte d are 
acc urate a n d c o m plete b y si g ni n g t he C R F.
Data c ollecte d via t he s p o ns or- pr o vi de d data ca pt ure s yste m will be st ore d at t hir d part y . T he 
i n vesti gat or will ha ve c o nti n u o us access t o t he data d uri n g t he st u d y a n d u ntil dec om missi o ni n g 
of  t he data ca pt ure s y st e m. Pri or t o dec o m missi o ni n g, t he i n vest i gat or will recei ve a n arc hi val 
c o p y of perti ne nt data f or rete nti o n.
Data m a na ge d b y a ce ntral ve n d or, s uc h as la b orat or y test data, will be st ore d electr o nicall y in 
t he ce ntral ve n d or’s data base s yst e m a n d electr o nic tra nsfers will be pr o vi de d t o t he i n vest i gat or 

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
5 2
f or re vie w a n d rete nti on. Data will s u bse q ue nt l y be tra nsferre d fr o m t he ce ntral ve n d or t o t he 
sp o ns or data ware h o use.
Data fr o m c o m p lai nt f or ms s u b mitte d t o t he sp o ns or will be e nc o de d a n d st ore d i n t he gl o bal 
pr o d uct c o m plai nt ma na ge me nt s y st e m.
1 0. 1. 7.
S o urce D oc u me nts

S o urce d oc u me nts pr o vi de e vi de nce f or t he e xiste nce of t he partici pa nt a n d s u bsta ntiate 
t he i nte grit y of  t he data c ollecte d. S o urce d oc u me nts are file d at t he i n vesti gat or’s site.

Data re p orte d o n t he C R F or e ntere d i n t he electr o nic C R F t hat are tra nscri be d fr o m 
s o urce d oc u me nts m ust be c o nsiste nt wit h t he s o urce d oc u me nts or t he discre pa ncies 
m ust be e x plai ne d. T he i n vest i gat or ma y nee d t o re q uest pre vi o us me dical rec or ds or 
tra nsfer rec or ds, de pe n di n g o n t he st u d y. Als o, c urre nt me dical rec or ds m ust be 
a vaila ble.
1 0. 1. 8.
St u d y a n d Site St art a n d Cl os ure
T he st u d y  start date is t he date o n w hic h t he cli nical st u d y will be o pe n f or recr uitme nt  of 
parti ci pa nts.
T he s p o ns or desi g nee reser ves t he ri g ht t o cl ose t he C R U or ter mi nate t he st u d y  at a n y time f or 
a n y reas o n at t he s ole discret i on of t he s p o ns or. C R Us will be cl ose d u p o n st u d y  c o mplet i on. A 
C R U is c o nsi dere d cl ose d w he n all re q uire d d oc u me nts a n d st u d y s u p plies ha ve bee n c ollecte d 
a n d a st u d y-sit e clos ure visit has bee n perf or me d.
T he i n vest i gat or ma y i nitiate st u d y-sit e clos ure at a n y  time, pr o vi de d t here i s reas o na ble ca use 
a n d s ufficie nt n otice is gi ve n i n a d va nce of t he i nte n de d ter mi nat i on.
Reas o ns f or t he earl y clos ure of a C R U b y t he s p o ns or or i n vest i gat or ma y i ncl u de b ut are n ot 
li mite d t o:

Fail ure of t he i n vest i gat or t o c o m pl y with t he pr ot oc ol, t he re q uire me nts of t he I R B/I E C 
or l o c al  healt h a ut h orities, t he s p o ns or ’s pr oce d ures, or G C P g ui deli nes

I na de q uate recr uitme nt  of p artici pa nts b y t he i n vestigat or

Di sc o nti n uatio n of  furt her st u d y int er ve nt i on de vel o p m e nt
If t he st u d y is pre mat urel y ter mi nate d or s us pe n de d, t he s p o ns or s hall pr o m ptl y i nf or m t he 
in vesti gat ors, t he I E Cs/I R Bs, t he re g ulat or y  a ut h orities, a n d a n y c o ntract researc h or ga nizat i on(s) 
use d i n t he st u d y  of t he reas o n f or ter mi nati on or s us pe nsi o n, as s pecifie d b y t he a p plica ble 
re g ulat or y r e q uire me nts. T he in vesti gat or s hall pr o m pt l y i nf or m t he parti ci pa nt a n d s h o ul d ass ure 
a p pr o priate partici pa n t t hera p y a n d/ or f ollo w - u p.
1 0. 1. 9.
P u blic ati o n P olic y
I n acc or da nce wit h t he s p o ns or’s p u blicati o n p olic y, t he res ults of t his st u d y will be s u b mitte d 
f or p u blicati on b y a peer -re vie we d j o ur nal if t he res ults are dee me d t o be of si g nifica nt me dical 
i m p orta nce.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
5 3
1 0. 1. 1 0.
L o n g -Ter m S a m ple Rete nti o n
S a m ple rete nti o n e na bles use of ne w tec h n o l ogi es, res p o nse t o re g ulat or y q uesti ons, a n d 
i n vesti gati on of varia ble res p o nse t hat ma y n ot be o bser ve d u nt il later i n t he de vel o p me nt 
of las mi dita n.
S a m ple T y pe
C ust o di a n
Rete nti o n Peri o d After 
L ast P atie nt Visit *
L o n g -t er m st ora ge sa mples
S p o ns or or Desi g nee
1 5 years
P K
S p o ns or or Desi g nee
2 year s
Ge net ics
S p o ns or or Desi g nee
1 5 years
* Rete nti o n peri o ds ma y differ l ocall y.
T he s p o ns or has a ri g ht t o retai n a p orti o n of s u b mitt e d bio ps y  tiss ue. Arc hi val bl o c ks will be 
ret ur ne d t o t he C R U . Sli des a n d tiss ue sa m ples c ollecte d o n st u d y  will not be ret ur ne d.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
5 4
1 0. 2.  
A p pe n di x 2: Cli nic al L a b or at or y Tests

T he tests detaile d b el o w will be p erf or m e d b y t he l ocal la b orat or y .

Pr ot oc ol -specific re q uire me nts f or i ncl usi o n or e xcl usi o n of partici pa nts are detaile d i n 
Secti o n 5 of  t his pr ot oc ol .

A d dit i onal tests ma y be perf or me d at a n y  time d uri n g t he st u d y  as deter mi ne d necessar y 
b y t he i n vesti gat or or re q uire d b y  lo c al  re g ulati ons.

Pre g na nc y testi n g 
I n vesti gat ors m ust d oc u me nt t heir re vie w of eac h la b orat or y  safet y re p ort.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
5 5
S af et y L a b or at or y T e st s
He m at ol o g y
Cli nic al C he mistr y
He mat ocrit
S o di u m
He m o gl o bi n
P otassi u m
Er y t hr oc yte c o u nt ( R B C)
Bicar b o nate
Mea n cell v ol u me 
C hl ori de 
Mea n cell he m o gl o bi n 
Calci u m 
Mea n cell he m o gl o bi n c o nce ntrati o n 
P h os p h at e
Le u k oc ytes ( W B C) 
Platelets
Gl uc ose (ra n d o m)
C o a g ul ati o n
Pr ot hr o m bi n ti me ( P T-I N R)a
Acti vate d partial t hr o m b o plasti n ti me (a P T T) a
Differe nti al W B C ( a bs ol ute c o u nts) of
Ur ea
Ne utr o p hils
L y m p h oc y t es
M o n oc ytes
T otal pr otei n
E osi n o p hils
Al b u mi n
Bas o p hils
T otal bilir u bi n
Al kali ne p h os p hatase ( A L P)
Uri n al ysis b
As partate a mi n otra nsferase ( A S T)
S pecific gra vit y
Ala ni ne a mi n otra nsferase ( A L T)
p H
Direct b ilir u bi n
Pr otei n
Creati ni ne
Gl uc ose
Ket o nes
Bilir u bi n
Ur o bili n o ge n
He patitis B s urface a nti ge n c, d
Bl o o d
He patitis C a nti b o d y c , d
Nitrite
HI V c, d
Le u k oc ytes
Pre g na nc y test (fe males o nl y)
Micr osc o p y
e
F S H (if a p plica ble)c
A b bre viati o ns: F S H = f ollicle -sti m ulati n g h or m o ne; 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 malizati o n rati o; R B C = re d bl o o d cell; W B C = w hite bl o o d cell.
a
Perf or me d at scree ni n g o n l y.
b
Perf or me d at scree ni n g, f oll o w- u p a n d earl y disc o nti n uati o n o nl y. 
c
Perf or me d at scree ni n g o nl y.
d
T est ma y be wai ve d if pre vi o usl y perf or me d wit hi n 6 m o nt hs bef ore scree ni n g , wit h re p orts a vaila ble f or re vie w .
O pti o nal he patitis C R N A testi n g ma y be perf or me d.
e
Micr osc o p y t o be perf or me d at t he l ocal safet y la b orat or y if cli nicall y i n dicate d, per i n ves ti gat or’s discreti o n.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
5 6
1 0. 2. 1.
Bl o o d S a m pli n g S u m m ar y
T his ta ble s u m marizes t he a p pr o xi mate n u m ber of ve ni p u nct ures a n d bl o o d v ol u mes f or all 
bl o o d sa m pli n g (scree ni n g, safet y lab orat ori es, a n d bi oa nal ytical assa ys) d uri n g t he st u d y.
Pr ot oc ol H 8 H -M C -L AI O S a m pli n g S u m m ar y
P ur p ose
Bl o o d V ol u me 
per S a m ple ( m L)
N u m ber of 
Bl o o d 
S a m ples
( P art 1)
P art 1
( D a bi g atr a n 
– ete xil ate)
T ot al 
V ol u me 
( m L)
N u m ber of 
Bl o o d 
S a m ples
( P art 2)
P art 2
( Ros u v ast ati n)
T ot al V ol u me 
( m L)
Scree ni n g tests a
2 3 . 4
1
2 3. 4
1
2 3. 4
Cli nical la b orat or y tests a
8
5
4 0
5
4 0
P har mac o ki netics –
Las mi dita n
2
1 5 b
3 0
1 5 b
3 0
P har mac o ki netics –
Da bi gatra n ( Part 1)
2
3 1 b
6 2
--
--
P har mac o ki netics –
R os u vastati n ( Part 2)
2
--
--
3 3 b
6 6
Bl o o d discar d f or 
ca n n ula pate nc y
0. 3
2 9
8. 7
2 9
8. 7
P har mac o ge netics
1 0
1
1 0
1
1 0
T ra ns p ort er ge n ot y pi n g c
1 0
1
1 0
1
1 0
T otal
1 8 4. 1
1 8 8. 1
T otal f or cli nical p ur p oses 
1 9 0
1 9 0
a
A d diti o nal sa m ples ma y be dra w n if nee de d f or safet y p ur p oses.
b
I ncl u des a d diti o nal 3 sa m ples, if re q uire d. N o m ore t ha n 3 a d diti o nal sa m ples ma y be ta ke n i n t he st u d y f or P K
(t otal i ncl u des c o m bi ne d las mi dita n, da bi gatra n, a n d r os u vastati n P K sa m ples).
c
Partici pa nts f or b ot h P art 1 a n d P art 2 will be c o nse nte d wit h a si n gle c o nse nt f or m, a n d ge n ot y pi n g will be 
perf or me d f or b ot h parts d uri n g scree ni n g. Part 2 will be pri oritize d t o c o m plete first. O nce P art 2 has ac hie ve d 
last patie nt d ose d, n o f urt her ge n ot y pi n g will be nee de d f or scree ni n g. 

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
5 7
1 0. 3.
A p pe n di x 3: A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or 
Rec or di n g, E v al u ati n g, F oll o w -u p, a n d Re p orti n g
1 0. 3. 1.
Defi niti o n of A E
A E Defi niti o n

A n A E i s a n y u nt o war d me dical occ urre nce i n a patie nt or cli nical st u d y p artici pa nt, 
t e mp orall y  ass o ciat e d wit h t he use of st u d y int er ve nt i on, w het her or n ot c o nsi dere d 
r elate d t o t he st u d y int er ve nt i on.

N O T E: A n A E ca n t heref ore 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 la b orat or y fi n di n g), s y m pt o m, or disease ( ne w or e xacer bate d) te m p orall y 
ass ociat e d wit h t he use of st u d y int er ve nt i on.
E ve nts Meeti n g
t he A E Defi niti o n

A n y a b n or mal la b orat or y  test res ults ( he mat olo g y , cli nical c he mistr y, or urinal ysis) or 
ot her safet y assess me nts (e . g., E C G, ra di ol ogical sca ns, vital si g n meas ure me nts), 
i ncl u di n g t h ose t hat w orse n fr om baseli ne, c o nsi dere d cli nicall y si g nifica nt i n t he 
me dical a n d scie nt ific j u d g me nt of t he i n vesti gat or (i.e. , n ot relate d t o pr o gressi o n of 
u n derl yi n g disease).

E xacer bat i on of a c hr o nic or i nter mitte nt pre -e xist i n g c o n diti on i ncl u di n g eit her a n 
i ncrease i n fre q ue nc y a n d/ or i nte nsity of  t he c o n ditio n .

Ne w c o n dit i ons detecte d or dia g n ose d after st u d y  i nter ve nti on a d mi nistrati o n e ve n 
t ho u g h it m a y ha ve bee n prese nt bef ore t he start of t he st u d y.

Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d dr u g -dr u g i nteracti o n.

Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d o ver d ose of eit her st u d y  
i nter ve nt i on or a c o nc o mita nt me dicat i on. O ver d ose per se will n ot be re p orte d as a n 
A E/ S A E u nless it is a n i nte nti o nal o ver d ose ta ke n wit h p ossi ble s uici dal/self -har mi n g 
i nte nt. S uc h o ver d o ses s h o ul d be re p orte d re gar dless of se q uelae.

T he si g ns, s y m pt o ms, a n d/ or cli nical se q uelae res ult i n g fr o m lac k of efficac y will be 
re p orte d as A E or S A E if t he y fulfil l t he defi nitio n of  a n A E or S A E. Al s o, “lac k of 
efficac y” or “fail ure of e x pecte d p harmac o l ogi cal actio n ” als o c o nstit utes a n A E or 
S A E.
E ve nts N O T Meeti n g t he A E D efi niti o n

A n y cli nicall y  sig nifica nt a b n or mal la b orat or y  fi n di n gs or ot her a b n or mal safety 
assess me nts t hat are ass ociate d wit h t he u n derl yi n g disease, u nless j u d ge d b y t he 
i n vesti gat or t o be m ore se vere t ha n e x pecte d f or t he partici pa nt’s c o n diti on.

T he disease/ dis or der bei n g st u die d or e x pecte d pr o gressi o n, si g ns, or s y m pt o m s of t he 
di sease/ dis or der bei n g st udie d, u nless m ore se vere t ha n e x pecte d f or t he partici pa nt’s 
c o n ditio n.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
5 8

Me dical or s ur gical pr oce d ure (e . g., e n d osc o p y, a p pe n dect o m y): t he c o n diti on t hat 
lea ds t o t he pr oce d ure is t he A E.

Si t u atio ns i n w hic h a n u nt o war d me dical occ urre nce di d n ot occ ur (s o cial a n d/ or 
c o n ve nie nce a d missi o n t o a h os pital).

A nt ici pate d da y-t o-da y fl uct uati o ns of pre-e xist i n g disease(s) or c o n diti on(s) prese nt or 
detecte d at t he start of t he st u d y  t hat d o n ot w orse n.
1 0. 3. 2.
Defi niti o n of S A E
If a n e ve nt is n ot a n A E per defi niti on a b o ve, t he n it ca n n ot be a n S A E e ve n if seri o us c o n dit i ons 
are met (e. g., h os pitalizati on f or sig ns/s y m pt o ms of t he disease u n der st u d y , deat h d ue t o 
pr o gressi o n of disease).
A n S A E is defi ne d as a n y u nt o w ar d me dic al occ urre nce t h at, at a n y d ose:
a.
Res ults i n de at h
b.
Is life-t hre ate ni n g
T he ter m  “life-t hreate ni n g” i n t he defi niti on of “s erio us ” refers t o a n e ve nt i n w hic h t he 
parti ci pa nt was at ris k of deat 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 heti call y mi g ht ha ve ca use d deat h, if it were m ore se vere.
c.
Re q uires i n p atie nt h os pit aliz ati o n or pr ol o n g ati o n of e xisti n g h os pit aliz ati o n

I n ge neral, h os pitalizati on si g nifies t hat t he partici pa nt has bee n a d mitte d t o h os pital 
f or o bser vati on a n d/ or treat me nt t hat w o ul d n ot ha ve bee n a p pr o priate i n t he 
p h ysicia n’s office or o ut patie nt setti n g. C o m plicat i o ns t hat occ ur d uri n g h os pi talizatio n 
are A Es. If a c o m plicat i on pr ol o n gs h os pi talizatio n or f ulfills a n y  ot her serio us cri t eria, 
t he e ve nt is seri o us. W he n i n d o u bt as t o w het her “ h os pitalizati o n” occ urre d or was 
necessar y , t he A E s h o uld be c o nsi dere d seri o us.

H os pitalizati o n f or elect i ve treat me nt of a pre-e xisti n g c o n dit i on t hat di d n ot w orse n 
fr om baseli ne is n ot c o nsi dere d a n A E.
d.
Res ults i n persiste nt dis a bilit y/i nc a p acit y

T he ter m disa bili t y mea ns a s u bsta nt ial disr u pt i on of a pers o n’s a bilit y t o c o n d uct 
n or m al lif e fu nc tio ns.

T his defi nit i on is n ot i nte n de d t o i ncl u de e x perie nces of relati vel y mi n or me dical 
sig nifica nce s uc h as u nc o m p licate d hea dac he, na usea, v o miti n g, diarr hea, i nfl ue nza, 
a n d acci de ntal tra u ma (e. g., s prai ne d a n kle) w hic h ma y i nterfere wit h or pre ve nt 
ever y da y life f u ncti o ns b ut d o n ot c o nstit ute a s u bsta ntial disr u pt i on.
e.
Is a c o n ge nit al a n o m al y/ birt h defect
f.
Ot her sit u ati o ns:

Me dical or scie nt ific j u d g me nt s h o ul d be e xercise d i n deci di n g w het her S A E 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 hreate 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 

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
5 9
parti ci pa nt or ma y re q uir e me dical or s ur gical i nter ve nt i on t o pre ve nt 1 of  t he ot her 
o utc o m es liste d i n t he a b o ve defi nit i on. T hese e ve nts s h o ul d us uall y be c o nsi dere d 
serio us.

E xa m ples of s uc h e ve nts i ncl u de i n vasi ve or mali g na nt ca ncers, i nte nsi ve treat me nt i n 
a n e mer ge nc y r o o m or at h o me f or aller gic br o nc h os pas m, bl o o d d yscrasias or 
c o n v ulsi o ns t hat d o n ot res ult i n h os pita lizati on, or de vel o p me nt of dr u g de pe n de nc y or 
dr u g a b use.
1 0. 3. 3.
Rec or di n g a n d F oll o w - Up of A E a n d/ or S A E
A E a n d S A E Rec or di n g

W he n a n A E/ S A E occ urs, it is t he res p o nsi bilit y of t he i n vesti gat or t o re vie w all 
d oc u m e nt atio n (e . g., h os pital pr o gress n otes, lab orat or y  re p orts, a n d dia g n ostics 
re p orts) relate d t o t he e ve nt.

T he i n vest i gat or will t he n rec or d all rele va nt A E/ S A E i nf or mati on i n t he C R F.

It is n ot acce pta ble f or t he i n vest i gat or t o se n d p h ot oc o pies of t he partici pa nt’s me dical 
rec or ds t o t he sp o ns or or desi g nee i n lie u of c o m pleti o n of t he A E/ S A E C R F pa ge.

T here m a y be i nsta nces w he n c o pies of me dical rec or ds f or certai n cases are re q ueste d 
b y t h e sp o ns or or desi g nee . I n t his case, all partici pa nt i de ntifiers, wit h t he e xce pti on of 
t he partici pa nt n u m ber, will be re dacte d o n t he c o pies of t he me dical rec or ds bef ore 
s u b missi on t o t he sp o ns or or desi g nee .

T he i n vest i gat or will atte m pt t o esta blis h a dia g n osis of t he e ve nt base d o n si g ns, 
s y m pt o ms, a n d/ or ot her cli nical i nf or mati on. W he ne ver p ossi ble, t he dia g n osis ( n ot t he 
i n di vi d ual si g ns/s y m pt o ms) will be d oc u me nte d as t he A E/ S A E.
Assess me nt of I nte nsit y
T he i n vest i gat or will ma ke a n assess me nt of i nte nsity f or eac h A E a n d S A E re p orte d d uri n g 
t he st u d y a n d assi g n it t o 1 of t he f oll owi n g cate g ories:

Mil d: A n e ve nt t hat is easil y t olerate d b y t he partici pa nt, ca usi n g mi ni mal disc o mf o rt 
a n d n ot i nterferi n g wit h e ver y da y act i vities.

M o derate: A n e ve nt t hat ca uses s ufficie nt disc o mf ort a n d i nterferes wit h n or m al 
e ver y da y act i vities.

Se vere: A n e ve nt t hat pre ve nts n or mal e ver y da y acti vi ties. A n A E t hat is assesse d as 
se vere s h o ul d n ot be c o nf use d wit h an S A E. Se vere is a cate g or y  utilize d f or rati n g t he 
i nte nsit y of a n e ve nt; a n d b ot h A Es a n d S A Es ca n be assesse d as se vere.
A n e ve nt is defi ne d as ‘serio us’ w he n i t meets at least 1 of t he pre defi ne d o utc o mes as 
descri be d i n t he defi nit i on o f a n S A E, N O T w he n it is rate d as se vere.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
6 0
Assess me nt of C a us alit y

T he i n vest i gat or is o bli gate d t o assess t he relati o ns hi p bet wee n st u d y i nter ve nti on a n d 
eac h occ urre nce of eac h A E/ S A E.

T he i n vest i gat or will c o nsi der a n y A Es, S A Es, a n d cli nicall y i m p orta nt la b orat or y 
a b n or malities as relate d t o t he st u d y int er ve nt i on u nless t here is clear e vi de nce t hat t he 
e ve nt is n ot relate d. 

T he i n vest i gat or will use cli nical j u d g me nt t o deter mi ne t he relati ons hi p.

Alt er nat i ve ca uses, s uc h as u n derl yi n g disease(s), c o nc o mita nt t hera p y, a n d ot her ris k 
fact ors, as well as t he te m p oral relati o ns hi p of t he e ve nt t o st u d y int er ve nt i on 
a d mi nistrati o n will be c o nsi dere d a n d i n vest i gate d.

T he i n vest i gat or will als o c o ns ult t he I B a n d/ or Pr o d uct I nf or mati o n, f or mar kete d 
pr o d ucts, i n his/ her assess me nt.

F or eac h A E/ S A E, t he i n vest i gat or m ust
d oc u me nt i n t he me dical n otes t hat he/s he has 
re vie we d t he A E/ S A E a n d has pr o vi de d a n assess me nt of ca usality.

T here m a y be sit u atio ns i n w hic h a n S A E has occ urre d a n d t he i n vest i gat or has 
mi ni mal i nf or mat i on t o i ncl u de i n t he i nit ial re p ort t o t he sp o ns or or desi g nee . 
H o we ver, it is ver y  im p orta nt t hat t he i n vest i gat or al wa ys ma ke a n assess me nt of 
ca usalit y f or e ver y e ve nt bef ore t he i nit ial tra ns missi o n of t he S A E data t o t he sp o ns or 
or desi g nee .

T he i n vest i gat or ma y c ha n ge his/ her o pi ni on of ca usalit y i n li g ht of f oll ow- u p 
i nf or mat i on a n d se n d a n S A E f oll o w -u p re p ort wi t h t he u p date d ca usality assess me nt.

T he ca usalit y assess me nt is 1 of  t he criteria use d w hile deter mi ni n g re g ulat or y 
re p orti n g re q uire me nts.
F oll o w -u p of A Es a n d S A Es

T he i n vest i gat or is o bli gate d t o perf or m or arra n ge f or t he c o n d uct of s u p ple me ntal 
meas ure me nts a n d/ or e val uat i ons as me dicall y i n dicate d or as re q ueste d b y t he sp o ns or 
or desi g nee t o eluci date t he nat ure a n d/ or ca usalit y of t he A E or S A E as f ull y as 
p ossi ble. T his ma y i ncl u de a d dit i onal la b orat or y  tests or i n vesti gati ons, 
hist o pat h ol o gical e xa mi nat i ons, or c o ns ultati o n wit h ot her healt h care pr ofessi o nals.

If a partici pa nt dies d uri n g partici pati o n i n t he st u d y or d uri n g a rec o g nize d f oll ow- u p 
p eri o d, t he i n vest i gat or will pr o vi de t he sp o ns or or desi g nee wi t h a c o p y of a n y 
p ost m ort e m  fi n din gs i ncl u di n g hist o pat h ol o g y .

Ne w or u p date d i nf or mat i on will be rec or de d i n t he ori gi nall y c o m p lete d C R F.

T he i n vest i gat or will s u b mit a n y u p date d S A E data t o t he sp o ns or or desi g nee wi t hi n 
2 4 h o urs of recei pt of t he i nf or mati o n.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
6 1
1 0. 3. 4.
Re p orti n g of S A Es
S A E Re p orti n g 

Facsi mile tra ns missi o n of t he S A E pa per C R F is t he preferre d met h o d t o tra ns mit t his 
i nf or mat i on t o t he sp o ns or .

I nitial notificati o n via tele p h o ne d oes n ot re place t he nee d f or t he i n vest i gat or t o 
c o mplete a n d si g n t he S A E C R F pa ges wit hi n t he desi g nate d re p orti n g ti me fra mes.

T he i n vest i gat or or site m ust alert t he Lill y C R P/ C P, or its desi g nee, of a n y S A E as 
s o o n as practicall y p ossi ble.

A d dit i onall y , t he i n vesti gat or or site m ust alert Lill y Gl o bal Patient  Safety,  or its 
desi g nee, of a n y S A E wit hi n 2 4 h o urs of i n vesti gat or a ware ness of t he e ve nt via a 
s p o ns or-a p pr o ve d met h o d. If alerts are iss ue d via tele p h o ne, t he y are t o be i m me diatel y 
f oll owe d u p wi t h official n otificati o n o n st u d y-s pecific S A E f or ms. T his 2 4 -h o ur 
n otificati o n re q uire me nt refers t o t he i nit ial S A E i nf or mati on a n d all f o ll ow- u p S A E 
i nf or mat i on.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
6 2
1 0. 4.
A p pe n di x 4: C o ntr ace pti ve G ui d a nce a n d C ollecti o n of Pre g n a nc y 
I nfor m ati o n
Defi niti o ns:
W o m a n of C hil d be ari n g P ote nti al ( W O C B P)
A w o ma n is c o nsi dere d fertile f oll owi n g me narc he a n d u nt il be c o mi n g p ost me n o pa usal u nless 
p er m a ne nt l y sterile (see bel o w).
If fertility is u nclear (e. g., a me n orr hea i n a d olesce nts or at hletes) a n d a me nstr ual c ycle ca n n ot be 
c o nfir me d bef ore t he first d ose of st u d y int er ve ntio n, a d ditio nal  e val uat i on s h o ul d be c o nsi dere d.
W o me n i n t he f oll owi n g cate g ori es are n ot c o nsi dere d W O C B P
1.
Pr e m e narc hal
2.
Pr e m e n o pa usal fe male wit h 1 of t h e fol l owi n g:

D oc u m e nte d h ysterect o m y

D oc u m e nte d bilateral sal pi n gect o m y

D oc u m e nte d bilateral o o p h orect o m y
F or i n di vi d uals wit h per m a ne nt i nfertility d ue t o a n alter nate me dical ca use ot her t ha n t he 
a b o ve (e. g., mulleria n a ge nesis, a n dr o ge n i nse nsit i vity) , i n vesti gat or discreti on s h o ul d be 
a p plie d t o deter mi ni n g st u d y e ntr y.
N ote: D oc u me ntati o n ca n c o me fr o m t he site pers o n nel: re vie w of t he partici pa nt’s me dical 
rec or ds, me dical e xa mi nati on, or m e dical hist or y int er vie w.
3.
P os t me n o pa usal fe male is defi ne d as, w o me n wit h:

A w o ma n at a n y  a ge at least 6 wee ks p osts ur gical bilateral o o p h orect o m y wit h or 
wi t ho ut h ysterect o m y , c o nfir me d t hr o u g h o perati ve n ote; or

A w o ma n a ge d at least 4 0 years a n d u p t o 5 5 years wit h a n i ntact uter us, n ot o n 
h or m o ne t hera p y *, w h o has ha d cessat i on of me nses f or at least 1 2 c o nsec ut i ve 
m o nt hs wit h o ut a n alter nati ve me dical ca use, A N D wit h a f o llicle-sti m ulati n g 
h or m o ne > 4 0 m I U/ m L; or

A w o ma n a ge d 5 5 years or ol der n ot o n h or m o ne t hera p y, w h o has ha d at least 1 2 
m o nt hs of s p o nta ne o us a me n orr hea; or

A w o ma n a ge d at least 5 5 years wit h a dia g n osis of me n o pa use pri or t o starti n g 
h or m o ne re pl ace me nt t hera p y
* W o m e n s ho ul d n ot be ta ki n g me dicat i ons d uri n g t he a me n orr hea s uc h as oral c o ntrace pti ves, 
h or m o nes, g o na d otr o pi n -r eleasi n g h or mo ne, a nt i-estr o ge ns, selecti ve estr o ge n rece pt or 
m o d ulat ors, or c he m ot hera p y  t hat c o uld i n d uce tra nsie nt a me n orr hea.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
6 3
C o ntr ace pti o n G ui d a nce:
C ollecti o n of Pre g n a nc y I nf or m ati o n
M ale p artici p a nts wit h p art ners w h o bec o me pre g n a nt
●
T he i n vest i gat or will atte m pt t o c ollect pre g na nc y i nf or mati on o n a n y male 
parti ci pa nt’s fe male part ner w h o bec o mes pre g na nt w hile t he male partici pa nt is 
i n t his st u d y. T his a p plies o nl y t o male partici pa nts w h o recei ve st u d y 
i nter ve nt i on.
●
After o btai ni n g t he necessar y  si g ne d i nf or me d c o nse nt fr o m t he pre g na nt fe male 
part ner direct l y, t he i n vesti gat or will rec or d pre g na nc y i nf or mati on o n t he 
a p pr o priate f or m a n d s u b mit it t o t he s p o ns or wit hi n 2 4 h o urs of  lear ni n g of t he 
part ner’s pre g na nc y. T he fe male part ner will als o be f o ll owe d u p t o deter mi ne t he 
o utc o m e of t he pre g na nc y. I nf or matio n o n t he stat us of t he m ot her a n d c hil d will 
be f or war de d t o t he s p o ns or. Ge nerall y, t he f oll ow- u p will be n o l o n ger t ha n 6 t o 
8 wee ks f oll o wi n g t he est i mate d deli ver y  date. A n y ter mi nati on of t he pre g na nc y 
will be re p orte d i ncl u di n g fetal stat us ( prese nce or a bse nce of a n oma lies) a n d
i n dicati on f or t he pr oce d ure. 
Fe m ale P a r tici p a nts w h o bec o me pre g n a nt
●
T he i n vest i gat or will c ollect pre g na nc y i nf or mati o n o n a n y fe male partici pa nt 
w h o bec o mes pre g na nt w hile part ici pati n g i n t his st u d y. T he i nit ial inf or m at i on 
will be rec or de d o n t he a p pr o priate f or m a n d s u b mitte d t o t he s p o ns or wit hi n 
2 4 h o urs of  lear ni n g of a partici pa nt ’s pre g na nc y. 
●
T he parti ci pa nt will be fol l owe d u p t o deter mi ne t he o utc o me of t he pre g na nc y. 
T he i n vest i gat or will c ollect f oll ow- u p i nf or mati o n o n t he parti ci pa nt a n d t he 
ne o nate a n d t he i nf or mat i on will be f or war de d t o t he s p o ns or. Ge nerall y, f o ll ow-
u p will n ot be re q uire d f or l o n ger t ha n 6 t o 8 wee ks be y o n d t he est i mate d deli ver y 
date. A n y ter mi nat i on of pre g na nc y will be re p orte d, i ncl u di n g fetal stat us 
( prese nce or a bse nce of a n oma lies) or i n dicati on f or t he pr oce d ure.
●
W hile pre g na nc y  itself is n ot c o nsi dere d t o be a n A E or S A E, a n y pre g na nc y 
c o mplicat i on or el ect i ve ter mi nati on of a pre g na nc y  f or me dical reas o ns will be 
re p orte d as a n A E or S A E. 
●
A s p o nta ne o us a b orti o n ( occ urri n g at < 2 0 wee ks gestati o nal a ge) or still birt h 
( occ urri n g at ≥2 0 wee ks gestati o nal a ge) is al wa ys c o nsi dere d t o be a n S A E a n d 
will be re p orte d as s uc h. 
●
A n y p ostst u d y  pre g na nc y-relate d S A E c o nsi dere d reas o na bl y relate d t o t he st u d y 
i nter ve nt i on b y t he i n vesti gat or will be re p orte d t o t he s p o ns or as descri be d i n 
Secti o n 8. 3. 4 . W hile t he i n vesti gat or is n ot o bli gate d t o acti vel y see k t his 
i nf or mat i on i n f or mer st u d y p artici pa nts, he or s he ma y lear n o f a n S A E t hr o u g h 
s p o nta ne o us re p orti n g.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
6 4
●
A n y fe male part ici pa nt w h o bec o mes pre g na nt w hile partici pat i n g i n t he st u d y 
will disc o nt i n ue st u d y int er ve nt i on. If t he partici pa nt is disc o nti n ue d fr o m
recei vi n g t he st u d y int er ve ntio n, f ol l ow t he sta n dar d disc o nt i n uati on pr ocess a n d 
c o nti n ue directl y t o t he f o ll ow- u p p hase.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
6 5
1 0. 5.
A p pe n di x 5 : Ge netics
Use/ A n al ysis of D N A

Ge net ic variat i on ma y i m pact a partici pa nt’s res p o nse t o st u d y int er ve nt i on, 
s usce pti bility t o, a n d se verity a n d pr o gressi o n o f disease. Varia ble res p o nse t o st u d y  
i nter ve nt i on ma y be d ue t o ge net ic deter mi na nts t hat i mpact dr u g a bs or pti o n, 
di stri b uti on, meta b o lis m, a n d e xcreti o n; mec ha nis m of act i on of t he dr u g; disease 
etiol o g y; a n d/ or m ol ec ular s u bt y p e of t he disease bei n g treate d. T heref ore, w here l ocal 
re g ulat i ons a n d I R B/I E C all o w, a bl o o d sa m p le will be c ollecte d f or D N A a nal ysis fr om 
c o nse nt i n g partici pa nts.

D N A sa m ples will be use d f or researc h relate d t o las mi dita n or mi grai ne a n d relate d 
di seases. T he y ma y als o be use d t o de vel o p tests/assa ys i ncl u di n g dia g n ost ic tests 
r elate d t o las mi dita n a n d/ or i nter ve ntio ns of  t his dr u g class a n d mi grai ne . Ge netic 
researc h ma y c o nsist of t he a nal ysis of 1 or m ore ca n di date ge nes or t he a nal ysis o f 
ge net ic mar kers t hr o u g h o ut t he ge n o me or a nal ysis of t he e nt ire ge n o me (as 
a p pr o priate).

A d dit i onal a nal yses ma y be c o n d ucte d if it is h y p ot hesize d t hat t his ma y hel p furt her 
u n dersta n d t he cli nical data.

T he sa m ples ma y be a nal yze d as part of a m ulti-st u d y assess me nt of ge netic fact ors 
i n v ol ve d i n t he res p o nse t o las mi dit a n or s t u d y int er ve nt i ons of t his class t o u n dersta n d 
st u d y disease or relate d c o n ditio ns.

T he res ults of ge net ic a nal yses ma y be re p orte d i n t he cli nical st u d y re p ort or i n a 
se parate st u d y s u m mar y.

T he s p o ns or will st ore t he D N A sa m ples i n a sec ure st ora ge s pace wit h a de q uate 
meas ures t o pr otect c o nfi de nt iality.

T he sa m ples will be retai ne d w hile researc h o n las mi dit a n or st u d y  int er ve nt i ons of t his 
class or i n dicat i on c o nti n ues b ut n o l o n ger t ha n 1 5 years or ot her peri o d as per l ocal 
re q uire me nts.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
6 6
1 0. 6.
A p pe n di x 6: Li ver S afet y: S u g geste d Acti o ns a n d F oll o w -u p 
Assess me nts
He p atic E v al u ati o n Testi n g – Refer t o pr ot oc ol He p atic S afet y M o nit ori n g Secti o n  8. 2. 5. 1 f or 
g ui d a nce o n a p pr o pri ate test selecti o n.

F or testi n g selecte d, a n al ysis is re q uire d t o be c o m plete d b y t he -Lill y desi g n ate d 
ce ntr al l a b or at or y e xce pt f or Micr o bi ol o g y.

L oc al testi n g m a y be perf or me d i n a d diti o n t o ce ntr al testi n g w he n re q uire d f or 
i m me di ate p atie nt m a n a ge me nt.

Res ults will be re p orte d if a v ali d ate d test or c alc ul ati o n is a v ail a ble.
He m at ol o g y
Cli nic al C he mistr y
He m o gl o bi n
T otal bilir u bi n
He mat ocrit
Direct bilir u bi n
Er yt hr oc ytes ( R B Cs - r ed bl o o d cells )
Al kali ne p h os p hatase ( A L P)
Le u k oc ytes ( W B Cs - w hite bl o o d c ells) 
Ala ni ne a mi n otra nsferase ( A L T)
Differ e ntial:
As partate a mi n otra nsferase ( A S T)
Ne utr o p hils, se g me nte d
Ga m ma -gl uta m yl tra nsferase ( G G T)
L y m p h oc ytes
Creati ne ki nase ( C K)
M o n oc ytes
Ot her C he mistr y
Bas o p hils
Aceta mi n o p he n
E osi n o p hils
Aceta mi n o p he n pr otei n a d d ucts
Platelets
Al kali ne p h os p hatase is o e nz y mes
Cell m or p h ol o g y ( R B C a n d W B C)
Cer ul o plas mi n
C o a g ul ati o n
C o p per
Et h yl a lc o h ol ( Et O H)
Pr ot hr o m bi n ti me, I N R (P T -I N R)
Ha pt o gl o bi n
Ser ol o g y
I m m u n o gl o b uli n A (q ua ntitati v e)
He patitis A Vir us ( H A V) T e sti n g:
I m m u n o gl o b uli n G (q ua ntitati v e)
H A V t otal a nti b o d y
I m m u n o gl o b uli n M (q ua ntitati ve)
H A V I g M a nti b o d y
P h os p hati d ylet ha n ol ( P Et h)
He patis B Vir us ( H B V) Testi n g:
Uri ne C he mistr y
He patitis B s urface a nti ge n ( H Bs A g)
Dr u g scree n
He patitis B s urface a nti b o d y ( a nt i-H Bs) 
Et h y l gl uc ur o ni de ( Et G)
He patitis B c ore t otal a nti b o d y ( a nti -H Bc)
Ot her Ser ol o g y

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
6 7
He patitis B c ore I g M a nti b o d y 
A nti -n uclear a nti b o d y ( A N A)
He patitis B c ore I g G a nti b o d y 
A nti -s m o ot h m uscle a nti b o d y ( A S M A) a
H B V D N A b
A nti -acti n a nti b o d y c
He patis C Vir us ( H C V) Testi n g:
E pstei n -Barr Vir us ( E B V) Testi n g:
H C V a nti b o d y
E B V a nti b o d y
H C V R N A b
E B V D N A b
He patitis D Vir us ( H D V) Testi n g:
C yt o me gal o vir us ( C M V) Testi n g:
H D V a nti b o d y
C M V a nti b o d y
He patitis E Vir us ( H E V) Testi n g:
C M V D N A b
H E V I g G a nti b o d y
Her pes Si m ple x Vir us ( H S V) Testi n g:
H E V I g M a nti b o d y
H S V ( T y pe 1 a n d 2) a nti b o d y
H E V R N A b
H S V ( T y pe 1 a n d 2) D N A b
Micr o bi ol o g y
d
Li ver Ki d ne y Micr os o mal T y pe 1 ( L K M -1) 
A nti b o d y
C ult ure:
Bl o o d
Uri ne
a T his is n ot re q uire d if a nti-acti n a nti b o d y is teste d.
b R e fle x/c o nfir mati o n de pe n de nt o n re g ulat or y re q uire me nts a n d/ or testi n g a vaila bilit y.
c T his is n ot re q uire d if a nti -s m o ot h m uscle a nti b o d y ( A S M A) is teste d.
d Assa ye d b y in vesti gat or -desi g nate d l ocal la b orat or y O N L Y; n o ce ntral testi n g is a vaila ble.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
6 8
E v al u ati o n of p atie nts wit h tre at me nt-e mer ge nt a b n or m al he p atic bi oc he mic al tests d uri n g 
a cli nic al tri al *
Test/ Pr oce d ure:
R ati o n ale 
Acti o n
Cl ose He p atic M o nit ori n g
Cli nic al C he mistr y:
T otal bilir u bi n
Direct bilir u bi n
Al kali ne p h os p hatase ( A L P)
Ala ni ne a mi n otra nsferase ( A L T)
As partate a mi n otra nsferase ( A S T) a
Ga m ma -gl uta m yl tra nsferase ( G G T)
Cr eati ne ki nase ( C K)
All: R o uti ne f oll o w - u p
C K: M uscle i nj ur y/r ha b d o m y ol ysis
Utilize a He patic 
M o nit ori n g ce ntral 
l a bor at or y c ollecti o n kit 
a n d select Cli nical 
C he mistr y 
He m at ol o g y
He m o gl o bi n
He mat ocrit
Er y t hr oc ytes ( R B Cs – re d bl o o d cells)
Le u k oc ytes ( W B Cs – w h ite bl o o d 
cells)
Differe ntial:
Ne utr o p hils, se g me nte d
L y m p h oc ytes
M o n oc ytes
Bas o p hils
E osi n o p hils
Platelets
Cell m or p h ol o g y ( R B Cs a n d W B Cs)
I nfecti o n
Utilize a He patic 
M o nit ori n g ce ntral 
l a bor at or y c ollecti o n kit 
a n d select He mat ol o g y
Me dic al H ist or y:b ,c
S y m pt o ms
C o -e xisti n g me dical c o n diti o ns
C o nc o mita nt me dicati o ns
Dietar y  a n d n utriti o nal s u p ple me nts
E xercise (e xcessi ve)
M uscle inj ur y
Alc o h ol c o ns u m pti o n
Illicit s u bsta nces
Use d t o e val uate/r ule o ut:
S yste mic i nfecti o n or se psis
Isc he mic or c o n gesti ve he patic i nj ur y
Gallst o ne disease
Alc o h olic li ver disease
M uscle i nj ur y/r ha b d o m y ol ysis
Aceta mi n o p he n t o xicit y
Dr u g- i n d uce d li ver i nj ur y (DI LI ) d ue t o 
a n ot her dr u g, her bal or dietar y 
s u bsta nces
If fi n di n gs are cli nicall y 
si g nifica nt, re p ort as a n 
a d verse e ve nt.
He p atitis A Vir us ( H A V) Testi n g:
H A V t otal a nti b o d y
H A V I g M anti b o d y
Use d t o e val uate/r ule o ut: Ac ute 
He patitis A v ir us ( H A V) i nfecti o n
Utilize a He patic 
M o nit ori n g ce ntral 
l a bor at or y c ollecti o n kit 
a n d select He patitis A 
( H A V)
He p atis B Vir us ( H B V) Testi n g:
He patitis B s urface a nti ge n ( H Bs A g)
He patitis B s urface a nti b o d y ( a nti -
H Bs) 
He patitis B c ore t otal a nti b o d y ( a nti -
H Bc)
He patitis B c ore I g M a nti b o d y
He patitis B c ore I g G a nti b o d y 
H B V D N A
Use d t o e val uate/r ule o ut: Ac ute or 
e xacer bati o n of c hr o nic He patitis B 
v ir us ( H B V) i nfecti o n. 
Utilize a He patic 
M o nit ori n g ce ntral 
l a bor at or y c ollecti on kit 
a n d select He patitis B

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
6 9
He p atis C Vir us ( H C V) Testi n g: d ,e
H C V a nti b o d y
H C V R N A
Use d t o e val uate/r ule o ut: Ac ute or 
e xacer bati o n of c hr o nic h e patitis C vir us 
( H C V) i nfecti o n. 
Utilize a He patic 
M o nit ori n g ce ntral 
l a bor at or y c ollecti o n kit 
a n d select He patitis C
He p atitis E Vir us ( H E V) Testi n g: f
H E V I g G a nti b o d y
H E V I g M a nti b o d y
H E V R N A
Use d t o e val uate/r ule o ut: Ac ute 
h e patitis E v ir us ( H E V) i nfecti o n.
Utilize a He patic 
M o nit ori n g ce ntral 
l a bor at or y c ollecti o n kit 
a n d select He patitis E
A nti- n uclear a nti b o d y ( A N A)
A nti- s m o ot h m uscle a nti b o d y ( A S M A)
A nti- acti n a nti b o d y
I m m u n o gl o b uli n A
I m m u n o gl o b uli n G
I m m u n o gl o b uli n M
Use d t o e val uate/r ule o ut: A ut oi m m u ne 
he patitis
Utilize a He patic 
M o nit ori n g ce ntral 
l a bor at or y c ollecti o n kit 
a n d select o n l y t he s pecific 
test/s re q uire d.
He p at o bili ar y Im a gi n g:
b ,c
Ultras o n o gra p h y
C T sca n
M RI
M R C P
g
E R C P g
Use d t o e val uate/r ule o ut:
Biliar y o bstr ucti o n
Pa ncreatitis
Gallst o nes
P ortal -vei n/ he patic vei n t hr o m b osis 
He patic metastasis
Perf or me d l ocall y.
If fi n di n gs are cli nicall y 
si g nifica nt, re p ort as a n 
a d verse e ve nt.
C o m pre he nsi ve He p atic M o nit ori n g
C o a g ul ati o n:
Pr ot hr o m bi n ti me, I N R ( P T-I N R)
Use d t o e val uate/r ule o ut:
S us pecte d li ver fail ure, f or patie nts wit h 
ele vate d t otal bilir u bi n le vel
Utilize a He patic 
M o nit ori n g ce ntral 
l a bor at or y c ollecti o n kit
E pstei n- B arr Vir us ( E B V) Testi n g:
E B V a nti b o d y
E B V D N A
C yt o me g al o vir us ( C M V) Testi n g:
C M V a nti b o d y
C M V D N A
Her pes Si m ple x Vir us ( H S V) 
Testi n g:
H S V ( T y pe s 1 a n d 2) a nti b o d y
H S V ( T y pe s 1 a n d 2) D N A
Use d t o e val uate/r ule o ut:
E pstei n -Barr v ir us ( E B V) or 
He patic i nj ur y d ue t o c yt o me gal o vir us 
( C M V), or
Her pes si m ple x vir us ( H S V) i nfecti o n.
Utilize a He patic 
M o nit ori n g
ce ntral 
l a bor at or y c ollecti o n kit
a n d select o nl y t he s pecific 
test/s nee de d.
Li ver bi o ps y h
Use d t o e val uate/r ule o ut:
A ut oi m m u ne he patitis ( AI H)
If fi n di n gs are cli nicall y 
si g nifica nt, re p ort as a n 
a d verse e ve nt.
A d diti o n al He p atic M o nit ori n g Tests
Al kali ne p h os p hatase is oe nz y mes
Use d t o e val uate/ differe ntiate: Ele vate d 
al kali ne p h os p ha tase ori gi nati o n fr o m
b o ne or li ver
Utilize a He patic 
M o nit ori n g ce ntral 
l a bor at or y c ollecti o n kit
Li ver ki d ne y micr os o mal t y pe 1 ( L M K -
1) anti b o d y
Use d t o e val uate: A ut oi m m u ne he patitis 
Utilize a He patic 
M o nit ori n g ce ntral 
l a bor at or y c ollecti o n kit
Uri ne C he mistr y:
Et h y l gl uc ur o ni d e ( Et G)i
Ot her C he mistr y:
P h os p hati d ylet ha n ol ( P Et h)j
Use d t o e val uate: Alc o h olic li ver 
disease
Utilize a He patic 
M o nit ori n g ce ntral 
l a bor at or y c ollecti o n kit
Ot her C he mistr y:
Aceta mi n o p he n
Aceta mi n o p he n pr otei n a d d ucts
Use d t o e val uate: Aceta mi n o p he n 
t o xicit y 
Utilize a He patic 
M o nit ori n g ce ntral 
l a bor at or y c ollecti o n kit
Et h y l Alc o h ol ( Et O H)
Use d t o e val uate rece nt alc o h ol 
c o ns u m pti o n
Utilize a He patic 
M o nit ori n g ce ntral 
l a bor at or y c ollecti o n kit

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
7 0
Ha pt o gl o bi n
Use d t o e val uate a dia g n osis of 
he m ol y sis
Utilize a He patic 
M o nit ori n g ce ntral la b 
c ollecti o n kit
Car di ol o g y c o ns ult b
Electr ocar di o gra m
Ec h ocar di o gra m
Vital Si g ns:
Bl o o d press ure
P ulse
Use d t o e val uate: Isc he mic or 
c o n gesti ve he patic i nj ur y
Perf or me d l ocall y.
If fi n di n gs are cli nicall y 
si g nifica nt, re p ort as a n 
a d verse e ve nt.
Uri ne C he mistr y:
Dr u g scree n
Use d t o e val uate: He pat ot o xicit y d ue t o 
c ocai ne, o piates, a n d ot her illicit 
s u bsta nces 
Utilize a He patic 
M o nit ori n g ce ntral 
l a bor at or y c ollecti o n kit
He p atitis D Vir us ( H D V) Testi n g:
H D V a nti b o d y
Use d t o e val uate/r ule o ut: Ac ute 
h e patitis D v ir us ( H D V) i nfecti o n.
Utilize a He patic 
M o nit ori n g ce ntral 
l a bor at or y c ollecti o n kit
a n d onl y  select re q uire d test 
nee de d.
Micr o bi ol o g y:
C ult ures:
Bl o o d
Ur i ne
Use d t o e val uate/r ule o ut:
Se psis or s yste mic i nfecti o n
Perf or m l ocall y.
If fi n di n gs are cli nicall y 
si g nifica nt, re p ort as a n 
a d verse e ve nt.
Slit la m p e ye e xa mi nati o n ( Ka y ser-
Fleis her ri n gs)
Ge netic e val uati o n
Use d t o e val uate/r ule o ut:
Wils o n’s disease 
Perf or m l ocall y. 
If fi n di n gs are cli nicall y 
si g nifica nt, re p ort as a n 
a d verse e ve nt.
Ot her C he mistr y:
Cer ul o plas mi n
C o p per
Use d t o e val uate/r ule o ut:
Wils o n’s disease 
Utilize a He patic 
M o nit ori n g ce ntral 
l a bor at or y c ollecti o n kit
A b bre viati o ns: C T = c o m p ute d t o m o gra p h y; E R C P = e n d osc o pic retr o gra de c h ola n gi o -pa ncreat o gra p h y ; I N R = 
i nter nati onal n o r malize d rati o; M R C P
= m a g netic res o na nce c h ola n gi o pa ncreat o gra p h y; M RI = ma g netic 
res o na nce i ma gi n g; P T = pr ot hr o m bi n ti me .
a
Ser u m A S T t y picall y (alt h o u g h n ot al wa ys) is hi g her t ha n A L T .
b
E xte nt a n d t y pe of w or k -u p ma y var y wit h patie nt’s hist or y, se verit y of li ver i nj ur y, u n derl yi n g disease, a n d 
ge o gra p h y.
c
Base d o n me dical hist or y a n d cli nical j u d g me nt .
d
If a nti-H C V p ositi ve, H C V R N A is re q uire d t o c o nfir m H C V i nfecti o n .
e
Ac ute he patitis C ma y be a nti -H C V ne gati ve b ut H C V R N A p ositi ve .
f
If a nti-H E V I g M p ositi ve, c o nsi der c o nfir mati o n wit h H E V R N A b y neste d p ol y merase c hai n reacti o n .
g
If c h olestatic i nj ur y, M R C P or  E R C P m a y  be rec o m me n de d.
h
A li ver bi o ps y is nee de d t o c o nfir m a dia g n osis of AI H .
i
Alc o h ol c o ns u m pti o n i n t he past 3 t o 5 da ys .
j
Alc o h ol c o ns u m pti o n i n t he past 3 wee ks .
*
T his t o ol is t o be use d b y t he cli nical researc h u nit f or refere nce d uri n g t he e val uati o n of a patie nt w h o met 
he patic m o nit ori n g criteria base d o n la b or at or y res ults a n d cli nical j u d g me nt f or a s us pecte d li ver i nj ur y d uri n g 
pr ot oc ol partici pati o n. 

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
7 1
1 0. 7.
A p pe n di x 7 : A b bre vi ati o ns
T er m
D efi niti o n
5- H T 1 F
5- h ydr o x y tra pta mi ne 1 F
A E
a d verse e ve nt
A L P
al kali ne p h os p hatase
A L T
ala ni ne a mi n otra nsferase
A S T
as partate a mi n otra nsferase
A U C
area u n der t he c o nce ntrati o n vers us ti me c ur ve
A U C ( 0- ∞)
area u n der t he c o nce ntrati o n vers us ti me c ur ve fr o m ti me zer o t o i nfi nit y
B C R P
br east ca ncer resista nce pr otei n
C m a x
ma xi m u m o bser ve d dr u g c o nce ntrati o n
c o m pl ai nt
A c o m plai nt is a n y writte n, electr o nic, or oral c o m m u nicati o n t hat alle ges deficie ncies 
relate d t o t he i de ntit y, q ualit y, p urit y, d ura bilit y, relia bilit y, safet y or effecti ve ness, or 
perf or ma nce of a dr u g or dr u g deli ver y s yste m.
c o m pli a n c e
A d here nce t o all st u d y -relate d, g o o d cli nical practice ( G C P), a n d a p plica ble re g ulat or y 
re q uire me nts.
C P
cli nical p har mac ol o gist
C R F
case re p ort f or m
C R P
cli nical researc h p h ysicia n: I n di vi d ual res p o nsi ble f or t he me dical c o n d uct of t he st u d y.
Res p o nsi bilities of t he C R P ma y be perf or me d b y a p h ysicia n, cli nical researc h 
scie ntist, gl o bal safet y p h ysicia n, or ot her me dical officer.
C R U
cli nical researc h u nit
C- S S R S
C ol u m bia -S uici de Se verit y Rati n g Scale
C V
c oefficie nt of variati o n
C Y P
c yt oc hr o me P 4 5 0
D DI
dr u g- dr u g i nteracti o n
E C G
electr ocar di o gra m
e nr oll
T he act of assi g ni n g a partici pa nt t o a treat me nt. Partici pa nts w h o are e nr olle d i n t he 
st u d y are t h ose w h o ha ve bee n assi g ne d t o a treat me nt.
e nt er
Partici pa nts e n tere d i nt o a st u d y are t h ose w h o si g n t he i nf or me d c o nse nt f or m directl y 
or  t hr o u g h t heir le gall y acce pta ble re prese ntati ves.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
7 2
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
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 nisati o n
I E C
I n de pe n de nt Et hics C o m mittee
inf or m e d c o n s e nt
A pr ocess b y w hic h a partici pa nt v ol u ntaril y c o nfir ms his or her willi n g ness t o 
partici pate i n a partic ular st u d y, after ha vi n g bee n i nf or me d of all as pects of t he st u d y 
t hat are rele va nt t o t he partici pa nt’s decisi o n t o partici pate. I nf or me d c o nse nt is 
d oc u me nte d b y mea ns of a writte n, si g ne d , a n d date d i nf or me d c o nse nt f or m .
I N R
i nter nati onal n o r malize d rati o
i nt eri m a n al y si s
A n i nteri m a nal ysis is a n a nal ysis of cli nical st u d y data, se parate d i nt o treat me nt gr o u ps, 
t hat is c o n d ucte d bef ore t he fi nal re p orti n g data base is create d/l oc ke d.
I R B
I nstit uti onal Re vie w B oar d
O A T P
or ga nic a ni o n -tra ns p orti n g p ol ype pti de
o p e n -l a b el
A st u d y  i n w hic h t here are n o restricti o ns o n k n o wle d ge of treat me nt all ocati o n, 
t heref ore t he i n vesti gat or a n d t he st u d y partici pa nt are a ware of t he dr u g t hera p y 
recei ve d d uri n g t he st u d y.
p arti ci p a nt
E q ui vale nt t o C DI S C ter m “s u bject”: a n i n di vi d ual w h o partici pates i n a cli nical trial, 
eit her as reci pie nt of a n i n vesti gati o nal me dici nal pr o d uct or as a c o ntr ol
P- g p
p- gl yc o pr otei n
P K
p har mac o ki netics
S A E
seri o us a d verse e ve nt
s cr e e n
T he act of deter mi ni n g if a n i n di vi d ual meets mi ni m u m re q uire me nts t o bec o me part of 
a p o ol of p ote ntial ca n di dates f or partici pati o n i n a cli nical st u d y. 
S N P
si n gle n ucle oti de p ol y m or p his m
S o A
Sc he d ule of Acti vities
t1/ 2
half -life ass ociate d wit h t he ter mi nal eli mi nati o n p hase
T B L
t otal bilir u bi n le vel
T E A E
Treat me nt -e mer ge nt a d verse e ve nt: A n  u nt o war d me dical occ urre nce t hat e mer ges 
d uri n g a defi ne d treat me nt peri o d, ha vi n g bee n a bse nt pretreat me nt, or w orse ns relati ve 
t o t he pretreat me nt state, a n d d oes n ot necessaril y ha ve t o ha ve a ca usal relati o ns hi p 
wit h t his treat me nt.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
7 3
tm a x
ti me of ma xi m u m o bser ve d dr u g c o nce ntrati o n
T O S T
t w o 1- si de d t-test
U L N
u p per li mit of n or mal

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
7 4
1 1.
Refere nces
Crest or ® (r os u vastati n calci u m) [prescri bi n g i nf or mat i on] . Wil mi n gt o n, D E: Astra Ze neca 
P har mace ut icals L P; N o ve m ber 2 0 2 0 . A vaila ble at :
ht t ps:// w w w.az pice ntral.c om/crest or/crest or. p df # pa ge = 1 . Accesse d A u g ust 1 8 , 2 0 2 0. 
C usat o J, Alle gra S, Massa n o D, et  al. I nfl ue nce of si n gle-n ucle oti de p ol y m or p his ms o n 
d ef erasir o x C tr o u g h le vels a n d effect i ve ness. P h ar m ac o ge n o mics J . 2 0 1 5; 1 5( 3): 2 6 3 -2 7 1.
E u dra C T N o.: 2 0 0 7 - 0 0 5 7 6 5-3 5. B oe hri n ger I n gel hei m. Cli nical st u d y s y n o psis f or p u blic 
di s clos ure. BI Tri al N o.: 1 1 6 0. 7 0 S y n o psis. 2 0 1 4. Accesse d A u g ust 2 9, 2 0 2 0. 
ht t ps://trials. b oe hri n ger-
i n gel hei m.c o m/ p u blic/trial _res ults _ d oc u me nts/ 1 1 6 0/ 1 1 6 0. 7 0 _ 1 1 6 7 U 9 1 5 1 2 C O p df. p df
[F D A ] U S F o o d a n d Dr u g A d mi nistrati o n. I n vitr o dr u g i nteractio n st u di es – c ytoc hr o m e P 4 5 0 
e nz y me- a n d tra ns p orter-me diate d dr u g i nteracti o ns , g uida nce f or i n d ustr y . Ja n uar y 2 0 2 0a ; 
A vaila ble at: htt ps:// w w w.f da. g o v/ me dia/ 1 3 4 5 8 2/ d o w nl oa d . Accesse d Se pte m ber 8 , 2 0 2 0.
[F D A ]. U S F o o d a n d Dr u g A d mi nistrati o n. Cli nical dr u g i nteracti o n st u dies – c yt oc hr o m e P 4 5 0 
e nz y me- a n d tra ns p orter- me diate d dr u g i nteracti o ns, g ui da nce f or i n d ustr y. Ja n uar y 2 0 2 0 b ; 
A vaila ble at: htt ps:// w w w.f da. g o v/ me dia/ 1 3 4 5 8 1/ d o w nl oa d . Accesse d Se pte m ber 8 , 2 0 2 0.
F ur u ka wa T, Wa ka ba yas hi K, Ta m ura A, et al. Maj o r S N P ( Q 1 4 1 K) varia nt of h u ma n A B C 
tra ns p orter A B C G 2 u n der g oes l ys os oma l a n d pr oteas omal de gra dat i ons. P h ar m Res . 
2 0 0 9; 2 6( 2): 4 6 9 - 4 7 9.
Härtter S, Se n ne wal d R, Ne h miz G, Reill y P. Oral bi oa vaila bilit y of  da bigatra n ete xilate 
( Pra da xa® ) after c o-me d icati on wi t h vera pa mil i n health y s u bjects . Br J Cli n P h ar m ac ol . 
2 0 1 3; 7 5( 4): 1 0 5 3 - 1 0 6 2.
I nter nati o nal Tra ns p orter C o ns orti u m, Giac o mi ni K M, H ua n g S M, T wee die DJ, et al. Me m bra ne 
tra ns p orters i n dr u g de vel o p me nt. N at Rev Dr u g Disc ov . 2 0 1 0; 9( 3): 2 15- 2 3 6.
Kes kital o J E, Z olk O, Fr o m m  M F, et al. A B C G 2 p ol y m or p his m mar ke dl y affects t he 
p har mac o ki net ics of at or vastati n a n d r os u vastati n. Cli n P h ar m ac ol T her . 2 0 0 9; 8 6( 2): 1 9 7-2 0 3.
Lee C A, O ’C o n n or M A, Ri tc hie C T K, et al. Breast ca ncer resista nce pr otei n ( A B CG 2) i n cli nical 
p har mac o ki net ics a n d dr u g i nteracti o ns: practical rec o m me n datio ns f or cli nical vict i m a n d 
per petrat or dr u g -dr u g i nteracti o n st u d y  desi g n. Dr u g Met a b Dis p os . 2 0 1 5; 4 3( 4): 4 9 0-5 0 9.
Malie paar d M, Sc heffer G L, Fa ne yte I F, et al. S u bcell ular lo c al izati on a n d distri b uti o n of t he 
breast ca ncer resista nce pr otei n tra ns p orter i n n or mal h u ma n t iss ues. C a ncer Res .
2 0 0 1; 6 1( 8): 3 4 5 8 - 3 4 6 4.
Ni e mi M, Pasa ne n M K, Ne u v o ne n PJ. Or ga nic a ni o n tra ns p orti n g p ol y pe pti de 1 B 1: a ge net icall y 
p ol y m or p hic tra ns p orter of maj or i m p orta nce f or he patic dr u g u pta ke. P h ar m ac ol Rev . 
2 0 1 1; 6 3( 1): 1 5 7 - 1 8 1.
Pasa ne n M K, Fre dri ks o n H, Ne u v o ne n PJ, Nie mi M. Differe nt effects of S L C O 1 B 1 
p ol y m or p his m o n t he p har mac o ki net ics of at or vastati n a n d r os u vastati n. Cli n P h ar m ac ol T her . 
2 0 0 7; 8 2( 6): 7 2 6 - 7 3 3.
Pra da xa ® ( da bi gatra n ete xilate) [ prescri bi n g inf or mat i on ]. Ri d gefiel d, C T : B o e hri n ger I n gel hei m 
P har mace ut icals, I nc.; N o ve m ber 2 0 1 9; A vaila ble at:
ht t ps:// w w w.access data.f da. g o v/ dr u gsatf da _ d ocs/la bel/ 2 0 1 1/0 2 2 5 1 2s 0 0 7l bl. p df . Accesse d
Marc h
1 1, 2 0 2 0.
Re y v o w T M - las mi dit a n t a blet [prescri bi n g i nf or mati o n ]. I n dia na p o lis, I N: Eli Lill y a n d 
C o m pa n y; Ja n uar y 2 0 2 0. A vaila ble at htt p:// pi.lill y.c o m/ us/re y v o w -us pi . p df. Accesse d 
Se pte m ber 8 , 2 0 2 0.

C O N FI D E N TI A L
H 8 H -M C -L AI O ( b)
7 5
Sta n gi er J. Cli nical p har mac o ki netics a n d p har mac o d y na mics of t he oral direct t hr o m bi n
i n hi bit or da bi gatra n ete xilate. Cli n P h ar m ac oki net . 2 0 0 8; 4 7( 5): 2 8 5- 2 9 5.
T he C ol u m bia Li g ht h o use Pr oject. T he C ol u m bia Pr ot oc ol f or Researc h. C ol u m bia -S uici d e 
Se verit y Rati n g Scale Sc ori n g a n d Data A nal ysis G ui de. Versi o n 2. 0. Accesse d Se pte m ber 8 , 
2 0 2 0 . htt p://cssrs.c ol u m bia.e d u/ w p -c o nte nt/ u pl oa ds/ Sc ori n ga n d Data A nal ysis G ui de -f or-
Cli nical -Tri als-1. p df .
Wa n Z, Wa n g G, Li T, et al. Mar ke d alt er atio n of  r os u vastati n p har mac o ki netics i n health y 
C hi nese wit h A B C G 2 3 4 G > A a n d 4 2 1 C > A h o m o z y g ote or c o m p o u n d heter oz y g ote . J 
P h ar m ac ol Ex p T her . 2 0 1 5; 3 5 4( 3): 3 1 0-3 1 5.

L e o  D o c u m e n t  I D  =  8 5 e 5 4 6 b 6 - f b d c - 4 1 d 9 - 8 f b e - 6 3 f 6 0 f c 9 b 1 6 8
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  0 6 - N o v - 2 0 2 0  1 3 : 5 9 : 5 6  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  0 6 - N o v - 2 0 2 0  1 5 : 3 4 : 5 0  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
P P D
P P D