Conditions: Healthy
Keywords: Drug Interaction Study
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 97
Healthy volunteers: yes

Brief summary:
The main purpose of the study is to investigate the blood concentrations of dabigatran etexilate and rosuvastatin when taken alone compared to when taken together with lasmiditan in healthy participants. The safety and tolerability of dabigatran etexilate or rosuvastatin in combination with lasmiditan will also be evaluated in healthy participants. The study has two parts. Each part will last up to 17 days, not including screening.

Detailed description:

Arms:
arm 1: Participants received 150 mg dabigatran etexilate on Day 1 followed by 200 mg lasmiditan once daily (QD) on Days 8 and 9, and 150 mg of dabigatran etexilate along with 200 mg lasmiditan on Day 10. All treatments were administered orally arm 2: Participants received 10 mg rosuvastatin on Day 1 followed by 200 mg lasmiditan QD on Days 8 and 9, and 10 mg of rosuvastatin along with 200 mg lasmiditan on Day 10. All treatments were administered orally.

Interventions: intervention 1: Lasmiditan intervention 2: Dabigatran Etexilate intervention 3: Rosuvastatin
Intervention descriptions: intervention 1: Administered orally. intervention 2: Administered orally. intervention 3: Administered orally.

Protocol document:
Prot_000.pdf: 
 
 
 
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

SAP_001.pdf: 
 
 
 
Statistical Analysis Plan Version 1 H8H-MC-LAIO (b) 
 
 
An Open-Label, 2-Part Study to Investigate the Effect of Lasmiditan on the Pharmacokinetics of 
Dabigatran and Rosuvastatin in Healthy Volunteers 
 
  
NCT04749914 
 
Approval Date: 03-Nov-2020 
 
 


STATISTICAL ANALYSIS PLAN
An Open-Label, 2-Part Study to Investigate the Effect of Lasmiditan on the 
Pharmacokinetics of Dabigatran and Rosuvastatin in Healthy Volunteers
Statistical Analysis Plan Status:  Final v1
Statistical Analysis Plan Date:  29-October-2020
Study Drug:  LY573144
Sponsor Reference:  H8H-MC-LAIO 
Covance CRU Study:  1001215-8446476
Clinical Phase I
Page 1 of 15
Approval Date: 03-Nov-2020 GMT


Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8446476
Sponsor Reference H8H-MC-LAIO
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS ............................................................................................... 2
2.
ABBREVIATIONS........................................................................................................ 3
3.
INTRODUCTION ......................................................................................................... 5
4.
STUDY OBJECTIVES.................................................................................................. 5
4.1
Primary Objective.................................................................................................... 5
4.2
Secondary Objectives .............................................................................................. 5
5.
STUDY DESIGN........................................................................................................... 6
6.
TREATMENTS............................................................................................................. 7
7.
SAMPLE SIZE JUSTIFICATION ................................................................................. 7
8.
DEFINITION OF ANALYSIS POPULATIONS............................................................ 7
9.
STATISTICAL METHODOLOGY ............................................................................... 8
9.1
General.................................................................................................................... 8
9.2
Demographics and Participant Disposition............................................................... 8
9.3
Pharmacokinetic Assessment................................................................................... 8
9.3.1
Pharmacokinetic Analysis............................................................................... 8
9.3.2
Pharmacokinetic Statistical Methodology ..................................................... 12
9.4
Safety and Tolerability Assessments...................................................................... 13
9.4.1
Adverse events ............................................................................................. 13
9.4.2
Concomitant medication............................................................................... 13
9.4.3
Clinical laboratory parameters...................................................................... 13
9.4.4
Vital signs .................................................................................................... 13
9.4.5
Electrocardiogram (ECG)............................................................................. 14
9.4.6
Hepatic Monitoring ...................................................................................... 14
9.4.7
Columbia-Suicide Severity Rating Scale (C-SSRS) / Self-Harm Supplement 14
9.4.8
Other assessments......................................................................................... 14
10. INTERIM ANALYSES ............................................................................................... 14
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ...... 14
12. REFERENCES ............................................................................................................ 14
13. DATA PRESENTATION ............................................................................................ 15
13.1 Derived Parameters ............................................................................................... 15
13.2 Missing Data ......................................................................................................... 15
13.3 Insufficient Data for Presentation .......................................................................... 15
Page 2 of 15


Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8446476
Sponsor Reference H8H-MC-LAIO
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
%AUC(tlast-∞)
Percentage of AUC(0-∞) extrapolated
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AUC
Area under the concentration versus time curve
AUC(0-∞)
Area under the concentration versus time curve from time zero to 
infinity
AUC(0-tlast)
Area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable concentration
BCRP
Breast cancer resistance protein
BQL
Below the lower limit of quantification
Clast
Last quantifiable drug concentration
Cmax
Maximum observed drug concentration
CI
Confidence interval
CL/F
Apparent total body clearance of drug calculated after extra-vascular 
administration
CRF
Case Report Form
CRU
Clinical Research Unit
CSR
Clinical Study Report
C-SSRS
Columbia-Suicide Severity Rating Scale
CV
Coefficient of variation
DDI
Drug-drug interaction
ECG
Electrocardiogram
ICF
Informed consent form
ICH
International Conference on Harmonisation
LLOQ
Lower limit of quantification
LS
Least square
MedDRA
Medical Dictionary for Regulatory Activities
MRE
Magnetic resonance elastography
P-gp
P-glycoprotein
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8446476
Sponsor Reference H8H-MC-LAIO
PK
Pharmacokinetic
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SD
Standard deviation 
SNP
Single nucleotide polymorphism
t1/2
Half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
TBL
Total bilirubin
TEAE
Treatment-emergent adverse event
TFLs
Tables, Figures, and Listings
tmax
Time of maximum observed drug concentration
TOST
Two 1-sided t-tests
ULN
Upper limit of normal
Vss/F
Apparent volume of distribution at steady state after extra-vascular 
administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extra-vascular administration
WHO
World Health Organization
Page 4 of 15


Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8446476
Sponsor Reference H8H-MC-LAIO
3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
11 September 2020) and Protocol Amendment (a) (final version dated 16 September 2020).
This SAP describes the planned analysis of the safety, tolerability and pharmacokinetic (PK) data 
from this study. A detailed description of the planned TFLs to be presented in the clinical study 
report (CSR) is provided in the accompanying TFL shell document.
The intent of this document is to provide guidance for the statistical and PK analyses of data. In 
general, the analyses are based on information from the protocol, unless they have been modified 
by agreement with Eli Lilly and Company. A limited amount of information concerning this 
study (e.g., objectives, study design) is given to help the reader’s interpretation. This SAP must 
be signed off prior to first participant visit for this study. When the SAP and TFL shells are 
agreed upon and finalized, they will serve as supporting material for this study’s CSR.
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon with 
Eli Lilly and Company and identified in the CSR. Any minor deviations from the TFLs may not 
be documented in the CSR.
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry:  Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry:  
Structure and Content of Clinical Study Reports2.
4. STUDY OBJECTIVES
4.1
Primary Objective 
The primary objective of the study is to evaluate the effect of lasmiditan on P-glycoprotein 
(P-gp) and breast cancer resistance protein (BCRP) activity in healthy participants.
The primary endpoints of the study are maximum observed drug concentration (Cmax) and area 
under the concentration (AUC) versus time curve from time zero to infinity (AUC [0-∞]) of 
dabigatran to assess P-gp activity and rosuvastatin to assess BCRP activity.
4.2
Secondary Objectives
The secondary objectives of the study are:

To evaluate the safety and tolerability of dabigatran etexilate or rosuvastatin in 
combination with lasmiditan in healthy participants

To evaluate the pharmacokinetics of lasmiditan and M8
Page 5 of 15


Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8446476
Sponsor Reference H8H-MC-LAIO
The secondary endpoints of the study are:

A summary of the number of treatment-emergent adverse events (TEAEs) and serious 
adverse events (SAE)

Cmax of lasmiditan and M8

Time of maximum observed drug concentration (tmax) of lasmiditan and M8

AUC (0-∞) of lasmiditan and M8
5. STUDY DESIGN
This is a Phase 1, two-part, two-period, open-label study in healthy participants. Part 1 will study 
dabigatran P-gp drug-drug interaction (DDI) with lasmiditan. Part 2 will study rosuvastatin 
BCRP DDI with lasmiditan. Parts 1 and 2 will have a similar design, i.e., dabigatran etexilate or 
rosuvastatin administration alone in Period 1 (Day 1) followed by a brief washout, then 
lasmiditan on Days 8, 9, and 10 (Period 2) with coadministration of dabigatran etexilate or 
rosuvastatin with lasmiditan on Day 10. Each part will consist of different participants and the 2 
parts may run in parallel. Participants for both Part 1 and Part 2 will be consented with a single 
consent form, and both genotyping and coagulation tests will be performed for both parts during 
screening. Part 2 will be prioritized to complete first due to an anticipated screen fail rate of
~50% secondary to genotype criteria. Once Part 2 has achieved last participant dosed, no further 
genotyping will be needed for LAIO screening. Participants who failed Part 2 screening due to 
genotyping only and have a normal coagulation profile will automatically be eligible for Part 1.
A general schema for this study can be seen in Figure 1.
Figure 1 – General schema for LAIO 
Page 6 of 15


Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8446476
Sponsor Reference H8H-MC-LAIO
6. TREATMENTS
The following is a list of the study treatment abbreviations that will be used in the TFLs.
Part
Day
Study Treatment Name
Treatment 
order in TFL
1
1
150 mg dabigatran etexilate 
1
8-9
200 mg lasmiditan
2
10
150 mg dabigatran etexilate + 200 mg lasmiditan
3
2
1
10 mg rosuvastatin 
4
8-9
200 mg lasmiditan
5
10
10 mg rosuvastatin + 200 mg lasmiditan
6
7. SAMPLE SIZE JUSTIFICATION
Approximately 72 participants will be enrolled to Part 1 of the study to ensure that at least 62 
evaluable participants complete that part. With 62 participants, we expect the two 1-sided t-tests 
(TOSTs) for equivalence applied to the log-normal mean ratio to have a power of at least 80% 
for the AUC (0-∞) and Cmax tests in Part 1. This assumes a nominal expected mean ratio of 1.05, 
a coefficient of variation (CV) of 39.3%, and a significance level of 0.05 of each 1-sided test 
when testing against an upper limit of 1.25 and a lower limit of 0.80. The tests will be displayed 
in the form of 90% confidence intervals (CI), which are equivalent to the according TOST. The 
source of the CV is Boehringer Ingleheim bioequivalence study (EudraCT number 
2007-005765-35), and the higher intrasubject CV observed in the second-generation dabigatran 
arm was chosen.
Approximately 32 participants will be enrolled to Part 2 to ensure that at least 28 evaluable 
participants complete that part. With 28 participants, we expect the TOSTs for equivalence 
applied to the lognormal mean ratio to have a power of at least 80% for the AUC(0-∞) and Cmax
tests in Part 2. This assumes a nominal expected mean ratio of 1.05, a CV of 25.1%, and 
significance level of 0.05 of each 1-sided test when testing against an upper limit of 1.25 and a 
lower limit of 0.80. The tests will be displayed in the form of 90% CI which are equivalent to the 
according TOST. The source of the CV is Study AZEB, and the higher of the rosuvastatin 
AUC(0-∞) and Cmax intrasubject CVs was chosen.
8. DEFINITION OF ANALYSIS POPULATIONS
The “Entered” population will consist of all participants who signed the informed consent form 
(ICF).
The “Enrolled” population will consist of all participants assigned to treatment, regardless of 
whether they take any doses of study intervention, or if they took the correct treatment.
The “Safety” population will consist of all participants assigned to dabigatran etexilate or 
rosuvastatin and who take at least 1 dose of 1 of those products. Participants will be analyzed 
according to the product they actually received.
Page 7 of 15


Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8446476
Sponsor Reference H8H-MC-LAIO
The “Pharmacokinetic” population will consist of all participants who receive at least 1 dose of 
dabigatran etexilate or rosuvastatin and have evaluable PK.
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when participants are assigned to analysis populations.
9. STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all data that is databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median, 
min, max and N; for log-normal data (e.g. the PK parameters: AUCs and Cmax) the geometric 
mean and geometric CV will also be presented. For categorical data, frequency count and 
percentages will be presented. Data listings will be provided for all participants up to the point of 
withdrawal, with any participants excluded from the relevant population highlighted. Summary 
statistics and statistical analyses will generally only be performed for participants included in the 
relevant analysis population. For the calculation of summary statistics and statistical analysis, 
unrounded data will be used. 
Mean change from baseline is the mean of all individual participants’ change from baseline 
values. Each individual change from baseline will be calculated by subtracting the individual 
participant’s baseline value from the value at the timepoint. The individual participant’s change 
from baseline values will be used to calculate the mean change from baseline using a SAS 
procedure such as PROC UNIVARIATE.
Data analysis will be performed using SAS® Version 9.4 or greater.
9.2
Demographics and Participant Disposition
Participant disposition will be summarized and listed. The demographic variables age, sex, race, 
ethnicity, body weight, height and body mass index will be summarized and listed. All other 
demographic variables will be listed only.
9.3
Pharmacokinetic Assessment
9.3.1
Pharmacokinetic Analysis
Noncompartmental methods applied with a validated software program (WinNonlin Phoenix v8.1 
or later) to the plasma concentrations of dabigatran, rosuvastatin, lasmiditan and its metabolite M8 
will be used to determine the following PK parameters, when possible: 
Page 8 of 15


Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8446476
Sponsor Reference H8H-MC-LAIO
Parameter
Units
Definition
AUC(0-tlast)
ng*h/mL
area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable 
concentration
AUC(0-∞)
ng*h/mL
area under the concentration versus time curve from time zero to 
infinity
%AUC(tlast-)
%
percentage of AUC(0-∞) extrapolated
Cmax
ng/mL
maximum observed drug concentration
tmax
h
time of maximum observed drug concentration
t1/2
h
half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
CL/F
L/h
apparent total body clearance of drug calculated after 
extra-vascular administration (not M8)
Vz/F
L
apparent volume of distribution during the terminal phase after 
extra-vascular administration (not M8)
Vss/F
L
apparent volume of distribution at steady state after extra-vascular 
administration (not M8)
Additional PK parameters may be calculated, as appropriate.  The software and version used for 
the final analyses will be specified in the clinical study report. Any exceptions or special handling 
of data will be clearly documented within the final study report.
Formatting of tables, figures and abbreviations will follow the Eli Lilly Global PK/PD/TS Tool: 
NON-COMPARTMENTAL PHARMACOKINETIC STYLE GUIDE. The version of the tool
effective at the time of PK analysis will be followed.
General PK Parameter Rules

Actual sampling times will be used in the final analyses of individual PK parameters, 
except for non-bolus pre-dose sampling times which will be set to zero.

Cmax and tmax will be reported from observed values.  If Cmax occurs at more than one time 
point, tmax will be assigned to the first occurrence of Cmax. 

AUC parameters will be calculated using a combination of the linear and logarithmic 
trapezoidal methods (linear-log trapezoidal rule).  The linear trapezoidal method will be 
applied up to tmax and then the logarithmic trapezoidal method will be used after tmax. The 
minimum requirement for the calculation of AUC will be the inclusion of at least three 
consecutive plasma concentrations above the lower limit of quantification (LLOQ), with 
at least one of these concentrations following Cmax. AUC(0-) values where the 
percentage of the total area extrapolated is more than 20% will be flagged. Any 
AUC(0-) value excluded from summary statistics will be noted in the footnote of the 
summary table.

Half-life (t½) will be calculated, when appropriate, based on the apparent terminal 
log-linear portion of the concentration-time curve. The start of the terminal elimination 
phase for each participant will be defined by visual inspection and generally will be the 
first point at which there is no systematic deviation from the log-linear decline in plasma 
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concentrations.  Half-life will only be calculated when a reliable estimate for this 
parameter can be obtained comprising of at least 3 data points.  If t½ is estimated over a 
time window of less than 2 half-lives, the values will be flagged in the data listings. Any 
t½ value excluded from summary statistics will be documented in the footnote of the 
summary table. 

A uniform weighting scheme will be used in the regression analysis of the terminal log-
linear portion of the concentration-time curve.

The parameters based on predicted Clast will be reported.
Individual PK Parameter Rules

Only quantifiable concentrations will be used to calculate PK Parameters with the 
exception of special handling of certain concentrations reported below the lower limit of 
quantification (BQL).  Plasma concentrations reported as BQL will be set to a value of 
zero when all of the following conditions are met: 

The compound is non-endogenous.

The samples are from the initial dose period for a participant or from a subsequent dose 
period following a suitable wash-out period.

The time points occur before the first quantifiable concentration.

All other BQL concentrations that do not meet the above criteria will be set to missing. 

Also, where two or more consecutive concentrations are BQL towards the end of a 
profile, the profile will be deemed to have terminated and therefore any further 
quantifiable concentrations will be set to missing for the calculation of the PK parameters 
unless it is considered to be a true characteristic of the profile of the drug.
Individual Concentration vs. Time Profiles

Individual concentrations will be plotted utilizing actual sampling times.

The terminal point selections will be indicated on a semi-logarithmic plot.
Average Concentration vs. Time Profiles

The average concentration profiles will be graphed using scheduled (nominal) sampling 
times. 

The average concentration profiles will be graphed using arithmetic average 
concentrations.

The pre-dose average concentration for single-dose data from non-endogenous 
compounds will be set to zero.  Otherwise, only quantifiable concentrations will be used 
to calculate average concentrations.

Concentrations at a sampling time exceeding the sampling time window specified in the 
protocol, or ± 10%, will be excluded from the average concentration profiles.

Concentrations excluded from the mean calculation will be documented in the final study 
report.

A concentration average will be plotted for a given sampling time only if 2/3 of the 
individual data at the time point have quantifiable measurements that are within the 
sampling time window specified in the protocol or ± 10%. An average concentration 
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Statistical Analysis Plan 
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estimated with less than 2/3 but more than 3 data points may be displayed on the mean 
concentration plot if determined to be appropriate and will be documented within the 
final study report.
Treatment of Outliers during Pharmacokinetic Analysis
Application of this procedure to all pharmacokinetic analyses is not a requirement. Rather, this 
procedure provides justification for exclusion of data when scientifically appropriate. This 
procedure describes the methodology for identifying an individual value as an outlier for potential 
exclusion, but does not require that the value be excluded from analysis.  The following 
methodology will not be used to exclude complete profiles from analysis.
Data within an Individual Profile
A value within an individual profile may be excluded from analysis if any of the following criteria 
are met:

For pharmacokinetic profiles during multiple dosing, the concentration of the pre-dose 
sample exceeds all measured concentrations for that individual in the subsequent post-
dose samples.

For pharmacokinetic profiles during single dosing of non-endogenous compounds, the 
concentration in a pre-dose sample is quantifiable.

For any questionable datum that does not satisfy the above criteria, the profile will be 
evaluated and results reported with and without the suspected datum. 
Data between Individual Profiles
1.
If n<6, then the dataset is too small to conduct a reliable range test.  Data will be analyzed 
with and without the atypical value, and both sets of results will be reported.  
2.
If n6, then an objective outlier test will be used to compare the atypical value to other 
values included in that calculation:
a.
Transform all values in the calculation to the logarithmic domain.
b. Find the most extreme value from the arithmetic mean of the log transformed 
values and exclude that value from the dataset.
c.
Calculate the lower and upper bounds of the range defined by the arithmetic 
mean ±3*SD of the remaining log-transformed values.
d. If the extreme value is within the range of arithmetic mean ±3*SD, then it is not 
an outlier and will be retained in the dataset.
e.
If the extreme value is outside the range of arithmetic mean ±3*SD, then it is 
an outlier and will be excluded from analysis.
If the remaining dataset contains another atypical datum suspected to be an outlier and n ≥ 6 
following the exclusion, then repeat step 2 above. This evaluation may be repeated as many times 
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Statistical Analysis Plan 
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as necessary, excluding only one suspected outlier in each iteration, until all data remaining in the 
dataset fall within the range of arithmetic mean ±3*SD of the log-transformed values.
Reporting of Excluded Values
Individual values excluded as outliers will be documented in the final report.  Approval of the final 
report will connote approval of the exclusion.
9.3.2
Pharmacokinetic Statistical Methodology
Pharmacokinetic parameters will be evaluated to estimate drug interaction for dabigatran and 
rosuvastatin with lasmiditan. Log-transformed Cmax and AUC(0-∞) parameters for dabigatran 
and rosuvastatin will be analyzed using a mixed effects linear model to compare dabigatran and 
rosuvastatin administered alone (reference), and dabigatran and rosuvastatin administered with 
lasmiditan (test). The model will include a fixed effect for treatment and a random effect for 
participant. The least squares (LS) means for each treatment, the difference between the 
treatment LS means ([dabigatran or rosuvastatin + lasmiditan] – dabigatran or rosuvastatin
alone), and the associated 90% CIs will be estimated from the model and back-transformed from 
the log scale to provide estimates of the geometric means, geometric mean ratio, and 
corresponding 90% CIs.
Example of the SAS code for the analysis:
proc mixed data=xxx alpha=0.1;
class treat subjid;
model log_pk = treat / residual ddfm=kr;
random subjid;
lsmeans treat / cl pdiff alpha=0.1;
ods output lsmeans=lsm01 diffs=estims01;
run;
The tmax will be analyzed non-parametrically using a Wilcoxon signed rank test. Estimates of the 
median difference, comparing dabigatran or rosuvastatin + lasmiditan (test) – dabigatran or 
rosuvastatin alone (reference), and the corresponding 90% CIs for the difference between 
treatments will be calculated and presented, alongside the p-value from the Wilcoxon 
signed-rank test.
Example SAS code to be used for the Wilcoxon signed-rank test:
proc univariate data = xxx cipctldf(alpha = 0.1); 
var ref test diff; 
ods output quantiles = quant01;
ods output testsforlocation = out01;
run;
The effect of polymorphisms in genes coding for certain transporters (e.g., ABCG2, ABCB1, 
ABCC2, SLCO1B3, NTCP, and SLCO2B1) on the magnitude of the interaction between 
rosuvastatin and lasmiditan may be explored. For each participant, the ratio of rosuvastatin 
exposures with and without concomitant lasmiditan exposures will be calculated. A graphical 
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Statistical Analysis Plan 
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analysis of these ratios between participants with and without single nucleotide polymorphism 
(SNPs) of interest is intended.
Additional analyses may be conducted as warranted.
9.4
Safety and Tolerability Assessments
9.4.1
Adverse events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the adverse event (AE) will be reported in the listings, only the most severe will be used in the 
summary tables. A pre-existing condition is defined as an AE that starts before the participant 
has provided written informed consent and is ongoing at consent. A non-treatment emergent AE 
is defined as an AE which starts after informed consent but prior to dosing. A TEAE is defined 
as an AE which occurs postdose or which is present prior to dosing and becomes more severe 
postdose. 
All AEs will be listed. TEAEs will be summarized by treatment, severity and relationship to the 
study drug. The frequency (the number of AEs, the number of participants experiencing an AE 
and the percentage of participants experiencing an AE) of TEAEs will be summarized by 
treatment, Medical Dictionary for Regulatory Activities (MedDRA) Version 23.1 system organ 
class and preferred term. The summary and frequency TEAE tables will be presented for all 
causalities and those considered related to the study drug by the investigator. Any serious AEs 
will be listed. AEs by day of onset will be presented.
Discontinuations due to AEs will be listed.
9.4.2
Concomitant medication
Concomitant medication will be coded using the WHO drug dictionary (Version WHODD 
SEP20B3). Concomitant medication will be listed.
9.4.3
Clinical laboratory parameters
All clinical chemistry, hematology, and coagulation data will be summarized by part and 
parameter, and listed. Urinalysis data will be listed only. Additionally, clinical chemistry, 
hematology, coagulation, and urinalysis data outside the reference ranges will be listed and 
flagged on individual participant data listings.
9.4.4
Vital signs
Vital signs data will be summarized by part together with changes from baseline, where baseline 
is defined as the predose assessment of each dosing period (Day 1 for period 1 and Day 10 for 
Period 2). Figures of mean vital signs and mean changes from baseline profiles will be presented 
by treatment. 
Values for individual participants will be listed.
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9.4.5
Electrocardiogram (ECG)
ECGs will be performed for safety monitoring purposes only and will not be presented. Any 
clinically significant findings from ECGs will be reported as an AE.
9.4.6
Hepatic Monitoring
If a participant experiences elevated alanine aminotransferase (ALT) ≥3× upper limit of normal 
(ULN), alkaline phosphatase (ALP) ≥2× ULN, or elevated total bilirubin (TBL) ≥2× ULN, liver 
tests will be performed to confirm the abnormality. Additional safety data may be collected if 
required, as defined in the protocol. Where applicable, the following will be presented.
The participants’ liver disease history and associated person liver disease history data will be 
listed. Any concomitant medications that have potential for hepatotoxicity, including 
acetaminophen will be listed. Results from any hepatic monitoring procedures, such as a 
magnetic resonance elastography (MRE) scan, and biopsy assessments will be listed, if 
performed.
Hepatic risk factor assessment data will be listed. Liver related signs and symptoms data will be 
summarized by treatment and listed. Alcohol and recreational drug use data will also be listed.
All hepatic chemistry, hematology, coagulation, and serology data will be listed. Values outside 
the reference ranges will be flagged on the individual participant data listings.
9.4.7
Columbia-Suicide Severity Rating Scale (C-SSRS) / Self-Harm Supplement
All C-SSRS and Self Harm Supplement data will be listed.
9.4.8
Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed.
10.
INTERIM ANALYSES
No interim statistical analyses are planned.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.
12.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
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Covance Clinical Study No. 1001215-8446476
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2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be reported as received. N and percentage 
values should be reported as whole numbers. Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.
13.2
Missing Data
Missing data will not be displayed in listings.
13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of participants or data for presentation. If 
this occurs, the blank TFL shell will be presented with a message printed in the center of the 
table, such as, “No serious adverse events occurred for this study.”
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Leo Document ID = 9e6ed614-1151-4314-90c6-1a23104322e5
Approver: 
Approval Date & Time: 02-Nov-2020 13:16:21 GMT
Signature meaning: Approved
Approver:
Approval Date & Time: 02-Nov-2020 15:22:28 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 03-Nov-2020 10:14:37 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 03-Nov-2020 11:51:39 GMT
Signature meaning: Approved
PPD
PPD
PPD
PPD