A Phase 1, Randomized, Participant-and Investigator-Blind, Placebo-Controlled, Single-and Multiple-Ascending Dose, Drug-Drug Interaction and Food Effect Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of LY3509754 in Healthy Non-Japanese and Japanese Participants
Phase: PHASE1
Conditions: Healthy
Sponsor: Eli Lilly and Company

 
 
 
Pr ot oc ol J3 D -M C -F N A A (i) 
 
 
A P hase 1, Ra n d o mize d, Partici pa nt - a n d I n vesti gat or-Bli n d, Place b o - C o ntr olle d, Si n gle- a n d 
M ulti ple - Asce n di n g D ose, Dr u g- Dr u g I nteracti o n a n d F o o d Effect St u d y t o E val uate t he Safet y, 
T olera bilit y, a n d P har mac o ki netics of L Y 3 5 0 9 7 5 4 i n Healt h y N o n- Ja pa nese a n d Ja pa nese 
Partici pa nts  
 
N C T 0 4 5 8 6 9 2 0 
 
A p pr o val Date: 0 1- Dec - 2 0 2 1 
 
 
 
 
 
 

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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 Y 3 5 0 9 7 5 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 el e a s e/r e d a ctio 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 . 
P r ot oc ol Title : A P h ase 1, R a n d o mize d, P artici p a nt - a n d I n vesti g at or -B li n d, Pl ace b o-
C o ntr olle d, Si n gle - a n d M ulti ple -Asce n di n g  D ose , Dr u g-Dr u g I nter acti o n  
a n d F o o d Effect St u d y t o E v al u ate t he S afet y, T oler a bilit y , a n d 
P h ar m a c o ki netics of L Y 3 5 0 9 7 5 4 in He alt h y N o n -J a p a nese a n d J a p a nese 
P a rtici p a nts  
Pr ot oc ol N u m ber:  J 3 D-M C -F N A A  
A me n d me nt N u m ber:  i 
C o m p o u n d : L Y 3 5 0 9 7 5 4  
St u d y P h ase:  1  
S h ort Title:  A P hase 1, Ra n d o mize d, Partici pa nt - a n d I n vesti gat or -B li n d, Place b o-C o ntr olle d, 
Si n gle - an d M ulti ple -As ce n di n g D os e, Dr u g -Dr u g I nteracti o n an d F o o d Effect St u d y t o E val uat e 
t he Safet y, T olera bilit y, a n d P har mac o ki netics of L Y 3 5 0 9 7 5 4 i n Healt h y Partici pa nts  
S p o ns or N a me:  Eli Lill y a n d C o m pa n y  
Le g al Re gistere d A d dress:  Eli 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 5 1 0 7 5  
E u dra C T:  2 0 2 0 -0 0 3 9 5 7 -3 0  
A p pr o v al D ate:  Pr ot oc ol A me n d me nt ( i) E lectr 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 vi de d bel o w . 
 
D oc u me nt I D: V V -C LI N -0 1 4 9 0 6   
 
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2  
Me dic al M o nit or N a me a n d C o nt act I nf or m ati o n will be pr o vi de d se p ar atel y . 
 
 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

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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 h  
1 7 -N o v e m b er -2 0 2 1  
A m e n d m e nt g  
1 0 -N o v e m b er -2 0 2 1  
A m e n d m e nt f  
1 9 -O ct o b er -2 0 2 1  
A m e n d m e nt e  
0 1 -O ct o b er -2 0 2 1  
A m e n d m e nt d  
1 8 -J u n e -2 0 2 1  
A m e n d m e nt c  
0 2 -A pril -2 0 2 1  
A m e n d m e nt b  
0 5 -F e br u ar y -2 0 2 1  
A m e n d m e nt a  
3 0 -D e c e m b er -2 0 2 0  
Ori gi n al Pr ot o c ol  
0 4 -S e pt e m b er -2 0 2 0  
A me n d me nt [i]  
O ver all R ati o n ale f or t he A me n d me nt:  
T his pr ot oc ol was a me n d e d t o all o w f or secti o n s of a n y li ver bi o psies t hat ma y b e perf or me d t o 
be se nt t o Lill y f or f urt her e x pl orat or y hist ol o gical e val uati o n s, i ncl u di n g b ut n ot li mite d t o  t he 
detecti o n of c yt o ki nes, i m m u n o gl o b uli ns , a n d a n y p ote ntial cell ular i nfiltrates . Ele vate d li ver 
e nz y mes ha v e  bee n o bs er ve d i n  s o me partici pa nts d ose d wit h L Y 3 5 0 9 7 5 4.  F urt her a nal ysis of 
t hese sa m ples ma y pr o vi de a d diti o nal mec ha nistic u n dersta n di n g of ele vate d li ver e nz y mes 
f oll o wi n g dr u g disc o nti n uati o n. 
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  
1 0. 1. 9 L o n g -Ter m Sa m pl e 
Rete nti o n  
A d de d Li ver Bi o ps y Secti o ns 
t o ta ble 
T o desi g n ate t he rete nti o n 
peri o d f or a n y li ver bi o ps y 
secti o ns t hat Lill y recei v es 
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 Ass ess me nts  
A d de d te xt all o wi n g f or a 
secti o n of a n y li ver bi o psies 
t hat are perf or m e d t o be se nt 
t o Lill y 
T o all o w f or f urt her a n al ysis  
 
 
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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  ............................................................................................................................1 1  
1. 3.  
Sc he d ule of A cti vities  .....................................................................................................1 2  
1. 3. 1.  
Part A: Si n gle -As ce n di n g D os e, C o h orts 1, 2, 3, 5, a n d 6  ..............................................1 2  
1. 3. 2.  
Part A: Si n gle -As ce n di n g D os e a n d F o o d Effect E val uati o n, 
C o h ort 4 ( 2 -Peri o d Cr oss o ver)  ........................................................................................1 5  
1. 3. 3.  
Part B: Dr u g -Dr u g I nteracti o n wit h C Y P 3 A 4 I n hi biti o n –  Fi x e d 
Se q ue nce  .........................................................................................................................1 9  
1. 3. 4.  
Part C: M ulti ple -Asce n di n g D os e –  C o h orts 1 a n d 3 –  Si n gle 
Peri o d  ..............................................................................................................................2 3  
1. 3. 5.  
Part C: M ulti ple -Asce n di n g D os e a n d Per petrat or D DI –  C o h ort 
2 Fi x e d Se q ue nce  ............................................................................................................2 7  
1. 3. 6.  
Part D: M ulti ple -D ose i n J a pa nese Healt h y Partici pa nts –  Si n gle 
Peri o d  ..............................................................................................................................3 3  
2.  
I ntr o d ucti o n ...................................................................................................................3 8  
2. 1.  
St u d y R ati o nale  ...............................................................................................................3 8  
2. 2.  
Bac k gr o u n d  .....................................................................................................................3 8  
2. 3.  
Be nefit/ Ris k Assess me nt  ................................................................................................3 9  
3.  
O bjecti ves a n d E n d p oi nts  ............................................................................................4 1  
4.  
St u d y Desi g n  ..................................................................................................................4 3  
4. 1.  
O verall Desi g n  ................................................................................................................4 3  
4. 2.  
Scie ntifi c Rati o nale f or St u d y Desi g n  ............................................................................4 3  
4. 2. 1.  
Part A  ( Si n gle-Asce n di n g D os e)  .....................................................................................4 4  
4. 2. 2.  
Part B ( C Y P 3 A 4 I n hi biti o n)  ...........................................................................................4 5  
4. 2. 3.  
Part C ( M ulti ple -Asce n di n g D os e/ C Y P 3 A 4 Per petrat or D DI)  ......................................4 6  
4. 2. 4.  
Part D ( M ulti ple D osi n g i n J a pa nese Healt h y Parti ci pa nts ) ...........................................4 8  
4. 2. 5.  
Rati o nale f or E x cl u di n g Se nti nel D osi n g  .......................................................................4 8  
4. 3.  
J ustificati o n f or D ose ......................................................................................................4 9  
4. 3. 1.  
J ustificati o n f or L Y 3 5 0 9 7 5 4 D ose ..................................................................................4 9  
4. 3. 2.  
J ustificati o n f or Itrac o naz ole D ose .................................................................................5 2  
4. 3. 3.  
J ustificati o n f or Mi daz ola m D ose ...................................................................................5 2  
4. 4.  
E n d of St u d y Defi niti o n  ..................................................................................................5 2  
5.  
S t u d y P o p ul ati o n ...........................................................................................................5 3  
5. 1.  
I n cl usi o n Criteria ............................................................................................................5 3  
5. 2.  
E x cl usi o n Criteria  ...........................................................................................................5 4  
5. 3.  
Lif es t yle C o nsi derati o ns .................................................................................................5 7  
5. 3. 1.  
Meals a n d Dietar y Restri cti o ns  .......................................................................................5 7  
5. 3. 2.  
Caffei ne, Al c o h ol, a n d T o bacc o  .....................................................................................5 8  
5. 3. 3.  
Acti vit y  ...........................................................................................................................5 9  
5. 3. 4.  
I nfecti o n Ris k ..................................................................................................................5 9  
5. 4.  
Scree n Fail ures  ................................................................................................................5 9  
6.  
St u d y I nter ve nti o n  ........................................................................................................6 0  
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5  
6. 1.  
St u d y I nter v e nti o ns A d mi nistere d  ..................................................................................6 0  
6. 2.  
Pre parati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y  ................................................................6 0  
6. 3.  
Meas ures t o Mi ni mize Bias: Ra n d o mizati o n a n d Bli n di n g  ............................................6 1  
6. 4.  
St u d y I nter v e nti o n C o m plia nce  ......................................................................................6 2  
6. 5.  
C o nc o mita nt T hera p y  .....................................................................................................6 2  
6. 6.  
D os e M o dificati o n  ..........................................................................................................6 3  
6. 6. 1.  
D ose Decisi o n/ Escalati o n  ...............................................................................................6 3  
6. 7.  
I nter ve nti o n aft er t he E n d of t he St u d y ...........................................................................6 4  
7.  
Disc o nti n u ati o n or Te m p or ar y H alt 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  ............................................................6 5  
7. 1.  
Disc o nti n uati o n of St u d y I nter ve nti o n or St o p of Ra n d o mizati o n  .................................6 5  
7. 2.  
Partici pa nt Disc o nti n uati o n/ Wit h dra wal fr o m t he St u d y  ................................................6 6  
7. 2. 1.  
Disc o nti n uati o n of I n a d v erte ntl y E nr olle d Partici p a nts  ..................................................6 7  
7. 3.  
L ost t o F oll o w -u p ............................................................................................................6 8  
8.  
St u d y A ssess me nts a n d Pr o ce d ures.............................................................................6 9  
8. 1.  
Efficac y Assess me nts  .....................................................................................................6 9  
8. 2.  
Safet y Assess me nts  .........................................................................................................6 9  
8. 2. 1.  
P h y sical E x a mi nati o ns ....................................................................................................6 9  
8. 2. 2.  
Vital Si g ns  .......................................................................................................................7 0  
8. 2. 3.  
Electr ocar di o gra ms  .........................................................................................................7 0  
8. 2. 4.  
Cli nical Safet y La b orat or y Assess me nts  ........................................................................7 1  
8. 2. 5.  
S uici dal I deati o n a n d Be ha vi or Ris k M o nit ori n g  ...........................................................7 2  
8. 3.  
A d verse E v e nts a n d Seri o us A d verse E v e nts  .................................................................7 2  
8. 3. 1.  
Ti me Peri o d a n d Fre q ue n c y f or C ollecti n g A E a n d S A E 
I nf or mati o n .....................................................................................................................7 2  
8. 3. 2.  
Met h o d of Dete cti n g A Es a n d S A Es  ..............................................................................7 3  
8. 3. 3.  
F oll o w -u p of A Es a n d S A Es  ...........................................................................................7 3  
8. 3. 4.  
Re g ulat or y Re p orti n g Re q uire me nts f or S A Es  ...............................................................7 3  
8. 3. 5.  
Pre g n a nc y  ........................................................................................................................7 3  
8. 3. 6.  
Pr o d uct C o m plai nts  .........................................................................................................7 3  
8. 4.  
Treat me nt of O v er d ose  ...................................................................................................7 4  
8. 5.  
P har mac o ki netics  ............................................................................................................7 5  
8. 6.  
P har mac o d y na mics  .........................................................................................................7 6  
8. 7.  
Ge netics  ..........................................................................................................................7 6  
8. 8.  
Bi o mar kers  ......................................................................................................................7 6  
8. 9.  
I m m u n o ge nicit y Assess me nts.........................................................................................7 6  
8. 1 0.  
Healt h Ec o n o mics  ...........................................................................................................7 6  
9.  
St atistic al C o nsi der ati o ns  .............................................................................................7 7  
9. 1.  
Sa m ple Siz e Deter mi nati o n  ............................................................................................7 7  
9. 2.  
P o p ulati o ns f or A nal ys es  ................................................................................................7 7  
9. 2. 1.  
St u d y Partici pa nt Dis p ositi o n  .........................................................................................7 7  
9. 2. 2.  
St u d y S u bje ct C haracteristics  .........................................................................................7 7  
9. 2. 3.  
Treat me nt C o m plia nce  ....................................................................................................7 7  
9. 3.  
S tatistical A nal yses .........................................................................................................7 7  
9. 3. 1.  
Safet y A nal yses  ...............................................................................................................7 8  
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9. 3. 2.  
P har mac o ki netic A n al ys es  ..............................................................................................7 8  
9. 3. 3.  
P har mac o d y na mic A n al yses  ...........................................................................................8 0  
9. 3. 4.  
P har mac o ki netic/ P har mac o d y n a mic A nal yses  ...............................................................8 0  
9. 3. 5.  
I nteri m Access t o Data (I A D) .........................................................................................8 0  
9. 4.  
I nteri m A nal yses .............................................................................................................8 0  
9. 5.  
Data M o nit ori n g C o m mittee ( D M C)  ..............................................................................8 0  
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  ..................................8 1  
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  ................................................................................................................8 1  
1 0. 1. 1.  Re g ulat or y a n d Et hical  C o nsi derati o ns  ...........................................................................8 1  
1 0. 1. 2.  I nf or me d C o nse nt Pr ocess ..............................................................................................8 1  
1 0. 1. 3.  Data Pr otecti o n ................................................................................................................8 2  
1 0. 1. 4.  Disse mi nati o n of Cli nical St u d y Data .............................................................................8 2  
1 0. 1. 5.  Data Q ualit y Ass ura nce  ..................................................................................................8 3  
1 0. 1. 6.  S o urce D oc u m e nts  ..........................................................................................................8 4  
1 0. 1. 7.  St u d y a n d Site Start a n d Cl os ure  ....................................................................................8 5  
1 0. 1. 8.  P u blicati o n P olic y  ...........................................................................................................8 6  
1 0. 1. 9 . L o n g -T er m Sa m ple Rete nti o n .........................................................................................8 6  
1 0. 2.  
A p pe n di x 2: Cli nical La b orat or y Tests  ...........................................................................8 7  
1 0. 2. 1.  Bl o o d Sa m pli n g S u m mar y  ..............................................................................................9 0  
1 0 . 3. 
A p pe n di x 3: A d verse E v e nts: Defi niti o ns a n d Pr oce d ures f or 
Rec or di n g, E val uati n g, F oll o w -u p, a n d Re p orti n g  .........................................................9 5  
1 0. 3. 1.  Defi niti o n  of A E  .............................................................................................................9 5  
1 0. 3. 2.  Defi niti o n of S A E  ...........................................................................................................9 6  
1 0. 3. 3.  Re p orti n g of S A Es  ..........................................................................................................9 7  
1 0. 3. 4.  Rec or di n g a n d F oll o w -U p of A E a n d/ or S A E  ................................................................9 8  
1 0. 4.  
A p pe n di x 4: C o ntrace pti ve G ui da nce a n d C ollecti o n of 
Pre g n a nc y I nf or mati o n  ...................................................................................................9 9  
1 0. 5.  
A p pe n di x 5: Ge netics ....................................................................................................1 0 3  
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  ..................................................................................................................1 0 4  
1 0. 7.  
A p pe n di x 9: A b br e viati o ns  ...........................................................................................1 0 8  
1 0. 8.  
A p pe n di x 1 0: Pr ot oc ol A me n d me nt Hist or y  ................................................................1 1 2  
1 1.  
Refere nces  ....................................................................................................................1 3 4  
 
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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 P has e 1, Ra n d o mize d, Partici pa nt -a n d I n vesti gat or -B li n d, Place b o-C o ntr olle d, 
Si n gle - an d M ulti ple -As ce n di n g  D os e,  Dr u g -Dr u g I nteracti o n  an d F o o d Effect St u d y t o E val uat e 
t he Safet y, T olera bilit y, a n d P har mac o ki netics of L Y 3 5 0 9 7 5 4 i n Healt h y N o n -J a pa nese a n d 
J a pa nese Partici pa nts  
S h ort Title:  A P hase 1, Ra n d o mize d, Partici pa nt -a n d I n vesti gat or -Bli n d , Place b o-C o ntr olle d, 
Si n gle - an d M ulti ple -As ce n di n g  D os e,  Dr u g -Dr u g I nteracti o n an d F o o d Effect St u d y t o E val uat e 
t he Safet y, T olera bilit y, a n d P har mac o ki netics of L Y 3 5 0 9 7 5 4 i n Healt h y Partici pa nts  
R ati o n ale:  L Y 3 5 0 9 7 5 4 is a n oral s mall m olec ule i n hi bit or f or I L -1 7 A t hat is bei n g de v el o pe d 
f or o nce-dail y treat me nt of ps oriasis ( Ps O) a n d ot her i m m u ne -me diate d dis eases . 
I L-1 7 A is a cli nic all y v ali date d c yt o ki ne i n v ol ve d i n t he e x acer ba ti o n of Ps O, ps oriatic art hritis 
( Ps A), a n k yl osi n g s p o n d ylitis ( A x S pa), a n d relate d a ut oi m m u ne dis or ders. 
L Y 3 5 0 9 7 5 4 h as n ot bee n a d mi nistere d t o h u ma ns.  T his first -i n-h u ma n st u d y will i n vesti gate t he 
safet y, t olera bilit y, a n d p har mac o ki netics ( P K) of si n gl e a n d m ulti ple d oses of L Y 3 5 0 9 7 5 4 i n 
healt h y p artici pa nts (i ncl u di n g J a pa nese h ealt h y p artici pa nts) i n a c o m bi ne d si n gle -asce n di n g 
d ose ( S A D) a n d m ulti ple -asce n di n g d os e ( M A D) desi g n. T h e st u d y will als o e val uate t he effect 
of f o o d o n t he P K of L Y 3 5 0 9 7 5 4.   L Y 3 5 0 9 7 5 4 has t he p ote ntial f or c yt o c hr o me P 4 5 0 3 A 4 
( C Y P 3 A 4) dr u g-dr u g i nt eracti o ns ( D DI). As s uc h, t he st u d y will i n vesti gate t he i m pact of 
L Y 3 5 0 9 7 5 4 as a s u bstrat e a n d as a n i n d u cer of C Y P 3 A 4.  T he data ge nerate d i n t his st u d y will be 
use d t o hel p desi g n  s u bs e q ue nt cli nical st u dies. 
O bjecti ves a n d E n d p oi nts  
O bjecti ves  
E n d p oi nts  
Pri m ar y  
 
 T he pri mar y o bje cti ve is t o assess t he 
safet y a n d t olera bilit y f oll o wi n g si n gle 
or m ulti ple d oses of L Y 3 5 0 9 7 5 4 
a d mi nistere d t o healt h y p artici pa nts  
 I n ci de nce of seri o us a d verse e ve nts 
(S A Es ) a n d treat me nt-e m er ge nt 
a d verse e ve nts ( T E A Es ) 
Sec o n d ar y  
 
 T he sec o n d ar y o bjecti ve is t o 
c haracteriz e t he P K f oll o wi n g si n gle 
or m ulti ple orall y a d mi nistere d d oses 
of L Y 3 5 0 9 7 5 4 i n healt h y partici pa nts  
 Ma xi m u m o bser ve d dr u g 
c o nce ntr ati o n ( C ma x ) a n d area u n d er 
t he c o nce ntr ati o n vers us ti me c ur ve 
( A U C) of L Y 3 5 0 9 7 5 4  
 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
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8  
O ver all Desi g n  
St u d y J 3 D-M C -F N A A  is a P hase 1, m ulti -ce nter st u d y i n healt h y partici pa nts  t o be c o n d ucte d i n 
4  parts:  
 Part A  ( S A D): Part A will be a partici pa nt - a n d i n vesti gat or -bli n d, place b o -c o ntr olle d, 
ra n d o mize d, S A D  st u d y t o e val uate t he s afet y, t olera bilit y, a n d P K of L Y3 5 0 9 7 5 4  i n 
healt h y p artici pa nts  i n u p t o 6 c o h orts. O ne c o h ort ( C o h ort 4) will i ncl u de a ra n d o mize d, 
si n gle-d o s e le vel, 2 peri o d cr oss o ver f o o d effect e val uati o n i n partici pa nts a d mi nistere d 
L Y 3 5 0 9 7 5 4 f oll o wi n g fasti n g a n d a hi g h fat meal ( peri o ds 1 a n d 2, res pecti vel y).  
 Part B  (D DI  –  C Y P 3 A 4  victi m):  Part B will be a  partici pa nt - a n d i n v esti gat or -bli n d , 
place b o -c o ntr olle d, si n gl e-d ose -le vel, si n gl e-ar m, dr u g -dr u g i nteracti o n ( D DI) st u d y t o 
e val uate t he m ulti ple d os e i m pact of t he C Y P 3 A 4 i n hi bit or , itrac o naz ole, o n t he si n gle 
d ose e x p os ure of L Y 3 5 0 9 7 5 4 . 
 Part C ( M A D): Part C  will be a partici pa nt - a n d i n vesti gat or -bli n d, place b o -c o ntr olle d,  
ra n d o mize d, 1 4-da y , si n gle-peri o d  M A D  st u d y wit h u p t o 3  c o h orts t o e val u ate t he safet y, 
t olera bilit y, a n d P K of L Y 3 5 0 9 7 5 4  i n healt h y p artici pa nts. O ne  c o h ort ( C o h ort 2) will 
i ncl u de a fi x e d se q ue nce, per p etr at or D DI e val uati o n t o u n dersta n d t he i m pact of 
L Y 3 5 0 9 7 5 4 (a d mi nistere d as m ulti ple d oses t o stea d y stat e) o n mi daz ola m P K . 
 Part D (J a pa nese partici pa nts ): Part D  will be a partici pa nt - a n d i n vesti gat or -bli n d, 
place b o -c o ntr olle d, ra n d o mize d, m ulti ple d ose st u d y t o e val uate t he safet y, t olera bilit y, 
a n d P K of L Y 3 5 0 9 7 5 4 i n healt h y J a pa nes e partici pa nts  i n 2 d ose le vels i n 2 se parat e  
c o h orts ( 1 d ose le v el per c o h ort). T he 2 d os e le vels will be c o n d ucte d c o n c urre ntl y . 
Discl os ure St ate me nt : T his is a P hase 1, ra n d o mize d, partici pa nt -a n d i n vesti gat or -bli n d , 
p lace b o-co ntr olle d, si n gl e- a n d m ulti ple -asce n di n g d ose, D DI  st u d y t o eval uate t he safet y, 
tolera bilit y , a n d P K  of L Y 3 5 0 9 7 5 4 i n h ealt h y n o n -J a pa nese a n d J a pa nes e p artici pa nts . 
N u m ber of P artici p a nt s: 
A p pr o xi matel y 1 0 5  p arti ci pa nts will be re q uire d t o c o m plete t his st u d y, w hic h i ncl u des t he 
4  parts bel o w.  
 P art A  ( S A D): Partici pa nt s will be  ra n d o ml y assi g ne d/ e nr olle d i nt o u p  t o 6  c o h orts wit h 
u p t o 5 1 partici pa nts c o m pleti n g t his part of t he st u d y. C o h orts 1 , 2, 3, a n d 5  will u n der g o 
t he d ose escalati o n wit h 6 L Y 3 5 0 9 7 5 4 : 2 place b o  partici pa nts c o m pleti n g t his part of t he 
st u d y. C o h ort 4 will ha ve a t otal of 1 1 partici pa nts  c o m pleti n g a 2 -peri o d  cr oss o ver wit h 
9  L Y 3 5 0 9 7 5 4: 2  pla ce b o  per peri o d . C o h ort 6  will ha ve u p t o 8 partici pa nts c o m pleti n g 
t his part of t he st u d y. T his c o h ort ma y be use d f or a d diti o nal safet y, t olera bilit y, P K , a n d 
f o o d effect e v al uati o n as dee me d necessar y b y t he s p o ns or a n d i n disc ussi o n wit h t he 
i n vesti gat or f oll o wi n g re vie w of e mer gi n g s afet y, t olera bilit y, a n d P K dat a fr o m 
C o h orts  1 t hr o u g h  5 . 
 P art B  (D DI –  C Y P 3 A 4  victi m) : P artici p a nts  will be ra n d o ml y assi g n e d/e nr olle d wit h 
u p t o 1 2 partici pa nts  (9 L Y 3 5 0 9 7 5 4 : 3 place b o) c o m plet i n g t his part of t he st u d y. 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

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9  
 P art C  ( M A D): Partici p a nts will be ra n d o ml y assi g ne d/e nr olle d i nt o u p t o 4 c o h orts wit h 
u p t o 2 6 partici pa nts c o m pleti n g t his part of t he st u d y. I n 1 c o h ort, a p er petrat or D DI 
e val uati o n will be c o n d u cte d.  C o h orts  1  a n d 3 will u n der g o t he d ose es calati o n wit h 6 
L Y 3 5 0 9 7 5 4: 2  pla ce b o  partici pa nts c o m pleti n g t his part of t he st u d y . C o h ort  2  will ha ve a 
t otal of 10  partici pa nts c o m pleti n g t he fi x e d se q ue nce D DI a n d d ose escal ati o n e val uati o n 
wit h 8 L Y 3 5 0 9 7 5 4: 2 pla ce b o partici p a nts . 
 P art D  (J a p a nese p artici p a nts ): Partici pa nts will be ra n d o ml y assi g ne d/e nr olle d i nt o u p 
t o 2 c o h orts wit h at least 1 6 partici pa nts c o m pleti n g t his part of t he st u d y . A t least 
8  partici pa nts [ 6 L Y 3 5 0 9 7 5 4: 2 place b o] are c o m pleti n g eac h d ose l e vel.  
I nter ve nti o n Gr o u ps  a n d D ur ati o n : 
St u d y J 3 D -M C -F N A A will be c o n d ucte d i n  4  parts. Partici pa nts will be scree ne d wit hi n 2 8  da ys  
pri or t o Da y 1 of d osi n g f or eac h gr o u p.  
T he pla n ne d  st u d y i nter ve nti o ns will be a d mi nistere d orall y f or t he 4  parts as f oll o ws : 
 Part A  ( S A D): 
o  C o h ort 1: 1 0 m g  
o  C o h ort 2: 3 0  m g  
o  C o h ort 3:  1 0 0 m g  
o  C o h ort 4:  3 0 0 m g  
▪ Peri o d 1 C o h ort 4 : 3 0 0 m g faste d c o n diti o ns  
▪ Peri o d 2 C o h ort 4: 3 0 0 m g fe d c o n diti o ns  
o  C o h ort 5:  1 0 0 0 m g  
o  C o h ort 6: 2 0 0 0 m g  
 Part B ( D DI –  C Y P 3 A 4 victi m):  
o  1 0  m g of L Y 3 5 0 9 7 5 4 o n Da y s 1 a n d 1 0 ; a n d 2 0 0 m g itrac o n az ole  o n Da ys  4  
t hr o u g h 1 3 . 
 Part C ( M A D): 
o  C o h ort 1:  1 0 0 m g/ o nce d ail y ( Q D ) ×  1 4 d a ys  
o  C o h ort 2 : Fi x e d se q ue nce  
▪ Si n gle 1. 2 -m g m i daz ola m d ose  foll o we d b y  
▪ 3 0 0 L Y 3 5 0 9 7 5 4 m g/ Q D × 1 4 da ys  foll o we d b y  
▪ S i n gle 1. 2 -m g mi daz ola m  d ose  a n d si n gle 3 0 0 -m g  d ose of  L Y 3 5 0 9 7 5 4 o n 
Da y 1 5  
o  C o h ort 3: 1 0 0 0 m g/ Q D x 1 4 da ys  
 Part D (J a pa nese partici pa nts): 
o  C o h orts 1 a n d 2:  O nce  dail y × 1 4 da ys. D ose le vel 1 will be  4 0 0 m g  L Y 3 5 0 9 7 5 4 ; 
d ose le vel 2 will be 1 0 0 0  m g L Y 3 5 0 9 7 5 4  (t h e ma xi m u m d ose e val uate d i n Part 
C) . 
 
 
 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A (i)  
 
1 0  
St atistic al A n al ysis:  
S afet y:  
Safet y p ara meters t o be assesse d i ncl u de a d v erse e ve nts  ( A Es), cli nical la b orat or y para meters, 
vital si g ns, a n d ele ctr ocar di o gra m ( 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 pti ve statistics. A d diti o nal a nal ysis will be perf or me d if 
war ra nte d u p o n re vie w of t he data. 
P h ar m a c o ki netic:  
T he pri mar y plas ma p h ar mac o ki netic ( P K ) p ara m eters t o be det er mi ne d f or L Y 3 5 0 9 7 5 4 base d 
o n sta n dar d n o nc o m part me ntal a nal ysis are C ma x , ti me t o ma xi m u m c o nce ntrati o n (tma x ), A U C, 
ter mi nal eli mi nati o n half-life (t1/ 2 ), a p pare nt cleara nce ( C L/ F), a n d a p pare nt v ol u me of 
distri b uti o n ( V/ F) after si n gle - a n d m ulti ple-d ose a d mi nistrati o n. A d diti o nall y, P K para meters of 
L Y 3 5 0 9 7 5 4 will be c o m pare d w h e n a d mi nistere d al o ne vers us i n t he pre se nce of itrac o naz ole 
wit h a hi g h -fat meal v ers us i n a faste d state, a n d b et wee n J a pa nes e a n d n o n-J a pa nese 
partici pa nts. T he C ma x  a n d A U C of mi daz ola m a n d its h y dr o x ylate d met a b olite will be assesse d 
after a d mi nistrati o n of mi daz ola m al o ne a n d c o nc o mita ntl y wit h L Y 3 5 0 9 7 5 4 . 
D at a M o nit ori n g C o m mittee: N o  
 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A (i)  
 
1 1  
1. 2.  
Sc he m a  
 
 
 
 
A b bre viati o ns: D DI = dr u g -dr u g i nteracti o n; H V = healt h y v ol u nteers; L Y  = L Y 3 5 0 9 7 5 4; M A D = m ulti ple -
asce n di n g d ose ; P B O =  place b o ; P K = p har mac o ki netics ; Q D = o nce dail y; S A D = si n gle -asce n di n g d ose; T B D 
= t o be deter mi ne d.  
Sc he ma d oes n ot re prese nt start or e n d ti mes of eac h st u d y part.  
a P art B will be gi n after e mer gi n g safet y, t olera bilit y, a n d P K data fr o m P art A has bee n re vi e we d.  
b  Fi xe d se q ue nce c o h o rt wit h 3 d osi n g e ve nts. In t he first d osi n g e ve nt,  all 1 0 partici pa nts recei v e mi daz ola m . I n 
t he sec o n d d osi n g e ve nt, L Y3 5 0 9 7 5 4  or place b o ( 8 L Y 3 5 0 9 7 5 4 ; 2 place b o) will be a d mi nistere d o nce dail y f or 
1 4 da ys . I n t he t hir d d osi n g e ve nt, b ot h L Y 3 5 0 9 7 5 4  a n d mi d az ola m  will be a d mi nistere d o n Da y 1 5 .  
c C o h orts t o r u n c o nc urre ntl y. At least 1 2 partici pa nts m ust c o m plete P art D of t he st u d y.  
d  D ose le vel selecte d base d o n t he res ults i n t he ot her parts of t he st u d y.  
 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
1 2  
1. 3.  
Sc he d ule of Acti vities  
1. 3. 1.  
P a rt A: Si n gle -Asce n di n g D ose, C o h orts 1, 2, 3, 5, a n d 6  
Pr o ce d ure  
Scree ni
n g  
 
Tre at me nt Peri o d  
E D  
F oll o w -u p e 
C o m me nts  
St u d y D a y  
-2 8 t o -
3  
-2  
-1  
1  
2  
3  
4  
5  
 
At le ast 
7  d a ys after 
disc h ar ge  
 
I nf or me d c o nse nt 
X  
 
 
 
 
 
 
 
 
 
 
A d missi o n t o C R U  
 
X  
 
 
 
 
 
 
 
 
 
Disc har ge fr o m 
C R U  
 
 
 
 
 
 
 
X  
 
 
 
P E/ M A a 
X  
X  
 
P  
 
 
 
X  
X  
X  
F ull P E/ M A at scree ni n g a n d pri or t o fi nal  
disc har ge fr o m t he st u d y. S y m pt o m -directe d 
P E/ M A at all ot her ti me p oi nts a n d as dee me d 
necessar y b y t he i n vesti gat or.  
C O VI D -1 9 test 
( P C R) 
X  
X  
 
 
 
 
 
X  
X  
X  
 
Pre g na nc y test  
X  
X  
 
 
 
 
 
 
X  
X  
Ser u m test at scree ni n g . Uri ne test at all 
ot her  ti me p oi nts.  
Uri ne dr u g scree n  
X  
X  
 
 
 
 
 
 
 
 
 
Breat h or uri ne 
et ha n ol test  
X  
X  
 
 
 
 
 
 
 
 
Et ha n ol test ma y be re p eate d at ot her ti me 
p oi nts at t he discreti o n of t he i n vesti gat or. 
Q ua nti F E R O N ® -T B 
G ol d test  
X  
 
 
 
 
 
 
 
 
 
 
A E/ me dicati o n 
re vie w 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Hei g ht/ wei g ht  
X  
 
 
 
 
 
 
 
X  
X  
Hei g ht at scree ni n g o nl y.  
L Y 3 5 0 9 7 5 4/ Place b o 
a d mi nistrati o n  
 
 
 
X  
 
 
 
 
 
 
P artici pa nts will fast o ver ni g ht b ef ore recei vi n g 
L Y 3 5 0 9 7 5 4/ place b o a n d f or a p pr o xi matel y 
2  h o urs after d osi n g. O n i nte nsi ve P K da ys, 
partici pa nts ma y recei ve a li g ht brea kfast 
a p pr o xi matel y 2  h o urs after d osi n g 
L Y 3 5 0 9 7 5 4/ place b o . 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
1 3  
Pr o ce d ure  
Scree ni
n g  
 
Tre at me nt Peri o d  
E D  
F oll o w -u p e 
C o m me nts  
St u d y D a y  
-2 8 t o -
3  
-2  
-1  
1  
2  
3  
4  
5  
 
At le ast 
7  d a ys after 
disc h ar ge  
 
Vital si g ns ( B P, P R 
[s u pi ne], 
te m perat ure) 
( h o urs)a 
X  
X  
 
P, 2, 4, 8, 
1 2  
2 4, 
3 6  
4 8  
7 2  
9 6  
X  
X  
Ti me p oi nts ma y be a d de d, if cli nicall y 
i n dicate d.  
O n Da y 1, te m perat ure will be meas ure d at 
pre d ose o nl y. O n Da y 2, te m p erat ure will be 
meas ure d at 2 4 h o urs o nl y.  
Cli nical la b orat or y 
testsb  
X  
X  
 
 
 
 
 
X  
X  
X  
 
1 2 -lea d E C G 
( h o urs)a,c 
X  
 
 
P, 0. 5, 1, 
2, 3, 4, 5, 
6, 8, 1 2  
2 4, 
3 6  
4 8  
7 2  
9 6  
X  
X  
 
P K sa m pli n g 
( h o urs)a 
 
 
 
P, 0. 5, 1, 
2, 3, 4, 5, 
6, 8, 1 2, 
1 6  
2 4, 
3 6  
4 8  
7 2  
9 6  
 
 
Sa m pli n g ti mes are relati ve t o t he ti me of st u d y 
treat me nt a d mi nistrati o n ( 0 h o ur).  
E x pl orat or y bl o o d 
sa m pli n g ( h o urs)a, d  
 
 
 
P, 1, 4, 1 2  
2 4, 
3 6  
4 8  
7 2  
9 6  
 
X f 
St ore d sa m ple f or bi o mar ker researc h. 
Sa m pli n g ti mes are relati ve t o t he ti me of st u d y 
treat me nt a d mi nistrati o n ( 0 h o ur). 
E x pl orat or y b uccal 
s wa bs a n d sali va 
sa m ples ( h o urs)a 
 
 
 
P, 8  
2 4  
 
7 2  
 
 
 
St ore d sa m ple f or bi o mar ker researc h. 
Sa m pli n g ti mes are relati ve t o t he ti me of st u d y 
treat me nt a d mi nistrati o n ( 0 h o ur). Sali va o nl y 
at 7 2  h c ollecti o n  ( C o h ort 6 o nl y). 
P G x sa m ple  
 
 
 
P  
 
 
 
 
 
 
F or st ora ge o nl y. Sa m ple ca n be ta ke n a n y ti me 
pri or t o d osi n g . 
Uri ne c ollecti o n 
( h o urs) 
 
 
 
0 -1 2  
1 2 -2 4  
 
 
 
 
 
 
Uri ne c ollecti o n ti me ma y start 2 0 mi n utes 
pri or t o act ual d osi n g ti me o n Da y 1 a n d 
fi nis hes wit hi n ± 3 0 mi n utes of t he 2 4 -h o ur ti me 
p oi nt.  
Ser u m creati ni ne  
 
 
 
P  
 
 
 
 
 
 
Sa m ple ca n be ta ke n a n y ti me pri or t o d osi n g i n 
P eri o d 1. Se nt t o Ce ntral La b orat or y.  
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
1 4  
A b bre viati o ns : A E = a d verse e ve nt; B P  =  bl o o d press ure; C R U = cli nical researc h  u nit; E C G  =  electr ocar di o gra m; E D = earl y disc o nti n uati o n; M A = me dical 
assess me nt; P = p re d ose; P C R = p ol y merase c hai n reacti o n ; P E = p h ysical e xa mi nati o n; P G x  =  p har mac o ge netic; P K  =  p har mac o ki netic; P R  = p ulse rate.  
N ote: Site s h o ul d sc he d ule acti vities as a p pr o priate. I n cases w here se veral st u d y pr oce d ures are sc he d ule d at t he sa me ti me,  f oll o w t his or der of pri orit y f or 
pr oce d ures: E C G, vital si g ns, P K sa m ples, cli nical la b orat or y tests, uri ne sa m ples, bi o mar kers, a n d st ora ge sa m ples.  
A d diti o nal dr u gs are t o be a v oi de d d uri n g t he st u d y u nless re q uire d t o treat a n A E or f or t he treat me nt of a n o n g oi n g me dical pr o ble m.  
If t he nee d f or c o nc o mita nt me dicati o n arises, i ncl usi o n or c o nti n uati o n of t he partici pa nt ma y be at t he discreti o n of t he i n vesti gat or after c o ns ultati o n wit h Lill y 
cli nical p har mac ol o gist. A n y a d diti o nal me dicati o n use d d u ri n g t he c o urse of t he st u d y m ust be d oc u me nte d. 
a Vital si g n meas ure me nts, P E/ M A, E C Gs, ma y be c ollecte d wit hi n ti me wi n d o ws de pe n di n g o n t he c ollecti o n ti me, as f oll o ws: Pre d ose ( wit hi n 2 h o ur bef ore 
d osi n g); 0. 5 h ( ± 1 0 mi n); 1 t o 4 h o urs ( ± 1 5 mi n); 5 t o 8 h o urs ( ± 2 0 mi n); 1 2 h o urs ( ± 3 0 mi n); 2 4 h o urs a n d l o n ger  ( ± 6 0 mi n). Bl o o d sa m ples c ollecte d f or P K, 
P D, or bi o mar ker p ur p oses ma y be c ollecte d wit hi n ti me wi n d o ws de pe n di n g o n t he c ollecti o n ti me, as f oll o ws: Pre d ose ( wit hi n 1 h o ur bef ore d osi n g); 0. 5  h 
( ± 5 mi n); 1 t o 4 h o urs ( ± 1 0 mi n); 5  t o 8 h o urs ( ± 1 5 mi n); 1 2 h o urs ( ± 3 0 mi n); 2 4 h o urs a n d l o n ger  ( ± 6 0 mi n). 
b  See Secti o n 1 0. 2  f or details. T he p ri nci pal i n vesti gat or m ust re vie w t he Da y -2 la b orat or y res ults bef ore d osi n g o n Da y 1.  
c Electr ocar di o gra ms o n Da y 1 will b e tri plicate f or t he first 5  h o urs a n d si n gle f or all ot her ti me p oi nts.  
d  Sa m ples ma y be f urt her pr ocesse d f or ser u m or plas ma. See  la b orat or y ma n ual f or f urt her details. 
e A d diti o nal  f oll o w-u p visits ma y be c o n d ucte d f or safet y la bs a n d m o nit ori n g after t he e xisti n g f oll o w -u p visit t hat is at l east 7 da ys after disc har ge. E ver y 
atte m pt s h o ul d be ma d e t o c o ntact s u bj ects f or t he f oll o w -u p visits; h o we ver, if s u bj ects are u n willi n g or u na ble t o ret ur n f or t he  a d diti o nal  visit s, t his is n ot 
c o nsi dere d a pr ot oc ol vi olati o n.  
f Plas ma sa m ples s h o ul d be c ollecte d f or  e x pl orat or y a nal ys es  at a d diti o nal f oll o w -u p visits ; h o we ver, if s u bj ects a re u n willi n g or u na ble t o ret ur n t o c oll ect t his 
sa m ple, t his is n ot c o nsi dere d a pr ot oc ol vi olati o n.  
 
 
 
 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

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J 3 D -M C -F N A A( i) 
 
1 5  
1. 3. 2.  
P a rt A: Si n gle -Asce n di n g D ose a n d F o o d Effect E v al u ati o n , C o h ort  4 (2 -P eri o d Cr oss o ver ) 
Pr o ce d ure  
Scree n
i n g 
 
Tre at me nt Peri o d 1 
( F aste d)  
Tre at me nt Peri o d 2 ( Fe d)  
E D  
F oll o w -
u p f 
C o m me nts  
St u d y D a y  
-2 8 t o 
-3  
-2  
-1  
1  
2  
3  
4  
5  
1  
2  
3  
4  
5  
 
At le ast 
7  d a ys 
after 
disc h ar ge  
 
I nf or me d c o nse nt 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A d missi o n t o C R U  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disc har ge fr o m C R U  
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
P E/ M A a 
X  
X  
 
P  
 
 
 
X  
P  
 
 
 
X  
X  
X  
F ull P E/ M A at scree ni n g a n d 
pri or t o fi nal disc har ge fr o m 
t he st u d y. S y m pt o m-directe d 
P E/ M A at all ot her ti me 
p oi nts a n d as dee me d 
necessar y b y t he i n vesti gat or.  
C O VI D -1 9 test 
( P C R) 
X  
X  
 
 
 
 
 
 
 
 
 
 
X  
X  
X  
 
Pre g na nc y test  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
X  
X  
Ser u m test at scree ni n g. 
U ri ne test at all ot her ti me 
p oi nts.  
Uri ne dr u g scree n  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Breat h or uri ne 
et ha n ol test  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Et ha n ol test ma y be re p eate d 
at ot her ti me p oi nts at t he 
discreti o n of t he i n vesti gat or . 
Q ua nti F E R O N ® -T B 
G ol d test  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A E/ me dicati o n 
re vie w 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Hei g ht/ wei g ht  
X  
 
 
 
 
 
 
 
 
 
 
 
 
X  
X  
Hei g ht at scree ni n g o nl y.  
L Y 3 5 0 9 7 5 4/ Place b o 
a d mi nistrati o n 
( h o urs)b   
 
 
 
X  
 
 
 
 
X  
 
 
 
 
 
 
 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
1 6  
Pr o ce d ure  
Scree n
i n g 
 
Tre at me nt Peri o d 1 
( F aste d)  
Tre at me nt Peri o d 2 ( Fe d)  
E D  
F oll o w -
u p f 
C o m me nts  
St u d y D a y  
-2 8 t o 
-3  
-2  
-1  
1  
2  
3  
4  
5  
1  
2  
3  
4  
5  
 
At le ast 
7  d a ys 
after 
disc h ar ge  
 
Vital si g ns ( B P, P R 
[s u pi ne], 
te m perat ure) ( h o urs) 
a 
X  
X  
 
P, 2, 
4, 8, 
1 2  
2 4, 
3 6  
4 8  
7 2  
9 6  
 
P, 2, 
4, 8, 
1 2  
 
 
 
2 4, 
3 6  
 
 
4 8  
7 2  
9 6  
X  
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 
cli nicall y i n dicate d.  
F or eac h peri o d, o n Da y 1, 
te m perat ure will be meas ure d 
at pre d ose o nl y. F or eac h 
peri o d, o n Da y  2, 
te m perat ure will be meas ure d 
at 2 4 h o urs o nl y.  
Cli nical la b orat or y 
testsc 
X  
X  
 
 
 
 
 
X  
 
 
 
 
X  
X  
X  
 
1 2 -lea d E C G 
( h o urs)a, d 
X  
 
 
P, 
0. 5, 
1, 2, 
3, 4, 
5, 6, 
8, 1 2  
2 4, 
3 6  
4 8  
7 2  
9 6  
P, 
0. 5, 
1, 2, 
3, 4, 
5, 6, 
8, 1 2  
2 4, 
3 6  
4 8  
7 2  
9 6  
X  
X  
 
P K sa m pli n g ( h o urs) a 
 
 
 
P, 
0. 5, 
1, 2, 
3, 4, 
5, 6,  
8, 
1 2, 
1 6  
2 4, 
3 6  
4 8  
7 2  
9 6  
P, 
0. 5, 
1, 2, 
3, 4, 
5, 6, 
8, 
1 2, 
1 6  
2 4, 
3 6  
4 8  
7 2  
9 6  
 
 
Sa m pli n g ti mes are relati ve 
t o t he ti me of st u d y treat me nt 
a d mi nistrati o n ( 0  h o ur). P K 
sa m pli n g will occ ur f or b ot h 
P eri o d 1 a n d P eri o d 2.  
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
1 7  
Pr o ce d ure  
Scree n
i n g 
 
Tre at me nt Peri o d 1 
( F aste d)  
Tre at me nt Peri o d 2 ( Fe d)  
E D  
F oll o w -
u p f 
C o m me nts  
St u d y D a y  
-2 8 t o 
-3  
-2  
-1  
1  
2  
3  
4  
5  
1  
2  
3  
4  
5  
 
At le ast 
7  d a ys 
after 
disc h ar ge  
 
E x pl orat or y bl o o d 
sa m pli n g ( h o urs)a,e 
 
 
 
P, 1, 
4, 1 2  
2 4, 
3 6  
4 8  
7 2  
9 6  
 
 
 
 
 
 
X g 
D o n ot c ollect f or P eri o d 2 of 
C o h ort 4. St ore d sa m ple f or 
bi o mar ker researc h. 
Sa m pli n g ti mes are relati ve 
t o t he ti me of st u d y treat me nt 
a d mi nistrati o n ( 0  h o ur).  
E x pl orat or y b uccal 
s wa bs a n d sali va 
sa m ples ( h o urs)a 
 
 
 
P, 8  
2 4  
 
 
 
 
 
 
 
 
 
 
P eri o d 1 o nl y. St ore d sa m ple 
f or bi o mar ker researc h. 
Sa m pli n g ti mes are relati ve 
t o t he ti me of st u d y treat me nt 
a d mi nistrati o n ( 0  h o ur).  
P G x sa m ple  
 
 
 
P  
 
 
 
 
 
 
 
 
 
 
 
F or st ora ge o nl y. Sa m ple ca n 
be ta ke n a n y ti me pri or t o 
d osi n g i n P eri o d  1.  
Uri ne c ollecti o n 
( h o urs) 
 
 
 
0 -1 2  
1 2 -
2 4  
 
 
 
 
 
 
 
 
 
 
 
D o n ot c ollect f or P eri o d 2 of 
C o h ort 4. Uri ne c ollecti o n 
ti me ma y start 2 0 mi n utes 
pri or t o act ual d osi n g ti me o n 
Da y 1 a n d fi nis hes wit hi n 
± 3 0  mi n utes of t he 2 4 -h o ur 
ti me p oi nt. 
Ser u m creati ni ne  
 
 
 
P  
 
 
 
 
 
 
 
 
 
 
 
Sa m ple ca n be ta ke n a n y 
ti me pri or t o d osi n g i n 
P eri o d  1. Se nt t o Ce ntral 
La b orat or y.  
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
1 8  
A b bre viati o ns: A E = a d verse e ve nt; B P  =  bl o o d press ure; C R U = cli nical researc h  u nit; E C G  =  electr ocar di o gra m; E D = earl y disc o nti n uati o n; M A = me dical 
assess me nt; P = pre d ose; P C R = p ol y merase c hai n reacti o n; P E = p h ysical e xa mi nati o n; P G x  =  p har mac o ge net ic; P K =  p har mac o ki netic; P R  = p ulse rate.  
N ote: Site s h o ul d sc he d ule acti vities as a p pr o priate. I n cases w here se veral st u d y pr oce d ures are sc he d ule d at t he sa me ti me,  f oll o w t his or der of pri orit y f or 
pr oce d ures: E C G, vital si g ns, P K sa m ples, cli nical la b orat or y tests, uri ne sa m ples, bi o mar kers, a n d st ora ge sa m ples.  
A d diti o nal dr u gs are t o be a v oi de d d uri n g t he st u d y u nless re q uire d t o treat a n A E or f or t he treat me nt of a n o n g oi n g me dical  pr o ble m.    
If t he nee d f or c o nc o mita nt me dicati o n arises, i ncl usi o n or c o nti n uati o n of t he partici pa nt ma y be at t he discreti o n of t he i n vesti gat or after c o ns ultati o n wit h Lill y 
cli nical p har mac ol o gist. A n y a d diti o nal me dicati o n use d d uri n g t he c o urse of t he s t u d y m ust be d oc u me nte d. 
a Vital si g n meas ure me nts, P E/ M A, E C Gs, ma y be c ollecte d wit hi n ti me wi n d o ws de pe n di n g o n t he c ollecti o n ti me, as f oll o ws: Pre d ose ( wit hi n 2 h o ur bef ore 
d osi n g); 0. 5 h ( ± 1 0 mi n); 1 t o 4 h o urs ( ± 1 5 mi n); 5  t o 8 h o urs ( ±2 0 mi n); 1 2 h o urs ( ± 3 0 mi n); 2 4 h o urs  a n d l o n ger  ( ± 6 0 mi n). B l o o d sa m ples c ollecte d f or P K, 
P D, or bi o mar ker  (i ncl u di n g b uccal a n d sali va sa m ples) p ur p oses ma y be c ollecte d wit hi n ti me wi n d o ws de p e n di n g o n t he c ollecti o n ti me, as f oll o ws: Pre d ose 
( wit hi n 1 h o ur bef ore d osi n g); 0. 5 h ( ± 5 mi n); 1 t o 4 h o urs ( ± 1 0 mi n); 5  t o 8 h o urs ( ± 1 5 mi n); 1 2 h o urs ( ± 3 0 mi n); 2 4 h o urs a n d l o n ger  ( ± 6 0 mi n). 
b  I n P eri o d 1, partici pa nts will fast o ver ni g ht f or at least 8 h o urs bef ore recei vi n g L Y 3 5 0 9 7 5 4/ place b o fast f or a p pr o xi matel y 2 h o urs after d osi n g. I n P eri o d 2, 
fe d treat me nts will f oll o w a hi g h-fat meal gi ve n 3 0 mi n utes pri or t o recei vi n g L Y 3 5 0 9 7 5 4/ place b o f oll o wi n g a n o ver ni g ht fast of at least 8 h o urs 
( Secti o n 5. 3. 1 ). T here will be at least a 5 -da y was h o ut bet we e n P eri o ds 1 a n d 2. F or C o h ort 4 i n P eri o ds 1 a n d 2, 8 L Y 3 5 0 9 7 5 4: 2 place b o partici pa nts will b e 
d ose d . S u bj ect u ni q ue I Ds will re mai n t he sa me f or P eri o d 1 a n d 2 ( see Secti o n 6. 3 .). 
c See Secti o n 1 0. 2 , f or details. T he PI m ust re vie w t he Da y -2 la b orat or y res ults bef ore d osi n g o n Da y 1 of P eri o d 1. T he PI m ust re vie w t he Da y 5 la b orat or y 
res ults i n P eri o d 1 bef ore d osi n g o n Da y 1 of P eri o d 2.  
d  Electr ocar di o gra ms o n Da y 1 will b e tri plicate f or t he first 5 h o urs a n d si n gle f or all ot her ti me p oi nts  i n P eri o d 1. Electr ocar di o gra ms will be si n glet f or all 
ti me p oi nts i n P eri o d 2. 
e Sa m ples ma y be f urt her pr ocesse d f or ser u m or plas ma. See la b orat or y ma n ual f or f urt her details. 
f A d diti o nal  f oll o w-u p visits ma y be c o n d ucte d f or safet y la bs a n d m o nit ori n g after t he e xisti n g f oll o w -u p visit t hat is at l east 7 da ys after disc har ge. E ver y 
atte m pt s h o ul d be ma d e t o c o ntact s u bj ects f or t he f oll o w -u p visits; h o we ver, if s u bj ects are u n willi n g or u na ble t o ret ur n f or t he  a d diti o nal  visit s, t his is n ot 
c o nsi dere d a pr ot oc ol vi olati o n.  
g  Plas ma sa m ples s h o ul d be c ollecte d f or e x pl orat or y a nal ys es at a d diti o nal f oll o w -u p visits ; h o we ver, if s u bj ects ar e u n willi n g or u na ble t o ret ur n t o c oll ect t his 
sa m ple, t his is n ot c o nsi dere d a pr ot oc ol vi olati o n.  
 
 
 
 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
1 9  
1. 3. 3.  
P a rt B: Dr u g -Dr u g I nter acti o n wit h C Y P 3 A 4 I n hi biti o n –  Fi xe d Se q ue nce  
Pr o ce d ure  
Scr
ee n
i n g 
 
Tre at me nt Peri o d  
E D  
F oll o w -
u p f 
 
St u d y D a y  
-2 8 
t o -
3  
-
2  
-
1  
1  
2  
3  
4  
5  
6  
7 -9  
1 0  
1 1  
1 2  
1 3  
1 4  
1 5  
1 6  
1 7  
 
A p pr o x 7 
d a ys 
after 
disc h ar ge  
C o m me nts  
I nf or me d 
c o nse nt  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A d missi o n t o 
C R U  
 
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disc har ge 
fr o m C R U 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
P E/ M A c 
X  
X   
P  
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
X  
X  
F ull P E/ M A at 
scree ni n g a n d 
pri or t o fi nal 
disc har ge fr o m 
t he st u d y. 
S y m pt o m -direc
te d P E/ M A at 
all ot her ti me 
p oi nts a n d as 
dee me d 
necessar y b y 
t he i n vesti gat or. 
C O VI D -1 9 
test ( P C R) 
X  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
X  
X  
 
Pre g na nc y test  
X  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
X  
Ser u m test at 
scree ni n g. 
U ri ne test at all 
ot her ti me 
p oi nts.  
Uri ne dr u g 
scree n 
X  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
2 0  
Pr o ce d ure  
Scr
ee n
i n g 
 
Tre at me nt Peri o d  
E D  
F oll o w -
u p f 
 
St u d y D a y  
-2 8 
t o -
3  
-
2  
-
1  
1  
2  
3  
4  
5  
6  
7 -9  
1 0  
1 1  
1 2  
1 3  
1 4  
1 5  
1 6  
1 7  
 
A p pr o x 7 
d a ys 
after 
disc h ar ge  
C o m me nts  
Breat h or 
uri ne et ha n ol 
test 
X  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Et ha n ol test 
ma y be 
re p eate d at 
ot her ti me 
p oi nts at t he 
discreti o n of 
t he i n vesti gat or. 
Q ua nti F E R O
N ® -T B G ol d 
test 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A E/ me dicati o
n re vie w  
X  
X  X  X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Hei g ht/ wei g ht  
X  
 
 
X  
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
X  
X  
Hei g ht at 
scree ni n g o nl y. 
L Y 3 5 0 9 7 5 4/  
place b o 
a d mi nistrati o n
a 
 
 
 
X  
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
A d mi nistrati o
n of 
itrac o naz oleb  
 
 
 
 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
 
 
 
Itrac o naz ole 
a d mi nistrati o n 
t o occ ur t wice 
o n Da y 4  o nl y . 
Vital si g ns 
( B P, P R 
[s u pi ne],) 
( h o urs)c, d 
X  
 
X  
P, 
2, 
4, 
8, 
1 2  
2 4  
4 8  
 
 
P, 
2, 
4  
 
P, 
2, 
4, 
8, 
1 2  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Ti me p oi nts 
ma y be a d de d, 
if cli nicall y 
i n dicate d.  
T e m perat ure  
c, d 
 
X   
P  
 
 
 
 
P  
 
P  
 
 
 
 
 
 
X  
X  
X  
 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
2 1  
Pr o ce d ure  
Scr
ee n
i n g 
 
Tre at me nt Peri o d  
E D  
F oll o w -
u p f 
 
St u d y D a y  
-2 8 
t o -
3  
-
2  
-
1  
1  
2  
3  
4  
5  
6  
7 -9  
1 0  
1 1  
1 2  
1 3  
1 4  
1 5  
1 6  
1 7  
 
A p pr o x 7 
d a ys 
after 
disc h ar ge  
C o m me nts  
Cli nical 
la b orat or y 
tests e  
X  
X   
  
 
X  
 
 
 
X 
( Da y 
8 
o nl y)  
P  
X  
 
 
 
 
 
X  
X  
X  
 
1 2 -lea d E C G 
( h o urs)c 
X  
 
 
P, 1  
 
 
P  
 
 
 
P, 1  
 
 
 
X  
 
 
 
X  
 
X  
X  
Si n gle safet y 
E C Gs.   E C Gs 
c oi nci di n g wit h 
P K sa m ple ti me 
p oi nts are t o be 
c o n d ucte d as 
cl ose as 
p ossi ble pri or 
t o P K 
sa m pli n g. 
L Y 3 5 0 9 7 5 4 
P K sa m pli n g 
( h o urs)c, d  
 
 
 
P, 
0. 5 ,
1, 
2, 
3, 
4, 
6, 
8, 
1 2, 
1 6  
2 4
, 
3 6  
4 8  
7 2  
9 6  
 
 
P, 
0. 5, 
1, 
2, 
3, 
4, 
6, 
8, 
1 2, 
1 6  
2 4
, 
3 6  
4 8  
7 2  
9 6  
1 2 0  
1 4 4  
1 6 8  
 
 
Sa m pli n g ti mes 
are relati ve t o 
t he ti me of 
L Y 3 5 0 9 7 5 4 
a d mi nistrati o n 
( 0 h o ur).  
Itrac o naz ole 
a n d meta b olite 
P K sa m pli n g 
( h o urs) 
 
 
 
 
 
 
 
 
 
 
P, 
1, 
2, 
5, 
8,  
1 2  
2 4  
 
 
 
 
 
 
 
 
 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
2 2  
Pr o ce d ure  
Scr
ee n
i n g 
 
Tre at me nt Peri o d  
E D  
F oll o w -
u p f 
 
St u d y D a y  
-2 8 
t o -
3  
-
2  
-
1  
1  
2  
3  
4  
5  
6  
7 -9  
1 0  
1 1  
1 2  
1 3  
1 4  
1 5  
1 6  
1 7  
 
A p pr o x 7 
d a ys 
after 
disc h ar ge  
C o m me nts  
P G x sa m ple  
 
 
 
P  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
F or st ora ge 
o nl y. Sa m ple 
ca n be ta ke n 
a n y ti me pri or 
t o d osi n g. 
A b bre viati o ns : A E = a d verse e ve nt; B P  =  bl o o d press ure; C R U = cli nical researc h u nit; C Y P  = c yt oc hr o me P 4 5 0; E C G  =  electr ocar di o gra m; E D  =  earl y 
disc o nti n uati o n; M A  =  me dical assess me nt; P  = p re d ose; P C R = p ol y merase c hai n reacti o n ; P E  =  p h ysical e xa mi nati o n; P K  =  p har ma c o ki netic; P R  =  p ulse 
rate. 
N ote: Site s h o ul d sc he d ule acti vities as a p pr o priate. I n cases w here se veral st u d y pr oce d ures are sc he d ule d at t he sa me ti me,  f oll o w t his or der of pri orit y f or 
pr oce d ures: E C G, vital si g ns, P K sa m ples, a n d cli nical la b orat or y te sts. 
A d diti o nal dr u gs are t o be a v oi de d d uri n g t he st u d y u nless re q uire d t o treat a n A E or f or t he treat me nt of a n o n g oi n g me dical  pr o ble m.    
If t he nee d f or c o nc o mita nt me dicati o n arises, i ncl usi o n or c o nti n uati o n of t he partici pa nt ma y be at t he discreti o n of t he i n vesti gat or after c o ns ultati o n wit h Lill y 
cli nical p har mac ol o gist. A n y a d diti o nal me dicati o n use d d uri n g t he c o urse of t he st u d y m ust be d oc u me nte d.  
a P artici pa nts will u n der g o a n o ver ni g ht fast ( Secti o n 5. 3. 1 ) bef ore recei vi n g t he first d ose o n Da y 1 a n d u ntil a p pr o xi matel y 2 h o urs after d osi n g. P artici pa nts 
will recei ve a si n gle oral d ose of L Y 3 5 0 9 7 5 4 or place b o o n Da y 1 0 after a n o ver ni g ht fast a n d a p pr o xi matel y 1 h o ur after t he d ose of itrac o naz ole.  T he 
was h o ut peri o d  bet wee n L Y 3 5 0 9 7 5 4 a n d itrac o naz ole d osi n g  ma y be e xte n de d b y u p  t o 5  da ys base d o n e mer gi n g P K data . 
b  Itrac o naz ole 2 0 0 m g will be a d mi nistere d as a n oral s ol uti o n t wice o n Da y 4 ( d ose se parate d b y a p pr o xi matel y 1 2 h o urs) a n d o nce dail y o n Da ys 5 t hr o u g h 
1 3. Itrac o naz ole s h o ul d be a d mi nistere d at a p pr o xi matel y t he sa me ti me e ver y m or ni n g.  P artici pa nts will u n der g o a n o ver ni g ht fast ( Secti o n 5. 3. 1 ) pri or t o t he 
da y w here 2 d oses of itrac o na z ole a d mi nistrati o n occ urs.  O n Da y 1 0 , itrac o naz ole s h o ul d be a d mi nistere d 1 h o ur bef ore L Y 3 5 0 9 7 5 4 a d mi nistrati o n (se e 
Secti o n 4. 2. 2 ). T he ti mi n g a n d d urati o n of itrac o naz ole d osi n g ma y be a dj uste d base d o n e mer gi n g P K data fr o m P art A.  
c Vital si g n meas ure me nts, P E/ M A, E C Gs, ma y be c ollecte d wit hi n ti me wi n d o ws de pe n di n g o n t he c ollecti o n ti me, as f oll o ws: Pre d ose ( wit hi n 2 h o ur s bef ore 
d osi n g); 0. 5 h ( ± 1 0 mi n); 1 t o 4 h o urs ( ± 1 5 mi n); 5 t o 8 h o urs ( ± 2 0 mi n); 1 2 h o urs ( ± 3 0 mi n); 2 4 h o urs a n d l o n ger  ( ± 6 0 mi n). Bl o o d sa m ples c ollecte d f or P K, 
P D, or bi o mar ker p ur p oses ma y be c ollecte d wit hi n ti me wi n d o ws de pe n di n g o n t he c ollecti o n ti me, as f oll o ws: Pre d ose ( wit hi n 1 h o ur bef ore d osi n g); 0. 5 h 
( ± 5 mi n); 1 t o 4 h o urs ( ± 1 0 mi n); 5 t o 8 h o urs ( ± 1 5 mi n); 1 2 h o urs ( ± 3 0 mi n); 2 4 h o urs a n d l o n ger  ( ± 6 0 mi n). 
d  Pre d ose ti me p oi nts refer t o d osi n g bef ore itrac o naz ole a n d L Y 3 5 0 9 7 5 4. All p ost d ose ti me p oi nts are relati ve t o t he L Y 3 5 0 9 7 5 4  d ose.  
e See  Secti o n 1 0. 2  f or details. T he PI m ust re vie w t he Da y -2 l a b orat or y res ults bef ore d osi n g o n Da y 1. L Y 3 5 0 9 7 5 4/ place b o o n Da y 1. T he PI m ust re vi e w 
Da y 3 la b orat or y res ults bef or e d osi n g itrac o naz ole o n Da y 4.   
f  A d diti o nal  f oll o w-u p visits ma y be c o n d ucte d f or safet y la bs a n d m o nit ori n g after t he e xisti n g f oll o w -u p visit t hat is ~  7 da ys after disc har ge. E ver y att e m pt 
s h o ul d be ma d e t o c o ntact s u bj ects f or t he f oll o w-u p visits; h o we ver, if s u bj ects are u n wi lli n g or u na ble t o ret ur n f or t he a d diti o nal visit s, t his is n ot 
c o nsi dere d a pr ot oc ol vi olati o n.  
 
 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
2 3  
1. 3. 4.  
P a rt C: M ulti ple -Asce n di n g D ose –  C o h orts 1  a n d  3 –  Si n gle Peri o d  
Pr o ce d ure  
Scree
ni n g  
 
 
Tre at me nt  
E
D  
F oll o w -
u p d  
C o m me nts  
St u d y D a ys  
-2 8 t o 
-3  
-
2  
-
1  
1  
2  
3 -6  
7  
8 -1 3  
1 4  
1 5  
1 6  
1 7  
1 8  
1 9  
 
A p pr o x 
7  d a ys 
after 
disc h ar ge  
 
I nf or me d c o nse nt 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A d missi o n t o C R U  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disc har ge fr o m 
C R U  
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
P E/ M A a 
X  
X  
 
P  
 
 
 
 
 
 
 
 
 
X  
X  
X  
F ull P E/ M A at scree ni n g 
a n d pri or t o fi nal disc har ge 
fr o m t he st u d y. 
S y m pt o m -directe d P E/ M A 
at all ot her ti me p oi nts a n d 
as dee me d necessar y b y 
t he i n vesti gat or. 
C O VI D -1 9 test 
( P C R) 
X  
X  
 
 
 
 
X  
 
 
 
 
 
 
X  
X  
X  
 
Pre g na nc y test  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
X  
X  
Ser u m test at scree ni n g . 
Uri ne test at all ot her ti me 
p oi nts per 
i n vesti gat or discreti o n.  
 
Uri ne dr u g scree n  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Breat h or uri ne 
et ha n ol test  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Et ha n ol test ma y be 
re p eate d at ot her ti me 
p oi nts at t he discreti o n of 
t he i n vesti gat or. 
Q ua nti F E R O N ® -
T B G ol d test  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A E/ me dicati o n 
re vie w 
X  
X  X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Hei g ht/ wei g ht  
X  
 
X  
 
 
 
 
 
 
 
 
 
 
X  
X  
 
Hei g ht at scree ni n g o nl y.  
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
2 4  
Pr o ce d ure  
Scree
ni n g  
 
 
Tre at me nt  
E
D  
F oll o w -
u p d  
C o m me nts  
St u d y D a ys  
-2 8 t o 
-3  
-
2  
-
1  
1  
2  
3 -6  
7  
8 -1 3  
1 4  
1 5  
1 6  
1 7  
1 8  
1 9  
 
A p pr o x 
7  d a ys 
after 
disc h ar ge  
 
L Y 3 5 0 9 7 5 4/  
place b o 
a d mi nistrati o n  
 
 
 
X  
X  
X  
X  
X  
X  
 
 
 
 
 
 
 
P artici pa nts will fast 
o ver ni g ht b ef ore recei vi n g 
L Y 3 5 0 9 7 5 4/ place b o a n d 
f or a p pr o xi matel y 2 h o urs 
after d osi n g. O n i nte nsi ve 
P K da y, partici pa nts ma y 
recei ve a li g ht meal at least 
2  h o urs after d osi n g.  
Vital si g ns ( B P, P R 
[s u pi ne], 
te m perat ure) 
( h o urs)a 
X  
 
X  
P, 
2, 
4, 
8, 
1 2  
P, 
2  
P, 2  
P, 
2, 
4, 
8, 
1 2  
P, 2  
P, 
2, 
4, 
8, 
1 2  
X  
X  
X  
X  
X  
X  
X  
O n Da ys 1 t o 1 4, 
te m perat ure will be 
meas ure d at pre d ose o nl y.  
Cli nical la b orat or y 
testsb  
X  
X  
 
 
 
 
P  
 
 
 
 
 
 
X  
X  
X  
 
1 2 -lea d E C G 
( h o urs)a 
X  
 
 
P,  
1, 
2, 3  
 
P,  1, 
2, 3 
( Da y 
3 
o nl y)  
P,  
1, 
2, 3  
P,  1, 
2, 3 
( Da y 
1 0 
o nl y)  
 
 
 
 
 
X  
X  
X  
Si n gle safet y E C Gs. E C Gs 
c oi nci di n g wit h P K sa m ple 
ti me p oi nts are t o be 
c o n d ucte d as cl ose as 
p ossi ble pri or t o P K 
sa m pli n g. 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
2 5  
Pr o ce d ure  
Scree
ni n g  
 
 
Tre at me nt  
E
D  
F oll o w -
u p d  
C o m me nts  
St u d y D a ys  
-2 8 t o 
-3  
-
2  
-
1  
1  
2  
3 -6  
7  
8 -1 3  
1 4  
1 5  
1 6  
1 7  
1 8  
1 9  
 
A p pr o x 
7  d a ys 
after 
disc h ar ge  
 
P K sa m pli n g 
( h o urs)a 
 
 
 
P, 
0. 5, 
1, 
2, 
3, 
4, 
6, 
8, 
1 2, 
1 6  
P  
 
P, 
0. 5, 
1, 
2, 
3, 
4, 
6,  
8, 
1 2, 
1 6  
P 
( Da y 
8 
o nl y)  
P, 
0. 5, 
1, 
2, 
3, 
4, 
6, 
8, 
1 2, 
1 6  
2 4  
4 8  
7 2  
9 6  
 
 
 
Sa m pli n g ti mes are relati ve 
t o t he ti me of L Y 3 5 0 9 7 5 4 
a d mi nistrati o n ( 0  h o ur).  
E x pl orat or y  plas ma  
bl o o d sa m pli n g 
( h o urs)a,c 
 
 
 
P, 
1, 
4, 
1 2  
P  
P  
P, 
1, 
4, 
1 2  
P  
P, 
1, 
4, 
1 2  
2 4  
4 8  
7 2  
9 6  
 
 
X e 
St ore d sa m ple f or 
bi o mar ker researc h. 
Sa m pli n g ti mes are relati ve 
t o t he ti me of st u d y 
treat me nt a d mi nistrati o n 
( 0 h o ur).  
E x pl orat or y  ser u m 
bl o o d sa m pli n g  
( h o urs)a,c 
 
 
 
P  
 
P 
( Da ys 
3 a n d 
6 
o nl y)  
 
P 
( Da ys 
9 a n d 
1 2 
o nl y)  
 
2 4  
 
 
 
 
 
 
St ore d sa m ple f or 
bi o mar ker researc h. 
Sa m pli n g ti mes are relati ve 
t o t he ti me of st u d y 
treat me nt a d mi nistrati o n 
( 0 h o ur).  
E x pl orat or y b uccal 
s wa bs a n d sali va 
sa m ples ( h o urs)a 
 
 
 
P, 8  
P  
 
P, 8  
 
P, 8  
2 4  
 
 
 
 
 
 
St ore d sa m ple f or 
bi o mar ker researc h. 
Sa m pli n g ti mes are relati ve 
t o t he ti me of st u d y 
treat me nt a d mi nistrati o n 
( 0 h o ur).  
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
2 6  
Pr o ce d ure  
Scree
ni n g  
 
 
Tre at me nt  
E
D  
F oll o w -
u p d  
C o m me nts  
St u d y D a ys  
-2 8 t o 
-3  
-
2  
-
1  
1  
2  
3 -6  
7  
8 -1 3  
1 4  
1 5  
1 6  
1 7  
1 8  
1 9  
 
A p pr o x 
7  d a ys 
after 
disc h ar ge  
 
P G x sa m ple  
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
F or st ora ge o nl y. Sa m ple 
ca n be ta ke n a n y ti me pri or 
t o d osi n g. 
A b bre viati o ns : A E = a d verse e ve nt; B P  =  bl o o d press ure; C R U = cli nical researc h u nit; E C G = electr ocar di o gra m; E D = earl y disc o nti n uati o n; M A  =  me dical 
assess me nt; P = p re d ose; P C R = p ol y merase c hai n reacti o n ; P E  =  p h ysical e xa mi nati o n; P G x = p har mac o ge netic; P K = p har ma c o ki netic; P R  =  p ulse rate.  
N ote: Site s h o ul d sc he d ule acti vities as a p pr o priate. I n cases w here se veral st u d y pr oce d ures are sc he d ule d at t he sa me ti me,  f oll o w t his or der of pri orit y f or 
pr oce d ures: E C G, vital si g ns, P K sa m ples, cli nical la b orat or y tests,  bi o mar kers, a n d st ora ge sa m ples.  
A d diti o nal dr u gs are t o be a v oi de d d uri n g t he st u d y u nless re q uire d t o treat a n A E or f or t he treat me nt of a n o n g oi n g me dical  pr o ble m.    
If t he nee d f or c o nc o mita nt me dicati o n arises, i ncl usi o n or c o nti n uati o n of t he partici pa nt ma y be at t he discreti o n of t he i n vesti gat or after c o ns ultati o n wit h Lill y 
cli nical p har mac ol o gist. A n y a d diti o nal me dicati o n use d d uri n g t he c o urse of t he st u d y m ust be d oc u me nte d.  
a 
Vital si g n meas ure me nts, P E/ M A, E C Gs, a n d bl o o d sa m ples c ollecte d f or P K, P D, or bi o mar ker (i ncl u di n g b uccal a n d sali va sa m ples) p ur p oses ma y be 
c ollecte d wit hi n ti me wi n d o ws de p e n di n g o n t he c ollecti o n ti me, as f oll o ws: Pre d ose ( wit hi n 1 h o ur bef ore d osi n g); 0. 5 h ( ± 5 mi n); 1 t o 4 h o urs ( ± 1 0 mi n); 5 
t o 8 h o urs ( ± 1 5 min); 1 2 h o urs ( ± 3 0 mi n); 2 4 h o urs a n d l o n ger  ( ± 6 0 mi n). 
b  
 See Secti o n 1 0. 2  f or details. T he pri nci pal i n vesti gat or m ust re vie w t he Da y -2 la b orat or y res ults bef ore d osi n g o n Da y 1.  
c Sa m ples ma y be f urt her pr ocesse d f or ser u m or plas ma. See la b orat or y ma n ual f or f urt her details. 
d  A d diti o nal  f oll o w-u p visits ma y be c o n d ucte d f or safet y la bs a n d m o nit ori n g after t he e xisti n g f oll o w -u p visit t hat is ~  7 da ys after disc har ge. E ver y att e m pt 
s h o ul d be ma d e t o c o ntact s u bj ects f or t he f oll o w-u p visits; h o we ver, if s u bj e cts are u n willi n g or u na ble t o ret ur n f or t he a d diti o nal visit s, t his is n ot 
c o nsi dere d a pr ot oc ol vi olati o n.  
e Plas ma  sa m ples s h o ul d be c ollecte d f or e x pl orat or y a nal ys es  at a d diti o nal f oll o w -u p visits ; h o we ver, if s u bj ects are u n willi n g or u na ble t o ret u r n t o c oll ect t his 
sam ple , t his is n ot c o nsi dere d a pr ot oc ol vi olati o n. 
 
 
 
 
 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
2 7  
1. 3. 5.  
P a rt C: M ulti ple -Asce n di n g D ose a n d Per petr at or D DI –  C o h ort 2 Fi xe d Se q ue nce  
Pr o ce d ure  
Scree
ni n g  
 
Tre at me nt  
E
D  
F oll o w -
u p e 
C o m me nts  
St u d y D a ys  
-2 6 t o  
-5  
-
4  
-
3  
-2  
-1  
1  
2  
3  
4  
5 -8  
9  
1 0 -1 4  
1 5  
1 6  
1 7
-
1 8  
1
9  
 
A p pr o x 
7  d a ys 
after 
disc h ar g
e 
 
I nf or me d 
c o nse nt  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A d missi o n t o 
C R U  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disc har ge 
fr o m C R U 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
P E/ M A a 
X  
X  
 
P  
 
 
 
 
 
 
 
 
 
 
 
X  
X  
X  
F ull P E/ M A at 
scree ni n g a n d pri or 
t o fi nal disc har ge 
fr o m t he st u d y. 
S y m pt o m -directe d 
P E/ M A at all ot her 
ti me p oi nts a n d as 
dee me d necessar y 
b y t he i n vesti gat or.  
C O VI D -1 9 
test ( P C R) 
X  
X  
 
 
 
X  
 
 
X  
 
 
 
 
 
 
X  
X  
X  
 
Pre g na nc y test  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
X  
Ser u m test at 
scree ni n g. U ri ne test 
at all ot her  ti me 
p oi nts per 
i n vesti gat or discreti
o n.  
Uri ne dr u g 
scree n 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
2 8  
Pr o ce d ure  
Scree
ni n g  
 
Tre at me nt  
E
D  
F oll o w -
u p e 
C o m me nts  
St u d y D a ys  
-2 6 t o  
-5  
-
4  
-
3  
-2  
-1  
1  
2  
3  
4  
5 -8  
9  
1 0 -1 4  
1 5  
1 6  
1 7
-
1 8  
1
9  
 
A p pr o x 
7  d a ys 
after 
disc h ar g
e 
 
Breat h or uri ne 
et ha n ol test  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Et ha n ol test ma y be 
re p eate d at ot her 
ti me p oi nts at t he 
discreti o n of t he 
i n vesti gat or. 
Q ua nti F E R O N
® -T B G ol d 
test 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A E/ me dicati o n 
re vie w 
X  
X  X  
X  
X  
X  
X  X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Hei g ht/ wei g ht  
X  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
X  
X  
 
Hei g ht at scree ni n g 
o nl y.  
L Y 3 5 0 9 7 5 4/  
place b o 
a d mi nistrati o n  
 
 
 
 
 
X  
X  X  
X  
X  
X  
X  
X  
 
 
 
 
 
P artici pa nts will fast 
o ver ni g ht b ef ore 
recei vi n g 
L Y 3 5 0 9 7 5 4/ place b o 
a n d f or 
a p pr o xi matel y 
2  h o urs after d osi n g. 
O n i nte nsi ve P K 
da ys, partici pa nts 
ma y recei ve a li g ht 
meal at least 2 h o urs 
after d osi n g.  
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
2 9  
Pr o ce d ure  
Scree
ni n g  
 
Tre at me nt  
E
D  
F oll o w -
u p e 
C o m me nts  
St u d y D a ys  
-2 6 t o  
-5  
-
4  
-
3  
-2  
-1  
1  
2  
3  
4  
5 -8  
9  
1 0 -1 4  
1 5  
1 6  
1 7
-
1 8  
1
9  
 
A p pr o x 
7  d a ys 
after 
disc h ar g
e 
 
D osi n g of 
L Y 3 5 0 9 7 5 4/ place b o 
will o cc ur at 
a p pr o xi mate l y t he 
sa me ti me of da y o n 
eac h da y of d osi n g 
a n d o n Da y -2 at 
a p pr o xi matel y t he 
sa me ti me of da y as 
mi daz ola m 
a d mi nistrati o n.  
A d mi nistrati o n 
of mi daz ola m 
( oral s yr u p) 
 
 
 
X  
 
 
 
 
 
 
 
 
X   
 
 
 
 
 
T he d osi n g of 
mi daz ola m will 
occ ur at least 1 h o ur 
after 
L Y 3 5 0 9 7 5 4/ place b o 
d osi n g o n Da y 1 5.  
Vital si g ns 
( B P, P R 
[s u pi ne], 
te m perat ure) 
( h o urs)a 
X  
 
X  
P, 2, 
4  
 
P, 
2, 
4, 
8, 
1 2  
 
P, 
2  
 
P, 2 4, 
8, 1 2  
( Da y 7 
o nl y)  
P, 
2  
P, 2 
( Da y 
1 0 -1 3)  
P, 2, 4, 8
, 1 2 
( Da y 
1 4)  
X  
X  
X  
X  
X  
X  
O n Da ys -2 t o 1 4, 
te m perat ure will be 
meas ure d at pre d ose 
o nl y.  
Cli nical 
la b orat or y 
testsb  
X  
X  
 
 
X  
 
 
 
P  
 
 
 
 
 
 
X  
X  
X  
 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
3 0  
Pr o ce d ure  
Scree
ni n g  
 
Tre at me nt  
E
D  
F oll o w -
u p e 
C o m me nts  
St u d y D a ys  
-2 6 t o  
-5  
-
4  
-
3  
-2  
-1  
1  
2  
3  
4  
5 -8  
9  
1 0 -1 4  
1 5  
1 6  
1 7
-
1 8  
1
9  
 
A p pr o x 
7  d a ys 
after 
disc h ar g
e 
 
1 2 -lea d E C G 
( h o urs)a 
X  
 
 
 
 
P,  
1, 
2, 3  
 
P,  
1, 
2, 
3  
 
P,  1, 2, 
3 ( Da y 
7 o nl y)  
 
P,  1, 2, 
3 ( Da y 
1 0 
o nl y)  
 
 
 
X  
X  
X  
Si n gle safet y E C Gs. 
E C Gs c oi nci di n g 
wit h P K sa m ple 
ti me p oi nts are t o be 
c o n d ucte d as cl ose 
as p ossi ble pri or t o 
P K sa m pli n g.  
L Y 3 5 0 9 7 5 4 
P K sa m pli n g 
( h o urs)a 
 
 
 
 
 
P, 
0. 5, 
1, 
2, 
3, 
4, 
5, 
6, 
8, 
1 2, 
1 6  
P  
 
 
P, 0. 5, 
1, 2, 3, 
4, 5, 6, 
8, 1 2, 
1 6  
( Da y 7 
o nl y)  
P ( Da y 
8 o nl y)  
 
P, 0. 5, 
1, 2, 3, 
4, 5, 6, 
8, 1 2, 
1 6  
( Da y 
1 4 
o nl y)  
2 4  
 
 
 
 
 
Sa m pli n g ti mes are 
relati ve t o t he ti me 
of L Y 3 5 0 9 7 5 4 
a d mi nistrati o n 
( 0 h o ur). C ollect 2 4 -
h o ur sa m ple o n Da y 
1 5 pri or t o d osi n g of 
L Y 3 5 0 9 7 5 4 or 
mi daz ola m.  
Mi d az ola m 
a n d meta b olite 
P K sa m pli n g 
( h o urs)a, d 
 
 
 
P, 
0. 2 5, 
0. 5, 
1, 2, 
3, 4, 
5, 6, 
8, 
1 2, 
1 6  
2 4  
  
 
 
 
 
 
 
P, 
0. 2 5 , 
0. 5, 
1, 2, 
3, 4, 
5, 6, 
8, 
1 2,  
1 6  
2 4  
 
 
 
 
 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
3 1  
Pr o ce d ure  
Scree
ni n g  
 
Tre at me nt  
E
D  
F oll o w -
u p e 
C o m me nts  
St u d y D a ys  
-2 6 t o  
-5  
-
4  
-
3  
-2  
-1  
1  
2  
3  
4  
5 -8  
9  
1 0 -1 4  
1 5  
1 6  
1 7
-
1 8  
1
9  
 
A p pr o x 
7  d a ys 
after 
disc h ar g
e 
 
E x pl orat or y 
bl o o d 
sa m pli n g 
( h o urs)a,c 
 
 
 
 
 
P, 
1, 
4, 
1 2  
P  
 
 
P, 1, 4, 
1 2  
( Da y 7 
o nl y)  
P ( Da y 
8 o nl y)  
 
P, 1, 4, 
1 2 
( Da y 
1 4 
o nl y)  
2 4  
 
 
 
 
X f 
St ore d sa m ple f or 
bi o mar ker researc h. 
Sa m pli n g ti mes are 
relati ve t o t he ti me 
of st u d y treat me nt 
a d mi nistrati o n 
( 0 h o ur).  
E x pl orat or y 
b uccal s wa bs 
a n d sali va 
sa m ples 
( h o urs)a 
 
 
 
 
 
P, 8  
P  
 
 
P, 8  
( Da y 7 
o nl y)  
 
P, 8 
( Da y 
1 4 
o nl y)  
2 4  
 
 
 
 
 
St ore d sa m ple  f or 
bi o mar ker researc h. 
Sa m pli n g ti mes are 
relati ve t o t he ti me 
of st u d y treat me nt 
a d mi nistrati o n 
( 0 h o ur).  
P G x sa m ple  
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
F or st ora ge o nl y. 
Sa m ple ca n be ta ke n 
a n y ti me pri or t o 
d osi n g . 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
3 2  
A b bre viati o ns: A E = a d verse e ve nt; B P  =  bl o o d press ure; C R U = cli nical researc h u nit; E C G = electr ocar di o gra m; E D = earl y disc o nti n uati o n; M A  =  me dical 
assess me nt; P = pre d ose; P C R = p ol y merase c hai n reacti o n; P E  =  p h ysical e xa mi nati o n; P G x = p har mac o ge net ic; PI = pri nci pal i n vesti gat or; P K = 
p har mac o ki netic; P R  =  p ulse rate.  
N ote: Site s h o ul d sc he d ule acti vities as a p pr o priate. I n cases w here se veral st u d y pr oce d ures are sc he d ule d at t he sa me ti me,  f oll o w t his or der of pri orit y f or 
pr oce d ures: E C G, vital s i g ns, P K sa m ples, cli nical la b orat or y tests, bi o mar kers, a n d st ora ge sa m ples.  
A d diti o nal dr u gs are t o be a v oi de d d uri n g t he st u d y u nless re q uire d t o treat a n A E or f or t he treat me nt of a n o n g oi n g me dical  pr o ble m.    
If t he nee d f or c o nc o mita nt me dicati o n arises, i ncl usi o n or c o nti n uati o n of t he partici pa nt ma y be at t he discreti o n of t he i n vesti gat or after c o ns ultati o n wit h Lil l y 
cli nical p har mac ol o gist. A n y a d diti o nal me dicati o n use d d uri n g t he c o urse of t he st u d y m ust be d oc u me nte d.  
a Vital si g n meas ure m e nts, P E/ M A, E C Gs, ma y be c ollecte d wit hi n ti me wi n d o ws de pe n di n g o n t he c ollecti o n ti me, as f oll o ws: Pre d ose ( wit hi n 2 h o ur bef ore 
d osi n g); 0. 5 h ( ± 1 0 mi n); 1 t o 4 h o urs ( ± 1 5 mi n); 5 t o 8 h o urs ( ± 2 0 mi n); 1 2 h o urs ( ± 3 0 mi n); 2 4 h o urs a n d l o n ger  ( ± 6 0 mi n). Bl o o d sa m ples c ollecte d f or P K, 
P D, or bi o mar ker (i ncl u di n g b uccal a n d sali va sa m ples) p ur p oses ma y be c ollecte d wit hi n ti me wi n d o ws de p e n di n g o n t he c ollecti o n ti me, as f oll o ws: Pre d ose 
( wit hi n 1 h o ur bef ore d osi n g); 0. 5 h ( ± 5 mi n); 1 t o 4 h o urs ( ± 1 0 mi n); 5 t o 8 h o urs ( ± 1 5 mi n); 1 2 h o urs ( ± 3 0 mi n); 2 4 h o urs a n d l o n ger  ( ± 6 0 mi n). 
b  
 See Secti o n 1 0. 2  f or details. T he pri nci pal i n vesti gat or m ust re vie w t he Da y -2 la b orat or y res ults bef ore d osi n g o n Da y 1.  
c 
Sa m ples ma y be f urt her pr ocesse d f or ser u m or plas ma. See la b orat or y ma n ual f or f urt her details.  
d  Pre d ose ti me p oi nts refer t o d osi n g bef ore mi daz ola m. All p ost d ose ti me p oi nts are relati ve t o t he mi daz ola m d ose.  
e A d diti o nal  f oll o w-u p visits ma y be c o n d ucte d f or safet y la bs a n d m o nit ori n g after t he e xisti n g f oll o w -u p visit t hat is ~  7 da ys after disc har ge. E ver y att e m pt 
s h o ul d be ma d e t o c o ntact s u bj ects f or t he f oll o w-u p visits; h o we ver,  if s u bj ects are u n willi n g or u na ble t o ret ur n f or t he a d diti o nal  visit s, t his is n ot 
c o nsi dere d a pr ot oc ol vi olati o n.  
f Plas ma  sa m ples s h o ul d be c ollecte d f or e x pl orat or y a nal ys es  at a d diti o nal f oll o w -u p visits ; h o we ver, if s u bj ects are u n willi n g or u na bl e t o ret ur n t o c oll ect t his 
sa m ple, t his is n ot c o nsi dere d a pr ot oc ol vi olati o n.  
 
 
 
 
 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
3 3  
1. 3. 6.  
P a rt D: M ulti ple -D ose i n J a p a nese H e alt h y P artici p a nts  –  Si n gle Peri o d  
Pr o ce d ure  
Scree
ni n g  
 
 
Tre at me nt Peri o d  
E
D  
F oll o w -
u p  e 
C o m me nts  
St u d y D a y  
-2 8 t o 
-3  
-
2  
-
1  
1  
2  
3 -6  
7  
8 -1 3  
1 4  
1 5  
1 6  
1 7  
1 8  
1 9  
 
A p pr o x 
7  d a ys 
after 
disc h ar ge  
 
I nf or me d 
c o nse nt  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A d missi o n t o 
C R U  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disc har ge 
fr o m C R U 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
P E/ M A a 
X  
X   
P  
 
 
 
 
 
 
 
 
 
X  
X  
X  
F ull P E/ M A at 
scree ni n g a n d pri or t o 
fi nal disc har ge fr o m t he 
st u d y. 
S y m pt o m -directe d 
P E/ M A at all ot her ti me 
p oi nts a n d as dee me d 
necessar y b y t he 
i n vesti gat or. 
C O VI D -1 9 
test ( P C R) 
X  
X   
 
 
 
X  
 
 
 
 
 
 
X  
X  
X  
 
Pre g na nc y test  
X  
X   
 
 
 
 
 
 
 
 
 
 
 
X  
X  
Ser u m test at scree ni n g .  
Uri ne test at all 
ot her  ti me p oi nts.  
 
Uri ne dr u g 
scree n 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Breat h or uri ne 
et ha n ol test  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Et ha n ol test ma y be 
re p eate d at ot her ti me 
p oi nts at t he discreti o n 
of t he i n vesti gat or . 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
3 4  
Pr o ce d ure  
Scree
ni n g  
 
 
Tre at me nt Peri o d  
E
D  
F oll o w -
u p  e 
C o m me nts  
St u d y D a y  
-2 8 t o 
-3  
-
2  
-
1  
1  
2  
3 -6  
7  
8 -1 3  
1 4  
1 5  
1 6  
1 7  
1 8  
1 9  
 
A p pr o x 
7  d a ys 
after 
disc h ar ge  
 
Q ua nti F E R O N
® -T B G ol d 
test 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A E/ me dicati o n 
re vie w 
X  
X  X  X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Hei g ht/ wei g ht  
X  
 
X  
 
 
 
 
 
 
 
 
 
 
X  
X  
 
Hei g ht at scree ni n g 
o nl y.  
L Y 3 5 0 9 7 5 4/  
place b o 
a d mi nistrati o n  
 
 
 
X  
X  
X  
X  
X  
X  
 
 
 
 
 
 
 
P artici pa nts will fast 
o ver ni g ht b ef ore 
recei vi n g 
L Y 3 5 0 9 7 5 4/ place b o 
a n d f or a p pr o xi matel y 
2  h o urs after d osi n g. 
O n i nte nsi ve P K da ys, 
partici pa nts ma y 
recei ve a li g ht meal at 
least 2 h o urs after 
d osi n g.  
Vital si g ns 
( B P, P R 
[s u pi ne], 
te m perat ure) 
( h o urs)a 
X  
 
X  
P, 
2, 
4, 
8, 
1 2  
P
, 
2  
P, 2  
P, 
2, 
4, 
8, 
1 2  
P, 2  
P, 
2, 
4, 
8, 
1 2  
X  
X  
X  
X  
X  
X  
X  
O n Da ys 1 t o 1 4, 
te m perat ure will be 
meas ure d at pre d ose 
o nl y.  
Cli nical 
la b orat or y 
testsb  
X  
X  
 
 
 
 
P  
 
 
 
 
 
 
X  
X  
X  
 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
3 5  
Pr o ce d ure  
Scree
ni n g  
 
 
Tre at me nt Peri o d  
E
D  
F oll o w -
u p  e 
C o m me nts  
St u d y D a y  
-2 8 t o 
-3  
-
2  
-
1  
1  
2  
3 -6  
7  
8 -1 3  
1 4  
1 5  
1 6  
1 7  
1 8  
1 9  
 
A p pr o x 
7  d a ys 
after 
disc h ar ge  
 
1 2 -lea d E C G 
( h o urs)a,c 
X  
 
 
P,  
0. 5  
1, 
2, 
3 , 
4, 
5, 
6, 
8, 
1 2   
P  
P,  1, 2, 3 
( Da y 3 
o nl y all 
ti me 
p oi nts)  
P,  
1, 
2, 3  
P,  1, 2, 3 
( Da y 1 0 
o nl y all 
ti me 
p oi nts)  
 
 
 
 
 
 
X  
X  
X  
E C Gs c oi nci di n g wit h 
P K sa m ple ti me p oi nts 
are t o be c o n d ucte d as 
cl ose as p ossi ble pri or 
t o P K sa m pli n g. E C Gs 
m ust b e ta ke n pri or t o 
d osi n g o n Da y 2 b ut as 
cl ose as p ossi ble t o 2 4 
h o urs f oll o wi n g d osi n g 
o n Da y  1.  
P K sa m pli n g 
( h o urs)a 
 
 
 
P, 
0. 5, 
1, 
2, 
3, 
4, 
5, 
6, 
8, 
1 2, 
1 6  
P  
 
P, 
0. 5, 
1, 
2, 
3, 
4, 
6, 
8, 
1 2, 
1 6  
P ( Da y 8 
o nl y)  
P, 
0. 5, 
1, 
2, 
3, 
4, 
6, 
8, 
1 2, 
1 6  
2 4  
4 8  
7 2  
9 6  
 
 
 
Sa m pli n g ti mes are 
relati ve t o t he ti me of 
L Y 3 5 0 9 7 5 4 
a d mi nistrati o n ( 0  h o ur).  
P K sa m p les m ust b e 
ta ke n pri or t o d osi n g o n 
Da y 2 b ut as cl ose as 
p ossi ble t o 2 4 h o urs 
f oll o wi n g L Y 3 5 0 9 7 5 4 
d osi n g  o n Da y 1.  
E x pl orat or y 
plas ma bl o o d 
sa m pli n g 
( h o urs)a,d  
 
 
 
P, 
1, 
4, 
1 2  
P  
P  
P, 
1, 
4, 
1 2  
P  
P, 
1, 
4, 
1 2  
2 4  
4 8  
7 2  
9 6  
 
 
X f 
St ore d sa m ple f or 
bi o mar ker researc h. 
Sa m pli n g ti mes are 
relati ve t o t he ti me of 
st u d y treat me nt 
a d mi nistrati o n ( 0  h o ur).  
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
3 6  
Pr o ce d ure  
Scree
ni n g  
 
 
Tre at me nt Peri o d  
E
D  
F oll o w -
u p  e 
C o m me nts  
St u d y D a y  
-2 8 t o 
-3  
-
2  
-
1  
1  
2  
3 -6  
7  
8 -1 3  
1 4  
1 5  
1 6  
1 7  
1 8  
1 9  
 
A p pr o x 
7  d a ys 
after 
disc h ar ge  
 
E x pl orat or y 
ser u m bl o o d 
sa m pli n g 
( h o urs)a,d  
 
 
 
P  
 
P ( Da ys 3 
a n d 6 o nl y 
 
P ( Da ys 9 
a n d 1 2 
o nl y)  
 
2 4  
 
 
 
 
 
 
St ore d sa m ple f or 
bi o mar ker researc h. 
Sa m pli n g ti mes are  
relati ve t o t he ti me of 
st u d y treat me nt 
a d mi nistrati o n ( 0  h o ur).  
E x pl orat or y 
b uccal s wa bs 
a n d sali va 
sa m ples 
( h o urs)a 
 
 
 
P, 8  
P  
 
P, 8  
 
P, 8  
2 4  
 
 
 
 
 
 
St ore d sa m ple f or 
bi o mar ker researc h. 
Sa m pli n g ti mes are 
relati ve t o t he ti me of 
st u d y treat me nt 
a d mi nistrati o n ( 0  h o ur).  
P G x sa m ple  
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
Si n gle sa m ple f or P G x 
a nal ysis ta ke n pri or 
t o/ o n Da y 1. 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
3 7  
A b bre viati o ns : A E = a d verse e ve nt; B P  =  bl o o d press ure; C R U = cli nical researc h u nit; E C G = electr ocar di o gra m; E D = earl y disc o nti n uati o n; M A  =  me dical 
assess me nt; P = pre d ose; P C R = p ol y merase c hai n reacti o n; P E  =  p h ysical e xa mi nati o n; P G x = p har mac o ge netic; P K = p har ma c o ki netic; P R  =  p ulse rate . 
N ote : Site s h o ul d sc he d ule acti vities as a p pr o priate. I n cases w here se veral st u d y pr oce d ures are sc he d ule d at t he sa me ti me, f oll o w t his or der of pri orit y f or 
pr oce d ures: E C G, vital si g ns, P K sa m ples, cli nical la b orat or y tests,  bi o mar kers, a n d st ora ge sa m ples.  
A d diti o nal dr u gs are t o be a v oi de d d uri n g t he st u d y u nless re q uire d t o treat a n A E or f or t he treat me nt of a n o n g oi n g me dical  pr o ble m.    
If t he nee d f or c o nc o mita nt me dicati o n arises, i ncl usi o n or c o nti n uati o n of t he partici pa nt ma y be at t he discreti o n of t he i n vesti gat or after c o ns ultati o n wit h Lill y 
cli nical p har mac ol o gist. A n y a d diti o nal me dicati o n use d d uri n g t he c o urse of t he st u d y m ust be d oc u me nte d.  
a Vital si g n meas ure me nts, P E/ M A, E C Gs, ma y be c ollecte d wit hi n ti me wi n d o ws de pe n di n g o n t he c ollecti o n ti me, as f oll o ws: Pre d ose ( wit hi n 2 h o ur bef ore 
d osi n g); 0. 5 h ( ± 1 0 mi n); 1 t o 4 h o urs ( ± 1 5 mi n); 5 t o 8 h o urs ( ± 2 0 mi n); 1 2 h o urs ( ± 3 0 mi n); 2 4 h o urs a n d l o n ger  ( ± 6 0 mi n). Bl o o d sa m ples c ollecte d f or P K, 
P D, or bi o mar ker  (i ncl u di n g b uccal a n d sali va sa m ples) p ur p oses ma y be c ollecte d wit hi n ti me wi n d o ws de p e n di n g o n t he c ollecti o n ti me, as f oll o ws: Pre d ose 
( wit hi n 1 h o ur bef ore d osi n g); 0. 5 h ( ±5  mi n); 1 t o 4 h o urs ( ± 1 0 mi n); 5 t o 8 h o urs ( ± 1 5 mi n); 1 2 h o urs ( ± 3 0 mi n); 2 4 h o urs a n d l o n ger  ( ± 6 0 mi n). 
b  
 See Secti o n 1 0. 2  f or details. T he pri nci pal i n vesti gat or m ust re vie w t he Da y -2 la b orat or y res ults bef ore d osi n g o n Da y 1.  
c  Electr ocar di o gra ms o n Da y s 1 a n d 2 will be tri plicate i n P art D.  O n all ot her da ys , electr ocar di o gra ms will be si n gle.  
d  Sa m ples ma y be f urt her pr ocesse d f or ser u m or plas ma. See la b orat or y ma n ual f or f urt her details.  
e A d diti o nal  f oll o w-u p visits ma y be c o n d ucte d f or safet y la bs a n d m o nit ori n g after t he e xisti n g f oll o w -u p visit t hat is ~  7 da ys after disc har ge. E ver y att e m pt 
s h o ul d be ma d e t o c o ntact s u bj ects f or t he f oll o w-u p  visits; h o we ver, if s u bj ects are u n willi n g or u na ble t o ret ur n f or t he  a d diti o nal  visit s, t his is n ot 
c o nsi dere d a pr ot oc ol vi olati o n.  
f Plas ma  sa m ples s h o ul d be c ollecte d f or e x pl orat or y a nal ys es  at a d diti o nal f oll o w -u p visits ; h o we ver, if s u bj ects are u n willi n g or u na ble t o ret ur n t o c oll ect t his 
sa m ple, t his is n ot c o nsi dere d a pr ot oc ol vi olati o n.  
 
 
 
 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
3 8  
2.  
I ntr o d ucti o n 
L Y 3 5 0 9 7 5 4 is a n oral s m all m olec ule i n hi bit or f or I L -1 7 A t hat is bei n g de v el o pe d f or o nce -d ail y 
treat me nt of ps oriasis ( Ps O) a n d ot her i m m u ne -m e diate d diseases.  
2. 1.  
St u d y R ati o n ale  
L Y 3 5 0 9 7 5 4 h as n ot bee n a d mi nistere d t o h u ma ns. T his first -i n-h u ma n st u d y will i n vesti gate t he 
safet y, t olera bilit y, a n d p har mac o ki netics ( P K) of si n gle-asce n di n g d ose  ( S A D; Part A) a n d 
m ulti ple -asce n di n g d oses  of L Y 3 5 0 9 7 5 4 i n healt h y n o n -J a pa nes e ( M A D; P art C) a n d J a pa nese 
partici pa nts (Part  D) . As L Y 3 5 0 9 7 5 4 is bei n g d e v el o pe d as a n oral f or m ulati o n a n d t he effect of 
f o o d o n t he P K of L Y 3 5 0 9 7 5 4 is cli nicall y u n k n o w n , 
 
 
2. 2.  
B ac k gr o u n d  
L Y 3 5 0 9 7 5 4 is a n oral s m all m olec ule i n hi bit or f or i nterle u ki n -1 7 A (I L -1 7 A) w hic h  is bei n g 
de vel o pe d f or o nce -dail y treat me nt of ps oriasis ( Ps O ) a n d ot her i m m u ne -m e diate d diseas es.  
I L-1 7 A is a pr oi nfl a m mat or y c yt o ki ne a n d a me m ber of t he I L-1 7 c yt o ki ne fa mil y, w hic h als o 
i ncl u des I L-1 7 B -F. T he acti ve , h o m o di meric I L-1 7 A c yt o ki n e is pr o d uce d b y T h 1 7 cells a n d 
ot her α β T  cells as well as mast cells, γ δ T  cells, a n d i n nate l y m p h oi d cells. I L -1 7 A si g nals 
t hr o u g h a rece pt or c o m pl e x c o nsisti n g of I L-1 7 R A:I L -1 7 R C. I L -1 7 A si g n ali n g lea ds t o t he 
pr o d ucti o n of pr oi nfla m mat o r y a n d pr oliferati ve c yt o ki nes, c he m o ki nes a n d vari o us 
a nti micr o bial pe pti des. Cell ular tar gets f or I L -1 7 A i ncl u de kerati n oc yt es (a m o n g ot her e pit helial 
cells, e. g., Pa net h c ells), fi br o blasts, oste oclasts, c h o n dr oc ytes, oste o blasts, e n d ot helial cells, a n d  
ne utr o p hils. I L -1 7 A is a maj or effect or c yt o ki n e t hat has bee n d e m o nstrate d t o dri ve t he 
pat h o ge nesis of m ulti ple ps oriatic diseases ( Bla u velt a n d C hiric ozzi 2 0 1 8).  
C urre ntl y, m ulti ple i nject a ble m o n ocl o nal a nti b o dies ( m A bs) tar geti n g I L -1 7 A ha ve bee n 
de m o nstrate d t o be safe a n d effecti ve i n t he treat me nt of a n d a p pr o ve d f or Ps O, ps oriatic art hritis 
( Ps A), a n d a n k yl osi n g s p o n d ylitis ( A x S pa). H o we ver, oral treat me nt o pti o ns i n Ps O are li mite d 
a n d hi g h er efficac y is desira ble. T he i nte nt of L Y 3 5 0 9 7 5 4 de vel o p me nt is t o deli ver a n orall y 
a vaila ble s mall m olec ule i n hi bit or of I L -1 7 A si g n ali n g t o pr o vi de p h ysicia ns wit h a 
c o m ple me ntar y oral treat me nt o pti o n f or patie nts wit h ps oriatic diseases . 
L Y 3 5 0 9 7 5 4 h as de m o nstrate d a fa v ora ble safet y pr ofile i n g o o d l a b orat or y practice ( G L P) 
c o m plia nt t o xic ol o g y a n d safet y p har m ac ol o g y st u dies t o s u p p ort cli nical trials.  L Y 3 5 0 9 7 5 4 was 
e val uate d i n 1 -m o nt h dail y oral -d osi n g t o xicit y st u dies i n S pra g u e Da wl e y rats a n d b ea gle d o gs 
( wit h 1-m o nt h re versi bilit y i n hi g h -d ose rats a n d d o gs). Safet y p har m ac ol o g y para meters were 
e val uate d i n a n i n vitr o ( h u ma n et her á -g o -g o – rel ate d ge ne [ h E R G]) assa y a n d i n vi v o (rat 
ce ntral ner v o us s yste m [ C N S], rat res pirat or y, d o g car di o vas c ular) st u dies. Ge netic t o xicit y was 
e val uate d i n a b acteria l m utati o n ( A mes) assa y, a n i n vitr o micr o n ucle us ( M N) assa y a n d a n i n 
vi v o rat M N assa y. I n vitr o p h ot ot o xic p ote ntial was e val uate d i n a Ne utr al Re d U pta ke 
P h ot ot o xicit y Assa y i n Bal b/c 3 T 3 m o use fi br o blasts.  
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I n rats, n o n-a d v erse effects i ncl u de d decreas e d b o d y wei g ht a n d f o o d c o ns u m pti o n, er yt hr o c yt e 
effects ( decrease d re d bl o o d cell c o u nt, he m o gl o bi n, a n d he mat ocrit; s p her oc yt es a n d 
aca nt h oc yt es), i ncrease d retic ul oc ytes, i ncrease d bilir u bi n, i ncrease d li ver wei g ht, stellate cell 
h y pertr o p h y i n t he li ve r a n d he pat ocell ular v ac u ol ati o n. T he fi n di n gs i n er yt hr oc yt e para meters 
a n d t otal bilir u bi n were of mi n or ma g nit u de a n d were c o nsiste nt wit h mi ni mal he m ol ysis.  I n rats, 
t he 1-m o nt h n o -o bser ve d -a d vers e-effect le vel ( N O A E L) was 1 0 0 0  m g/ k g b ase d o n n o a d v ers e 
effects at t he hi g hest d os e teste d.  
I n d o gs, n o n-a d verse effects i ncl u de d v o miti n g, diarr hea, i ncrease d h eart rate, a n d decreas e d 
t h y mic wei g hts. I n d o gs, t he 1-m o nt h N O A E L was 1 5 0 m g/ k g base d o n n o a d verse effects at t he 
hi g hest d ose teste d. I n a d diti o n  t o effects o bser ve d i n 1-m o nt h st u dies, a hi g her d ose ( 5 0 0 m g/ k g) 
a d mi nistere d t o d o gs f or 7 da ys ( n o n -G L P d ose -ra n ge fi n di n g st u d y) was n ot t olerate d a n d 
res ulte d i n se vere b o d y w ei g ht l oss a n d a d v erse effects i n t he li ver, ki d ne y, heart, a n d l u n g. 
All f i n di n gs i n t he 1-m o nt h st u dies were c o m pletel y re versi ble e x ce pt f or li ver wei g hts, stellate 
cell h y p ertr o p h y a n d he p at ocell ular vac u olati o n, o bser ve d i n rats, w hi c h were partiall y re versi ble 
(l o wer i nci de n ce a n d se v erit y after t h e rec o ver y p hase). See Secti o n 4. 2. 1 of t he I n vesti gat or’s 
Br oc h ure  (I B) f or m or e d etails o n n o ncli nical t o xic ol o g y a n d safet y p h ar m ac ol o g y. 
L Y 3 5 0 9 7 5 4 h as de m o nstrate d s uita ble a bs or pti o n, distri b uti o n, meta b olis m, a n d e x creti o n 
pr o perties i n i n vitr o e x peri me nts a n d i n n o nc li nical i n vi v o st u dies t o warra nt cli nical 
i n vesti gati o n. Its predi cte d h u ma n pr o perties are fa v ora ble  ( bi oa v aila bilit y, F = 0. 6 2) . 
 
 
 
 
 
 
 
2. 3.  
Be nefit/ Ris k Assess me nt  
M ore detaile d i nf or mati o n 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 n a bl y 
e x pecte d A Es of L Y 3 5 0 9 7 5 4  ma y b e f o u n d i n t he I B. 
T he n o ncli nical safet y i nf or mati o n f or L Y 3 5 0 9 7 5 4 a de q uatel y s u p p orts t he tra nsiti o n fr o m 
precli nical stat us t o cli nical , si n gle- a n d m ulti ple-d ose  e val uati o n s. T he s p o ns or has e val u ate d t he 
ris ks ass ociate d wit h L Y 3 5 0 9 7 5 4 a n d d oes n ot c o nsi der it t o be a hi g h u n certai nt y c o m p o u n d, 
base d o n  p u blis he d criteria ( B utler et al. 2 0 1 7).  
Na mel y:  
1.  T he e xiste nce of p har mac ol o g y i n vi v o m o dels t hat ca n reas o na bl y pre dict i n te n de d a n d 
e x a g gerate d p har mac ol o gic all y acti ve a n d e x cessi ve p har mac ol o gi cal res p o nses i n 
relati o n t o meas ura bl e dr u g c o n ce ntr ati o n i n vi v o a n d beca use t he tar get is a n e n d o ge n o us 
h u ma n tar get . 
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2.  T he a ni mal t o xicit y m o d els are b elie ve d t o a de q u atel y refl ect  h u ma n t o xicit y f or t his 
tar get i n a si n gle a n d re p eat d ose st u dies. 
3.  
4.  L Y 3 5 0 9 7 5 4 h as de m o nstrate d a fa v ora ble safet y pr ofile i n G L P -c o m plia nt 1 -m o nt h 
t o xicol o g y st u dies i n rats a n d d o gs ( wit h re v ersi bilit y i n hi g h d ose rats a n d d o gs), s afet y 
p har mac ol o g y a n d ge neti c t o xicit y st u dies t o s u p p ort cli nical trials . 
5.  A ntici pate d ris ks  i n t he si n gle a n d re p eat d ose st u dies i ncl u de p ote ntial effects o n 
er yt hr oc yte s (i ncl u di n g d ecrease d re d bl o o d cell c o u nt, decrease i n he m o gl o bi n, a n d 
he mat ocrit; s p her oc yt es a n d aca nt h oc yt es), i ncreas e d retic ul oc yte  c o u nt , i ncrease i n 
bilir u bi n  le vel, i ncrease d li ver wei g ht, a n d he p at ocell ular vac u olati o n, as re p orte d i n rat 
t o xicit y st u dies. T hese effects were n o n -a d verse a n d  are c o nsi d ere d m o nit ora ble a n d 
meas ura ble. Ot her p ote ntial ris ks are t h ose ass o ciate d wit h i ncreas e d heart rate as 
re p orte d i n d o g st u dies a n d decrease d b o d y wei g ht as re p orte d i n t he rat t o xicit y st u dies, 
b ot h o f w hic h are m o nit ora ble a n d acc o u nt f or t he ca uti o us m o nit ori n g of vital si g ns a n d 
meas ure me nt of wei g ht pla n ne d f or t his trial.  
T his pr ot oc ol reflects t he fact t hat L Y 3 5 0 9 7 5 4 has n ot bee n a d mi nistere d t o h u ma ns pre vi o usl y, 
a n d t o miti gate t his ris k, t he s t u d y h as bee n d esi g n e d t o  be c o n d uct e d i n acc or da nce wit h 
pri nci ples o utli ne d i n t he a p plica ble g ui da nce, s uc h as t he G ui deli ne o n Str ate gies t o I de ntif y a n d 
Miti gate Ris ks f or First -i n-H u ma n a n d E arl y Cli nical Trials wit h I n vesti gati o nal Me dici nal 
Pr o d uct s ( E M A 2 0 1 7). T here is n o a ntici pat e d t hera pe utic be n efit f or t he p artici pa nts . M ore 
i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be n efits, ris ks, S A Es, a n d reas o na bl y a ntici pate d A Es  
of L Y 3 5 0 9 7 5 4 ca n b e f o u n d i n t he I B.  
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3.  
O bjecti ves a n d E n d p oi nts  
O bjecti ves a n d  E n d p oi nts  
O bjecti ves  
E n d p oi nts  
Pri m ar y  
 
 
T he pri mar y o bj ecti ve is t o assess t he safet y 
a n d t olera bilit y f oll o wi n g si n gle or m ulti ple 
d oses of L Y 3 5 0 9 7 5 4 a d mi nist ere d t o healt h y 
partici pa nts  
 
I nci de nce of S A Es a n d T E A Es 
Sec o n d ar y  
 
 
T he sec o n dar y o bj ecti ve is t o c haracterize t he 
P K f oll o wi n g si n gle or m ulti pl e orall y 
a d mi nistere d d oses of L Y 3 5 0 9 7 5 4 i n healt h y 
partici pa nts  
 
C ma x  a n d A U C  of L Y 3 5 0 9 7 5 4   
Terti ar y/ E x pl or at or y  
 
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A b bre viati o ns : A U C  = area u n der t he c o nce ntrati o n -ti me c ur ve;
C ma x  = ma xi m u m 
o bser ve d dr u g c o nce ntrati o n;
; P K = p har mac o ki netics; 
; S A E = seri o us a d vers e e ve nt; T E A E = treat me nt -e mer ge nt a d verse e ve nt ; tma x  =  ti me t o ma xi m u m 
o bser ve d dr u g c o nce ntrati o n .  
 
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4.  
St u d y Desi g n  
4. 1.  
O ver all  Desi g n  
St u d y J 3 D-M C -F N A A  is a P hase 1, m ulti -ce nter st u d y i n healt h y partici pa nts  t o be c o n d ucte d i n 
4  parts:  
 Part A ( S A D):  Part A will be a partici pa nt -a n d i n v esti gat or -bli n d, place b o -c o ntr olle d, 
ra n d o mize d, S A D st u d y t o e val uate safet y, t olera bilit y, a n d P K of L Y 3 5 0 9 7 5 4 i n healt h y 
partici pa nts i n u p t o 6 c o h orts. O ne c o h ort ( C o h ort 4) will i ncl u de a ra n d o mize d, si n gle -
d ose le vel, 2 peri o d cr oss o ver
 
 
 Part B ( D DI –  C Y P 3 A 4  victi m):  Part B will be a  partici pa nt - a n d i n v esti gat or -bli n d , 
place b o -c o ntr olle d, si n gl e-d ose -le vel, si n gl e-ar m, D DI  st u d y t o e val uate t h e m ulti ple 
d ose i m pact of t he C Y P 3 A 4 i n hi bit or, itrac o naz ole, o n t he si n gle d os e e x p os ure of 
L Y 3 5 0 9 7 5 4.  
 Part C ( M A D): Part C will be a partici pa nt -a n d i n vesti gat or -bli n d, place b o -c o ntr olle d, 
ra n d o mize d, 1 4-da y, si n gle -peri o d M A D st u d y wit h u p t o 3 c o h orts t o e val u ate safet y, 
t olera bilit y, a n d P K of L Y 3 5 0 9 7 5 4 i n healt h y p artici pa nts.
 
 
 Part D ( J a pa nese partici pa nts ): Part D  will be a partici pa nt -a n d i n vesti gat or -bli n d, 
place b o -c o ntr olle d, ra n d o mi ze d, m ulti ple d ose st u d y t o e val uate t he safet y, t olera bilit y, 
a n d P K of L Y 3 5 0 9 7 5 4 i n healt h y J a pa nes e partici pa nts  i n 2 d ose le vels i n 2 se parat e 
c o h orts ( 1 d ose le v el per c o h ort) . T he 2  d os e le vels  will  be c o n d ucte d c o n c urre ntl y. 
4. 2.  
Scie ntific R ati o n ale f or  St u d y Desi g n  
L Y 3 5 0 9 7 5 4 h as n ot bee n a d mi nistere d t o h u ma ns. T his first -i n-h u ma n st u d y will i n vesti gate t he 
safet y, t olera bilit y, a n d p har mac o ki netics ( P K) of si n gle-asce n di n g d ose ( S A D; Part A) a n d 
m ulti ple -asce n di n g d oses of L Y 3 5 0 9 7 5 4 i n healt h y n o n -J a panes e ( M A D; P art  C) a n d J a pa nese 
partici pa nts ( Part  D). As L Y 3 5 0 9 7 5 4 is bei n g d e v el o pe d as a n oral f or m ulati o n a n d t he effect of 
f o o d o n t he P K of L Y 3 5 0 9 7 5 4 is cli nicall y u n k n o w n, 
 
 
 
T here is n o a ntici pat e d t hera pe utic b e nefit f or t he partici pa nts i n t his st u d y. C o n d ucti n g t he st u d y 
i n a healt h y partici pa nt  p o p ulati o n  miti gates t he p ote ntial  f or disease stat e a n d c o nc o mita nt 
me dicati o n  use  t o c o nf o u n d t he i nter pretati o n of res ults. I n all P arts (A -D ), t he partici pa nts a n d 
site staff (e x cl u di n g p h ar mac y staff) will be bli n de d t o treat me nt all ocati o n t o all o w f or u n biase d 
assess me nt of t he data.  T he res ults of t his st u d y will i nf or m  t he d osi n g t olera bilit y ra n ge f or 
s u bse q ue nt trials, i n a d diti o n t o pr o vi d i n g i nf or mati o n o n t he P K a n d p ote ntial f o o d a n d D DI 
effects of L Y 3 5 0 9 7 5 4 . 
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4. 2. 1.  
P a rt A  ( Si n gle-Asce n di n g D ose)   
Partici pa nts  i n Part A will be  ra n d o ml y assi g n e d/e nr olle d i nt o u p t o 6  c o h orts wit h u p t o 5 9  
partici pa nts c o m pleti n g t his part of t he st u d y.  T a ble  F N A A. 1  s h o ws t he pla n ne d  L Y 3 5 0 9 7 5 4  
d ose a n d n u m ber  of parti ci pa nts  t o c o m plete eac h c o h ort i n Part A. 
T a ble  F N A A. 1 . 
Pl a n ne d L Y 3 5 0 9 7 5 4 D ose a n d N u m ber of P arti ci p a nts t o C o m plete 
E ac h C o h ort ( P art A)  
C o h ort  
D ose Fre q ue nc y  
Pl a n ne d D ose  
Pl a n ne d # of 
C o m pleters  
1  
Si n gle oral d ose  
1 0 -m g L Y 3 5 0 9 7 5 4 or place b o  
6 L Y 3 5 0 9 7 5 4; 2 place b o  
2  
Si n gle oral d ose  
3 0 -m g L Y 3 5 0 9 7 5 4 or place b o  
6 L Y 3 5 0 9 7 5 4; 2 place b o  
3  
Si n gle oral d ose  
1 0 0 -m g L Y 3 5 0 9 7 5 4 or place b o  
6 L Y 3 5 0 9 7 5 4; 2 place b o  
4  
Si n gle oral d ose ( P eri o ds 1 a n d 2) a 
3 0 0 -m g L Y 3 5 0 9 7 5 4 or place b o  
9 L Y 3 5 0 9 7 5 4; 2 place b o  
5  
Si n gle oral d ose  
1 0 0 0 -m g L Y 3 5 0 9 7 5 4 or place b o  
6 L Y 3 5 0 9 7 5 4; 2 place b o  
6  
Si n gle oral d ose  
2 0 0 0  m g L Y 3 5 0 9 7 5 4 b 
U p t o 8 t otal  
a  P artici pa nts i n t his c o h ort will be a d mi nistere d  L Y 3 5 0 9 7 5 4 u n der faste d ( P eri o d 1) or fe d ( P eri o d 2) c o n diti o ns .  
b  B ase d o n re vie w of safet y dat a fr o m C o h orts 1  t o 5 . 
 
T he ma xi m u m i ncrease i n L Y 3 5 0 9 7 5 4 d os es bet wee n se q u e ntial c o h orts i n t he S A D will be n o 
m ore t ha n se mi -l o g i ncreases t o e x pl ore t he L Y 3 5 0 9 7 5 4 d ose ra n ge, w hile pr o vi di n g a d e q uate 
se parati o n of t he d os es t o c haracteriz e L Y 3 5 0 9 7 5 4 safet y, t olera bilit y, a n d P K. See Secti o n 4. 3. 1  
f or d ose j ustificati o n. 
C o h orts 1,  2, 3, 5 , a n d 6 
P artici pa nts will be a d mitte d t o t he cli nical researc h u nit ( C R U) o n Da y -2 . P artici pa nts will 
re mai n i n t he C R U f or at least 9 6  h o urs after d osi n g ( u ntil Da y 5 ) acc or di n g t o t he Sc he d ule of 
Acti vities ( S o A ) ( Secti o n 1. 3. 1 ), after w hic h t he y ma y b e disc har ge d at t he discretio n of t he 
i n vesti gat or. 
C o h ort 4  
C o h ort 4 will be a 2 -peri o d ra n d o mize d (eac h peri o d) cr oss o ver desi g n
 
P artici pa nts will be a d mitte d t o t he cli nical researc h u nit ( C R U) o n Da y -2. Partici pa nts  will 
re mai n i n t he C R U f or at least 9 6  h o urs after d osi n g Peri o d 2 ( u ntil Da y 5 of Peri o d 2 ) acc or di n g 
t o t he S o A ( Secti o n 1. 3. 2 ), after w hic h t he y ma y b e disc har ge d at t he discreti o n of t he 
i n vesti gat or. 
T he was h o ut bet w ee n t he L Y 3 5 0 9 7 5 4 d osi n g da ys i n Peri o d 1 a n d Peri o d 2 will be at least 
5  da ys.
 
 
 
 
Peri o d 2 will be c o n d ucte d as descri be d f or Peri o d 1; h o we ver, partici pa nts will recei ve a si n gl e 
oral d ose of L Y 3 5 0 9 7 5 4 
 
 
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C o h orts 1 -6 (all c o h orts)  
A p ostst u d y f oll o w -u p visit f or eac h c o h ort will be c o n d ucte d at least 7 da ys after disc h ar ge . 
Partici pa nts  will pr o vi de t otal uri ne c ollecti o ns f or t he 2 4  h o urs p ost d ose i n eac h c o h ort (f or 
e x pl orat or y meta b olis m a n d assess me nt of re n al eli mi nati o n); a n a d diti o nal bl o o d sa m ple will be 
c ollecte d t o deter mi ne ser u m creati ni ne meas ure me nts.  
See Secti o n 6. 6. 1  f or i nf or mati o n re gar di n g d os e m o dificati o ns, i ncl u di n g d ose decisi o n a n d 
escalati o n.  
4. 2. 2.  
P a rt B ( C Y P 3 A 4 I n hi biti o n)  
Part B will c o nsist of a p pr o xi matel y 1 2  p artici pa nts  ( 9 L Y 3 5 0 9 7 5 4: 3 place b o) a n d 
 
 
 
 
 
 
T he L Y 3 5 0 9 7 5 4 d ose t o be st u die d i n Part B is 1 0 m g. T his d ose was  deter mi ne d base d o n 
safet y, t olera bilit y, a n d P K data fr o m Part A, a n d will be a d mi nistere d as a n  oral  f or m ulati o n. 
See Secti o n 4. 3. 1  f or d os e j ustificati o n . 
As detaile d i n t he Sc he d ule of Acti vities ( S o A; Secti o n  1. 3. 3 ), partici pa nts  will be a d mitte d t o 
t he C R U o n Da y -2  bef ore recei vi n g a si n gle oral d ose of L Y 3 5 0 9 7 5 4 or pl ace b o o n Da y 1 . 
 
 
Partici pa nts  will u n der g o a n o ver ni g ht fast o n Da y 9 , bef ore recei vi n g a si n gle oral d ose of 
L Y 3 5 0 9 7 5 4 or place b o o n Da y 1 0 , a p pr o xi matel y 1 h o ur after t h e d ose of itrac o naz ole. Bl o o d 
sa m pli n g f or P K p ur p os es ( L Y 3 5 0 9 7 5 4 a n d itrac o naz ole) a n d ot her assess me nts will occ ur 
acc or di n g t o t he S o A  (Secti o n  1. 3. 3 ). T he ti mi n g a n d d urati o n of t he itrac o n az ole d osi n g ma y be 
a dj uste d base d o n e m er gi n g dat a fr o m Part A.  
Partici pa nts  will re mai n i n t he C R U u ntil disc har ge o n t he m or ni n g of Da y  1 7 , a p pr o xi matel y 9 6 
h o urs after t h e fi nal d ose of itrac o naz o le a n d a p pr o xi matel y 7  da ys after t h e fi nal d ose of 
L Y 3 5 0 9 7 5 4 . A j oi nt s p o ns or a n d i n vesti gat or safet y re vie w will be c o m plete d  a p pr o x i matel y 5 
da ys  after eac h L Y 3 5 0 9 7 5 4 a d mi nistrati o n. A p ostst u d y f oll o w -u p visit will be c o n d ucte d 
a p pr o xi matel y 7 da ys after disc har ge.  See Fi g ure  F N A A. 1  f or a s c he matic of t he st u d y d esi g n f or 
Part B.  
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4 6 
 
A b bre viati o ns: BI D = t wice dail y; C R U = cli nical researc h u nit; L Y = L Y 3 5 0 9 7 5 4; P K = p har mac o ki netic; 
P L  = place b o; Q D = o nce dail y. 
Fi g ure F N A A. 1.  
P art B: Dr u g- Dr u g I nter acti o n wit h C Y P 3 A 4 I n hi biti o n 
4. 2. 3.  
P a rt C ( M ulti ple- Asce n di n g D ose/ C Y P 3 A 4 Per pe tr at or D DI) 
Part C will i ncl u de u p t o 3 c o h orts a n d will c o m me nce o n ce safet y data has bee n re vi e we d fr o m 
t he 1 0 0 0 m g c o h ort ( P art  A) , as well as t h e re vie w of P K data fr o m i nteri m a nal ys es fr o m Part A. 
D oses will be i nf or me d b y e m er gi n g data fr o m Part A (see Secti o n 4. 2. 1 f or details). T he 
ma xi m u m i ncrease i n L Y 3 5 0 9 7 5 4 d oses bet wee n s e q ue ntial c o h orts i n t he M A D will be n o m ore 
t ha n se mi-l o g i ncreas es t o e x pl ore t he L Y 3 5 0 9 7 5 4 d ose ra n ge, w hile pr o vi di n g a d e q uate 
se parati o n of t he d os es t o c haracteriz e L Y 3 5 0 9 7 5 4 safet y, t olera bilit y, a n d P K.  See Secti o n 4. 3. 1 
f or d ose j ustificati o n. Ta ble F N A A. 2  s h o ws t he pl a n ne d L Y 3 5 0 9 7 5 4 d ose a n d n u m ber of 
partici pa nts t o c o m plete eac h c o h ort i n Part C. 
T a ble F N A A. 2.  
Pl a n ne d L Y 3 5 0 9 7 5 4 D ose a n d N u m ber of P arti ci p a nts t o C o m plete 
E ac h C o h ort ( P art C) 
C o h ort  
D ose Fre q ue nc y  
Pl a n ne d D ose  
Pl a n ne d # of 
C o m pleters  
1  
1 x dail y oral f or 1 4 da ys  
L Y 3 5 0 9 7 5 4 1 0 0 -m g  
6 L Y 3 5 0 9 7 5 4; 2 place b o  
2 a 
1 x dail y oral f or 1 4 da ys b  
L Y 3 5 0 9 7 5 4 3 0 0 -m g  
8  L Y 3 5 0 9 7 5 4; 2 place b o  
3  
1 x dail y oral f or 1 4 da ys  
L Y 3 5 0 9 7 5 4 1 0 0 0 -m g  
6 L Y 3 5 0 9 7 5 4; 2 place b o  
a  P artici pa nts i n t his c o h ort will be a d mi nistere d  1. 2 -m g mi da z ola m i n oral s yr u p o n Da y s - 2 a n d 1 5 . O n Da y 1 5 , 
mi daz ola m a d mi nistrati o n will occ ur  at least 1 h o ur after partici pa nts recei ve  a si n gle oral d ose  of L Y 3 5 0 9 7 5 4 . 
C o h orts 1 a n d 3 ( Si n gle Peri o d) 
A dail y d os e of L Y 3 5 0 9 7 5 4 f or 1 4 da ys all o ws f or a de q uate d urati o n of ass ess me nt of t he safet y, 
t olera bilit y, a n d P K dat a at t he pr ojecte d L Y 3 5 0 9 7 5 4 h u ma n stea d y state c o nce ntrati o ns. 
Partici pa nts will re mai n i n t he C R U f or greater t ha n 9 6 h o urs f oll o wi n g t he last d ose, after w hic h 
t he y ma y b e disc har ge d o n Da y 1 9 at t he discreti o n of t he i n vesti gat or. 
 
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4 7  
C o h ort 2  ( Fi x e d Se q ue nce) 
 
 
 
 
 
 P artici pa nts will be a d mitte d t o t he C R U o n Da y -4 . 
P artici pa nts will be d ose d wit h 1. 2 -m g mi daz ola m  i n oral s yr u p  f or m o n Da y -2  a n d s erial bl o o d 
sa m ples will be c ollecte d f or deter mi nati o n of pl as ma mi daz ola m c o nce ntrati o ns  ( See Secti o n 
4. 3. 3 . f or d ose j ustificati o n). F oll o wi n g mi daz ola m d osi n g, 8 partici pa nts will be ra n d o ml y 
assi g ne d t o recei ve 3 0 0  m g of L Y 3 5 0 9 7 5 4  a n d 2 t o recei ve pl ace b o  ( See S ecti o n 4. 3. 3 . f or d ose 
j ustificati o n). T he M A D d ose escal ati o n  will  b e gi n o n Da y 1 . 
O n Da y 1 5 , partici pa nts will recei ve an ot her  si n gl e d ose of L Y 3 5 0 9 7 5 4 3 0 0 -m g  (see S o A 
[ Secti o n 1. 3. 5 ] f or details). At least 1 h o ur f oll o wi n g L Y 35 0 9 7 5 4 a d mi nistrati o n, partici pa nts 
will  be gi ve n a n ot her 1. 2 m g d ose of mi daz ola m  (i n oral s yr u p f or m) a n d serial bl o o d sa m ples 
will be c ollecte d f or deter mi nati o n of plas ma mi daz ola m c o nce ntrati o ns . T he d osi n g of 
L Y 3 5 0 9 7 5 4 or mi daz ola m will occ ur at a p pr o xi matel y t h e sa me ti me eac h d osi n g  da y t hr o u g h 
Da y 1 4  as det aile d i n t he S o A ( Secti o n 1. 3. 5 ). P artici pa nts will re mai n i n t he C R U f or at least 
9 6  h o urs after d osi n g ( u ntil Da y 1 9 ) acc or di n g t o t he S o A ( Secti o n 1. 3. 5 ), after w hic h t he y m a y 
be disc har ge d at t he discreti o n of t he i n vesti gat or. See Fi g ure  F N A A. 2  f or a sc he matic dia gra m 
of t he st u d y d esi g n f or P art C ( C o h ort 2).  
C o h orts 1 -3 (all C o h orts) 
All a vaila ble P K a n d  safet y data, i n cl u di n g A Es, vital si g ns ( B P a n d P R), E C Gs, a n d cli nical 
la b orat or y tests, fr o m at least 6 partici pa nts i n eac h c o h ort will be assesse d pri or t o escalati n g t o 
t he ne xt d ose le vel (see S ecti o n 6. 6. 1 ). Safet y d ata m ust i ncl u de data fr o m at least 5 da ys fr o m a 
mi ni m u m of 6 partici pa nts ( Secti o n s 6. 6. 1  a n d 9. 3. 5 ). 
See Secti o n 6. 6. 1  f or i nf or mati o n re gar di n g d os e m o dificati o ns, i ncl u di n g d ose decisi o n a n d 
escalati o n.  
A d diti o nal  c o h orts ma y b e re q uir e d t o safel y i n vesti gate ma xi m u m e x p os ure t o L Y 3 5 0 9 7 5 4 ; t his 
decisi o n will be ma de bet wee n t he s p o ns or a n d t he i n vesti gat or, f oll o wi n g t he necessar y re vie w 
of t he safet y d ata. T he P K data e mer gi n g d uri n g  t he M A D part of t he st u d y will  be use d t o assist 
i n M A D d ose -escalati o n decisi o ns . 
I n all c o h orts, P K  sa m pli n g will be c o n d u cte d as d etaile d i n t he S o A ( Secti o n 1. 3. 4  a n d 1. 3. 5 ) 
a n d a p ostst u d y f oll o w -u p visit will be c o n d ucte d a p pr o xi matel y 7 da ys afte r disc har ge.  
F or a d diti o nal details o n t he ti mi n g of st u d y acti vities see Secti o n 1. 3  
 
 
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4 8 
 
Fi g ure F N A A. 2.  
P art C: M ulti ple- Asce n di n g D ose a n d Per petr at or D DI 
 C o h ort 2 
Fi xe d Se q ue nce) 
4. 2. 4.  
P a rt D ( M ulti ple D osi n g i n J a p a nese H e alt h y P artici p a nts) 
Part D c haracterizes L Y 3 5 0 9 7 5 4 safet y, t olera bilit y, a n d P K i n a J a pa n ese healt h y p o p ul ati o n t o 
i nf or m t he i ncl usi o n of patie nts of J a panese ori gi n i n f ut ure P s O a n d ot her disease state st u dies. 
Part D will be c o n d ucte d after re vie w of safet y, t ol era bilit y, a n d P K data fr o m ot her parts of t he 
st u d y. 
Part D will e x pl ore 2 d ose le vels i n 2 se parate c o h orts (see Secti o n 4. 3. 1 . f or d ose j ustificati o n). 
Eac h c o h ort will c o nsist of at least 8 partici p a nts ( 6 L Y 3 5 0 9 7 5 4: 2 place b o). T he 2 c o h orts will 
be r u n si m ulta ne o usl y, a n d 
partici pa nts (see Secti o n 4. 2. 3 f or det ails). F or f urt her i nf or mati o n o n t he st u d y desi g n 
f or Part D, refer t o t he Part C ( M A D) descri bi n g C o h orts 1 a n d 3 a n d C o h orts 1- 4 (all C o h orts) i n 
Secti o n 4. 2. 3 . 
See Secti o n 5. 3. 1 f or me als a n d dietar y restricti o ns f or all Parts ( A- D) of t h e st u d y 
4. 2. 5.  
R ati o n ale f or E xcl u di n g Se nti nel D osi n g 
W hile a rece ntl y p u blis he d E ur o pea n Me dici nes A ge nc y g ui deli ne ( E M A 2 0 1 7) rec o m me n ds us e 
of se nti nel d osi n g i n first- i n- h u ma n st u dies, it als o all o ws f or fle xi bilit y i n a pr o p ose d d osi n g 
a p pr oac h b ase d o n t he a v aila ble scie ntific dat a a n d precli nical ass ess me nt of a gi ve n m olec ule. 
Base d o n t h e ris k assess me nt of t he a vaila ble dat a, L Y 3 5 0 9 7 5 4 d oes n ot prese nt a hi g h 
u ncertai nt y pr ofile as des cri be d b y De Ge or ge et al. ( 2 0 1 8), w hic h w o ul d necessitate i ncl usi o n of 
t he se nti nel d osi n g a p pr oac h. 
Na mel y, t he f oll o wi n g c h aract eristics of t he m olec ule w o ul d tri g ger a hi g her le vel of c o n cer n, 
n o ne of w hic h is t he case wit h L Y 3 5 0 9 7 5 4: 
 Lac k of n o n cli nical p har mac ol o g y m o d el i n vi v o t hat ca n reas o na bl y pre dict 
i nte n de d a n d e x a g gerate d p har mac ol o gicall y acti v e a n d e x cessi ve 
p har mac ol o gic al res p o ns es i n relati o n t o meas ura ble dr u g c o nce ntrati o n i n vi v o 
a n d beca use t he tar get is a n e n d o ge n o us h u ma n tar get, 
A N D  
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 A ni mal t o xicit y m o dels are u n derst o o d ( or e x pecte d) t o p o orl y reflect k n o w n 
h u ma n t o xicit y f or t h e tar get,  
O R  
 T he t y p es of t o xicit y t h at are k n o w n or ca n b e a nti ci pate d are se v ere, li kel y 
irre versi ble, a n d wit h o ut a de q uate pr o dr o mal si g ns. 
N o ncli nical p har ma c ol o g y m o dels e xist f or t he pre dicti o n of i nte n de d a n d e x a g gerat e d 
p har mac ol o g y i n c o nj u ncti o n wit h meas ure me nts of dr u g c o nce ntrati o n. T h e i nte n de d a n d 
e x a g gerate d p har mac ol o gic al res p o nses of L Y 3 5 0 9 7 5 4  ha ve bee n well c h aract erize d i n 
precli nical p har mac ol o g y m o dels. T he n o ncli nical safet y pr ofile of L Y 3 5 0 9 7 5 4 , as c haracterize d 
i n 1 -m o nt h rat a n d d o g  t o xic ol o g y st u dies, s h o we d all fi n di n gs were c o m pletel y re versi ble e x ce pt 
f or li ver wei g hts, stellate cell h y p ertr o p h y a n d he p at ocell ular vac u olati o n, o bser ve d i n rats, 
w hic h were partiall y re versi ble (l o wer i nci d e nc e a n d se verit y after t he rec o ver y p hase).  
Secti o n 4. 3. 1  pr o vi des  t he d ose j ustificati o n. T he l ar ge mar gi ns of safet y f or t he pla n ne d starti n g 
d ose of 1 0  m g i n t he S A D ( Part A) s u bj u gate t h e nee d f or s e nti nel d osi n g.  
See Secti o n 4. 2. 1 of t he I B f or m or e details o n n o ncli nical t o xic ol o g y a n d safet y p har m ac ol o g y.  
T he t y p es of a d v erse fi n di n gs a ntici pate d are mil d, gra d ual i n o nset, tra nsie nt, re versi ble a n d 
m o nit ora ble. Bas e d o n t he a b o ve -s u m marize d data, L Y3 5 0 9 7 5 4  d o es n ot prese nt a n u ncertai nt y 
pr ofi le necessitati n g a se nti nel d osi n g a p pr oac h. F urt her m ore, s e nti nel d osi n g wit h l o w-
u ncertai nt y  c o m p o u n ds, s uc h as  L Y 3 5 0 9 7 5 4 , ma y lea d t o i na bilit y t o i nter pret data d ue t o false 
p ositi ve A E fi n di n gs i n t he a bse nce of data fr o m all c o h orts or place b o -treated partici pa nts.  
4. 3.  
J ustific ati o n f or D ose  
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5 2  
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5.  
St u d y P o p ul ati o n  
Pr os pecti ve a p pr o val of pr ot oc ol de viati o ns t o recr uit me nt a n d e nr oll me nt criteria, als o 
k n o w n as pr ot oc ol wai v e rs or e x e m pti o ns, is n ot per mitte d . 
Eli gi bilit y of partici pa nts  f or t he st u d y will be bas e d o n t he res ults of scree ni n g me dical 
hist or y, p h ysical e x a mi nati o n, vital si g ns, cli nical la b orat or y tests, a n d E C G s. T he nat ur e of 
a n y c o n di ti o ns prese nt at t he ti me of t he p h ysi cal e x a mi nati o n a n d a n y pree xisti n g c o n diti o ns 
will be d oc u me nte d. Scree ni n g ma y o cc ur u p t o 2 8 da ys pri or t o e nr oll me nt. Partici pa nts  w h o 
are n ot e nr olle d wit hi n 2 8  da ys of scree ni n g ma y be s u bjecte d t o a n a d diti o nal me dical 
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.  
5. 1.  I ncl usi o n Criteri a 
Partici pa 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 f oll o wi n g criteria a p pl y  
at scree ni n g: 
A ge  
1.  Partici pa nt m ust be bet w ee n t he a ges of 1 8  a n d 6 5 years of a ge, i ncl usi ve, at t he ti me 
of si g ni n g t he i nf or m e d c o nse nt.  
a. In Part D , J a pa nese partici pa nts m ust be bet wee n t he a ges of 2 0 a n d 6 5 years 
of ol d , incl usi ve, at t he ti me of si g ni n g t he i nf or me d c o nse nt.  
T y pe of P artici p a nt a n d Dise ase C h ar a cteristi cs  
2.  O vertl y h ealt h y males or fe males, as d eter mi ne d b y me dical hist or y a n d p h ysical 
e x a mi nati o n . 
a. T o q ualif y as J a pa nese f or Part D  of t his st u d y , t he partici pa nt m ust be 
first-ge nerati o n J a pa nese, defi ne d as t he p artici pa nt’s bi ol o gical pare nts a n d 
all of t he partici pa nt’s bi ol o gical gra n d pare nts m ust be of e x cl usi ve J a pa nese 
desce nt, a n d m ust ha v e b ee n b or n i n J a pa n.  
3.  H a ve cli nic al la b orat or y t est res ults wit hi n n or mal refere nce ra n ge f or t he p o p ulati o n 
or i n vesti gati ve site, or res ults wit h acce pta b le de viati o ns 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; ha ve a uri nar y pr otei n val ue < 2 + o n di pstic k 
uri nal ysis . 
4.  H a ve ve n o us access s uffi cie nt t o all o w f or bl o o d s a m pli n g a n d/ or a d mi nistrati o n of 
st u d y i nter ve nti o n f or i ntra ve n ous  a d mi nistrati o n as per t he pr ot o c ol . 
5.  A re relia ble a n d willi n g t o ma ke t he msel ves a v aila 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 . 
B MI  
6.  B o d y mass i n de x ( B MI) wit hi n t he ra n ge of 1 8 t o 3 5  k g/ m 2 (i ncl usi ve) i n Parts A, B, 
a n d C . I n Part D  (J a pa nes e partici pa nts), b o d y wei g ht bet w ee n 5 0 a n d 8 5 k g a n d B MI 
wit hi n t he ra n ge of 1 8 t o 2 8 k g/ m 2. 
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Se x  
7.   M ale a n d/ or fe 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 ul ati o ns re gar di n g 
t he met h o ds of c o ntrace pti o n f or t h ose partici pati n g i n cli nical st u dies. 
a. M ale partici pa nts  
Please refer t o A p p e n di x 4 ( Secti o n 1 0. 4 ) f or d efi niti o ns a n d a d diti o nal g ui da nce 
relate d t o c o ntrace pti o n. 
b.  F e male p artici pa nts  
1)  W o me n of c hil d beari n g p ote ntial are e x cl u de d fr o m t he trial.  
2)  W o me n n ot of c hil d beari n g p ote ntial ma y p ar tici p ate a n d i ncl u de t h ose w h o 
are:  
A.  i nfertile d ue t o s ur gical steriliz ati o n ( h ysterect o m y, bilateral 
o o p h orect o m y, or t u bal li gati o n), c o n ge nital a n o m al y s uc h as 
M ülleria n a ge n esis; or   
B.  p ost -me n o pa usal –  d efi n e d  i n A p pe n di x 4  ( Secti o n 1 0. 4 )   
I nf or me d C o nse nt  
8.  Ca pa ble of gi vi n g si g n e d i nf or me d c o nse nt as d es cri be d i n A p pe n di x 1 (Secti o n  
1 0. 1. 2 ), w hic h i ncl u des c o m plia nce wit h t he re q uire me nts a n d restricti o ns 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   
Partici pa nts are e x cl u de d fr o m t he st u d y if a n y of t he f oll o wi n g criteria  a p pl y:  
Me dic al C o n diti o ns  
S u bjects will be e x cl u de d fr o m t he st u d y if t h e y meet a n y of t he f oll o wi n g criteria at 
scree ni n g a n d/ or e nr oll m e nt: 
9.  A re i n vesti gati ve site pers o n nel directl y affiliate d wit h t his st u d y a n d t h eir 
i m me diate fa milies. I m m e diate fa mil y is defi ne d as a s p o use, bi ol o gical or l e gal 
g uar dia n, c hil d, or si bli n g . 
1 0.  Are  Lill y e m pl o yees . 
1 1.  Are  c urre ntl y e nr olle d i n a cli nical st u d y i n v ol vi n g a n i n vesti gati o nal pr o d uct or 
a n y ot h er t y pe of m e dical researc h j u d ge d n ot t o b e scie ntificall y or me di ca ll y 
c o m pati ble wit h t his st u d y. 
1 2.  Ha ve  partici pate d, wit hi n t he last  3 0 da ys, i n a cli nical st u d y i n v ol vi n g a n 
i n vesti gati o nal pr o d u ct. If t he pre vi o us i n vesti gati o nal pr o d uct has a l o n g h alf-life, 
5 half -li ves or 3 0 da ys ( w hic he ver is l o n ger) s h o ul d ha ve pa sse d. 
1 3.  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 h er st u d y 
i n vesti gati n g L Y 3 5 0 9 7 5 4 , a n d ha ve pre vi o usl y recei ve d L Y3 5 0 9 7 5 4 . 
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1 4.  Ha ve  k n o w n aller gies t o L Y 3 5 0 9 7 5 4 , relate d c o m p o u n ds or a n y c o m p o ne nts of 
t he f or m ulati o n, itrac o naz ole, mi daz ola m , or hist or y of si g nifi ca nt at o p y . 
1 5.  Ha ve  a n a b n or malit y i n t he 1 2 -lea d E C G t hat, i n t he o pi ni o n of t he i n vesti gat or, 
i ncreas es t he ris ks ass oci ate d wit h partici pati n g i n t he st u d y. 
1 6.  Ha ve  a m ar ke d b aseli ne pr ol o n gati o n of c orrecte d Q T ( Q Tc) i nter val  (f or 
e x a m ple, re peate d d e m o nstrati o n of a Q Tc F  i nter val > 4 5 0 msec f or males or 
> 4 7 0  msec f or  fe mal es). 
o  A hist or y of a d diti o nal ris k fact ors f or T orsa d es d e P oi ntes (f or e x a m ple, h eart 
fail ure, h y p o kal e mia, fa mil y hist or y of L o n g Q T S y n dr o me). 
o  T he use of c o nc o mita nt me dicati o ns t hat pr ol o n g t he Q T/ Q Tc i nter val . 
1 7.  Ha ve  a n a b n or mal B P (ta ke n after t he s u bject has bee n i n a s u pi ne p ositi o n f or at 
least 5 mi n utes) f or t he p o p ulati o n, as deter mi ne d b y a s yst olic B P > 1 4 0  m m H g 
or a diast olic B P > 9 0  m m H g at s cree ni n g or  a pree xisti n g hist or y of 
h y perte nsi o n. U p t o 2 a d diti o nal meas ure me nts ma y b e ta ke n after a n a p pr o priate 
resti n g i nter val at scree ni n g t o c o nfir m eli gi bilit y. 
1 8.  Ha ve  a si g nifica nt hist or y of or c urre nt car di o vas c ular, res pirat or y, he p atic, re nal, 
gastr oi ntesti nal, e n d o cri n e (s uc h as C us hi n g s y n dr o me, h y p ert h yr oi dis m, 
h y peral d oster o nis m), he mat ol o gical, or n e ur ol o gi cal dis or ders ca pa bl e of 
si g nifica ntl y alteri n g t h e a bs or pti o n, meta b olis m, or eli mi nati o n of dr u gs; of 
c o nstit uti n g a ris k w he n t a ki n g t he i n v esti gati o nal me dici nal pr o d uct (I M P); or of 
i nterferi n g wit h t he i nter pretati o n of data. 
1 9.  Ha ve  a hist or y of or c urre nt si g nifica nt ps yc hiatri c dis or ders . 
2 0.  Ha ve  a hist or y of hea d i nj ur y ( e. g., s k ull fract ure, cere bral c o nt usi o n, tra u m a 
res ulti n g i n pr ol o n ge d u n c o nsci o us ness), i ntracra nial ne o plas m or he m orr h a ge, 
pri or seiz ure ( ot her t h a n re m ote hist or y of c hil d h o o d fe brile  seiz ure), or ot h er 
c o n diti o n t hat w o ul d place t he s u bject at i ncreas e d ris k of  seiz ure. 
2 1.  Re g ularl y  us e k n o w n dr u gs of a b use a n d/ or  s h o w p ositi ve fi n di n gs o n dr u g 
scree ni n g. 
2 2.  S h o w  e vi de nce of h u ma n i m m u n o deficie nc y vir us ( HI V) i nf ecti o n a n d/ or p ositi ve 
h u ma n HI V a nti b o dies . 
2 3.  S h o w  e vi de nce of he patitis B a n d/ or p ositi ve he patitis B s urface a nti ge n . 
2 4.  S h o w  e vi de nce of he patitis C a n d/ or p os iti ve he patitis C a nti b o d y. 
2 5.  F or fe male partici pa nts  
a. 
are w o me n w h o are lact ati n g  
b.  
are w o me n wit h a p ositi ve pre g na n c y test at scree ni n g  
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2 6.  Ha ve  use d or i nte n d t o use o ver -t h e-c o u nter/ her bal s u p ple me nts ( e. g., St. J o h n’s 
w ort)  or pres cri pti o n me dicati o n wit hi n 1 4  da ys or 5 half -li ves, w hic he v er is 
l o n ger, bef ore i nitial d osi n g or d uri n g t h e st u d y ( vita mi n/ mi neral s u p ple me nts a n d 
occasi o nal paraceta m ol/ aceta mi n o p he n u p t o 3 -g d ose i n a 2 4 -h o ur p eri o d are 
all o we d). If t his sit uat i o n arises, i ncl usi o n of a n ot her wise s uita ble s u bject ma y b e 
at t he discreti o n of t he i n vesti gat or a n d s p o ns or. Me dicati o ns t hat i n hi bit or 
i n d uce C Y P 3 A 4 are s p ecificall y e x cl u de d wit hi n 1 4 da ys pri or t o d osi n g a n d 
d uri n g t he st u d y . 
2 7.  Ha ve  d o nat e d bl o o d of m ore t ha n 4 5 0 m L or ha v e partici pate d i n a cli nical  st u d y 
t hat re q uire d si milar bl o o d v ol u me dra w n wit hi n t he past 3 cale n dar m o nt hs . 
2 8.  Ha ve  a n a vera ge w ee kl y alc o h ol i nta ke t hat e x cee ds 2 1 u nits per wee k ( m ales) 
a n d 1 4 u nits per wee k ( f emales ) or are u n wil li n g t o st o p alc o h ol c o ns u m pti o n f or 
2 4 h o urs pri or t o C R U a d missi o ns u ntil t he c o m pleti o n of eac h st u d y p eri o d ( 1 
u nit = 1 2 oz or 3 6 0 m L of beer; 5  oz or 1 5 0  m L of wi ne; 1. 5 oz or 4 5 m L of 
distille d s pirits) . 
2 9.  H a ve t o ba cc o c o ns u m pti o n of m ore t ha n 1 0 ci gar ettes per da y ( or t he e q ui vale nt) 
or are u n a ble or u n willi n g t o refrai n fr o m nic oti ne use w hile resi de nt at t he C R U . 
3 0.  C o ns u me Se ville ora n ges or Se ville ora n ge – c o ntai ni n g pr o d u cts, re d wi ne, 
gra pefr uit or gra p efr uit -c o ntai ni n g pr o d ucts, star fr uits or star fr uit-c o nt ai ni n g 
pr o d ucts, p o me gra n ates, a n d/ or p o mel os wit hi n 1 4  da ys pri or t o d osi n g or d uri n g 
t he st u d y. 
3 1.  I n t he o pi ni o n of t h e i n vesti gat or or s p o ns or, are u ns uita ble f or i ncl usi o n i n 
t he st u d y. 
3 2.  Ha ve a c urre nt or rece nt ac ute acti ve i nfecti o n. F or at le ast 3 0 da ys pri or t o scree ni n g, 
patie nts m ust ha ve n o si g nifica nt s y m pt o ms i ncl u di n g fe v er of 1 0 0. 5° F ( 3 8° C) or a b o ve, 
at scree ni n g or baseli ne, a n d/ or si g ns of c o nfir me d or s us pecte d i nfecti o n, a n d m ust ha ve 
c o m plete d a n y a p pr o priat e a nti -i nfecti ve treat me nt. 
a. I n Part D , J a pa nese partici pa nts wit h b o d y te m perat ure a b o v e 3 7. 5°C will be 
e x cl u de d.  
3 7.  s h o w e vi de nce of acti ve or late nt t u berc ul osis ( T B), bas e d o n a p ositi ve m e dical hist or y, 
e x a mi nati o n, a n d/ or T B test res ults.  Q ua nti F E R O N -T B G ol d Pl us test ( Q F T Pl us or 
e q ui vale nt) will be use d f or T B testi n g, a n d p artici pa nts m ust test ne gati ve t o partici pate.  
If t he i nitial res ult is i n deter mi nate, a si n gle re peat test is all o we d.  If t he re peat test res ult 
is p ositi ve or i n deter mi nate, t he partici pa nt is dee me d i neli gi ble. 
 
I n a d diti o n, f or P art B o nl y: 
3 3.  Ha ve i m paire d h eari n g or a hist or y of heari n g pr o ble ms (rati o nale: beca use itrac o naz ole 
has bee n ass o ciate d wit h tra nsie nt or per m a ne nt heari n g  l oss). 
 
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Pri or/ C o nc urre nt Cli nic al St u d y E x perie nce  
3 4.  A re c urre ntl y e nr olle d i n a cli nical trial i n v ol vi n g a st u d y i nter ve nti o n or off -la bel use of 
a dr u g or de vi ce, or are c o nc urre ntl y e nr olle d i n a n y ot her t y p e of me dical researc h 
j u d ge d n ot t o be sci e ntificall y or me dicall y c o m p ati ble wit h t his trial. 
3 5.  Ha ve bee n treate d wit h bi ol o gic a ge nts (s uc h as m A bs, i ncl u di n g mar k ete d dr u gs) wit hi n 
3  m o nt hs or 5 half -li ves ( w hic he ver is l o n ger) pri or t o d osi n g. 
Ot her E xcl usi o ns  
3 6.  A re u n willi n g t o st o p alc o h ol c o ns u m pti o n d uri n g st u d y visits/ti me i n t he researc h u nit. 
5. 3.  Lifest yle C o nsi de r ati o ns 
T hr o u g h o ut t he st u d y, partici pa nts  ma y u n d er g o me dical assess me nts a n d re vie w of 
c o m plia nce wit h re 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.  Refrai n fr o m c o ns u m pti o n of re d wi ne, Se ville ora n ges  or Se ville ora n ge – c o ntai ni n g 
pr o d ucts , gra p efr uit or gra pefr uit-c o ntai ni n g pr o d ucts, star  fr uits or star  fr uit-
c o ntai ni n g pr o d u cts, p o me gra nat es, a n d/ or p o mel o  fr o m 1 4 da ys bef ore t he start of 
st u d y i nter ve nti o n u ntil after t he fi nal d os e . 
2.  Part A  ( S A D): P artici pa nts  i n all c o h orts will be re q uire d t o fast o ver ni g ht ( at least 
8  h o urs) pri or t o d osi n g o n Da y 1 a n d f or at least 2 h o urs after d osi n g wit h 
L Y 3 5 0 9 7 5 4/ pla ce b o, wit h t he e x ce pti o n of water, w hic h will be freel y a vail a ble after 
d osi n g.  L Y 3 5 0 9 7 5 4  s h o ul d be a d mi nistere d wit h a p pr o xi matel y 2 4 0 m L of r o o m 
te m perat ur e water. O n i nte nsi ve P K da ys, p artici p a nts ma y recei ve a li g ht brea kfast 
a p pr o xi matel y 2  h o ur s after d osi n g.  
S A D c o h ort u n der g oi n g f o o d effect e val u ati o n  ( Part A, C o h ort 4): Partici pa nts will be 
re q uire d t o f ast o ver ni g ht (at least 8 h o urs) pri or t o d osi n g o n Da y 1 o f Peri o ds 1 a n d 
2 . Partici pa nts will start t he hi g h-fat meal (see b el o w) 3 0 mi n utes pri or t o 
a d mi nistrati o n of L Y 3 5 0 9 7 5 4 o n Da y 1  of  Peri o d 2 . Partici pa nts will c o ns u me t his 
e ntire meal i n 3 0 mi n utes or less , a n d L Y 3 5 0 9 7 5 4 will be a d mi nistere d 3 0  mi n utes 
after t he start of t he meal. I n Peri o ds 1 a n d 2, L Y 3 5 0 9 7 5 4 s h o ul d be a d mi nistere d 
wit h a p pr o xi matel y 2 4 0 m L of r o o m te m perat ur e water. N o f urt her f o o d will be 
all o we d f or at least 2 h o urs p ost d ose i n Peri o d 1 a n d at least 4  h o urs p ost d ose  i n 
Peri o d 2 . Fl ui ds will be restricte d fr o m 1 h o ur pri or t o a n d u n til 1 h o ur after d osi n g, 
e x ce pt f or fl ui d pr o vi de d wit h t he meal i n Peri o d 2 a n d water re q uir e d f or d ose 
a d mi nistrati o n  i n b ot h peri o ds. O n i nte nsi ve P K da ys, p artici pa nts ma y recei ve a li g ht 
brea kfast a p pr o xi matel y 2  h o urs after d osi n g L Y 3 5 0 9 7 5 4/ place b o i n Peri o d 1.  
 
T he sta n dar dize d hi g h -fat, hi g h-cal orie meal (fat c o m prises a p pr o xi matel y 5 0 % of 
t otal cal oric c o nte nt of t h e meal) i n Peri o d 2 s h o ul d c o nsist of a p pr o xi matel y 
1 0 0 0  cal ories. N o a d diti o nal f o o d or s u bstit ute is all o we d. A t y pical test meal is 
2  e g gs frie d or s cra m ble d i n b utter, 2  stri ps of bac o n, 2 slices of t oast wit h b utter, 
4  o u nces of has h br o w n p otat oes, a n d 8  o u nces of w h ole mil k. T his test meal deri ves 
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a p pr o xi matel y 1 5 0, 2 5 0, a n d 5 0 0 t o 6 0 0  cal ories fr o m pr otei n, car b o h y drat es, a n d fat,  
res pecti vel y. 
3.  Part B  ( D DI victi m): Partici pa nts  will be re q uire d t o fast o ver ni g ht (at least 8 h o urs) 
pri or t o eac h d osi n g da y a n d f or at least 2 h o urs after d osi n g wit h L Y 3 5 0 9 7 5 4, a n d 
c oa d mi nistrati o n of L Y 3 5 0 9 7 5 4 a n d itrac o naz ole, wit h t he e x ce pti o n of water t hat 
will be freel y a vaila ble after d osi n g . L Y 3 5 0 9 7 5 4 s h o ul d be a d mi nistere d wit h 
a p pr o xi matel y 2 4 0  m L of r o o m te m perat ure water. O n t he da y w here  2 d os es of 
itrac o naz ole a d mi nistrati o n occ urs , partici pa nts will als o nee d t o fast f or 
a p pr o xi matel y 2  h o urs pri or t o t he e ve ni n g d ose of itrac o naz ole a n d at least 2 h o ur s 
after d osi n g, wit h t he e x ce pti o n of water, w hic h will be freel y a v aila ble after d osi n g.  
 
4.  Part C  (M A D) : I n all c o h orts, partici pa nts  will be re q uire d t o f ast o ver ni g ht (at least 
8  h o urs) o n all d osi n g d a ys a n d f or at least 2  h o urs after d osi n g  ( o n i nte nsi ve PK  
sa m pli n g da ys (s ee S o A i n S ecti o n 1. 3 ), wit h t he e x ce pti o n of water, w hic h will be 
freel y a vaila ble 1 h o ur after d osi n g. L Y 3 5 0 9 7 5 4 s h o ul d be a d mi nistere d wit h 
a p pr o xi matel y 2 4 0 m L of r o o m te m perat ure water. O n i nte nsi ve P K da ys, p artici pa nts  
ma y recei ve a li g ht brea kfast a p pr o xi matel y 2  h o ur s after d osi n g.  
I n Part C c o h ort u n der g oi n g per petr at or  D DI e val u ati o n : Partici pa nts will be re q uir e d 
t o fast o ver ni g ht (at least 8 h o urs) pri or t o eac h d osi n g da y (i n cl u di n g mi daz ola m a n d 
L Y 3 5 0 9 7 5 4 d osi n g ) a n d f or at least 2  h o urs after d osi n g wit h L Y 3 5 0 9 7 5 4, a n d 
c oa d mi nistrati o n of L Y 3 5 0 9 7 5 4 a n d mi daz ola m , wit h t he e x ce pti o n of water t hat will 
be freel y a vaila ble after d osi n g. L Y 3 5 0 9 7 5 4 s h o ul d be a d mi nistere d wit h 
a p pr o xi matel y 2 4 0  m L of r o o m te m perat ure water. F o o ds t hat are k n o w n  m o d ulat ors 
(i n hi bit ors or i n d ucers)  of C Y P 3 A m ust be s pecifi call y e x cl u de d 1 4 da ys b ef ore t h e 
first st u d y d osi n g da y u ntil t he last P K sa m ple has bee n o btai ne d. A d diti o nal dr u gs 
are t o be a v oi de d d uri n g t he st u d y u nless re q uire d  t o treat a n A E or f or t he treat me nt 
of a n o n g oi n g me dical pr o ble m.  If t he nee d f or c o nc o mita nt me dicati o n arises, 
i ncl usi o n or c o nti n uati o n of t he partici pa nt ma y b e at t he discreti o n of t he i n vesti gat or 
after c o ns ultati o n wit h Lill y cli nical p har mac ol o gi st. A n y a d diti o nal me dicati o n use d 
d uri n g t he st u d y m ust be d oc u me nte d.  
 
5.  Part D  (J a pa nese m ulti ple d ose): Partici pa nts  will be re q uir e d t o fast o ver ni g ht (at least 
8  h o urs) o n all d osi n g d a ys a n d f or at least 2  h o urs after d osi n g o n i nte nsi ve P K da ys, wit h  
t he e x ce pti o n  of water, w hic h will be freel y a vaila ble 1 h o ur after d osi n g. L Y 3 5 0 9 7 5 4 s h o ul d 
be a d mi nistere d wit h a p pr o xi matel y 2 4 0 m L of r o o m te m perat ure water. O n i nte nsi ve P K 
da ys, p artici pa nts  ma y recei ve a li g ht brea kfast a p pr o xi matel y 2  h o ur s after d osi n g.  
 
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 s essi o n, partici pa nt s will a bstai n fr o m i n gesti n g caffei ne- or 
x a nt hi ne -c o ntai ni n g pr o d ucts ( e.g ., c offee, tea, c ola dri n ks , a n d c h o c olate) f or 4 8 h o urs 
bef ore t h e start of d osi n g u ntil after c ollecti o n o f t he fi nal P K  sa m ple. 
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2.  D uri n g eac h d osi n g s essi o n, partici pa nt s will a bstai n fr o m alc o h ol f or 4 8 h o urs bef ore  t he 
start of d osi n g u ntil after c ollecti o n o f t he fi nal P K  sa m ple. D uri n g t he st u d y, w hile n ot 
resi de nt at t he C R U, t he ma xi m u m dail y alc o h ol i nta ke s h o ul d n ot e xcee d 2 u nits (see 
E x cl usi o n Criteri o n [ 2 8 ], Secti o n 5. 2 , f or u nit defi niti o n). 
3.  S m o ki n g, t o bacc o c o ns u m pti o n, or use of a n y nic oti ne -re place me nt t hera p y is n ot 
per mitte d w hile resi de nt at t he C R U. Partici pa nts m ust be willi n g t o c o m pl y wit h t he 
C R U s m o ki n g restricti o ns.   W hile n ot resi de nt i n t he C R U, s m o ki n g s h o ul d n ot e xcee d 
1 0 ci garettes p er da y or e q ui vale nt i n nic oti ne use or nic oti ne s u bstit utes.  
 
5. 3. 3.  
Acti vit y  
4.  Partici pa nt s will a bstai n fr o m stre n u o us e x ercise f or 7 2  h o urs bef ore eac h bl o o d 
c ollecti o n f or cli nical la b orat or y tests.  Partici pa nt s ma y p artici pate i n li g ht r ecreati o nal 
acti vities d uri n g st u dies ( e.g ., watc h i n g tele visi o n, rea di n g). Partici p a nts s h o ul d a v oi d 
stre n u o us e x ercise a n d/ or acti vit y f or at least 7 2 h o urs pri or t o C R U a d missi o n a n d w hile 
resi de nt at t he C R U. Partici pa nts s h oul d re mai n u pri g ht f or at least 2 h o urs after d osi n g, 
wit h t he e x ce pti o n of a n y re q uire me nts f or pr ot oc ol pr oce d ures ( e. g., s u pi ne f or E C Gs). 
5.  Partici pa nts are n ot per mitte d t o ma ke bl o o d or plas ma d o nati o ns w hile partici pati n g i n 
t he st u d y. 
5. 3. 4.  
I nfecti o n Ris k 
Partici pa nts  s h o ul d f oll o w l ocal g ui da nce a n d C R U  preca uti o ns  t o mi ni mize ris k f or C O VI D -1 9 
i nfecti o n. 
5. 4.  
Scree n F ail ures  
Scree n fail ures are defi ne d as partici 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 e nr olle d i n t he st u d y a n d were n ot alter nates. 
Partici pa nts w h o d o n ot q ualif y at scree ni n g d ue t o a tra nsie nt mi n or ill ness (s uc h as a c ol d) ma y 
be rescree n e d o nce, 4 or m ore wee ks  after d oc u m e nte d res ol uti o n of s y m pt o ms. Partici pa nts w h o 
are ta ki n g a n y m e dicati o n or me dicati o ns s pecifi e d i n t he E x cl usi o n Criteria ( Secti o n 5. 2 ) ma y 
be rescree n e d o nce, f oll o wi n g a s ufficie nt w as h o ut peri o d deter mi ne d b y t h e i n vesti gat or base d 
o n t he e x cl usi o n criteria. W he n 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  a n d 
will be assi g ne d a ne w st u d y i de ntificati o n n u m ber. Partici pa nts w h o were eli gi ble f or i ncl usi o n 
i n pre vi o us c o h orts, b ut w h o were n ot ra n d o mize d f or n o n me dical r eas o ns, ma y b e reassesse d f or 
i ncl usi o n i n s u bse q ue nt c o h orts. 
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6.  
St u d y I nter ve nti o n  
St u d y inter ve nti o n is defi ne d as a ny i n vesti gati o nal i nter ve nti o n(s), mar ket e d pr o d uct(s), 
place b o , or me di cal de vi ce (s) i nte n d e d t o be a d mi nistere d t o/ use d b y 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 ns A d mi nistere d  
St u d y P art 
N a me  
Parts A, B, C, 
D a 
Parts A, B, C, 
D a 
Parts B  
Part C, 
C o h ort 2  
I nter ve nti o n 
N a me  
L Y 3 5 0 9 7 5 4  
Place b o  
Itr ac o n az ole Mi daz ola m  
D ose 
F or m ul ati o n 
a n d R o ute of 
A d mi nistr ati
o n  
Ca ps ule ta ke n 
orall y  
Ca ps ule ta ke n 
orall y  
Oral 
S ol uti o n  
Oral S ol uti o n 
(s yr u p) 
U nit D ose  
Stre n gt h  
E x peri me ntal/  
E xte m p ora ne o
us pre parati o n   
N/ A  
C o m bi nati o
n dr u g  
( 1 0 m g/ m L) 
C o m bi nati o n 
dr u g  
Pl a n ne d 
D os a ge 
Le vels  
1 0 m g –  2 0 0 0 
m g  
N/ A  
2 0 0 m g  
1. 2 m g  
S o urci n g  
N A  
Pr o vi de d 
ce ntrall y b y 
t he s p o ns or  
Pr o vi de d 
l ocall y b y 
t he trial site  
Pr o vi de d 
l ocall y b y t he 
trial site 
a Ca ps ules of 2 0 0 m g  L Y 3 5 0 9 7 5 4  d osa ge stre n gt h a n d c orres p o n di n g place b o  will be pr o vi de d b y t he sp o ns or  f or 
P art D . 
N ote: I nf or mati o n pr o vi de d i n t his ta ble ( d ose f or m ulati o n, s o urci n g, pac ka gi n g a n d la beli n g) ma y c ha n ge 
t hr o u g ho ut t he st u d y or ma y var y b y c o u ntr y.  
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 vesti 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 o ns ha ve bee n 
mai ntai ne d d uri n g tra nsit f or all st u d y i nter ve nti o n recei v e d a n d a n y dis cre p a ncies are  
re p orte d a n d res ol ve d b ef ore use of t he st u d y i nter ve nti o n. 
2.  O nl y partici pa nts e nr olle d i n t he st u d y ma y recei v e st u d y i nter ve nti o n a n d o nl y 
a ut h orize d site staff ma y s u p pl y or a d mi nister st u d y i nter ve nti o n. All st u d y i nter ve nti o n 
m ust be st ore d i n a sec ur e, 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 i n a cc or da nce wit h t he la bele d st ora ge c o n diti o ns wit h access li mite d t o 
t he i n vesti gat or a n d a ut h orize d site staff. 
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3.  T he i n vesti gat or, i nstit uti o n, or t he hea d of t he me dical i nstit uti o n ( w here a p plica ble) is 
res p o nsi ble f or st u d y i nter ve nti o n acc o u nt a bilit y, rec o nciliati o n, a n d rec or d mai nte na nce 
(i.e., recei pt, rec o nciliati o n, a n d fi nal dis p ositi o n rec or ds). 
4.  F urt her g ui d a nce a n d i nf or mati o n f or t he fi nal dis p ositi o n of u n use d st u d y i nter ve nti o ns 
are pr o vi d e d i n t he p har mac y  m a n ual. 
F or a n y s p ecific c o h ort/ d osi n g peri o d, t he t otal n u m ber of ca ps ules a d mi nistere d will be t he sa m e 
f or all part ici pa nts, re gar dless of w het her assi g n e d t o place b o or L Y 3 5 0 9 7 5 4. H o we ver, t he 
n u m ber of ca ps ules ma y var y bet wee n d osi n g peri o ds a n d c o h orts.  
L Y 3 5 0 9 7 5 4 will be s u p plie d i n t he f or m of L Y 3 5 0 9 7 5 4 p ure c o m p o u n d wit h n o i nacti ve 
i n gre di e nts f or e xte m p ora ne o us pre p arati o n of t h e st u d y i nter ve nti o n at t he C R U. T his will be 
perf or me d b y trai ne d p ers o n nel ( e. g., p har macist) wit hi n a facilit y at t he C R U, w hic h has bee n 
q ualifie d t o perf or m t hese t y p es of o perati o ns. I nstr ucti o ns f or e xte m p ora n e o us pre parati o n of 
t he st u d y i nter ve nti o n ( L Y 3 5 0 9 7 5 4 p ure c o m p o u n d fille d directl y i nt o a ca ps ule) will be 
pr o vi de d b y t he s p o ns or.  F or St u d y Part  D, a n a d diti o nal site has bee n  a d d e d t o recr uit t he 
re q uire d n u m ber of J a pa nese s u bjects. T h e sp o ns or is pr o vi d i n g L Y 3 5 0 9 7 5 4 i n t he f or m of 
2 0 0 -m g d osa ge stre n gt h ca ps ules  a n d c orres p o n di n g place b o.  
Cli nical trial materials will be la bele d acc or di n g t o t he c o u ntr y’s re g ulat or y re q uire me nts. T h e 
s u p plies will be st ore d at r o o m te m perat ur e. U n use d s u p pl y of st u d y i nter ve nti o n will re mai n i n 
t he p har mac y arc hi ves u ntil ret ur ne d t o t he s p o ns or or destr o ye d wit h t heir writte n per missi o n. 
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  
All parts  of t he st u d y are bli n de d wit h a n u n bli n de d site p har macist t hat will dis pe nse t h e dr u g. 
O n Da y 1, partici pa nts will be assi g ne d a u ni q ue n u m ber (ra n d o mizati o n n u m ber). T he 
ra n d o mizati o n n u m ber e nc o des t he partici pa nt’s assi g n me nt t o t he st u d y, acc or di n g t o t he 
ra n d o mizati o n sc he d ule. Eac h partici pa nt will be dis pe nse d st u d y i nter ve ntio n, la bele d wit h 
his/ her u ni q ue ra n d o mizati o n n u m ber, t hr o u g h o ut t he st u d y. Partici pa nts e nteri n g Peri o d 2 of 
Part A (2 -peri o d cr oss o v er ) will c o nti n ue wit h t heir assi g ne d u ni q ue n u m ber fr o m Peri o d 1.  
Partici pa nts will be se q ue ntiall y e nr olle d t o c o h orts. Wit hi n t he f oll o wi n g C o h orts, partici pa nts 
will be ra n d o mize d t o recei ve L Y 3 5 0 9 7 5 4 or place b o as descri be d i n Secti o n 4. 2 . 
I n v esti gat ors will re mai n bli n de d t o eac h partici pa nt’s assi g ne d st u d y i nter ve nti o n t hr o u g h o ut t he 
c o urse of t he st u d y. I n or der t o mai ntai n t his bli n d, a n ot her wise u ni n v ol ve d t hir d pa rty (f or 
ex a m ple a p h ar m a cist) will be res p o nsi ble f or t he rec o nstit uti o n a n d dis pe ns ati o n of all st u dy 
i nterve nti o n a n d will e n de av or t o e ns ure t h at t her e are n o differe nces i n ti me t ake n t o dis pe nse 
f oll o wi n g r a n d o miz ati o n. 
I n t he e ve nt of a Q ualit y Ass ura nce a u dit, t he a u dit or(s) will be all o we d access t o u n bli n de d 
st u d y i nter ve nti o n rec or ds at t he site(s) t o verif y t h at ra n d o mizati o n/ dis pe nsi n g has b ee n d o ne 
acc uratel y. 
Bli n di n g will be mai ntai ne d t hr o u g h o ut t he c o n d uct of t he st u d y as descri be d i n t he se parate 
Bli n di n g Pla n.  
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E mer ge nc y c o des will be a vaila ble t o t he i n vesti gat or. A c o de, w hi c h re v ea ls t he st u d y 
i nter ve nti o n c o h ort f or a s pecific st u d y partici p a nt, ma y b e o pe ne d d uri n g t he st u d y o nl y if t he 
partici pa nt’s well -b ei n g re q uires k n o wle d ge of t he partici pa nt’s treat me nt assi g n me nt  
If a partici pa nt’s st u d y tr eat me nt assi g n me nt is u n bli n de d, t he partici pa nt m ust be disc o nti n ue d 
fr o m t he st u d y, u nless t h e i n vesti gat or o btai ns s pecific a p pr o val fr o m a n Eli Lill y a n d C o m pa n y 
( Lill y) cli nic al p har ma c ol o gist ( C P) or cli nical r esearc h p h ysi cia n ( C R P) f or t he st u d y p artici pa nt 
t o c o nti n ue i n t he st u dy. D uri n g t h e st u d y, e mer ge nc y u n bli n di n g s h o ul d occ ur o nl y b y accessi n g 
t he st u d y partici pa nt’s e mer ge nc y c o de. 
I n case of a n e m er ge n c y, t he i n vesti gat or h as t he s ole res p o nsi bilit y f or d eter mi ni n g if u n bli n di n g 
of a partici p a nt’s treat me nt assi g n me nt is warra nte d f or me dical ma n a ge me nt of t he e ve nt. T he 
partici pa nt’s safet y m ust al wa ys be t he first c o nsi derati o n i n ma ki n g s u c h a deter mi nati o n. 
W here feasi ble a n d w he n ti mi n g of t he e mer ge nt sit uati o n per mits, t he i n vesti gat or s h o ul d 
atte m pt t o c o ntact t he Lill y me dical m o nit or bef ore u n bli n di n g a p artici pa nt’s treat me nt 
assi g n me nt. If t he i n vesti gat or d eci des t h at u n bli n di n g is warra nte d, it is t he res p o nsi bilit y of t he 
i n vesti gat or t o pr o m ptl y d oc u me nt t he decisi o n a n d rati o nale a n d n otif y Lill y as s o o n as p ossi ble.  
U p o n c o m pleti o n of t he st u d y, all c o d es m ust be ret ur ne d t o Lill y or its desi g nee.  
6. 4.  
St u d y I nter ve nti o n C o m pli a nce  
W he n t he i n di vi d ual d ose f or a p artici pa nt is pre p are d fr o m a b ul k s u p pl y, t he pre parati o n of t he 
d ose will be c o nfir me d b y a s ec o n d  m e m ber of t h e st u d y site staff.  
W he n partici pa nts are d ose d at t he site, t he y will recei ve st u d y i nter ve nti o n directl y fr o m t he 
i n vesti gat or or d esi g nee, u n der me dical s u p er visi o n. T he date a n d ti me of eac h d ose a d mi nistere d 
i n t he cli nic will be rec or ded i n t he s o urce d o c 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 i nter ve nti o n a n d st u d y partici pa nt i de ntificati 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 h e st u d y sit e staff ot her t ha n t he pers o n a d mi nisteri n g t he st u d y i nter ve nti o n . S t u d y 
site pers o n nel will m o nit or eac h p artici pa nt t o e ns ure t hat t he st u d y i nter ve nti o n was ta ke n 
acc or di n gl y t o t he i n vesti gati o nal pr o d u ct (I P) ma n ual . 
6. 5.  
C o nc o mit a nt T her a p y  
I n ge neral, c o nc o mita nt me dicati o n s h o ul d be a v oi de d. C Y P 3 A i n d ucers, i n hi bit ors a n d 
s u bstrates s h o ul d be a v oi de d u nless ot her wise i n di cate d as p art of t he D DI e val uati o ns i n Part C 
C o h ort 4. O nl y vita mi n/ mi neral  s u p ple me nts, H R T  a n d occasi o nal paracet a m ol/aceta mi n o p he n 
u p t o 3 -g d ose i n a 2 4 -h o ur peri o d are all o we d , at t he discreti o n of in vesti gat or f or t he tr eat me nt  
of hea dac hes, etc . (see E x cl usi o n Criteri o n  [2 6 ]). A n y me di cati o n  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  
 d ates of a d mi nistrati o n i ncl u di n g start a n d e n d dat es  
 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 
If t he nee d f or c o nc o mita nt me dicati o n ( ot her t ha n aceta mi n o p he n  or  H R T ) arises, i ncl usi o n or 
c o nti n uati o n of t he partici pa nt  i n t he st u d y ma y be at t he discreti o n of t he i n vesti gat or after 
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c o ns ultati o n wit h a Lill y cli nical p har mac ol o gist. Dr u gs t hat are k n o w n i n d ucers or i n hi bit ors of 
C Y P 3 A 4 are s pecific all y e x cl u de d  ( Secti o n 5. 2 ). A n y me di cati o n use d d uri n g t he c o urse of t he 
st u d y m ust be d oc u me nte d. 
T he Me dical M o nit or s h o ul d be c o ntacte d if t h ere are a n y q u esti o ns re gar di n g c o n c o mita nt or 
pri or t hera p y.  
6. 6.  
D ose M o dific ati o n  
D ose le vels or i ncre me nts, sa m pli n g sc he d ule, ti mi n g of pr o ce d ures ( e. g., P K a n d E C G 
assess me nts) a n d le n gt h of sta y at t he C R U ma y b e a dj uste d i n vie w of e mer gi n g s afet y, 
t olera bilit y, or P K dat a d uri n g t he st u d y. If c o nsi d ere d a p pr o priate, d os e i n cre me nts ma y b e 
re d uce d, a d ose le v el ma y be re peate d, or a l o wer/i nter me diate d ose ma y b e a d mi nistere d, b ut 
d ose escal ati o ns will n ot e x cee d a se mi -l o g ( 3. 3-f ol d) i ncreas e i n d ose. T he ti mi n g of t he 
sa m pli n g ma y be a dj uste d a n d a d diti o nal sa m ples ma y b e c ollecte d, as des cri be d i n t he S o A i n 
Secti o n  1. 3 . T he d urati o n of t he C R U sta y or t he d urati o n of safet y f oll o w-u p ma y b e i ncrease d 
(e. g., if t he half-life of L Y 3 5 0 9 7 5 4  is l o n ger t h a n a ntici pate d) b ut n ot decrease d. T hese c ha n ges 
m ust be a p pr o priatel y d o c u me nte d a n d c o m m u nicate d b y t he s p o ns or t o t he i n vesti gat or. 
Beca use t hes e a dj ust me nts t o ti mi n gs or d ose le vels are all o wa bl e c ha n ges per mitte d b y t he 
pr ot oc ol, t he y w o ul d n ot re q uire a pr ot oc ol a me n d me nt.  
6. 6. 1.  
D ose Decisi o n/ Esc al ati o n  
B y nat ur e of bei n g a d os e -escalati o n st u d y, d ata will be e val uate d o n a n o n g oi n g basis u ntil t he 
ma xi m u m t olerate d d ose ( M T D) is deter mi ne d , t h e hi g h est pla n ne d d ose is a d mi nistere d, or 
w he n di sc o nti n uati o n  crit eria are met  ( Secti o n 7 ). N o d ose escalati o n ca n o cc ur wit h o ut pri or 
disc ussi o n a n d a gree me nt bet wee n t he i n vesti gat or a n d t he Lill y  st u d y tea m. See Secti o ns 4. 2. 1  
a n d 4. 2. 3  f or f urt her details. 
P art s A  (S A D ) a n d C ( M A D): 
T he hi g h est d ose le vel t h at is t olerate d will be desi g nate d as t he M T D f or si n gle ( S A D) or 
m ulti ple ( M A D) d oses i n healt h y p artici pa nts. I nteri m  access t o st u d y data is sc he d ule d t o occ ur 
d uri n g t he st u d y t o i nf or m d ose escalati o n decisi o ns, as s pecifie d i n Secti o n 9. 3. 5 . 
I n Part A, safet y d ata  fr o m at least 5 da ys after t he last d ose of L Y 3 5 0 9 7 5 4 , i n partic ular A Es, 
S A Es, vital si g ns ( bl o o d press ure [ B P] a n d p ulse rate [ P R]), electr ocar di o gra ms ( E C Gs) a n d 
cli nicall y i m p orta nt la b orat or y a b n or malities, fr o m at least 6 partici pa nts i n eac h S AD c o h ort, 
will be t he pri mar y criteria f or d ose es calati o n decisi o ns. E mer gi n g P K data ma y als o be 
re vie we d. A vaila ble P K data fr o m t he first 2 d ose le vels i n t he S A D ( C o h orts 1 a n d 2) will be 
re vie we d pri or t o escalati o n t o t he t hir d d ose le vel ( d osi n g i n C o h ort 3). A vaila ble P K data fr o m 
t he t hir d a n d f o urt h d ose le vels i n t he S A D ( C o h ort 3 a n d C o h ort 4 Peri o d 1, res pecti vel y) will 
be re vie we d pri or t o es calati o n t o d osi n g i n C o h ort 5 . E mer gi n g d ata fr o m C o h orts 1 t o 5 of t he 
S A D will be re vie we d  pri or t o  escalati o n t o t he pla n ne d hi g hest S A D d ose le vel ( d osi n g i n 
C o h ort 6 ). After re vie w of t hese data, a n escalati o n t o t he ne xt d ose le vel will be j oi ntl y deci de d 
b y t he i n vesti gat or a n d s p o ns or.  
I n Part C, safet y data fro m at least 5 da ys  after t he last d ose of L Y 3 5 0 9 7 5 4 , fr o m at least 6 
partici pa nts i n S A D ( Part A) C o h ort 5, will be t he pri mar y criteria f or b e gi n ni n g d osi n g C o h ort 1 
of t he M A D. All a vaila bl e P K data fr o m t he S A D will be use d t o assist i n t he M A D C o h ort 1 
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d ose decisi o n. D ose escal ati o n will be base d o n safet y d ata, i n partic ular , 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, fr o m at least 6 partici pa nts i n eac h M A D c o h ort. 
A vaila ble P K data fr o m a l o wer d ose c o h ort will be re vie we d pri or t o es cal ati o n t o t he ne xt d ose 
le vel. After re vie w of t hese data, a n escal ati o n t o t he ne xt d ose le vel will be j oi ntl y d eci de d b y 
t he i n vesti gat or a n d s p o ns or. 
F or b ot h Parts A a n d C, a d diti o nal partici pa nts ma y be d os e d, if necessar y, t o mai ntai n at least 6 
partici pa nts c o m pleti n g eac h d ose le v el f or t he s afet y re vie w pri or t o t he ne xt d ose escalati o n. 
All a vaila ble P K data will be re vie we d o n a n o n g oi n g basis a n d ma y b e use d as s u p p orti n g d ata 
f or d ose es calati o n de cisi o ns f or b ot h parts . Safet y data, i n partic ular A Es, S A Es, a n d cli nicall y 
i mp orta nt la b orat or y a b n or malities, will be i n de pe n de ntl y ass esse d b y t he i n vesti gat or ( w h o will 
be bli n de d), as w ell as t he s p o ns or,  a n d will be c o nsi dere d rel ate d t o st u d y dr u g u nless t h ere is 
clear e vi de nce t hat t he e v e nt is n ot relate d. If d ose escalati o n is ter mi nate d pri or t o reac hi n g t h e 
ne xt hi g her d ose le v el be ca use of t olera bilit y iss ues, pre vi o us d ose le vels m a y b e re p eate d o r 
l o wer d ose le v els ma y b e teste d or a n alter nate d osi n g sc he d ule ( BI D) ma y be use d. F or Part C, 
a d diti o nal c o h orts ma y b e re q uir e d t o safel y i n vesti gate ma xi m u m e x p os ure t o L Y 3 5 0 9 7 5 4; t his 
decisi o n will be ma de bet wee n t he s p o ns or a n d t he i n vesti gat or, f o ll o wi n g t he necessar y re vie w 
of t he safet y d ata.  
P art B: L Y 3 5 0 9 7 5 4 I n hi biti o n  
T he d ose decisi o n f or Part B will be base d o n safet y dat a,  i n partic ular 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 fr o m Part A. All a vaila ble P K  data fr o m t he S A D will be 
use d t o assist i n t he Part B d ose sel ecti o n. T he sel ecte d d ose will be pre dict e d t o ha ve a n 
e x p os ure ra n ge less t ha n t he u p per li mit of t he M T D  i n Part A ( S A D), bas e d o n t he e x pecte d 
a p pr o xi matel y 9 -f ol d i ncrease i n L Y 3 5 0 9 7 5 4 e x p os ure w he n c o-ad mi nistere d wit h itrac o n az ole. 
See Secti o n 4. 3  f or f urt her L Y 3 5 0 9 7 5 4 d ose j ustificati o n. 
P art D: M ulti ple D osi n g in J a p a nese He alt h y P artici p a nts  
T he d ose decisi o n f or Part D  will be base d o n t he re vie w of safet y, t olera bilit y, a n d  a n y a vaila bl e  
P K data fr o m Part C ( M A D). T he d os e decisi o n f or Part D  will be base d o n safet y data, i n 
partic ular 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 m ali ties, fr o m at least 6 
partici pa nts i n t he ma xi m u m d ose e val uate d  i n t he M A D ( Part C) fr o m at least 5 da ys  after t he 
last d ose of L Y 3 5 0 9 7 5 4. 
Part D  will e x pl ore 2 d ose le vels i n 2 se parate c o h orts d ose d dail y f or 1 4  da ys. T he  2 d os e le vels 
st u die d will be  ru n si m ulta ne o usl y. T he C o h ort 1 a n d C o h ort 2 d ose le vels will n ot e xcee d t he 
ma xi m u m d ose e val uate d i n Part C ( M A D i n n o n -Ja pa nese p artici pa nts ). 
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.  
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7.  
Disc o nti n u ati o n or T e m p or ar y H alt  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  
7. 1.  
Disc o nti n u ati o n of St u d y I nter ve nti o n or St o p of R a n d o miz ati o n  
I n rare i nsta nces, it ma y be necessar y f or a partici pa nt t o per ma ne ntl y disc o nti n ue ( defi niti ve 
disc o nti n uati o n) st u d y i nter ve nti o n. If st u d y i nter ve nti o n is defi niti vel y disc o nti n ue d, t he 
partici pa nt will  re mai n i n t he st u d y t o be e v al uate d f or safet y a n d P K assess me nts. See t he S o A 
f or data ( Secti o n 1. 3 ) t o be c ollecte d at t he ti me of disc o nti n uati o n of st u d y i nter ve nti o n a n d 
f oll o w-u p a n d f or a n y f urt her e val uati o ns t hat nee d t o be c o m plete d. 
S h o ul d a treat me nt -e mer ge nt S A E d escri be d i n A p pe n di x 3 ( Secti o n 1 0. 3 ) occ ur , d osi n g a n d 
e nr oll me nt i n t he c o h ort will be s us pe n de d a n d t h e i n vesti gat or will c o ns ult t he me dical m o nit or 
f or rec o m me n dati o n. 
P ossi ble rec o m me n dati o ns i ncl u de:  
 res u me d osi n g/e nr oll me nt i n t he c o h ort,  
 m o ve t o a l o wer d ose, or  
 pa use  st u d y u ntil f urt h er e val uati o n. 
If a n y of t he f oll o wi n g s ce nari os occ ur, d osi n g at t he c urre nt le vel a n d f urt h er d ose es calati o n 
will be disc o nti n ue d:  
1)  a si n gle p artici pa nt e x perie nces a n S A E t hat is relate d  t o L Y 3 5 0 9 7 5 4 a d mi nistrati o n.  
2)  2 partici pa nts e x perie nce a cli nicall y si g nifica nt e ve nt ( C S E) of t o xic ol o gical fi n di n g 
t hat is dee me d t o be relate d t o L Y 3 5 0 9 7 5 4 a d mi nistrati o n.  
3)  2  partici pa nts e x perie nce cli nicall y si g nifica nt c ha n ges i n sc h e d ule d vital si g ns a n d 
la borat or y  res ults t hat are dee me d t o be relate d t o L Y 3 5 0 9 7 5 4 a d mi nistrati o n.  
4)  2 or m ore partici p a nts at 1 d ose le vel e x perie nce ot her m o derat e or se v ere 
treat me nt-relate d A E s t h at i m pair n or mal acti vities a n d are d ee me d t o b e relate d t o 
L Y 3 5 0 9 7 5 4 a d mi nistrati o n.  
If m o derat e or se v ere A Es are c o nsiste ntl y o bser ve d acr oss p artici pa nts i n a c o h ort, or if 
u nacce pta ble p har mac ol o gic al effects r eas o na bl y attri b uta ble t o st u d y i nter ve nti o n , i n t he 
o pi ni o n of t he i n vesti gat or , are o bs er ve d i n m ore t ha n 2 5 %  of t he partici pa nts i n a c o h ort, t he n 
d ose escal ati o n will be te m p oraril y h alte d a n d n o f urt her partici p a nts will be d ose d u ntil a f ull 
safet y re vi e w of t he st u d y has ta k e n place. Rele va nt re p orti n g a n d disc ussi o n wit h t he Me dical 
M o nit or, ot her rele v a nt pers o n nel, a n d t he I nstit uti o nal Re vie w B o ar d (I R B)/I n d e pe n d e nt Et hics 
C o m mittee (I E C) will ta ke place b ef ore res u m pti o n of d osi n g.  
F urt her m ore, a  p artici pa nt  will be disc o nti n ue d fr o m recei vi n g f urt h er d oses of st u d y 
i nter ve nti o n if t he i n vesti gat or assesses t hat c o nti n uati o n o n st u d y i nter ve nti o n ma y p ose a ris k t o 
t he well-bei n g of t he p artici pa nt  i n q uesti o n. Partici pa nts  ma y als o b e disc o nti n ue d fr o m t he 
st u d y i nter ve nti o n if a C S E occ urs, i n t he o pi ni o n of t he i n vesti gat or. F oll o wi n g t he 
i n vesti gat or’s d eter mi nati o n t hat C S E criteria ha v e bee n met, a n d t he i n vesti gat or’s j u d g me nt of 
relate d ness t o t he st u d y i nter ve nti o n is d oc u me nte d, a decisi o n will be ma de bet wee n t he 
i n vesti gat or a n d Lill y or its desi g nee re gar di n g partici pa nt disc o nti n uati o n. Disc o nti n uati o n of 
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t he st u d y i nter ve nti o n f or a b n or mal li ver tests s h o ul d be c o nsi dere d b y t h e i n vesti gat or w h e n a 
partici pa nt  meets 1 of t he f oll o wi n g c o n diti o ns , aft er c o ns ultati o n wit h t he Lill y d esi g nate d 
me dical m o nit or:  
 Ala ni ne a mi n otra nsf eras e ( A L T) or a s partate a mi n otra nsferase ( A S T) > 5 x u p per li mit of 
n or mal  ( U L N). 
 A L T or A S T > 3 x U L N s ustai ne d f or m ore t h a 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 nter nati o nal 
n or malize d rati o > 1. 5 or  
 A L T or A S T > 3 x U L N wit h t he a p pear a nce of fati g ue, na us ea, v o miti n g, ri g ht u p per -
q ua dra nt pai n or t e n der ness, fe ver, ras h, a n d/ or e osi n o p hilia ( > 5 %) . 
 Al kali 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 x U L N wit h t he a p peara n ce of fati g ue, na usea, v o miti n g, ri g ht q ua dra nt pai n or 
te n der ness, f e ver, ras h, a n d/ or e osi n o p hilia ( > 5 %). 
Partici pa nts  disc o nti n ui n g fr o m t he treat me nt pre mat urel y f or a n y reas o n s h o ul d c o m plete A E 
a n d ot her f oll o w -u p pr oce d ures per Secti o n 1. 3  of t his pr ot oc ol . 
If a cli nic all y si g nifica nt fi n di n g is i de ntifie d,i ncl u di n g, b ut n ot li mite d t o, c ha n ges fr o m b aseli ne 
i n Q T i nter val c orrecte d usi n g Fri dericia’s f or m ul a (Q Tc F ) after e nr oll me nt, t he i n vesti gat or or 
q ualifie d desi g nee will deter mi ne if t he partici pa nt  ca n c o nti n ue i n t he st u d y a n d if a n y c h a n ge i n 
partici pa nt  ma na ge me nt is nee de d . T his  re vie w of t he E C G pri nte d at t he ti me of c ollecti o n m ust 
be d oc u me nte d . A n y n e 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.  
See t he S o A  f or dat a t o be c ollecte d at t he ti me of i nter ve nti o n disc o nti n uati o n a n d f oll o w -u p a n d 
f or a n y f urt her e v al uati o ns t hat nee d t o be c o m plete d . 
7. 2.  
P artici 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 partici pa nt  ma y wit h dr a 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 (f or e x a m ple, pare nts or le gal g uar di a n) 
 at t he discreti o n of t he i n vesti gat or f or safet y, be h a vi oral, c o m plia nce, or a d mi nistrati ve 
reas o ns 
 if t he partici pa nt bec o mes 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 n i n vestigati o nal pr o d uct or 
e nr oll me nt i n a n y ot h er t y p e of me dical researc h j u d ge d n ot t o be s cie ntificall y or 
me dicall y c o m pati ble wit h t his st u d y  
 if t he partici pa nt , f or a n y reas o n, re q uires tr eat me nt wit h a n ot her t hera p e utic a ge nt t hat 
has bee n de m o nstr ate d t o  be effecti ve f or treat me nt of t he st u d y i n dicati o n, 
disc o nti n uati o n fr o m t he st u d y occ urs pri or t o i ntr o d ucti o n of t he ne w a ge nt  
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 te m p orar y wit h h ol di n g of st u d y i nter ve nti o n is all o we d w he n t he partici pa nt has p ositi ve 
micr o bial la b res ults or cli nical si g ns of a c o nfir me d or s us pecte d i nfecti o n after 
c o ns ultati o n wit h t he s p o ns or’s me dical m o nit or  
 te m p orar y wit h h ol di n g of st u d y i nter ve nti o n is re q uire d f or t he de vel o p me nt of a n y of t he 
f oll o wi n g i nfecti o n-rel ate d criteri a d uri n g t he st u d y: 
o  Seri o us or o p p or t u nistic i nfecti o ns, as defi ne d i n E x cl usi o n Criteria ( Secti o n 5. 2 ). 
St u d y i nter ve nti o n is t o be wit h hel d u ntil res ol uti o n of all ac ute cli nical si g ns a n d 
s y m pt o ms, a n d c o m pleti o n of all a p pr o priat e a nti-i nfecti ve treat me nt (e x ce pti o n f or 
late nt t u berc ul osis i nfecti o n [L T BI ], n ote d bel o w). 
o  Partici pa nts dia g n os e d wit h L T B I d uri n g t he st u d y are t o be per ma n e ntl y 
disc o nti n ue d fr o m st u d y i nter ve nti o n u nless a partici pa nt is a ca n di date f or L T BI 
treat me nt, a n d is treate d f or L T BI as f oll o ws: 
▪ St u d y i nter ve nti o n is te m p oraril y hel d f or at least t he first 4 wee ks of L T BI 
treat me nt. 
▪ After recei vi n g at least 4 wee ks of a p pr o priat e L T BI t hera p y (as per W orl d Healt h 
Or ga niz ati o n a n d/ or t he U nite d States Ce nters f or Disease C o ntr ol g ui deli nes), if 
t here is n o e vi de n ce of he pat ot o xicit y ( A L T/ A S T m ust re mai n ≤2 ti mes U L N) or 
ot her treat m e nt i nt olera n ce, st u d y i nter ve nti o n ma y be res u me d.  
▪ T he partici pa nt m ust c o m plete a p pr o priat e L T BI t hera p y t o re m ai n eli gi bl e t o 
recei v e st u d y i nter ve nti o n. 
Disc o nti n uati o 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 bl e, a n earl y disc o nti n u ati o n 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 dat a 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 o w -u p a n d f or a n y f urt her e val uati o ns t hat nee d t o b e c o m plete d . T he 
partici pa nt will be per ma ne ntl y d isc o nti n ue d b ot h fr o m t he st u d y i nter ve nti o n a n d fr o m t he st u d y 
at t hat ti me.  
If t he partici p a nt  wit h dra ws c o nse nt  f or discl osure of f ut ure i nf or mati o n, t he s p o ns or ma y ret ai n 
a n d c o nti n ue t o use a n y d ata c ollecte d bef ore s uc h a wit h dra wal of c o nse nt . If a partici pa nt  
wit h dra ws fr o m t he st u d y, he/s he m a y re q u est destr ucti o n of a n y sa m ples ta ke n a n d n ot teste d , 
a n d t he i n vesti 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 arti ci p a nts 
If t he s p o ns or or i n vesti gat or i de ntifies 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 vert e ntl y e nr olle d, t he n t he partici pa nt  s h o ul d be disc o nti n ue d fr o m st u d y treat me nt 
u nless t here are e xte n uati n g cir c u msta nces t hat ma ke it me dicall y n ecess ar y f or t he partici p a nt  t o 
c o nti n ue o n st u d y tr eat m e nt . If t he i n vesti gat or a n d t he s p o ns or C R P a gree it is me dicall y 
a p pr o priate t o c o nti n ue, t he i n vesti gat or m ust o btai n d oc u me nte d a p pr o val fr o m t he s p o ns or C R P 
t o all o w t he i na d verte ntl y e nr olle d partici p a nt t o c o nti n ue i n t he st u d y wit h or wit h o ut treat me nt 
wit h i n vesti gati o nal pr o d uct . Safet y f oll o w u p is as o utli ne d i n Secti o n 1. 3  (S o A ), Secti o n 8. 2  
( Safet y Assess me nts), a n d Secti o n 8. 3  ( A d verse E ve nts a n d Seri o us A d verse E ve nts) of t he 
pr ot oc ol . 
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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 st u d y site. Site 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 p a nts w h o fail t o ret ur n f or a sc h e d ule d visit or were 
ot her wise u na ble t o b e f oll o we d u p b y t he site . 
Site pers o n nel will atte m pt t o c ollect t he vital stat us of t he partici pa nt wit hi n le gal a n d et hical 
b o u n daries f or all partici pa nts ra n d o mize d, i ncl u di n g t h ose w h o di d n ot get i n vesti gati o nal 
pr o d uct . P u blic s o urces ma y b e searc he d f or vital stat us i nf or mati o n . If vital stat us is deter mi ne d 
t o be decease d, t his will be d oc u me nte d a n d t he partici pa nt will n ot be c o nsi dere d l ost t o f oll o w-
u p . S p o ns or pers o n nel will n ot be i n v ol ve d i n a n y atte m pts t o c ollect vital stat us i nf or mati o n . 
Disc o nti n uati o n of s pecific sites or of t he st u d y as a w h ole are ha n dle d as p art of A p pe n di x 1  
( Secti o n 1 0. 1 ). 
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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 x e m pti o ns are n ot all o we d.  
 I m me diat e safet y c o ncer ns s h o ul d be disc usse d wit h t he sp o ns or i m me diatel y u p o n 
occ urre nce or a w are 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 nti o n. 
 A d here n ce t o t he st u d y d esi 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 ntial a n d re q uire d f or st u d y c o n d u ct . 
 All scree ni n g e v al uati o ns m ust be c o m plete d a n d re vie we d t o c o nfir m t hat  p ote ntial 
partici pa nt s meet all eli gi bilit y criteria. T h e 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 parti ci pa nt s scree ne d a n d t o c o nfir m eli gi bilit y or recor 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 n cl u di n g t olera nce 
li mits f or ti mi n g). T he s pecificati o ns i n t his pr ot oc ol f or t he ti mi n g of safet y a n d s a m ple 
c ollecti o n are gi v e n as tar gets t o be ac hi e ve d wit hi n reas o na ble li mits. M o dificati o ns ma y b e 
ma de t o t he ti me p oi nts base d u p o n e mer gi n g cli nical i nf or mati o n. T he s c he d ule d ti me p oi nts 
ma y b e s u bject t o mi n or alterati o ns; h o we ver, t he act ual pr oce d ure ti me has t o be c orrectl y 
rec or de d i n t he C R F, i ncl u di n g sa m ples t hat are c ollecte d o utsi de of t he all o wa ble ti me wi n d o w. 
Fail ure or bei n g late ( i. e., o utsi de sti p ulated 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 ult y, or s u bj ect defa ulti n g or t ur ni n g u p late o n a n a gree d sc h e d ule d pr oce d ure) will n ot be 
c o nsi dere d as  pr ot oc ol de viati o ns , b ut t he C R U will still 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 2 (Secti o n  1 0. 2 ) lists t he la b orator y t ests t hat will be perf or m e d 
a n d pr o vi des a s u m mar y of t he ma xi m u m n u m ber a n d v ol u me of i n vasi ve s a 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 t he s u bsecti o ns bel o w, all sa m ples 
c ollecte d f or s pecifie d l a b orat or y tests will be d estr 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 b e ret ai ne d f or a l o n ger peri o d, if necessar y, t o c o m pl y wit h 
a p plica ble la ws, re g ulati o ns, or la b orat or y certificati o n sta n dar ds . 
8. 1.  
Ef fic ac y Assess me nts 
N ot a p plica ble . Efficac y is n ot e val uate d i n t his st u d y. 
8. 2.  
S afet y Assess me nts  
Pla n ne d ti me p oi nts f or all safet y assess me nts are pr o vi de d i n t he S o A  ( Secti o n 1. 2 ). 
8. 2. 1.  
P h ysic al E x a mi n ati o ns  
 A c o m plete p h ysical e x a mi nati o n will i ncl u de, at a mi ni m u m, assess me nts of t he s ki n, 
car di o vas c ular ( C V ), res pirat or y, a bd o me n , a n d n e ur ol o gi cal  s yste ms. Hei g ht a n d wei g ht 
will als o be meas ure d a n d rec or de d.  
 A brief p h ysic al e x a mi nati o n will i ncl u de, at a mi ni m u m, assess me nts of t he  C V  s yste m, 
res pirat or y s yste m, a n d a b d o me n. 
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 I n v esti gat ors s h o ul d pa y s pecial atte nti o 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  partici pa nt , vital si g ns 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 ). Vital si g ns will c o m prise B P, P R, a n d b o d y te m perat ur e.  
 F or s u pi ne me as ure me nts of B P a n d P R, partici pa nts  s h o ul d be i n t he s u pi ne 
p ositi o n f or at least 5  mi n utes bef ore t h e pr oce d ure.  
 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 dizzi ness o r p ost ure-i n d uce d s y m pt o ms. A d diti o nal vital si g ns ma y be 
meas ure d d uri n g eac h st u d y peri o d if  warra nte d.  
 F or ort h ostatic me as ure m e nts of B P a n d P R, partici pa nts  s h o ul d be s u pi ne f or at 
least 5 mi n utes a n d sta n d f or at least 2 mi n utes f or s u pi ne a n d sta n di n g 
meas ure me nts, r es pecti v el y . If t he partici pa nt feels u na ble t o sta n d, s u pi ne vital 
si g ns o nl y will be rec or de d. 
8. 2. 3.  
Electr oc a r di o gr a ms  
F or eac h partici pa nt , E C Gs s h o ul d be c ollecte d acc or di n g t o t he S o A  ( Secti o n 1. 3 ). 
A n y cli nicall y si g nifica nt fi n di n gs fr o m E C Gs t hat res ult i n a dia g n osis a n d t hat occ ur after t he 
partici pa nt  recei ves t he first d ose of t he i n vesti gati o nal pr o d uct s h o ul d be re p orte d t o Lill y or its 
desi g nee as a n A E via t h e C R F.  
F or all p arts of t he st u d y, a t scree ni n g, earl y disc o nti n uati o n, a n d f oll o w-u p, a si n gle E C G will be 
o btai ne d a n d d oes n ot nee d t o be tra ns mitte d t o t he E C G ve n d or . T h e scree ni n g E C G will be 
i nter prete d b y t he i n v esti gat or or q ualifie d d esi g n ee at t he site t o deter mi ne w het her t h e 
partici pa nt  meets e ntr y criteria . 
I n Parts A, C , a n d Part  D  ( base d o n fin di n gs i n Part A a n d C ), at t he ti me p oi nts s pecifie d i n t he 
S o A , eit her si n gle or  tri plicate E C G rec or di n gs will be c ollected  (see Secti o n 1. 3  f or details). 
D uri n g Part B, si n gle E C Gs will be c ollecte d at s p ecifie d ti me p oi nts (see S o A, Secti o n 1. 3 , f or 
details).  
T wel ve -le a d E C G will be o btai ne d ( w h et her as a si n gle or tri plicat e rec or di n g de p e n di n g o n t h e 
part of t he st u d y) usi n g a n E C G mac hi ne t hat a ut o maticall y calc ulates t h e H R  a n d meas ures P R, 
Q R S, Q T, a n d Q Tc i nter vals. Refer t o Secti o n 7  f or Q Tc  wit h dr a wal criteria a n d a n y a d diti o nal 
Q Tc  rea di n gs t hat ma y b e necessar y. 
Electr ocar di o gra ms s h o ul d prefera bl y be rec o r de d bef ore c ollecti n g a n y bl o o d sa m ples. 
Partici pa nts  m ust be s u pi ne f or a p pr o xi matel y 5 mi n utes bef ore E C G c ollecti o n a n d re mai n 
s u pi ne b ut a wa ke d uri n g E C G c ollecti o n. At eac h ti me p oi nt at w hic h tri plicate E C G are 
re q uire d, 3 i n di vi d ual E C G traci n gs s ho ul d be o btai ne d as cl osel y as p ossi ble i n s uccessi o n, b ut 
n o m ore t ha n 2  mi n utes a part. T he f ull set of tri pli cates s h o ul d be c o m plet e d i n less t ha n 
4  mi n utes.  Electr ocar di o gra ms ma y be o btai ne d at a d diti o nal ti mes , w he n dee me d cli nicall y 
necessar y . C olle cti o n of m ore E C G re plicates t ha n e x pecte d at a partic ular ti me p oi nt will be 
per mitte d t o e ns ure hi g h -q ualit y rec or ds.  
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Electr ocar di o gra ms will be i nter pret e d b y a q ualifie d i n vesti gat or ( p h ysicia n 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 h e 
partici pa nt  is still prese nt, t o deter mi ne w het her t h e partici pa nt  meets e ntr y criteria at t he rele va nt 
visit(s) a n d f or i m me diat e 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 nic all y si g nifica nt q ua ntitati ve or q ualitati ve c ha n ge fr o m bas eli ne is i de ntifie d after 
e nr oll me nt, t he i n vesti gat or will assess t he partici p a nt  f or s y m pt o ms (e. g., p al pitati o ns, near 
s y nc o p e, s y nc o pe) t o det er mi ne w het her t he parti ci pa nt ca n c o nti n ue i n t he st u d y. T h e 
i n vesti gat or or q u alifie d desi g nee is res p o nsi ble f or deter mi ni n g if a n y c h a n ge i n p artici pa nt 
ma na ge me nt is nee d e 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 
e val uati o n fr o m at le ast 1 of t he t ri plicate E C Gs fr o m eac h ti me p oi nt. 
Di gital E C Gs will be ele ctr o nicall y tra ns mitte d t o a ce ntr al E C G la b orat or y desi g nat e d b y Lill y . 
T he ce ntr al E C G la b orat or y will perf or m a b asic q ualit y c o ntr ol c hec k ( e. g., de m o gra p hics a n d 
st u d y details), t he n st or e the E C Gs i n a data bas e . At a f ut ure ti me, t he st or e d E C G data ma y b e 
o verrea d at t he ce ntral E C G la b orat or y f or f urt her e val uati o n of mac hi n e -rea d meas ure me nts or 
t o meet re g ulat or y re q uir e me nts. 
T he mac hi ne -rea d E C G i nter vals a n d H R  ma y be use d f or data a n al ysis a n d re p ort writi n g 
p ur p oses, u nless a car di ol o gist o verrea d of t h e E C Gs is c o n d ucte d pri or t o c o m pleti o n of t he 
fi nal st u d y re p ort (i n w hi c h case, t h e o verrea d d at a w o ul d be use d). 
8. 2. 4.  
Cli nic al S afet y L a b or at or y Assess me nts  
Pr oce d ures f or cli nical s afet y l a b orat or y assess me nts are as f oll o ws:  
1.  See A p pe n di x 2 ( Secti o n 1 0. 2 ) f or t he list of cli nical la b orat or y tests t o be p erf or me d a n d see 
t he S oA ( Secti o n 1. 3 ) f or t he ti mi n g a n d fre q ue n c y. 
2.  T he i n vesti 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 v a nt c ha n ges occ urri n g d uri n g t he st u d y i n t he A E s ecti o n of t he C R F. T he 
la b orat or y re p orts m ust be file d wit h t he s o urce d o c u me nts. 
3.  All la b orat or y tests wit h val ues c o nsi dere d cli nicall y si g nifi ca ntl y a b n or mal d uri n g 
partici pati o n i n t he st u d y s h o ul d be r e 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 wit hi n a peri o d of ti me j u d ge d 
reas o na bl e b y t he i n vesti gat or, t h e eti ol o g y s h o ul d be i de ntifie d a n d t he s p o ns or 
n otifie d.  
o  All pr ot oc ol -re q uir e d la b orat or y assess me nts, as defi ne d i n A p pe n di x 2 
( Secti o n 1 0. 2 ), m ust be c o n d ucte d i n acc or da n ce wit h t he la b 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 pecifi e d la b orat or y assess me nts perf or me d at 
t he i nstit uti o n’s l ocal la b orat or y re q uire a c ha n ge i n partici pa nt ma na ge m e nt or are 
c o nsi dere d cli ni call y si g nifica nt b y t h e i n vesti gat or (e .g ., S A E or A E or d os e 
m o dificati o n), t he n t he res ul ts m ust be rec or de d i n t he C R F. 
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8. 2. 5.  
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  
N ot a p plica ble.  
8. 3.  
A d verse E ve nts a n d Seri o us A d verse E ve nts  
Se verit y a n d seri o us ness of  a n A E are n ot s y n o n y m o us. Se verit y is gra di n g t he i nte nsit y of a n  
e ve nt. Seri o us ness of a n e ve nt is base d o n t he s u bject/e ve nt o utc o me.  Details a b o ut c ollecti n g  
S A E/ A E data a n d S A E/ A E defi niti o ns  are pr o vi d e d i n A p pe n di x 3  ( Secti o n 1 0. 3 ). 
A Es  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 v er, s urr o gate, or t he 
partici pa nt ’s le gall y a ut h orize d re pres e ntati ve). 
T he i n vesti gat or a n d a n y q ualifie d 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 o n of a n A E or S A E a n d re m ai n res p o nsi ble f or f oll o wi n g 
u p A Es  t hat are s eri o us, c o nsi dere d rel ate d t o t he st u d y i nter ve nti on or st u d y pr oce d ures, or t hat 
ca use d t he p artici pa nt t o disc o nti n ue t he st u d y i nt er ve nti o n (see Secti o n 7 ). 
I n v esti gat ors are res p o nsi ble f or m o nit ori n g t he s afet y of partici pa nts w h o h a ve e ntere d t his 
st u d y a n d f or alerti n g Lill y or its desi g nee t o a n y e ve nt t hat see ms u n us ual, e ve n if t his e ve nt 
ma y b e c o nsi dere d a n u n a ntici pate d be nefit t o t he partici pa nt . 
T he i n vesti gat or is res p o nsi ble f or t he a p pr o priate me dical care of partici pa nts d uri n g t he st u d y.  
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 ollecte d fr o m t he si g ni n g of t h e IC F  u ntil partici pati o n i n st u d y has e n d e d . 
All A Es  will be c ollecte d fr o m t he si g ni n g of I C F u ntil t he f oll o w-u p visit . 
A d verse e ve nts  t hat be gi n bef ore t h e start of st u d y i nter ve nti o n b ut after si g ni n g of t he I C F will 
be  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  re p orte d after t he I C F has b ee n si g ne d are rec or de d b y t he site i n t he 
C R F/electr o nic dat a e ntr y  s yste m, S A E re p orti n g t o s p o ns or be gi ns after t h e partici pa nt  has 
si g ne d t he I C F a n d h as recei ve d t he st u d y i nter ve nti o n. 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 parti ci pa nts  recei vi n g L Y 3 5 0 9 7 5 4 , it nee ds t o be re p orte d O N L Y if it is 
c o nsi dere d reas o n a 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 ort e d t o t he s p o ns or or desi g nee i m me di atel y a n d u n der n o 
circ u msta nce s h o ul d t his e x cee d 2 4 h o urs, as i n dicate d i n A p pe n di x 3  ( Secti o n 1 0. 3 ). T he 
i n vesti gat or will s u b mit a n y u p dat e d S A E data t o t he s p o ns or wit hi n 2 4 h o urs of it bei n g 
a vaila ble. 
I n v esti gat ors are n ot o bli gat e d t o acti vel y see k A Es  or S A E s after c o ncl usi o n of t he st u d y 
partici pati o n . H o we v er, if t he i n vesti gat or lear ns of a n y S A E, i ncl u di n g a d eat h, at a n y ti me after 
a partici pa nt has b ee n dis c 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 n a bl y 
relate d t o t he st u d y i nter ve nti o n or st u d y partici pati o 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. 
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8. 3. 2.  
Met h o d of Detecti n g A Es  a n d S A Es  
T he met h o d of rec or di n g, e val uati n g, a n d ass essi n g ca usalit y of A Es  a n d S A Es, a n d t he 
pr oce d ures f or c o m pleti n g a n d tr a ns mitti n g S A E re p orts , is pr o vi de d i n A p pe n di x  3 
( Secti o n 1 0. 3 ). 
Care will be ta ke n n ot t o i ntr o d uce bias w he n d etecti n g A Es  a n d/ or S A Es. O pe n -e n d e d a n d 
n o n -lea di n g ver bal q uesti o ni n g of t he p artici pa nt is t he preferre d m et h o d t o i n q uire a b o ut A E 
occ urre nces . 
8. 3. 3.  
F oll o w -u p of A Es  a n d S A Es  
After t he i nitial A E/ S A E re p ort, t he i n vesti gat or is re q uire d t o pr o acti vel y f oll o w eac h partici pa nt 
at s u bse q ue nt visits/c o ntacts. All S A Es  will be f oll o we d u ntil res ol uti o n, sta bilizati o n, 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 o w-u p (as defi ne d i n Secti o n  7. 3 ). F urt her 
i nf or mati o n o n f oll o w-u p pr oce d ures is pr o vi de d  i n A p pe n di x 3 ( Secti o n  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 otificati o n b y t he i n vesti gat or t o t he s p o ns or of a S A E is esse ntial s o t hat le gal 
o bli gati o ns a n d et hical res p o n si bilities t o war ds t he safet y of partici pa nts a n d t he safet y of 
a st u d y i nter ve nti o n u n der cli nical i n vesti gati o n are met.  
 T he s p o ns or has a l e gal r es p o nsi bilit y t o n otif y b ot h t he l ocal re g ulat or y a ut h orit y a n d 
ot her re g ulat or y a ge n cies a b o ut t he safet y of a st u d y i nter ve nti o n u n der cli nical 
i n vesti gati o n. T he s p o ns or will c o m pl y wit h c o u ntr y-s p ecific re g ulat or y re q uire me nts 
relati n g t o s afet y re p orti n g t o t he re g ulat or y a ut h orit y, I R Bs/I E C, a n d i n v esti 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 a S A E or ot her 
s pecific safet y i nf or mati o n (e. g., s u m mar y or listi n g of S A Es) fr o m t he s p o ns or will  
re vie w a n d t h e n file it al o n g wit h t he I B a n d ot h er rele va nt d oc u me nts a n d will n otif y t h e 
I R B/I E C, if a p pr o priate acc or di n g t o l ocal r e q uire me nts. 
8. 3. 5.  
Pre g n a nc y  
 Details of all pre g n a ncies i n fe male partici pa nts a n d fe male part ners of m ale partici pa nts  
will be c ollecte d after t he start of st u d y i nter ve nti o n a n d u ntil at least 5 ter mi nal half -li ves 
after t he l ast d ose.  
 If a pre g na nc y is r e 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 n c y a n d s h o ul d f oll o w t he pr oce d ures o utli ne d i n A p pe n di x 4 
( Secti o n 1 0. 4 ). 
 A b n or mal pre g n a nc y o ut c o mes (e .g ., s p o nta n e o us a b orti o n, fetal deat h, still birt h, 
c o n ge nital a n o malies, ect o pic pre g na n c y) are c o nsi dere d S A Es . 
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 ni c, or oral c o m m u nicati o n t hat alle ges defi cie ncies 
relate d t o t he i de ntit y, q u alit y, d ura bilit y, relia bilit y, safet y, effecti ve ness or perf or ma n ce of a 
trial i nter ve nti o n. 
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S p o ns or c ollects pr o d uct c o m plai nts o n i n vesti gati o nal pr o d ucts a n d dr u g d eli ver y s yste ms use d 
i n cli nical st u dies i n or der t o e ns ure t he s afet y of st u d y partici p a nts, m o nit 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. 
Partici pa nts will be i nstr ucte d t o c o ntact t he i n vesti gat or  as s o o n as p ossi ble if he or s he has a 
c o m plai nt or pr o ble m wit h t he i n vesti gati o nal pr o d uct s o t hat t he sit uati o n ca n be assess e d.  
N O T E: A Es / S A Es t hat are ass ociat e d wit h a pr o d uct c o m plai nt will als o f oll o w t he pr ocesses 
o utli ne d i n Secti o n 8. 3. 3  a n d A p pe n di x 3 ( Secti o n 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 nts t hat res ult i n a n A E  will be det ecte d, d oc u m e 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 h ic h t h e dr u g/ de vice is use d. 
 If t he i n vesti gat or lear 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 u c h i nci de nt is c o nsi dere d reas o na bl y relat e d t o a 
dr u g/ de vi ce pr o vi d e d f or t he st u d y, t he i n vesti gat or will pr o m ptl y n otif y t h e 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 o ns or  
 Pr o d uct c o m plai nts will be re p ort e d t o t he s p o ns or wit hi n 2 4 h o urs after t h e i n vesti gat or 
bec o mes a w are of t he c o m plai 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 b y t he m et h o d  pr o vi de d i n t he 
f or m. If t he pri mar y met h o d  is u na vaila ble, t he n a n alter nati ve met h o d  as pr o vi de d i n t he 
f or m s h o ul d be use d . 
8. 3. 6. 3.  
F oll o w -u p of Pr o d uct C o m pl ai nts  
 F oll o w -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 nti n ue st u d y i nter ve nti o n.  
 T he i n vesti 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 d es a n y s u p ple me ntal 
i n vesti gati o ns as i n dicate d t o el uci date t he nat ur e a n d/ or ca us alit y of t he pr o d uct 
c o m plai nt . 
 Ne w or u p d ate d i nf or mati o n will be rec or de d o n t he ori gi n all y c o m plete d f or m wit h all 
c ha n ges si g ne d a n d date d b y t he i n vesti gat or  a n d s u b mit te 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  
N ot a p plica ble i n t his st u d y . 
8. 4.  
Tre at me nt of O ver d ose  
F or eac h part i n t his st u d y, a n y d os e of st u d y i nter ve nti o n greater t ha n t he d ose descri be d f or t hat 
part  wit hi n a 2 4 -h o ur ti me peri o d ± 1 2  h o urs  will b e c o nsi dere d a n o ver d ose.  
S p o ns or d oes n ot rec o m me n d s pecific tr eat me nt f or a n o ver d ose . 
I n t he e ve nt of a n o ver d ose, t he i n vesti gat or s h o ul d: 
1.  C o ntact t he Me dical M o nit or i m me diatel y.  
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2.  Cl osel y m o nit or t he parti ci pa nt f or a n y A E/ S A E a n d la b orat or y a b n or malities u ntil st u d y 
i nter ve nti o n ca n n o l o n ger be detecte d s yste micall y (at least  7  da ys).  Refer t o Secti o n 8. 3  
f or re p orti n g d etails. 
3.  O btai n a plas ma sa m ple f or P K a nal ysis wit hi n 1  da y fr o m t he dat e of t he last d ose of 
st u d y i nter ve nti o n if re q u este d b y t h e Me dical M o nit or ( deter mi ne d o n a case -b y -case 
basis).  
4.  D oc u me nt t he q ua ntit y of t he e x cess d ose as w ell as t he d urati o n of t he o ver d ose i n t he 
C R F.  
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 h e i n vesti gat or i n 
c o ns ultati o n wit h  t he Me dical M o nit or base d o n t he cli nical e val u ati o n of t he partici pa nt.  
8. 5.  
P h ar m ac o ki netics  
Plas ma sa m ples will be a nal yze d f or L Y 3 5 0 9 7 5 4, itrac o naz ole a n d its h y dr o x y itrac o naz ole 
meta b olite , a n d mi daz ola m a n d its 1 -h y dr o x y mi dza ola m meta b olite . A d diti o nall y, uri ne s a m ples 
will be a nal yze d f or L Y 3 5 0 9 7 5 4.  
 L Y 3 5 0 9 7 5 4: Plas ma sa m ples of a p pr o xi matel y 2  m L will be c ollecte d f or meas ure me nt 
of c o nce ntrati o ns of L Y 3 5 0 9 7 5 4  as s pecifie d i n t h e S o A i n Secti o n 1. 3 . 
 Uri ne sa m ples of a p pr o xi matel y 1  m L will be c oll ecte d as s p ecifie d i n t he S o A i n Secti o n 
1. 3 . 
 T otal uri ne o ut p ut f or t he 2 4  h o ur  peri o d  p ost -L Y 3 5 0 9 7 5 4 a d mi nistrati o n will be 
c ollecte d, p o ole d, a n d refri gerate d.  At t he e n d of t he c ollecti o n peri o d, t he t otal uri ne 
v ol u me will be rec or d e d.  Uri ne sa m ples will be use d t o deter mi ne creati ni ne, 
q ua ntificati o n of L Y 3 5 0 9 7 5 4 a n d e x pl orat or y m eta b olite i de ntificati o n.   Assess me nt of 
re nal cleara nce will be a n e x pl orat or y ass ess me nt; t heref ore, fail ure t o c ollect sa m ples or 
a nal yze all c ollecte d  s a m ples will n ot be a de viati o n.  Sa m ples will be a nal yz e d usi n g a 
vali date d fit -f or-p ur p ose li q ui d c hr o mat o gra p h y –  ta n de m mass s pectr o metr y ass a y.  
 Itr ac o n az ole: Plas ma sa m ples of a p pr o xi matel y 2  m L will be c ollecte d f or meas ure me nt 
of c o nce ntrati o ns of itrac o naz ole a n d h y dr o x yitrac o naz ole as s pecifie d i n t h e S o A . 
 
Mi daz ola m: Plas ma sa m ples of a p pr o xi matel y 2  m L will be c ollecte d f or meas ure me nt of 
c o nce ntr ati o ns of mi daz ola m  a n d 1-h y dr o x y mi daz ola m  as s pecifie d i n t he S o A . 
 A ma xi m u m of 3 sa m ples ma y be c ollecte d at a d diti o nal ti 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 t he i n v esti gat or a n d t he s p o ns or. T h e ti mi n g of 
sa m pli n g ma y be altere d d uri n g t he c o urse of t he st u d y base d o n ne wl y a v aila ble data 
(e. g., t o o btai n data cl os er t o t he ti me of pea k plas ma c o nce ntr ati o ns) t o e ns ure 
a p pr o priate m o nit ori n g.  
 I nstr u cti o ns f or t he c ollecti o n a n d ha n dli n g of bi ol o gical sa m ples will be pr o vi de d b y t he 
s p o ns or. T he act u al date a n d ti me ( 24 -h o ur cl o c k ti me) of eac h sa m ple will be rec or de d.  
T he re mai ni n g plas ma fr o m t he sa m ples c ollecte d f or p har mac o ki netics ma y be p o ol e d a n d use d 
f or e x pl orat or y meta b olis m w or k as dee m e d a p pr o priate. Ali q u ots of t he uri ne will be fr oze n a n d 
st ore d u ntil q ualitati vel y a nal yze d f or L Y3 5 0 9 7 5 4  a n d p ote ntial meta b olites. Si nce t he uri nar y 
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w or k is c o nsi dere d e x pl orat or y, fail ure t o o btai n a uri ne sa m ple f or a n y reas o n will n ot be 
c o nsi dere d a pr ot oc ol vi olati o n.  
T he meta b olis m w or k is c o nsi dere d e x pl orat or y a n d n o  q ua ntitati o n will be perf or me d o n t hese 
data. Res ults of t he e x pl orat or y w or k are n ot n ecessar y f or i ncl usi o n i n t he fi nal i nte grate d 
cli nical st u d y re p ort.  
Dr u g c o nce ntrati o n i nf or mati o n t hat ma y u n bli n d t he st u d y will n ot be re p orte d t o i n vesti gati ve 
sites or bli n de d pers o n nel u ntil t he st u d y has b ee n u n bli n de d. 
8. 6.  
P h ar m ac o d y n a mics  
P har mac o d y na mic p ara m eters a re n ot e val u ate d i n t his st u d y. 
8. 7.  
Ge netics  
A bl o o d sa m ple f or de o x yri b o n ucl eic aci d ( D N A ) is olati o n will be c ollecte d fr o m partici pa nts. 
See A p pe n di x 5 ( Secti o n 1 0. 5 ) f or I nf or mati o n re gar di n g ge netic researc h a n d A p pe n di x  1 
( Secti o n 1 0. 1. 9 ) f or d etai ls a b o ut sa m ple rete nti o n a n d cust o d y . 
8. 8.  
Bi o m ar kers  
E x pl or at or y sa m ples ( s er u m, pl as m a, s ali v a, a n d ri b o n ucleic aci d fr o m b ucc al s w a b s) f or 
e x pl or at or y bi o m ar ker assess me nt  
Ser u m, plas ma, sali va, a n d ri b o n ucleic aci d sa m ples fr o m b uccal s wa b s will be st ore d a n d 
a nal ysis ma y b e perf or m e d o n e x pl orat or y bi o mar ker vari a nts t h o u g ht t o pla y r ole i n 
I L-1 7 -relate d pat h w a ys. 
T his ma y i ncl u de c he m o ki nes a n d c he m o ki ne rece pt ors i n v ol ve d i n pat h o ge nic defe nse, vari o us 
I L-1 7 m olec ules, t heir rece pt ors a n d si g nali n g m olec ules, a n d i m m u ne res p o nse ge nes, i ncl u di n g 
b ut n ot li mite d t o t h ose wit hi n t he maj or hist oc o m pati bilit y c o m ple x, ge n es relate d t o t he 
I L-1 7/ 2 3 pat h wa y a n d cell s u bt y p es pr o d uci n g a n d/ or res p o nsi ve t o t hese c yt o ki nes.  
Plas ma sa m ples , i ncl u di n g t h ose re mai ni n g w he n bi oa nal ysis is c o m plete, ma y b e use d f or t he 
a nal ysis of e x os o mal mar kers.  
A list of t he ma xi m u m rete nti o n peri o d f or sa m ple t y pes ca n be f o u n d i n A p pe n di x  1  
( Secti o n 1 0. 1. 9 ). Refer t o t he la b orat or y ma n ual f or a d diti o nal details . 
8. 9.  
I m m u n o ge nicit y Assess me nts 
N ot a p plica ble . 
8. 1 0.  
He alt h Ec o n o mic s 
T his secti o n is n ot a p plica ble f or t his st u d y.  
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9.  
St atistic al C o nsi der ati o ns  
9. 1.  
S a m ple Size Deter mi n ati o n  
T he sa m ple siz e is c ust o mar y f or P hase 1 st u dies e val uati n g safet y, t olera bilit y, a n d P K, a n d is 
n ot p o were d o n t he b asis of a n y a pri ori statistical h y p ot hesis testi n g.   T he s a m ple siz es f or all 
parts of t he st u d y are bas e d u p o n pr e vi o us st u dies.  
Partici pa nts  w h o are ra n d o mize d b ut n ot a d mi nistere d treat me nt ma y be re place d t o e ns ure t hat  
a de q uate p artici pa nt  dat a will be a vaila ble f or safet y a n d e x p os ure assess me nts i n t his p hase of  
cli nical de vel o p me nt. T h e re pla ce me nt partici pa nt s h o ul d be assi g n e d t o t he sa me treat me nt ar m 
as t he disc o nti n ue d partici pa nt . 
9. 2.  
P o p ul ati o ns f or A n al yses  
9. 2. 1.  
St u d y P artici p a nt Dis p ositi o n  
A detaile d descri pti o n of partici pa nt  dis p ositi o n will be pr o vi de d at t he e n d of t he st u d y.  
All partici pa nts  w h o disc o nt i n ue fr o m t he st u d y will be i de ntifie d, a n d t he e xte nt of t heir 
partici pati o n i n t he st u d y will be re p orte d. If k n o w n, a reas o n f or t heir disc o nti n uati o n will be 
gi ve n.  
9. 2. 2.  
St u d y S u bject C h ar acteristics  
T he partici pa nt’s b aseli n e c haracteristics a n d ot her de m o gra p hic c haracteristics will be rec or de d, 
liste d, a n d s u m mariz e d b y treat me nt gr o u p a n d o v erall. 
9. 2. 3.  
Tre at me nt C o m pli a nce  
T he st u d y I P will be a d mi nistere d at t he C R U a n d d oc u me ntati o n of d osi n g a d mi nistrati o n will 
occ ur at t he C R U. E ver y atte m pt will be ma de b y t he C R U t o e nr oll partici p a nts  w h o ha ve t he 
a bilit y t o u n dersta n d a n d c o m pl y wit h i nstr ucti o ns. N o d oses s h o ul d be misse d. T he ti me a n d da y 
of st u d y i nter ve nti o n a d mi nistrati o n will be acc uratel y rec or de d i n t he electr o nic cas e re p ort f or m 
(e C R F). Dr u g acc o u nta bilit y rec or ds will be mai ntai ne d b y t he C R U. 
A n y maj or m o dificati o ns t hat mi g ht affect t he c o n d uct of t he st u d y, p artici pa nt  safet y, a n d/ or 
data i nte grit y will be detaile d i n a pr ot oc ol a me n d me nt.  
9. 3.  
St atistic al A n al yses  
Statistical a nal ysis of t his st u d y will be t he res p o nsi bilit y of Eli Lill y a n d C o m pa n y or its  
desi g nee.  
P har mac o ki netic a n al yses will be c o n d ucte d o n data fr o m all s u bjects w h o recei ve at least 1  d ose 
of t he I P a n d ha v e e val u a ble P K.  
Safet y a nal yses will be c o n d ucte d f or all e nr olle d s u bjects, w het her or n ot t he y c o m plete d all  
pr ot oc ol re q uire m e nts.  
S u m mar y statistics, data ta b ulati o ns, a n d data gra p hs b y p o p ulati o n (J a pa n ese a n d n o n -J a pa n ese) 
will be pr o vi de d as a p pr o priate.  
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A d diti o nal e x pl orat or y a nal yses of t he data will be c o n d ucte d as dee m e d a p pr o priate. St u d y  
res ults ma y b e p o ole d wit h t he res ults of other st u dies f or p o p ulati o n P K a nal ysis p ur p oses.  
9. 3. 1.  
S afet y A n al yses  
9. 3. 1. 1.  
Cli nic al E v al u ati o n of S afet y  
All I P a n d pr ot o c ol pr oce d ure A Es  will be liste d, a n d if t he fre q u e nc y of e v e nts all o ws, safet y 
data will be s u m marize d usi n g descri pti ve met h o d ol o g y.  
T he i nci de nce of s y m pt o ms f or eac h treat me nt will be prese nte d b y s e verit y a n d b y ass ociati o n 
wit h I P as percei ve d b y t he i n vesti gat or. S y m pt o ms re p orte d t o occ ur pri or t o st u d y I P d osi n g 
will be disti n g uis he d fr o m t h ose re p orte d as n e w or i ncrease d i n se verit y d uri n g t he st u d y. Eac h 
s y m pt o m will be classifi e d b y t h e m ost s uita ble ter m fr o m t he me dical re g ulat or y dicti o nar y.  
T he n u m ber of I P -relat e d S A Es a n d A Es will be re p orte d.  
9. 3. 1. 2.  
St atistic al E v al u ati o n of S afet y  
Safet y p ara meters t hat will be assesse d i ncl u de A E s, cli nical la b orat or y p ara meters, vital si g ns, 
a n d E C G  para m eters. T h e para m eters will be liste d a n d s u m marize d usi n g sta n dar d descri pti ve 
statistics. A d diti o nal a nal ysis will be perf or me d if warra nte d u p o n re vie w of t he data.  
9. 3. 2.  
P h ar m a c o ki netic A n al yses  
9. 3. 2. 1.  
P h ar m a c o ki netic P ar a meter Esti m ati o n  
P har mac o ki netic para met er esti mates f or L Y 3 5 0 9 7 5 4 will be  calc ulate d b y sta n dar d 
n o nc o m part me ntal met h o ds of a nal ysis a n d s u m marize d b y d ose usi n g descri pti ve statistics. T he 
pri mar y para meters f or a nal ysis will be C ma x  an d A U C of L Y 3 5 0 9 7 5 4 aft er  si n gle- a n d 
m ulti ple -d ose a d mi nistrati o n. Ot her n o nc o m part m e ntal para m eters s uc h as t ma x , t1/ 2, a p pare nt 
cleara nce, a p pare nt v ol u me of distri b uti o n , a n d acc u m ulati o n rati o ma y be calc ulate d . P o p ulati o n 
a nal ysis of t he c o nce ntrati o n -ti me data base d o n a c o m part me ntal m o del ma y als o be perf or me d 
t o s u p p ort P K si m ulati o ns. 
If a p pr o priate dat a are o btai ne d, re nal cleara nce of L Y 3 5 0 9 7 5 4  will be esti mate d b y di vi di n g  t he 
a m o u nt of L Y 3 5 0 9 7 5 4 e x crete d i n uri ne o ver a gi ve n ti me  i nter val t o t he plas ma A U C of 
L Y 3 5 0 9 7 5 4 o v er t he s a me i nter val.  
I n Part B, if a vaila ble, pl as ma c o nce ntrati o n data f or itrac o n az ole a n d its meta b olite will be liste d 
i n t he st u d y re p ort. A P K a nal ysis of itrac o n az ole a n d its meta b olite ma y b e c o n d ucte d if d ee me d 
val ua ble t o t he i nter pretati o n of t he st u d y res ults b ut is n ot re q uire d t o c o m plete t he cli nical st u d y 
re p ort. 
I n t he per petrat or D DI p orti o n of Part C  ( M A D), t he pri mar y para meters f or a nal ysis will be Cma x  
a n d A U C of mi daz ola m a n d its  h y dr o x ylat e d met a b olite after a d mi nistrati o n of mi daz ola m 
al o ne, a n d c o n c o mita ntl y wit h L Y 3 5 0 9 7 5 4 . Ot h er n o nc o m part me ntal para meters s uc h as h alf -
life, a p pare nt cleara n ce, a n d a p pare nt v ol u me of distri b uti o n  ma y b e re p ort e d.  
A d diti o nal a nal ys es ma y be c o n d ucte d as a p pr o priate.  
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9. 3. 2. 2.  
P h ar m a c o ki netic St atistic al I nfere nce  
I n Part A ( S A D) a n d t he M A D  p orti o n of Part C  of t he st u d y, p h ar mac o ki n etic para m eters C ma x  
a n d A U C f or L Y 3 5 0 9 7 5 4  will be e val uate d t o esti mate d ose pr o p orti o nalit y  of L Y 3 5 0 9 7 5 4  usi n g 
a li near-mi x e d -effect  p o wer m o del . L o g-tr a nsf or me d Cma x  a n d A U C para meters will be 
e val uate d usi n g a p o w er m o del ( w here l o g d os e acts as a n e x pla nat or y varia ble) t o esti mate 
rati os of d ose-n or m alize d ge o m etric mea ns , t h e rati os of ge o m etric mea ns a n d c orres p o n di n g 
9 0 % c o nfi de n ce i nter vals  ( CIs). T he esti mate d rati o of d ose-n or malize d ge o metric mea ns of P K 
para meters bet wee n t he hi g hest a n d l o w est d oses will be use d t o assess d ose pr o p orti o nalit y. 
A  s u bi nter val wit hi n t he hi g hest a n d l o w est d oses ma y als o be c o nsi dere d f or assess me nt of d ose 
pr o p orti o nalit y usi n g t he sa me a p pr oac h. F or t he d ose pr o p orti o nalit y assess me nt, data fr o m t he 
place b o gr o u p will be e x cl u de d. F or t he M A D p orti o n of Part C , L Y 3 5 0 9 7 5 4 d ose 
pr o p orti o nalit y will be assesse d o n D a y 1 a n d Da y 1 4.  
F or t he f o o d effect p orti o n of Part A, C ma x  a n d A U C f or L Y 3 5 0 9 7 5 4, w he n a d mi nistere d wit h a 
hi g h -fat meal vers us i n a faste d state, will be c o m p are d. T h ese c o m paris o ns will be perf or me d 
usi n g a mi x e d effects a nal ysis of vari a nce m o d el. T he  m o del will i ncl u de a fi x e d effect f or t he 
treat me nt a n d a ra n d o m effect f or partici p a nt. T he rati o of least s q uares ge o metric mea ns f or t he 
test treat me nt c o m pare d t o refere nce treat me nt, as well as t he 9 0 % CI of t he rati o will be 
esti mate d a n d re p orte d. T he t ma x  of L Y 3 5 0 9 7 5 4 will be a nal yze d usi n g a Wilc o x o n si g ne d -ra n k 
test. A n esti mate of t he me dia n differe nce a n d 9 0 % CI f or t he differe nce b et wee n tr eat me nts will 
be calc ul ate d.  
F or Part B, C ma x  a n d A U C f or L Y 3 5 0 9 7 5 4 , w he n a d mi nistere d al o ne vers us i n t he prese nce of 
itrac o naz ole, will be c o m pare d  usi n g a n a nal ysis of varia n ce ( A N O V A) m o del. T he para meters 
will be l o g -tr a nsf or me d pri or t o a nal ysis. T he m o d el will i ncl u de a fi x e d effect f or t he treat me nt 
a n d a ra n d o m effect f or s u bject. T he least-s q u ares mea ns f or eac h tr eat me nt, t he differe nce 
bet wee n t he treat me nt le ast-s q uare m ea ns ( L Y 3 5 0 9 7 5 4  + itrac o naz ole –  L Y 3 5 0 9 7 5 4 ), a n d t he 
ass ociate d 9 0 % CIs will be esti mate d fr o m t he A N O V A m o del a n d b ac k -tra nsf or me d fr o m t he 
l o g scal e t o pr o vi de esti mates of t he ge o metri c mea ns, ge o metri c mea n rati o, a n d c orres p o n di n g 
9 0 % CIs.  
F or t he p er petr at or D DI p orti o n of Part C , P K  para meter esti mates will be e val uate d t o deli neate 
effects of L Y 3 5 0 9 7 5 4 o n t he P K of mi daz ola m.  L o g -tr a nsf or me d Cma x  a n d A U C esti mates f or 
mi daz ola m will be e val uate d t o esti mate rati os of ge o m etric mea ns i n t he prese nce a n d a bse nce 
of L Y 3 5 0 9 7 5 4 al o n g wit h t he c orres p o n di n g 9 0 % C Is. A mi x e d effects m o del wit h treat me nt as 
fi x e d effect a n d s u bj ect as ra n d o m effect will be use d.  
F or Part D , L Y 3 5 0 9 7 5 4 P K para meters will be c o m pare d bet w ee n J a pa nes e a n d n o n -J a pa nes e 
partici pa nts  ( usi n g S A D, M A D data f or n o n-J a pa n ese partici p a nts). Descri pti ve statistics f or 
C ma x , A U C, tma x , ter mi nal half-life, a p p are nt cleara nce, a n d a p pare nt v ol u me of distri b uti o n will 
be i ncl u de d i n t he ta b ular c o m paris o ns. B o d y -wei g ht n or malize d P K para meters ma y be 
calc ulate d if warra nte d. Gra p hical c o m paris o ns of C ma x , A U C, a n d c o nce ntrati o n-ti me pr ofiles 
will als o be pre pare d.  
A d diti o nal a nal ys es ma y be  c o n d ucte d f or eac h p art as a p pr o pri ate.  
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9. 3. 3.  
P h ar m a c o d y n a mi c A n al yses  
9. 3. 3. 1.  
P h ar m a c o d y n a mi c P ar a meter Esti m ati o n  
N ot a p plica ble.  
9. 3. 4.  
P h ar m a c o ki netic/ P h ar m a c o d y n a mic A n al yses  
N ot a p plica ble.  
9. 3. 5.  
I nteri m Access t o D at a (I A D) 
I nteri m access t o safet y a n d t olera bilit y data is sc he d ule d t o occ ur after e ver y d osi n g sessi o n. T he 
i n vesti gat or a n d t he Lill y st u d y tea m will ma ke t h e deter mi nati o n re gar di n g d ose escal ati o n 
base d u p o n t heir re vie w of t he safet y a n d t olera bilit y data. A c cess t o P K data will als o occ ur o n a 
r olli n g basis d uri n g d ose escalati o n as it bec o mes a vaila ble, b ut will n ot be a re q uir e me nt f or 
selecti n g s u bs e q ue nt d os e le vels. T he f oll o wi n g I A Ds are pl a n ne d t o e val uate e x p os ure data. T he 
p ur p ose of t hese re vie ws is  t o g ui de d ose es calati o n, d ose selecti o n f or s u bs e q ue nt c o h orts, 
a n d/ or t o i nf or m t he desi g n of s u bs e q ue nt st u dies . 
I n Part A ( S A D), I A D is pla n ne d t o occ ur f or eac h c o h ort, w he n a p pr o xi matel y 6 partici pa nts 
ha ve a v aila ble data u p t o 5  da ys  p ost d ose. I n Part B ( C Y P 3 A 4 victi m D DI), I A D is pla n ne d t o 
occ ur w h e n a p pr o xi matel y 9 partici pa nts ha ve a vaila ble data u p t o Da y 1 7 . I n Part C ( M A D a n d 
C Y P 3 A 4 per petrat or D DI), I A D is pla n n e d t o occ ur f or eac h c o h ort. F or C o h orts 1 a n d 3, t his 
occ urs w h e n a p pr o xi matel y 6 p artici pa nts ha v e a v aila ble data u p t o Da y 1 9 . F or C o h ort 2, t his 
occ urs w h e n a p pr o xi matel y 8 p artici pa nts ha v e a v aila ble data u p t o Da y 1 9 . 
After Parts A -D ha v e bee n c o m plete d, a f urt her I A D is pla n ne d t o i ncl u de all a vaila ble safet y 
a n d P K data t o s u p p ort P hase 2 de vel o p me nt of t he m olec ule.  
T he i n vesti gat or a n d t he Lill y s p o ns or tea m will ma ke t he deter mi nati o n re gar di n g d ose 
escalati o n bas e d u p o n t heir re vie w of t he dat a. T h e i n vesti gat or will re mai n bli n de d a n d t he Lill y 
s p o ns or tea m will be un bli n de d d uri n g t hes e re vie ws. U n bli n di n g details are s pecifie d i n t he 
u n bli n di n g/ bli n di n g pla n d oc u me nt.  
T he i n vesti gat or a n d t he Lill y cli nical p har m ac ol o gist, Lill y C R P, a n d Lill y st u d y tea m will 
ma ke t he deter mi nati o n re gar di n g d ose escalati o n.  
A d diti o nal data re vie ws ma y o cc ur d uri n g t h e st u d y t o s u p p ort e v al uati o n  of a n y safet y iss u e 
a n d/ or t o i nf or m t he desi g n of f ut ure st u dies.  
9. 4.  
I nteri m A n al yses  
N o f or mal i nteri m a nal ys es are pl a 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 de e me d 
necessar y, t he Lill y cli nical p har ma c ol o gist, i n vesti gat or, or d esi g n ee will c o ns ult wit h t he 
a p pr o priate m e dical direct or or desi g nee t o det er mi ne if it is necessar y t o a me n d t he pr ot oc ol.  
9. 5.  
D at a M o nit ori n g C o m mittee ( D M C)  
N o D M C is pla n ne d f or t his st u d y.  
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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 u cte d i n acc or da n ce wit h t he pr ot oc ol a n d wit h t he 
f oll o wi n g: 
○ C o nse ns us et hical pri nci ples deri ve d fr o m i nter nati o nal g ui deli nes i ncl u di n g 
t he Declarati o n of H elsi n ki a n d C o u ncil f or I nter n ati o nal Or ga nizati o ns of 
Me dical Scie nces ( CI O M S) I nter nati o nal Et hical G ui deli nes  
○ A p plica ble I nter nati o nal C o u ncil f or Har m o nisati o n (I C H) g o o d cli nical 
p ractice ( G C P) g ui deli nes  
○ A p plica ble la ws a n d re g ulati o ns  
● T he pr ot oc ol, pr ot oc ol a me n d me nts, I C F, I n vesti gat or Br oc h ure, a n d ot her 
rele va nt d oc u m e 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 x ce pt f or c ha n ges 
necessar y t o eli mi nate a n i m me diate hazar d t o st u d y partici pa nts. 
● T he i n vesti gat or will be res p o nsi ble f or t he f oll o wi n g:  
○ Pr o vi di n g writte 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 u e ntl y i n acc or da n ce wit h t h e re q uir e 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 h e 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 F R, I C H g ui deli nes, t he I R B/I E C, E ur o pean 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 ulati o ns 
● I n v esti gat or sites are c o m pe nsate d f or partici pati o n i n t he st u d y as det aile d i n t he 
cli nical trial a gree me nt . 
1 0. 1. 2.  
I nf or me d C o nse nt Pr ocess 
● T he i n vesti gat or or his/ her re prese nt ati ve will e x plai n t he nat ure of t h e st u d y, 
i ncl u di n g t he ris ks a n d b e nefits, t o t he partici pa nt or his/ her le gall y a ut h ori ze d 
re pres e ntati ve a n d a ns wer all q uesti o ns re gar di n g t he st u d y.  
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● Partici pa nts m ust be i nf or me d t ha t t heir partici p ati o n is v ol u ntar y. Partici pa nts or 
t heir le gall y a ut h orize d re prese nt ati ve will be re q uire d t o si g n a stat e me nt of 
i nf or me d c o nse nt t hat meets t he re q uire m e nts of 2 1 C F R 5 0, l ocal re g ulati o ns, 
I C H g ui deli nes, Healt h I ns ura nce P ort a bilit y an d Acc o u nta bilit y Act ( HI P A A) 
re q uire me nts, w h ere a p plica ble, a n d t he IR B/I E C or st u d y ce nter.  
● T he me dical r ec or d m ust i ncl u de a state me nt t hat writte n i nf or me d c o ns e nt was 
o btai ne d bef ore t he partici pa nt was e ntere 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 h e a ut h orize d pers o n o btai ni n g t he i nf or m e d c o nse nt m ust 
als o si g n t he I C F.  
● Partici pa 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 heir partici pati o n i n t he st u d y.  
● A c o p y of t he I C F(s) m ust be pr o vi d e d t o t he partici pa nt or t he partici pa nt’s 
le gall y a ut h orize d re pres e ntative  a n d is ke pt o n fil e . 
A partici pa nt w h o is res cree ne d is n ot r e q uire d t o si g n a n ot her I C F if t he rescree ni n g o cc urs 
wit hi n 2 8  da ys fr o m t he pre vi o us I C F si g nat ur e d ate.  
1 0. 1. 3.  
D at a Pr otec ti o n 
● Partici pa nts will be assi g ne d a u ni q ue i de ntifier b y t he s p o ns or. A n y partici pa nt 
rec or ds, d atasets  or tiss ue sa m ples  t hat are tr a nsferre d t o t he s p o ns or will c o ntai n 
t he i de ntifier o nl y; p artici pa nt na mes or a n y i nf or mati o n w hic h w o ul d ma ke t he 
partici pa nt i de nti fia ble will n ot be tra nsferre d. 
● T he partici pa nt m ust be i nf or me d t hat his/ her pers o nal st u d y -relate d d ata will be 
use d b y t h e s p o ns or i n acc or da nce wit h l ocal dat a pr otecti o n la w. T he l e vel of 
discl os ure m ust als o b e 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 d ata t o be use d as des cri be d i n t he i nf or me d c o ns e nt .  
● T he partici pa nt m ust be i nf or me d t hat his/ her me dical rec or ds ma y be e x a mi ne d 
b y Cli nical Q ualit y Ass ura nce a u dit ors or ot h er a ut h orize d pers o n nel a p p oi nte d b y 
t he s p o ns or, b y a p pr o pri ate I R B/I E C me m bers, a n d b y i ns pe ct ors fr o m re g ulat or y 
a ut h orities.  
● T he sp o ns or has pr o cesses i n place t o e ns ure d ata pr otecti o n, i nf or mati o n s ec urit y 
a n d data i nte grit y. T hes e pr ocesses i ncl u d e a p pr o priate c o nti n ge nc y pl a n(s) f or 
a p pr o priate a n d ti mel y res p o nse i n t he e ve nt of a d ata sec urit y breac h.  
1 0. 1. 4.  
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  
If a decisi o n 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 s afet y fi n di n gs, t his 
decisi o n will be c o m m u nicate d b y t he sp o ns or t o all i n vesti gat ors ( e. g., b y 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 uir e 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 the y u n d ersta n d t he c o m m u nicati o n 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 p artici pa nts wit h st u d y i nter ve nti o n. A n y i n vesti gat or n ot res p o n di n g will be 
f oll o we d u p b y t he sp o ns or pers o n nel pri or t o a n y f urt her pla n ne d d osi n g. If a d ose is pla n ne d 
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i m mi ne ntl y, t he sp o ns or pers o n nel will i m me diatel y, a n d c o nti n uall y, use all eff orts t o reac h 
i n vesti gat ors u ntil c o ntact is ma de a n d i nstr ucti o ns verifie d. 
Re p orts  
T he sp o ns or will discl ose a s u m mar y of st u d y i nf or mati o n, i ncl u di n g ta b ular  st u d y res ults, o n 
p u blicl y a v aila ble we bsit es w here re q uir e d b y l ocal la w or re g ulati o n.  
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 v al uate d o n a cas e b y case basi s ta ki n g i nt o c o nsi derati o n 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 h e data c ollecte d.  
1 0. 1. 5.  
D at a Q u alit y Ass ur a nce  
● All partici pa nt data relati n g t o t he st u d y will be rec or de d o n pri nte d or e 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 b orat or y data). 
T he i n vesti gat or is res p o nsi ble f or verif yi n g t hat d ata e ntries are acc urate a n d 
c orrect b y p h ysicall y or electr o nicall y si g ni n g t he C R F.  
● T he i n vesti gat or m ust mai nta i n acc urate d oc u me nt ati o n (s o urce d ata) t hat 
s u p p orts t he i nf or mati o n e ntere d i n t he C R F. 
● S o urce data ma y i n cl u de la b orat or y tests, me dical rec or ds, a n d cli nical n otes.  
● T he i n vesti ga t or m ust per mit st u d y-rel ate d m o nit 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 n c y i ns pecti o ns a n d pr o vi de direct a ccess t o s o urce data 
d oc u me nts.  
● M o nit ori n g details descri bi n g strate g y (e .g ., ris k-b ase d i nitiati 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 miti gati o n strate gies  a n d a n al yti cal ris k -
base d m o nit ori n g ), m et h o ds, res p o nsi bilities a n d re q uire me nts, i ncl u di n g h a n dli n g 
of n o nc o m plia nce iss ues a n d m o nit ori n g tec h ni q u es are  pr o vi de d i n t he 
M o nit 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 dat a ma na ge m e nt of t his st u d y 
i ncl u di ng q ualit y c hec ki n g of t he d ata.  
● T he s p o ns or ass u mes acc o u nta bilit y f or acti o ns dele gate d t o ot her i n di vi d uals 
(e.g ., c o ntr act res earc h or ga niz ati o ns ). 
● 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 site pers o n nel are acc urate, c o m plete, a n d 
verifia ble fr o m s o urce d o c u me nts; t hat t he safet y a n d ri g hts of p artici pa nts  are 
bei n g pr ot ecte d; a n d t h at t he st u d y is bei n g c o n d u cte d i n acc or da nce wit h t he 
c urre ntl y a p pr o ve d pr ot o c 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 u lat or y re q uire me nts. 
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● Rec or ds a n d d o c u me nts, i ncl u di n g si g n e d I C Fs, p ertai ni n g t o t he c o n d uct of t his 
st u d y m ust be retai n e d b y t he i n vesti gat or f or t he ti me peri o d o utli ne d i n t he 
Cli nical Trial A gree me nt ( C T A ) u nless  l ocal r e g ulati o ns or i nstit uti o nal p olicies 
re q uire a l o n 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 wit h o ut t he writte n a p pr o val of t h e 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 h o ut writte n n otificati o n t o t he s p o ns or. 
● I n a d diti o n, sp o ns or  or its re pres e ntati ves will peri o dicall y c h ec k a s a m ple of t he 
par tici pa nt data rec or de d a gai nst s o urce d o c u me nts at t he st u d y site. T he st u d y 
ma y b e a u dite d b y sp o ns or  or its re pres e ntati ves, a n d/ or re g ulat or y a ge n cies at 
a n y ti me. I n v esti gat ors will be gi ve n n otice b ef ore a n a u dit occ urs. 
D at a C a pt ure S yste m  
T he i n vesti 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 bilit y, a n d ti meli ness 
of t he data re p orte d t o t h e s p o ns or.  
A n electr o nic d ata ca pt ur e ( E D C) s yste m will be use d i n t his st u d y f or t he c ollecti o n of C R F 
data . T he i n vesti gat or mai ntai ns a se parat e 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 E D C s yste m . T he i n vesti gat or is res p o nsi ble f or t he 
i de ntificati o n 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 mati o n t hat data re p orte d are 
acc ur ate 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 dat a ca pt ure s yste m will be  st ore d at t hir d-part y site. T he 
i n vesti gat or will ha v e c o nti n u o us access t o t he dat a d uri n g t h e st u d y a n d u ntil dec o m missi o ni n g 
of t he data ca pt ure s ys te m. Pri or t o dec o m missi o ni n g, t he i n vesti gat or will recei ve a n arc hi val 
c o p y of perti ne nt d ata f or rete nti o n.  
Data ma na ge d b y a ce ntr al ve n d or, s uc h as la b orat or y test d ata, will be st ore d electr o ni call y i n 
t he ce ntral v e n d or’s d ata base s yste m a n d re p orts will be pr o vi de d t o t he i n vesti gat or f or re vie w 
a n d rete nti o n . Dat a will s u bse q ue ntl y b e tra nsferre d fr o m t he ce ntr al ve n d or t o t he sp o ns or  data 
ware h o us e.  
Data fr o m c o m plai nt f or ms s u b mitte d t o 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 yste m.  
1 0. 1. 6.  
S o urce D oc u me nts  
● S o urce d oc u me nts pr o vi d e e vi de nce f or t h e e xiste nce of t he p artici 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 m e 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 e C R F t hat are tr a 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 p a ncies 
m ust be e x plai ne d. T he i n vesti gat or m a y nee d t o r e q uest pre vi o us me dical rec or ds 
or tra nsfer rec or ds, de p e n di n g o n t he st u d y. A ls o, c urre nt me di cal rec or ds m ust be 
a vaila ble.  
● Defi niti o n of w hat c o nstit utes s o urce data ca n b e f o u n d i n A p pe n di x 1 ( Secti o n 
1 0. 1. 5 ). 
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1 0. 1. 7.  
St u d y a n d Si te St art a n d Cl os ure  
1 0. 1. 7. 1.  Disc o nti n u ati o n of t he St u d y  
T he st u d y start date is t he date o n w hic h t h e cli nical st u d y will be o pe n f or recr uit me nt of 
partici pa nts.  
T he st u d y will be disc o nti n ue d if Lill y or its desi g nee j u d ges it necessar y f or me dical, safet y, 
reg ulat or y, or ot her reas o ns c o nsiste nt wit h a p plica ble la ws, re g ulati o ns, a n d G C P.  
Me dic al O versi g ht a n d S afet y Re vie w  
O n g oi n g safet y re vie w(s) b y desi g n ate d s p o ns or p ers o n nel will occ ur a n d b e d oc u me nte d. S uc h 
re vie ws will i ncl u de: 
M o nit ori n g a n d ass essi n g t he safet y i nf or m ati o n c ollecte d d uri n g t he trial b ot h i n real 
ti me a n d peri o dicall y, a n d 
Re vie wi n g  s afet y dat a f or tre n ds t hat nee d acti o n, a n d 
Detecti n g  a d v erse dr u g/ de vice effects.  
A safet y i n vesti gati o n will be tri g gere d t o deter mi ne if t he st u d y s h o ul d be ter mi nate d earl y 
base d o n t he f oll o wi n g criteria:  
T w o st u d y partici pa nts de vel o p t he sa me tr eat me nt-e mer ge nt a d verse e ve nt ( T E A E ) or 
S A E c o nsi dere d p ossi bl y or pr o ba bl y relate d t o st u d y i nter ve nti o n t hat is se vere or 
me dicall y si g nifi ca nt b ut n ot i m me diatel y life -t hr eate ni n g, or w here h os pitalizati o n or 
pr ol o n gati o n of h os pitali zati o n is i n dicate d , or is disa bli n g , or li mits self -care acti vities 
of dail y li vi n g.  
O ne st u d y p artici pa nt d e vel o ps a n y T E A E or S A E re gar dl ess of attri b uti o n  t o st u d y 
i nter ve nti o n t hat has life-t hreate ni n g c o ns e q ue nces or re q uires ur ge nt i nter ve nti o n. 
Deat h of a n y st u d y p artici pa nt at a n y ti me.  
A n y ot her cli nicall y si g nifica nt safet y si g nal.  
If t he st u d y is pre mat urel y ter mi nat e d or s us pe n d e d, t he sp 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 ntr act r esearc h or ga nizati o n(s) 
use d i n t he st u d y of t he reas o n f or ter mi nati o n or s us pe nsi o n, as s pecifie d b y t he a p plica ble 
re g ulat or y re q uire me nts. T he in vesti gat or s hall pr o m ptl y i nf or m t he partici pa nt s a n d s h o ul d 
ass ure a p pr o priate p artici pa nt t hera p y a n d/ or f oll o w -u p.  
1 0. 1. 7. 2.  Disc o nti n u ati o n of St u d y Sites  
T he sp o ns or desi g nee res er ves t he ri g ht t o cl ose t h e st u d y site or ter mi nate t he st u d y at a n y ti me 
f or a n y reas o n at t he s ole discreti o n of t he sp o ns or. St u d y sites will be cl ose d u p o n st u d y 
c o m pleti o n. A st u d y site is c o nsi dere d cl ose d w he n all re q uire d d o c 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 -site cl os ure visit has bee n perf or m e d.  
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T he i n vesti gat or ma y i nitiate st u d y -site cl os ure at a n y ti me, pr o vi d e d t here is 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 nt e n de d ter mi nati o n.  
Reas o ns f or t he earl y cl os ure of a st u d y site b y t he sp o ns or or i n vesti gat or  ma y i ncl u d e, b ut are 
n ot li mite d t o:  
 Fail ure of t he i n vesti gat or t o c o m pl y wit h t he pr ot oc ol, t he re q uir e me nts of t he I R B/I E C 
or l ocal healt h a ut h orities, t he sp o ns or’s pr oce d ures, or G C P g ui deli nes;  
 I n a de q uat e recr uit me nt of partici pa nts b y t he i n vesti gat or; 
 Disc o nti n uati o n of f urt her st u d y i nter ve nti o n de vel o p me nt.  
1 0. 1. 8.  
P u blic ati o n P olic y  
I n acc or da n ce 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 o n b y a peer-re vie we d j o ur nal if t he res ults are dee me d t o b e of si g nifica nt me di cal 
i m p orta nce. 
1 0. 1. 9.  
L o n g -Ter m S a m ple Rete nti o n  
Sa m ple rete nti o n e na bles use of ne w tec h n ol o gies, res p o nse t o re g ul at or y q uesti o ns, a n d 
i n vesti gati o n of varia ble res p o nses t hat ma y n ot b e o bser ve d u ntil later i n t he de vel o p me nt of 
L Y 3 5 0 9 7 5 4  o r aft er L Y 35 0 9 7 5 4 bec o mes c o m merciall y a vaila ble.  
T he rete nti o n peri o d be gi ns after t he last p artici pa nt visit f or t he st u d y.  
T he ma xi m u m rete nti o n ti mes ma y be s h orter, if s pecifie d i n l ocal r e g ulati o ns a n d/ or if 
E R Bs/I R Bs i m p ose s h ort er ti me li mits, or b y decisi o n of t he s p o ns or . 
A n y s a m ples re mai ni n g after t he s pecifie d rete nti o n peri o d will be destr o ye d.  
T he sa m ple ret e nti o n facilit y will be selecte d b y t h e s p o ns or or its desi g n ee. 
T he f oll o wi n g t a ble lists t he ma xi m u m rete nti o n peri o d f or sa m ple t y p es . 
S a m ple T y pe  
C ust o di a n  
Rete nti o n Peri o d after L ast 
P artici p a nt Visit  
P har mac o ki netics  
S p o ns or or desi g n ee  
2 years  
E x pl orat or y Bi o mar ker S a m ples  
S p o ns or or desi g n ee  
1 5 years  
Li ver Bi o ps y Secti o n s 
S p o ns or or desi g n ee  
1 5 years  
P har mac o ge n etics  
S p o ns or or  desi g n ee  
1 5 years  
I m m u n o ge nicit y 
S p o ns or or desi g n ee  
1 5 years  
 
 
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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 bel o w will be perf or me d b y t h e l ocal la b orat or y.  
 Pr ot oc ol -s pecific re q uire me nts f or i ncl usi o n or e x cl usi o n of partici pa nts are 
detaile d i n Secti o n 5  of t he pr ot oc ol.  
 A d diti o nal tests ma y be p erf or me d at a n y ti me d uri n g t he st u d y as d eter mi ne d 
necessar y b y t he i n vesti gat or or re q uire d b y l ocal re g ulati o ns.  
 Pre g n a nc y testi n g : See S ecti o n 5. 1  (I ncl usi o n Criteria f or s cree ni n g pre g n a nc y 
criteria) a n d Secti o n 1 0. 4  ( A p pe n di x 4 C o ntrace pti ve G ui da nce a n d C ollecti o n 
of Pre g na nc y I nf or m ati o n).  
I n v esti 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. 
La b orat or y res ults t hat c o ul d u n bli n d t h e st u d y will n ot be re p orte d t o i n vesti gati ve sites or ot her 
bli n de d pers o n nel.  
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S af et y L a b or at or y T e st s  
He mat ol o g y a 
Cli nical C he mistr y (fasti n g) a 
He mat ocrit  
S o di u m  
He m o gl o bi n  
P otassi u m  
Er yt 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 hate  
Le u k oc ytes ( W B C)  
Ma g nesi u m  
A bs ol ute co u nts of  
Creati ni ne  
Ne utr o p hils  
Gl uc ose  
L y m p h oc ytes  
Urea  
M o n oc ytes  
Uric aci d  
E osi n o p hils  
T otal  pr otei n  
B as o p hils  
Al b u mi n  
Platelets  
T otal bilir u bi n  
 
 
Uri nal ysis a 
Direct bilir u bi n  
S pecific gra vit y  
Ga m ma -gl uta m yl tra nsferase  
p H  
 
Pr otei n  
Al kali ne p h os p hatase ( A L P)  
Gl uc ose  
As partate a mi n otra nsferase ( A S T)  
Ket o nes  
Ala ni ne a mi n otra nsferase ( A L T)  
Bilir u bi n  
 
Ur o bili n o ge n  
 
Nitrite  
 
Bl o o d  
Q ua nti F E R O N -T B G ol d test c,g  
Le u k oc ytes  
 
Micr osc o p y b  
 
W B C esterase  
 
 
Ser ol o g y  
 
He p atitis B s urface a nti ge n c,d  
 
He p atitis C vir us ser ol o g y c,d  
 
H u ma n i m m u n o deficie nc y vir us ( HI V) c, d 
 
 
 
Pre g na nc y test e,f 
 
F S H c  
 
a Cli nical safet y la b orat or y tests.  
b If cli nicall y i n dicate d, per i n vesti gat or’s discreti o n. 
c P erf or me d at scree ni n g o nl y.  
d Tests ma y be wai ve d if t he y ha ve bee n 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.  
e F or fe males o nl y: A ser u m pre g na nc y test will be perf or me d at scree ni n g a n d uri ne pre g na nc y test at all ot her 
ti me p oi nts . 
f Refer t o Secti o n 1. 3  f or sc he d ule of c ollecti o n. 
g Res ults will be vali date d b y  t he l ocal la b orat or y at t he ti me of i nitial testi n g. 
 
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N ote: Res ults of t hese assa ys will b e vali date d b y t h e l ocal l a b orat or y at t he ti me of testi n g. A d diti o nal tests ma y be 
perf or me d or a ut o -calc ulate d b y t he la b orat or y as part of its sta n dar d pa nel t hat ca n n ot be re m o ve d. S o me of t he 
a b o ve para meters are calc ulat e d fr o m meas ure d val ues. I ncl usi o n or o missi o n of calc ulate d val ues will n ot b e 
c o nsi dere d as a pr ot oc ol d e viati o n.  
N ote: C oc kc r oft-Ga ult pre dicti o n of creati ni ne cleara nce fr o m ser u m creati ni ne ( 1 9 7 6)  
F or ser u m creati ni ne c o nce ntrati o n i n m g/ d L:  
Cr Cl =  
( m L/ mi n) 
(1 4 0 –  a ge a )  (wt )  0. 8 5 (if fe male), or   1. 0 (if male) 
7 2   ser u m cre ati ni ne (m g/ d L ) 
F or ser u m creati ni ne c o nce ntrati o n i n µ m ol/ L:  
Cr Cl  =  
( m L/ mi n) 
 (1 4 0 –  a ge a )  (wt )  0. 8 5 (if fe male), or   1. 0 (if male) 
0. 8 1   ser u m cre ati ni ne (m ol/ L ) 
a A ge i n years, wei g ht ( wt) i n kil o gra ms.  
S o urce:  C oc kcr oft a n d Ga ult 1 9 7 6.  
 
 
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C O N FI D E N TI A L  
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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 la b orat ories, a n d bi oa nal ytical assa ys) d uri n g t he  st u d y. 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
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9 1  
Pr ot oc ol J 3 D -M C -F N A A S a m pli n g S u m m ar y f or P a rt A  ( SA D)  [C o h orts  1, 2, 3, 5 , a n d 6 ] 
P ur p ose  
Bl o o d 
V ol u me 
per 
S a m ple  
( m L) 
A p pr o xi m ate 
N u m ber of 
Bl o o d 
S a m ples  
A p pr o xi m ate 
T ot al 
V ol u me 
( m L) 
Scree ni n g tests a (l ocal la b orat or y) 
1 0  
1  
1 0  
Cli nical la b orat or y tests a (l ocal la b orat or y) 
 
 
 
St u d y visits  
E D/f oll o w u p  
4. 5  
4. 5  
2  
1  
9  
4. 5  
L Y 3 5 0 9 7 5 4  p har mac o ki netics  
2  
1 6  
3 2  
P har mac o ge netic a nal ysis sa m ple (st ore d)  
1 0  
1  
1 0  
E x pl orat or y bl o o d sa m ples b 
1 8. 5  
9  
1 6 6 . 5 
T otal  
 
 
2 3 2  
T otal r o u n de d u p t o t he nearest 1 0 m L  
2 4 0  
A b bre viati o n: E D = earl y disc o nti n uati o n .  
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  A d diti o nal sa m ples (6  m L) ma y be dra w n  d uri n g a d diti o nal s afet y f oll o w -u p visits . 
 
 
 
 
Pr ot oc ol J 3 D -M C -F N A A S a m pli n g S u m m ar y f or P a rt A S A D  F o o d E ffect E v al u ati o n  
[C o h ort 4 ] 
P ur p ose  
Bl o o d 
V ol u me 
per 
S a m ple  
( m L) 
A p pr o xi m ate 
N u m ber of 
Bl o o d 
S a m ples  
A p pr o xi m ate 
T ot al 
V ol u me 
( m L) 
Scree ni n g tests a (l ocal la b orat or y) 
1 0  
1  
1 0  
Cli nical la b orat or y tests a (l ocal la b orat or y) 
 
 
 
St u d y visits  
E D/f oll o w u p  
4. 5  
4. 5  
3  
1  
1 3 . 5 
4. 5  
L Y 3 5 0 9 7 5 4 p har mac o ki netics  
2  
3 2  
6 4  
P har mac o ge netic a nal ysis sa m ple (st ore d)  
1 0  
1  
1 0  
E x pl orat or y bl o o d sa m ples b 
1 8. 5  
9  
1 6 6 . 5 
T otal  
 
 
2 6 8 . 5 
T otal r o u n de d u p t o t he nearest 1 0 m L  
2 7 0  
A b bre viati o n: E D = earl y disc o nti n uati o n . 
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  A d diti o nal sa m ples (6  m L) ma y be dra w n  d uri n g a d diti o nal s afet y f oll o w -u p visits . 
 
 
 
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9 2  
Pr ot oc ol J 3 D -M C -F N A A S a m pli n g S u m m ar y f or P a rt B ( D DI wit h C Y P 3 A 4 I n hi biti o n –
Fi xe d Se q ue nce ) 
P ur p ose  
Bl o o d V ol u me per 
S a m ple  
( m L) 
A p pr o xi m ate 
N u m ber of Bl o o d 
S a m ples  
A p pr o xi m ate 
T ot al V ol u me 
( m L) 
Scree ni n g tests a (l ocal la b orat or y) 
1 0  
1  
1 0  
Cli nical la b orat or y tests a (l ocal la b orat or y) 
 
 
 
St u d y visits  
E D/f oll o w u p  
4. 5  
4. 5  
6  
1  
2 7  
4. 5  
L Y 3 5 0 9 7 5 4 p har mac o ki netics  
2  
3 3  
6 6  
Itrac o naz ole p har mac o ki netics   
2  
7  
1 4  
P har mac o ge netic a nal ysis sa m ple (st ore d)  
1 0  
1  
1 0  
T otal  
 
 
1 3 1 . 5 
T otal r o u n de d u p t o t he nearest 1 0 m L  
 
 
1 4 0  
A b bre viati o ns: E D = earl y dis c o nti n uati o n.   
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.  
 
 
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Pr ot oc ol J 3 D -M C -F N A A S a m pli n g S u m m ar y f or P a rt C  (M A D)  [ C o h o rts 1 a n d  3 ] 
P ur p ose  
Bl o o d 
V ol u me 
per 
S a m ple  
( m L) 
A p pr o xi m ate 
N u m ber of 
Bl o o d 
S a m ples  
A p pr o xi m ate 
T ot al V ol u me 
( m L) 
Scree ni n g tests a (l ocal la b orat or y) 
1 0  
1  
1 0  
Cli nical la b orat or y testsa (l ocal la b orat or y) 
 
 
 
St u d y visits  
E D/f oll o w u p  
4. 5  
4. 5  
3  
1  
1 3 . 5 
4. 5  
L Y 3 5 0 9 7 5 4 p har mac o ki netics  
2  
3 6  
7 2  
P har mac o ge netic a nal ysis sa m ple (st ore d)  
1 0  
1  
1 0  
E x pl orat or y bl o o d plas ma  sa m plesb 
6  
2 7  
1 6 2  
E x pl orat or y bl o o d ser u m sa m ples  
6  
6  
3 6  
T otal  
 
 
3 0 8  
T otal r o u n de d u p t o t he nearest 1 0 m L  
3 1 0  
A b bre viati o n: E D = earl y disc o nti n uati o n . 
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  A d diti o nal sa m ples (6  m L) ma y be dra w n  d uri n g a d diti o nal s afet y f oll o w -u p visits . 
 
 
Pr ot oc ol J 3 D -M C -F N A A S a m pli n g S u m m ar y f or P a rt C ( M A D + Mi d az ol a m D DI)  
[ C o h ort 2]  
P ur p ose  
Bl o o d 
V ol u me 
per 
S a m ple  
( m L) 
A p pr o xi m ate 
N u m ber of 
Bl o o d 
S a m ples  
A p pr o xi m ate 
T ot al V ol u me 
( m L) 
Scree ni n g tests a (l ocal la b orat or y) 
1 0  
1  
1 0  
Cli nical la b orat or y tests a (l ocal la b orat or y) 
 
 
 
St u d y visits  
E D/f oll o w u p  
4. 5  
4. 5  
4  
1  
1 8  
4. 5  
L Y 3 5 0 9 7 5 4 p har mac o ki netics  
2  
3 6  
7 2  
Mi d az ola m p har mac o ki netics  
2  
2 6  
5 2  
P har mac o ge netic a nal ysis sa m ple (st ore d)  
1 0  
1  
1 0  
E x pl orat or y bl o o d sa m ples b 
1 8. 5  
1 5  
2 7 7. 5  
T otal  
 
 
4 4 4  
T otal r o u n de d u p  t o t he nearest 1 0 m L 
4 5 0  
A b bre viati o n: E D = earl y disc o nti n uati o n.  
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  A d diti o nal sa m ples (6  m L) ma y be dra w n  d uri n g a d diti o nal s afet y f oll o w -u p visits . 
 
 
 
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C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
9 4  
Pr ot oc ol J 3 D -M C -F N A A  S a m pli n g S u m m ar y f or P a rt D  M A D  ( J a p a nese P arti ci p a nts) 
P ur p ose  
Bl o o d 
V ol u me 
per 
S a m ple  
( m L) 
A p pr o xi m ate 
N u m ber of 
Bl o o d 
S a m ples  
A p pr o xi m ate 
T ot al V ol u me 
( m L) 
Scree ni n g tests a (l ocal la b orat or y) 
1 0  
1  
1 0  
Cli nical la b orat or y tests a (l ocal la b orat or y) 
 
 
 
St u d y visits  
E D/f oll o w u p  
4. 5  
4. 5  
3  
1  
1 3. 5  
4. 5  
L Y 3 5 0 9 7 5 4 p har mac o ki netics  
2  
3 7  
7 4  
E x pl orat or y bl o o d plas ma sa m plesb 
6  
2 7  
1 6 2  
E x pl orat or y bl o o d ser u m sa m ples  
6  
6  
3 6  
P har mac o ge netic a nal ysis sa m ple (st ore d)  
1 0  
1  
1 0  
T otal  
 
 
3 1 0  
T otal r o u n de d u p t o t he nearest 1 0 m L  
3 1 0  
A b bre viati o n: E D = earl y disc o nti n uati o n . 
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  A d diti o nal sa m ples (6  m L) ma y be dra w n  d uri n g a d diti o nal s afet y f oll o w -u p visits . 
 
 
 
 
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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 is a n y u nt o war d me dical occ urre n ce i n a patie nt or cli nical st u d y p artici pa nt, 
te m p orall y ass ociate d wit h t he use of st u d y i nter ve nti o n, w het her or n ot c o nsi dere d 
relate d t o t he st u d y i nter ve nti o n. 
 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 n cl 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 diseas e ( ne w or e x acer bate d) t e m p orall y 
ass ociate d wit h t he use of st u d y i nter ve nti o n.  
 
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 ol o g y, cli nical c he mistr y, or uri nal ysis) or 
ot her safet y assess me nts ( e. g., E C G, ra di ol o gical sca ns, vital si g ns meas ure me nts), 
i ncl u di n g t h ose t hat w ors e n fr o m baseli ne, b ut n ot relate d t o t he pr o gressi o n of t he 
u n derl yi n g dise ase , a n d c o nsi dere d cli nicall y si g nifica nt i n t he me dical a n d scie ntific 
j u d g me nt of t he i n vesti gat or. 
 E x acer bati o n of a c hr o ni c or i nter mitte nt pre -e xisti n g c o n diti o n i ncl u di n g eit her a n 
i ncreas e i n fre q u e nc y a n d/ or i nte nsit y of t he c o n diti o n. 
 Ne w c o n diti o ns detect e d or dia g n os e d after st u d y i nter ve nti o n a d mi nistrati o n e ve n 
t h o u g h it ma y ha ve b ee 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 nti o n or a c o n c o mita nt me dicati o n. 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/s elf-har mi n g 
i nte nt. S uc h o ver d ose s h o ul d be re p orte d re gar dless of se q uelae. 
 
E ve nts N O T  Meeti n g t he A E D efi niti o n 
 A n y cli nicall y si g 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 s afet y 
assess me nts w hic h are ass ociate d wit h t he u n derl yi n g diseas e, u nless j u d ge d b y t he 
i n vesti gat or t o be m or e s e vere t h a n e x pecte d f or t he partici pa nt’s c o n diti o n. 
 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 ms of t he 
disease/ dis or der bei n g st u die d, u nless m ore se vere t ha n e x pect e d f or t he p artici pa nt’s 
c o n diti o n.  
 Me dical or s ur gic al pr oce d ure ( e. g., e n d os c o p y, a p pe n dect o m y): t he c o n diti o n t hat 
lea ds t o t he pr oce d ure is t he A E. 
 Sit uati o ns i n w hic h a n u nt o war d me dical o cc urre n ce di d n ot occ ur (s ocial a n d/ or 
c o n ve nie nce a d missi o n t o  a h os pital). 
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 A ntici pate d da y -t o-d a y fl uct uati o ns of pre -e xisti n g disease(s) or c o n diti o n(s) prese nt or 
detecte d at t he start of t h e st u d y t hat d o n ot w ors e n.  
1 0. 3. 2.  
Defi niti o n of S A E  
If a n e v e nt is n ot a n A E per defi niti o n a b o ve, t h e n it ca n n ot be a n S A E e v e n if seri o us c o n diti o ns 
are met ( e. g., h os pitaliz ati o n f or si g ns/s y m pt o ms of t he disease u n d er st u d y, deat h d ue t o 
pr o gressi o n of diseas e).  
A n  S A E is defi ne d as a n y u nt o w ar d me dic al o cc urre nce t h at, at a n y d ose:  
a.  Res ults i n de at h  
b.  Is lif e-t hre ate ni n g 
T he ter m ‘life-t hreat e ni n g’ i n t he d efi niti o n of ‘seri o us’ refers t o a n e ve nt i n w hic h t he 
partici pa nt was at ris k of deat h at t he ti me of t he e ve nt. It d o es n ot refer t o a n e ve nt, w hic h 
h y p ot hetic all y mi g ht ha v e ca use d d eat h, if it were m ore se vere.  
c. 
Re q u ires 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 o n 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 o n a n d/ or treat me nt t hat w o ul d n ot ha ve bee n a p pr o priat e i n t he 
p h ysicia n’s office or o ut patie nt setti n g. C o m plicati o ns t hat occ ur d uri n g h os pitaliz ati o n 
are A E s. If a c o m plicati o n pr ol o n gs h os pitalizati o n or f ulfills a n y ot h er seri ous criteria, 
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 ul d be c o nsi dere d seri o us.  
 H os pitalizati o n f or electi ve treat me nt of a pre -e xisti n g c o n diti o n t hat di d n ot w orse n 
fr o m 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 bilit y me a ns a s u bsta ntial disr u pti o n of a pers o n’s a bilit y t o c o n d uct 
n or mal life f u ncti o ns.  
 T his defi niti o n is n ot i nte n de d t o i ncl u de e x perie n ces of relati vel y mi n or me dical 
si g nifica n ce s uc h as u nc o m plicate d hea dac he, n a 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 
e ver 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 pti o n.  
e. 
Is a c o n ge nit al a no m al y/ birt h defect  
f. 
Ot her sit u ati o ns:  
 Me dical or scie ntifi c j u d g me nt s h o ul d be e x ercise d i n deci di n g w het her 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 hreat e ni n g or res ult i n deat h or h os pitalizati o n b ut ma y je o par dize t he 
partici pa nt or ma y re q uir e me dical or s ur gi cal i nter ve nti o n t o pre ve nt 1  of t he ot her 
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o utc o mes liste d i n t he a b o ve defi niti o n. T hese e v e nts s h o ul d us uall y b e c o nsi dere d 
seri o us. 
 
E x a m ples of s uc h e ve nts i ncl u de i n vas i 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 gi c 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 pitalizati o n, or de vel o p me nt of dr u g d e pe n de nc y or 
dr u g a b use.  
1 0. 3. 3.  
Re p orti n g of S A Es  
S A E Re p orti n g vi a S A E Re p ort  
 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 mati o n t o t he s p o ns or or desi g nee. 
 I nitial n otificati o n via tel e p h o ne d oes n ot re place t he nee d f or t he i n vesti gat or t o 
c o m plete a n d si gn t he S A E re p ort wit hi n t he desi g nat e d re p orti n g ti me fra mes.  
 C o ntacts f or S A E re p orti n g ca n be f o u n d i n t he S A E re p ort. 
 
 
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1 0. 3. 4.  
Rec or di n g a n d F oll o w -U p 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 r e vie w all 
d oc u me ntati o n (e .g ., h os pital pr o gress n otes, la b orat or y re p orts, a n d dia g n ostics 
re p orts) relate d t o t he e v e nt. 
 T he i n vesti gat or will t he n rec or d all rele va nt A E/ S A E i nf or mati o n i n t he C R F.  
 It is n ot  acce pta bl e f or t h e i n vesti gat or t o se n d p h ot oc o pies of t he partici p a nt’s me dical 
rec or ds t o 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 p a ge. 
 T here ma y b e i nsta nces w he n c o pies of m e dical r ec or ds f or certai n cas es are re q u este d 
b y sp o ns or or d esi g nee . I n t his case, all partici pa nt i de ntifiers, wit h t he e x ce pti o n 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 r ec or ds bef ore 
s u b missi o n t o sp o ns or or desi g nee . 
 T he i n vesti 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 o n. 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 vesti gat or will ma ke a n assess me nt of i nte nsit y f or eac h 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 o wi n g cat e g ories:   
 Mil d: A n e ve nt t hat is easil y t olerate d b y t h e parti ci pa nt, ca usi n g mi ni mal disc o mf ort 
a n d n ot i nterferi n g wit h e ver y da y acti 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 ma l 
e ver y da y acti vities.  
 Se vere: A n e v e nt t hat pre ve nts n or mal e ver y d a y acti vities. 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 a 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 ‘s eri o us’ w he n it meets at least 1 of t he pre defi n e d o utc o mes as 
descri be d i n t he d efi niti o n of a n S A E, N O T w h e n it is rate d as se vere.  
 
Assess me nt of C a us alit y  
 T he i n vesti 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 o n a n d 
eac h o cc urre nce of eac h A E/ S A E.  
 A “reas o na ble p ossi bilit y” of a relati o ns hi p c o n ve ys t hat t here are facts, e vi de n ce, 
a n d/ or ar g u me nts t o s u g gest a ca us al relati o ns hi p, rat her t ha n a rel ati o ns hi p ca n n ot be 
r ule d o ut. 
 T he i n vesti gat or will use cli nical j u d g me nt t o deter mi ne t he relati o ns hi p.  
 Alter nati 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 h e e ve nt t o st u d y i nter ve nti o n 
a d mi nistrati o n will be c o nsi dere d a n d i n vesti gate d.  
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 T he i n vesti 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 m ar 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 vesti 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 h e A E/ S A E a n d has pr o vi de d a n assess me nt of ca usalit y. 
 T here ma y b e sit uati o ns i n w hic h a n S A E has occ urre d a n d t h e i n vesti gat or has 
mi ni mal i nf or mati o n t o i ncl u de i n t he i nitial re p ort t o sp o ns or or desi g n ee . H o we ver, it 
is ver y i m p orta nt t hat t he i n vesti gat or al wa ys ma k e a n assess me nt of ca us alit y f or 
e ver y e v e nt bef ore t he i nitial tra ns missi o n of t he S A E data t o sp o ns or or d esi g nee . 
 T he i n vesti gat or ma y c h a n ge his/ her o pi ni o n of ca usalit y i n li g ht of f oll o w -u p 
i nf or mati o n a n d se n d a S A E f oll o w-u p re p ort wit h t he u p date d ca usalit y assess me nt.  
 T he ca us alit y ass ess me nt is 1  of t he criteria us e d w he n 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 E s a n d S A Es 
 T he i n vesti gat or is o bli gate d t o perf or m or arra n ge f or t he c o n d u ct of s u p ple me ntal 
meas ure me nts a n d/ or e val uati o ns as me dicall y i n dicate d or as re q uest e d b y sp o ns or or 
desi g nee  t o el uci dat e 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 diti o nal la b orat or y tests or i n v esti gati o ns, hist o pat h ol o gical 
e x a mi nati o ns, 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 o w-u p 
peri o d,  t he i n vesti gat or will pr o vi de sp o ns or or desi g nee  wit h a c o p y of a n y 
p ost -m orte m fi n di n gs i ncl u di n g hist o pat h ol o g y.  
 Ne w or u p d ate d i nf or mati o n will be rec or de d i n t he ori gi n all y c o m plete d C R F.  
 T he i n vesti gat or will s u b mit a n y u p date d S A E d ata t o sp o ns or or desi g nee  wit hi n 
2 4  h o urs of recei pt of t he i nf or mati o n.  
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 nf or 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 o wi n g m e narc h e a n d u ntil bec o mi n g p ost -me n o pa usal u nless 
per ma ne ntl y sterile (see bel o w).  
If fertilit y is u nclear (e.g ., a me n orr hea i n a d oles ce 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 first  d ose of st u d y i nter ve nti o n, a d diti o nal e val uati o n s h o ul d be c o nsi dere d.  
W o me n i n t he f oll o wi n g cate g ories are n ot c o nsi dere d W O C B P : 
Article I.  Pre me narc hal  
Article II.  Pre me n o pa usal f e male wit h 1 of t he f oll o wi n g:  
 D oc u me nte d h ysterect o m y  
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 D oc u me 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 ma ne nt i nfertilit y d ue t o a n alter nat e me dical ca us e ot her t ha n t he 
a b o ve, (e.g ., M ülleria n a ge n esis, a n dr o ge n i nse nsiti vit y), i n v esti gat or discreti o n 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’s : re vie w of t he partici pa nt’s 
me dical rec or ds, me dic al e x a mi nati o n, or me dical hist or y i nter vie w.  
Article III.   T he p ost -me n o pa usal state s h o ul d be defi ne d as:  
1.  A w o ma n at a n y a ge at least 6 wee ks p ost -s ur gical bilateral o o p h orect o m y 
wit h or wit h o ut h ysterect o m y, c o nfir me d b y o perati ve n ote; or 2  
2.  A w o ma n at least 4 0 years of a ge a n d u p t o 5 5 years ol d 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 cessati o n of me nses f or at least 1 2 
c o nsec uti ve m o nt hs wi t h o ut a n alter nati ve me di cal ca use, A N D Wit h a 
f ollicle-sti m ulati n g h or m o ne > 4 0 mI U/ m L; or  
3.  A w o ma n 5 5 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 h ea, or  
4.  A w o ma n at least 5 5 years of a ge wit h a dia g n osis of me n o p a use pri or t o 
starti n g h or m o ne re place me nt t hera p y. 
 
*  W o me n s h o ul d n ot be ta ki n g me dicati o ns d uri n g 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 -releasi n g h or m o ne, a nti-estr o ge ns, 
selecti ve estr o ge n rece pt or m o d ulat ors ( S E R Ms), or c he m ot hera p y t hat c o ul d 
i n d uce tra nsie nt a m e n orr hea. 
C o ntr ace pti o n G ui d a nce:  
T he ta ble bel o w d escri bes c o ntrace pti o n g ui da nce f or all me n.  
 
T o pic  
G ui d a nce  
A ll me n 
S h o ul d  refrai n fr o m s per m d o nati o n f or t he 
d urati o n of t he st u d y a n d f or at least 3 0 da ys after 
t he last d ose f or Parts A-D  
C o ntrace pti o n f or me n wit h part ners of 
c hil d beari n g p ote ntial  
 
E it her re mai n a bsti ne nt (if t his is t heir 
preferre d a n d us ual lifest yle), or  
 
M ust  use c o n d o ms d uri n g i nterc o urse f or 
t he d urati o n of t he st u d y, a n d  
 
F or  at least 3 0 da ys after t he last d ose   
C o ntrace pti o n f or me n i n e xcl usi vel y sa me se x 
relati o ns hi ps, as t heir preferre d a n d us ual lifest yle 
Are n ot re q uire d t o use c o ntrace pti o n . 
 
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E x a m ples of hi g hl y effecti ve, effecti ve a n d u nacce pta ble met h o ds of c o ntrace pti o n ca n b e f o u n d 
bel o w.  
Met h o ds  
E x a m ples  
Hi g hl y effecti ve c o ntrace pti o n  
 
C o m bi nati o n  oral c o ntrace pti ve pill a n d 
mi ni pill  
 
I m pla nte d c o ntrace pti ves  
 
I nj ecta ble c o ntrace pti ves  
 
C o ntrace pti ve  patc h ( o nl y w o me n 
< 1 9 8  p o u n ds or 9 0 k g)  
 
T otal  a bsti ne nce 
 
Vasect o m y  (if o nl y se x ual part ner) 
 
Fall o pi a n t u be i m pla nts (if c o nfir me d b y 
h yster osal pi n g o gra m)  
 
C o m bi ne d  c o ntrace pti ve va gi nal ri n g, or  
 
I ntra uteri ne de vices  
Effecti ve c o ntrace pti o n  
 
M ale c o n d o ms wit h s per mici de pl us 
cer vical s p o n ges  wit h s per mici de  
I neffecti ve f or ms of c o ntrace pti o n 
 
S per mici de al o ne  
 
I m m u n oc o ntrace pti ves 
 
Peri o dic  a bsti ne nce 
 
Fertilit y  a ware ness (cale n dar met h o d, 
te m perat ure met h o d, c o m bi nati o n of 
a b o ve 2, cer vical m uc us, s y m pt ot her mal)  
 
Wit h dra wal , 
 
P ost -c oital d o uc he 
 
Lactati o nal  a me norr hea  
 
 
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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 wi t h p art ners w h o bec o me pre g n a nt 
● T he i n vesti gat or will atte m pt t o c ollect pre g na nc y i nf or mati o n o n a n y male 
partici pa nt’s f e male part ner w h o bec o mes pre g na nt w hile t he male partici p a 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 L Y 3 5 0 9 7 5 4 . 
● After o btai ni n g t he ne cessar y si g n e d i nf or me d c o nse nt fr o m t he pre g n a nt fe male 
part ner directl y, t he i n vesti gat or will rec or d pre g na nc y i nf or mati o n 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 n c y. T he fe male part ner wi ll als o be f oll o we d t o deter mi ne t he 
o utc o me of t he pre g na nc y. I nf or mati o n o n t he stat us of t he m ot her a n d c hil d will 
be f or w ar de d t o t he s p o ns or. Ge nerall y, t he f oll o w -u p will be n o l o n ger t h a n 6 t o 
8  wee ks f oll o wi n g t he esti mate d deli ver y date. A n y ter mi nati o n of t h e pre g na nc y 
will be re p orte d i ncl u di n g fetal stat us ( pres e nce or a bse nce of a n o malies) a n d 
i n dicati o n f or t he pr oce d ure.  
Fe m ale P a rtici p a nts w h o bec o me pre g n a nt  
● T he i n vesti gat or will c ollect pre g n a nc y i nf or m ati o n o n a n y fe male p artici pa nt 
w h o bec o mes pre g na nt w hile partici pati n g i n t his st u d y . T he i nitial i nf or mati o n 
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 partici pa nt will be f oll o we d t o deter mi ne t he o utc o me of t he pre g na nc y. T he 
i n vesti gat or will c ollect f oll o w-u p i nf or mati o n o n t he partici pa nt a n d t he ne o nate 
a n d t he i nf or mati o n will be f or war de d t o t he s p o ns or. Ge nerall y, f oll o w -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 b e y o n d t he esti mate d deli ver y date. 
A n y ter mi nati o n of pre g n a 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 o malies) or i n dicati o n f or t he pr oce d ure.  
● W hile pre g na n c 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 n c y 
c o m plicati o n or elec ti ve t er mi nati o n of a pre g na nc y f or me dical r eas 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 w ee ks gestati o nal a ge) is al w a ys c o nsi dere d t o be a n S A E a n d 
will be r e p orte d as s uc h.  
● A n y p ostst u d y pre g n a 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 nti o n b y t he i n v esti 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 gat e d t o acti vel y see k t his 
i nf or mati o n i n f or mer st u d y partici pa nts, he or s he ma y lear n of a n S A E t hr o u g h 
s p o nta ne o us re p orti n g. 
● A n y fe male p artici pa nt w h o bec o mes pre g na nt w hile partici pati n g i n t he st u d y 
will disc o nti n ue st u d y i nt er ve nti o n  or be wit h dra w n  fr o m t he st u d y. 
 
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1 0. 5.  
A p pe n di x  5 : Ge netics 
Use/ A n al ysis of D N A  
● Ge netic variati o n ma y i m pact a partici pa nt’s res p o nse t o st u d y i nter ve nti o n, 
s usce pti bility t o, a n d se v erit y a n d pr o gressi o n of disease. Varia ble res p o ns e t o 
st u d y i nter ve nti o n ma y b e d ue t o ge netic d eter mi n a nts t hat i m pact dr u g 
a bs or pti o n, distri b uti o n, meta b olis m, a n d e x creti o n; mec ha nis m of acti o n of t he 
dr u g; disease eti ol o g y; a n d/ or m olec u lar s u bt y pe of t he disease b ei n g treat e d. 
T heref ore, w h ere l o cal r e g ulati o ns a n d I R B/I E C all o w, a  bl o o d  sa m ple will be 
c ollecte d f or D N A a nal ysis fr o m c o nse nti n g p arti ci pa nts.  
● D N A sa m ples will be use d f or res earc h rel ate d t o L Y 3 5 0 9 7 5 4 . T h e 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 ostic tests relate d t o  L Y 3 5 0 9 7 5 4 . 
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 n es or t he 
a nal ysis of ge netic mar kers t hr o u g h o ut t he ge n o me (as a p pr o priate).  
● D N A sa m ples ma y be a n al yze d  f or g e nes i n v ol ve d i n effects of L Y 3 5 0 9 7 5 4 . 
● T he res ults of ge n etic a n al yses m a y be re p orte d i n t he cli nical st u d y re p ort ( C S R) 
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 s ec ure st ora ge s p ace wit h a de q uate 
meas ures t o p r otect c o nfi de ntialit y. 
● T he sa m ples will be ret ai ne d w hile res earc h o n L Y 3 5 0 9 7 5 4 c o nti n ues , b ut n o 
l o n ger t h a n 1 5  years or ot her peri o d as p er l ocal re q uire me nts.  
 
 
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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  
Cl ose he p atic m o nit ori n g  
La b orat or y tests ( A p pe n di x 2 , Secti o n 1 0. 2  i ncl u di n g A L T, A S T, A L P, T B L, D. Bil, G G T, a n d 
C K, s h o ul d 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 m alit y a n d t o deter mi ne if it is 
i ncreasi n g or decreasi n g, if o ne or m ore of t hese c o n diti o ns occ ur:  
If a p artici p a nt wit h b aseli ne 
res ults of...  
de vel o ps t he f oll o wi n g ele v ati o ns:  
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 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  
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 o me) 
A b bre viati o ns: A L T = ala ni ne a mi n otra nsferase; A L P = al kali ne p h os p hatase; A S T = as partate a mi n otra nsferase; 
T B L = t otal bilir u bi n; U L N = u p per li mit of n or mal. 
If t he a b n or m alit y persists or w orse ns, cli nical a n d la b orat or y m o nit ori n g, a n d e val uati o n f or 
p ossi ble ca uses of a b n or mal li ver tests s h o ul d be i nitiate d b y t he i n vesti gat or i n  c o ns ultati o n wit h 
t he Lill y-desi g nat e d me dical m o nit or. At a mi ni m u m, t his e val uati o n s h o ul d i ncl u de p h ysic al 
e x a mi nati o n 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 (f or e x a m ple, 
heart fail ure, s yste mic i nf ecti o n, h y p ot e nsi o n, or  seiz ures), rece nt tra v el, hist or y of c o nc o mita nt 
me dicati o ns (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 ol 
dri n ki n g a n d ot her s u bsta nce a b use.  
I nitiall y, m o nit ori n g of s y m pt o ms a n d he patic bi o c he mical tests s h o ul d be d one at a fre q ue n c y of 
1 t o 3 ti mes wee kl y, base d o n t he partici pa nt ’s cli nical c o n diti o n a n d he pati c bi oc he mical tests. 
S u bse q ue ntl y, t h e fre q ue nc y of m o nit ori n g ma y b e l o were d t o o n ce e v er y 1 t o 2 wee ks, if t he 
partici pa nt ’s cli nical c o n diti o n a n d la b 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 ntil le vels n or maliz e or ret ur n t o a p pr o xi mate baseli ne le vels.  
 
 
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C o m pre he nsi ve he p atic e v al u ati o n  
A c o m pr e he nsi ve e v al uati o n s h o ul d be perf or me d t o searc h f or p ossi ble ca uses of li ver i n j ur y if 
o ne or m ore of t hese c o n diti o ns occ ur:  
If a p artici p a nt wit h b aseli ne 
res ults of...  
de vel o ps t he f oll o wi n g ele v ati o ns:  
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
a, 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 patic si g ns/s y m pt o ms
a, 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 ≥2 x baseli ne (e xce pt f or patie nts wit h Gil bert’s s y n dr o me)  
A b bre viati o ns: A L T = ala ni ne a mi n otra nsferase; A L P = al kali ne p h os p hatase; A S T = as partate a mi n otra nsferase; 
T B L = t otal bilir u bi n; U L N = u p per li mit of n or mal. 
a He p atic si g ns/s y m pt o ms are s e vere fati g ue, na usea, v o miti n g, ri g ht u p per q ua dra nt a b d o mi nal pai n, fe ver, ras h, 
a n d/ or e osi n o p hilia > 5 %.  
At a mi ni m u m, t his e val uati o n s h o ul d i ncl u de p h ysical e xa mi nati o n a n d a t h or o u g h m e dical 
hist or y, as o utli ne d a b o ve, as well as tests f or P T -I N R; tests f or viral he patitis A, B, C, or E; tests 
f or a ut oi m m u ne he patitis; a n d a n a b d o mi nal i ma gi n g st u d y (f or e x a m ple, ultras o u n d or C T sca n).  
Base d o n t h e patie nt ’s hist or y a n d i nitial res ults, f urt her testi n g s h o ul d b e c o nsi dere d i n 
c o ns ultati o n wit h t he Lill y-d esi g n ate d me dical m o nit or, i ncl u di n g tests f or he patitis D vir us 
( H D V), c yt o m e gal o vir us ( C M V), E pstei n-Barr vir us ( E B V), 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 ol o g y scree n, Wils o n ’s disease, bl o o d alc o h ol le vels, 
uri nar y et h yl gl uc ur o ni de, a n d bl o o d p h os p hati d yl et ha n ol. Bas e d o n t he cir c u msta nces a n d t h e 
i n vesti gat or’s assess me nt of t he partici pa nt’s cli nical c o n diti o n, t he i n vesti 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 gist or gastr oe nter ol o gist c o ns ultati o n, ma g n etic res o n a nce 
c h ola n gi o pa ncreat o gra p h y ( M 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 ( E R C P), 
car diac ec h o car di o gra m, or a li ver bi o ps y.  Secti o ns  of a n y li ver bi o psies t hat are p erf or me d ma y 
be se nt t o Lill y f or f urt her a nal ysis.  
A d diti o n al he p atic 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 tests d uri n g t he st u d y  
A d diti o nal he patic safet y data c ollecti o n i n he pati c safet y case re p ort f or ms ( C R F) s s h o ul d be 
perf or me d i n st u d y partici pa nts w h o meet 1 or m ore of t he f oll o wi n g 5 c o n diti o ns:  
1.  Ele vati o n of ser u m A L T 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 p artici pa nts wit h baseli ne A L T ≥1. 5 x U L N, t he t hres h ol d is A LT ≥3 x baseli ne 
o n 2 or m ore c o ns ec uti ve tests  
2.  Ele vate d T B L t o ≥ 2 x  U L N (if baseli ne T B L < 1. 5 x U L N) (e x ce pt f or cas es of k n o w n 
Gil bert ’s s y n dr o me) 
➢ I n p artici pa nts wit h baseli ne T B L ≥1. 5 x U L N, t he t hres h ol d s h o ul d be T B L ≥2 x 
baseli ne  
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3.  Ele vati o n 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 p artici pa nts wit h baseli ne A L P ≥1. 5 x U L N, t h e t hres h ol d is A L P ≥2 x baseli ne 
o n 2 or m ore c o ns ec uti ve bl o o d tests  
4.  He patic e v e nt c o nsi dere d t o be a seri o us a d v erse e ve nt ( S A E)  
5.  Disc o nti n uati o n of st u d y dr u g d u e t o a he p atic e ve nt  
N ote: T he i nter val b et wee n t he t w o c o nsec uti ve bl o o d tests s h o ul d be at least 2 da ys  
He p atic E v al u ati o n Testi n g  
T he Lill y -d esi g n ate d ce ntral la b orat or y m ust c o m plete t he a nal ysis of all s electe d testi n g e x c e pt 
f or micr o bi ol o g y t esti n g. 
L ocal 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 necessar y f or i m me diate 
partici pa nt ma na ge me nt.  
Res ults will be re p orte d if a vali date d test or calc ulati o n is a vaila 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 - re d 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 cells)  
Ala ni ne a mi n otra nsferase ( A L T)  
Differe 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  
    B as 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 oe 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 alc 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 I g A ( q ua ntit ati ve) 
He p atitis A vir us ( H A V) testi n g:  
I m m u n o gl o b uli n I g G ( q ua ntit ati ve) 
    H A V t otal a nti b o d y  
I m m u n o gl o b uli n I g M ( q ua ntit ati 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)  
 
 
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He p atis B vir us ( H B V) testi n g:  
Uri ne C he mistr y  
    He p atitis B s urface a nti ge n ( H Bs A g)  
Dr u g scree n  
    He p atitis B s urface a nti b o d y (a nti -H Bs)  
Et h yl gl uc ur o ni de ( Et G)  
    He p atitis B c ore t otal a nti b o d y (a nti -H B c)  
Ot her Ser ol o g y  
    He p atitis 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 p atitis 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 p atis 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 p atitis 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 p atitis 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 N ot re q uire d if a nti -acti n a nti b o d y is teste d.  
b Refle x/c o nfir mati o n de p e n de nt o n re g ulat or y re q uire me nts, testi n g a vaila bilit y, or b ot h.  
c 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 test e d. 
d Assa ye d O N L Y b y i n vesti gat or-desi g nate d l ocal la b orat or y; n o ce ntral testi n g a vaila ble.  
 
 
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1 0. 7.  
A p pe n di x 9: A b bre vi ati o ns  
T er m  
D efi niti o n  
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 N O V A  
a nal ysis of varia nce  
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 x S p a  
a n k yl osi n g s p o n d ylitis  
BI D  
t wice dail y 
bli n di n g/ m a s ki n g  
A si n gle -bli n d st u d y is o ne i n w hic h t he i n vesti gat or a n d/ or his staff are a ware of t he 
treat me nt b ut t he partici pa nt is n ot, or vice versa, or w he n t he s p o ns or is a ware of t he 
treat me nt b ut t he i n vesti gat or a n d/ his staff a n d t he partici pa nt are n ot.  
A d o u ble -bli n d st u d y is o ne i n w hic h neit her t he partici pa nt n or a n y of t he i n vesti gat or 
or s p o ns or staff w h o are i n v ol ve d i n t he treat me nt or cli nical e val uati o n of t he 
partici pa nts  are a ware of t he tr eat me nt recei ve d.  
B MI  
b o d y mass i n de x  
B P  
bl o o d press ure  
CI  
c o nfi de nce i nter val  
CI O M S  
C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical Scie nces  
C K  
creati ne ki nase  
C m a x  
ma xi m u m o bser ve d dr u g c o nc e ntrati o n  
C mi n, s s  
mi ni m u m o bser ve d dr u g c o nc e ntrati o n d uri n g a d osi n g i nter val at stea d y state  
C L/ F  
a p pare nt cleara nce  
C M V  
C yt o me gal o vir us  
C N S  
ce ntral ner v o us s yste m  
c o m pl ai nt  
A c o m plai nt is a n y writte n, el ectr 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 
per f or ma nce of a dr u g or dr u g deli ver y s yste m. 
C P  
cli nical p har mac ol o gist  
C R F  
case re p ort f or m  
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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 ysici a n or ot her me dical officer.  
C R U  
cli nical researc h u nit  
C S E  
cli nicall y si g nifica nt e ve nt  
C S R  
cli nical st u d y re p ort  
C T A  
cli nical trial a gree me nt  
C V  
car di o vasc ular   
C Y P 3 A 4  
c yt oc hr o me P 4 5 0  3 A 4  
D DI  
dr u g -dr u g i nteracti o n  
D M C  
data m o nit ori n g c o m mittee  
D N A  
de o x yri b o n ucleic aci d  
E B V  
E pstei n -B arr vir us  
E C G  
E lectr ocar di o gra m 
e C R F  
electr o nic case re p ort f or m  
E D C  
electr o nic data ca pt ure  
e nr oll  
T he act of assi g ni n g a partici p a nt t o a treat me nt . P artici 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  
P artici pa nts e ntere 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.  
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 
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F S H  
f ollicle-sti m ulati n g h or m o ne 
G C P  
G o o d C li nical P ractice 
G G T  
ga m ma -gl uta m yl tra nsferase  
G L P  
g o o d la b orat or y practices  
H D V  
he p atitis D vir us  
h E R G  
h u ma n et her - á -g o -g o -relate d ge ne  
HI P A A  
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act  
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HI V  
h u ma n i m m u n o deficie nc y vir us  
H R T  
h or m o ne re place me nt t hera p y  
H V  
healt h y v ol u nteers  
I A D 
interi m access t o data  
I B 
I n vesti gat or’s Br oc h ure 
I C5 0  
half -ma xi mal i n hi bit or y c o nce ntrati o n  
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 p e n de nt Et hics C o m mitte e 
I M P 
i n vesti gati o nal me dici nal pr o d uct 
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 . 
Int 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 p arate 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 b ase is creat e d/l oc ke d. 
I P 
i n vesti gati o nal pr o d uct: A p har mace utical f or m of a n acti ve i n gre die nt or place b o bei n g 
teste d or use d as a refere nce i n a cli nical trial, i ncl u di n g pr o d ucts alrea d y o n t he mar ket 
w he n use d or asse m ble d (f or m ulate d or pac ka ge d) i n a wa y differe nt fr o m t he 
a ut h orize d f or m, or mar kete d pr o d ucts use d f or a n u na ut h orize d i n dicati o n, or mar kete d 
pr o d ucts use d t o gai n f urt her i nf or mati o n a b o ut t he a ut h oriz e d f or m.  
I R B 
I nstit uti o nal Re vie w B oar d 
L T BI  
late nt t u berc ul osis i nfecti o n 
m A b  
m o n ocl o nal a nti b o d y  
M A D  
m ulti ple -asce n di n g d ose  
M N  
M icr o n ucle us 
M T D  
ma xi m u m t olerate d d ose  
N O A E L  
n o -o bser ve d -a d verse -effect le vel  
P arti ci p a nt  
E q ui vale nt t o  C DI S C ter m  “s u bj ect”: 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 A SI  
Ps oriasis Area a n d Se verit y I n de x  
P B P K  
p h ysi ol o gicall y base d p har ma c o ki netic  
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P C  
pr o d uct c o m plai nt  
P K  
P har mac o ki netics  
P R  
p ulse rate  
P s A  
ps oriatic art hritis  
P s O  
P s oriasis 
Q D  
o nce dail y  
Q T c  
c orrecte d Q T i nter val  
Q T c F  
Fri d ericia’s f or m ula  
S A D  
si n gle-asce n di n g d ose  
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 E R M  
selecti ve estr o ge n rece pt or m o d ulat or 
SI B  
s uici dal i deati o n a n d be ha vi or 
S o A  
S c he d ule of Acti vities  
T 1/ 2  
ter mi nal eli mi nati o n half-life 
T B D  
t o be deter mi ne d 
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.  
T m a x  
ti me t o ma xi m u m c o nce ntrati o n 
U L N  
u p per li mit of n or mal  
V/ F  
a p pare nt v ol u me of distri b uti o n  
W O C B P  
w o me n of c hil d beari n g p ote ntial  
 
 
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1 0. 8.  
A p pe n di x 1 0: Pr ot oc ol A me n d me nt Hist or y  
T he Pr ot oc ol A me n d me nt S u m mar y of C ha n ges T a ble f or t he c urre nt pr ot o c ol a me n d me nt is 
l ocate d directl y b ef ore t he Ta ble of C o nte nts ( T O C). 
A me n d me nt h: 1 7 N o ve m ber 2 0 2 1  
O ver all R ati o n ale f or t he A me n d me nt 
T his pr ot oc ol was a me n d e d t o all o w f or a d diti o nal plas ma sa m ples t o be c ollecte d f or 
i n vesti gati o n fr o m partici pa nts w h o ret ur n f or a d diti o nal f oll o w-u p visits. A d diti o nal f oll o w -u p 
visits were a d de d t o t he S o A i n pre vi o us a me n d me nts afte r ele vate d li ver e nz y m e le vels were 
o bser ve d i n s o me J a pa nese partici pa nts i n Part D. T his a me n d me nt will all o w f or t he c ollecti o n 
of a d diti o nal bl o o d sa m ples f or e x pl orat or y bi o mar ker a n al ys es at a d diti o nal f oll o w -u p visits (f or 
all partici pa nts w h o ha d e x pl orat or y bl o o d sa m ples c ollecte d d uri n g t he st u d y). E x pl orat or y 
a nal ys es  fr o m bl o o d sa m ples c ollecte d at t hes e a d diti o nal f oll o w-u p visits ma y pr o vi d e 
a d diti o nal mec ha nistic u n dersta n di n g of t he el e vate d li ver e nz y me l e vels f oll o wi n g dr u g 
disc o nti n uati o n . 
 
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  
1. 3 Sc he d ule of A cti vities  
A d de d ti me p oi nt at f oll o w -
u p t o all o w f or e x pl orat or y 
bl o o d sa m pli n g at a d diti o nal 
f oll o w-u p visits f or Parts A, 
C, a n d D  
T his will all o w f or 
e x pl orat or y a n al ys es at t h ose 
visits  
1 0. 2. 1 Bl o o d Sa m pli n g 
S u m mar y  
A d de d f o ot n ote t o 
e x pl orat or y bl o o d sa m pli n g 
r o ws t o Parts A, C, a n d D 
all o wi n g a d diti o nal sa m ples 
at t he a d diti o nal f oll o w -u p 
visits  
A d diti o nal sa m ples will eac h 
re q uire 6 m L 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A(i)  
 
1 1 3  
A me n d me nt g: 1 0 N o v e m ber 2 0 2 1  
O ver all R ati o n ale f or t he A me n d me nt  
T his pr ot oc ol was a me n d e d t o re m o ve Part E a n d t o all o w all partici pa nts t o ret ur n f or a d diti o nal 
f oll o w u p healt h assess m e nt visits f oll o wi n g t he e n d of st u d y visit.  
As of 0 5 N o ve m ber 2 0 2 1, e le vate d A S T a n d A L T ha ve bee n o bser ve d i n 3 J a pa nese partici pa nts 
after c o m pleti n g t he 1 4 -d a y d osi n g of 1 0 0 0 m g L Y 3 5 0 9 7 5 4 or place b o. I nitial ele vate d A L T a n d 
A S T a p pr o xi matel y 1. 5 -f ol d t o 2. 7-f ol d a b o ve t he U L N f or 2 of t h e patie nts was n ote d 1 2 da ys 
p ost  last L Y 3 5 0 9 7 5 4 or place b o d ose a n d re m ai ns greater t ha n 5 ti mes a b o v e t he U L N u p t o 4 0 
da ys p ost t he a d mi nistrati o n. I n a d diti o n, f or a t hir d J a pa nese partici pa nt, el e vate d A L T a n d A S T 
greater t ha n 5 ti mes U L N was i nitiall y n ote d be gi n ni n g 3 3 da ys p ost t h e last a d mi nistrati o n of 
L Y 3 5 0 9 7 5 4 or place b o a n d c o nti n ui n g t hr o u g h 4 4 da ys after t h e last d ose. T he 3 partici pa nts 
s h o we d n o si g ns of h e patic dec o m pe nsati o n at t he e n d of st u d y f oll o w-u p visit (a p pr o xi matel y 7 
da ys p ost disc h ar ge fr o m t he C R U a n d 1 2 da ys  p ost t he last L Y 3 5 0 9 7 5 4 or place b o d ose) a n d at 
u nsc he d ule d visits occ urri n g greater t h a n 7 da ys after t he e n d of st u d y f oll o w -u p assess me nts. 
Des pite t he 3 partici p a nts prese nti n g as as y m pt o m atic a n d ha vi n g n or mal A S T a n d A L T w hile 
ta ki n g L Y 3 5 0 9 7 5 4 or place b o ( Q D x 1 4 da ys) a n d u p o n disc har ge fr o m t he C R U, t he dela ye d 
ele vati o ns i n A S T a n d A L T ma y b e rel ate d t o L Y 3 5 0 9 7 5 4.  
A d diti o nall y, o n 0 2 N o ve m ber 2 0 2 1, Eli Lill y a n d C o m pa n y ( Lill y) was i nf or me d b y t h e site t hat 
a male partici p a nt i n Part D C o h ort 1 ( 4 0 0 -m g d os e of L Y 3 5 0 9 7 5 4 or pl ace b o Q D x 1 4 da ys) 
self-re p orte d ele v ate d A L T a n d A S T U L N after t he e n d of st u d y f oll o w-u p visit ( 1 2 da ys p ost t he 
last L Y 3 5 0 9 7 5 4 or place b o d ose). T hese are c urre ntl y bei n g c o nfir me d t hr o u g h re peat la b orat or y 
testi n g. 
T he pre v i o us a me n d m e nt ( A me n d me nt f) all o we d partici pa nts w h o di d n ot s h o w ele vate d A S T 
a n d A L T at t he e n d of st u d y f oll o w -u p assess me nt a n d c o m plete d Part D t o be re q uest e d t o 
partici pate  i n a d diti o nal f oll o w-u p healt h assess me nts f or safet y m o nit ori n g, i ncl u di n g  safet y 
la bs. Bas e d o n t he fi n di n gs fr o m t he safet y la bs, a d diti o nal f oll o w-u p safet y ass ess me nts ma y be 
c o m plete d at t he discreti o n of t he pri nci pal i n vesti gat or.  
Base d o n t h e o n g oi n g i n v esti gati o n of p artici pa nts i n Part D, t his a me n d me nt will all o w 
par tici pa nts fr o m Parts A-C t o als o be i ncl u de d i n t his a d diti o nal safet y m o nit ori n g. Gi ve n t he 
o n g oi n g i n vesti gati o n, Part E will n ot be i m ple me nte d, a n d n o patie nts will be f urt her d os e d wit h 
L Y 3 5 0 9 7 5 4.   
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  
1. 1 S y n o psis — N u m ber of P artici pa nts  
C ha n ge d n u m ber of 
partici pa nts fr o m 
a p pr o xi matel y 1 1 5 t o 
a p pr o xi matel y 1 0 5  
P art E will n o l o n ger be 
i m ple me nte d, w hic h 
re d uces n u m ber of 
partici pa nts  
1. 1 S y n o psis — N u m ber of P artici pa nts , 1. 1 S y n o psis —
I nter ve nti o n Gr o u ps a n d D urati o n , 1. 1 S y n o psis —
P har mac o ki netic , 1. 2 Sc he ma , 1. 3. 7 Sc he d ule of 
Acti vities , 2. 1 St u d y Rati o nal e , 3 O bj ecti ves a n d 
Re m o ve d i nf or mati o n 
rele va nt t o P art E o nl y  
 
P art E will n o l o n ger be 
i m ple me nte d 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A(i)  
 
1 1 4  
E n d p oi nts , 4. 1 O verall Desi g n , 4. 2 Scie ntific Rati o nale 
f or St u d y Desi g n, 4. 2. 5 P art E ( D DI: L Y 3 5 0 9 7 5 4 Victi m 
wit h t he C Y P 3 A 4  i n d ucer Car ba maze pi ne), 4. 3. 1 
J ustificati o n f or L Y 3 5 0 9 7 5 4 D ose, 4. 3. 4 J ustificati o n f or 
Car ba maze pi ne D ose , 5. 1 I ncl usi o n Criteria , 5. 2 
E xcl usi o n Criteria , 5. 3. 1 Meals a n d Dietar y Restricti o ns , 
6. 1 St u d y I nter ve nti o ns A d mi nistere d , 6. 1. 1 
Car ba maze pi ne A d mi nistrati o n Details , 6. 3 Meas ures t o 
Mi ni mize Bias: Ra n d o mizati o n a n d Bli n di n g , 6. 5 
C o nc o mita nt T hera p y , 6. 6. 1 D ose Decisi o n/ Escalati o n , 
7. 2 P artici pa nt Disc o nti n uati o n/ Wit h dra wal fr o m t he 
St u d y , 8. 2. 3 Electr ocar di o gra ms , 8. 2. 5 S uici dal I deati o n 
a n d B e ha vi or Ris k M o nit ori n g , 8. 5 P har mac o ki netics , 9. 1 
Sa m ple Size Deter mi nati o n , 9. 3. 2. 1 P har mac o ki netic 
P ara meter Esti mati o n , 9. 3. 2. 2 P har mac o ki netic Statistical 
I nfere nce, 9. 3. 5 I nteri m Access t o Data (I A D) , 1 0. 2. 1 
Bl o o d Sa m pli n g S u m mar y , 1 0. 4 A p pe n di x 4: 
C o n trace pti ve G ui da nce a n d C ollecti o n of Pre g na nc y 
I nf or mati o n, 1 0. 7 A p pe n di x 9: A b bre viati o ns , 1 1 
Refere nces  
T here were als o sli g ht c ha n ges i n hea di n g n u m beri n g as a 
res ult of re m o vi n g secti o ns rel e va nt t o P art E o nl y. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. 3 Sc he d ule of Acti vities  
A d de d f o ot n ote t o f oll o w -
u p c ol u m n f or P arts A -C 
a n d m o difie d f o ot n ote e i n 
P art D  
  
M o difie d w or di n g of 
f o ot n ote “e” f or P art D 
T o all o w f or a d diti o nal 
safet y m o nit ori n g visits  
 
T o pr o vi de clarit y f or 
c o nse q ue nces of 
missi n g a d diti o nal 
f oll o w-u p visits  
4. 2. 3 P art C ( M ulti ple -Asce n di n g D ose/ C Y P 3 A 4 
P er petrat or D DI)  
4. 3. 3 J ustificati o n f or Mi d az ola m D ose  
C ha n ge d citati o n f or i n -
te xt refere nces 
Re m o ve d a  refere nce 
5. 2 E xcl usi o n Criteria  
Re m o ve d k n o w n aller g y 
t o car ba maze pi ne as a n 
e xcl usi o n criteria  
Car ba maze pi ne will n o 
l o n ger be use d i n t he 
st u d y 
1 0. 8 A p pe n di x 1 0: Pr ot oc ol A me n d me nt Hist or y  
Create d secti o n  
T his secti o n ha d bee n 
i na d verte ntl y left o ut i n 
pre vi o us a me n d me nts  
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
1 1 5  
A me n d me nt f: 1 9 Oct o ber 2 0 2 1   
O ver all R ati o n ale f or t he A me n d me nt  
T his pr ot oc ol was a me n d e d t o i ncl u de t he o pti o n f or a d diti o nal healt h assess me nt visits 
f oll o wi n g t he e n d of st u d y visit i n t he c o m plete d Part D ( M A D i n J a pa nes e healt h y p artici pa nts). 
T w o partici pa nts i n Part D C o h ort 2 ( 1 0 0 0 m g L Y 3 5 0 9 7 5 4 Q D x 1 4 da ys) ha ve s h o w n el e vate d 
A S T a n d A L T A Es wit h well -preser ve d h e patic f u ncti o n a n d n o si g ns of he patic dec o m pe ns ati o n 
at t he e n d of st u d y f oll o w -u p visit ( ~ 7 da ys p ost disc har ge fr o m t he C R U) a n d 2 u nsc he d ule d 
visits occ urri n g great er t ha n 7 da ys aft er t he e n d of st u d y f oll o w -u p assess me nts. At t he 
u nsc he d ule d f oll o w -u p visits, b ot h t he A S T a n d A L T s h o we d cli nicall y si g nifica nt ele vati o ns of 
> 5 ti mes a b o ve t he u p per li mit of n or mal. Des pite t he t w o partici pa nts pres e nti n g as 
as y m pt o matic a n d h a vi n g n or mal A S T a n d A L T w hile ta ki n g L Y 3 5 0 9 7 5 4 ( Q D x 1 4 da ys) a n d 
u p o n disc har ge fr o m t he C R U, t he dela ye d ele vati o ns i n A S T a n d A L T m a y p ossi bl y b e relate d 
t o L Y 3 5 0 9 7 5 4. T his a me n d me nt will all o w partici pa nts w h o di d n ot s h o w ele vate d A S T a n d 
A L T at t he e n d of st u d y f oll o w -u p assess me nt a n d c o m plete d t he Part D, t o be re q uest e d t o 
partici pate  i n a d diti o nal f oll o w-u p healt h assess me nts f or safet y m o nit ori n g.  
A n ot her c ha n ge i ncl u des t he o pti o nalit y t o c o n d uct m ore t ha n o ne a d diti o nal f oll o w -u p healt h 
assess me nt visit f or safet y m o nit ori n g i n Part E.   
 
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  
Secti o n 1. 3. 6. Part D S o A  
A d de d f o ot n ote “e” t o f oll o w -
u p c ol u m n  
T o all o w f or a d diti o nal s afet y 
m o nit ori n g visits  
Secti o n 1. 3. 7 Part E S o A  
A d de d f o ot n ote “c” t o f oll o w -
u p/ E D c ol u m n  
T o all o w f or a d diti o nal s afet y 
m o nit ori n g visits  
 
 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
1 1 6  
 
A me n d me nt e: 0 1 O ct o ber 2 0 2 1  
O ver all R ati o n ale f or t he A me n d me nt  
T his pr ot oc ol was a me n d e d t o a d d a n a d diti o nal c o h ort ( Part E) t o t he st u d y. E mer gi n g d ata fr o m 
Part B of t his st u d y i n dicates t hat L Y 3 5 0 9 7 5 4 is a victi m of C Y P 3 A, as data s h o we d t here was a 
si g nifica nt i ncreas e of L Y 3 5 0 9 7 5 4 e x p os ure u p o n c o-a d mi nistrati o n wit h a str o n g i n hi bit or of 
C Y P 3 A 4. T he p ur p ose of t his a me n d me nt is t o f urt her e val uat e t he C Y P 3 A victi m pr ofile of 
L Y 3 5 0 9 7 5 4 i n t he prese n ce of a str o n g C Y P 3 A 4 i n d ucer. T h e data fr o m Part E will ai d i n 
i nf or mi n g L Y 3 5 0 9 7 5 4 d ose(s) a n d rec o m me n d ati o ns f or c o nc o mita nt me dicati o ns f or f ut ure 
patie nt st u dies.  
Ot her c ha n ges i n t he pr ot oc ol i ncl u de u p dates t o s o me of t he he patic s afet y g ui deli nes, a c ha n ge 
t o t he defi niti o n of p ost-me n o pa usal, c orrecti o ns t o fi x P K v ol u me discre pa ncies a n d i nc orrectl y 
refere nce d e x cl usi o n criteria, a n d ot her mi n or e dit orial u p dates. 
 
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R a ti o n ale 
Secti o n 1. 1. S y n o psis 
( O verall Desi g n) 
Part E was a d d e d  
Part E is bei n g a d d e d f or t he 
assess me nt of P K of 
L Y 3 5 0 9 7 5 4 w he n d ose d wit h 
car ba m aze pi ne.  
Secti o n 1. 1. S y n o psis 
( N u m ber of Partici pa nts) 
U p date d n u m ber of 
partici pa nts re q uir e d t o 
c o m plete t he st u d y, a n d t he 
n u m ber of parts i n t he st u d y, 
a n d a d de d n u m ber of 
partici pa nts t o be e nr olle d i n 
Part E  
B y a d di n g Part E t here are 
a d diti o nal partici pa nts i n a n 
a d diti o nal part  
Secti o n 1. 1. S y n o psis 
(I nter ve nti o n Gr o u ps a n d 
D urati o n)  
A d de d a n a d diti o na l part a n d 
t he d osi n g sc h e d ule 
ass ociate d wit h it , a n d 
u p date d t he n u m ber of parts 
i n t he st u d y 
Part E will ha ve its o w n 
d osi n g sc he d ul e  
Secti o n 1. 1. S y n o psis 
( Statistical A nal ysis —  
P har mac o ki netics)  
A d de d la n g ua ge descri bi n g 
t he c o m paris o n of t he P K of 
L Y w he n a d mi nistere d al o ne 
vers us i n t he pres e nce of 
car ba m aze pi ne  
T he a d diti o n of Part E will be 
l o o ki n g at t his 
Secti o n 1. 2. Sc he ma  
Part E was a d d e d  
U p date d t o reflect t he 
a d diti o n of Part E  
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
1 1 7  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R a ti o n ale 
Delete d a b bre viati o n “ T B D” 
fr o m f o oter 
T o c orrect err or as t hi s 
a b bre viati o n is n ot i n t he 
sc he ma 
Secti o n 1. 3. 7. Part E (D DI: 
L Y 3 5 0 9 7 5 4 Victi m wit h t he 
C Y P 3 A 4 i n d ucer 
Car ba maze pi ne )  
S o A f or Part E was a d de d  
T he a d diti o n of t his ne w 
c o h ort re q uir es its o w n 
sc he d ule 
Secti o n 2. 1. St u d y R ati o nale  
A d de d rati o nal f or Part E  
Part E will e val uate 
L Y 3 5 0 9 7 5 4 as a s u bstrat e of 
C Y P 3 A 4  
Secti o n 3. O bjecti ves a n d 
E n d p oi nts  
A d de d a n a d diti o nal 
tertiar y/e x pl orat or y o bjecti ve 
a n d e n d p oi nt  
A d diti o n of Part E all o ws f or 
ne w o bjecti ve  a n d e n d p oi nt  
Secti o n 4. 1. O verall Desi g n  
A d de d Desi g n of Part E  
T his  is a D DI: L Y 3 5 0 9 7 5 4 
Victi m wit h t he C Y P 3 A 4 
i n d ucer car ba m aze pi ne  c o h ort 
Secti o n 4. 2 Scie ntific 
Rati o nale f or St u d y D esi g n  
A d de d rati o nale f or Part E  
 
 
 
U p date d la n g ua ge t o sa y t hat 
Parts A -D are bli n de d, a n d 
t hat Part E is u n bli n de d 
Part E will e val uate 
L Y 3 5 0 9 7 5 4 as a s u bstrat e of 
C Y P 3 A 4  
 
T he te xt pre vi o usl y 
refere nce d all parts as P arts 
A -D, w hic h is n o l o n ger t he 
case wit h t he a d diti o n of Part 
E  
Secti o n 4. 2. 3. Part C 
( M ulti ple-Asce n di n g 
D ose/ C Y P 3 A 4 Per petrat or 
D DI)  
U p date d s o urce r efere nce  
Differe ntiati o n is i m p orta nt as 
t here are n o w t w o differe nt 
F D A 2 0 2 0 s o urces  
Secti o n 4. 2. 5. Part E (D DI: 
L Y 3 5 0 9 7 5 4 Victi m wit h t he 
C Y P 3 A 4 i n d ucer 
Car ba maze pi ne)   
 
Create d ne w s u b -secti o n: 
A d de d rati o nale f or Part E  
 
A d de d fi g ure f or desi g n of 
Part E  
 
Car ba maze pi ne is a  C Y P 3 A 4 
i n d ucer 
Offer vis ualizati o n of desi g n  
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
1 1 8  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R a ti o n ale 
U p date d meal a n d dietar y 
restricti o ns refere n ce t o 
i ncl u de Part E 
A d diti o n of Part E 
necessitates i ncl usi o n  
Secti o n 4. 3. 1 J ustificati o n f or 
L Y 3 5 0 9 7 5 4 D ose  
Descri be d j ustificati o n f or 
d ose of L Y 3 5 0 9 7 5 4 use d i n 
Part E  
3 0 0 m g of L Y 3 5 0 9 7 5 4 will 
be use d i n Part E  
Secti o n 4. 3. 3. J ustificati o n f or 
Mi daz ola m D ose  
U p date d s o urce refere nce  
Differe ntiati o n is i m p orta nt as 
t here are n o w t w o differe nt 
F D A 2 0 2 0 s o urces  
Secti o n 4. 3. 4. J ustificati o n  f or 
Car ba maze pi ne D ose  
Create d ne w s u b -secti o n: 
Descri be d j ustificati o n of 
d ose of car ba maze pi ne use d 
i n Part E 
 
D osi n g f or car ba maze pi n e 
has bee n sel ecte d base d o n 
rec o m me n dati o ns fr o m F D A 
a n d ot her c urre nt k n o wle d ge  
Secti o n 5. 1. I n cl usi o n Criteria  A d de d Part E t o t he B MI 
ra n ge des cri be d f or P arts A, 
B, a n d C  
 
Re m o ve d defi niti o n of p ost -
me n o pa usal a n d referre d t o 
A p pe n di x 4 , a n d u p date d 
defi niti o n i n A p pe n di x 4  
T o s pecif y w hat B MI is 
acce pta ble f or i ncl usi o n i n 
Part E  
 
T o c orrect discre p a ncies 
wit hi n  t he e xisti n g pr ot o c ol 
a n d better ali g n wit h c urre nt 
g ui da nce  
Secti o n 5. 2. E x cl usi o n 
Criteria  
A d de d car ba maze pi ne t o t he 
list of aller gies/ at o p y as a n 
e x cl usi o n criteria  
 
A d de d e x cl usi o n criteria f or 
Part E o nl y  
Car ba maze pi ne will be gi ve n 
t o partici pa nts i n Part E 
 
Nat ure of Part E re q uir es 
a d diti o nal e x cl usi o n criteria  
Secti o n 5. 3. 1. Meals a n d 
Dietar y Restricti o ns  
A d de d Part E details  
Nat ure of Part E re q uir es 
s pecific meal a n d dietar y 
restricti o ns 
Secti o n 6. 1. St u d y 
I nter ve nti o ns A d mi nistere d 
A d de d c ol u m n f or Part E  a n d 
a d de d E t o t he list of parts i n 
w hic h L Y 3 5 0 9 7 5 4  is 
a d mi nistere d   
Part E will use 
car ba m aze pi ne  a n d 
L Y 3 5 0 9 7 5 4  
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
1 1 9  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R a ti o n ale 
Secti o n 6. 1. 1. Car ba maze pi ne 
A d mi nistrati o n Details  
Create d ne w s u b -secti o n: 
A d de d Car ba m aze pi ne 
A d mi nistrati o n Details  
 
Pr o vi de d t o all o w st u d y 
feasi bilit y 
Secti o n 6. 3. Meas ures t o 
Mi ni mize Bias: 
Ra n d o mizati o n a n d Bli n di n g  
C ha n ge d w or di n g t o s pecif y 
o nl y Parts A -D i nstea d of all 
parts  
Part E is n ot s u bject t o 
ra n d o mizati o n a n d bli n di n g 
Secti o n  6. 5. C o nc o mita nt 
T hera p y  
I n cl u de d Part E i n t he 
la n g u a ge re gar di n g 
c o nc o mita nt t hera p y  
 
C ha n ge d E x cl usi o n Criteri o n 
[ 2 0] t o [ 2 6] 
 
A d de d la n g ua ge descri bi n g 
t hat H R T is n ot all o we d i n 
Part E  
 
Clarifie d la n g ua ge t o stat e 
“ w he n a p plica ble” after H R T  
Part E is a D DI e v al uati o n  
 
 
C orrecte d err or i n e xisti n g 
pr ot oc ol  
 
Car ba maze pi ne is pre di cte d 
t o decrease t he efficac y of 
H R T  
 
H R T is n ot all o we d i n Part E  
Secti o n 6. 6. 1. D ose 
Decisi o n/ Escalati o n  
Descri be d reas o ni n g b e hi n d 
Part E d ose of L Y 3 5 0 9 7 5 4  
D osa ge f or L Y 3 5 0 9 7 5 4 i n 
Part E was selecte d ba se d o n 
safet y data i n ot her parts of 
t he st u d y 
Secti o n 7. 2. Partici pa nt 
Disc o nti n uati o n/ Wit h dra wal 
fr o m t he St u d y 
A d de d a d diti o nal 
disc o nti n uati o n criteria f or 
Part E  
T he use of car ba maze pi ne 
re q uires t hese a d diti o nal 
criteria  
Secti o n 8. 2. 3. 
Electr ocar di o gra ms  
I n cl u de d Part E as a part t hat 
w o ul d ha ve si n gle E C Gs 
c ollecte d at s pe cific ti me 
p oi nts  
Part E will ha ve si n gle E C Gs 
c ollecte d at s pe cifie d ti me 
p oi nts  
Secti o n 8. 2. 5. S uici dal 
I d eati o n a n d Be h a vi or Ris k 
M o nit ori n g  
A d de d te xt u n der “ S uici dal 
I d eati on a n d Be h a vi or Ris k 
M o nit ori n g” secti o n  
Car ba maze pi ne is c o nsi d ere d 
t o be a ce ntr al ner v o us s yste m 
acti ve dr u g a n d , t h eref ore, 
re q uires m o nit ori n g 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
1 2 0  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R a ti o n ale 
Secti o n 8. 5. 
P har mac o ki netics  
A d de d car ba maze pi ne a n d its 
car ba m aze pi ne 1 0, 1 1 -
e p o xi de meta b olite t o list of  
w hat plas ma sa m ples will be 
a nal yze d f or a n d d escri b e d 
w hat size sa m ples will be 
c ollecte d  
 
C ha n ge d v ol u me of plas ma 
sa m ples t hat are c ollecte d f or 
meas ure me nt of 
c o nce ntr ati o ns of 
L Y 3 5 0 9 7 5 4 , mi daz ola m, a n d 
itrac o naz ole fr o m 
a p pr o xi matel y 1 t o  
a p pr o xi mate l y 2 m L  
T hese are rele va nt t o Part E  
 
 
 
 
 
N u m bers u p date d t o c orrect 
discre pa n c y bet wee n te xt a n d 
bl o o d sa m pli n g s u m mar y 
ta bles i n e xisti n g pr ot oc ol 
Secti o n 9. 1. Sa m ple Siz e 
Deter mi nati o n  
A d de d te xt descri bi n g 
reas o ni n g f or s a m ple siz e 
deter mi nati o n f or P art E  
Sa m ple siz e will all o w f or 
desire d statistical a nal yses t o 
be perf or me d  
Secti o n 9. 3. 2. 1. 
P har mac o ki netic Para meter 
Esti mati o n  
A d de d te xt descri bi n g w hat 
will occ ur wit h data fr o m  
Part E  
T o descri be h a n dli n g of data 
c ollecte d fr o m Part E  
Secti o n 9. 3. 2. 2. 
P har mac o ki netic Statistical 
I nfere nce 
A d de d te xt descri bi n g w hat 
will occ ur wit h data fr o m Part 
E  
T o descri be h a n dli n g of data 
c ollecte d fr o m Part E  
Secti o n 9. 3. 5. I nteri m Access 
t o Data (I A D) 
A d de d te xt descri bi n g w hat 
will occ ur wit h i nteri m ac cess 
t o data f or Parts A-D a n d Part 
E  
T o u p date w he n I A D will 
ta ke place 
Secti o n 1 0. 2. 1. A p pe n di x 2: 
Cli nical La b orat or y Tests  
Bl o o d Sa m pli n g S u m mar y  
A d de d bl o o d sa m pli n g ta ble 
f or Part E 
Part E will c ollect differe nt 
bl o o d sa m ple a m o u nts t ha n 
ot her parts  
Secti o n 1 0. 4. A p pe n di x 4: 
C o ntrace pti ve G ui da n ce a n d 
C ollecti o n of Pre g n a nc y 
I nf or mati o n 
U p date d defi niti o n of  p ost -
me n o pa usal state  
 
T o  better  ali g n wit h c urre nt 
sta n dar dize d safet y g ui da nce 
 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
1 2 1  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R a ti o n ale 
A d de d male c o ntr ace pti ve 
g ui da nce f or males i n Part E 
a n d differe ntiate d bet w ee n 
i nstr ucti o ns f or Parts E a n d 
all ot her parts  
Part E re q uires strict er 
c o ntrace pti ve g ui da nce d ue t o 
use of car ba maze pi ne  
Secti o n 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  
U p date d he p atic safet y 
g ui deli nes  
T o better ali g n wit h c urre nt 
sta n dar dize d safet y g ui da nce 
Secti o n 1 0. 7 A p pe n di x 9: 
A b bre viati o ns  
A d de d 3 a d diti o nal 
a b bre viati o n ter ms a n d t h eir 
defi niti o ns  
 
U p date d a b bre viati o n f or 
C Y P  
T he a d de d te xt i n t his 
a me n d me nt uses t hese 
a b bre viati o ns /ter ms 
 
T o pr o vi de clarit y  
Secti o n 1 1. Refere n ces  
A d de d 3  refere nces t o t his 
secti o n 
T o pr o vi de refere nces f or 
a d de d te xt  
 
 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
1 2 2  
A me n d me nt d : 1 8 J u ne 2 0 2 1  
O ver all R ati o n ale f or t he A me n d me nt  
T he pr ot oc ol was a me n d e d t o i de ntif y t he d os e f or C o h ort 1 ( 4 0 0 m g L Y 3 5 0 9 7 5 4) a n d C o h ort 2 
( 1 0 0 0 m g L Y 3 5 0 9 7 5 4) f or Part D base d o n s afet y, t olera bilit y, a n d p h ar mac o ki netic data fr o m 
Parts A a n d C. T he 4 0 0 -m g d ose f or C o h ort 1 was als o c h ose n base d o n a vaila bilit y of a 2 0 0 m g 
L Y 3 5 0 9 7 5 4 ca ps ule str e n gt h t hat will be pr o vi de d b y t he s p o ns or f or Part D o nl y. A n a d diti o nal 
U S site was a d de d t o e n a ble e nr oll me nt of J a pa nese s u bjects re q uir e d f or P art D. T he a d diti o nal 
U S site will be pr o vi de d 2 0 0 -m g L Y 3 5 0 9 7 5 4 ca ps ules a n d place b o ca ps ules as t he site has n ot 
bee n q ualifie d b y Eli Lill y a n d C o m pa n y f or e xte m p ora ne o us pre parati o ns. T he o pti o nal C o h orts 
7 ( Part A) a n d 4 ( Part C) ha ve bee n re m o ve d as t h ere is n o pla n t o e v al uate a d diti o nal d ose 
le vels. 
 
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  
1. 1.  S y n o psis ( O verall 
Desi g n)  
T he st u d y d escri pti o n has bee n u p date d 
fr o m “si n gle-ce nter” t o “ m ulti -ce nter”  
T his u p date was 
ma de f or 
o perati o nal/ 
recr uit me nt 
c o nsi derati o ns  
1. 1.  S y n o psis ( O verall 
Desi g n)  
T he n u m ber of c o h orts i n Part A has bee n 
u p date d fr o m “ u p t o 7 ” t o “ u p t o 6”, a n d 
t he n u m ber of c o h orts i n Part C has bee n 
u p date d fr o m “ u p t o 4 ” t o “ u p t o 3”  
See o verall 
rati o nale f or t h e 
a me n d me nt  
1. 1.  S y n o psis ( N u m ber of 
Partici p a nts) 
T he n u m ber of partici pa nts re q uire d t o 
c o m plete t he st u d y h as b ee n u p date d fr o m 
“a p pr o xi matel y 1 2 1” t o “a p pr o xi matel y 
1 0 5”. T he n u m ber of partici pa nts f or Part 
A has bee n u p d ate d fr o m “ u p t o 5 9” t o 
“ u p t o 5 1”. T he o pti o nal C o h ort 7 ( Part A) 
has bee n re m o ve d. T he n u m ber of 
partici pa nts f or Part C has bee n u p date d 
fr o m “ u p t o 3 4” t o “ u p t o 2 6”. T he 
o pti o nal C o h ort 4 ( Part C) has bee n 
re m o ve d.  
T his u p date was 
ma de f or 
o perati o nal 
c o nsi derati o ns 
a n d t he reas o ns 
state d i n t he 
o verall rati o nale 
f or t he 
a men d me nt  
1. 1.  S y n o psis (I nter v e nti o n 
Gr o u ps a n d D urati o n)  
C o h ort 7 ( Part A) a n d C o h ort 4 ( Part C) 
ha ve bee n re m o ve d. Pla n ne d d oses f or 
C o h orts 1 a n d 2 ( Part D) ha ve bee n a d de d.  
See o verall 
rati o nale f or t h e 
a me n d me nt  
1. 2.  Sc he ma  
T he o pti o nal C o h orts 7 ( Part A) a n d  4 
( Part C) ha ve b ee n re m o ve d, a n d pla n ne d 
d oses f or C o h orts 1 a n d 2 ( Part D) ha v e 
bee n a d d e d  
See o verall 
rati o nale f or t h e 
a me n d me nt  
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
1 2 3  
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  
1. 3. 1. Sc he d ule of A cti vities 
( Part A) 
T he o pti o nal C o h ort 7 has bee n re m o v e d  
See o verall 
rati o nale f or t h e 
a me n d me nt  
1. 3. 4. Sc he d ule of A cti vities 
( Part C) 
T he o pti o nal C o h ort 4 has bee n re m o v e d  
See o verall 
rati o nale f or t h e 
a me n d me nt  
1. 3. 6. Sc he d ule of A cti vities 
( Part D) 
A d diti o nal E C G c ollecti o n ti me p oi nts 
ha ve bee n a d de d t o D a ys 1 a n d 2 of t he 
treat me nt peri o d. E C Gs o n Da ys 1 a n d 2 
of t he treat me nt p eri o d h a ve bee n c ha n ge d 
fr o m si n gle t o tri plicate. A n a d diti o nal P K 
sa m ple has bee n a d de d t o Da y 1 of t he 
treat me nt peri o d. 
U p date ma de t o 
c ollect a d diti o nal 
safet y/ 
t olera bilit y 
i nf or mati o n 
4. 1. O verall D esi g n  
Te xt has b ee n u p date d t o state t hat St u d y 
J 3 D-M C -F N A A will be a m ulti -ce nter, 
rat her t ha n si n gle-ce nt er st u d y 
T his u p date was 
ma de f or 
o perati o nal /recr u
it me nt 
c o nsi derati o ns  
4. 1. O verall D esi g n  
T he n u m ber of c o h orts i n Part A has bee n 
u p date d fr o m “ u p t o 7 ” t o “ u p t o 6”. T he 
n u m ber of c o h orts i n Part C has bee n 
u p date d fr o m “ u p t o 4 ” t o “ u p t o 3”  
See o verall 
rati o nale f or t h e 
a me n d me nt  
4. 1. O verall D esi g n  
La n g u a ge  h as bee n u p d at e d t o s pecif y t hat 
i n Part D, C o h orts 1 a n d 2 will be r u n 
c o nc urre ntl y 
T his u p date was 
ma de f or 
o perati o nal 
c o nsi derati o ns  
4. 2. 1. Part A a n d Ta ble 
F N A A. 1.  
T he o pti o nal C o h ort 7 has bee n re m o v e d  
See o verall 
rati o nale f or t h e 
a me n d me nt  
4. 2. 3. Part C a n d Ta ble 
F N A A. 2.  
T he o pti o nal C o h ort 4 has bee n re m o v e d  
See o verall 
rati o nale f or t h e 
a me n d me nt  
4. 2. 4. Part D ( M ulti ple 
D osi n g i n Healt h y J a pa n ese 
Partici pa nts)  
T he n u m ber of partici pa nts f or Part D 
( C o h orts 1 a n d 2) has bee n u p date d fr o m 
“a p pr o xi matel y” 8 p er c o h ort ( 6 L Y: 2 
place b o) t o “at least” 8 p er c o h ort ( 6 L Y: 2 
place b o)  
T his u p date was 
ma de f or 
o perati o nal 
c o nsi derati o ns  
4. 3. 1. J ustificati o n f or 
L Y 3 5 0 9 7 5 4 D ose  
T he o pti o nal C o h orts 7 ( Part A) a n d 4 
( Part C) ha ve b ee n re m o ve d, a n d pla n ne d 
d oses f or C o h orts 1 a n d 2 ( Part D) ha v e 
bee n a d d e d  
See o verall 
rati o nale f or t h e 
a me n d me nt  
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
1 2 4  
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  
6. 1. St u d y I nter v e nti o ns 
A d mi nistere d  
A f o ot n ote has bee n a d de d t o n ote t hat 
2 0 0 m g L Y 3 5 0 9 7 5 4 d osa ge str e n gt h 
ca ps ules a n d c orres p o n di n g place b o will 
be pr o vi de d b y t he s p o ns or f or Part D  
See o verall 
rati o nale f or t h e 
a me n d me nt  
6. 2. 
Pre parati o n/ Ha n dli n g/ St ora ge/
Acc o u nta bilit y  
La n g u a ge h as bee n a d de d t o n ote t hat a n 
a d diti o nal site has bee n a d de d t o t he st u d y 
t o recr uit t he s u bjects r e q uire d f or Part D. 
T he s p o ns or will s u p pl y L Y 3 5 0 9 7 5 4 i n 
t he f or m of 2 0 0-m g ca ps ules a n d 
c orres p o n di n g place b o   
T his u p date was 
ma de f o r 
o perati o nal /recr u
it me nt 
c o nsi derati o ns  
6. 6. 1. D ose 
Decisi o n/ Escalati o n ( Part D)  
T he se nte nce, “ T h e decisi o n t o c o n d uct 
Part D will be at t he discreti o n of t he 
i n vesti gat or ” has bee n delete d. La n g ua ge 
stati n g t hat a n alter nate d osi n g para di g m 
ma y b e use d  f or Part D h as bee n del ete d.  
Part D will be 
c o n d ucte d, a n d 
t he d osi n g 
para di g m has 
bee n i de ntifie d  
6. 6. 1. D ose 
Decisi o n/ Escalati o n ( Part D)  
La n g u a ge i n t his secti o n has bee n u p dat e d 
t o state t hat t he 2 d osi n g c o h orts i n Part D 
will be r u n si m ulta ne o usl y  
T his u p date was 
ma de f or 
o perati o nal 
c o nsi derati o ns  
8. 2. 3. Electr ocar di o gra ms  
La n g u a ge h as bee n u p d at e d t o state t hat i n 
t he ti me p oi nts s pecifie d i n t he S o A, 
tri plicate E C G rec or di n gs will  be 
c ollecte d  
U p date ma de t o 
c ollect a d diti o nal 
safet y/t olera bilit
y i nf or m ati o n  
Ta ble 1 0. 2. 1. Bl o o d Sa m pli n g 
S u m mar y  
T he o pti o nal C o h orts 7 ( Part A) a n d 4 
( Part C) ha ve b ee n re m o ve d 
See o verall 
rati o nale f or t h e 
a me n d me nt  
Ta ble 1 0. 2. 1. Bl o o d Sa m pli n g 
S u m mar y  
Ta ble f or Part D has bee n u p date d t o 
i ncl u de a n a dditi o nal P K sa m pli n g ti me 
p oi nt  
T he u p date was 
ma de t o acc o u nt 
f or a n a d d e d P K 
sa m ple c ollecti o n 
o n Da y 1 of Part 
D  
 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
1 2 5  
 
A me n d me nt c: 0 2 A pril 2 0 2 1  
O ver all R ati o n ale f or t he A me n d me nt  
T here is u ncertai nt y ar o u n d t he effic aci o us d ose ra n ge pr ojecti o ns f or L Y 3 5 0 9 7 5 4. C urre nt 
e x pl orat or y bi o mar ker data fr o m C o h orts 2 -4 s h o w a d ose -relate d i ncrease i n tar get 
c o nce ntr ati o ns wit h n o e vi de nce of s at urati o n u p t o 3 0 0  m g . F urt her, t here is p ote ntial f or a n 
i ncreas e i n e x p os ure ( u p t o a p pr o xi matel y 8. 8 x) i n t he prese n ce of a str o n g C Y P 3 A 4 i n hi bit or 
( Part B D DI). F or t hes e reas o ns, d osi n g at 2 0 0 0 m g is necessar y t o pr o vi de i nf or mati o n t o 
s u p p ort d ose selecti o n i n s u bse q ue nt st u dies, i n a d diti o n t o f urt her i nsi g ht r e gar di n g safet y, 
t olera bilit y, P K, a n d e x pl orat or y bi o mar kers.  
  
Re vie w of preli mi nar y s afet y d ata u p t o 1 9 Marc h 2 0 2 1 s h o ws t here ha v e b ee n n o st u d y 
disc o nti n uati o ns, L Y -relate d A Es or S A Es i n t he S A D u p t o 1 0 0 0 m g.  Preli mi nar y a nal ysis of 
t he a vaila ble P K dat a fr o m 1 0 t o 3 0 0 m g i n dicates t hat A U C is a p pr o xi matel y d ose-pr o p orti o nal 
wit hi n t his d ose ra n ge aft er si n gl e d oses . Base d o n t his i nf or mati o n, t he mar gi n of safet y at 2 0 0 0 
m g  is esti mate d t o be 5 x f or rat a n d 6 x f or d o g ( base d o n 1 -m o nt h N O A E L A U Cs)  a n d s u p p orts 
t he e val uati o n of t he s afet y, t olera bilit y, a n d P K of t he L Y 3 5 0 9 7 5 4 d ose le vel of 2 0 0 0 m g f or 
C o h ort 6.   
 
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  
1 . 1. S y n o psis 
T he C o h ort 6 L Y 3 5 0 9 7 5 4 d ose le vel has 
bee n u p date d fr o m T B D t o 2 0 0 0 m g  
See o verall rati o nale 
f or t he a me n d m e nt 
1 . 2. Sc he ma 
T he sc he ma has bee n u p date d t o refl ect t he 
2 0 0 0 -m g d ose f or C o h ort 6  
See o verall rati o nale 
f or t he a me n d m e nt 
1. 3. 1.  Part A: Si n gle -
Asce n di n g D ose, 
C o h orts 1, 2, 3, 5, 6, 
a n d 7 ( So A)  
A n e x pl orat or y s ali va sa m ple has bee n 
a d de d at 7 2 h o urs p ost -L Y 3 5 0 9 7 5 4 d osi n g 
f or C o h ort 6 
A nal ysis of t h e 
preli mi nar y 
e x pl orat or y bi o mar ker 
data s u g gest a n 
i nc o m plete 
c haracterizati o n of t h e 
bi o mar kers d ue t o t he 
li mite d nat ure of t he 
sa m ple c ollecti o ns i n 
t he S A D. Lill y is 
c urre ntl y e x pl ori n g t he 
p ossi bilit y of 
le vera gi n g t he 
bi o mar ker fi n di n gs as 
a n as pect of d ose 
selecti o n a n d 
refi ne me nt i n f ut ure 
patie nt st u dies. F or 
t his reas o n a n d bas ed 
o n t he e mer gi n g 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
1 2 6  
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  
e x pl orat or y bi o mar ker 
data fr o m S A D 
C o h orts 2 -4 ( 3 0, 1 0 0 
a n d 3 0 0 m g 
L Y 3 5 0 9 7 5 4 ), 
a d diti o nal sa m ple 
c ollecti o n has bee n 
a d de d t o t he M A D a n d 
C o h ort 6 of t he S A D.  
1. 3. 4.  Part C: 
M ulti ple -Asce n di n g 
D ose –  C o h orts 1, 3, 
a n d 4 –  Si n gle Peri o d  
( So A)  
E x pl orat or y bl o o d sa m pli n g has b ee n 
di vi de d i nt o 2 r o ws, 1 f or plas ma bl o o d 
sa m pli n g ti me p oi nts a n d 1 f or ser u m bl o o d 
sa m pli n g ti me p oi nts. Pre d ose plas ma 
sa m ples ha ve bee n a d d e d o n Da ys 3-6, a n d 
Da ys 9 -1 3 ( pre d ose sa m ple o n Da y 8 will 
still be c ollecte d). Plas ma c ollecti o ns at 4 8, 
7 2, a n d 9 6 h o urs aft er t he fi nal d ose ha ve 
als o bee n a d d e d. Pre d ose ser u m bl o o d 
sa m ples ha ve bee n a d d e d o n Da ys 1, 3, 6, 9, 
a n d 1 2. A ser u m c ollecti o n at 2 4 h o urs after 
t he fi nal d ose has als o b ee n a d de d. 
See rati o nale f or  
u p date i n Secti o n 
1. 3. 1.  Part A: Si n gle -
Asce n di n g D ose, 
C o h orts 1, 2, 3, 5, 6, 
a n d 7 ( S o A) . 
1. 3. 6.  Part D: 
M ulti ple -D ose i n 
J a pa nese Healt h y 
Partici pa nts –  Si n gle 
Peri o d ( S o A)  
E x pl orat or y bl o o d sa m pli n g has b ee n 
di vi de d i nt o 2 r o ws, 1 f or plas ma bl o o d 
sam pli n g ti me  p oi nts a n d 1 f or ser u m bl o o d 
sa m pli n g ti me p oi nts. Pre d ose plas ma 
sa m ples ha ve bee n a d d e d o n Da ys 3-6, a n d 
Da ys 9 -1 3 ( pre d ose sa m ple o n Da y 8 will 
still be c ollecte d). Plas ma c ollecti o ns at 4 8, 
7 2, a n d 9 6 h o urs aft er t he fi nal d ose ha ve 
als o bee n a d d e d. Pre d ose ser u m sa m ples 
ha ve bee n a d de d o n Da ys 1, 3, 6, 9, a n d 1 2. 
A ser u m c ollecti o n at 2 4 h o urs after t h e 
fi nal d ose has als o be e n a d de d. 
See rati o nale f or 
u p date i n Secti o n 
1. 3. 1.  Part A: Si n gle -
Asce n di n g D ose, 
C o h orts 1, 2, 3, 5, 6, 
a n d 7 ( S o A ) 
4. 2 .1. P art A ( Si n gle -
Asce n di n g D ose)  
I n T a ble F N A A. 1, t he pl a n ne d L Y 3 5 0 9 7 5 4 
d ose le vel f or C o h ort 6 h as bee n u p dat e d t o 
2 0 0 0 m g  
See o verall rati o nale 
f or t he a me n d m e nt 
4 . 3. 1. J ustificati o n f or 
L Y 3 5 0 9 7 5 4 D ose  
La n g u a ge h as bee n u p d at e d t o n ote t hat t he 
L Y 3 5 0 9 7 5 4 d os e f or C o h ort 6 of S A D is 
2 0 0 0 m g, a n d is bas e d o n e mer gi n g data 
fr o m S A D C o h orts 1-5. La n g u a ge i n t his 
secti o n a n d t he mar gi n of safet y ta ble 
( Ta ble F N A A. 3) ha ve b ee n als o bee n 
Se e o verall rati o nale 
f or t he a me n d m e nt 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
1 2 7  
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  
u p date d base d o n a vaila ble P K data fr o m 
C o h orts 1 -4 of t he S A D.  
6. 1. St u d y 
I nter ve nti o ns 
A d mi nistere d  
T he pla n ne d L Y 3 5 0 9 7 5 4 d ose ra n ge f or 
Parts A -D has bee n u p dat e d fr o m 1 0 – 1 0 0 0  
t o 1 0– 2 0 0 0 m g  
See o verall rati o nale 
f or t he a me n d m e nt 
6 . 6. D ose 
M o dificati o n  
La n g u a ge h as bee n u p d at e d t o n ote t hat t he 
d ose i n C o h ort 6 is t he pla n ne d hi g hest S A D 
d ose le vel ( was pre vi o usl y C o h ort 5), a n d 
t hat e mer gi n g data fr o m C o h orts 1-5 of t he 
S A D will be re vie we d pri or t o escalati o n t o 
t his d ose le vel. 
See o verall rati o nale 
f or t he a me n d m e nt 
1 0. 2. 1. Bl o o d 
Sa m pli n g S u m mar y  
(Part C ( M A D) 
[ C o h orts 1, 3, a n d 4]) 
a n d Part D M A D 
(J a pa nese Partici pa nts) 
T he sa m pli n g ta bl es f or Parts C ( M A D) a n d 
D ( M A D; J a pa nese partici pa nts) ha ve b ee n 
u p date d. E x pl orat or y bl o o d sa m pli n g has 
bee n di vi de d i nt o 2  r o ws, 1  f or plas ma 
bl o o d sa m pli n g a n d 1  f or ser u m bl o o d 
sa m pli n g. 
T his di visi o n of 
e x pl orat or y sa m pli n g 
is base d o n e mer gi n g 
data fr o m C o h orts 1 -5 
of t he S A D a n d 
o perati o nal 
c o nsi derati o ns  
 
 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
1 2 8  
 
A me n d me nt b : 0 5 Fe br u ar y 2 0 2 1  
O ver all R ati o n ale f or t he A me n d me nt  
Preli mi nar y d ata fr o m C o h orts 1 a n d 2 of t he S A D p orti o n of t his st u d y i n dicate a ter mi nal 
eli mi nati o n half -life (t1/ 2 ) f or L Y 3 5 0 9 7 5 4 of a p pr o xi matel y 1 4-1 7 h o urs base d o n 
n o nc o m part me ntal a n al ysis w hic h is l o n ger t ha n t he pr ojecte d t 1/ 2  of a p pr o xi matel y 5 h o urs. T his 
a me n d me nt e xte n ds safet y a n d t olera bilit y c ollecti o n ti mes i n t he M A D ( Parts C a n d D) 
c o m p o ne nts of t he st u d y i n acc or da nce wit h t his fi n di n g.  
 
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  
1. 1. S y n o psis –  
I nter ve nti o n 
Gr o u ps a n d 
D urati o n ( Part B)  
T he L Y 3 5 0 9 7 5 4 d ose f or Part B ( D DI –  
C Y P 3 A 4 victi m) has bee n u p date d t o 1 0 m g  
T his d ose is base d o n 
safet y, t olera bilit y, a n d 
P K data fr o m Part A  
1. 2. Sc he ma  
La n g u a ge h as bee n u p d at e d i n t he fi g ure t o 
n ote t hat t he M A D will start after re vie w of 
safet y a n d P K dat a fr o m t he 1 0 0 0-m g 
L Y 3 5 0 9 7 5 4 S A D c o h ort, rat her t ha n t h e 
3 0 0 -m g c o h ort as pre vi o usl y state d  
T his u p date c orrects 
a n err or i n t he ori gi nal 
pr ot oc ol  
1. 3. Sc he d ule of 
Acti vities   
T he n otes c ol u m n f or pre g na n c y tests i n all 
parts of t he S o A has bee n u p date d t o refl ect 
t hat ser u m pre g na n c y tests will be 
perf or me d at scree ni n g a n d uri ne tests will 
be perf or me d at all ot her ti me p oi nts.  
T his u p date was ma de 
f or c o nsiste nc y 
1. 3. 2.  Part A: Si n gle -
Asce n di n g D ose a n d 
F o o d Effect 
E val uati o n, C o h ort 4 
( 2-Peri o d Cr oss o ver)  
 
F o ot n ote “b ” h as bee n u p date d t o refl ect 
t hat t he was h o ut bet wee n Peri o ds 1 a n d 2 
will be at least 5 da ys. F o ot n ote “c” h as 
bee n u p date d t o reflect t hat t he PI m ust 
re vie w t he Da y 5 la b orat or y res ults i n 
Peri o d 1 bef ore d osi n g o n Da y 1 of Peri o d 
2.  
T hese u p dates were 
ma de t o ali g n wit h t he 
i ncreas e d le n gt h of 
sta y t hat was i ncl u de d 
i n A me n d me nt a  
 
1. 3. 3. Part B: Dr u g -
Dr u g I nteracti o n wit h 
C Y P 3 A 4 I n hi biti o n –  
Fi x e d Se q ue nce  
P K sa m pli n g has bee n e xte n de d t o 9 6 h o urs 
p ost d ose i n t he L Y 3 5 0 9 7 5 4 al o ne ar m 
( d osi n g occ urs o n Da y 1). Disc har ge, 
P E/ M A, a n d cli nical la b orat or y tests ha ve 
bee n m o ve d fr o m Da y 1 4 t o Da y 1 7. 
C O VI D -1 9 testi n g a n d si n gle sa fet y E C Gs 
ha ve bee n a d de d t o D a y 1 7. A E/ me dicati o n 
re vie w, vital si g n assess me nts, a n d P K 
sa m ples ha ve bee n a d d e d f or t he a d diti o nal 
da ys i n t he C R U. T he 5 h o ur p ost d ose 
L Y 3 5 0 9 7 5 4 P K sa m ples o n Da ys 1 a n d 1 0, 
Refer t o  t he o verall 
rati o nale f or t h e 
a me n d me nt  
 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
1 2 9  
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  
a n d t he 6 0 h o ur p ost d ose sa m ple o n Da y 1 2 
ha ve bee n re m o ve d. F o ot n ote “a” h as bee n 
u p date d t o refl ect t hat t he was h o ut peri o d 
bet wee n L Y 3 5 0 9 7 5 4 a n d itrac o naz ole 
d osi n g ma y be e xte n de d b y u p t o 5 da ys 
base d o n e mer gi n g P K data.  
 
Te m perat ur e has b ee n re m o ve d fr o m t he 
vital si g ns r o w, a n d a r o w f or te m perat ure 
has bee n a d d e d. Te m p erat ure assess me nts 
will be d o ne at c hec k -i n ( Da y -2), pre d ose 
o n Da ys 1, 6 , a n d 1 0, a n d o n Da y 1 7, earl y 
disc o nti n uati o n, a n d f oll o w -u p.  
T his u p date was ma de 
t o i m pr o ve clarity 
s urr o u n di n g 
te m perat ur e 
assess me nts  
1. 3. 4 . Part C : 
M ulti ple -Asce n di n g 
D ose –  C o h orts 1, 3, 
a n d 4 –  Si n gle Peri o d  
 
T he d urati o n of sta y f or C o h orts 1, 3, a n d 4 
of t he M A D has b ee n i ncrease d t o greater 
t ha n 9 6 h o urs f oll o wi n g t he last L Y 3 5 0 9 7 5 4 
d ose, afte r w hic h partici pa nts ma y b e 
disc har ge d o n Da y 1 9 at t he discreti o n of 
t he i n vesti gat or. Disc har ge, P E/ M A, cli nical 
la b orat or y tests, C O VI D-1 9 testi n g, a n d 
si n gle safet y E C Gs ha ve bee n m o ve d fr o m 
Da y 1 5 t o Da y 1 9. A E/ m e dicati o n re vie w, 
vital si g n assess me nt s, a n d P K sa m pli n g 
ti me p oi nts ha ve bee n a d de d f or t he 
a d diti o nal da ys i n t he C R U. T he 5 -h o ur 
p ost d ose P K sa m ples o n Da ys 1, 7, a n d 1 4 
ha ve bee n re m o ve d.  
Refer t o  t he o verall 
rati o nale f or t h e 
a me n d me nt  
 
T he Da y 1 5 ti me  p oi nts f or e x pl orat or y 
bl o o d sa m pli n g a n d  e x pl orat or y b uccal 
s wa bs a n d sali va sam ples ha ve bee n 
u p date d fr o m “ P” t o “ 2 4 h o urs”  
T his u p date  c orrects 
a n err or i n t he ori gi nal 
pr ot oc ol  
1. 3. 5. Part C: 
M ulti ple -Asce n di n g 
D ose a n d Per petrat or 
D DI –  C o h ort 2 Fi x e d 
Se q ue nce  
T he d urati o n of sta y f o r C o h ort 2 of t he 
M A D has bee n i n crease d t o 9 6 h o urs 
f oll o wi n g t he last L Y 3 5 0 9 7 5 4 d ose. 
Disc har ge, P E/ M A, cli ni cal la b orat or y tests, 
C O VI D -1 9 testi n g, a n d si n gle safet y E C Gs 
ha ve bee n m o ve d fr o m Da y 1 7 t o D a y 1 9. 
A E /me dicati o n re vie w a n d vital si g n 
assess m e nts ha ve b ee n a d de d f or t he 
a d diti o nal da ys i n t he C R U. T he P K sa m ple 
o n Da y 1 6 has bee n re m o ve d.  
Refer t o  t he o verall 
rati o nale f or t h e 
a me n d me nt  
 
T he Da y 1 5 ti me  p oi nts f or e x pl orat or y 
bl o o d sa m pli n g a n d  e x pl orat or y b uccal 
T his u p date  c orrects 
a n err or i n t he ori gi nal 
pr ot oc ol  
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
1 3 0  
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  
s wa bs a n d sali va sam ples ha ve  bee n 
u p date d fr o m “ P” t o “ 2 4 h o urs”  
1. 3. 6. Part D: 
M ulti ple -D ose i n 
J a pa nese Healt h y 
Partici pa nts –  Si n gle 
Peri o d  
T he d urati o n of sta y f or Part D ( M A D i n 
J a pa nese Healt h y Partici pa nts) has bee n 
i ncreas e d t o great er t ha n 9 6 h o urs f oll o wi n g 
t he last L Y 3 5 0 9 7 5 4 d os e. Disc har ge, 
P E/ M A, cli nical la b orat or y tests, C O VI D -
1 9 testi n g, a n d si n gle safet y E C Gs h a ve 
bee n m o ve d fr o m Da y 1 5 t o Da y 1 9. 
A E/ me dicati o n re vie w, vital si g n 
assess me nts, a n d P K sa m pli n g ti me  p oi nts 
ha ve bee n a d de d f or t he a d diti o nal da ys i n 
t he C R U. T he 5-h o ur P K sa m ples o n Da ys 
1, 7, a n d 1 4 ha ve b ee n re m o ve d.  
Refer t o  t he o verall 
rati o nale f or t h e 
a me n d me nt  
 
T he Da y 1 5 ti me  p oi nts f or e x pl orat or y 
bl o o d sa m pli n g a n d  e x pl orat or y b uccal 
s wa bs a n d sali va sam ples ha ve bee n 
u p date d fr o m “ P” t o “ 2 4 h o urs”  
T his u p date  c orrects 
a n err or i n t he ori gi nal 
pr ot oc ol  
 
 
 
4. 2. 1. Part A ( Si n gle -
Asce n di n g D ose)  
La n g u a ge i n t his secti o n has bee n u p dat e d 
t o reflect a n a p pr o xi mate half-life of 1 4 t o 
1 7 h o urs f or L Y 3 5 0 9 7 5 4.  
Refer t o  t he o verall 
rati o nale f or t h e 
a me n d me nt  
4. 2. 2. Part B 
( C Y P 3 A 4 I n hi biti o n) 
T he L Y 3 5 0 9 7 5 4 d ose t o be st u die d i n t his 
p orti o n of t he st u d y has b ee n i de ntifie d as 
1 0 m g.  
La n g u a ge d escri bi n g t he was h o ut peri o d has 
bee n u p date d fr o m “ u p t o 3 da ys ” t o “ u p t o 
5 da ys ”.  
La n g u a ge i n t his secti o n detaili n g le n gt h of 
partici pa nt sta y  has bee n u p date d i n 
acc or da nce wit h t he c ha n ges ma d e t o t he 
S o A  i n t his a me n d me nt. 
Fi g ure F N A A. 1 has bee n u p date d t o refl ect 
t he i ncreas e d sta y a n d P K sa m pli n g c h a n ges 
ma de t o t he S o A.  
T his d ose is base d o n 
safet y, t olera bilit y, a n d 
P K data fr o m Part A.  
Refer t o t he o verall 
rati o nale f or t h e 
a me n d me nt.  
P K sa m pli n g d urati o n 
a n d partici pa nt sta y i n 
t he C R U has bee n 
i ncreas e d t o acc o u nt 
f or predict e d l o n ger 
half -life of 
L Y 3 5 0 9 7 5 4 after 
itrac o naz ole i n hi biti o n 
of C Y P 3 A 4 -me diate d 
cleara nce.  
4. 2. 3 .  Part C 
( M ulti ple-Asce n di n g 
D ose/ C Y P 3 A 4 
Per petrat or D DI)    
La n g u a ge i n t his secti o n detaili n g le n gt h of 
partici pa nt sta y  has bee n u p date d i n 
acc or da nce wit h t he c ha n ges ma d e t o t he 
S o A  i n t his a me n d me nt 
Refer t o  t he o verall 
rati o nale f or t h e 
a me n d me nt  
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
1 3 1  
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  
 
Fi g ure F N A A. 2 has bee n u p date d t o refl ect 
t he i ncreas e d d urati o n of sta y i n t he C R U 
a n d t o c orrect a n err or i n L Y 3 5 0 9 7 5 4 P K  
sa m pli n g ti mes 
Refer t o t he o verall 
rati o nale f or t h e 
a me n d me nt  
4. 3. 1. J ustificati o n f or 
L Y 3 5 0 9 7 5 4 D ose;  
Ta ble F N A A. 3.  
F o ot n otes “c” a n d “d ” ha ve bee n u p d ate d t o 
n ote t hat e x p os ure is pre dicte d A U C or 
C ma x  at stea d y state  
T his u p date was ma de 
f or clarit y 
 
 
T he L Y 3 5 0 9 7 5 4 d ose t o be st u die d i n Part 
B ( L Y 3 5 0 9 7 5 4 C Y P 3 A 4 Victi m 
Assess me nt) has bee n i de ntifie d as 1 0 m g  
T his d ose was 
deter mi ne d bas e d o n 
safet y, t olera bilit y, a n d 
P K data fr o m Part A  
6. 6. 1. D ose 
Decisi o n/ Escalati o n  
T he n u m ber of da ys f oll o wi n g t he last d ose 
of L Y 3 5 0 9 7 5 4 ( 5) t hat s afet y d ata are 
re q uire d t o be re vie we d f or S A D a n d M A D 
d ose escal ati o ns has bee n a d de d  
T his u p date was ma de 
f or clarit y 
9. 3. 5. I nt eri m Access 
t o Data (I A D) 
T he n u m ber of da ys t hat data will be 
c ollecte d f or partici pa nts  i n eac h c o h ort 
bef ore I A D is pla n ne d t o occ ur has b ee n 
u p date d fr o m “ u p t o D a y 1 4” t o “ u p t o Da y 
1 7” f or Part B ( C Y P 3 A 4 victi m D DI), fr o m 
“ u p t o Da y 1 5” t o “ u p t o Da y 1 9” f or 
C o h orts 1 a n d 3, a n d fr o m “ u p t o Da y 1 6” 
t o “ u p t o Da y 1 9” f or C o h ort 2 i n t he MA D 
c o m p o ne nt of t he st u d y.  
Refer t o t he o verall 
rati o nale f or t h e 
a me n d me nt  
1 0. 2. A p pe n di x 2: 
Cli nical La b orat or y 
Tests  
W B C esterase testi n g has bee n a d d e d t o t he 
uri nal ysis  
T his c ha n ge c orrects 
a n o missi o n i n t he 
ori gi nal pr ot o c ol  
 
F o ot n ote “e ” has bee n  u p date d t o refl ect 
t hat a ser u m pre g n a nc y t est will be 
perf or me d at scree ni n g a n d uri ne pre g n a nc y 
tests will be perf or me d at all ot her ti me 
p oi nts  
T his u p date was ma de 
f or c o nsiste nc y 
1 0. 2. 1. Bl o o d 
Sa m pli n g S u m mar y  
T he n u m ber of L Y 3 5 0 9 7 5 4 P K sa m ples a n d 
c orres p o n di n g bl o o d v ol u mes ha ve bee n 
u p date d i n t he bl o o d sa m pli n g ta bles f or 
Part B ( D DI wit h C Y P 3 A 4 I n hi biti o n –  
Fi x e d Se q ue nce) a n d Part C ( M A D + 
Mi daz ola m D DI [ C o h ort 2])  
T hese c h a n ges were 
ma de i n acc or da n ce 
wit h u p dates t o P K 
sa m pli n g ma de i n t he 
c orres p o n di n g secti o ns 
of t he S o A  
 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
1 3 2  
 
A me n d me nt a : 3 0 Dece m ber 2 0 2 0 
O ver all R ati o n ale f or t he A me n d me nt  
Preli mi nar y d ata fr o m C o h ort 1 of t he S A D p orti o n of t his st u d y i n dicate a ter mi nal eli mi nati o n 
half -life (t1/ 2 ) f or L Y 3 5 0 9 7 5 4 of great er t ha n 5 h o urs base d o n n o n -c o m part me ntal a nal ysis 
w hic h is l o n ger t ha n t he pr ojecte d t1/ 2  of a p pr o xi matel y 5 h o urs. T hi s a me n d me nt e xte n ds safet y, 
t olera bilit y, a n d P K c ollecti o n ti mes i n acc or da n ce wit h t his fi n di n g 
 
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  
1. 3. Sc he d ule of 
Acti vities ; 
1. 3. 1.  Part A: Si n gle -
Asce n di n g D ose, 
C o h orts 1, 2, 3, 5, 6, 
a n d 7  
 
T he d urati o n of sta y f or t he S A D p orti o n of 
t his st u d y ( Part A, C o h orts 1-3 a n d 5 -7) has 
bee n i ncrease d t o 9 6 h o urs p ost d ose. P K, 
safet y, a n d t olera bilit y c ollecti o ns were 
a d de d at 7 2 a n d 9 6 h o urs p ost d ose. F oll o w -
u p will occ ur at least 7 d a ys after dis c ha r ge, 
n ot fi nal d ose as pre vi o usl y state d.  
Refer t o t he o verall 
rati o nale f or t h e 
a me n d me nt  
1. 3. Sc he d ule of 
Acti vities ;  
1. 3. 2.  Part A: Si n gle -
Asce n di n g D ose a n d 
F o o d Effect 
E val uati o n, C o h ort 4 
( 2-Peri o d Cr oss o ver)  
 
T he d urati o n of sta y f or t he S A D p orti o n of 
t his st u d y ( Part A, C o h ort 4) has bee n 
i ncreas e d t o 9 6 h o urs p ost d ose. P K, safet y, 
a n d t olera bilit y c ollecti o ns were a d de d at 7 2 
a n d 9 6 h o urs p ost d ose f or Treat me nt Peri o d 
1 ( Faste d) a n d Treat me nt Peri o d 2 ( Fe d). 
F oll o w -u p will occ ur at least 7 da ys aft er 
disc har ge, n ot fi nal d os e as pre vi o usl y 
state d. 
Refer t o  t he o verall 
rati o nale f or t h e 
a me n d me nt  
4. 2. Scie ntific 
Rati o nale f or St u d y 
Desi g n;  
4. 2. 1.   Part A ( Si n gle - 
Asce n di n g D ose)   
 
La n g u a ge i n t his secti o n detaili n g le n gt h of 
partici pa nt sta y  a n d ti mi n g of f oll o w -u p has 
bee n u p date d i n acc or da n ce wit h t he 
c ha n ges ma d e t o t he S o A  i n t his a me n d me nt 
Refer t o  t he o verall 
rati o nale f or t h e 
a me n d me nt  
5. 1. I n cl usi o n Criteria  
Criteri o n 7. b has bee n u p date d t o c ha n ge t he 
F S H c ut off fr o m > 4 0 mI U/ m L t o ≥4 0 
mI U/ m L  
T his c orrects a n err or 
i n t he ori gi nal pr ot o c ol 
5. 2. E x cl usi o n Criteria  Criteri o n 1 6 has bee n u p date d t o re place 
Q Tc B wit h Q Tc F f or cal c ulati o n of 
c orrecte d Q T i nter val  
T his c orrects a n  err or 
i n t he ori gi nal pr ot o c ol 
5. 2. E x cl usi o n Criteria  Criteri o n 3 7 has bee n a d de d t o i ncl u de 
testi n g f or acti ve or l ate nt t u berc ul osis at 
scree ni n g 
T his c orrects a n 
o missi o n i n t he 
ori gi nal pr ot o c ol  
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
1 3 3  
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  
 
8. 5. P har mac o ki netics  
 
La n g u a ge h as bee n a d de d t o descri be 
e x pl orat or y meta b olite pr ofili n g i n uri ne 
a n d plas ma  
 
T his c orrects a n 
o missi o n i n t he 
ori gi nal pr ot o c ol  
 
 
9. 3. 5. I nt eri m Access 
t o Data (I A D) 
T he n u m ber of da ys t hat data will be 
c ollecte d f or partici pa nts i n eac h c o h ort i n 
t he S A D c o m p o ne nt of t he st u d y ( Part A), 
bef ore I A D is pla n ne d t o occ ur , has  b ee n 
u p date d fr o m u p t o 3 da ys p ost d ose t o u p t o 
5 da ys p ost d ose.  
Refer t o t he o verall 
rati o nale f or t h e 
a me n d me nt  
 
1 0. 2. A p pe n di x 2: 
Cli nical La b orat or y 
Tests  
 
Q ua nti F E R O N -T B G ol d test i n g, a n d F S H 
testi n g ha ve b ee n a d de d t o be d o ne at 
scree ni n g. 
E q uati o ns f or cal c ulati o n of creati ni ne 
cleara nce h a ve b ee n a d d e d t o t he f o ot n otes.  
 
T hese c h a n ges c orrect 
o missi o ns i n t he 
ori gi nal pr ot o c ol  
 
 
 
1 0. 2. 1. Bl o o d 
Sa m pli n g S u m mar y  
 
U p dates t o t he sa m pli n g t a bles f or t he S A D 
c o m p o ne nt of t he st u d y ( Part A) ha v e b ee n 
ma de i n acc or da n ce wit h i ncreas e d 
partici pa nt sta y i n t he C R U as detaile d i n 
t he So A.  
 
Refer t o t he o verall 
rati o nale f or t h e 
a me n d me nt  
 
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

C O N FI D E N TI A L  
J 3 D -M C -F N A A( i) 
 
1 3 4  
1 1.  
Refere nces  
Bla u velt A,  C hiric ozzi  A. T he i m m u n ol o gic r ole of I L -1 7 i n ps oriasis a n d ps oriatic art hritis 
pat h o ge nesis . Cli n Rev  Aller gy I m m u n ol. 2 0 1 8 ; 5 5: 3 7 9-3 9 0.  htt ps:// d oi. or g/ 1 0. 1 0 0 7/s 1 2 0 1 6 -
0 1 8 -8 7 0 2 -3  
B utler L D, G uzzie -Pec k P, Hart ke J, et al. C urre nt n o ncli nical testi n g para di g ms i n s u p p ort of 
safe cli nic al trials: A n I Q C o ns orti u m Dr u Safe pers pecti ve. Re g ul T oxic ol P h ar m ac ol . 2 0 1 7; 8 7 
S u p pl 3: S 1 -S 1 5. htt ps:// d oi. or g/ 1 0. 1 0 1 6/j. yrt p h. 2 0 1 7. 0 5. 0 0 9  
C he n Y, Ca bal u T D, Call e gari E, et al. Rec o m me n dati o ns f or t he desi g n of cli nical dr u g-dr u g 
i nteracti o n st u dies wit h itrac o naz ole usi n g a mec h a nistic p h ysi ol o gicall y-b as e d 
p har mac o ki netic m o d el . C P T P h ar m ac o metrics Syst P h ar m ac ol . 2 0 1 9; 8( 9): 6 8 5-6 9 5. 
htt ps:// d oi. or g/ 1 0. 1 0 0 2/ ps p 4. 1 2 4 4 9  
C oc kcr oft  D W, Ga ult M H. Pre dicti o n of creati ni ne cleara nce fr o m s er u m  creati ni ne.  
Ne p hr o n . 1 9 7 6; 1 6( 1): 3 1-4 1. htt ps:// d oi . or g/1 0. 1 1 5 9/ 0 0 0 1 8 0 5 8 0  
De Ge or ge J, R o berts o n S, B utler L, et al. A n i n d ustr y pers pecti ve o n t h e 2 0 1 7 E M A g ui deli ne o n 
first-i n-h u ma n a n d earl y cli nical trials. Cli n P h ar m ac ol T her . 2 0 1 8; 1 0 3( 4): 5 6 6-5 6 9.  
htt ps:// d oi. or g/ 1 0. 1 0 0 2/c pt. 9 8 4  
[E M A ] E ur o pea n Me dici nes A ge nc y.  G ui deli ne o n strate gies t o i de ntif y a n d miti gate ris ks f or 
first-i n-h u ma n a n d earl y cli nical trials wit h i n vesti gati o nal me di ci nal pr o d u cts . 
E M E A/ C H M P/ S W P/ 2 8 3 6 7/ 0 7 Re v. 1. P u blis he d J ul y 2 0, 2 0 1 7. Accesse d A u g ust 1 7, 2 0 2 0.  
htt p:// w w w.e ma.e ur o pa. e u/ d ocs/e n _ G B/ d oc u m e nt _li brar y/ Sci e ntific _ g ui deli ne/ 2 0 1 7/ 0 7/ W C 5 0
0 2 3 2 1 8 6. p df  
[ F D A] F o o d a n d Dr u g A d mi nistrati o n. G ui da nce f or i n d ustr y.  Cli nical d r u g interacti o n st u dies - 
c yt o c hr o me P 4 5 0 enz y m e - a n d tra ns p orter-m e diat e d d r u g interacti o ns . Se pte m ber 2 0 2 0. 
Access e d A u g ust 2 6, 2 0 2 0. htt ps:// w w w.f da. g o v/r e g ul at or y -i nf or m ati o n/searc h-f da-g ui d a nce -
d oc u me nts/cli nical -dr u g -i nteracti o n-st u dies-c yt o c hr o me -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 
[ F D A] F o o d a n d Dr u g A d mi nistrati o n. G ui da nce f or in d ustr y. Esti mati n g t he ma xi m u m safe 
starti n g d ose i n i nitial cli nical trials f or t hera pe uti cs i n a d ult healt h y v ol u nt eers. J ul y 2 0 0 5. 
Access e d A u g ust 3, 2 0 2 0.  htt ps:// w w w.f da. g o v/ me dia/ 7 2 3 0 9/ d o w nl oa d  
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T

Si g nat ure Pa ge f or V V- C LI N- 0 1 4 9 0 6 v 1. 0
Si g nat ure Pa ge f or V V- C LI N- 0 1 4 9 0 6 v 1. 0
A p pr o val
0 1- Dec- 2 0 2 1 1 4: 3 5: 3 8 G M T + 0 0 0 0
A p pr o val
0 1- Dec- 2 0 2 1 1 5: 3 8: 4 9 G M T + 0 0 0 0
A p pr o ve d o n 0 1 Dec 2 0 2 1 G M T
P P D
P P D