A Single Dose Pharmacokinetic Study of Tirzepatide in Subjects With Varying Degrees of Hepatic Impairment
Phase: PHASE1
Conditions: Hepatic Insufficiency
Sponsor: Eli Lilly and Company

Pr ot oc ol I 8 F- M C- G P G Q(a)
A Si n gle D ose P har mac o ki netic St u d y of Tirze pati de i n S u bjects Wit h Var yi n g De grees of He patic 
I m pair me nt
N C T 0 3 9 4 0 7 4 2
A p pr o val Date: 1 8-J ul- 2 0 1 9

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 1
L Y 3 2 9 8 1 7 6
Pr ot o c ol I 8 F-M C -G P G Q ( a)
A Si n gl e D o s e P h ar m a c o ki n eti c St u d y of Tir z e p ati d e i n 
S u bj e ct s wit h V ar y i n g D e gr e e s of H e p ati c I m p air m e nt
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 pr ot o c ol 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 
tir z e p ati d e ( L Y 3 2 9 8 1 7 6), 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 a ll 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 cti o n pri or t o a n y p u bli c r el e a s e.  I n 
t h e U nit e d St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m ati o n A ct ( F OI A) 
E x e m pti o n 4 a n d m a y n ot b e r e pr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e writt e n 
a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s .  
Tir z e p ati d e ( L Y 3 2 9 8 1 7 6)
Eli Lill y a n d C o m p a n y
I n di a n a p oli s, I n di a n a U S A 4 6 2 8 5
Cli ni c al P h ar m a c ol o g y Pr ot o c ol El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y :  
0 1 A pril 2 0 1 9
A m e n d m e nt ( a) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y
o n a p pr o v al d at e pr o vi d e d b el o w.
A p pr o v al D at e: 1 8- J ul- 2 0 1 9 G M T

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 2
L Y 3 2 9 8 1 7 6
T a bl e of C o nt e nt s
A Si n gl e D o s e P h ar m a c o ki n eti c St u d y  of Tir z e p ati d e i n 
S u bj e ct s wit h V ar y i n g D e gr e e s of H e p ati c I m p airm e nt
S e cti o n
P a g e
Pr ot oc ol  I 8 F-M C -G P G Q(a) A Si n gle D ose P har mac o ki net ic St u d y of 
Ti rze patide i n S u bjects wi t h Var yi n g De grees of He patic I m pair me nt................................. 1
Ta ble of C o nte nts ........................................................................................................................2
1.
Pr ot oc ol  S y n opsi s................................................................................................................8
2.
Sc he d ule of Act i vities .......................................................................................................1 0
3.
I ntr o d ucti o n ......................................................................................................................1 3
3. 1.
St u d y  Ratio n a le............................................................................................................1 3
3. 2.
Bac k gr o u n d ..................................................................................................................1 3
3. 3.
Be nefit/ Ris k Assess me nt ..............................................................................................1 5
4.  
O bject i ves a n d E n d p oi nts ..................................................................................................1 6
5.
St u d y  Desi g n.....................................................................................................................1 7
5. 1.
O verall Desi g n .............................................................................................................1 7
5. 1. 1.
C hil d - Pu g h Cl assificat i on .....................................................................................1 8
5. 2.
N u m ber of S u bjects ......................................................................................................1 9
5. 3.
E n d of St u d y  Defi niti on ...............................................................................................2 0
5. 4.
S ci e nt ific Rati o nale f or St u d y Desi g n...........................................................................2 0
5. 5.
J ustificati o n f or D ose ...................................................................................................2 0
6.
St u d y  P o p ulat i on ...............................................................................................................2 1
6. 1.
I ncl usi on Cri t eria ..........................................................................................................2 1
6. 1. 1.
I ncl usi on Cri t eria for All S u bjects ........................................................................2 1
6. 1. 2.
A d dit i onal I ncl usi o n Criteria f or C o ntr ol S u bjects ( Gr o u p 1) ................................2 3
6. 1. 3.
A d dit i onal I ncl usi o n Criteria f or S u bjects wit h Mil d t o 
Se vere He pat ic I m pair me nt ( Gr o u ps 2 t o 4) ..........................................................2 3
6. 1. 4.
A d dit i onal I ncl usi o n Criteria f or S u bjects wit h b ot h T 2 D M 
a n d He pat ic I m pair me nt.......................................................................................2 3
6. 2.
E xcl usi o n Cri t eria ........................................................................................................2 4
6. 2. 1.
E xcl usi o n Cri t eria for All S u bjects U nless Ot her wise 
S pecifie d ..............................................................................................................2 4
6. 2. 2.
A d dit i onal E xcl usi o n Cri t eria for S u bjects wi t h Mil d t o 
Se vere He pat ic I m pair me nt ( Gr o u ps 2 t o 4) ..........................................................2 6
6. 2. 3.
A d dit i onal E xcl usi o n Cri t eria for S u bjects wi t h T 2 D M a n d 
He pati c I mp ai r me nt ..............................................................................................2 6
6. 3.
Lifest yle a n d/ or Dietar y Re q uire me nts .........................................................................2 7

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 3
L Y 3 2 9 8 1 7 6
6. 3. 1.
Meals a n d Dietar y  Restrict i ons .............................................................................2 7
6. 3. 2.
Caffei ne, Alc o h o l, a n d T o bacc o ...........................................................................2 7
6. 3. 3.
Act i vity ................................................................................................................2 7
6. 4.
Scree n Fail ures .............................................................................................................2 7
7.
Treat me nt ..........................................................................................................................2 8
7. 1.
Treat me nt A d mi nistere d ...............................................................................................2 8
7. 1. 1.
Pac ka gi n g a n d La beli n g .......................................................................................2 8
7. 2.
Met h o d of Treat me nt Assi g n me nt
................................................................................2 8
7. 2. 1.
S el ect i on a n d Ti mi n g o f D oses .............................................................................2 9
7. 3.
Bli n di n g .......................................................................................................................2 9
7. 4.
D ose M o dificat i on ........................................................................................................2 9
7. 5.
Pre pa r atio n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y ...............................................................2 9
7. 6.
Treat me nt C o m plia nce ................................................................................................. 2 9
7. 7.
C o nc o mita nt T hera p y ...................................................................................................2 9
7. 8.
Treat me nt after t he E n d of t he St u d y ............................................................................3 0
8.
Di sc o nti n uatio n Cri t eri a....................................................................................................3 1
8. 1.
Di sc o nti n uatio n f r o m t he St u d y....................................................................................3 1
8. 1. 1.
Di sc o nti n uatio n of  I na d verte ntl y Enr olle d S u bjects ..............................................3 1
8. 2.
S u bjects L ost t o F oll o w - u p...........................................................................................3 1
9.
St u d y  Assess me nts a n d Pr oce d ures...................................................................................3 2
9. 1.
Efficac y Assess me nts ...................................................................................................3 2
9. 2.
A d v erse E ve nts ............................................................................................................3 2
9. 2. 1.
S eri o us A d verse E ve nts ........................................................................................3 3
9. 2. 1. 1.
S us pecte d U ne x pecte d Seri o us A d verse React i ons ..........................................3 4
9. 2. 2.
C o m plai nt Ha n dli n g .............................................................................................3 4
9. 3.
Tr e at me nt of O ver d ose ................................................................................................. 3 4
9. 4.
S af et y ...........................................................................................................................3 4
9. 4. 1.
Cli nical La b orat or y  Tests.....................................................................................3 4
9. 4. 1. 1.
A m ylase a n d Li pase Meas ure me nts ................................................................3 4
9. 4. 2.
Gl uc ose M o ni t ori n g .............................................................................................3 5
9. 4. 2. 1.
H y per gl yce mia a n d H y p o gl yce mia Re p orti n g .................................................3 5
9. 4. 3.
Vi t al Sig ns........................................................................................................... 3 6
9. 4. 4.
Electr o car di o gra ms ..............................................................................................3 7
9. 4. 5.
I njecti on- site Reacti ons ........................................................................................3 7
9. 4. 6.
H y perse nsi tivi t y R e a ctio ns ...................................................................................3 8
9. 4. 7.
S af et y M o ni t ori n g ................................................................................................3 8
9. 4. 7. 1.
He pati c Safet y M o ni t ori n g i n S u bjects wit h Treat me nt-
e mer ge nt A b n or mal Li ver Tests ......................................................................3 9

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 4
L Y 3 2 9 8 1 7 6
9. 4. 7. 2.
A d dit i onal He pat ic Data C ollecti o n ( He patic Safet y 
e C R F) i n S u bjects wit h Treat me nt -e mer ge nt A b n or mal 
Li ver Tests ......................................................................................................4 0
9. 5.
P har mac o ki net ics .........................................................................................................4 0
9. 5. 1.
Bi oa nal ysis ...........................................................................................................4 0
9. 6.
P har mac o d y na mics ......................................................................................................4 1
9. 6. 1.
I mm u n o ge nicit y Assess me nts ..............................................................................4 1
9. 7.
Ge net ics .......................................................................................................................4 2
9. 8.
Bi o m ar kers ...................................................................................................................4 2
9. 9.
Heal t h Ec o n o mics........................................................................................................4 2
1 0.
Stati stical C o nsi derati o ns a n d Data A nal ysis.....................................................................4 3
1 0. 1.
S a m ple Si ze Deter mi nat i on ..........................................................................................4 3
1 0. 2.
P o p ul at i ons f or A nal yses..............................................................................................4 3
1 0. 2. 1.
St u d y  P artici pa nt Dis p osit i on ...............................................................................4 3
1 0. 2. 2.
St u d y  P artici pa nt C haracterist ics..........................................................................4 3
1 0. 3.
Stati stical A nal yses ......................................................................................................4 3
1 0. 3. 1.
S af et y A nal yses ....................................................................................................4 3
1 0. 3. 1. 1.
Cli nical E val uati o n of Safet y ..........................................................................4 3
1 0. 3. 1. 2.
Stati stical E val uati on of Safet y .......................................................................4 4
1 0. 3. 1. 3.
I njecti on- site Reacti ons ...................................................................................4 4
1 0. 3. 2.
P har mac o ki net ic A nal yses ....................................................................................4 4
1 0. 3. 2. 1.
P har mac o ki net ic Para meter Esti mati on ...........................................................4 4
1 0. 3. 2. 2.
P har mac o ki net ic Statistical I nfere nce .............................................................4 4
1 0. 3. 3.
E val uat i on of I m m u n o ge nicit y .............................................................................4 5
1 0. 3. 4.
Data Re vie w D uri n g t he St u d y .............................................................................4 5
1 0. 3. 5.
I nteri m A nal yses ..................................................................................................4 5
1 1.
Refere nces ........................................................................................................................4 6

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 5
L Y 3 2 9 8 1 7 6
Li st of T a bl e s
T a bl e
P a g e
Ta ble G P G Q. 1.
O bject i ves a n d E n d p oi nts .......................................................................1 6
Ta ble G P G Q. 2.
C hil d -P u g h Cl assificat i on .......................................................................1 9
Ta ble G P G Q. 3.
Treat me nts A d mi nistere d ........................................................................2 8

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 6
L Y 3 2 9 8 1 7 6
Li st of Fi g ur e s
Fi g ur e
P a g e
Fi g ure G P G Q . 1.
Ill ustratio n of  st u d y desi g n f or Pr ot oc ol I 8 F-M C -G P G Q. ........................1 8

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 7
L Y 3 2 9 8 1 7 6
Li st of A p p e n di c e s
A p p e n di x
P a g e
A p pe n di x 1.
A b bre viat i ons a n d Defi nit i ons ................................................................4 7
A p pe n di x 2.
Cli nical La b orat or y  Tests........................................................................5 0
A p pe n di x 3.
St u d y  G o ver na nce, Re g ulat or y a n d Et hic al C o nsi deratio ns .....................5 1
A p pe n di x 4.
He pati c M o nit orin g Tests f or Treat me nt -E m er ge nt A b n or malit y ............5 4
A p pe n di x 5.
Bl o o d S a m pli n g S u m mar y ......................................................................5 5
A p pe n di x 6.
Cl assificat i on of C o ntrace pti ve Met h o ds .................................................5 6
A p pe n di x 7.
Pa ncreat ic M o nit ori n g ............................................................................5 7
A p pe n di x 8. 
Reas o na bl y A nt ici pate d Seri o us A d verse E ve nts ....................................6 0
A p pe n di x 9.
Per mi tte d Me dicati ons f or S u bjects wit h He patic I m pair me nt.................6 1
A p pe n di x 1 0.
Pr ot oc ol  A me n d me nt I 8 F-M C - G P G Q(a) S u m mar y - A Si n gle 
D ose P har m ac o ki net ic St u d y of Tirze pati de i n S u bjects wit h 
Var yi n g De grees of He pat ic I m pair me nt.................................................6 2

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 8
L Y 3 2 9 8 1 7 6
1. Pr ot o c ol S y n o p si s
Title of St u d y:
A Si n gl e D ose P har mac o ki netic St u d y of Tirze pati de i n S u bjects wit h Var yi n g De grees of He patic I m pair me nt
R ati o n ale :  
Tirze pati de ( L Y 3 2 9 8 1 7 6) is a d ual a g o nist of gl uc ose -de pe n de nt i ns uli n otr o pic p ol y pe pti de a n d gl uca g o n -li ke 
pe pti de- 1 rece pt ors bei n g de vel o pe d f or t he treat me nt of t ype 2 dia betes mellit us.  As t he patie nt p o p ulati o n f or 
tirze pati de ma y i ncl u de patie nts wit h he patic i m pair me nt, it is i m p orta nt t o ascertai n w het her tirze pati de ca n be 
safel y prescri be d t o t his p o p ulati o n wit h o ut d ose a dj ust me nt, o nce mar kete d.  T he fatt y aci d c o m p o ne nt of 
tirze pati de is e x pecte d t o bi n d t o al b u mi n; h o we ver , al b u mi n c o nce ntrati o n i n he patic i m paire d s u bjects ca n be l o wer 
t ha n t hat see n i n c o ntr ol s u bjects. T heref ore, t his st u d y will e val uate t he p har mac o ki netics ( P K ) of tirze pati de i n 
s u bjects wit h he patic i m pair me nt c o m pare d t o healt h y  c o ntr ol s u bjects t o i n vesti gate t he i m pact of he patic 
i m pair me nt, if a n y, o n t he P K of tirze pati de.  
O bjecti ve s/ E n d p oi nts:  
O bjecti ves
E n d p oi nts
Pri m ar y
T o e val uate t he P K of a si n gle S C d ose of tirze pati de i n 
s u bjects wit h mil d, m o derate, a n d se vere he patic 
i m pair me nt c o m pare d t o c o ntr ol s u bjects wit h n or mal 
he patic f u ncti o n.
A U C ( 0-∞) a n d C ma x
Sec o n d ar y
T o e val uate t he safet y a n d t olera bilit y of a si n gle S C
d ose of tirze pati de i n s u bjects wit h mil d, m o derate, a n d 
se vere he patic i m pair me nt c o m pare d t o c o ntr ol 
s u bjects wit h n or mal he patic f u ncti o n.
I nci de nce of A Es
A b bre viati o ns: A E = a d verse e ve nt; A U C ( 0-∞) = area u n der t he dr u g c o nce ntrati o n -ti me c ur ve fr o m zer o t o i nfi nit y; Cma 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 C = s u bc uta ne o us .
S u m m ar y of St u d y Desi g n :  
St u d y I 8 F-M C -G P G Q will be a m ulti ce nter, parallel, si n gle-d ose, o pe n -la bel, si n gle-peri o d st u d y of tirze pati de i n 
s u bjects wit h n or mal he patic f u ncti o n a n d s u bjects wit h mil d, m o derate, a n d se vere he patic i m pair me nt. S u bjects 
e nr olle d i n Gr o u p 1 ( n or mal he patic f u ncti o n) will be matc he d b y wei g ht ( ±1 0 k g ), a ge ( ± 1 0 years), a n d se x t o 
s u bjects wit h he patic i m pair me nt , as far as practicall y p ossi ble.
S u bjects will u n der g o a scree ni n g e xa mi nati o n wit hi n 2 8 da ys pri or t o e nr oll me nt , c hec k i n t o t he cli nical researc h 
u nit ( C R U) o n Da y  -1, a n d recei ve a si n gle s u bc uta ne o us d ose of 5 m g tirze pati de o n Da y 1, f oll o wi n g a n o ver ni g ht 
fast of at least 8 h o urs.  S u bjects will re mai n at t he C R U u ntil disc har ge o n Da y 5 , a n d ret ur n t o t he C R U o n Da ys 8 
a n d 1 5 f or P K bl o o d sa m pli n g a n d ot her st u d y pr oce d ures . Eac h s u bje ct will be re q uire d t o ret ur n t o t he C R U f or a 
f oll o w-u p visit a n d fi nal P K bl o o d sa m ple c ollecti o n at least 2 8 da ys p ost d ose .  
Tre at me nt Ar ms a n d Pl a n ne d D ur ati o n f or a n I n di vi d u al S u bject :  
S u bjects will be e nr olle d wit hi n t he f oll o wi n g gr o u ps :
Gr o u p 1: at least 6 s u bjects a n d u p t o 1 2 s u bjects wit h n or mal he patic f u ncti o n ( C o ntr ol).

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 9
L Y 3 2 9 8 1 7 6
Gr o u p 2:
at least 6 s u bjects wit h mil d he patic i m pair me nt (C hil d P u g h [ C P] A).
Gr o u p 3: at least 6 s u bjects wit h m o derate he patic i m pair me nt (C P B).
Gr o u p 4: u p t o 6 s u bjects wit h se vere he patic i m pair me nt (C P C).
Eff orts will be ma de t o ac hie ve 6 c o m pleters wit h se vere he patic i m pair me nt ( Gr o u p 4) ; h o we ver, ac k n o wle d gi n g 
t he diffic ult y i n recr uiti n g t his s u bject p o p ulati o n, 2 t o 3 s u bjects wit h se vere he patic i m pair me nt ma y be a n 
acce pta ble tar get.
S u bjects wit h n or mal he patic f u ncti o n ca n n ot be matc he d t o m ore t ha n 1 he paticall y -i m paire d s u bject wit hi n a n 
i m pair me nt gr o u p; h o we ver, s u bjects wit h n or mal he patic f u ncti o n ma y be matc he d t o 1 s u bject fr o m m ore t ha n 
1 he patic i m pair me nt gr o u p , t heref ore re q uiri n g fe wer s u bjects t o be e nr olle d t o Gr o u p 1 ( mi ni m u m of 6). S u bjects 
m a y  be re place d at t he discreti on of t he i n vesti gat or i n disc ussi o n wit h t he s p o ns or .
T he t otal d urati o n of st u d y partici pati o n f or eac h s u bject (fr o m scr ee ni n g t hr o u g h foll o w - u p visit ) is a ntici pate d t o be 
a p pr o xi matel y 8 wee ks.
N u m ber of S u bjects :  
U p t o 3 0 s u bjects ma y be e nr olle d t o ac hie ve t he tar get mi ni m u m n u m ber of c o m pleters i n eac h of t he 4 st u d y 
gr o u ps.
St atistic al A n al ysis:
P har mac o ki netic :  Bl o o d sa m ples will be c ollecte d f or t he meas ure ment of tirze pati de c o nce ntrati o ns, usi n g 
vali date d li q ui d c hr o mat o gra p h y ta n d e m mass s pectr o metr y met h o ds.  P har mac o ki netic para meter esti mates f or 
tirze pati de 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.  T he pri mar y para meters a nal yze d 
will be ma xi m u m o bser ve d dr u g c o nce ntrati o n ( C ma x ) a n d area u n der t he dr u g c o nce ntrati o n -ti me c ur ve fr o m zer o 
t o i nfi nit y (A U C [ 0-∞]).  Ot her n o nc o m part me ntal para meters ma y be re p orte d as a p pr o priate.  
T he pri mar y P K a nal ysis is t he e val uati o n of l o g -tra nsf or me d A U C ( 0-∞) a n d C ma x usi n g a n a nal ysis of c ovaria nce 
( A NC O V A) m o d el wit h he patic f u ncti o n gr o u p as a fi xe d fact or a n d b o d y wei g ht as a c o variate .  T he ge o metric 
least s q uares mea ns f or eac h gr o u p, ge o metric least s q uare s mea n rati o s bet wee n eac h he patic i m pair me nt le vel 
vers us t he c o ntr ol gr o u p, a n d t he c orres p o n di n g 9 0 % c o nfi de nce i nter vals will be esti mate d fr o m t he A N C O V A 
m o del .  I n t he e ve nt of d ose a dj ust me nt base d o n t he i nteri m a nal yses res ults, d ose n or malize d P K para meters ma y 
be use d i n t he a b o ve m o del.   T he a nal ysis of t ma x will be base d o n a n o n para metric met h o d.  Me dia ns a n d 
differe nces i n me dia ns f or he patic f u ncti o n gr o u ps a n d t he p -val ue fr o m a Wilc o x o n ra n k s u m test will be prese nte d .  
T he relati o ns hi p bet wee n t he P K para meters a n d C hil d -P u g h Classificati o n para meters (ser u m al b u mi n 
c o nce ntrati o n , t otal bilir u bi n c o nce ntrati o n, a n d pr ot hr o m bi n ti me) will be assesse d gra p hicall y .  T he P K para meters 
A U C ( 0-∞), Cma x , a n d a p pare nt cleara nce will be pl otte d a gai nst eac h C hi l d-P u g h Classificati o n para meter 
se paratel y.  
A d diti o nal P K para meters ma y be a nal yze d if dee me d a p pr o priate f oll o wi n g a re vie w of t he data .
Safet y :  All i n vesti gati o nal pr o d uct a n d pr ot oc ol pr oce d ure a d verse e ve nts will be liste d a n d, if t he fre q ue nc y of 
e ve nts all o ws, safet y data will be s u m marize d usi n g descri pti ve met h o d ol o g y.  

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 1 0
L Y 3 2 9 8 1 7 6
2. S c h e d ul e of A cti viti e s

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 1 1
L Y 3 2 9 8 1 7 6
St u d y Sc he d ule Pr ot oc ol I 8 F-M C -G P G Q
Scree ni n g
St u d y D a ys
F oll o w -u p 
or E D c
C o m me nts
Pr oce d ure
D- 2 9 t o D - 2  
D- 1
D 1  
D 2
D 3
D 4
D 5
D 8
D 1 5
I nf or me d C o nse nt
X
S u bject A d missi o n t o 
C R U
X
Tirze pati de
A d mi nistrati o n
X
( 0 h o ur)
St u d y dr u g will be a d mi nistere d after a n o ver ni g ht fast 
of at least 8 h o urs.
S u bject Disc har ge 
fr o m C R U
X
S u bjects ma y be re q uire d t o sta y l o n ger i n t he C R U at 
t he i n vesti gat or’s discreti o n f or safet y m o nit ori n g.
O ut patie nt Visit
X
X
X
X
Me dical Hist or y
X
P h y sical E xa mi nati o n
X
X
X
X
X
After scree ni n g, me dical assess me nt o nl y perf or me d t o 
i ncl u de me dical re vie w a n d tar gete d e xa mi nati o n, as 
a p pr o priate.
Wei g ht
X
X
X
Hei g ht
X
Te m perat ure
X
X
Ur i ne Dr u g Scree n
X
X
X
X
Et ha n ol Testi n g
X
X
X
Safet y 1 2 -lea d E C G 
( h o urs)
X
Pre d ose
4 8
X
X
Si n gle E C G will be c ollecte d.  E C Gs m ust be rec or de d 
bef ore c ollecti n g a n y bl o o d sa m ples.  S u bjects m ust be 
s u pi ne f or a p pr o xi matel y 5 t o 1 0 mi n utes bef ore E C G 
c 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.
S u pi ne Vital Si g ns 
( h o urs)a
X
X
Pre d ose,
1 2
2 4
4 8
7 2
9 6
X
X
X
A d diti o nal t i me p oi nts ma y be a d de d, if warra nte d a n d 
a gree d u p o n bet wee n Lill y a n d t he i n vesti gat or.
Cli nical La b orat or y 
Tests b
X
X
X
X
X
X
X
See A p pe n di x 2 f or details. Da y -1 sa m ples ma y be 
c ollecte d bet wee n Da y -4 t o Da y - 1, pr o vi de d t hat t he 
res ults are re vie we d pri or t o act ual d osi n g o n Da y 1.
C hil d -P u g h 
Classificati o n
X
X
Pre g na nc y Test
X
X
X
X
Fe male s u bjects o nl y.  See A p pe n di x 2 f or details.
A Es/ C o nc o mita nt 
Me dicati o ns
X
X
X
X
X
X
X
X
X
X
P har mac o ge n etic 
Sa m ple
Pre d ose
Si n gle sa m ple f or p har mac o ge netic a nal ysis.

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 1 2
L Y 3 2 9 8 1 7 6
Scree ni n g
St u d y D a ys
F oll o w -u p 
or E D c
C o m me nts
Pr oce d ure
D- 2 9 t o D - 2  
D- 1
D 1  
D 2
D 3
D 4
D 5
D 8
D 1 5
I m m u n o ge nicit y
( h o urs)
Pre d ose
X
X
W here a p plica ble, c ollecti o n ti mes s h o ul d matc h wit h
P K sa m pli n g ti me p oi nts.  
I n t he e ve nt of dr u g h y perse nsiti vit y reacti o ns 
(i m me diate or n o n-i m me diate), sa m ples will be 
c ollecte d as cl ose t o e ve nt o nset as p ossi ble, at e ve nt 
res ol uti o n, a n d 3 0 ( ± 3) d a ys f oll o wi n g t he e ve nt.  
S u bjects wit h T E A D A at f oll o w -u p/ E D will u n der g o 
a d diti o nal f oll o w-u p.  See Secti o n 9. 6. 1 f or details.
Bl o o d G l uc ose 
M o nit ori n g
( h o urs)
Pre d ose,
8 , 1 2
2 4 , 
3 6
4 8
7 2
9 6
X
X
X
Perf or me d usi n g a be dsi de gl uc ose m o nit or.  A d diti o nal 
meas ure me nts ma y be ta ke n at t he discreti o n of t he 
i n vesti gat or as cli nicall y i n dicate d.
P K Sa m pli n g ( h o urs)
Pre d ose,
8 , 1 2 
2 4
4 8
7 2
9 6
1 6 8
3 3 6
X
T he e xact ti me of sa m pli n g m ust be rec or de d.
A b bre viati o ns:  A E = a d verse e ve nt; C R U = cli nical researc h u nit; D = da y; E C G = electr ocar di o gra m; E D = earl y disc o nti n uati o n; P K = p har mac o ki netic(s); 
T E A D A = treat me nt -e mer ge nt a nti dr u g a nti b o dies.  
N ote:  All sa m pli n g ti mes are gi ve n relati ve t o d osi n g ( Ti me 0 h o ur) wit h tirze pati de ( pre d ose or h o urs p ost d ose).
If m ulti ple pr oce d ures ta ke place at t he sa me ti me p oi nt, t he f oll o wi n g or der of t he pr oce d ures s h o ul d be use d:  E C Gs, vital si g ns, cli nical la b orat or y sa m ple, P K 
sa m ple (rec or d of act ual P K sa m pli n g ti me is t he pri orit y), i m m u n o ge nicit y, bl o o d gl uc ose a n d p har mac o ge netic sa m ple.
a
S pecifie d ti mes are a p pr o xi mate a n d act ual ti mes will be rec or de d.  Act ual ti me s h o ul d n ot e xcee d 1 h o ur pri o r t o d osi n g f or t he pre d ose assess me nt .
b
Scree ni n g sa m ple a n d a n y u nsc he d ule d sa m ples f or i m me diate safet y assess me nts ma y be perf or me d b y t he l oc al la b orat or y affiliate d wit h t he sites.  All ot her 
sc he d ule d cli nical safet y la b orat or y sa m ples will be assa ye d b y a ce ntral la b orat or y f or st u d y re p orti n g p ur p ose.
c
At least 2 8 da ys p ost d ose or wit hi n 7 t o 1 4 da ys u p o n c o nfir mati o n of earl y disc o nti n uati o n.

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 1 3
L Y 3 2 9 8 1 7 6
3. I ntr o d u cti o n
3. 1.
St u d y R ati o n al e
T irze patide ( L Y 3 2 9 8 1 7 6) is a d ual  a g o nist of gl uc ose -de pe n de nt i ns uli n otr o pic p ol y pe pt i de 
( GI P) a n d gl uca g o n-li ke pe pti de-1 ( G L P -1) rece pt ors bei n g de vel o pe d f or t he treat me nt of t ype 2 
di a betes mellit us ( T 2 D M).  As t he patie nt p o p ulati o n f or tirze pati de ma y i ncl u de patient s wit h 
he pat ic i m pair me nt, it is i m p orta nt t o ascertai n w het her tirze pati de ca n be safel y prescri be d t o 
t his p o p ulat i on wi t ho ut d ose a dj ust me nt , o nce mar kete d. Ti rze pati de is a s y nthet ic pe pti de 
c o nju gate d t o a C 2 0 fatt y  di-aci d moi et y a n d is pres u me d t o be de gra de d i nt o c o m p o ne nt a mi n o 
acids b y pr otei n cata b olis m pat h wa ys.  It is n ot e x pecte d t o be bi otra nsf or me d b y  dr u g 
meta b o lizi n g e nz y mes. H o we ver, t he fatt y aci d c o m p o ne nt is e x pecte d t o bi n d t o al b u mi n, 
t here b y lea di n g t o a pr ol o n ge d half-life, w hic h s u p p orts a o nce wee kl y d osi n g re gi me n. Al b u mi n 
c o nce ntrati o n i n he pat ic i m paire d s u bjects ca n be l o wer t ha n t hat see n i n c o ntr ol s u bjects.
T he li ver pla ys a ce ntral r ole i n gl uc ose meta b o lism.  Al m o st all patient s wit h cirr h osis are 
i ns uli n-resista nt, 6 0 % t o 8 0 % are gl uc ose i nt olera nt, a n d a b o ut 2 0 % de vel o p dia betes [H o n da F 
et al 2 0 1 8].  T he mai n feat ure of bl o o d gl uc ose d y na mics i n patie nts wit h c hr o nic li ver disease 
(C L D ) is mar ke d bl o o d gl uc ose fl uct uati o ns, s uc h as p ost pra n dial h y per gl yce mia a n d 
h y p o gl yce mia. T o a d dress t his iss ue, re g ular blo o d gl uc ose m o nit ori n g has bee n i ncl u de d i n t he 
S c he d ule of A ct i vities. A d dit i onall y , St u d y  I 8 F-M C -G P G Q ( G P G Q) will e val uate t he 
p har mac o ki net ics ( P K) of  tirze pati de i n s u bjects with he patic i m pair me nt c o m pare d t o healt h y 
c o ntr ol s u bjects t o i n vesti gate t he i m pact of he patic i m pair me nt, if a n y, o n t he P K pr ofile of  
tirze pati de.
3. 2.
B a c k gr o u n d
Ti rze patid e is bei n g de vel o pe d as a t hera p y  t o i m pr o ve gl yce mic c o ntr ol in a d ults wit h T 2 D M as 
a n a dj u nct t o diet a n d e xercise. Ti rze pati de has a g o ni st acti vit y at b ot h t h e GI P a n d G L P - 1 
rece pt ors. As a d ual a g o nist, tirze pati de c o m bi nes t he si g nali n g of eac h rece pt or f or i m pr o ve d 
gl yce mic c o ntr ol .  B y  virt u e of bei n g a d ual a g o nist i ncreti n mi met ic, tirze pati de has t he p ote ntial 
of  reac hi n g hi g her efficac y in tar get ti ss ues s uc h as t he i ns uli n-pr o d uci n g pa ncreat ic ß- cells t hat 
e x press b ot h GI P rece pt ors a n d G L P -1 rece pt ors bef ore reac hi n g its t hera pe utic li mitati o n.
Ti rze patid e ma y attai n a d dit i onal efficac y  b y recr uitin g m eta b o licall y acti ve tiss ues n ot tar gete d
b y classical G L P -1 a nal o gs (f or e xa m ple, a di p ose tiss ue as i n dicate d b y  t he o bser vati on of
i ncrease d e ner g y utilizati o n a n d res ulti n g b o d y wei g ht loss).
Ti rze patid e is a 3 9-a mi n o aci d s y nt het ic pe pti de.  Its str uct ure is base d o n t he GI P se q ue nce a n d
i ncl u des a C 2 0 fatt y di-a ci d moi et y t hat pr olo n gs t he d urati o n of  acti on .  It has a c he mical
str uct ure a n d p har mac olo gi c pr ofile t hat is disti nct fr om t he G L P -1 rece pt or a g o nists d ue t o t he
a d ditio n of  GI P, w hic h is u niq u e a m o n g t he m ar kete d increti n mi met ics. It is a d mi nistere d o nce
wee kl y b y  s u bc uta ne o us ( S C) i njecti on.   
Res ults fr o m 4 tirze pati de cli nical trials t hat ha ve c o m plete d d osi n g are a vaila ble, i ncl u di n g t w o 
P hase 1 st u d ies, St u d y I 8 F-M C -G P G A ( St u d y  G P G A) a n d St u d y I 8 F-J E-G P G C ( St u d y  G P G C), 

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 1 4
L Y 3 2 9 8 1 7 6
a n d t w o P hase 2 st u dies, St u d y I 8 F-M C -G P G B ( St u d y G P G B) a n d St u d y  I 8 F-M C -G P G F 
(St u d y G P G F).
St u d y  G P G A was a c o m bi nati on si n gle -asce n di n g d ose ( S A D) a n d a m ult i ple asce n di n g-d ose 
( M A D) st u d y in healt h y s u bjects ( Part A a n d B) a n d a m ulti-d ose st u d y  in pat ient s wit h T 2 D M 
( Part C).  T he st u d y i n vesti gate d t he safety,  t olera bilit y, P K, a nd p har mac o d y na mics ( P D) of 
tirze pati de a d mi nistere d as S C i njecti ons.  Wee kl y d oses of ti rze patide ra n ge d fr o m  0. 2 5 m g t o 
8 m g i n t he S A D. Ma xi m u m t olerate d
d ose i n healt h y  s u bjects foll o wi n g si n gle -d ose 
a d mi nistrati o n was 5 m g. I n t he 4-wee k M A D part of t he st u d y , d oses u p t o 1 0 mg i n heal t h y 
s u bjects or 1 5 m g i n patient s wit h T 2 D M were attai ne d via a d ose escalati on a p pr oac h. A d ose 
of  1 5 mg ti rze pati de attai ne d b y fast d ose escalati o n o ver 4 wee ks ( 5/ 5/ 1 0/ 1 5 m g), w hile 
c o nsi dere d t o be safe, was ass ociate d wit h hi g h i nci de nce o f gastr oi ntesti nal ( GI ) e ve nts.  
Ter mi nal half -life was esti mate d t o be a p pr o xi matel y 5 da ys, t h us s u p p orti n g a o nce wee kl y
d osi n g re gi me n , wi t h ma xi m u m o bser ve d dr u g c o nce ntrati o n ( C ma x) occ urrin g bet wee n 2 4 t o 7 2 
h o urs p ost d ose, a n d stea d y-state tirze patide e x p os ures e x pecte d t o be attai ne d wi t hi n 4 wee ks o f 
o nce wee kl y d osi n g. St u d y  G P GC was a M A D st u d y  t o i n vesti gate t he safety,  t olera bilit y, P K ,
a n d P D i n Ja pa nese patient s wit h T 2 D M.  O verall, tirze pat i de P K para meters i n Ja pa nese patie nts 
wi t h T 2 D M a p peare d c o m para ble t o c orres p o n di n g para meters fr o m n o n-Ja pa nese patient s wit h 
T 2 D M o bser ve d i n St u d y  G P G A.
Gas tr oi ntesti nal a d verse e ve nts ( A Es ) ( na usea, v o miti n g, diarr hea, a b d omi nal diste nsi o n) a n d 
decrease d a p pet ite were t he m ost fre q ue nt l y re p orte d e ve nts b y b ot h healt h y s u bjects a n d pat ient s 
wi t h T 2 D M a n d were d ose relate d i n t he t w o P hase 1 st u dies. A d ose -de pe n de nt i ncrease i n 
heart rate was detecte d f or b ot h healt h y s u bjects a n d patie nts wit h T 2 D M w h o recei ve d 
tirze pati de, si milar t o w hat was o bser ve d wit h selecti ve G L P- 1 rece pt or a g o nists.  A fe w s u bjects 
e x perie nce d tra nsie nt ele vat i ons i n li pase a n d/ or a m ylase le vels, b ut t hese e pis o des were n ot 
ass ociat e d wit h a n y rele va nt cli nical o utc o mes. T here were n o ot her cli nicall y rele va nt safet y 
o bser vat i ons i n t he P hase 1 st u dies.
P hase 2 st u die s e val uate d t he efficac y, t olera bilit y, a n d safety of  5 d oses of tirze pati de ( 1 mg, 
5 m g, 1 0 m g, 1 2 m g a n d 1 5 mg) i n patie nts wit h T 2 D M wi t h ina de q uate gl yce mic c o ntr ol o n diet 
a n d e xercise al o ne or o n a sta ble d ose of met f or mi n m o n ot hera p y u p t o 2 6 wee ks .  R es ults 
d e m o nstrate d t hat tirze pati de i n d oses bet wee n 5 m g a n d 1 5 m g pr o vi des a cli nicall y mea ni n gf ul 
gl uc ose -l oweri n g a n d b o d y  wei g ht-l oweri n g efficac y .  Si milar t o data fr o m St u d y G P G A, most 
of  t he A Es ass ociate d wit h tirze pati de were GI-relate d, c o nsisti n g ma i nl y of na usea, v omit i n g, 
a n d diarr hea a n d were d ose -de pe n de nt.  I n a d diti o n, patie nts treate d wit h t irze pat i de re p orte d 
A Es of decrease d a p petite m ore fre q ue ntl y t ha n patie nts w h o recei ve d 1. 5 -m g d ose of 
d ul a gl ut i de, a selecti ve G L P- 1 rece pt or a go ni sts.
A n i nte grate d cli nical a n d P K/ P D assess me nt of t he GI t olera bilit y A Es, a n d t he i m pact of d ose 
escalat i on re gi me ns i n t he P hase 2 trials, s u g geste d t hat d osi n g al g orit h ms starti n g at a l o w d ose 
of  2. 5 mg acc o m pa nie d b y d ose escalat i on of 2. 5 m g i nc re me nts e ver y 4 wee k s w o ul d per mi t 
ti me f or de vel o p me nt of t olera nce t o GI e ve nts a n d are pre dicte d t o mi ni mize GI t olera bilit y 
c o ncer ns.

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 1 5
L Y 3 2 9 8 1 7 6
O verall, the safet y a n d t olera bilit y, a n d P K/ P D pr ofiles of tirze patid e s u p p ort f urt her 
de vel o p me nt of tirze pati de i n patient s wit h T 2 D M.
3. 3.
B e n efit/ Ri s k A s s e s s m e nt
Ris ks of tirze pati de ha ve bee n c o nsiste nt wit h ris ks ass ociate d wit h ot her G L P- 1 rece pt or 
a g o nists c urre ntl y mar kete d.  P ote ntial ris ks i ncl u de, b ut are n ot li mite d t o, GI effects, ac ute 
pa ncreat itis, i ncreases i n heart rate, a n d h y p o gl yce mic e ve nts ( G L P-1 rece pt or a g o nist class 
effect) .
N o cli nicall y  sig nifica nt safet y or t ol era bilit y c o ncer ns ha ve bee n i de ntifie d d uri n g cli nical 
i n vesti gati on of t irze pat i de u p t o t he hi g hest si n gle-d ose l e vel of 8 mg or m ul ti ple d oses, w he n 
titrate d u p t o 1 5 m g.  Base d o n t his i nf or mati on, a si n gle 5 -m g d ose t o be a d mi nistere d i n 
St u d y G P G Q i s reas o na bl y a ntici pate d t o be t olera ble i n s u bjects wit h he patic i m pair me nt a n d i n 
c o ntr ol health y s u bjects.
S u bjects will resi de i n t h e cli nical researc h u nit ( C R U) u n der cl ose m o nit ori n g f or 5 da ys, wit h 
t he o ptio n of  r e mai ni n g i n pat ient  for l o n ger if dee me d necessar y  b y t he i n vesti gat or f or 
a d ditio nal  s af et y mo ni t ori n g; t he s u bject’s disc har ge fr o m t he C R U will be per i n vesti gat or 
di s cr etio n aft er me dical assess me nts f or safet y .  A n i nteri m a nal ysis f or safety,  t olera bilit y, a n d 
P K data is pla n ne d t o deter mi ne w het her a n y d ose a dj ust me nt is nee de d (see Sect i on 1 0. 3. 5 ).
T here i s n o a nticipate d t hera pe uti c be nefit for t he s u bjects.
M ore i nf or mat i on a b o ut t he k n o w n a n d e x pecte d be nefits, ris ks, seri o us a d verse e ve nts ( S A Es) ,
a n d reas o na bl y a nt ici pate d A Es of  tirze pati de are t o be f o u n d i n t he I n vesti gat or’s Br oc h ure (I B).  

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 1 6
L Y 3 2 9 8 1 7 6
4. O bj e cti v e s a n d E n d p oi nt s
T a ble G P G Q . 1 s h o ws t he o bjecti ves a n d e n d p oi nts of t he st u d y.
T a bl e G P G Q . 1.
O bj e cti v e s a n d E n d p oi nt s
O bjecti ves
E n d p oi nts
Pri m ar y
T o e val uate t he P K of a si n gle S C d ose of 
tirze pati de i n s u bjects wit h mil d, m o derate, 
a n d se vere he pat ic i m pair me nt c o m pare d t o 
c o ntr ol s u bjects wit h n or mal he p atic f u nct i on.
A U C ( 0-∞) a n d C m a x
Sec o n d ar y
T o e val uate t he safety a n d t olera bilit y of a 
si n gle S C d ose of tirze pati de i n s u bjects wit h 
mil d, m o derate, a n d se vere he pat ic 
i m pair me nt c o m pare d t o c o ntr ol s u bjects wit h 
n or m al he pat ic f u ncti on.
I nci de nce of A Es
E x pl or at or y
T o e val uate t he f or mat i on of A D A t o 
tirze pati de after a si n gle 5-m g S C d ose 
a d mi nistere d t o s u bjects wit h mil d, m o derate, 
or se vere he patic i m pair me nt c o m pare d t o 
c o ntr ol s u bjects wit h n or mal he p atic f u nct i on.
Prese nce of A D A t o tirze pati de
A b br e viati o ns:  A D A = a nti dr u g a nti b o dies; A E = a d verse e ve nt; A U C ( 0-∞) = area u n der t he dr u g 
c o nce ntrati o n-ti me c ur ve fr o m zer o t o i nfi nit y; Cma x = ma xi m u m  obser ve d dr u g c o nce ntrati o n; P K = 
p har mac o ki netics; S C = s u bc uta ne o us.

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 1 7
L Y 3 2 9 8 1 7 6
5. St u d y  D e si g n
5. 1.
O v er all D e si g n
T his will be a mul tice nter, parallel, si n gle-d ose, o pe n -la bel, si n gle-p eri o d st u d y  of tirze pati de i n 
s u bjects wit h n or mal he pat ic f u ncti o n a n d s u bjects wit h mil d, m o derate, a n d se vere he patic 
i m pair me nt. S u bjects w h o ha ve a c o nc o mita nt T 2 D M dia g n osis will n ot be s pec ificall y 
e xcl u de d.
S u bjects will be e nr o lle d wit hi n t he f oll owi n g gr o u ps:

Gr o u p 1:  at  least 6 s u bjects a n d u p t o 1 2 s u bjects wit h n or mal he patic f unct i on ( C o ntr ol).

Gr o u p 2:  at  least 6 s u bjects wit h mil d he pat ic i m pair me nt ( C hil d P u g h [ C P] A).

Gr o u p 3: at  least 6 s u bjects wit h m o derate he patic i m pair me nt ( C P B).

Gr o u p 4:  u p t o 6 s u bjects wit h se vere he patic i m pair me nt ( C P C).  
Eff orts will be ma de t o ac hie ve 6 c o m pleters wi t h se vere he patic i m pair me nt ( Gr o u p 4);
h o we ver, ac k n o wle d gi n g t he diffic ult y i n recr uitin g t his s u bject p o p ulat i on, 2 t o 3 s u bjects wit h 
se vere he patic i m pair me nt ma y be a n acce pta ble tar get.
T he C hil d -P u g h classificat i on is descri be d i n Sect i o n 5. 1. 1 .  
S u bjects e nr o lle d i n Gr o u p 1 ( n or mal he patic f u ncti on) will be matc he d b y w ei g ht ( ±1 0 k g ), a ge 
(± 1 0 y ears) , a nd se x t o s u bj ects i n Gr o u ps 2 t hr o u g h 4, as far as pract icall y p ossi ble.  S u bjects 
wi t h n or mal h e p atic fu nct i on ca n n ot be matc he d t o m ore t ha n 1 he pat icall y-i m paire d s u bject 
wi t hi n a n i m pair me nt gr o u p; h o we ver, s u bjects wit h n or mal he patic f unct i on ma y be matc he d t o 
1 s u bject fr o m m o re t ha n 1 he patic i m pair me nt gr o u p, t heref ore re q uiri n g fe wer s u bjects t o be 
e nr o lle d t o Gr o u p 1 ( mi ni m u m o f 6).   S u bjects w h o wit h dra w bef ore c o mplet i n g all st u d y 
pr oce d ure s ma y be re pl ace d at t he discretio n of  t he i n vesti gat or i n disc ussi on wi t h t he s p o ns or.
S u bjects will u n der g o a scree ni n g e xa mi na tio n wi t hi n 2 8 da ys pri or t o e nr oll me nt , c hec k i n t o t he 
C R U o n Da y - 1, a n d recei ve a si n gle S C d os e of 5 m g tirze pati de o n Da y 1 , fol l owi n g a n 
o ver ni g ht fast of at least 8 h o urs .  S u bjects will re mai n at t he C R U u nt il disc har ge o n Da y 5, a n d 
ret ur n t o t he C R U o n Da y s 8 a n d 1 5 f or P K bl o o d sa m pli n g a n d ot her st u d y pr oce d ures.  Eac h 
s u bject will be re q uire d t o ret ur n t o t he C R U f or a f o ll ow- u p visit a n d fi nal P K bl o o d sa m ple 
c ollect i on at least 2 8 da ys p ost d ose .
P har mac o ki net ic bl o o d sa m pli n g a n d safet y assess me nts, i ncl u di n g vit al sig n meas ure me nt, 
p h ysical e xa mi nat i on, cli nical la b orat or y  tests, electr ocar di o gra ms ( E C Gs) , a n d A E rec or di n g,
will be perf or me d acc or di n g t o t he Sc he d ule o f Acti vit ies ( Secti o n 2 ).
S u bjects wit h n or mal he pat ic f unct i on a n d wit h mil d a n d m o derate he patic i m pair me nt ( Gr o u ps 1 
t o 3 ) ca n be d ose d c o nc urre ntl y (Fi g ure G P G Q . 1).  D osi n g of t he first s u bject i n Gr o u p 4 (se vere 
he pat ic i m pair me nt) ma y pr ocee d o nl y after sat isfact or y re vie w of safety , t olera bilit y, a n d P K
data fr o m  at least 2 s u bjects i n Gr o u p 2 (mil d he patic i m pair me nt), at least 2 s u bjects i n Gr o u p 3 
(m o d erate he patic i m pair me nt ), a n d at least 2 s u bjects i n Gr o u p 1 (a p pr o priate matc he d-c o ntr ol 

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 1 8
L Y 3 2 9 8 1 7 6
s u bjects wit h n or mal he pat ic f u ncti o n).  B ase d o n c o nti n u o us re vie w of  safety a n d t olera bilit y 
data, t he d ose of tir ze pat i de ma y be re d uce d t o 2. 5 m g for t he re mai n der of s u bjects i n Gr o u ps 2
a n d 3 ( mil d a n d m o derate i m pair me nt) a n d all s u bjects i n Gr o u p 4 (se vere i m pair me nt), as well 
as f or c o ntr ol s u bjects i n Gr o u p 1.
N ote:  d osi n g of t he first s u bject wit h se vere he patic i m pair me nt ( Gr o u p 4) ma y pr ocee d o nl y after satisfact or y re vie w of safet y ,
t olera bilit y a n d P K data fr o m at least 2 s u bjects wit h mil d he patic i m pair me nt ( Gr o u p 2), a n d at least 2 s u bjects wit h m o derate 
he patic i m pair me nt ( Gr o u p 3) , a n d at least 2 s u bjects i n Gr o u p 1 (a p pr o priate matc he d-c o ntr ol s u bjects wit h n or mal he patic 
f u ncti o n).
Fi g ur e G P G Q .1.
Ill ustr ati o n of st u d y d e si g n f or Pr ot o c ol I 8 F-M C -G P G Q .
T he t otal  d uratio n of  st u d y p artici p atio n f or eac h s u bject (fr o m scree nin g t hr o u g h fol l ow -u p 
visit) is a nt ici pate d t o be a p pr o xi matel y 8 wee ks.
5. 1. 1.
C hil d -P u g h Cl a s sifi c ati o n
He pati c i m pair me nt is classifie d usi n g t he C hil d-P u g h s yste m.  T he classificat i on para meters will 
be c o llecte d at scree ni n g t o deter mi ne t he C hil d-P u g h class f or eac h s u bject pri or t o tirze pati de
d ose a d mi nistrati o n ( Ta ble G P G Q. 2 ).

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 1 9
L Y 3 2 9 8 1 7 6
T a bl e G P G Q. 2.
C hil d -P u g h Cl a s sifi c ati o n
  P ar a meter
1 p oi nt
2 p oi nts
3 p oi nts
Ser u m Al b u mi n ( g/ d L)
> 3. 5
2. 8 t o 3. 5
< 2. 8
T otal Bilir u bi n ( m g/ d L)
< 2
2 t o 3
> 3
Pr ot hr o m bi n Ti me (sec. pr ol o n ge d)
or
Pr ot hr o m bi n Ti me I N R
< 4
< 1. 7
4 t o 6
1. 7 t o 2. 3 
> 6
> 2. 3
Ascites a
A bse nt
Sli g ht
M o derate
He patic E nce p hal o pat h y b
N o ne
1 or 2
Or c urre nt treat me nt 
wit h lact ul ose or 
ne o m yci n or  ot her 
a nti bi otics
3 or 4
Or c o nti n ue d e n ce p hal o pat h y 
w h ile recei vi n g treat me nt wit h 
lact ul ose a n d/ or ne o m yci n or 
ot her a nti bi otics
C hil d -P u g h A ( mil d):  5 or 6 p oi nts; C hil d -P u g h B ( m o der ate):  7 t o 9 p oi nts; C hil d -P u g h C (se vere):  1 0 t o 
1 5 p oi nts.  A da pte d fr o m C hil d a n d T urc otte ( 1 9 6 4) a n d P u g h et al. ( 1 9 7 3).
A b bre viati o ns:  I N R = i nter nati o nal n or malize d rati o.
a
A bse nt:  n o detecta ble ascites.
Sli g ht:  n o diste nsi o n; ascites are o nl y detecta ble b y ultras o u n d e xa mi nati o n.
M o derate:  ascites ca usi n g m o derate s y m metrical diste nsi o n of t he a b d o me n.
b
Gra de 0:  n or mal c o nsci o us ness, pers o nalit y, ne ur ol o gical e xa mi nati o n, electr oe nce p hal o gra m.
Gra de 1:  restless, slee p dist ur be d, irrita ble/a gitate d, tre m or, i m paire d ha n d writi n g, 5 c ycles per sec o n d wa ves.
Gra de 2:  let har gic, ti me -dis orie nte d , i na p pr o priate, asteri xis, ata xia, sl o w tri p hasic wa ves.
Gra de 3:  s o m n ole nt, st u p or o us, place -dis orie nte d, h y peracti ve refle xes, ri gi dit y, sl o wer wa ves.
Gra de 4:  u nr o usa ble c o ma, n o pers o nalit y/ be ha vi or, decere brate, sl o w 2 t o 3 c ycles per sec o n d delta acti vit y.
5. 2.
N u m b er of S u bj e ct s
U p t o 3 0 s u bjects ma y be e nr olle d t o ac hie ve t he t ar get mi ni m u m n u m ber of c om p leters i n eac h 
of  t he 4 st u d y gr o u ps .
Gr o u p 1:  at  least 6 s u bjects a n d u p t o 1 2 s u bjects wit h n or mal he patic f unct i on ( C o ntr ol).
Gr o u p 2:  at  least 6 s u bjects wit h mil d he patic i m pair me nt (C P A).
Gr o u p 3:  at  least 6 s u bjects wit h m o derate he patic i m pair me nt ( C P B).
Gr o u p 4:  u p t o 6 s u bjects wit h se ver e he pat ic i m pair me nt ( C P C).
Matc hi n g s u bjects wit h n or mal he pat ic f u ncti on will be e nr o lle d o n u p t o a o ne-t o-o ne basis; 
h o we ver, s u bjects wit h n or mal he p atic f u nct i on ma y b e m atc he d t o 1 s u bject fr o m m ore t ha n 1 
he pat ic i m pair me nt gr o u p, t heref ore re q uiri n g fe wer s u bjects t o be e nr olle d t o Gr o u p 1 
( mi ni m u m of 6).
Eff orts will be ma de t o i ncl u de a reas o n a ble n u m ber of s u bjects wit h se vere he pat ic i m pair me nt, 
ac k n o wled gi n g t hat recr uit me nt  of C P C s u bjects is diffic ult.  T he s p o ns or ma y elect t o c o m plete 
fe wer t ha n 6 s u bjects ( 2 t o 3 s u bjects) i n Gr o u p 4 if t he i n vesti gati ve sites ca n n ot recr uit 
s ufficie nt n u m bers f or t his gr o u p.  S u bjects ma y be re place d at t he discret i on of t he i n vesti gat or 
i n disc ussi on wi t h t he s p o ns or.

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 2 0
L Y 3 2 9 8 1 7 6
5. 3.
E n d of St u d y D efi niti o n
E n d of t he st u d y is t he date of t he last visit or l ast sc he d ule d pr oce d ure s h o w n i n t he Sc he d ule o f 
Act i vities (Secti o n 2 ) f or t he last s u bject.
5. 4.
S ci e ntifi c R ati o n al e f or St u d y D e si g n
T his st u d y  has bee n desi g ne d i n acc or da nce wit h t he F o o d a n d Dr u g A d mi nistrati o n ( F D A )
re g ulat or y g ui da nce f or t he st u d y of P K i n s u bjects wit h i m paire d he patic f u ncti on ( F D A 2 0 0 3).
T his st u d y  will b e o p e n-label as t he st u d y  e n d p oi nts are o bjecti ve rat her t ha n s u bjecti ve.
T h ose wi t h he patic i m pair me nt will be cate g orize d base d o n t he C hil d-P u g h classificat i on s yste m 
( Sectio n 5. 1. 1 ; C hil d a n d T urc otte 1 9 6 4; P u g h et  al. 1 9 7 3) f or he patic i m pair me nt ( Class A, B, or 
C) as rec o m me n de d b y t he F D A a n d i nter nat i onal g ui da nce d oc u m e nts.  As s u g geste d i n t he 
g ui da nce, t he c o ntr ol  gr o u p s h o uld be as si milar as p ossi ble t o t he he pat icall y-i m paire d gr o u p, 
a part fr o m he pat ic fu nct i on.  F or t his reas o n, s u bjects e nr olle d i n t he c o ntr ol gr o u p ( Gr o u p 1) 
will ha ve n or mal he patic f u nct i on a n d will be matc he d b y wei g ht ( ±1 0 k g ), a ge ( ± 1 0 years), a n d 
se x t o s u bjects i n Gr o u ps 2 t hr o u g h 4, w here p ossi ble.
5. 5.
J u stifi c ati o n f or D o s e
S u bc uta ne o us i nject i on is t he i nte n de d cli nical r o ute of a d mi nistrati o n.  R es ults fr o m 
St u d y G P G A i n dicate t he 5 -m g d ose was relat i vel y well t olerate d b y health y s u bjects a n d 
pati e nts wit h T 2 D M, a n d is e x pecte d t o be a cli nicall y mea ni n gf ul d ose .  D o ses hi g her t ha n 5 m g 
were ac hie ve d via titrati o n a n d a 5 -m g d ose was c o nsi dere d t he ma xi m u m t olerate d d ose w he n
a d mi nistere d as a si n gle d ose.
If t he i nteri m a nal ysis s h o ws t hat safety a n d t olera bilit y meas ures ma nifest at a hi g her t ha n 
e x pecte d rate, or if t he P K  a p pears t o be i nfl ue nce d b y he pat ic i m pair me nt a n d t he e x p os ure i n 
s u bjects wit h im pair me nt is n ota bl y  hi g her t ha n e x pecte d, a d ose re d uc tio n t o 2. 5 mg ma y be 
a d mi nistere d i n t he re mai n der of s u bjects i n Gr o u ps 2 a n d 3 ( mil d a n d m o derate i m pair me nt) a n d 
all s u bjects i n Gr o u p 4 (se vere i m pair me nt), as well as f or c o n tr ol s u bjects i n Gr o u p 1 (see 
Secti o n 1 0. 3. 5 ).

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 2 1
L Y 3 2 9 8 1 7 6
6. St u d y  P o p ul ati o n
T he cri t eria for e nr oll me nt m ust be f o ll owe d e x plici tly.   If a s u bject w h o d oes n ot meet 
e nr o ll me nt criteria or is i na d verte ntl y e nr olle d, t hat s u bject s h o ul d be disc o nti n ue d fr o m t he 
st u d y a n d Lill y or its desi g nee must be c o ntacte d.  Eli gi bilit y of  s u bjects for s t u d y e nr oll me nt 
will be base d o n t he res ults of a scree ni n g me dical hist or y , p h ysical e xa mi nati on, cli nical 
la b orat or y tests, a n d E C Gs.  T he nat ure of a n y c o n diti ons prese nt at t he ti me o f t he p h ysical 
e xa mi nat i on a n d a n y pre -e xist i n g c o n diti ons w ill be d oc u m e nte d.  
C hil d -P u g h cl assificat i on of he pat ic i m pair me nt will be base d o n t he scree ni n g data a n d 
c o nfir me d pri or t o d osi n g ( D a y - 1).  Scree ni n g f or all s u bjects ma y occ ur u p t o 2 8 da ys prior t o 
d osi n g of tirze pati de.  
I n Gr o u p 4 (se vere he patic i m pair me nt) he patic f u ncti on tests (al a ni ne a mi n otra nsferase [ A L T], 
as partate a mi n otra nsferase [ A S T], t otal bilir u bi n, a n d al kali ne p h os p hatase [ A L P]) a n d 
pr ot hr o m bi n t i me i nter natio n al  nor malize d rati o m ust be re peate d wit hi n 2 4 h o urs pri or t o d osi n g 
of tirze pati de as a n a d dit i onal safet y meas ure .  
Pr os pecti ve a p pr o val o f pr ot oc ol  de viatio ns t o recr ui t me nt a n d e nr o ll me nt criteria, als o k n o w n as 
pr ot oc ol  wai vers or e xe m pti ons, are n ot per mitte d.
6. 1.
I n cl u si o n Crit eri a
All s u bjects must m eet t he f oll o wi n g crit eria for e nr oll me nt (I ncl usi o n  Crit eria [ 1] t hr o u g h [ 6]).  
A d dit i onal s u b gr o u pi n gs of i ncl usi on cri t eria bel o w are s pecific t o t he s u bjects’ he patic f unct i on 
(I nclusi o n  Crit eria [ 7] t hr o u g h [ 1 2]) a n d dia betic stat us (I ncl usi o n Cri t eria [ 1 3] t hr o u g h [ 1 6]).
6. 1. 1.
I n cl u si o n Crit eri a f or All S u bj e ct s
[ 1]
male a n d fe male s u bjects ma y part ici pate i n t his st u d y
[ 1a] Male s u bjects:
Me n, re gar dless of t heir fertilit y stat us, wit h n o n-pre g na nt w o m e n of c hil d beari n g 
p ote nti al part ners m ust a gree t o ei t her re mai n a bsti ne nt (if t his is t heir preferre d 
a n d us ual lifest yle) or use c o n d o ms pl us o ne a d dit i o nal hi g hl y effecti ve (less t ha n 
1 % fail ure rate) met h o d of c o ntrace pti o n (s uc h as c o m bi nat i on oral  
c o ntrace pti ves, i m pla nte d c o n trace pti ves, or i ntra uteri ne de vice) or effecti ve 
met h o d of c o ntrace pti o n (s uc h as dia p hra g ms wit h s per mici de or cer vical s p o n ge) 
f or t he d uratio n of  t he st u d y a n d f or at least 3 mo nt hs after d osi n g.
o
Me n a n d t heir part ners ma y  c h o ose t o use a d o u ble-barri er met h o d of 
c o ntrace pti o n.  Barrier pr otecti o n met h o ds wit h o ut c o nc o mita nt use of a 
s per mici de are n ot a n effecti ve or acce pta ble met h o d of c o ntrace pti o n.  T h us, 
eac h barrier met h o d m ust i ncl u de use of a s per mici de.  It s h o ul d be n ote d ,
h o we ver , t hat t he use of male a n d fe male c o n d o ms as a d o u ble-barrier m et h o d 
is n ot c o nsi dere d acce pta ble d ue t o t he hi g h fail ure rate w he n t hese barrier 
met h o ds are c o m bi ne d.

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 2 2
L Y 3 2 9 8 1 7 6
o
P eri o dic a bst i ne nce (e g, cale n dar, o v ulati on, s y m pt ot her mal, p ost o v ul at i on
met h o ds), declarati o n of a bst i ne nce j ust f or t he d urati o n of a trial, a n d 
wi t hdra wal  are n ot acce pta ble met h o ds of c o ntrace pti o n.
Me n wi t h pre g na nt part ners s h o ul d 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 u nt il t he e n d of esti mate d rele va nt p ote ntial e x p os ure i n 
w o m e n of c hil d beari n g p otent ial.
Me n w h o are i n e xcl usi vel y sa me -se x relat i ons hi ps (as t heir preferre d a n d us ual 
lifestyle) are n ot re q uire d t o use c o ntrace pti o n.
Me n s h o ul d refrai n fr o m s per m d o nati on f or t he d uratio n of  t he st u d y a n d f or at 
least 3 m o nt hs after d osi n g .
[ 1 b] Fe male s u bjects:
W o me n of c hil d beari n g p ote n tial are e xclu d e d f r o m t he st u d y.
W o me n n ot of c hil d beari n g p ote ntial ma y partici pate a n d i ncl u de t h ose w h o are:
A.
i nfertile d ue t o s ur gical sterilizati on ( h ysterect o m y, bilateral o o p h ore ct o m y, or 
t u bal li gati on), c o n ge nital a n o ma l y s uc h as mulleria n a ge nesis; or
B.
p ost m e n o pa usal – defi ne d as eit her:
i.
A w o ma n at l east 5 0 years of a ge 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 eit her:
a)
cessat i on of me nses f or at least 1 y ear, or
b)
at least 6 mo nt hs of s p o nta ne o us a me n orr hea wit h a 
f ollicle-sti m ulati n g h or m o ne > 4 0 I U/ m L; or
ii.
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 
6 m o nt hs of s p o nta ne o us a me n orr hea; or
iii.
A w o ma n at l east 5 5 years of a ge wit h a dia g n osis of me n o pa use pri or t o 
starti n g h or m o ne re place me nt t hera p y.
[ 2]
are bet wee n t he a ges of 1 8 a n d 8 5 y ears, i ncl usi ve
[ 3]
are bet wee n t he b o d y  mass i n de x ( B MI ) of  1 9. 0 a n d 4 0. 0 k g/ m2, i ncl usi ve, at scree ni n g
[ 4]
ha ve ve n o us access s ufficie nt t o all o w bl o o d sa m pli n g as per t he p r ot oc ol
[ 5]
are relia ble a n d willi n g t o ma ke t he msel ves a vaila ble f or t he d urati o n of t he st u d y a n d 
are willi n g t o f o ll ow st u d y  pr oce d ures
[ 6]
ha ve gi ve n wri tte n i nf or me d c o nse nt a p pr o ve d b y Lill y a n d t he I nstituti o nal R e vie w 
B o ar d (IR B) g o ver ni n g t he site

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 2 3
L Y 3 2 9 8 1 7 6
6. 1. 2.
A d diti o n al I n cl u si o n Crit eri a f or C o ntr ol S u bj e ct s ( Gr o u p 1)
[ 7]
h ealt hy males or fe males as deter mi ne d b y me dical hist or y, p h ysical e xa mi nat i on, a n d 
ot her scree ni n g pr oce d ures, wit h cli nicall y n or m al he pat ic f uncti o n at scree ni n g
[ 8]
h a ve cli nical la b orat or y test res ults wit hi n n or mal refere nce ra n ge f or t he p o p ulati o n or 
i n vesti gat or site, or res ults wit h acce pta ble 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
[ 9]
h a ve n or mal bl o o d press ure ( B P ) a n d p ulse rate, as deter mi ne d b y t he i n vesti gat or
6. 1. 3.
A d diti o n al I n cl u si o n Crit eri a f or S u bj e ct s wit h Mil d t o S e v er e 
H e p ati c I m p air m e nt ( Gr o u p s 2 t o 4)
[ 1 0] are i n di vi d uals wit h he pat ic i m pair me nt classifie d as C hil d-P u g h sc ore A, B, or C 
( mil d, m o derate, or se vere i m pair me nt) ( Secti o n 5. 1. 1 ; C hil d a n d T urc otte 1 9 6 4; P u g h 
et al. 1 9 7 3), w h o are c o nsi dere d acce pta ble f or partici pati on i n t his st u d y b y t he 
i n vesti gat or.  S u bjects m ust ha ve a dia g n osis of c hr o nic he patic i m pair me nt 
( > 6 m o nt hs) per p h y sicia n dia g n osis a n d sta n dar d of care practice, wit h n o cli nicall y 
sig nifica nt c ha n ges wi t hi n 9 0 da ys pri or t o st u d y  dr u g a d mi nistratio n.  S u bj ects ma y 
ha ve mil d sta ble baseli ne me dical c o n dit i ons f or w hic h neit her t he c o n ditio n n or 
treat me nts recei ve d w o ul d ne gat i vel y i m pact t he healt h of t he s u bject or st u d y c o n d uct.
[ 1 1] cli nical la b orat or y test res ults wit h de viati ons t hat are j u d ge d b y t he i n vesti gat or t o be 
c o mpat i ble wit h t he he patic i m pair me nt of t he s ubject, or of n o a d dit i onal cli nical 
sig nifica nce f or t hi s st u d y
[ 1 2] ha ve acce pta ble B P a n d p ulse rate, as deter mi ne d b y t he i n vesti gat or
[ 1 3] n o si g nifica nt hi st or y of s p o nta ne o us or et ha n ol i n d uce d h y p o gl yce mia
6. 1. 4.
A d diti o n al I n cl u si o n Crit eri a f or S u bj e ct s wit h b ot h T 2 D M a n d 
H e p ati c I m p air m e nt
[ 1 4] h a ve T 2 D M c o ntr olle d wi t h diet or e xercise alo n e or o n sta ble d oses of metf or mi n f or 
at least 8 wee ks
[ 1 5] su bjects ta ki n g sta ble d oses of o ver -t he- c o u nter or prescri pt i on me d icati o ns (e g, 
a nt i h y perte nsi ve a ge nts, as piri n, li pi d-l oweri n g a ge nts) f or treat me nt of c o nc urre nt 
me dical c o n dit i ons are per mitte d t o partici pate pr o vi di n g t he y ha ve bee n sta ble o n t heir 
treat me nt re gi me n f or at least 4 wee ks
[ 1 6] h a ve a he mo gl o bi n A 1c ≥6 . 0 % a n d ≤1 1. 0 % at t he scree ni n g visit
[ 1 7] h a ve cli nical la b orator y  test res ults wit hi n n or mal ra n ge or dee me d cli nicall y 
i nsi g nifica nt b y t he i n vesti gat or.  A b n or malities of ser u m gl uc ose, ser u m li pi ds, uri nar y
gl uc ose, a n d uri nar y  pr otei n c o nsiste nt wit h T 2 D M are acce pta ble.

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 2 4
L Y 3 2 9 8 1 7 6
6. 2.
E x cl u si o n Crit eri a
S u bjects will be e xcl u d e d fr o m st u d y e nr oll me nt if t he y meet a n y of t he fol l owi n g cri teria at 
scree ni n g a n d/ or e nr oll me nt.  F or all s u bjects, E xcl usi o n Criteria [ 1 8] t hr o u g h [4 4 ] a p pl y; 
ad di tio nal s u b gr o u pi n gs of e xcl usio n  crit eria belo w  are s pecific t o t he s u bjects’ he patic f un ct i on 
(E xcl usi o n Cri t eria [ 4 5 ] t hr o u g h [5 6] ) a n d dia betic stat us ( E xcl usi o n Criteria [5 7 ] t hr o u g h [6 0 ]).
6. 2. 1.
E x cl u si o n Crit eri a f or A ll S u bj e ct s U nl e s s Ot h er wi s e S p e cifi e d
[ 1 8] are i n vest i gati ve site pers o n nel directl y affiliate d wit h t his st u d y a n d t heir i m me diate
fa milies.  I m me diate fa mil y is defi ne d as a s p o use, bi ol ogi c al or le gal g uar dia n, c hil d, 
or si bli n g.
[ 1 9] are Lill y e m pl o yees, or e m pl o yees of t hir d -part y  or ga nizati ons i n v ol ve d wit h t he st u d y 
t hat re q uire e xcl usi o n of t heir e m pl o yees
[ 2 0] are c urre ntl y e nr olle d i n a cli nical st u d y in v o l vi n g a n i n vesti gati onal pr o d uct or a n y  
ot her t y pe of me dical researc h j u d ge d n ot t o be scie nt ificall y or me dicall y c om pat i ble 
wi t h t his st u d y
[ 2 1] ha ve k n o w n aller gies t o tirze patid e or relate d c o m p o u n ds
[ 2 2] h a ve a hist or y of at o p y or cli nicall y si g nifica nt mul tiple or se vere dr u g aller gies, 
i ntol era nce t o t o pical c ortic oster oids, or se vere p osttreat m e nt h y perse nsit i vity reacti ons 
(incl u di n g, b ut n ot li mite d t o, er y t he ma m ultif or me maj o r, li near i m m u n o gl o b uli n A 
d er m at osis, t o xic e pi der mal nec r ol ysis, or e xf oliati ve der matitis)
[ 2 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 her st u d y 
i n vesti gati n g tirze pat i de, a n d ha ve pre vi o usl y recei ve d t he i n vesti gati onal pr o d uct
[ 2 4] pers o ns w h o ha ve a c urre nt, f u nct i oni n g or ga n tra ns pla nt
[ 2 5] h a ve a pers o nal or fa mil y hist or y of me d ullar y t h yr oid carci n o ma or ha ve m ult i ple 
e n d ocri ne ne o plasia s y n dr o me t y pe 2
[ 2 6] fe brile ill ness wit hi n 3 da ys pri or t o d osi n g
[ 2 7] ha ve a hist or y of sec o n d- or t hi r d-de gree heart bl oc k or a n y  a b n or malit y in t he 1 2 -lea d 
E C G at sc ree ni n g t hat, i n t he o pi ni on of t he i n vesti gat or, i ncreases t he ris ks ass ociate d 
wi t h p artici pat i n g i n t he st u d y
[ 2 8] ha ve esti mate d creati ni ne cleara nce ( C Lcr) < 5 0 m L/ mi n ( usi n g t he 4 fact or 
m o dificati o n of  diet i n re nal disease [M D R D - 4]) at scree ni n g.  E xce pti ons t o t his ma y 
be all o we d o n a case - b y-case basis after 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 s p o ns or or desi g nate d me dical re prese ntati ve ( n o esti mate d C Lcr 
< 3 0 m L/ mi n will be a p pr o ve d).
[ 2 9] ha ve a si g nifica nt hist or y  of or prese nce of car di o vasc ular (e g, m y o car dial i nfarcti on, 
cere br o vasc ular acci de nt, etc. wit hi n t he past 6 m o nt hs), res pirat or y , he patic (a p plies t o 
Gr o u p 1 c o ntr ol s u bjects o nl y), GI, e n d ocri ne (e xce pt T 2 D M), he mat ol o gical, or 

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 2 5
L Y 3 2 9 8 1 7 6
ne ur o l ogi cal disor ders ca pa ble of si g nifica ntl y alteri n g t he a bs or pti o n, meta b olis m, or 
eli mi nat i on of dr u gs; of c o nstit uti n g a ris k w he n ta ki n g t he st u d y  me dicat i on; or of 
i nterferi n g wit h t he i nter pretatio n of  data
[ 3 0] s h o w e vi de nce of si g nifica nt acti ve ne ur o ps yc hiatric disease
[ 3 1] ha ve a hist or y  of mali g na nc y wit hi n 5 years pri or t o scree ni n g
[ 3 2] ha ve a hist or y  or prese nce of pa ncreatitis ( hist or y of c hr o nic pa ncreatitis or idi o pat hic 
ac ute pa ncreatit is), ele vati on i n ser u m a m ylase a n d/or li pase > 1. 5 × t he u p per li mit of 
n or m al ( UL N) or GI di s or der (e g, rele va nt es o p ha geal refl u x or gall bla d der disease) or 
a n y GI disease w hic h i m pacts gastric e m ptyi n g (e g, gastric b y pass s ur ger y, p yl oric 
ste n osis, wit h t he e xce pti on of a p pe n dect o m y) or c o ul d be a g gra vate d b y G L P - 1 
a nal o gs or d i pe ptid yl pe pt i dase-I V i n hi bit ors.  S u bjects wit h d ysli pi de mia a n d s u bjects 
w h o ha d c h o lec yst olithiasis tr e at me nt (re mo val  of gall st o nes) a n d/ or c h olec ystect o m y 
(re mo v al  of gall bla d der) i n t he past, wit h n o f urt her se q uelae, ma y be i ncl u de d i n t he 
st u d y at the discreti o n of t he i n vest i gat or.
[ 3 3] ha ve ser u m A S T or A L T > 2 × U L N or t otal bilir u bi n > 1. 5 × U L N (a p plies t o Gr o u p 1
c o ntr ol s u bjects o nl y )
[ 3 4] ha ve a ser u m tri gl yceri de ≥5 m m o l/ L ( 4 4 2. 5 m g/ d L) at scree ni n g (a p plies t o Gr o u p 1 
c o ntr ol s u bjects o nl y )
[ 3 5] 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 nfectio n a n d/ or p osi tive HI V 
a nt i b o dies
[ 3 6] s h o w e vi de nce of he patitis C a n d/ or p ositi ve he patitis C a nti b o d y (a p plies t o Gr o u p 1 
c o ntr ol s u bjects o nl y)
[ 3 7] s h o w e vi de nce of he patitis B a n d/ or p ositi ve he patitis B s urface ant i ge n (a p plies t o 
Gr o u p 1 c o ntr ol s u bjects o nl y)
[ 3 8] are w o me n wit h a p ositi ve pre g na nc y test or w o me n w h o are lactati n g
[ 3 9] re g ularl y use k n o w n dr u gs of a b use a n d/ or s h o w p osit i ve fi n di n gs o n uri nar y dr u g 
scree n t hat are n ot ot her wise e x plai ne d b y per mitte d c o nc o mita nt me dicat i ons
[ 4 0] i nte n d t o use:
a.
o ver -t he- c o u nter me dicat i on wi t hi n 7 da ys pri or t o d osi n g (e xce pt f or 
he pat ic i m pair me nt a n d T 2 D M s u bjects o n sta ble d oses)
b.
prescri pt i on me d icatio n ( ot her t ha n t h ose list e d i n Sectio n 7. 7 a nd
A p pe n di x 9 ) wi t hi n 1 4 da ys pri or t o d osi n g
c.
her bal pre parat i ons wit hi n t he 1 4 da ys pri or t o scree ni n g
If a n y of t he a b o ve sit u atio n arises, a n ot her wise s uita ble s u bject ma y  be 
i ncl u de d at t he discreti on of t he i n vesti gat or.

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 2 6
L Y 3 2 9 8 1 7 6
[ 4 1] ha ve d o nate d m ore t ha n 4 5 0 m L bl o o d, i ncl u di n g plas ma a n d platelets, wit hi n 1 m o nt h 
pri or t o C hec k -i n
[ 4 2] ha ve a n a vera ge wee kl y  alc o h ol int a ke t hat e xcee ds 2 1 u nits per wee k ( males u p t o 
a ge 6 5) a n d 1 4 u nits per wee k ( males o ver 6 5 a n d fe males), or are u n willi n g t o st o p 
alc o h o l c o ns u m pt i on fr om 4 8 h o urs pri or t o C hec k -i n o n Da y  -1 a n d t he f o ll ow- u p visi t,
a n d w hile resi de nt i n t he C R U ( 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 o z  or 4 5 m L of dist ille d s pirits)
[ 4 3] are c urre ntl y hea v y users of nic oti ne ( > 10/ci garettes/ da y ) or ca n n ot c o mpl y  wit h t he 
restrict i ons of t he st u d y  site d uri n g c o nfi ne d perio ds or a bstai n f or 1 h o ur pri or t o 
d osi n g a n d 4 h o urs f o ll owi n g d osi n g
[ 4 4] i n t he o pi ni on of t he i n vest i gat or or s p o ns or, are u ns uita ble f or i ncl usi on i n t he st u d y
6. 2. 2.
A d diti o n al E x cl u si o n Crit eri a f or S u bj e ct s wit h Mil d t o S e v er e 
H e p ati c I m p air m e nt ( Gr o u p s 2 t o 4)
[ 4 5] are a ntici pat i n g or ga n tra ns pla nt wit hi n 6 m ont hs
[ 4 6] prese nce of act i ve p ortal s h u nt
[ 4 7] re q uires parace ntesis m ore ofte n t ha n 2 ti mes per m ont h
[ 4 8] ha ve e vi de nce of s p o nta ne o us bacterial perit o nit is wi t hi n 6 mo n t hs of d osi n g
[ 4 9] ha ve ha d variceal blee di n g wit hi n 3 m o nt hs of C hec k -i n t o t he C R U
[ 5 0] s h o w prese nce of he pat ocell ular carci n o ma
[ 5 1] s h o w e vi de nce of se vere h y p o natre mia (s o di u m < 1 2 0 m m o l/ L)
[ 5 2] he pat ic e nce p hal o pat h y of Gra de 2 or hi g her
[ 5 3] ha ve he m o gl o bi n < 8. 5 g/ d L
[ 5 4] ha ve a platelet c o u nt < 3 0 × 1 0 9 cells/ L
[ 5 5] ha ve t ot al bilir u bi n > 1 5 m g/ d L
[ 5 6] ha ve A L T ≥6 × U L N
6. 2. 3.
A d diti o n al E x cl u si o n Crit eri a f or S u bj e ct s wit h T 2 D M a n d 
H e p ati c I m p air m e nt
[ 5 7] ha ve ta ke n a n y gl uc ose-l oweri n g me dicat i ons ot her t ha n metf or mi n (refer t o I ncl usi o n 
Cri t erio n [ 1 3]), i ncl u di n g i ns uli n, i n t he past 3 m o nt hs bef ore scree ni n g
[ 5 8] ha ve ha d m ore t ha n 1 e pis o de of se vere h y p o gl yce mia, as defi ne d b y t he A merica n 
Di a betes Ass ociati o n criteria, wit hi n 6 m o nt hs bef ore e ntr y int o t he st u d y  or has a 
hist or y  of h yp o gl yce mia u na ware ness or p o or rec o g nit i on of h y p o gl yce mic s y m pt o ms.  

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 2 7
L Y 3 2 9 8 1 7 6
A n y s u bject t hat ca n n ot c o m m u nicate a n u n dersta n di n g of h y p o gl yce mic s y m pt o ms 
a n d t he a p pr o priate treat me nt of h y p o gl yce mia pri or t o d osi n g s h o uld als o be e xcl u de d.
[ 5 9] ha ve ha d a bl o o d tra nsf usi o n or se vere bl o o d l oss or ha ve k n o w n he m o gl o bi n o pat h y 
( alp ha- t halasse mia), he m o l ytic a ne mia, sic kle cell a ne mia, or a n y ot her c o n ditio n 
k n o w n t o i nterfere wit h he m o gl o bi n A 1c met h o d ol o g y
[ 6 0] ha ve recei ve d c hr o nic (last i n g > 1 4 c o nsec uti ve da ys) s yste mic gl uc oc ortic o i d t hera p y 
(e xcl u di n g t o pical, i ntra-artic ular, a n d i n hale d pre parati o ns) i n t he past year or ha ve 
recei ve d a n y s yste mic gl uc oc orti c o i d t hera p y wit hi n 3 0 da ys bef ore scree ni n g
6. 3.
Lif e st yl e a n d/ or Di et ar y R e q uir e m e nt s
T h r o u g h o ut t he stu d y, s u bjects ma y u n der 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.  
6. 3. 1.
M e al s
a n d Di et ar y R e stri cti o n s
S u bjects will be re q uire d t o fast o ver ni g ht f or at least 8 h o urs bef ore bei n g gi ve n a n S C d ose of 
tirze pat i de, a n d w he n cli nical la b orat or y test sa m ples are ta ke n (see Sc he d ule of Acti vities 
[Secti o n 2 ]). Water ma y be c o ns u me d freel y. 
Sta n dar d meals will be a d mi nistere d w hile 
s u bjects are resi de nt at t he C R U.
6. 3. 2.
C aff ei n e, Al c o h ol, a n d T o b a c c o
N o al c o h o l will be all o we d fr om 4 8 h o urs pri or t o C hec k -i n o n Da y  -1 a n d t he f o ll ow- u p visit,
a n d w hile resi de nt i n t he C R U . A n y nic oti ne usa ge w hi le i n patient will be restricte d i n 
acc or da nce t o t he C R U’s r ules a n d o perati n g pr oce d ure . W hile n ot resi de nt i n t he C R U, s u bjects 
m ust c o ns u me n o m ore t ha n 1 0 ci garettes or t he e q ui vale nt per da y.
S u bjects will be all o we d t o mai ntai n t heir re g ular caffei n e c o ns u m pt i on t hr o u g h o ut t he st u d y 
p eri o d.
6. 3. 3.
A cti vit y
N o stre n u o us p h y sical acti vity will be all o we d f or 4 8 h o urs pri or t o d osi n g u nt il disc har ge fr o m 
t he st u d y or c o mpleti o n of  all st u d y pr oce d ures.
6. 4.
S cr e e n F ail ur e s
S cree ni n g tests s uc h as cli nical la b orat or y tests a n d vit al si g ns/ E C Gs ma y be re peate d at t he 
di scretio n of  t he i n vesti gat or.  I n di vi d uals w h o d o n ot meet t he criteria f or partici pati on i n t his 
st u d y (scree n fail ure) ma y be re -scree ne d u p t o 2 times.  T he i nt er val bet wee n re-scree ni n gs 
s ho ul d be at l east 1 wee k.  Eac h ti me re -scree 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 nf or me d c o nse nt f or m (I C F) a n d will  be assi g ne d a ne w s u bject scree ni n g n u m ber.

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 2 8
L Y 3 2 9 8 1 7 6
7. Tr e at m e nt
7. 1.
Tr e at m e nt A d mi ni st er e d
Ti rze patide will  be a d mi nistere d at t he C R U as a si n gle S C i njecti on of eit her 5 m g or, de pe n di n g 
o n t he res ults of i nteri m a nal ysis, a d ose re d uce d b y a p pr o xi matel y 5 0 %.  D osi n g will occ ur after 
a n o ver ni g ht fast of at least 8 h o urs .  I nstr ucti o ns f or pre parati o n a n d ha n dli n g are s u m marize d i n 
Secti o n 7. 5 .
Ti rze patid e will be s u p plie d as prefille d s yri n ges ( P F S) b y Lill y or i ts re prese ntati ve i n 
acc or da nce wit h c urre nt g o o d ma n ufact uri n g practices a n d will be s u p plie d wit h l ot n u m bers.  
Eac h P F S will c o ntai n eit her 2. 5 mg or 5 m g of tirze patid e f or S C a d mi nistrati o n.  D etaile d 
i nstr uctio ns o n t he ha n dli n g, st ora ge, a n d S C a d mi nistrati o n of t he tirze pat i de P F S will be
descri be d i n t he se parate P har mac y Ma n ual .
W he ne ver p ossi ble, i n vesti gati onal pr o d uct a d mi nistrati o n s h o ul d be carrie d o ut b y t he sa me 
pers o n nel. T he act ual t i me of d osi n g will be rec or de d i n t he s u bject’s electr o nic case re p ort f or m 
(e C R F).
T a bl e G P G Q . 3.
Tr e at m e nt s A d mi ni st er e d
Tre at me nt N a me
Tirze pati de
D os a ge F or m ul ati o n
Prefille d s yri n ge
D os a ge stre n gt h
2. 5 m g / 0. 5 m L or 5 m g / 0. 5 m L
R o ute of A d mi nistr ati o n
S u bc uta ne o us
D osi n g i nstr ucti o ns
Si n gle i njecti o n i nt o a b d o me n o n Da y 1
T he i n vest i gat or or desi g nee is res p o nsi ble f or:

e x plai ni n g t he c orrect use of t he i n vesti gati o nal pr o d uct t o t he site pers o n nel 

verif yi n g t hat i nstr ucti o ns are f o ll owe d pr o perl y

mai ntai ni n g acc urate rec or ds of i n vesti gati o nal pr o d uct dis pe nsi n g a n d c o llecti on

a n d ret ur ni n g all u n use d me dicat i on t o Lill y or i ts desi g nee at t he e n d of t he st u d y
7. 1. 1.
P a c k a gi n g a n d L a b eli n g
Ti rze patid e will be pr o vi de d as P F S a n d pr o vi de d i n i n di vi d ual c art o ns t o be dis pe nse d.
T he i n vest i gati o nal pr o d uct 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.
7. 2.
M et h o d of Tr e at m e nt A s si g n m e nt
All s u bjects will recei ve t he sa me treat me nt; t his st u d y will n ot be s u bject t o ra n d o mizati on.

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 2 9
L Y 3 2 9 8 1 7 6
7. 2. 1.
S el e cti o n a n d Ti mi n g of D o s e s
D oses will be a d mi nistere d o n t he m or ni n g of Da y 1, prece de d b y  a n o ver ni g ht fast of at least 
8 h o urs.  A m eal ma y be ser ve d a p pr o xi matel y 2 h o urs p ost d ose.  See Secti o n 6. 3. 1 f or meal a n d 
di et ar y restrict i ons.  T he act ual t i me of all d ose a d mi nistrati o ns will be rec or de d i n t he s u bject’s
e C R F.
7. 3.
Bli n di n g
T his is a n o pe n -la bel st u d y.
7. 4.
D o s e M o difi c ati o n
I nteri m re vie w of safety/ t olera bility a n d P K data will be c o n d ucte d d uri n g t he c o urse of t his 
st u d y (Secti o n 1 0. 3. 5 ). If it a p pears t hat t he P K are i nfl ue nce d b y he pat ic i m pair me nt a n d t he 
e x p os ure i n s u bjects wit h i m pair me nt is hi g her t ha n e x pecte d or if t here are safet y/ t olera bilit y 
e ve nts t hat ma nifest at a hi g her t ha n e x pecte d rate i n t hese s u bjects, t he n t he d ose w o ul d be 
re d uce d b y a p pr o xi matel y 5 0 %.
N o d ose decisi o n ca n occ ur wit ho ut pri or di sc ussio n a n d a gree m e nt bet wee n t he i n vesti gat or a n d 
t he Lill y st u d y tea m.
7. 5.
Pr e p ar ati o n/ H a n dli n g/ St or a g e/ A c c o u nt a b ilit y
T he i n vesti gat or or desi g nee m u st c o nfir m a p pr o priate te m perat ure c o n dit i ons ha ve bee n 
mai ntai ne d , as c o m m u nicate d b y s p o ns or, d uri n g tra nsit f or all i n vesti gati onal pr o d uct recei ve d 
a n d a n y discre pa ncies are re p orte d a n d res ol ve d bef ore use of t he st u d y  treat me nt.
O nl y partici pa nts e nr o lle d i n t he st u d y ma y recei ve i n vesti gati onal pr o d uct or st u d y  materials, 
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 i n vesti gati onal pr o d uct . All 
i n vesti gati onal pr o d uct s h o ul d be st ore d i n a n e n vir o n me ntall y c o ntr olle d a n d m onit ore d ( m a n ual 
or a ut o mate d) area i n acc or da nce wit h t he labele d st ora ge c o n diti ons 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.
T he i n vest i gat or, i nstit uti o n, or t he hea d of t he me dical i nstituti o n ( w here a p plica ble) is 
res p o nsi ble f or st u d y tr e at me nt acc o u nta bilit y, rec o nciliat i on, a n d rec or d mai nte na nce ( s uc h as
receipt, rec o nciliat i on, a n d fi nal dis p osit i on rec or ds) .
7. 6.
Tr e at m e nt C o m pli a n c e
T he i n vest i gati o nal pr o d uct will be a d mi nistere d at t he C R U , a n d d oc u me ntatio n of  treat me nt 
a d mi nistrati o n will occ ur at t he site.
7. 7.
C o n c o mit a nt T h er a p y
S ta ble d oses of o ver -t he- c o u nter or prescri pti on me dicat i ons ( e g, a nti h y perte nsi ve a ge nts, 
as pirin, li pi d -l oweri n g a ge nts) f or treat me nt of c o nc urre nt me dical c o n ditio n s are all o we d f or 
s u bjects wit h he patic i m pair me nt a n d T 2 D M.  Su bjects o n sta bl e c o nc o mit a nt me dicatio n (s) at 
t he ti me o f st u d y e ntr y s h o uld c o nt i n ue t heir re g ular, u nc ha n ge d d ose t hr o u g h o ut t he st u d y.  

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 3 0
L Y 3 2 9 8 1 7 6
A p pe n di x 9 lists s ome of t he c o m m o n all o wa ble treat me nt o pti o ns f or s u bjects wi t h he patic 
i ns ufficie nc y.
Sta bl e si n gle oral d oses of met f or mi n (f or at least 8 wee ks) are all o we d f or s u bjects wit h T 2 D M.  
A d dit i onal c o nc o mit a nt me dicat i ons f or treat me nt of T 2 D M, ot her t ha n metf or mi n, are n ot 
per mitte d d uri n g t he st u d y .  
I n t he case of mil d i nterc urre nt ill ness d uri n g t he st u d y, c o nc o mita nt treat me nt wit h 
paraceta m o l/aceta mi n o p he n ma y be all owe d at t he discret i on of t he i n vesti gat or a n d is t o be
rec or de d i n t he eC R F.
N o start i n g of  ne w c o nc omit a nt t hera p y, a part fr o m occasio n al i nta ke of vita mi n/ mi neral 
s u p ple me nts, all o wa ble a ntiemet ics, a n d aceta mi n o p he n, will be per mitte d f or 1 4 da ys bef ore t he 
d os i n g of  tirze pati de t hr o u g h t he fi nal p ost d osi n g f oll ow- u p visit.  If t he nee d f or ne w or 
c ha n ges t o c o nc o mita nt me dicat i on ari ses, i ncl usi on or c o nti n uat i on of t he s u bject ma y be at t he 
di scretio n of  t he i n vesti gat or, prefera bl y after c o ns ult atio n wi t h a Lill y C P or cli nical researc h 
p h ysicia n ( C R P).
A d dit i onal dr u gs are t o be a v o i 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.  A n y dr u g gi ve n f or t he treat me nt of a n A E s h o ul d be 
d oc u m e nte d as s uc h.
7. 8.
Tr e at m e nt aft er t h e E n d of t h e St u d y
N ot a p plica ble f or t his st u d y .

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 3 1
L Y 3 2 9 8 1 7 6
8. Di s c o nti n u ati o n Crit eri a
8. 1.
Di s c o nti n u ati o n fr o m t h e St u d y
S u bjects w h o disc o nt i n ue t he st u d y earl y will ha ve pr oce d ures perf or me d as s h o w n i n t he 
Sc he d ule of Act i vities (Secti o n 2 ).
S u bjects will be disc o nt i n ue d i n t he f oll owi n g ci r c u msta nces:

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 vesti gati onal pr o d uct or e nr oll me nt 
i n a n y ot her t ype of me dical researc h j u d ge d n ot t o be scie nt ificall y or me dicall y 
c o mpat i ble wit h t his st u d y

P arti cip ati o n i n t he st u d y  nee ds t o be st o p pe d f or me dical, safet y,  re g 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 oo d cli nical pract ice ( G C P)

I n vesti gat or Decisi on
o
t he i n vest i gat or deci des t hat t he s u bject s h o uld be di sc o nti n ue d fr om t he st u d y
o
if t he s u bject, f or a n y reas o n, re q uires treat me nt wit h a n ot her t hera pe utic a ge nt 
t hat has bee n de m o nstrate d t o be effect i ve f or treat me nt of t he st u d y in dicat i on, 
di sc o nti n uati on fr om t he st u d y occ urs prior t o i ntr o d ucti o n of  t he ne w a ge nt

S u bject Decisi o n
o
t he s u bject, or l e g al re prese ntati ve, re q uests t o be wit h dra w n fr o m t he st u d y.
8. 1. 1.
Di s c o nti n u ati o n of I n a d v ert e ntl y E nr oll e d S u bj e ct s
If t he s p o ns or or i n vesti gat or i de ntifies a s u bject w h o di d n ot meet e nr oll me nt criteria a n d was 
i na d verte ntl y e nr olle d, a disc ussi on m u st occ ur bet wee n t he Lill y  cli nical p har mac olo gi st or C R P
a n d t he i n vest i gat or t o deter mi ne if t he s u bject ma y c o nti n ue i n t he st u d y.  If bot h  a gree it is 
me dicall y a p pr o priate t o c o nti n ue, t he i n vest i gat or m ust o btai n d oc u me nte d a p pr o val fr om t he 
Lill y cli nical p har mac o l ogist or C R P t o all o w t he i na d verte ntl y e nr olle d s u bject t o c o nti n ue i n 
t he st u d y wit h or wit ho ut c o nti n ue d treat m e nt wit h i n vesti gati onal pr o d uct.  
8. 2.
S u bj e ct s L o st t o F oll o w -u p
A s u bject 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 
visit s a n d is u na ble t o be c o ntacte d b y t he st u d y sit e.  Site pers o n nel are ex pecte d t o ma ke 
dili ge nt atte m pts t o c o ntact s u bjects w h o fail t o ret ur n f or a sc he d ule d visit or were ot her wise 
u na ble t o be f o ll owe d u p b y  t he sit e.

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 3 2
L Y 3 2 9 8 1 7 6
9. S t u d y As s e s s m e nt s a n d Pr o c e d ur e s
Secti o n 2 lists t he Sc he d ule of Acti vities, detaili n g t he st u d y pr oce d ures a n d t heir ti mi n g 
(incl u di n g t olera nce li mit s for ti mi n g).
A p pe n di x 2 lists t he cli nical la b orat or y tests t hat will be perf or m e d for t his st u d y .
A p pe n di x 5 pr o vi des a s u m mar y of  t he ma xi m u m nu m ber a n d v o l ume of  i n vasi ve sa m ples, f or
all sa m pli n g, d uri n g t he st u d y.
T he s pecificat i ons i n t his pr ot oc ol f or t he ti mi n gs of safety a n d sa m ple c o llecti ons are gi ve n as 
tar gets t o be ac hie ve d withi n reas o na ble li mits.  M o dificat io ns ma y  be 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 mat i on.  T he sc he d ule d t i me p oi nts ma y be s u bject t o mi n or 
alt er atio ns; h o we ver, t he act ual ti me m ust be rec or de d c orrectl y i n t he e C R F.  Fail ure or dela ys 
(ie, o utsi de st i p ulate d ti me all owa nces) i n perf or mi n g pr oce d ures or o btai ni n g sa m ples d ue t o 
le giti mate cli nical iss ues (e g, e q uip me nt tec h nical pr o ble ms, ve n o us access diffic ult y,  or s u bject
d efa ul tin g or t ur ni n g u p late f or a n a gree d sc he d ule d pr oce d ure) will n ot be c o nsi dere d as 
pr o t oc ol de viati ons, b ut sites will st ill be re q uire d t o n otif y  t he s p o ns or i n writin g via a file n ote.
U nless ot her wise state d i n s u bsect i ons bel o w, all s a mples c ollecte d f or s pecifie d la b orat or y  tests 
will be destr o y e d wit hi n 6 0 da ys of recei pt of c o nfir me d test res ults.  Certai n sa m ples ma y be 
retai ne d f or a l o n ger peri o d, if necessar y, t o c o mpl y  wit h a p plica ble la ws, re g ulati ons, or 
la b orat or y certificatio n sta n dar ds.
9. 1.
Effi c a c y A s s e s s m e nt s
N ot a p plica ble f or t his st u d y .
9. 2.
A d v er s e E v e nt s
I n vesti gat ors are res p o nsi ble f or m o nit ori n g t he safet y of s u bjects w h o ha 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 be 
c o nsi dere d a n u na nt ici pate d be nefit t o t he s u bject.
T he i n vest i gat or is res p o nsibl e f or t he a p pr o pri ate me dical care of s u bjects d uri n g t he st u d y .
I n vesti gat ors m ust d oc u me nt t heir re vie w of eac h la b orat or y safet y re p ort.
T he i n vest i gat or re mai ns res p o nsi ble f or f oll owi n g, t hr o u g h a n a p pr o priate healt h care o pti o n, 
A Es t hat are seri o u s or ot her wise me dicall y i m p orta nt, c o nsi dere d relate d t o t he i n vesti gati onal 
pr o d uct or t he st u d y , or t hat ca use d t he s u bject t o disc o nti n ue t he i n vesti gati onal pr o d uct bef ore 
c o mplet i n g t he st u d y.  T he s u bject s h o ul d be f oll owe d u nt il t he e ve nt res ol ves, sta bilizes wi t h 
a p pr o priate dia g n ostic e val uati o n, or is reas o na bl y e x plai ne d.  T he fre q ue nc y o f f oll ow- u p 
e val uat i ons of t he A E is left t o t he discret i on of t he i n vest i gat or.
After t he I C F is si g ne d, s t u d y site pers o n nel will rec or d, via e C R F, t he occ urre nce a n d nat ure of 
eac h s u bject’s pre-e xist i n g c o n ditio ns, i ncl u di n g cli nicall y  si g nifica nt sig ns a n d s y m pt o m s of t he 
di sease u n der treat me nt i n t he st u d y.  A d dit i onall y , site pers o n nel will rec or d a n y c ha n ge i n t he 
c o n ditio n(s) a n d t he occ urre n ce a n d nat ure of a n y A Es.  

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 3 3
L Y 3 2 9 8 1 7 6
T he i n vest i gat or will i nter pret a n d d oc u me nt w het her or n ot a n A E has a reas o na ble p ossi b ility 
of  bei n g relate d t o stu d y treat me nt or a st u d y pr oce d ure, ta ki n g i nt o acc o u nt t he disease, 
c o nc o mita nt treat me nt , or pat h ol o gies.  
A “r eas o na ble p ossi bilit y” mea ns t hat t here is a p ote nti al ca use a n d effect relat i ons hi p bet wee n 
t he i n vest i gati onal pr o d uct , a n d/ or st u d y pr oce d ure a n d t he A E.
Pl a n ne d s ur geries s h o ul d n ot be re p orte d as A Es u nless t he u n derl yi n g me dical c o n dit i on has 
w ors e ne d d uri n g t he c o urse of t he st u d y.
If a s u bject’s i n vesti gati onal pr o d uct is disc o nti n ue d as a res ult of a n A E, st u d y site pers o n nel 
m ust re p ort t his t o Lill y or its desi g nee via eC R F.
9. 2. 1.
S eri o u s A d v er s e E v e nt s
A n S A E is a n y  AE f r o m t his st u d y t hat res ults i n o ne of t he f oll owi n g:

deat h

i nitial or pr ol o n ge d i n patie nt h os pitalizati on

a life-t hreate ni n g e x perie nce (t hat is, i m me diate ris k of d yi n g)

persiste nt or si g nifica nt disa bilit y/ i nca pacity

c o n ge nital a n o ma l y/ birt h defect

i m p orta nt me dical e ve nts t hat ma y n ot be i m me diatel y life -t hreate ni n g or res ult i n deat h 
or h os pitalizati o n b ut m a y je o par dize t he s u bject or m a y re q uire i nter ve ntio n t o pre ve nt 
o ne of t he ot her o utc o mes liste d i n t he defi nit i on a b o ve.
St u d y  site pers o n nel must al ert t he Lill y C R P/ C P, or its desi g nee, of a n y S A E as s o o n as 
pract icall y p ossi ble.
A d dit i onall y , st u d y site pers o n nel must al ert Lill y Gl o bal Patie nt Safet y, or i ts desig nee , of  a n y 
S A E wi t hi n 2 4 h o urs of i n vesti gat or a ware ness of t he e ve nt via a s p o ns or-a p pr o ve d met h o d.  If 
alert s are iss ue d via tele p h o ne, t he y are t o be i m me diatel y f o ll owe d wi t h official n otificati o n o n 
st u d y-s pecific S A E f or ms.  T his 2 4-h o ur n otificat i o n re q uire me nt refers t o t he i nitial S A E 
i nf or mat i on a n d all f o ll ow- u p S A E i nf or mati o n .  
Alt h o u g h all A Es are rec or de d i n t he eC R F after si g ni n g i nf or me d c o nse nt, S A E re p orti n g t o t he 
s p o ns or be gi ns after t he s u bject has si g ne d i nf or me d c o nse nt a n d has recei ve d i n vest i gati onal 
pr o d uct.  H o we ver, if a n S A E occ urs after si g ni n g i nf or me d c o nse nt, b ut pri or t o recei vi n g 
i n vesti gati onal pr o d uct , A N D is c o nsi dere d reas o na bl y p ossi bl y relate d t o a st u d y pr oce d ure t he n 
it M U S T be re p orte d.
I n vesti gat ors are n ot o bli gate d t o acti vel y see k A Es or S A Es i n s u bjects o nce t he y ha ve 
di sc o nti n ue d fr om a n d/ or c o mplete d t he st u d y (t he s u bject s u m mar y eC R F has bee n c o m p lete d).  
H o we ver, if t he i n vest i gat or lear ns of a n y S A E, i ncl u di n g a deat h, at a n y ti me after a s u bject has 

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 3 4
L Y 3 2 9 8 1 7 6
bee n disc har ge d fr o m t he st u d y , a n d he/s he c o nsi ders t he e ve nt reas o na bl y p ossi bl y relate d t o t he 
st u d y tr e at me nt or st u d y p artici pat i on, t he i n vest i gat or must pr o m ptl y n otif y Lill y .  
Pre g na nc y ( mater nal or pater nal e x p os ure t o i n vesti gati onal pr o d uct ) d oes n ot meet t he defi niti on 
of  a n A E .  H o we ver, t o f ulfill re g ulat or y re q uire me nts a n y pre g na nc y s ho ul d b e re p orte d 
f oll owi n g t he S A E pr ocess t o c ollect data o n t he o utc o me f or b ot h m ot her a n d fet us.
9. 2. 1. 1.
S u s p e ct e d U n e x p e ct e d S eri o u s A d v er s e R e a cti o n s 
S us pecte d u ne x pecte d seri o us a d verse react i ons ( S U S A Rs) are seri o us e ve nts t hat are n ot liste d 
i n t he I B a n d t hat t he i n vesti gat or re p orts as relate d t o i n vest i gati onal pr o d uct or pr oce d ure.  Lill y  
has pr oce d ures t hat will be f o ll owe d f or t he rec or di n g a n d e x pe dite d re p orti n g of S U S A Rs t hat 
are c o nsiste nt wit h gl o bal re g ulati o ns a n d t he ass ociate d detaile d g ui da nce .
A p pe n di x 8 prese nts e xa m ples of A Es t hat are reas o na bl y a nt ici pate d d ue t o disease state a n d 
ma y n ot be c o nsi dere d relate d t o t irze pati de.
9. 2. 2.
C o m pl ai nt H a n dli n g
Lill y c o llects pr o d uct c o m plai nts o n i n vesti gati onal pr o d ucts a n d dr u g deli ver y s yste ms use d i n 
cli nical trials i n or der t o e ns ure t he safet y of  st u d y partici pa nts, mo ni t or q ualit y, a n d t o facilitate 
pr ocess a n d pr o d uct i m pr o ve me nts.
S u bjects s h o ul d be i nstr ucte d t o c o ntact t he i n vest i gat or as s o o n as p ossi ble if he or s he has a 
c o mplai nt or pr o bl e m wit h t he i n vesti gati onal pr o d uct s o t hat t he sit uati o n ca n be assesse d.
9. 3.
Tr e at m e nt of O v er d o s e
F or t he p ur p oses of t his st u d y , an o ver d ose of tirze patide is c o nsi dere d a n y d ose hi g her t ha n t he 
assi g ne d d ose . T he treat me nt f or a n o ver d ose of tirze pati de is s u p p orti ve care.
Refer t o t he I B f or tirze pati de.
9. 4.
S af et y
9. 4. 1.
Cli ni c al L a b or at or y T e st s
F or eac h s u bject, la b orat or y test s detaile d i n A p pe n di x 2 s h o uld be c o n d ucte d acc or di n g t o t he 
Sc he d ule of  Act i vities (Secti o n 2 ).  
A d dit i onal bl o o d dra ws ma y  be dra w n f or safet y p ur p oses at  t he i n vesti gat or’s discreti o n.  
9. 4. 1. 1.
A m yl a s e a n d Li p a s e M e a s ur e m e nt s
S er u m  a m ylase a n d li pase meas ure me nts will be c ollecte d as part of  t he cli nical la b orat or y 
testi n g a n d as s pecifie d i n t he Sc he d ule of Acti vities (Secti o n 2 ).  A d diti onal meas ure me nts ma y 
be perf or m e d at t he i n vest i gat or’s discreti o n. F urt her dia g n ost ic assess me nts will be 
rec o m me n de d as per t he al g orit h m (refer t o A p pe n di x 7 ) f or t he mo ni t ori n g of pa ncreatic e ve nts 
w he ne ver li pase a n d/ or a m ylase is c o nfir me d t o be ≥3 × U L N at a n y visit p ost d ose, e ve n if t he 
s u bject is as y m pt o matic.

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 3 5
L Y 3 2 9 8 1 7 6
9. 4. 2.
Gl u c o s e M o nit ori n g
F or safet y p ur p oses, bl o o d gl uc ose meas ure me nts will be perf or me d usi n g a be dsi de gl uc ose 
m o nit or as s pecifie d i n t he Sc he d ule of Act i vities (Secti o n 2 ).  A d ditio n al  s afet y bl o o d gl uc ose 
meas ure me nts ma y  als o be ta ke n d uri n g t he st u d y as dee me d necessar y b y t he i n vesti gat or.  
9. 4. 2. 1.
H y p er gl y c e mi a a n d H y p o gl y c e mi a R e p orti n g
E pis o des of h y per gl yce mia (fasti n g plas ma/ser u m gl uc ose > 2 7 0 m g/ d L [ 1 5 m m o l/L]) or 
h y p o gl yce mia ( plas ma/ser u m gl uc ose ≤7 0 m g/ d L [ 3. 9 m m o l/ L]) will be re p orte d b y t he 
i n vesti gat or or desi g nate d p h ysicia n w h o will be res p o nsi ble f or a d visi n g t he s u bject o n w hat 
f urt her acti o ns t o ta ke. A d dit i onal m o nit ori n g ma y be re q ueste d at t he i n vest i gat or’s discreti o n.
If t he fasti n g plas ma/ser u m gl uc ose d uri n g t he d osi n g peri o d e xcee ds t he acce pta ble le vel 
defi ne d as h y per gl yce mia o n 3 or m ore se parate da ys o ver a n y 2 -wee k peri o d bet wee n scree ni n g
a n d t he e n d o f t he d osi n g peri o d, t he s u bject will be e val uate d f urt her at t he st u d y  sit e. If fasti n g 
pl as ma/ser u m gl uc ose c o nti n ues t o e xcee d t he acce pta ble le vel, treat me nt wit h a n a p pr o priate 
a nt i dia betic a ge nt ma y be i nitiate d b y t he i n vesti gat or. If h y per gl yce mia occ urs d uri n g t he 
f oll ow- u p peri o d, t he s u bject will re mai n i n t he st u d y u nt il c om p leti on of t he pla n ne d f o ll ow- u p.
H y p o gl yce mia e pis o de s will be rec or de d o n s pecific eC R F pa ges. H y p o gl yce mia will be treate d 
a p pr o priatel y b y t he i n vestig at or a n d a d dit i onal m o ni t ori n g of plas ma/ser u m gl uc ose le vels ma y 
be perf or m e d. T he f o ll owi n g cate g ori es of t he 2 0 1 7 A merica n Dia betes Ass ociat i on p osit i on 
state me nt o n gl yce mic tar gets (A D A 2 0 1 7) base d o n rec o m me n dati o ns of t he I nter nati o nal 
H y p o gl ycae mia St u d y  Gr o u p (I H S G 2 0 1 7) s h o ul d b e a p plie d f or re p ortin g i n t he eC R F a n d 
e val uat i n g h y p o gl yce mic e ve nts.
H y p o gl yce mia will be descri be d usi n g t he f oll o wi n g defi nit i ons :  

D oc u me nte d Gl uc ose Alert Le vel ( Le vel 1), Pl as m a Gl uc ose ( P G) ≤7 0 m g/ d L 
( 3. 9 m m ol/ L) : 
o
S y m pt o m atic h y p o gl yce mi a :  a n e ve nt d uri n g w hic h t y pical s y m pt o ms of 
h y p o gl yce mia are acc o m pa nie d b y P G ≤7 0 m g/ d L ( 3. 9 m m o l/L)
o
As y m pt o m atic h y p o gl yce mi a :  a n e ve nt n ot acc o m pa nie d b y t y p ical s y m pt o ms 
of  h y p o gl yce mia b ut wit h P G ≤7 0 m g/ d L ( 3. 9 m m ol/ L)
o
U ns pecifie d h y p o gl yce mi a : a n e ve nt d uri n g w hic h P G ≤7 0 m g/ d L ( 3. 9 m m o l/ L) 
b ut n o i nf or mat i on rel at i ve t o s y m pt o ms of h y p o gl yce mia was rec or de d

D oc u me nte d Cli nic all y Si g nific a nt H y p o gl yce mi a ( Le vel 2) P G < 5 4 m g/ d L 
( 3. 0 m m ol/ L):
o
S y m pt o m atic h y p o gl yce mi a: an e ve nt d uri n g w hic h t y pi c al  s ym pt o ms of 
h y p o gl yce mia are acc o m pa nie d b y P G < 5 4 m g/ d L ( 3. 0 m m o l/L)
o
As y m pt o m atic h y p o gl yce mi a: a n e ve nt n ot acc o m pa nie d b y t y p ical s y m pt o ms 
of  h y p o gl yce mia b ut wit h P G < 5 4 m g/ d L ( 3. 0 m m ol/ L)
o
U ns pecifie d h y p o gl yce mi a : a n e ve nt  d urin g w hic h P G < 5 4 m g/ d L ( 3. 0 m m o l/ L) 
b ut n o i nf or mat i on rel at i ve t o s y m pt o ms of h y p o gl yce mia was rec or de d

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 3 6
L Y 3 2 9 8 1 7 6

Se vere h y p o gl yce mi a ( Le vel 3): a n e ve nt re q uiri n g assista nce o f a n ot her pers o n t o 
acti vel y a d mi nister car b o h ydrate, gl uca g o n, or ot h er res uscitati ve acti ons .  D uri n g t hese 
e pis o des, t he s u bject has a n altere d me ntal stat us a n d ca n n ot assist i n t heir care, is 
se mic onsci o us or u nc o nsci o us, or e x perie nce d c o ma wit h or wit h o ut seiz ures a n d ma y 
re q uire pare nteral t hera p y. Plas ma gl uc ose meas ure me nts m a y n ot be a vaila ble d uri n g 
s uc h a n e ve nt, b ut ne ur ol o gical rec o ver y attri b uta ble t o t he rest orati o n of bl o o d gl uc ose 
c o nce ntrati o n t o n or mal is c o nsi dere d s ufficie nt e vi de nce t hat t he e ve nt was i n d uce d b y a 
l ow P G c o nce ntrati o n ( P G ≤7 0 m g/ d L [ 3. 9 m m o l/L])
o
Se vere h y p o gl yce mi a re q uiri n g me dic al atte nti o n : a se vere h y p o gl yce mic 
e ve nt w he n s u bjects re q uire t hera p y b y healt hcare pr ofessi o nals (e g, e mer ge nc y 
me dical tec h nicia ns , e mer ge nc y r o o m pers o n nel, etc.)
Ot her H y p o gl yce mi a:

N oct ur n al h y p o gl yce mi a: a n y h y p o gl yce mic e ve nt ( d oc u me nte d s y m pt o mat ic, 
as y m pt o mat ic, pr o ba ble s y m pt o matic, or se vere h y p o gl yce mia) t hat occ urs bet wee n 
be dt i me a n d wa ki n g

Rel ati ve h y p o gl yce mi a: a n e ve nt d uri n g w hic h t y pical s y m pt o ms of h y p o gl yce mia, t hat 
d o n ot re q ui re t he assista nce of  a n ot her pers o n, are acc o m pa nie d b y P G > 7 0 m g/ d L 
( 3. 9 m m o l/L), b ut t hese le vels ma y be q uic kl y a p pr oac hi n g t he 7 0 m g/ d L ( 3. 9 m m o l/L) 
t hres h ol d

O ver all ( or t ot al) h y p o gl yce mi a:
T hi s o ptio n al  cate g or y c o m bi nes all cases of 
h y p o gl yce mia. If a n e ve nt of h y p o gl yce mia falls i nt o m ult i ple s u bcate g ories, t he e ve nt is 
o nl y  c o u nte d o nce i n t his cate g or y

Pr o b a ble s y m pt o m atic h y p o gl yce mi a: A n e ve nt d uri n g w hic h s y m pt o ms of 
h y p o gl yce mia are n ot acc o m pa nie d b y a P G meas ure me nt b ut t hat was pres u ma bl y 
ca use d b y a bl oo d gl uc ose c o nce ntrati o n ≤7 0 m g/ d L ( 3. 9 m m o l/L).
T he deter mi nat i on of a h y p o gl yce mic e ve nt as a n e pis o de of se vere h y p o gl yce mia as defi ne d 
a b o ve will be ma de b y t he i n vesti gat or base d o n t he me dical nee d of t he s u bject t o ha ve re q uire d 
assista nce a n d is n ot pre dicate d o n t he re p ort of a s u bject si m pl y ha vi n g recei ve d assista nce.
H y p o gl yc e mic e ve nts will be rec or de d in t he h y p o gl yc e mia mo d ule of t he e C R F t o all o w f or t he 
c ollect i on of c o m pre he nsi ve safet y i nf or mati on relati n g t o t hese e ve nts.  All e pis o des of  se vere 
h y p o gl yce mia will a d dit i onall y be re p orte d as S A Es (see Secti o n 9. 2. 1 f or details).
9. 4. 3.
Vit al Si g n s
F or eac h s u bject, vital si g ns meas ure me nts ( B P, p ulse rate, a n d b o d y t e mperat ure) s h o ul d be 
c o n d ucte d acc or di n g t o t he Sc he d ule of  Acti vities (Secti o n 2 ).
Bl o o d press ure a n d p ulse rate s h o uld be me as ure d after at least 5 mi n utes i n t he s u pi ne p osi tio n .
D uri n g a n y A E of dizzi ness or p ost ure -i n d uce d s y m pt o ms, unsc he d ule d ort h ostatic vital si g ns 
s h o uld be assesse d if p ossi ble.  If t he s u bject feels u na ble t o sta n d, s u pi ne vital si g ns o nl y will be 
rec or de d.  A d diti onal vital si g ns ma y be meas ure d d uri n g t he st u d y if warra nte d .

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 3 7
L Y 3 2 9 8 1 7 6
9. 4. 4.
El e ctr o c ar di o gr a m s
F or eac h s u bject, a si n gle 1 2 -lea d di gital E C G will be c ollecte d acc or di n g t o t he Sc he d ule of  
Act i vities (Secti o n 2 ).  El ectr ocar dio gr a ms m ust be rec or de d bef ore c ollecti n g a n y  blo o d 
sa m ples.  S u bjects m u st be s u pi ne f or a p pr o xi matel y 5 t o 1 0 mi n utes bef ore E C G c ollecti o n a n d 
r e mai n s u pi ne b ut a wa ke d uri n g E C G c ollecti o n.  Electr ocar di o gra ms ma y be o btai ne d at 
a d ditio nal  times , w he n dee me d cli nicall y necessar y.   All E C Gs rec or de d s h o ul d be st ore d at t he 
i n vesti gati onal site.
Electr ocar di o gra ms will  be i nter prete d b y a q ualifie d p h ysicia n (t he i n vesti gat or or q ualifie d 
desi g nee) at t he site as s o o n after t he ti me of E C G c ollect i on as p ossi ble, a n d i deall y w hile t he 
s u bject is still prese nt, t o deter mi ne w het her t he s u bject meets e ntr y criteria at t he rele va nt 
visit(s) a n d f or i m me diate s u bject ma na ge me nt, s h o ul d a n y cli nicall y rele va nt fi n di n gs be 
i de ntifie d.  
If a cli nicall y si g nifica nt fi n di n g is i de ntifie d (i ncl u di n g, b ut n ot li mite d t o, c ha n ges i n Q T/ Q Tc 
i nter val fr o m baseli ne) after e nr oll me nt, t he i n vesti gat or will deter mi ne if t he s u b ject ca n 
c o nti n ue i n t he st u d y.  T he i n vesti gat or, or q ualifie d desi g nee , is res p o nsi ble f or deter mi ni n g if 
a n y c ha n ge i n s u bject ma na ge me nt is nee de d , a n d m ust d oc u me nt his/ her re vie w of t he E C G 
pri nte d at t he ti me of c o llecti on.  A n y ne w cli nicall y rele va nt fi n di n g s h o ul d be re p orte d as a n 
A E .
A n y cli nicall y  sig 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 
d osi n g of  t he i n vesti gati onal 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 
e C R F.
9. 4. 5.
I nj e cti o n-sit e R e a cti o n s
I njecti on- site assess me nts f or lo c al  t olera bilit y will be c o n d ucte d, w he n re p orte d as:

a n A E fr o m a s u bject, or

a cli nical o bser vat i on fr o m a n i n vesti gat or.
Re p orte d i nject i on- site reactio ns will  be c haracterize d wit hi n t he f oll owi n g cate g ori es:

e de ma

er yt he ma

in d urati o n

itc hi n g

pai n .
All i njectio n -sit e r e a ctio ns re p orte d as A Es will be cl osel y m o nit ore d u ntil res o l uti on.  T he re p ort 
of  a cli nicall y si g nifica nt A E of i njecti on- site reactio n  ma y pr o mpt n otificati o n of  t he s p o ns or, 
cli nical p h ot o gra p h y , a n d referral for der m at olo gi c e val uat i on a n d c o nsi derati o n of a s ki n bi o ps y 
a n d la b orat or y e val uati ons ( A L T, A S T, c o m plete bl o o d c o u n t wit h perce nt e osi n o p hils, a n d 
a d ditio nal  i m m u n o ge nicit y testi n g).

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 3 8
L Y 3 2 9 8 1 7 6
I n vesti gati onal site staff will be pr o vi de d wi t h se parate i nstr ucti o ns/trai ni n g o n h o w t o e val uate 
i njecti on- site reactio ns a n d t hei r se verit y in a c o nsiste nt ma n ner.  P h ot o gra p hs of i nject i on- sit e 
reactio ns ma y be ta ke n i n a sta n dar dize d ma n ner f or rec or d -kee pi n g p ur p oses; h o we ver, t he 
p h ot o gra p h s will n ot be use d t o e val uate t he se verit y of injecti o n -site reactio n.
9. 4. 6.
H y p er s e n siti vit y R e a cti o n s
All h y perse nsit i vity reacti ons will be re p orte d b y  t he i n vesti gat or as eit her A Es or, if a n y seri o us 
crit erio n is met, as S A Es.
I n t he e ve nt of s us pecte d dr u g h y perse nsi tivit y reactio ns (i m me diate or n o n -i m me diate) i n 
s u bjects w h o e x perie nce m o derate t o se vere i nject i o n reacti o ns as assesse d b y t he i n vesti gat or, 
u nsc he d ule d bl o o d sa m ples will be c ollecte d f or P K a n d a nt i dr u g a nti b o d y ( A D A) a nal yses at t he 
fol l owi n g t i me p oi nts:  

as close as p ossi ble t o t he o nset of t he e ve nt

at t he res ol ut i on of t he e ve nt

3 0 ( ± 3) da y s fol l owi n g t he e ve nt.  
A d dit i onall y , u nsc he d ule d ser u m sa m ples f or i m m u ne safety la b orat or y testi n g (i ncl u di n g, b ut 
n ot li mite d t o β tr y ptase , t ot al I g E, c o mple me nt a n d c y t o kine pa nel  testi n g) s h o uld als o be 
c ollecte d at a p pr o xi matel y 6 0 t o 1 2 0 mi n utes a n d 4 t o 6 wee ks after t he o nset of t he e ve nt i n 
t hese s u bjects.  
I nstr uctio ns f or t he c ollect i on a n d ha n dli n g of bl o o d sa m ples will be pr o vi de d b y t he s p o ns or.  
T he act ual  date a n d ti me ( 2 4- h o ur cl oc k ti me) of eac h sa m pli n g will be rec or de d.
9. 4. 7.
S af et y M o nit ori n g
T he Lill y C P or C R P /scie nt ist will m onit or safet y data t hr o u g h o ut t he c o urse of t he st u d y .
Lil l y will re vie w S A Es withi n t i mefra mes ma n date d b y c o mpa n y pr oce d ures.  T he Lill y  C P or 
C R P will p eri o dicall y re vie w t he f oll owi n g data :

tre n ds i n safet y d at a

la b orat or y a nal yt es i ncl u di n g gl uc ose, a m ylase, a n d li pase

serio us a n d n o nseri o us A Es, i ncl u di n g A Es of i nterest (GI e ve nts, h y p o gl yce mia,
i njecti on- site reactio ns, h y perse nsi tivit y react i ons) a n d re p orte d a n d a dj u dicate d 
pa ncreat itis
F urt her di a g n ostic assess me nts will be rec o m me n de d w he ne ver li pase a n d /or a m ylase are 
c o nfir me d t o be ≥3 × U L N at a n y  visit p ost d ose e ve n if t he s u bject is as y mpt o m atic (as per t he 
alg ori t h m for t he m o ni t ori n g of pa ncreatic e ve nts i n A p pe n di x 7 ) a n d, if pa ncreatitis is s us pecte d, 
t he case will be f urt her defi ne d d uri n g a n a dj u dicati o n pr ocess.
W he n a p pr o priate, t he Lill y C P or C R P will c o ns ult wit h t he f u nct i onall y  in de pe n de nt Gl o bal 
P ati e nt Safet y t hera pe utic area p h ysicia n or cli nical researc h scie ntist.

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 3 9
L Y 3 2 9 8 1 7 6
9. 4. 7. 1.
H e p ati c S af et y M o nit ori n g in S u bj e ct s wit h Tr e at m e nt - em er g e nt 
A b n or m al Li v er T e st s
A b n or m al liver tests i n st u dy p artici p a nts wit h n or m al or ne ar n or m al b aseli ne A L T, A S T, 
A L P , a n d t ot al bilir u bi n ( T B L; < 1. 5 × U L N)
If a s u bject w h o was e nr olle d wit h baseli ne A L T, A S T, A L P, T B L < 1. 5 × U L N, e x perie nces 
ele vate d A L T ≥3 × U L N, A L P ≥2 × U L N, or T B L ≥2 × U L N, li ver tests ( A p pe n di x 4 ) s h o uld be 
re peate d wit hi n 4 8 t o 7 2 h o urs, i ncl u di n g A L T, A S T, A L P, T B L, ga m ma -gl uta m yl  tr a nsferase
(G G T ), a n d creat i ne ki nase (C K ) t o c o nfir m t he a b n or malit y a n d t o deter mi ne if it is i ncreasi n g 
or decreasi n g.  
If t he a b n or mality persists or w orse ns, cli nical a n d la b orat or y  mo ni t ori n g, a n d e val uati on f or 
p ossi ble ca uses of a b n or mal li ver tests s h o ul d be i nit iate d b y t he i n vesti gat or i n c o ns ultat i on wi t h 
t he Lill y C P or C R P.  M o nit ori n g s h o uld c o nti n ue u nt il le vels n or malize a n d/ or are ret ur ni n g t o 
a p pr o xi mate baseli ne le vels.
Elev ate d A L T/ A S T i n s u bjects wit h b aseli ne A L T/ A S T ≥1. 5 × U L N
If a s u bject, w h o was e nr olle d wit h baseli ne A L T/ A S T ≥1. 5 × U L N, e x perie nces ele vate d 
A L T/ A S T ≥2 × baseli ne (res pect i vel y), li ver tests (A p pe n di x 4 ) s h o uld be re peate d wi t hi n 4 8 t o 
7 2 h o urs, i ncl u di n g A L T, A S T, A L P, T B L, G G T , a n d C K t o c o nfir m t he a b n or malit y a n d t o 
deter mi ne if it is i ncreasi n g or decreasi n g.  
If t he a b n or mality persists or w orse ns, cli nical a n d la b orat or y  mo ni t ori n g, a n d e val uati on f or 
p ossi ble ca uses of a b n or mal li ver tests s h o ul d be i nit iate d b y t he i n vesti gat or i n c o ns ultati on wi t h 
t he Lill y C P or C R P.  M o nit ori n g s h o ul d c o nti n ue u nt il le vels n or malize a n d/ or are ret ur ni n g t o 
a p pr o xi mate baseli ne le vels.
Elev ate d A L P i n s u bjects wit h b aseli ne A L P ≥1. 5 × U L N
If a s u bject, w h o was e nr olle d wit h baseli ne A L P ≥1. 5 × U L N, e x perie nces ele vate d A L P ≥2 ×
baseli ne, li ver tests (A p pe n di x 4 ) s h o uld be re peate d wi t hi n 4 8 t o 7 2 h o urs, i ncl u di n g A L T, A S T, 
A L P, T B L, G G T , a n d C K t o c o nfir m t he a b n or malit y a n d t o deter mi ne if it is i ncreasi n g or 
decreasi n g.  
If t he a b n or mality 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 uat i on f or 
p ossi ble ca uses of a b n or mal li ver tests s h o ul d be i nit iate d b y t he i n vesti gat or i n c o ns ultati on wi t h 
t he Lill y C P or C R P.  M o nit ori n g s h o uld c o nti n ue u nt il le vels n or malize a n d/ or are ret ur ni n g t o 
a p pr o xi mate baseli ne le vels.
Elev ate d T B L i n s u bjects wit h b aseli ne T B L ≥1. 5 × U L N
If a s u bject, w h o was e nr olle d wit h baseli ne T B L ≥1. 5 × U L N, e x perie nces ele vate d T B L ≥1. 5 ×
baseli ne, li ver tests ( A p pe n di x 4 ) s h o uld be re peate d wi t hi n 4 8 t o 7 2 h o urs, i ncl u di n g A L T, A S T, 
A L P, T B L, d irect b iliru bi n , G G T, a n d C K t o c o nfir m t he a b n or malit y a n d t o deter mi ne if it is 
i ncreasi n g or decreasi n g.  
If t he a b n or mality persists or w orse ns, cli nical a n d la b orat or y  mo ni t ori n g, a n d e val uati on f or 
p ossi ble ca uses of a b n or mal li ver tests s h o ul d be i nit iate d b y t he i n vesti gat or i n c o ns ultati on wi t h 

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 4 0
L Y 3 2 9 8 1 7 6
t he Lill y C P or C R P.  M o nit ori n g s h o uld c o nti n ue u nt il le vels n or malize a n d/ or are ret ur ni n g t o 
a p pr o xi mate baseli ne le vels.
9. 4. 7. 2.
A d diti o n al H e p ati c D at a C oll e cti o n ( H e p ati c S af et y e C R F ) in S u bj e ct s
w it h Tr e at m e nt - em er g e nt A b n or m al Li v er T e st s
Tre at me nt -e mer ge nt a b n or m al liver tests i n s u bjects wit h n or m al or ne ar n or m al b aseli ne 
A L T, A S T, A L P , a n d T B L ( < 1. 5 × U L N)
I n a s u bject, w h o was e nr olle d wit h baseli ne A L T, A S T, A L P, a n d T B L < 1. 5 × U L N, a d dit i onal 
he pat ic safety data s h o ul d be c o llecte d, if 1 or m ore of t he f oll owi n g c o n di tio ns occ ur :  

ele vat i on of ser u m  AL T t o ≥ 5 × U L N o n 2 or m ore c o nsec uti ve bl o o d tests

ele vate d t otal bilir u bi n t o ≥ 2 × U L N (e xce pt f or cases of k n o w n Gil bert’s 
s y n dr ome)

ele vat i on of ser u m  AL P t o ≥ 2 × U L N o n 2 or m ore c o nsec uti ve bl o o d tests 

he pat ic e ve nt c o nsi dere d t o be a S A E
Elev ate d A L T/ A S T i n s u bjects wit h b aseli ne A L T/ A S T ≥1. 5 × U L N
I n a s u bject, w h o was e nr olle d wit h baseli ne A L T/ A S T ≥1. 5 × U L N, ele vate d A L T/ A S T ≥3 ×
baseli ne (res pecti vel y) o n t w o or m ore c o nsec ut i ve tests s h o ul d pr o m pt a d diti o nal he pat ic safety 
data c ollect i on.
A b n or m al A L P i n s u bjects wit h b aseli ne A L P ≥1. 5 × U L N
I n a s u bject, w h o was e nr olle d wit h baseli ne A L P ≥1. 5 × U L N, ele vate d A L P ≥2 × baseli ne o n 
t wo or m ore c o nsec ut i ve tests s h o ul d pr o m pt a d diti o nal he patic safety data c ollect i on.  
A b n or m al T B L i n s u bjects wit h b aseli ne T B L ≥1. 5 × U L N
I n a s u bject, w h o was e nr olle d wit h baseli ne T B L ≥1. 5 × U L N, ele vate d T B L ≥2 × baseli ne o n 
t wo or m ore c o nsec ut i ve tests s h o ul d pr o m pt a d diti o nal he patic safety data c ollect i on.
9. 5.
P h ar m a c o ki n eti c s
At  t he visits a n d ti mes s pecifie d i n t he Sc he d ule of Act i vities ( Sectio n 2 ), ve n o us bl o o d sa m ples 
of  a p pr o xi matel y 3 m L eac h will be c o llecte d t o deter mi ne t he plas ma c o nce ntrati o ns of 
tirze pati de.  A ma xi m u m o f 3 u nsc he d ule d sa m ples ma y be c ollecte d at a d dit i onal t i me p oi nts 
d uri n g t he st u d y  if warra nte d a n d a gree d u p o n bet wee n b ot h t he i n vesti gat or a n d s p o ns or.  
I nstr uctio ns f or t he c ollect i on a n d ha n dli n g of bl o o d sa m ples will be pr o vi de d b y t he s p o ns or.   
T he act ual  date a n d 2 4 -h o ur cl oc k ti me of  eac h sa m pli n g will be rec or de d.
9. 5. 1.
Bi o a n al y si s
S a m ples will  be a nal yze d at a la b orat or y a p pr o ve d b y t he s p o ns or a n d st ore d at a facility 
desi g nate d b y  t he s p o ns or.
C o nce ntrati o ns of tirze pati de will  be assa ye d usi n g a vali date d li q ui d chr o mat o gra p h y ta n de m
mass s pectr o metr y met h o d.

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 4 1
L Y 3 2 9 8 1 7 6
Bi oa nal y tic al sa m ples c ollecte d t o meas ure i n vest i gati o nal pr o d uct c o nce ntrati o ns will be 
retai ne d f or a ma xi m u m of 2 year s f oll owi n g last s u bject visit f or t he st u d y .  D uri n g t his ti me, 
sa m ples re mai ni n g after t he bi oa nal yses ma y be use d f or e x pl orat or y a nal yses s uc h as 
meta b o lis m w or k, pr otei n bi n di n g, or bi o a nal ytical met h o d cr oss-vali dat i on.
9. 6.
P h ar m a c o d y n a mi c s
9. 6. 1.
I m m u n o g e ni cit y A s s e s s m e nt s
F or i m m u n o ge nicit y testi n g, ve n o us bl o o d sa m ples of a p pr o xi matel y 1 0 m L will be c ollecte d 
fr om eac h s u bject acc or di n g t o t he Sc he d ule of Acti vit ies ( Secti o n 2 ) t o deter mi ne a nti b o d y 
pr o d ucti o n a gai nst L Y 3 2 9 8 1 7 6 .  A d diti onal sa m ples ma y be c ollecte d if t here is a p ossi bilit y t hat 
a n A E i s i m m u n ol ogi call y me diate d.  All sa m ples f or i m m u n o ge nicit y testi n g s h o uld ha ve a 
ti me-matc he d sa m ple f or P K a nal ysis w here rel e va nt .  I n t he e ve nt of dr u g h yperse nsi tivi t y 
reactio ns (i m me diate or n o n -i m me diate), a d ditio n al  sa m ples will be c ollecte d as close t o t he 
o nset of t he e ve nt as p ossi ble, at t he res ol ut i on of t he e ve nt, a n d 3 0 ( ± 3) da ys f oll owi n g t he 
e ve nt.  I nstr ucti o ns f or t he c ollecti on a n d ha n dli n g of bl o o d sa m ples will be pr o vi de d b y t he 
s p o ns or.  T he act ual date a n d 2 4-h o ur cl oc k ti me of eac h sa m pli n g will be rec or de d.
I mm u n o ge nicit y will  be assesse d b y a vali date d assa y desi g ne d t o detect A D A i n t he prese nce of 
L Y 3 2 9 8 1 7 6 .  A nti b o dies ma y be f urt her e val uate d f or t heir a bility t o ne utralize t he acti vity of  
L Y 3 2 9 8 1 7 6.  P osit i ve L Y 3 2 9 8 1 7 6 A D A sa m ples ma y als o be teste d f or cr oss-reacti vity wi t h 
nat i ve G L P-1 a n d GI P, a n d, if p osit i ve, ma y t he n be teste d f or ne utralizi n g a nt i b o dies a gai nst 
nat i ve G L P-1 a n d GI P.
All s u bjects will ha ve a n A D A sa m ple meas ure d at earl y disc o nti n uati on or at t he f oll o w - u p 
visit.  A ris k -base d a p pr oac h will be use d t o m o nit or s u bjects w h o de vel o p treat me nt -e mer ge nt 
A D A ( T E A D A), defi ne d as a tit er 2-f ol d ( 1 dil uti o n) greater t ha n t he mi ni m u m re q uire d dil uti on 
of  t he assa y if n o A D A were detecte d at baseli ne, or a 4-f ol d ( 2 dil uti ons) i ncrease i n titer, 
c o mpare d t o baseli ne, if A D A were detecte d at baseli ne.  T he mi ni m u m re q uire d dil uti o n o f t he 
A D A assa y is 1: 1 0.
Cli nicall y si g nifica nt T E A D A will be defi ne d as a n y T E A D A at t he last visit wit h:

a hi g h tit er (1 2 8 0) or a n i ncreasi n g titer fr o m last meas ure d val ue

a n ass ociat i on wi t h a mo d er at e -t o-se vere i njecti on- site reactio n

cr oss-reacti ve a nd/ or ne utralizi n g bi n di n g of a n A D A wit h e n d o ge n o us G L P -1 or GI P.
S u bjects w h o ha ve cli nicall y si g nifica nt T E A D A at earl y disc o nti n uati on or at t he f o ll ow- u p 
visit s h o uld b e f ol l owe d wi t h AD A testi n g e ver y  3 m o nt hs f or a p pr o xi matel y 1 ye ar or u ntil t he 
A D A t iters ha ve ret ur ne d t o t he baseli ne A D A titer ( defi ne d as A D A titer wit hi n 2 -f ol d of 
baseli ne). A P K sa m ple ma y be c ollecte d at t he f oll o w -u p i m m u n o ge nicit y assess me nt(s), if 
warra nte d a n d a gree d u p o n b y  t he i n vesti gat or a n d s p o ns or.

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 4 2
L Y 3 2 9 8 1 7 6
E ver y  att e mpt s h o u l d be ma de t o c o ntact s u bjects f or t he f o ll ow- u p i m m u n o ge nicit y assess me nt; 
h o we ver, if s u bjects are u n willi n g or u na ble t o ret ur n f or t he visit, t his is n ot c o nsi dere d a 
pr ot oc ol  de via tio n.
S u bjects f oll o we d f or at least 1 y ear after d osi n g w h o ha ve n ot ret ur ne d t o baseli ne, as defi ne d 
a b o ve, will be assesse d f or safet y c o ncer ns a n d, if n o cli nical se q uelae are rec o g nize d b y t he 
cli nical tea m, n o f urt her f o ll ow- u p will be re q uire d.  S u bjects w h o ha ve cli nical se q uelae t hat are 
c o nsi dere d p ote ntiall y relate d t o t he prese nce of T E A D A ma y als o be as ke d t o ret ur n f or 
a d ditio nal  foll o w -u p testi n g.
S a m ples will  be retai ne d f or a ma xi m u m of 1 5 years after t he last s u bject visit, or f or a s h orter 
p eri o d if l ocal  re g ulati ons a n d IR B all o w, at a facilit y selecte d b y t he s p o ns or.  T he d urati o n 
all o ws t he s p o ns or t o res p o n d t o f ut ure re g ulat or y re q uests relate d t o t he tirze pati de.  A n y 
sa m ples re mai ni n g after 1 5 years will be destr o ye d .  
9. 7.
G e n eti c s
A bl o o d sa m ple will be c ollecte d f or p har mac o ge netic a nal ysis as s pecifie d i n t he Sc he d ule o f 
Act i vities ( Sectio n 2 ), w here l ocal re g ulat i ons all o w.  
S a mples will n ot be use d t o c o n d uct u ns pecifie d disease or p o p ulat i on ge net ic researc h eit her 
n o w or i n t he f ut ure.  Sa m ples will be use d t o i n vesti gate varia ble e x p os ure or res p o nse t o 
tirze pati de a n d t o in vest i gate ge netic varia nts t h o u g ht t o pla y a r ole i n T 2 D M .  Assess me nt of 
varia ble res p o nse ma y i ncl u de e val uat i on of A Es or differe nces i n efficac y .  
All sa m ples will be c o de d wit h t he s u bject n u m ber.  T hese sa m ples a n d a n y data ge nerate d ca n 
be li n ke d bac k t o t he s u bject o nl y b y t he i n vesti gati ve site pers o n nel.  
S a m ples will  be retai ne d f or a ma xi m u m of 1 5 yea rs after t he last s u bject visit, or f or a s h orter 
p eri o d if l oc al re g ulati ons a n d/ or IR Bs i m p ose s h orter ti me li mits, for t he st u d y  at a facilit y 
selecte d b y Lill y or i ts desig nee .  T his rete ntio n p eri o d e na bles use of ne w tec h n o l ogi es, res p o nse 
t o re g ulat or y q uesti ons, a n d i n vest i gati on of varia ble res p o nse t hat ma y  not be o bser ve d u nt il 
later i n t he de vel o p m e nt of  tirze pati de or aft er tirze patide is c om merciall y a vaila ble.  
M ole c ular tec h n o l ogi es are e x pecte d t o i m pr o ve d uri n g t he 1 5 -ye ar st ora ge peri o d a n d t heref ore 
ca n n ot be s pecificall y na me d.  H o we ver, e xist i n g a p pr oac hes i ncl u de w h ole ge n ome or e x o me 
se q ue nci n g, ge n ome wi de ass ociati o n st u dies, m ult i ple x assa ys, a n d ca n di dat e ge ne st u dies.  
Re gar dless of tec h n o l og y  utilize d, data ge nerate d will be use d o nl y for t he s pecific researc h 
sc o pe descri be d i n t his secti on .  
9. 8.
Bi o m ar k er s
N ot a p plica ble .  
9. 9.
H e alt h E c o n o mi c s
T h is secti on is n ot a p plica ble f or t his st u d y.

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 4 3
L Y 3 2 9 8 1 7 6
1 0.
St ati sti c al C o n si d er ati o n s a n d D at a A n al y si s
1 0. 1. S a m pl e Si z e D et er mi n ati o n
It is pla n ne d t hat u p t o 3 0 s u bjects ma y be e nr olle d. T o s u p p ort t he pla n ne d a nal yses, at least 
6 s u bjects i n t he mil d a n d m o derate he patic i m pair me nt gr o u ps ( Gr o u ps 2 a n d 3), at least 6 a n d 
u p t o 1 2 c o ntr ol s u bjects ( Gr o u p 1) are e x pecte d t o c o m plete t he st u d y.  Eff orts will be ma de t o 
ac hie ve 6 c o m pleters wit h se vere he pat ic i m pair me nt ( Gr o u p 4); h o we ver, ac k n o wle d gi n g t he 
diffic ult y i n recr uiti n g t his s u bject p o p ulati o n, 2 t o 3 s u bjects wit h se vere he pat ic i m pair me nt 
ma y be a n acce pta ble tar get.
T his sa m ple size is base d o n t he F D A g ui da nce ( F D A 2 0 0 3), w hic h a d vises t hat at least 
6 s u bjects i n eac h st u d y ar m ( gr o u p) are re q uire d t o pr o vi de e val ua ble data.  T he sa m ple size was 
n ot sel ecte d t o satisf y a n a priori  st atistical re q uire me nt.
1 0. 2. P o p ul ati o n s f or A n al y s e s
1 0. 2. 1. St u d y P arti ci p a nt Di s p o siti o n
A detaile d descri pti o n o f s u bject dis p ositi on will be pr o vi de d at t he e n d of t he st u d y .  All 
s u bjects w h o disc o nti n ue fr o m t he st u d y will b e ide nt ifie d, a n d t he e xte nt of t heir partici patio 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.
1 0. 2. 2. St u d y P arti ci p a nt C h ar a ct eri sti c s
T he s u bject’s a ge, se x, wei g ht, hei g ht, B MI, race/s u b -race, t o bacc o/ nic oti ne ha bits, C hil d-P u g h 
sc ore, or ot her de m o gra p hic c haracterist ics will be rec or de d a n d ma y be use d i n t he P K a n d 
safety a nal yses as q ua nt itati ve or classificat i on varia bles.
1 0. 3. St ati sti c al A n al y s e s
Stati stical 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 mp a n y  or its 
desi g nee .
P har mac o ki net ic a nal ysis will  be c o n d ucte d o n data fr o m all s u bjects w h o were d ose d a n d ha ve 
e val ua ble data.  
S af et y a nal yses will be c o n d ucte d f or all e nr o lle d s u bjects, w het her or n ot t he y c o mplete d all  
pr ot oc ol  r e q uire me nts.
A d dit i onal e x plor at or y  a nal yses of t he data will be c o n d ucte d as dee me d a p pr o priate.  St u d y  
res ults ma y be p o ole d wit h t he res ults of ot her st u dies f or p o p ulati on P K a nal ysis p ur p oses t o 
a v o i d iss ues wit h p ost-h oc a nal yses a n d i nc o m p lete disclos ures of a na l yses.  
1 0. 3. 1. S af et y A n al y s e s
1 0. 3. 1. 1. Cli ni c al E v al u ati o n of S af et y
All i n vesti gati onal pr o d uct a n d pr ot oc ol pr oce d ure A Es will be liste d, a n d if t he fre q ue nc y o f 
e ve nts all o ws, safet y data will be s u m marize d usi n g descri pt i ve met h o d ol o g y .

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 4 4
L Y 3 2 9 8 1 7 6
T he i nci de nce of s y m pt o ms wil l be prese nte d b y  se verit y a n d b y ass o ciat i on wi t h i n vesti gati onal 
pr o d uct 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 e nr oll me nt will be 
di sti n g uis he d fr o m t h ose re p orte d as ne w or i ncrease d i n se verity d uri n g t he st u d y .  Eac h 
sy m pt o m will be classifie d b y t he m ost s uita ble ter m fr o m t he me dical reg ulat or y  dict i onar y .
T he n u m ber of i n vest i gati onal pr o d uct -relate d S A Es will be re p orte d.
1 0. 3. 1. 2. St ati sti c al E v al u ati o n of S af et y
S af et y para m eters t hat will be assesse d i ncl u de safet y cli nica l la bor at or y para m eters (i ncl u di n g 
a m ylase, li pase, a n d bl o o d gl uc ose), vit al sig ns, p h ysical e xa mi nat i ons, a n d E C G para meters.  
T he para meters will be liste d a n d s u m marize d usi n g sta n dar d descri pti ve statist ics.  P h ysical 
e xa mi nat i ons a n d E C Gs will be per f or me d for safet y  mo ni t orin g p ur p oses a n d will n ot be 
prese nte d.   If warra nte d , ad dit i onal a nal ysis will be perf or me d u p o n re vie w of t he data.
1 0. 3. 1. 3. I nj e cti o n-sit e R e a cti o n s
I nci de nce of er yt he ma, i n d urati o n, pai n, itc hi n g, a n d e de ma will be liste d a n d s u m marize d.  T he 
p ost -i njecti on pai n sc ore will be s u m marize d b y treat me nt.  A d diti o nal a nal yses ma y be 
perf or m e d, if a p pr o priate.
1 0. 3. 2. P h ar m a c o ki n eti c A n al y s e s
1 0. 3. 2. 1. P h ar m a c o ki n eti c P ar a m et er E sti m ati o n
P har mac o ki net ic para meter esti mates f or tirze pati de will be cal c ulate d b y sta n dar d 
n o nc o m part me nt al met h o ds of a nal ysis.
T he pri mar y  para meters f or a nal ysis will be C m a x an d A U C ( 0- ∞) of tirze pati de.  Ot her 
n o nc o m part me nt al para meters, s uc h as half-life, a p pare nt cleara nce, a n d a p pare nt v ol u me of 
di stri b uti on, ma y be r e p orte d.
A d dit i onal a nal yses ma y be c o n d ucte d as dee me d a p pr o priate.
1 0. 3. 2. 2. P h ar m a c o ki n eti c St ati sti c al I nf er e n c e
T he pri mar y  P K a nal ysis is t he e val uat i on of l o g -tra nsf or me d A U C( 0-∞) a n d C m a x usi n g a n 
a nal ysis of c o varia nce ( A N C O V A) m o d el  wit h he patic fu nct i on gr o u p as fi xe d fact or a n d b o d y 
w ei g ht as c o vari at e.  T he ge o metric least s q uares mea ns f or eac h gr o u p, ge o metric least s q uares
mea n rati o s bet wee n eac h he pat ic i m pair me nt le vel vers us t he c o ntr ol gr o u p, a n d t he 
c orres p o n di n g 9 0 % c o nfi de nce i nter vals will be esti mate d fr o m t he A NC O V A m o d el .  I n t he 
e ve nt of d ose a dj ust me nt base d o n t he i nteri m a nal yses res ults, d ose n or malize d P K para meters 
ma y be use d i n t he a b o ve m o del.
T he a nal ysis of t m a x will be base d o n a n o n para metric met h o d.  Me dia ns a n d differe nces i n 
me dia ns f or he patic f u ncti o n gr o u ps a n d t he p -val ue fr o m a Wilc o x o n ra n k s u m test will be 
prese nte d.
T he rel at i ons hi p bet wee n t he P K para meters a n d C hil d -P u g h Classificat i on para meters (ser u m 
al b u mi n c o nce ntrati o n, t otal bilir u bi n c o nce ntrati o n, a n d pr o t hr o m bi n ti me) will be assesse d 
gra p hicall y .  T he P K para meters A U C( 0 -∞), C ma x , a n d a p pare nt cleara nce will be pl otte d a gai nst 

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 4 5
L Y 3 2 9 8 1 7 6
eac h C hil d -P u g h Classificat i on para meter se paratel y .  A n a p pr o priate m o del ma y  be fitte d t o t he 
data.
A d dit i onal P K para meters ma y be a nal yze d if dee me d a p pr o priate f o ll owi n g a re vie w of t he data.
1 0. 3. 3. E v al u ati o n of I m m u n o g e ni cit y
T he fre q ue nc y a n d perce nta ge of  s u bjects wi t h pre-e xist i n g A D A a n d wit h T E A D A + t o 
tirze pati de will be ta b ulate d. Treat me nt -e mer ge nt A D As are defi ne d as t hose wi t h a tit er 2-f ol d 
( 1 dil uti on) greater t ha n t he mi ni m u m re q uire d dil uti o n if n o A D As were detecte d at baseli ne 
(treat me nt-i n d uce d A D A) or t h ose wit h a 4-f ol d ( 2 dil uti ons) i ncrease i n t iter c o m pare d t o 
baseli ne if A D As were detecte d at baseli ne (tr eat me nt -b o oste d A D A). T he mi ni m u m re q uire d 
dil ut i on of t he A D A assa y is 1: 1 0. F or t he T E A D A + s u bjects t he distri b utio n of  ma xi m u m titers 
will be descri be d .  If cr oss-reacti vity wi t h nat i ve G L P- 1 a n d GI P or ne utralizi n g a nt i b o dies 
a gai nst nati ve G L P -1 a n d GI P assa ys are perf or m e d, t he fre q ue nc y of  eac h will be re p orte d.
T he relat i ons hi p bet wee n t he prese nce of a nt i b o dies a n d t he P K para meters a n d safet y ma y be 
assesse d.
1 0. 3. 4. D at a R e vi e w D uri n g t h e St u d y
Data m a y be a nal yze d w hile t he trial is o n g oi n g.  A n assess me nt c o m mittee will n ot be f or me d.  
S af et y data will be re vie we d b y t he Lill y st u d y tea m o n a re g ular basis w hile s u bjects are 
e nr o lle d i n t he st u d y.
1 0. 3. 5. I nt eri m A n al y s e s
O ne i nteri m a nal ysis is pla n ne d t o occ ur d uri n g St u d y  G P GQ.   T w o s u bjects eac h fr o m Gr o u ps 2 
a n d 3 (s u bjects wit h mil d a n d m o derate he patic i m pair me nt, res pecti vel y) a n d at least 2 s u bjects 
i n Gr o u p 1 (a p pr o priate matc he d-c o ntr ol s u bjects wit h n or mal he pat ic f unct i on) will be e nr o lle d 
i n parallel a n d d ose d wit h 5 m g tirze pati de, fol l owe d b y a n i nteri m a nal ysis t o e val uate safet y,  
t olera bilit y, a n d P K data.  Ba se d o n t his i nteri m a nal ysis, d osi n g will eit her c o nti n ue at 5 mg or 
be re d uce d t o 2. 5 m g f or t he re mai n der of s u bjects i n Gr o u ps 2 a n d 3 ( mil d a n d m o derate 
i m pair me nt) a n d all s u bjects i n Gr o u p 4 (se vere i m pair me nt), as well as f or c o nt r ol s u bjects i n 
Gr o u p 1. T he fi nal d ose deter mi nat i ons will be ma de b y  t he i n vesti gat or a n d t he Lill y st u d y 
tea m.  If a n a d diti onal u n pla n ne d i nteri m a nal ysis is dee me d necessar y , t he Lill y C P, C R P, 
in vesti gat or, or desi g nee will c o ns ult wit h t he a p pr o priate me dical direct or or desi g nee t o 
deter mi ne if it is necessar y t o a me n d t he pr ot oc ol.

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 4 6
L Y 3 2 9 8 1 7 6
1 1.
R ef er e n c e s
A merica n Dia betes Ass ociat i on. Gl yce mic Tar gets. Sec 6. I n Sta n dar ds of Me dical Care i n 
Di a betes— 2 0 1 7 . Di a betes C are . 2 0 1 7; 4 0(S u p pl  1): S 4 8-S 5 6. A vaila ble at:
ht t p://care. dia betesj o ur nals. or g/c o nte nt/ 4 0/ S u p ple me nt _ 1/ S 4 8. Accesse d J u ne 0 4, 2 0 1 8.
C hil d C G, T urc otte J G. S ur ger y  a n d p ortal h y perte nsi on. T he li ver a n d p ortal h y perte nsi o n. 
E di te d b y C G C hil d. P hila del p hia: Sa u n ders ; 1 9 6 4:5 0 - 6 4.
[ F D A, 2 0 0 3] U S De part me nt of Healt h a n d H u ma n Ser vices, F o o d a n d Dr u g A d mi nistrati o n, 
Ce nter f or Dr u g E val uati o n a n d Researc h, Ce nter f or Bi o l ogi cs E val uat i on a n d Researc h. 
G ui da nce f or i n d ustr y : P har mac o ki netics i n patie nts wit h im paire d he pat ic f unct i on: St u d y  
desi g n, data a nal ysis, a n d i m pact o n d osi n g a n d la beli n g. Ma y  2 0 0 3.
H o n da F, Hi r a mats u A, H yo g o H, Ai kata H, Daij o K, Tera o ka Y, et al. E val uat i on of gl yce mic 
varia bilit y i n c hr o nic li ver disease patient s wit h t y pe 2 di a betes mellit us usi n g c o nt i n u o us 
gl uc ose m o ni t ori n g. P L o S O ne . 2 0 1 8 A pr 3; 1 3( 4):e 0 1 9 5 0 2 8. d oi: 1 0. 1 3 7 1
[I H S G] I nter nati o nal H y p o gl ycae mia St u d y Gr o u p. Gluc ose c o nce ntrati o ns of less t ha n 3. 0 
m m ol/ L ( 5 4 mg/ d L ) s h o uld be re p orte d i n cli nical trials: a j o i nt p ositio n state m e nt of t he 
A merica n Dia betes Ass ociat i on a n d t he E ur o pea n Ass ociat i on f or t he St u d y of Dia betes.
Di a betes C are . 2 0 1 7; 4 0( 1): 1 5 5- 1 5 7.
P u g h R N H, M urra y -L y o n  I M, Da ws o n J L, Pietr o ni M C, Willia ms R. Tra nsect i on of t he 
oes o p ha g us f or blee di n g oes o p ha geal varices. Br J S ur g . 1 9 7 3; 6 0: 6 4 6- 6 5 4.

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 4 7
L Y 3 2 9 8 1 7 6
A p p e n di x 1.
A b br e vi ati o n s a n d D efi niti o n s
T er m
D efi niti o n
A D A
a nti dr u g a nti b o d y
A E
a d verse e ve nt:  A n y u nt o war d me dical occ urre nce i n a patie nt or cli nical i n vesti gati o n 
s u bject a d mi nistere d a p har mace utical pr o d uct t hat d oes n ot necessaril y ha ve a ca usal 
relati ons hi p wit h t his treat me nt.  A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d 
si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g), s y m pt o m, or disease te m p orall y ass ociate d 
wit h t he use of a me dici nal (i n vesti gati o nal) pr o d uct, w het her or n ot relate d t o t he me dici nal 
(i n vesti gati o nal) pr o d uct.
A L P
al kali ne p h os p hatase
A L T
ala ni ne a mi n otra nsferase
A N C O V A
a nal ysis of c ovaria nce
A S T
as partate a mi n otra nsferase
A U C( 0 - ∞)
area u n der t he dr u g c o nce ntrati o n -ti me c ur ve fr o m zer o t o i nfi nit y
B M I
b o d y mass i n de x
B P
bl o o d press ure
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 L cr
creati ni ne cleara nce
C L D
c hr o nic li ver disease
C m a x
ma xi m u m o bser ve d dr u g c o nce ntrati o n
c o m pl ai nt
A c o m plai nt is a n y writte n, electr o nic, or oral c o m m u nicati o n t hat alle ges deficie ncies 
relate d t o t he i de ntit y, q ualit y, p urit y, d ura bilit y, relia bilit y, safet y or effecti ve ness, or 
perf or ma nce of a dr u g or dr u g deli ver y s yste m.
c o m pli a n c e
A d here nce t o all t he st u d y-relate d re q uire me nts, g o o d cli nical practice ( G C P) re q uire me nts, 
a n d t he a p plica ble re g ulat or y re q uire me nts.
c o nfir m ati o n
A pr ocess use d t o c o nfir m t hat la b orat or y test res ults meet t he q ualit y re q uire me nts defi ne d 
b y t he la b orat or y ge nerati n g t he data a n d t hat Lill y is c o nfi de nt t hat res ults are acc urate.  
C o nfir mati o n will eit her occ ur i m me diatel y after i nitial testi n g or will re q uire t hat sa m ples 
be hel d t o be reteste d at s o me defi ne d ti me p oi nt, de pe n di n g o n t he st e ps re q uire d t o o btai n 
c o nfir me d res ults.
C P
C hil d -P u g h

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 4 8
L Y 3 2 9 8 1 7 6
C R P
cli nical researc h p h y sicia n:  I n di vi d ual res p o nsi ble f or t he me dical c o n d uct of t he st u d y.  
Res p o nsi bilities of t he C R P ma y be perf or me d b y a p h ysicia n, cli nical researc h scie ntist, 
gl o bal safet y p h ysicia n or ot her me dical officer.
C R U
cli nical researc h u nit
e C R F
electr o nic case re p ort f or m
E C G
electr ocar di o gra m
e nr oll
T he act of assi g ni n g a s u bject t o a treat me nt.  S u bjects 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
S u bjects 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.
IR B
I nstit uti onal Re vie w B oar d
F D A
F o o d a n d Dr u g A d mi nistrati o n
G C P
g o o d cli nical practice
G G T
ga m ma -gl uta m yl tra nsferase
GI
gastr oi ntesti nal
GI P
gl uc ose -de pe n de nt i ns uli ntr o pic p ol y pe pti de
G L P - 1
gl uca g o n -li ke pe pti de- 1
HI V
h u ma n i m m u n o deficie nc y vir us
I B
I n vesti gat or’s Br oc h ure
I C F
i nf or me d c o nse nt f or m
I C H
I nter nati o nal C o u ncil f or Har m o nizati o n
i nf or m e d c o n s e nt
A pr ocess b y w hic h a s u bject 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 s u bject’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 
wr itte n, si g ne d a n d date d i nf or me d c o nse nt f or m.  
i nt eri m a n al y si s
A n i nteri m a nal ysis is a n a nal ysis of cli nical st u d y data, se parate d i nt o treat me nt gr o u ps, 
t hat is c o n d ucte d bef ore t he fi nal re p orti n g data base is create d/l oc ke d.
in v e sti g ati o n al 
pr o d u ct
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 st u d y, 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 orize d f or m.

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 4 9
L Y 3 2 9 8 1 7 6
i n v e sti g at or
A pers o n res p o nsi ble f or t he c o n d uct of t he cli nical st u d y a t a st u d y site.  If a st u d y is 
c o n d ucte d b y a tea m of i n di vi d uals at a st u d y site, t he i n vesti gat or is t he res p o nsi ble lea der 
of t he tea m a n d ma y be calle d t he pri nci pal i n vesti gat or.
le g al 
re pr e s e nt ati v e
A n i n di vi d ual or j u dicial or ot her b o d y a ut h orize d u n der a p plica ble la w t o c o nse nt, o n 
be half of a pr os pecti ve s u bject, t o t he s u bject’s partici pati o n i n t he cli nical st u d y.
M A D
m ulti ple asce n di n g d ose
M D R D - 4
t he 4 fact or m o dificati o n of diet i n re nal disease
o p e n -l a b el
A st u d y  i n w hic h t here are n o restricti o ns o n k n o wle d ge of treat me nt all ocati o n, t heref ore 
t he i n vesti gat or a n d t he st u d y partici pa nt are a ware of t he dr u g t hera p y recei ve d d uri n g t he 
st u d y.
P D
p har mac o d y na mic
P F S
prefille d s yri n ge
P G
plas ma gl uc ose
P K
p har mac o ki netic
S A E
seri o us a d verse e ve nt
S A D
si n gle asce n di n g d ose
S C
s u bc uta ne o us
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 U S A R s
s us pecte d u ne x pecte d seri o us a d verse reacti o ns
T 2 D M
t ype 2 dia betes mellit us
T B L
t otal bilir u bi n
T E A D A
treat me nt-e mer ge nt a nti dr u g a nti b o d y
tm 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

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 5 0
L Y 3 2 9 8 1 7 6
A p p e n di x 2.
Cli ni c al L a b or at or y  T e st s
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 a:
He mat ocrit
S o di u m
He m o gl o bi n
P otassi u m
Er y t hr oc yte c o u nt ( R B C)
Bicar b o nate
Mea n cell v ol u me 
C hl ori de 
Mea n cell he m o gl o bi n 
Calci u m 
Mea n cell he m o gl o bi n c o nce ntrati o n 
P h os p h o r us
Le u k oc ytes ( W B C)
Ma g nesi u m
A bs ol ute c o u nts of:
Gl uc ose, fasti n g
Ne utr o p hils
Bl o o d urea nitr o ge n 
L y m p h oc y t es
Ur ic aci d
M o n oc ytes
T otal c h olester ol
E osi n o p hils
Tri gl yceri des
Bas o p hils
T otal pr otei n
Platelets
Al b u mi n
Cell m or p h ol o g y b
T otal bilir u bi n c
Al kali ne p h os p hatase 
C oa g ulati o n Pa nel c
As partate a mi n otra nsferase 
a P T T, P T/I N R
Ala ni ne a mi n otra nsferase 
Creati ni ne
Ur i nal ysisa:
Ga m ma -gl uta m yl tra nsferase 
S pecific gra vit y
A m ylase
p H
Li pase
Pr otei n
Gl uc ose
Et ha n ol testi n g e
Ket o nes
Ur i ne dr u g scree ne
Bilir u bi n
He patitis B s urface a nti ge n d
Ur o bili n o ge n
He patitis C a nti b o d y d
Bl o o d
HI V d
Nitrite
Pre g na nc y test f
Micr osc o pic e xa mi nati o n of se di me nt b
F S H d, g
A b bre viati o ns:  a P T T = acti vate d partial t hr o m b o plasti n ti me; F S H = f ollicle -sti m ulati n g h or m o ne; HI V = h u ma n 
i m m u n o deficie nc y vir us ; I N R = i nter nati o nal n or malize d rati o; P T = pr ot hr o m bi n ti me; R B C = re d bl o o d cells; 
W B C = w hite bl o o d cells.
a
Perf or me d b y l ocal la b orat or y at scree ni n g (a n d a n y u nsc he d ule d sa m ples f or i m me diate safet y assess me nts) a n d 
b y ce ntral la b orat or y at all ot her ti me p oi nts.
b
If cli nicall y i n dicate d, per i n vesti gat or’s discreti o n.  
c
Perf or me d at Scree ni n g a n d Da y -1 wit h C P classificati o n.
d
Perf or me d b y l ocal la b orat or y at scree ni n g o nl y.
e
Ur i ne dr u g scree n perf or me d i n cli nic or b y l ocal la b orat or y at scree ni n g a n d re peate d pri or t o a d missi o n t o t he 
cli nical researc h u nit.  Et ha n ol testi n g will be perf or me d at a d missi o n t o t he cli nical researc h u nit.  Ur i ne dr u g 
scree n a n d et ha n ol le vel will be re peate d at ot her ti mes i n dicate d i n t he Sc he d ule of Ac ti vities.  A ser u m or 
sali var y dr u g scree n ma y be perf or me d o n s u bjects w h o are u na ble t o pr o d uce a uri ne sa m ple.
f
Fe male s u bjects o nl y.   Ser u m pre g na nc y test perf or me d b y l ocal la b orat or y at scree ni n g; uri ne pre g na nc y test 
perf or me d i n cli nic at all ot he r ti mes.
g
Fe male s u bjects o nl y.   T o c o nfir m p ost me n o pa usal stat us as nee de d.

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 5 1
L Y 3 2 9 8 1 7 6
A p p e n di x 3.
St u d y  G o v er n a n c e, R e g ul at or y a n d Et hi c al 
C o n si d er ati o n s
I nf or m e d C o n s e nt
T he i n vest i gat or is res p o nsi ble f or:

e ns uri n g t hat t he s u bject u n dersta n ds t he nat ure of t he st u d y , t he p ote ntial ris ks a n d 
be nefits of part ici pati n g i n t he st u d y, a n d t hat t heir partici pat i on is v ol unt ar y.

e ns uri n g t hat i nf or me d c o nse nt is gi ve n b y eac h s u bject or le gal re prese ntati ve.  T his 
i ncl u des o btai ni n g t he a p pr o priate si g nat ures a n d dates o n t he I C F pri or t o t he 
perf or m a nce of a n y pr ot oc ol pr oce d ures a n d pri or t o t he a d mi nistrati o n of i n vesti gati onal 
pr o d uct.

a ns weri n g a n y q uest i ons t he s u bject ma y  ha ve t hr o u g h o ut t he st u d y a n d s hari n g i n a 
ti mel y ma n ner a n y ne w i nf or mat i on t hat m a y be rele va nt t o t he s u bject ’s willi n g ness t o 
c o nti n ue his or her partici pat i on i n t he st u d y.

pr o vi d i n g a c o p y of t he I C F t o t he partici pa nt or t he partici pa nt’s le gal re prese ntati ve a n d 
retai ni n g a c o p y o n file .
R e cr uit m e nt
Lill y or i ts desig nee is res p o nsi ble f or t he ce ntral recr uit me nt  strate g y for s u bjects.  I n di vi d ual 
i n vesti gat ors ma y ha ve a d diti onal l ocal re q uire me nts or pr ocesses.   St u d y -s pecific recr uitme nt  
materi al s ho ul d be a p pr o ve d b y Lill y .
Et hi c al R e vi e w
T he i n vest i gat or m ust gi ve ass ura nce t hat t he IR B was pr o perl y  c o nstit ute d a n d c o n ve ne d as 
re q uire d b y I nter nati onal C o u ncil f or Har m o nizat i o n (I C H) g ui deli nes a n d ot her a p plica ble la ws 
a n d re g ulati o ns.
D oc u m e nt atio n of  IR B a p pr o val of t he pr ot oc ol a n d t he I C F m ust be pr o vi de d t o Lill y before t he 
st u d y ma y be gi n at t he i n vesti gati ve sites.  Lill y or its re prese ntati ves must a p pr o ve t he I C F 
bef ore i t is use d at t he i n vesti gati ve sites.  All I C Fs m ust be c o m plia nt wit h t he I C H g ui deli ne o n 
G C P.
T he st u d y  site’s IR B (s) s h o uld be pr o vi de d wi t h t h e fol l owi n g:

t he c urre nt I B a n d u p dates d uri n g t he c o urse of t he st u d y

I C F

r ele va nt c urric ula vit a e

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 5 2
L Y 3 2 9 8 1 7 6
R e g ul at or y C o n si d er ati o n s
T his st u d y  will be c o n d ucte d i n acc or da nce with t he pr ot oc ol a n d wit h:
1)
c o nse ns us et hics pri nci ples deri ve d fr o m i nter nat i onal et hics g ui deli nes, 
i ncl u di n g t he Declarati on of Helsi n ki a n d C o u ncil f or I nter nati o nal 
Or ga nizat i ons o f Me dical Scie nces ( CI O M S) I nter nat i onal Et hi cal G ui deli nes 
2)
a p plica ble I C H G C P G ui deli nes 
3)
a p plica ble la ws a n d re g ulati o ns
S o m e of t he o bli gati ons of t he s p o ns or will be assi g ne d t o a t hir d part y or ga nizati on.
Pr ot o c ol Si g n at ur e s
T he s p o ns or’s res p o nsi ble me dical o fficer will a p pr o ve t he pr ot oc ol, c o nfir mi n g t hat, t o t he best 
of  his or her k n o wle d ge, the pr ot oc ol acc uratel y descri bes t he pla n ne d desi g n a n d c o n d uct of t he 
st u d y.  
After rea di n g t he pr ot oc ol, eac h pri nci pal i n vest i gat or will si g n t he pr ot oc ol si g nat ure pa ge a n d 
se n d a c o p y of t he si g ne d pa ge t o a Lill y re prese ntati ve.
Fi n al R e p ort Si g n at u r e
T he fi nal re p ort c o or di nat i n g i n vesti gat or or desi g nee will si g n t he cli nical st u d y re p ort f or t his 
st u d y, i n dicati n g a gree me nt t hat, t o t he best of his or her k n o wle d ge, t he re p ort acc uratel y 
descri bes t he c o n d uct a n d res ults of t he st u d y .
T he i n vest i gat or wit h t h e most a nal yza ble s u bjects will ser ve as t he fi nal re p ort c o or di nat i n g 
i n vesti gat or.  If t his i n vesti gat or is u na ble t o f ulfill t his f u ncti o n, a n ot her i n vesti gat or will be 
c h ose n b y Lill y t o ser ve as t he fi nal re p ort c o or di nati n g i n vest i gat or.
T he s p o ns or’s res p o nsi ble me dical of ficer a n d statisticia n will si g n/a p pr o ve t he fi nal cli nical 
st u d y re p ort f or t his st u d y, c o nfir mi n g t hat, t o t he best of his or her k n o wle d ge, t he re p ort 
acc uratel y descri bes t he c o n d uct a n d res ults of t he st u d y.
D at a Q u alit y A s s ur a n c e
T o e ns ure acc urate, c o m plete, a n d relia ble data, Lill y or its re prese ntati ves will d o t he f o ll owi n g:

pr o vi de i nstr ucti o nal materi al t o t he st u d y sites, as a p pr o priate.

pr o vi de trai ni n g t o instr uct t he i n vest i gat ors a n d st u d y c o or di nat ors.  T his trai ni n g will 
gi ve i nstr ucti o n o n t he pr ot oc ol, t he c o m plet i on of t he eC R Fs, a n d st u d y  pr oce d ures.

ma ke peri o dic visit s t o t he st u d y sit e.

be a vaila ble f or c o ns ultati o n a n d sta y  in c o ntact wit h t he st u d y site pers o n nel b y mail, 
t ele p h o ne, a n d/ or fa x.

re vie w a n d e val uate eC R F data a n d/ or use sta n dar d c o m p uter e dits t o detect err ors i n data 
c ollect i on.

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 5 3
L Y 3 2 9 8 1 7 6

c o n d uct a q ualit y re vie w of t he data base.
I n a d diti on, Lill y or i ts re prese ntati ves will p eri o dicall y c hec k a sa m ple of t he s u bject data 
rec or de d a gai nst s o urce d oc u me nts at t he st u d y sit e.  T he st u d y ma y be a u dit e d b y Lill y a n d/ or 
re g ulat or y a ge ncies at a n y time.  I n vest i gat ors will be gi ve n n otice bef ore a n a u dit occ urs.
T he i n vest i gat or will kee p rec or ds of all ori gi nal s o urce data.  T his mi g ht i ncl u de la b orat or y  
tests, me dical rec or ds, a n d cli nical n otes.  If re q ueste d, t he i n vest i gat or will pr o vi de t he s p o ns or, 
a p plica ble re g ulat or y a ge ncies, a n d a p plica ble IR Bs wi t h direct access t o t he origi nal s o urce 
d oc u m e nts.
D at a C oll e cti o n T o ol s/ S o ur c e D at a
A n electr o nic data ca pt ure s y st e m will be use d i n t his st u d y.  T he sit e must defi ne a n d retai n all 
s o urce rec or ds a n d m u st mai ntai n a rec or d of a n y data w here s o urce data are directl y e ntere d i nt o
t he data ca pt ure s yste m.
D at a Pr ot e cti o n
Data s yste ms use d f or t he st u d y  will ha ve c o ntr ols a n d re q uire me nts i n acc or da nce with l ocal 
data pr otecti o n l a w.   
T he p u r p ose a n d use of s u bject pers o nal i nf or mat i o n c ollecte d will be pr o vi de d i n a writte n
d oc u m e nt  t o t he s u bject b y t he s p o ns or.
St u d y a n d Sit e Cl o s ur e
Di s c o nti n u ati o n of St u d y Sit e s
St u d y  sit e p artici pat i on ma y be disc o nt i n ue d if Lill y  or its desig nee , the i n vesti gat or, or t he IR B 
of  t he st u d y sit e j u d ges it necessar y f or me dical, safety,  re g ulat or y, or ot her reas o ns c o nsiste nt 
wi t h a p plica ble la ws, re g ulat i ons, a n d G C P.
Di s c o nti n u ati o n of t h e St u d y
T he st u d y  will b e disc o nti n ue d if Lill y or its desi g nee j u d ges it necessar y for m e dical, safet y,  
re g ulat or y, or ot her reas o ns c o nsiste nt wit h ap plica ble la ws , re g ulat i ons, a n d G C P.

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 5 4
L Y 3 2 9 8 1 7 6
A p p e n di x 4.
H e p ati c M o nit ori n g T e st s f or Tr e at m e nt -
E m er g e nt A b n or m alit y
S el ecte d tests ma y be o btai ne d i n t he e ve nt of a treat me nt -e mer ge nt he patic a b n or malit y a n d ma y 
be re q uire d i n f o ll o w-u p wi t h s u bjects i n c o ns ultati o n wit h L ill y or its desig nee C R P .
He p atic M o nit ori n g Tests
He p atic He m at ol o g y a
H a pt o gl o bi n a
He m o gl o bi n
He mat ocrit
He p atic C o a g ul ati o n a
R B C
Pr ot hr o m bi n Ti me
W B C
Pr ot hr o m bi n Ti me, I N R
Ne utr o p hils, se g me nte d
L y m p h oc y t es
He p atic Ser ol o gies a, b
M o n oc ytes
He patitis A a nti b o d y, t otal
E osi n o p hils
He patitis A a nti b o d y, I g M
Bas o p hils
He patitis B s urface a nti ge n
Platelets
He patitis B s urface a nti b o d y
He patitis B C ore a nti b o d y
He p atic C he mistr y a
He patitis C a nti b o d y
T otal bilir u bi n
He patitis E a nti b o d y, I g G
Al kali ne p h os p hatase
He patitis E a nti b o d y, I g M
A L T
A S T
A nti -n ucle ar a nti b o d y a
G G T
C P K 
Al k ali ne P h os p h at ase Is oe nz y mes a
A nti -s m o ot h m uscle a nti b o d y ( or a nti-acti n 
a nti b o d y) a
A b bre viati o ns:  A L T = ala ni ne a mi n otra nsferase; A S T = as p artat e a mi n otra nsferase; C P K = creati ne p h os p h o ki nase; 
G G T = ga m ma -gl uta m yl tra nsferase; I g = i m m u n o gl o b uli n; I N R = i nter nati o nal n or malize d rati o; R B C = re d 
bl o o d cells; W B C = w hite bl o o d cells.
a
Assa y e d b y Lill y-desi g nate d or l ocal la b orat or y.
b
Refle x/c o nfir mati o n de pe n de nt o n re g ulat or y re q uire me nts a n d/ or testi n g a vaila bilit y .

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 5 5
L Y 3 2 9 8 1 7 6
A p p e n di x 5.
Bl o o d S a m pli n g S u m m ar y
T his ta ble s u m marizes t he a p pr o xi mate n u m ber of ve ni p u nct ures a n d bl o o d v ol u mes f or all 
bl o o d sa m pli n g (scree ni n g, safet y lab orat ori es, a n d bi oa nal ytical assa ys) d uri n g t he st u d y.  
Pr ot oc o l I 8 F-M C -G P G Q S a m pli n g S u m m ar y
P ur p ose
Bl o o d V ol u me per 
S a m ple ( m L)
N u m ber of Bl o o d 
S a m ples
T ot al V ol u me 
( m L)
Scree ni n g tests a
2 1
1
2 1
Cli nical la b orat or y tests a

He mat ol o g y

C he mistr y, i ncl u di n g a m ylase 
a n d li pase

C oa g ulati o n pa nel
1 8
6
1 0 8
P har mac o ki netics 
3
1 0 ( + 3)
3 9
I m m u n o ge nicit y
1 0
3
3 0
P har mac o ge netics
1 0
1
1 0
T otal
2 4
2 0 8
T otal f or cli nical p ur p oses r ou n de d u p t o nearest 1 0 m L
2 1 0
a
A d diti o nal sa m ples ma y be dra w n if nee de d f or safet y p ur p oses.

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 5 6
L Y 3 2 9 8 1 7 6
A p p e n di x 6.
Cl a s sifi c ati o n of C o ntr a c e pti v e M et h o d s
Hi g hl y Effecti ve Met h o ds of C o ntr ace pti o n:

C o m bi ne d oral c o ntrace pti ve pill a n d mi ni pill

N u va Ri n g

I mpla nta ble c o ntrace pti ves

I njecta ble c o ntrace pti ves (s uc h as De p o-Pr o vera ® )

I ntra uteri ne de vice (s uc h as Mire na® a n d Para Gar d ® )

C o ntrace pti ve patc h – O N L Y w o me n < 1 9 8 p o u n ds or 9 0 k g

T ot al  a bsti ne nce or i n a sa me -se x relat i ons hi p (if t his is t heir pr eferre d a n d us ual 
lifestyle).  N ote:  peri o dic a bst i ne nce (f or e xa m ple, c ale n dar, o v ulat i on, s y m pt ot her mal, 
p ost o v ulat io n met h o ds), decl arat i on of a bst i ne nce j ust f or t he d urati o n of a trial, a n d 
wi t hdra wal  are n ot acce pta ble met h o ds of c o ntrace pti o n

Vasect o m y  – f or me n i n cli nical trials
Effecti ve Met h o ds of C o ntr ace pti o n ( m ust use c o m bi n ati o n of 2 met h o ds):

Male c o n d o m w ith s per mici de

Fe male c o n d o m wi t h s per mici de

Di a p hra g m wit h s per mici de

Cer vical s p o n ge

Cer vical ca p wit h s per mici de

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 5 7
L Y 3 2 9 8 1 7 6
A p p e n di x 7. P a n cr e ati c M o nit ori n g
Gl uca g o n -li ke pe pti de-1 a g o ni sts ha ve bee n ass ociate d wit h a p ossi ble ris k of ac ute pa ncreat itis.  
E pi de mi ol o gi c st u di es ha ve i n dicate d t hat t here is a n i ncrease d i nci de nce a n d pre vale nce of 
pa ncreat itis i n pers o ns wit h T 2 D M.
T o e n ha nce u n dersta n di n g of t he nat ural varia bilit y o f pa ncreat ic e nz y mes i n t he T 2 D M 
p o p ul at i on a n d, i n or der t o assess f or a n y p ote nti al effects of tirze pati de o n t he e x ocri ne 
pa ncreas, a m ylase a n d li pase val ues will be m o nit ore d i n all c urre nt a n d f ut ure cli nical trials wit h 
tirze pati de.
A d dit i onal m o nit ori n g will be re q ueste d f or a m ylase or li pase val ues ≥3 × t he U L N at a n y visit, 
e ve n i n as y m pt o mat ic s u bjects (see fi g ure bel o w).  Li pase a n d a m ylase ma y als o be o btai ne d at 
a n y ti me d uri n g t he cli nical trials f or a n y s u bject s us pecte d of ha vi n g s y m pt o ms s u g gesti ve of 
pa ncreat itis (s uc h as se vere GI si g ns a n d/ or s y m pt o ms), at t he i n vesti gat or’s discreti on.
Ac ute pa ncreat itis is a n A E defi ne d as a n ac ute i nfla m mat or y pr ocess of t he pa ncreas t hat ma y 
als o i n v o l ve peri pa ncreatic tiss ues a n d/ or re m ote or ga n s yste ms.  T he dia g n osis of ac ute 
pa ncreat itis re q uires 2 of  t he f oll owi n g 3 feat ures:

a b d o mi nal pai n c haracteristic of ac ute pa ncreatit is

ser u m a m ylase a n d/ or li pase ≥3 × U L N

c haracterist ic fi n di n gs of ac ute pa ncreatitis o n c o m p ute d t o m o gra p h y sca n or 
ma g net ic res o na nce i ma gi n g
M ost s u bjects wi t h ac ute pa ncreatitis e x perie nce a b d omi na l pai n t hat is l ocate d ge nerall y i n t he 
e pig astri u m, a n d ra diates t o t he bac k i n a p pr o xi matel y  o n e-half of t he cases.  T he pai n is ofte n 
ass ociat e d wit h na usea a n d v omit i n g.  H o we ver, e x perie nce with G L P -1 a g o ni sts has 
d e m o nstrate d t hat s o m e s u bjects as y m pt o mat ic f or classic pa ncreatit is ma y de m o nstrate 
sig nifica nt el e vat i ons of li pase a n d/ or a m ylase.  F or s u bjects c o nsi dere d b y i n vest i gat ors t o be 
as y m pt o mat ic f or pa ncreatitis, b ut w h ose val ue(s) f or li pase a n d/ or a m ylase are ≥3 × U L N, a n 
alg ori t h m is i n place t o f o ll ow t hese s u bjects safel y a nd t o q ui c kl y reac h ( or not reac h) a 
di a g n osis of pa ncreat itis.

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 5 8
L Y 3 2 9 8 1 7 6
A b bre viati o ns:  C B C = c o m plete bl o o d c o u nt; C T = c o m p ute d t o m o gra p h y; 
L F Ts = li ver f u ncti o n tests; M RI = ma g netic res o na nce i ma gi ng.
(if a p pli c a bl e)

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 5 9
L Y 3 2 9 8 1 7 6
S u bjects di a g n ose d wit h pa ncreatitis will be disc o nti n ue d fr om t he st u d y.  I n vesti gat ors will be 
res p o nsi ble f or f oll owi n g, t hr o u g h a n a p pr o priate healt hcare o pti o n, t hese pa ncreat itis A Es u nt il 
t he e ve nts res ol ve or are e x plai ne d.  A d verse e ve nts t hat me et t he dia g n ostic crit eria of ac ute 
pa ncreat itis will be ca pt ure d as S A Es.  F or all ot her pa ncreatic A Es (s uc h as i di o pat hic or 
as y m pt o mat ic pa ncreatic e nz y me a b n or malities), t he i n vesti gat or will be res p o nsi ble f or 
deter mi ni n g t he seri o us ness of t he e v e nt ( A E or S A E) a n d t he relate d ness of t he e ve nt t o st u d y 
dr u g.

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 6 0
L Y 3 2 9 8 1 7 6
A p p e n di x 8.
R e a s o n a bl y  Anti ci p at e d S eri o u s A d v er s e 
E v e nt s
R e a s o n a bl y A nti ci p at e d S eri o u s A d v er s e E v e nt s
I n dic ati o n or St u d y P o p ul ati o n:  T y pe 2 Di a betes Mellit us
Gr o u p 1:  A n tici pate d c o m or bi dities e x pecte d t o be re p orte d as seri o us a d verse e ve nts i n cli nical st u dies:

M y ocar dial i nfarcti o n (fatal a n d n o nfatal) a

Cere bral vasc ular acci de nt (fatal a n d n o nfatal) b

M y ocar dial isc he mia c

Peri p heral vasc ular disease d

I nfecti o ns
Gr o u p 2:  E ve nts w hic h m a y  or ma y n ot be a ntici pate d c o m or bi dities of t y pe 2 dia betes mellit us, ma y i nfre q ue ntl y 
be re p orte d as seri o us a d verse e ve nts i n cli nical st u dies:

Reti n o pat h y e

Ne p hr o pat h y f

Ne ur o pat h y g

S u d de n deat h a n d car di o vasc ular deat h n ot d ue t o m y ocar dial i nfarcti o n or str o ke

Car diac fail ure

Dia betic ket oaci d osis

Dia betic f o ot

Fract ures

Ne o plasia

H y p o gl yce mia

H y per gl yce mic h y per os m olar s y n dr o me or state
E x a m ples of ter ms i n t he c ate g ories a b o ve i ncl u de, b ut are n ot li mite d t o:
a
Ac ute m y ocar dial i n farcti o n, m y ocar dial i nfarcti o n, ac ute c or o nar y s y n dr o me.
b
Cere br o vasc ular acci de nt, str o ke, cere bral i nfarct, isc he mic cere bral i nfarcti o n, isc he mic st r oke, tra nsie nt 
isc he mic attac k.
c
A n gi na, u nsta ble a n gi na, ac ute c or o nar y s y n dr o me, c or o nar y arter y di sease, c or o nar y arter y b y pass graft, 
perc uta ne o us c or o nar y i nt er ve nti o n, c or o nar y a n gi o plast y.
d
Peri p heral vasc ular disease, dia betic peri p heral vasc ular disease, dia betic vasc ular disease, car oti d 
e n darterect o m y, peri p heral re vasc ularizati o n.
e
Bli n d ness, pr oliferati ve reti n o pat h y, n o n pr oliferati ve ( bac k gr o u n d) reti n o pat h y, dia betic reti n o pat h y, reti nal laser 
c oa g ulati on, p h ot oc oa g ulati o n, l oss of visi o n.
f
Dia betic ne p hr o pat h y, re nal fail ure, ac ute re nal fail ure, re nal i ns ufficie nc y.   S h o ul d n ot i ncl u de ter ms ass ociate d 
wit h prere nal az ote mia d ue t o de h y drati o n.
g
Peri p heral ne ur o pat h y, m o n o ne ur o pat h y, a ut o n o mic ne ur o pat h y, ort h ostatic or p ost ural h y p ote nsi o n .

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 6 1
L Y 3 2 9 8 1 7 6
A p p e n di x 9.
P er mitt e d M e di c ati o n s f or S u bj e ct s wit h 
H e p ati c I m p air m e nt
E xa m ples of p er mitte d me d icati ons i n s u bjects wi t h he patic i m pair me nt are prese nte d i n t he ta ble
bel o w , w hic h ser ves as a g ui da nce a n d is neither i nte n de d t o be prescri pt i ve n or e x ha usti ve. 
Ot her dr u gs n ot liste d i n t his ta ble (s uc h as a nti h y perte nsi ve a ge nts) ma y be a ut h orize d d uri n g 
t he st u d y at t he discret i on of t he s p o ns or a n d i n vesti gat or.
T her a pe utic C ate g or y Dr u gs
Dr u gs
A nti bi otics
Ofl o xaci n 
N orfl o xaci n 
Ne o m yci n 
Pr urit us Treat me nt
Ur s o de o x yc h olic aci d 
C h olest yra mi ne 
N utriti o nal s u p ple me ntati o n
Vita mi ns A, D, E, K a n d Calci u m
Di uretics
F ur ose mi de 
S pir o n olact o ne 
H y dr oc hl or ot hiazi de 
A m m o ni u m Det o xica nt
Lact ul ose 
Ne o m yci n 
Metr o ni daz ole
Rifa xi mi n
I m m u n os u p pressi ve a ge nts
C ortic oster oi ds
I nterfer o n α 2a 
I nterfer o n α 2 b 
A nti virals
La mi v u di ne 
Ri ba viri n 
E nteca vir 
Le di pas vir/ S of os b u vir

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 6 2
L Y 3 2 9 8 1 7 6
A p p e n di x 1 0.
Pr ot o c ol A m e n d m e nt I 8 F-M C -G P G Q ( a) 
S u m m ar y - A Si n gl e D o s e P h ar m a c o ki n eti c St u d y  of 
Tir z e p ati d e i n S u bj e ct s wit h V ar y i n g D e gr e e s of H e p ati c 
I m p air m e nt
O v er vi e w
Pr ot oc ol  I 8 F-M C -G P G Q , A Si n gle D ose P har ma c o ki net ic St u d y of Tirze pati de i n S u bjects wit h 
Var yi n g De grees of He pat ic I m pair me nt, has bee n a me n de d.  T he ne w pr ot oc ol is i n dicate d b y 
A me n d me nt ( a) a n d will be use d t o c o n d uct t he st u d y i n place of a n y prece di n g versi o n of t he 
pr ot oc ol .
T he o verall c ha n ges a n d rati o nale f or t he c ha n ges ma de t o t his pr ot oc ol are as f o ll ows:

Pr o vi de i m pr o ve d cl arit y o n w he n a d ditio n al  he patic mo ni t orin g tests , as descri be d i n 
A p pe n di x 4 , s h o uld be perf or m e d.  T here i s a nee d t o differe ntiate bet wee n t he c ut -off 
trig ger f or testi n g i n s u bjects wit h n or mal li ver f u ncti o n e nz y me tests a n d patie nts wit h 
he pat ic i m pair me nt wit h ele vate d baseli ne li ver e nz y mes.  
o
A me n de d Sect i on 9. 4. 7. 1 .
o
A d de d Sect i on 9. 4. 7. 2 .

A d de d clarificat i on t o E xcl usi o n  Crit erio n [ 3 7] t o a p pl y o nl y t o G r o u p 1 healt h y c o ntr ols.

A d de d clarificat i on t o E xcl usi o n  Crit erio n [ 6 0] s pecif yi n g s yste mic gl uc oc orti c o i ds.

Mi n or e di t orial c ha n ges a n d f or matti n g c orrecti o ns were ma de b ut n ot necessaril y  
detaile d bel o w.

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 6 3
L Y 3 2 9 8 1 7 6
R e vi s e d Pr ot o c ol S e cti o n s
N ote:
All deleti o ns h a ve bee n ide nt ifie d b y striket hr o u g hs .
All a d ditio ns ha ve bee n i de nt ifie d b y t he use of u n dersc ore .
6. 2. 1.
E x cl u si o n Crit eri a f or All S u bj e ct s U nl e s s Ot h er wi s e S p e cifi e d
[ 3 7]
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 (a p plies t o Gr o u p 
1 c o ntr ol s u bjects o nl y)
6. 2. 3.
A d diti o n al E x cl u si o n Crit eri a f or S u bj e ct s wit h T 2 D M a n d H e p ati c I m p air m e nt
[ 6 0]
ha ve recei ve d c hr o nic (last i n g > 1 4 c o nsec uti ve da ys) s yste mic gl uc oc ortic oi d t hera p y 
(e xcl u di n g t o pical, i ntra-artic ular, a n d i n hale d pre parati o ns) i n t he past year or ha ve recei ve d a n y  
s yste mic gl uc oc orti c o i d t hera p y withi n 3 0 da ys bef ore scree ni n g
9. 4. 7. 1.
H e p ati c S af et y M o nit ori n g i n S u bj e ct s wit h T r e at m e nt- em er g e nt A b n or m al 
L i v er T e st s
If a st u d y s u bject e x perie nces ele vate d A L T ≥3 × U L N, A L P ≥2 × U L N , or ele vate d t otal bilir u bi n 
≥2 × U L N, li ver tests ( A p pe n di x 4 ) s h o uld be re peate d wi t hi n 3 t o 5 da ys i ncl u di n g A L T, A S T, 
A L P, t otal bilir u bi n, ga m ma -gl uta m yl  tra nsferase, a n d creati ni ne p h os p h o ki nase t o c o nfir m t he 
a b n or malit y a n d t o deter mi ne if it is i ncreasi n g or decreasi n g.  If t he a b n or mality persists or 
w orse ns, cli nical a n d la b orat or y  mo ni t ori n g s h o uld be i ni tiate d b y t he i n vesti gat or base d o n 
c o ns ultati o n wit h t he Lill y C P or C R P .  M o ni t ori n g s h o uld c o nti n ue u nt il le vels n or malize a n d/ or 
are ret ur ni n g t o a p pr o xi mate baseli ne le vels.  
A d dit i onal safety data s h o ul d be c o llecte d if 1 or m ore of t he f oll o wi n g c o n diti ons occ ur :  

ele vat i on of ser u m  AL T t o ≥ 5 × U L N o n 2 or m ore c o nsec uti ve bl o o d tests

ele vate d t otal bilir u bi n t o ≥ 2 × U L N (e xce pt f or cases of k n o w n Gil bert’s 
s y n dr ome)

ele vat i on of ser u m  AL P t o ≥ 2 × U L N o n 2 or m ore c o nsec uti ve bl o o d tests 

he pat ic e ve nt c o nsi dere d t o be a n S A E
A b n or m al liver tests i n st u dy p artici p a nts wit h n or m al or ne ar n or m al b aseli ne A L T, A S T, 
A L P, a n d t ot al bilir u bi n (T B L; < 1. 5 × U L N)
If a s u bject w h o was e nr olle d with baseli ne A L T, A S T, A L P, T B L < 1. 5 × U L N, e x perie nces 
ele vate d A L T ≥3 × U L N, A L P ≥2 × U L N, or T B L ≥2 × U L N, li ver tests ( A p pe n di x 4) s h o ul d be 
re peate d wit hi n 4 8 t o 7 2 h o urs, i ncl u di n g A L T, A S T, A L P, T B L, ga m ma -gl uta m yl  tr a nsferase 
(G G T ), a n d creati ne ki nase ( C K ) t o c o nfir m t he a b n or mality a n d t o deter mi ne if it is i ncreasi n g 
or decreasi n g.  
If t he a b n or mality persists or w orse ns, cli nical a n d la b orat or y  mo ni t ori n g, a n d e val uati on f or 
p ossi ble ca uses of a b n or mal li ver tests s h o ul d be i nit iate d b y t he i n vesti gat or i n c o ns ultati on wi t h 

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 6 4
L Y 3 2 9 8 1 7 6
t he Lill y C P or C R P.  M o nit ori n g s h o uld c o nti n ue u nt il le vels n or malize a n d/ or are ret ur ni n g t o 
a p pr o xi mate baseli ne le vels.
Elev ate d A L T/ A S T i n s u bjects wit h b aseli ne A L T/ A S T ≥1. 5 × U L N
If a s u bject, w h o was e nr olle d wit h baseli ne A L T/ A S T ≥1. 5 × U L N, e x perie nces ele vate d 
A L T/ A S T ≥2 × baseli ne (res pect i vel y), li ver tests ( A p pe n di x 4) s h o ul d be re peate d wit hi n 4 8 t o 
7 2 h o urs, i ncl u di n g A L T, A S T, A L P, T B L, G G T, a n d C K t o c o nfir m t he a b n or malit y a n d t o 
deter mi ne if it is i ncreasi n g or decreasi n g.  
If t he a b n or mality persists or w orse ns, cli nical a n d la b orat or y  mo ni t ori n g, a n d e val uati on f or 
p ossi ble ca uses of a b n or mal li ver tests s h o ul d be i nit iate d b y t he i n vesti gat or i n c o ns ultati on wi t h 
t he Lill y C P or C R P.  M o nit ori n g s h o uld c o nti n ue u nt il le vels n or malize a n d/ or are ret ur ni n g t o 
a p pr o xi mate baseli ne le vels.
Elev ate d A L P i n s u bjects wit h b aseli ne A L P ≥1. 5 × U L N
If a s u bject, w h o was e nr olle d wit h baseli ne A L P ≥1. 5 × U L N, e x perie nces ele vate d A L P ≥2 × 
baseli ne, li ver tests ( A p pe n di x 4) s h o ul d be re peate d wit hi n 4 8 t o 7 2 h o urs, i ncl u di n g A L T, A S T, 
A L P, T B L, G G T, a n d C K t o c o nfir m t he a b n or malit y a n d t o deter mi ne if it is i ncreasi n g or 
decreasi n g.  
If t he a b n or mality p er sists or w orse ns, cli nical a n d la b orat or y mo ni t ori n g, a n d e val uati on f or 
p ossi ble ca uses of a b n or mal li ver tests s h o ul d be i nit iate d b y t he i n vesti gat or i n c o ns ultati on wi t h 
t he Lill y C P or C R P.  M o nit ori n g s h o uld c o nti n ue u nt il le vels n or malize a n d/ or are ret ur ni n g t o 
a p pr o xi mate baseli ne le vels.
Elev ate d T B L i n s u bjects wit h b aseli ne T B L ≥1. 5 × U L N
If a s u bject, w h o was e nr olle d wit h baseli ne T B L ≥1. 5 × U L N, e x perie nces ele vate d T B L ≥1. 5 × 
baseli ne, li ver tests ( A p pe n di x 4) s h o ul d be re peate d wit hi n 4 8 t o 7 2 h o urs, i ncl u di n g A L T, A S T, 
A L P, T B L, direct bilir u bi n, G G T, a n d C K t o c o nfir m t he a b n or malit y a n d t o deter mi ne if it is 
i ncreasi n g or decreasi n g.  
If t he a b n or mality persists or w orse ns, cli nical a n d la b orat or y  mo ni t ori n g, a n d e val uati on f or 
p ossi ble ca u ses of a b n or mal li ver tests s h o uld be i ni tiate d b y t he i n vesti gat or i n c o ns ultati on wi t h 
t he Lill y C P or C R P.  M o nit ori n g s h o uld c o nti n ue u nt il le vels n or malize a n d/ or are ret ur ni n g t o 
a p pr o xi mate baseli ne le vels.
9. 4. 7. 2
A d diti o n al H e p ati c D at a C oll e cti o n ( H e p ati c S af et y e C R F) i n S u bj e ct s wit h 
Tr e at m e nt -e m er g e nt A b n or m al Li v er T e st s
Tre at me nt -e mer ge nt a b n or m al liver tests i n s u bjects wit h n or m al or ne ar n or m al b aseli ne 
A L T, A S T, A L P, a n d T B L ( < 1. 5 × U L N)
I n a s u bject, w h o was e nr olle d wit h baseli ne A L T, A ST, A L P, a n d T B L < 1. 5 × U L N, a d dit i onal 
he pat ic safety data s h o ul d be c o llecte d, if 1 or m ore of t he f oll owi n g c o n di tio ns occ ur :  

ele vat i on of ser u m  AL T t o ≥ 5 × U L N o n 2 or m ore c o nsec uti ve bl o o d tests

I 8 F-M C -G P G Q ( a) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 6 5
L Y 3 2 9 8 1 7 6

ele vate d t otal bilir u bi n t o ≥ 2 × U L N (e xce pt f or cases of  k n o w n Gil bert’s 
s y n dr ome)

ele vat i on of ser u m  AL P t o ≥ 2 × U L N o n 2 or m ore c o nsec uti ve bl o o d tests 

he pat ic e ve nt c o nsi dere d t o be a S A E
Elev ate d A L T/ A S T i n s u bjects wit h b aseli ne A L T/ A S T ≥ 1. 5 × U L N
I n a s u bject, w h o was e nr olle d wit h baseli ne A L T/ A S T ≥1. 5 × U L N, ele vate d A L T/ A S T ≥3 × 
baseli ne (res pecti vel y) o n t w o or m ore c o nsec ut i ve tests s h o ul d pr o m pt a d diti o nal he patic safety 
data c ollect i on.
A b n or m al A L P i n s u bjects wit h b aseli ne A L P ≥1. 5 × U L N
I n a s u bject, w h o was e nr olle d wit h baseli ne A L P ≥1. 5 × U L N, ele vate d A L P ≥2 × baseli ne o n 
t wo or m ore c o nsec ut i ve tests s h o ul d pr o m pt a d diti o nal he patic safety data c ollect i on.  
A b n or m al T B L i n s u bjects wit h b aseli ne T B L ≥1. 5 × U L N
I n a s u bject, w h o was e nr olle d wit h baseli ne T B L ≥1. 5 × U L N, ele vate d T B L ≥2 × basel i ne o n 
t wo or m ore c o nsec ut i ve tests s h o ul d pr o m pt a d diti o nal he patic safety data c ollect i on.

L e o  D o c u m e n t  I D  =  5 a e 2 3 6 1 e - e d c 8 - 4 7 c 2 - 9 4 4 8 - f 4 b 8 f 0 a 3 6 7 f 8
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  1 7 - J u l - 2 0 1 9  1 4 : 5 9 : 2 4  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  1 8 - J u l - 2 0 1 9  1 9 : 2 6 : 2 1  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
P P D
P P D