Conditions: Hepatic Insufficiency
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 32
Healthy volunteers: yes

Brief summary:
The purpose of this study is to assess how fast tirzepatide gets into the blood stream and how long it takes the body to remove it in participants with impaired liver function compared to healthy participants. The study will last about two months and will include five visits to the study center.

Detailed description:

Arms:
arm 1: Participants with normal hepatic function received single subcutaneous dose of 5 milligrams (mg) tirzepatide. arm 2: Participants with mild hepatic impairment received single subcutaneous dose of 5 mg tirzepatide. arm 3: Participants with moderate hepatic impairment received single subcutaneous dose of 5 mg tirzepatide. arm 4: Participants with severe hepatic impairment received single subcutaneous dose of 5 mg tirzepatide.

Interventions: intervention 1: Tirzepatide
Intervention descriptions: intervention 1: Administered SC

Protocol document:
Prot_000.pdf: 
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
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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
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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
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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
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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.


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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 


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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
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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.


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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 ).


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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.


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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


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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.


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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 


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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.


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[ 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.  


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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.


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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.


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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.  


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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 .


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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.


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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.  


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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 


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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.


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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


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
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 .


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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).


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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.


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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 


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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.


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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.


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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.


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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 .


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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 


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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

SAP_001.pdf: 
Statistical A nal ysis Pla n:  I 8 F- M C- G P G Q
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: 2 0- Ma y- 2 0 1 9


Fi nal, 1 5 Ma y 2 0 1 9
             Pa ge 1 of 1 9
S T A TI S TI C A L A N A L Y SI S P L A N
A Si n gle D ose P h ar m ac o ki netic St u d y of Tirze p ati de i n S u bjects wit h V ar yi n g De grees of 
He p atic I m p air me nt
Stati stical A nal ysis Pla n Stat us : Fi nal
Stati stical A nal ysis Pla n Date : 1 5 -Ma y - 2 0 1 9
St u d y  Dr u g: Ti rze pati de (L Y 3 2 9 8 1 7 6 )
S p o ns or Refere nce : I 8 F-M C -G P G Q
C o va nce C R U St u d y : 1 0 0 0 0 7 1 - 8 3 9 9 7 1 5
Cli nical P hase I
A p pr o v al D at e: 2 0- M a y- 2 0 1 9 G M T


Fi nal, 1 5 Ma y 2 0 1 9
             Pa ge 2 of 1 9
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
C o va nce Cli nical St u d y  N o. 1 0 0 0 0 7 1- 8 3 9 9 7 1 5
S p o ns or Refere nce I 8 F -M C -G P G Q
1. T A B L E O F C O N T E N T S
1.
T A B L E O F C O N T E N T S .....................................................................................................2
2.
A B B R E VI A TI O N S ..............................................................................................................4
3.
I N T R O D U C TI O N ...............................................................................................................6
4.
S T U D Y O BJ E C TI V E S ........................................................................................................6
4. 1
Pri mar y O bject i ve..........................................................................................................6
4. 2
Sec o n dar y  O bjecti ve......................................................................................................6
4. 3
E x pl or at or y  O bjecti ve ....................................................................................................7
5.
S T U D Y D E SI G N .................................................................................................................7
5. 1
C hil d -P u g h Cl assificat i on ..............................................................................................8
6.
T R E A T M E N T S ...................................................................................................................9
7.
S A M P L E SI Z E J U S TI FI C A TI O N .......................................................................................9
8.
D E FI NI TI O N O F A N A L Y S I S P O P U L A TI O N S................................................................1 0
9.
S T A TI S TI C A L M E T H O D O L O G Y ...................................................................................1 0
9. 1
Ge neral ........................................................................................................................1 0
9. 2
D e m o gra p hics a n d S u bject Dis p osit i on ........................................................................1 0
9. 3
P har mac o ki net ic Assess me nt .......................................................................................1 1
9. 3. 1
P har mac o ki net ic A nal ysis ...................................................................................1 1
9. 3. 2
P h ar mac o ki net ic Statistical Met h o d ol o g y ...........................................................1 4
9. 4
P har mac o d y na mic Assess me nt ....................................................................................1 5
9. 4. 1
I mm u n o ge nicit y ................................................................................................. 1 5
9. 5
S af et y a n d T olera bilit y Assess me nts ............................................................................1 6
9. 5. 1
A d verse e ve nts ...................................................................................................1 6
9. 5. 2
C o nc o mita nt me dicat i on .....................................................................................1 6
9. 5. 3
Cli nical la b orat or y  para meters............................................................................1 6
9. 5. 4
Gl uc ose M o ni t ori n g a n d H yper gl yce mia/ H y p o gl yce mia Re p orti n g .....................1 6
9. 5. 5
Vi t al si g ns ..........................................................................................................1 6
9. 5. 6
Electr ocar di o gra m ( E C G) ...................................................................................1 7
9. 5. 7
I njecti on- site Assess me nts..................................................................................1 7
9. 5. 8
He pati c M o nit orin g ............................................................................................1 7
9. 5. 9
H y perse nsi tivi t y R e a ctio ns .................................................................................1 7
9. 5. 1 0
Ot her assess me nts ...............................................................................................1 7
9. 5. 1 1
S af et y a n d T olera bilit y Statisti c al Met h o d olo g y.................................................. 1 8


Fi nal, 1 5 Ma y 2 0 1 9
             Pa ge 3 of 1 9
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
C o va nce Cli nical St u d y  N o. 1 0 0 0 0 7 1- 8 3 9 9 7 1 5
S p o ns or Refere nce I 8 F -M C -G P G Q
1 0. I N T E RI M A N A L Y S E S .....................................................................................................1 8
1 1. C H A N G E S F R O M T H E P R O T O C O L S P E CI FI E D S T A T I S TI C A L A N A L Y S E S ............1 8
1 2. R E F E R E N C E S ..................................................................................................................1 8
1 3. D A T A P R E S E N T A TI O N ..................................................................................................1 8
1 3. 1 Deri ve d Para meters .....................................................................................................1 8
1 3. 2 Missi n g Data ...............................................................................................................1 9
1 3. 3 I ns ufficie nt Dat a for Prese ntati o n ................................................................................1 9


Fi nal, 1 5 Ma y 2 0 1 9
             Pa ge 4 of 1 9
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
C o va nce Cli nical St u d y  N o. 1 0 0 0 0 7 1- 8 3 9 9 7 1 5
S p o ns or Refere nce I 8 F -M C -G P G Q
2. A B B R E VI A TI O N S
A b bre viat i ons pertai n t o t he Stati stical A nal ysis Pla n ( S A P ) o nl y ( n ot t he ta bles, fi g ures a n d 
listi n gs [T F Ls ]).
% A U C(t
last-∞)
P erce nta ge of A U C( 0 -∞) e xtra p olate d
A D A
A nt i-dr u g a nt i b o d y
A E
A d verse e ve nt
A N C O V A
A nal ysis of c o varia nce
A U C
A rea u n der t he c o nce ntrati o n vers us ti me c ur ve
A U C ( 0-tlast)
A rea u n der t he c o nce ntrati o n vers us ti me c ur ve fr o m ti me zer o t o 
ti me t, w here t is t he last ti me p o i nt wit h a meas ura ble c o nce ntratio n
A U C ( 0-∞)
A rea u n der t he c o nce ntrati o n vers us ti me c ur ve fr o m ti me zer o t o 
i nfi nity
B Q L
B elo w t he l o wer li mit of q ua nt itatio n
CI
C o nfi de nce i nter val
C L/ F
A p pare nt t otal  bo d y  cleara nce of dr u g calc ulate d after e xtra vasc ular 
a d mi nistrati o n
C last
L ast q ua nt ifia ble dr u g c o nce ntrati o n
C ma x
M a xi m u m o bser ve d dr u g c o nce ntrati o n
C P
C hil d -P u g h
C R U
Cli nical Researc h U nit
C S R
Cli nical St u d y  Re p ort
C V
C oefficie nt of variat i on
E C
Earl y Cli nical 
E C G
E lectr ocar di o gra m
I C H
I nter nati o nal C o nfere nce o n Har m o nis atio n
I N R
Int er nati o nal n or malize d rati o
L L O Q
L o wer li mit of q ua nt itatio n
P D
P har mac o d y na mic
P K
P har mac o ki net ic
S A P
Stati stical A nal ysis Pla n
S C
S u bc uta ne o us
S D
S ta n dar d de viati on 
t½
Half -life ass ociat e d wit h t he ter mi nal rate c o nsta nt ( λz) i n 


Fi nal, 1 5 Ma y 2 0 1 9
             Pa ge 5 of 1 9
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
C o va nce Cli nical St u d y  N o. 1 0 0 0 0 7 1- 8 3 9 9 7 1 5
S p o ns or Refere nce I 8 F -M C -G P G Q
n o n -c o m part me ntal a nal ysis
T 2 D M
T y pe 2 dia betes mellit us
T F Ls
Ta bles, Fi g ures, a n d List i n gs
tma x
Ti me o f ma xi m u m o bser ve d dr u g c o nce ntrati o n
U L N
U p per li mit of n or mal
V ss/ F
A p pare nt v ol u m e of  di stri b uti on at stea d y  state after e xtra-vasc ular 
a d mi nistrati o n
V z/ F
A p pare nt v ol u m e of  distri b uti on d uri n g t he ter mi nal p hase after 
e xtra-vasc ular a d mi nistrati o n


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Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
C o va nce Cli nical St u d y  N o. 1 0 0 0 0 7 1- 8 3 9 9 7 1 5
S p o ns or Refere nce I 8 F -M C -G P G Q
3. I N T R O D U C TI O N
T his S A P has bee n de vel o pe d after re vie w of t he Cli nical St u d y  Pr ot oc ol (fi nal versi o n date d 
0 1 A pril 2 0 1 9 ).
T his S A P descri bes t he pla n ne d a nal ys is of t he safet y, t olera bilit y, p har m ac o ki netic (P K ) a n d 
p har mac o d y na mic ( P D) data fr o m t his st u d y . A detaile d descri pt i on of t he pla n ne d T F Ls t o be 
prese nte d i n t he cli nical st u d y  r ep ort ( C S R) i s pr o vi de d i n t he acc om pa n yi n g T F L s hell 
d oc u m e nt.
T he i nte nt of t his d oc u me nt is t o pr o vi de g ui da nce f or t he statist ical a n d P K a nal yses of data. I n 
ge neral, t he a nal yses are base d o n i nf or mat i on fr o m t he pr ot oc ol, u nless t he y ha ve bee n mo difi e d 
b y a gree me nt bet wee n El i Lill y a n d C o m pa n y a n d C o va nce Earl y  Cli nical ( E C) Bi o m etrics. A 
li mite d a m o u nt of i nf or mati on c o ncer ni n g t his st u d y (e. g., o bj ecti ves, st u d y desi g n) is gi ve n t o 
hel p t he rea der’s i nter pretati o n . T his S A P m ust be si g ne d off pri or t o first s u bject a d mi nistrati o n
f or t his st u d y. W he n t he S A P a n d T F L s hells are a gree d u p o n a n d fi nalize d, t he y  will ser ve as t he 
t e mplate f or t his st u d y’s C S R.
T his S A P s u perse des t he statistical c o nsi derati ons i de ntifie d i n t he pr ot oc ol; w here 
c o nsi derati o ns are s u bsta nt iall y differe nt, t he y will be s o ide nt ifie d. If a d diti on al  a nal yses are 
re q uire d t o s u p ple me nt t he pla n ne d a nal yses descri be d i n t his S A P, t he y ma y be perf or me d a nd 
will be i de nt ifie d i n t he C S R. A n y s u bsta ntial de viati o ns fr o m t his S A P will be a gree d u p o n 
bet wee n Eli Lill y a n d C o m pa n y  a n d C o va nce E C Bi o m etrics a n d ide ntifie d i n t he C S R . A n y 
mi n or de viat i ons fr om t he T F Ls ma y n ot be d oc u me nte d i n t he C S R.
T his S A P i s writt e n wit h c o nsid er ati o n of  t he rec o m me n dati ons o utli ne d i n t he I nte r nati o nal 
C o nfere nce o n Har m o nis at i on (I C H) E 9 G ui deli ne e ntit le d G ui da nce f or I n d ustr y: St ati stical 
Pri nci ples f or Cli nical Trials 1 a n d t he I C H E 3 G ui deli ne e nt itle d G ui da nce f or I n d ustr y: Str uct ure 
a n d C o nte nt of Cli nical St u d y R e p orts2.
4. S T U D Y O B J E C TI V E S
4. 1
Pri m ar y O bjecti ve

T o e val uate t he P K of a si n gle s u bc uta ne o us (S C ) d ose of tirze pat i 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 pat ic f uncti o n.
4. 2
Sec o n d ar y O bjecti ve

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 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 pat ic f uncti o n.


Fi nal, 1 5 Ma y 2 0 1 9
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C O N FI D E N TI A L
C o va nce Cli nical St u d y  N o. 1 0 0 0 0 7 1- 8 3 9 9 7 1 5
S p o ns or Refere nce I 8 F -M C -G P G Q
4. 3
E x pl or at or y O bjecti ve

T o e val uate t he f or mat i on of a nti-dr u g a nt i b o dies (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 patic f unct i on.
5. S T U D Y D E SI G N
T his will be a m ult ice 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 omit a nt t ype 2 di a betes mellit us (T 2 D M ) di a g n osis will 
n ot be s pecificall 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 pat ic 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 pat ic 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 uitin g t h is s u bject p o p ulati 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 .
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 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, 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 of 6). S u bjects w h o wit h dra w bef ore c o m plet i n g all st u d y 
pr oce d ures ma y  b e r e place 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 nat i on 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 
cli nical researc h u nit ( C R U ) o n Da y  -1, a n d recei ve a si n gle S C d ose of 5 m g tirze pat i de o n 
D a y 1, f o ll 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 
di sc 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 bject 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 on at l east 2 8 da ys p ost d ose.
P K bl o o d sa m pli n g a n d safet y assess me nts, i ncl u di n g vital si g 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 d verse e ve nt (A E )
rec or di n g, will be perf or me d.


Fi nal, 1 5 Ma y 2 0 1 9
             Pa ge 8 of 1 9
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
C o va nce Cli nical St u d y  N o. 1 0 0 0 0 7 1-8 3 9 9 7 1 5
S p o ns or Refere nce I 8 F -M C -G P G Q
S u bjects wit h n or mal he pat ic f unct i on a n d wi t h mil d an d m o derate he pati c 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  aft er s atisfact 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 
( mo derate 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 o l 
s u bjects wit h n or mal he pat ic f u ncti o n). Base 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 tirze pat i de ma y 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 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 mild 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 ure G P G Q. 1. Ill ustr ati o n of st u d y desi g n f or Pr ot oc 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 ni n g t hr o u g h f oll o w -u p 
visit) is a nt ici pate d t o be a p pr o xi matel y 8 wee ks.
5. 1
C hil d - P u g h Cl assific ati o n
He pati c i m pair me nt is classifie d usi n g t he C hil d - Pu g h s yste m. T he classificatio n para meters will 
be c o llecte d at scree ni n g t o deter mi ne t he C P 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. 1 ).


Fi nal, 1 5 Ma y 2 0 1 9
             Pa ge 9 of 1 9
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
C o va nce Cli nical St u d y  N o. 1 0 0 0 0 7 1- 8 3 9 9 7 1 5
S p o ns or Refere nce I 8 F -M C -G P G Q
T a ble G P G Q. 1. C hil d -P u g h Cl assific 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 Ser u m 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 nce 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 3 a n d P u g h et al. 4.
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.
6. T R E A T M E N T S
T he T F Ls will i ncl u de a s u b hea der f or treat me nt ( 5 m g tirze pati de S C) t hr o u g h o ut . T he 
f oll owi n g is a list of t he gr o u p a b bre viat i ons t hat will be use d i n t he T F Ls.
Gr o u p
O r der i n T F L
C o ntr ol ( n o r mal he patic f u ncti o n)
1
Mil d he patic i m pair me nt
2
M o derate he patic i m pair me nt
3
Se vere he patic i m pair me nt
4
7. S A M P L E SI Z E J U S TI FI C A TI 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 patic i m pair me nt 
ma y be a n acce pta ble tar get.


Fi nal, 1 5 Ma y 2 0 1 9
             Pa ge 1 0 of 1 9
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
C o va nce Cli nical St u d y  N o. 1 0 0 0 0 7 1- 8 3 9 9 7 1 5
S p o ns or Refere nce I 8 F -M C -G P G Q
T his sa m ple size is base d o n t he F D A g ui da nce 5, 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 vide e val ua ble data. T he sa m ple size was n ot selecte d t o 
satisf y a n a priori  statistical re q uire me nt.
8.
D E FI NI TI O N O F A N A L Y SI S P O P U L A TI O N S
T he “ Safet y” p o p ul at i on will c o nsist of all e nr olle 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.
T he “ P har mac o ki net ic” p o p ulat i on will c o nsist of a ll s u bjects w h o recei ve d tirze pat i de a n d ha ve 
e val ua ble P K  data . 
T he “ P har mac o d y na mic” p o p ulat i on will c o nsist of all s u bjects w h o recei ve d tirze patide a n d 
ha ve e val ua ble P D data . 
All pr ot oc ol de viat i ons t hat occ ur d uri n g t he st u d y  will be c o nsi dere d f or t heir se verit y/ i m pact 
a n d will be ta ke n i nt o c o nsi derat i on w he n s u bjects are assi g ne d t o a nal ysis p o p ul at i ons .
9. S T A TI S TI C A L M E T H O D O L O G Y
9. 1
Ge ner al
Data list i n gs will be pr o vi de d f or all data t hat is data base d . S u m mar y  statistics a n d statistical 
a nal ysis will o nl y be prese nte d f or data w here detaile d i n t his S A P . F or c o nti n u o us data, 
s u m mar y statistics will i ncl u de t he arit h met ic mea n, arit h metic sta n dar d de viat i on ( S D), m e dia n, 
mi n, ma x a n d N; f or l o g -n or mal dat a (e. g. t he P K para meters : area u n der t he c o nce ntrati o n 
vers us ti me c ur ve [A U C ] a n d m a xi m u m o bser ve d dr u g c o nce ntrati o n [ Cma x ] t he ge o metric mea n 
a n d ge o met ric c oefficie nt of variati on ( C V %) will als o be prese nte d . F or cate g orical data, 
fre q ue nc y c o u nt a n d perce nta ges will be prese nte d . Data list i n gs will be pr o vi de d f or all s u bjects 
u p t o t he p oi nt of wit h dra wal, wit h a n y s u bjects e xcl u de d fr o m t he rele va nt p o p ulati o n 
hi g hli g hte d. S u m mar y statist ics a n d statistical a nal yses will ge nerall y o nl y be perf or me d f or 
s u bjects i ncl u de d i n t he rele va nt a nal ysis p o p ulat i on . F or t he calc ulat i on of s u m mar y  statistics 
a n d statist ical a nal ysis, u nr o u n de d data will be use d. 
Mea n c ha n ge fr o m baseli ne is t he mea n of all i n di vi d ual s u bjects’ c ha n ge fr o m baseli ne val ues . 
Eac h i n di vi d ual c ha n ge fr om baseli ne will be calc ulate d b y  s u btracti n g t he i n di vi d ual s u bject’s 
baseli ne val ue fr o m t he val ue at t he ti me p o i nt. T he i n di vi d ual s u bject’s c ha n ge fr o m baseli ne 
val ues will be use d t o calc ulate t he mea n c ha n ge fr o m baseli ne usi n g a S A S pr oce d ure s uc h as 
Pr oc U ni variate.
Data a nal ysis will be perf or me d usi n g S A S ® Versi o n 9. 4 or greater.
9. 2
De m o gr a p hics a n d S u bject Dis p ositi o n
S u bj ect dis p ositio n will be liste d . T he de m o gra p hic varia b les a ge, se x, race, et h nicity, c o u ntr y of 
e nr o l me nt, site I D, b o d y wei g ht, hei g ht , b o d y mass i n de x , a n d C hil d -P u g h sc ore will be 
s u m marize d b y gr o u p a n d liste d. All ot her de m o gra p hic varia bles will be liste d o nl y.


Fi nal, 1 5 Ma y 2 0 1 9
             Pa ge 1 1 of 1 9
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
C o va nce Cli nical St u d y  N o. 1 0 0 0 0 7 1- 8 3 9 9 7 1 5
S p o ns or Refere nce I 8 F -M C -G P G Q
9. 3
P h ar m ac o ki netic Assess me nt
9. 3. 1
P h ar m ac o ki netic A n al ysis
T he P K para meter esti mates will be deter mi ne d usi n g n o n -c o m part me nt al pr oce d ures i n 
vali date d s oft ware pr o gra m ( P h oe ni x Wi n N o nli n Versi o n
8. 1 or l ater).
Pl as ma c o nce ntratio ns of  tirze patide will be use d t o deter mi ne t he f o ll owi n g P K para meters, 
w he n p ossi ble : 
P ar a meter
U n its
Defi niti o n
A U C ( 0-tlast)
h * n g/ m L
ar ea u n der t he c o nce ntrati o n vers us ti me c ur ve fr o m ti me zer o t o 
ti me t, w here t is t he last ti me p oi nt wit h a meas ura ble 
c o nce ntrati o n
A U C ( 0-∞)
h * n g/ m L
ar ea u n der t he c o nce ntrati o n vers us ti me c ur ve fr o m ti me zer o t o 
i nfi nit y
% A U C (tlast-)
%
perce nta ge of A U C( 0 -∞) e xtra p olate d
C ma x
n g/ m L
ma xi m u m  obser ve d dr u g c o nce ntrati o n
tma x
h
ti me of ma xi m u m o bser ve d dr u g c o nce ntrati o n
t½
h
half -life ass ociate d wit h t he ter mi nal rate c o nsta nt ( λz) i n 
n o n- c o m part me ntal a nal ysis
C L/ F
L/ h
a p pare nt t otal b o d y cleara nce of dr u g calc ulate d after 
e xtra -vasc ular a d mi nistrati o n
V z/ F
L
a p pare nt v ol u me of distri b uti o n d uri n g t he ter mi nal p hase after 
e xtra -vasc ular a d mi nistrati o n
V ss/ F
L
a p pare nt v ol u me of distri b uti o n at stea d y state after e xtra -vasc ular
a d mi nistrati o n
A d dit i onal P K para meters ma y  be calc ulate d, as a p pr o priate.
T he s oft ware a n d versi o n use d f or t he fi nal a nal yses will be s pecifie d i n t he cli nical st u d y  re p ort. 
A n y e xce pt i ons or s pecial ha n dli n g of data will be clearl y  d oc u me nte d wit hi n t he fi nal st u d y 
re p ort.
F or matti n g of ta bles, fi g ures a n d a b bre viat i ons will f o ll o w t he Eli Lill y Gl o bal P K/ P D/ T S T o ol: 
N O N -C O M P A R T M E N T A L P H A R M A C O KI N E TI C S T Y L E G UI D E . T he versi o n of  t he t o ol
effect i ve at t he ti me of P K a nal ysis will  be f oll ow e d.
Ge ner al P K P ar a meter R ules

Act ual  sa m pli n g ti mes will be use d i n t he fi nal a nal yses of i n di vi d ual P K para meters, 
e xce pt f or pre-d ose sa m pli n g ti mes w hic h will be set t o zer o.

C ma x a n d t ma x will be re p orte d fr o m o bser ve d val ues . If Cma x occ urs at m ore t ha n o ne ti me 
p oi nt, t ma x will be assi g ne d t o t he first occ urre nce of C ma x. 


Fi nal, 1 5 Ma y 2 0 1 9
             Pa ge 1 2 of 1 9
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
C o va nce Cli nical St u d y  N o. 1 0 0 0 0 7 1- 8 3 9 9 7 1 5
S p o ns or Refere nce I 8 F -M C -G P G Q

A U C para meters will be calc ulate d usi n g a c o m bi nati o n of t he li near a n d l o garit h mic 
tra pez oidal met h o ds (li near -l og tra pez oi d al  r ule). T he li near tra pez oi dal met h o d will be 
a p plie d u p t o t ma x a n d t he n t he l o garit h mic tra pez oi dal met h o d will be use d after tma x . T he 
mi ni m u m re q uire me nt f or t he calc ulat i on of A U C will be t he i ncl usi o n of at least t hree 
c o nsec ut i ve c o nce ntrati o ns a b o ve t he l ower li mit of q ua nt itatio n ( L L O Q ), wit h at least 
o ne of t hese c o nce ntrati o ns f o ll owi n g C ma x.

A U C ( 0-) val ues w here t he perce nta ge of  t he t otal area e xtra p olat e d is m o re t ha n 2 0 % 
will be fla g ge d . A n y A U C ( 0-) val ue e xcl u de d fr o m s u m mar y statistics will be n ote d i n 
t he f o ot n ote of t he s u m mar y ta ble.

Half -life (t½ ) will be calc ulate d, w he n a p pr o priate, base d o n t he a p pare nt ter mi nal 
l og -li near p orti o n of t he c o nce ntrati o n-ti me c ur ve. T he start of t he ter mi nal eli mi nati on 
p hase f or eac h s u bject will be defi ne d b y  vis ual ins pecti o n a n d ge nerall y will be t he first 
p oi nt at w hic h t here is n o s y st e mat ic de viati on fr o m t he l og -li near decli ne i n plas ma 
c o nce ntrati o ns. Half -life will  o nl y be calc ulate d w he n a relia ble esti mate f or t his 
para m eter ca n be o btai ne d c o m prisi n g o f at least 3 data p oi nts . If t½ is esti mate d o ver a 
ti me wi n d o w of less t ha n 2 half -li ves, t he val ues will be fla g ge d i n t he data list i n gs. A n y 
t½ val ue e xcl u de d fr o m s u m mar y st atistics will be d oc u m e nte d i n t he f o ot n ote of t he 
s u m mar y ta ble. 

A u nif or m wei g ht i n g sc he me will be use d i n t he re gressio n  a nal ysis of t he ter mi nal 
l og -li near p orti o n of t he c o nce ntrati o n-ti me c ur ve.

T he para m eters base d o n t he pre dicte d last q ua ntifia ble dr u g c o nce ntrati o n ( Clast) will be 
re p orte d.
I n di vi d u al P K P ar a meter R ules

O nl y q ua ntifia ble c o nce ntrati o ns will be use d t o calc ulate P K para meters wit h t he 
e xce pti o n of s pecial ha n dli n g of certai n c o nce nt rati ons re p orte d bel o w t he l o wer li mit of 
q ua nt itatio n ( B Q L) . Pl as ma c o nce ntratio ns re p orte d as B Q L will be set t o a val ue o f zer o
w he n all o f t he foll o wi n g c o n dit i ons are met:
o
T he c o m p o u n d is n o n -e n d o ge n o us.
o
T he sa m ples are fr o m t he i nit ial d ose perio d f or a s u bject or fr o m a s u bse q ue nt 
d ose peri o d f ol l owi n g a s ui ta ble was h-o ut peri o d.
o
T he ti me p oi nts occ ur bef ore t he first q ua nt ifia ble c o nce ntrati o n.

All ot her B Q L c o nce ntrati o ns t hat d o n ot meet t he a b o ve criteria will  be set t o missi n g .

Als o, w here t w o  or m ore c o nsec uti ve c o nce ntrati o ns are B Q L t o war ds t he e n d of a 
pr ofile, t he pr ofile will be dee me d t o ha ve ter mi nate d a n d t heref ore a n y f urt her 
q ua nt ifia ble c o nce ntrati o ns will be set t o missi n g f or t he calc ulati on of t he P K para meters 
u nless it i s c o nsi dere d t o be a tr ue c haracteristic of t he pr ofile of t he dr u g.


Fi nal, 1 5 Ma y 2 0 1 9
             Pa ge 1 3 of 1 9
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
C o va nce Cli nical St u d y  N o. 1 0 0 0 0 7 1- 8 3 9 9 7 1 5
S p o ns or Refere nce I 8 F -M C -G P G Q
I n di vi d u al C o nce ntr ati o n vs. Ti me Pr ofiles

I n di vi d ual c o nce ntrati o ns will be pl otte d utilizi n g act ual sa m pli n g ti mes.

T he ter mi nal p o i nt select i ons will be i n dicate d o n a se mi -l og ari t h mic pl ot .
A ver a ge C o nce ntr ati o n vs. Ti me Pr ofiles

T he a vera ge c o nce ntrati o n pr ofiles will be gra p he d usi n g sc he d ule d ( n omi nal) sa m pli n g 
ti mes.

T he a vera ge c o nce ntrati o n pr ofiles will be gra p he d usi n g arit h met ic a vera ge 
c o nce ntrati o ns.

T he pre -d ose a vera ge c o nce nt r atio n f or si n gle -d ose data fr om n o n- e n d o ge n o us 
c o mp o u n ds will be set t o zer o . Ot her wise, o nl y q ua nt ifia ble c o nce ntrati o ns will be use d 
t o calc ulate a vera ge c o nce ntrati o ns .

C o nce ntrati o n s at a sa mpli n g ti me e xcee di n g t he s a mpli n g ti me wi n d o w s pecifie d i n t he 
pr ot oc ol , or ± 1 0 % , will be e xcl u de d fr o m t he a vera ge c o nce ntrati o n pr ofiles.

C o nce ntrati o ns e xcl u de d fr o m t he mea n calc ulati o n will be d oc u me nte d i n t he fi nal st u d y  
re p ort.

A c o nce ntrati o n a vera ge will be pl otte d f or a gi ve n sa m pli n g ti me o nl y  if 2/ 3 of t he 
i n di vi d ual data at t he ti me p oi nt ha ve q ua ntifia ble meas ure me nts t hat are wit hi n t he 
sa m pli n g ti me wi n d o w s pecifie d i n t he pr ot oc ol or ± 1 0 %. A n a vera ge c o nce ntrati o n 
esti mate d wit h less t ha n 2/ 3 b ut m ore t ha n 3 data p oi nts ma y be dis pla ye d o n t he me a n 
c o nce ntrati o n pl ot if deter mi ne d t o be a p pr o priate a n d will be d oc u me nte d wit hi n t he 
fi nal st u d y re p ort.
Tre at me nt of O utliers d uri n g P h ar m ac o ki netic A n al ysis
A p plicat i on of t his pr oce d ure t o all P K a nal yses is n ot a re q uire me nt. Rat her, t his pr oce d ure 
pr o vi des j ust ificati o n f or e xcl usi o n of data w he n scie nt ificall y a p pr o priate. T his pr oce d ure 
descri bes t he met h o d ol o g y  for i de nt if yi n g a n i n di vi d ual val ue as a n o utlier f or p ote ntial 
e xcl usi o n, b ut d oes n ot re q uire t hat t he val ue be e xcl u de d fr om a nal ysis. T he f o ll owi n g 
met h o d ol o g y  will n ot be use d t o e xcl u de c o m plete pr ofiles fr o m a nal ysis.
Data wi t hi n a n I n di vi d ual Pr ofile
A val ue wit hi n a n i n di vi d ual pr ofile ma y be e xcl u de d fr o m a nal ysis if a n y of t he fol l owi n g 
criteria are met:

F or P K pr ofiles d uri n g si n gle d osi n g of n o n -e n d o ge n o us c o m p o u n ds, t he c o nce ntrati o n i n 
a pre-d ose sa m ple is q ua nt ifia ble.


Fi nal, 1 5 Ma y 2 0 1 9
             Pa ge 1 4 of 1 9
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
C o va nce Cli nical St u d y  N o. 1 0 0 0 0 7 1- 8 3 9 9 7 1 5
S p o ns or Refere nce I 8 F -M C -G P G Q

F or a n y q uest i ona ble d at u m  that d oes n ot satisf y t he a b o ve crit eria, t he pr ofile will be 
e val uate d a n d res ults re p orte d wit h a n d wit h o ut t he s us pecte d dat u m.
Data bet wee n I n di vi d ual Pr ofiles
1.
If n < 6, t he n t he dataset is t o o s mall t o c o n d uct a relia ble ra n ge test. Data will be a nal yze d 
wi t h a n d wit ho ut t he at y pical val ue, a n d b ot h sets of res ults will be re p orte d . 
2.
If n6, t he n a n o bject i ve o utlier test will be use d t o c o m p are t he at ypical val ue t o ot h er 
val ues i ncl u de d i n t hat calc ulat i on:
a.
Tra nsf or m all val ues i n t he calc ulati o n t o t he l o garit h mic d o mai n .
b.
F i n d t he m o st e xtre me val ue fr om t he arit h metic mea n of  the l og tra nsf or me d
val ues a n d e xcl u de t hat val ue f r o m t he dataset.
c.
Calc ulate t he l ower a n d u p per b o u n ds of t he ra n ge defi ne d b y t he arit hmet ic 
mea n ± 3 * S D of t he re m ai ni n g lo g -tra nsf or me d val ues.
d.
If t he e xtr e me val ue is wi t hi n t he ra n ge of  arit hmetic mea n ± 3 * S D, t he n it is n ot 
a n o utlier a n d will be retai ne d i n t he dataset .
e.
If t he e xtr e me val ue is o utsi de t he ra n ge of  arit h m etic mea n ± 3 * S D, t he n it is a n 
o utlier a n d will be e xcl u de d fr o m a nal ysis.
If t he re mai ni n g dataset c o ntai ns a n ot her at ypi c al  d at u m s us pecte d t o be a n o utlier a n d n ≥ 6 
f oll owi n g t he e xc l usi on, t he n re peat ste p 2 a b o ve. T his e val uat i on ma y be re peate d as ma n y 
ti mes as necessar y, e xcl u di n g o nl y o ne s us pecte d o utlier i n eac h iterati o n, u nt il all data 
r e mai ni n g i n t he dataset fall wi t hi n t he ra n ge of arit h met ic mea n ± 3 * S D of t he l o g -tra nsf or me d 
val ues.
Re p orti n g of E xcl u de d Val ues
I n di vi d ual val ues e xcl u de d as o utliers will be d oc u me nte d i n t he fi nal re p ort. A p pr o val of t he 
fi nal re p ort will c o n n ote a p pr o val of t he e xcl usi on.
9. 3. 2
P h ar m ac o ki netic St atistic al Met h o d ol o g y
T he pri mar y  P K a nalysis 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 ma x usi n g a n 
a nal ysis of c o varia nce ( A N C O V A) m o del wit h he patic f u 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 ate. 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 
m ea n ratios 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 ( CIs) will be est i 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 m et ers ma y be use d i n t he a b o ve m o del. 


Fi nal, 1 5 Ma y 2 0 1 9
             Pa ge 1 5 of 1 9
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
C o va nce Cli nical St u d y  N o. 1 0 0 0 0 7 1- 8 3 9 9 7 1 5
S p o ns or Refere nce I 8 F -M C -G P G Q
E xa m ple S A S c o de:
p r o c
m i x e d
d a t a = D A T A I N  a l p h a = 0 . 1 ;
  b y
p a r a m e t e r ;
  c l a s s
g r o u p ;
  m o d e l
l o g _ p k  =  g r o u p  w e i g h t  /  c l
r e s i d u a l
d d f m = k r ;
  l s m e a n s
g r o u p  /  p d i f f = c o n t r o l ( ' C o n t r o l ' )  a l p h a = 0 . 1 ;
r u n ;
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 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 Classifi c atio n para m eters (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 t i me) will be assesse d 
gra p hicall y . T he P K para meters A U C( 0-∞) , Cma x , a n d C L/ F will  be plotte d a gai nst eac h 
C hil d -P u g h Cl assificat i on para meter se paratel y. A re gressi o n li ne a n d c orres p o n di n g 9 0 % CI 
fr om a si m ple li near m o del will be pl otte d, if a p pr o pri at e. 
Si milarl y, t he P K para meters vers us C hil d -P u g h Sc ore will be assesse d gra p hicall y. T he c o ntr ol 
gr o u p will be ke pt i n t he a nal ysis ( wit h C hil d -P u g h sc ore set t o 0).
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.
A d dit i onal e x plor at or y  a nal ysis (s uc h as meta b o lis m w or k, pr otei n bi n di n g, or bi oa nal ytical 
met h o d cr oss -vali dat i on ) ma y b e p erfor m e d at a later date. S uc h a nal ysis will be detaile d i n a 
se parate a nal ysis pla n.
9. 4
P h ar m ac o d y n a mic Assess me nt
9. 4. 1
I m m u n o ge nicit y
I mm u n o ge nicit y data will be liste d a n d fre q ue nc y  ta bles will be prese nte d. T he fre q ue nc y a n d 
perce nta ge of patie nts wit h pre -e xist i n g A D A a n d wit h treat me nt -e mer ge nt A D As ( T E A D As) 
will be prese nte d. T E A D As are t h ose t hat are i n d uce d or b o oste d b y  e x p os ure t o st u d y dr u g, 
wi t h a 4-f ol d i ncrease i n titer c o mpare d t o baseli ne if A D As were detecte d at baseli ne or a titer 
2 -f ol d greater t ha n t he mi ni m u m re q uire d dil ut i on ( 1: 1 0) if n o A D As were detecte d at baseli ne.
If cr oss-reacti vity wi t h nat i ve G L P-1 a n d GI P or a ne utralizat i on assa y  is perf or me d, t he 
fre q ue nc y of eac h will be deter mi ne d. 
T he rel at i ons hi p bet wee n t he prese nce ( or a bse nce) of a nt i b o dies a n d cli nical para meters ( A Es) 
will be assesse d. Li ke wise, 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 m et ers ma y be assesse d if dee me d a p pr o priate.


Fi nal, 1 5 Ma y 2 0 1 9
             Pa ge 1 6 of 1 9
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
C o va nce Cli nical St u d y  N o. 1 0 0 0 0 7 1- 8 3 9 9 7 1 5
S p o ns or Refere nce I 8 F -M C -G P G Q
9. 5
S afet y a n d T oler a bilit y Assess me nts
9. 5. 1
A d verse e ve nts
W here c ha n g es i n se verit y are rec or de d i n t he Case Re p ort F or m ( C R F ), eac h se parate se verity 
of  t he A E will be re p orte d i n t he list i n gs, o nl y t he m ost se vere will be use d i n t he s u m mar y 
ta bles. A pre -e xist i n g c o n diti on is defi ne d as a n A E t hat starts bef ore t he s u bject has pr o vide d 
wri tte n i nf or me d c o nse nt a n d is o n g oi n g at c o nse nt . A n o n -treat me nt e mer ge nt A E is defi ne d as 
a n A E w hic h st arts aft er inf or me d c o nse nt b ut pri or t o d osi n g . A treat me nt -e mer ge nt A E is 
defi ne d as a n A E w hic h occ urs p ost d ose or w hic h is prese nt  prior t o d osi n g a n d bec o m es mor e 
se vere p ost d ose. 
All A Es will be liste d . Treat me nt -e mer ge nt A Es will be s u m mariz e d b y gr o u p , se verity a n d 
r elat i ons hi p t o t he st u d y  dr u g. T he fre q ue nc y (t he n u m ber of A Es , t he n u m ber of s u bjects 
e x perie nci n g a n A E a n d t he perce nta ge of s u bjects e x perie nci n g a n A E ) of treat me nt -e mer ge nt 
A Es will be s u m mariz e d b y gr o u p , Me di cal Dict i onar y  for Re g ulat or y  Act i vities (Me d D R A )
versi o n 2 1. 1 s yste m or ga n class a n d preferre d ter m. T he s u m mar y a n d fre q ue nc y A E ta bles will 
be prese nte d f or all ca usalit ies a n d t h ose c o nsi dere d relate d t o t he st u d y dr u g. A n y seri o us A Es
will be liste d.
9. 5. 2
C o nc o mit a nt me dic ati o n
C o nc o mita nt me dicat i on will be c o de d usi n g t he W H O dr u g dict i onar y  ( Versio n  
Se pte m ber 2 0 1 8 ). C o nc o mita nt me dicat i on will be liste d.
9. 5. 3
Cli nic al l a b or at or y p ar a meters
A ll cli nical c he mistr y, he m at olo g y a n d c oa g ulat i on data w ill be s u m marize d b y para meter a n d 
gr o u p , a n d liste d. Uri nal ysis data will be liste d . C ha n ges fr o m baseli ne will als o be prese nte d, 
w here baseli ne is defi ne d as Da y  -1. A d dit i onall y , cli nical c he mistr y , he mat olo g y , c oa g ulat i on 
a n d uri nal ysis data o utsi de t he r efere nce ra n ges will be liste d.
V al ues o utsi de t he refere nce ra n ges will be fla g ge d o n t he i n di vi d ual s u bject data listi n gs
9. 5. 4
Gl uc ose M o nit ori n g a n d H y per gl yce mi a/ H y p o gl yce mi a Re p orti n g
H y p o gl yce mic e ve nts will be a p pr o priatel y rec or de d i n t he C R F. I n t he case of a h y p o gl yce mic 
e ve nt, t he act ual bl o o d gl uc ose val ue, if meas ure d, will be rec or de d i n t he C R F, t o get her wit h 
a n y treat me nts a d mi nistere d. Eac h cate g or y of h y p o gl yce mic e ve nt ( defi ne d i n Secti on 9. 4. 2. 1 of 
t he Pr ot oc ol) will be liste d a n d s u m marize d b y gr o u p.
Bl o o d gl uc ose l e vels will be liste d f or i n di vi d ual patie nts a n d s u m marize d b y gr o u p.
9. 5. 5
Vit al si g ns
Vi t al si g ns data will be s u m marize d b y gr o u p t o get her wit h c ha n ges fr o m baseli ne, w here 
baseli ne is defi ne d as t he D a y  1 pre d ose assess me nt . Fi g ures of mea n vital si g ns a n d mea n 
c ha n ges fr o m baseli ne pr ofiles will be prese nte d b y  gr o u p . 


Fi nal, 1 5 Ma y 2 0 1 9
             Pa ge 1 7 of 1 9
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
C o va nce Cli nical St u d y  N o. 1 0 0 0 0 7 1- 8 3 9 9 7 1 5
S p o ns or Refere nce I 8 F -M C -G P G Q
F urt her m ore, val u es f or i n di vi d ual s u bjects will be liste d.
9. 5. 6
Electr oc ar di o gr a m ( E C G)
E C Gs will be perf or me d f or safet y m o nit ori n g p ur p oses o nl y a n d will n ot be prese nte d. A n y 
cli nicall y si g nifica nt fi n di n gs fr o m E C Gs will be rec or de d as A Es.
9. 5. 7
I njecti o n-site Assess me nts
I njecti on-s ite assess me nts f or l ocal 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.
I njecti on site assess me nt data (er y t he ma, i n d urat i on, cate g orical pai n, pr urit us, a n d e de ma) will 
be liste d a nd s u m marize d b y  gr o u p i n fre q ue nc y ta bles.
9. 5. 8
He p atic M o nit ori n g
If a s u bject e x perie nces ele vate d ala ni ne a mi n otra nsferase ( A L T) ≥3 × u p per li mit of n or mal 
( U L N), al kali ne p h os p hatase ( A L P) ≥2 × U L N, or ele vate d t otal bilir u bi n ( T B L) ≥2 × U L N, li ver 
tests will be perf or me d t o c o nfir m t he a b n or malit y . A d dit i onal safet y data ma y  be c ollecte d if 
re q uire d, as defi ne d i n t he pr ot oc ol. W here a p plica ble, t he f o ll owi n g will be prese nte d.
T he s u bjects’ li ver disease hist or y  a n d ass ociate d pers o n li ver disease hist or y data will be liste d. 
A n y c o nc o mit a nt me dicatio n of  aceta mi n o p he n/ paraceta m ol will be liste d. Res ults fr o m a n y 
he pat ic m o nit ori n g pr oce d ures, s uc h as a ma g net ic res o na nce elast o gra p h y ( M R E) sca n, a n d a 
bi o ps y assess me nt will be liste d, if perf or me d.
He pati c ris k fact or assess me nt data will be liste d. Li ver relate d si g ns a n d s y m pt o ms data will be 
s u m marize d b y gr o u p a n d liste d. Alc o h ol a n d recreati o nal dr u g use data will als o be liste d.
All he pat ic c he mistr y, he mat ol o g y, c oa g ulati on, a n d ser ol o g y  data will be liste d. Val ues o utsi de 
t he refere nce ra n ges will be fla g ge d o n t he i n di vi d ual s u bject data list i n gs.
9. 5. 9
H y perse nsiti vit y Re acti o ns
F or all dr u g h y perse nsit i vity r e a ctio ns t hat occ ur, a d di tio nal  foll o w -u p data will be c o llecte d t o 
assess t he patie nt’s me dical hist or y , alter nati ve ca uses, a n d s y m pt o ms.
T hese data will be liste d.
9. 5. 1 0
Ot her assess me nts
All ot her safet y assess me nts n ot detaile d i n t his secti o n will be liste d b ut n ot s u m marize d or 
statisticall y a nal yze d.


Fi nal, 1 5 Ma y 2 0 1 9
             Pa ge 1 8 of 1 9
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
C o va nce Cli nical St u d y  N o. 1 0 0 0 0 7 1- 8 3 9 9 7 1 5
S p o ns or Refere nce I 8 F -M C -G P G Q
9. 5. 1 1
S afet y a n d T oler a bilit y St atistic al Met h o d ol o g y
N o i nfere nt ial statistical a nal yses are pla n ne d.
1 0.
I N T E RI M A N A L 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 G Q. 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 pri at e matc he d-c o ntr ol s u bjects wit h n or mal h e p atic fu nct i on) will be e nr o lle d 
i n parallel a n d d ose d wit h 5 m g tirze pat i de, f oll owe d b y  a n i nteri m a nal ysis t o e val uate safety,  
t olera bilit y, a n d P K data. Base 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 m g or be 
re d uce d t o 2. 5 m g f or t he re mai ni n g s u bjects 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. T he fi nal d ose deter mi nati o ns will be ma de b y t he i n vest i gat or a n d t he Lill y st u d y 
tea m.
1 1.  
C H A N G E S F R O M T H E P R O T O C O L S P E CI FI E D S T A TI S TI C A L A N A L Y S E S
T here were n o c ha n ges fr o m t he pr ot oc ol s pecifie d statistical a nal yses.
1 2.
R E F E R E N C E S
1.
I nter nati o nal C o nfere nce o n Har m o nizat i on of Tec h nical Re q uire me nts f or Re gistrati o n of 
P har mace ut icals f or H u ma n Use, I C H Har mo niz e d Tripar tit e G uideli ne, Stati stical Pri nci ples 
f or Cli nical Trials ( E 9), 5 Fe br uar y 1 9 9 8.
2.
I nter nati o nal C o nfere nce o n Har m o nizati on of Tec h nical Re q uire me nts f or Re gistrati o n of 
P har mace ut icals f or H u ma n Use, I C H H ar mo niz e d Triparti t e G uideli ne, Str uct ure a n d 
C o nt e nt of Cli nical St u d y Re p orts ( E 3), 3 0 N o ve m ber 1 9 9 5.
3.
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.
4.
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.
5.
[ 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 i m paire d he patic 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.
1 3.
D A T A P R E S E N T A TI O N
1 3. 1
Deri ve d P ar a meters
I n di vi d ual deri ve d para meters (e. g. P K para meters) a n d a p pr o priate s u m mar y statist ics will be 
re p orte d t o t hree si g nifica nt fi g ures. O bser ve d c o nce ntrati o n data, e. g. C ma x , s h o uld be re p orte d 
as recei ve d . O bser ve d ti me data, e. g. t ma x , s h o ul d be re p orte d as recei ve d. N a n d perce nta ge 


Fi nal, 1 5 Ma y 2 0 1 9
             Pa ge 1 9 of 1 9
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
C o va nce Cli nical St u d y  N o. 1 0 0 0 0 7 1- 8 3 9 9 7 1 5
S p o ns or Refere nce I 8 F -M C -G P G Q
val ues s h o ul d be re p orte d as w h ole n u m bers. Me dia n val ues s h o ul d be treate d as a n o bser ve d 
para m eter a n d re p orte d t o t he sa me n u m ber of deci mal places as mi ni m u m a n d ma xi m u m val ues.
1 3. 2
Missi n g D at a
Missi n g data will n ot be dis pla ye d i n list i n gs.
1 3. 3
I ns ufficie nt D at a f or Prese nt ati o n
S o m e of t he T F Ls ma y n ot ha ve s ufficie nt n u m bers of s u bjects or data f or prese ntati o n . If t his 
occ urs, t he bla n k T F L s hell will be prese nte d wit h a messa ge pri nte d i n t he ce ntre of t he ta ble, 
s uc h as, “ N o seri o us a d verse e ve nts occ urre d f or t his st u d y. ”


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