A Randomized, Double-blind, Placebo-Controlled Trial Comparing the Efficacy and Safety of Three Tirzepatide Doses Versus Placebo in Patients With Type 2 Diabetes, Inadequately Controlled With Diet and Exercise Alone
Phase: PHASE3
Conditions: Type 2 Diabetes Mellitus
Sponsor: Eli Lilly and Company

Pr ot oc ol I 8 F- M C- G P G K( b)
A Ra n d o mize d, D o u ble- bli n d, Place b o- C o ntr olle d Trial C o m pari n g t he Efficac y a n d Safet y of T hree 
Tirze pati de D oses Vers us Place b o i n Patie nts Wit h T y pe 2 Dia betes, I na de q uatel y C o ntr olle d Wit h Diet a n d 
E xercise Al o ne
N C T 0 3 9 5 4 8 3 4  
A p pr o val Date: 1 5- A pr- 2 0 2 0

I 8 F-M C -G P G K( b) Cli ni c al 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 K ( b)
A R a n d o mi z e d, D o u bl e -bli n d, Pl a c e b o -C o ntr oll e d Tri al 
C o m p ari n g t h e Effi c a c y  a n d S af et y of T hr e e Tir z e p ati d e
D o s e s v er s u s Pl a c e b o i n P ati e nt s wit h T y p e 2 Di a b et e s ,
I n a d e q u at el y C o ntr ol l e d wit h Di et a n d E x er ci s e A l o n e
( S U R P AS S -1)
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt i s c o nfi d e nti al a n d i s i nt e n d e d f or t h e u s e of 
cli ni c al i n v e sti g at or s.  It i s t h e pr o p ert y of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s a n d 
s h o ul d n ot b e c o pi e d b y or di stri b ut e d t o p er s o n s n ot i n v ol v e d i n t h e cli ni c al i n v e sti g ati o n of 
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 all y c o nfi d e nti al i nf or m ati o n e x e m pt fr o m p u bli c di s cl o s ur e. Eli Lill y a n d 
C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r el e a s e/r e d a 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 u t 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
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 : 1 3 -D e c -2 0 1 8
A m e n d m e nt ( a ) El e ctr o ni c all y Si g n e d a nd A p pr o v e d b y Lill y : 0 3 -M a y -2 0 1 9
A m e n d m e nt ( b ) 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 5- A pr- 2 0 2 0 G M T

I 8 F-M C -G P G K( b) Cli ni c al 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
S e cti o n
P a g e
Pr ot oc ol  I 8 F-M C -G P G K( b) A Ra n d o mize d, D o u ble -bli n d, Place b o -
C o ntr olle d Trial C o m par i n g t he Efficac y a n d Safet y of T hree 
Ti rze patide D oses vers us Pl ace b o i n Patie nts wit h T ype 2 Di a betes, 
I na de q uatel y C o ntr olle d with Diet a n d E xercise Al o ne ( S U R P A S S - 1) ................................1
Ta ble of C o nte nts ........................................................................................................................2
1.
S y n o psis .............................................................................................................................9
2.
Sc he d ule of Act i vities .......................................................................................................1 3
3.
I ntr o d ucti o n ......................................................................................................................2 1
3. 1.
St u d y  Ratio nale ............................................................................................................2 1
3. 2.
Bac k gr o u n d ..................................................................................................................2 1
3. 3.
Be nefit/ Ris k Assess me nt ..............................................................................................2 2
4.
O bject i ves a n d E n d p oi nts ..................................................................................................2 3
5.
St u d y Desi g n .....................................................................................................................2 5
5. 1.
O verall Desi g n .............................................................................................................2 5
5. 2.
N u m ber of Partici pa nts ................................................................................................. 2 8
5. 3.
E n d of St u d y  Defi niti on ...............................................................................................2 8
5. 4.
S ci e nt ific Rati o nale f or St u d y Desi g n...........................................................................2 8
5. 5.
J ustificati o n f or D ose ...................................................................................................2 8
6.
St u d y  P o p ulat i on ...............................................................................................................3 0
6. 1.
I ncl usi on Cri t eria ..........................................................................................................3 0
6. 2.
E xcl usi o n Cri t eria ........................................................................................................3 1
6. 3.
Lifest yle Restrict i ons ....................................................................................................3 4
6. 4.
S cree n Fail ures .............................................................................................................3 4
7.
Treat me nts ........................................................................................................................3 5
7. 1.
Treat me nts A d mi nistere d .............................................................................................3 5
7. 1. 1.
Pac ka gi n g a n d La belli n g ......................................................................................3 6
7. 1. 2.
Me dical De vices ...................................................................................................3 6
7. 2.
Met h o d of Treat me nt Assi g n me nt
................................................................................3 6
7. 2. 1.
S el ect i on a n d Ti mi n g o f D oses of St u d y  Dr u gs ....................................................3 6
7. 3.
Bli n di n g .......................................................................................................................3 6
7. 4.
D osa ge M o dificati o n ....................................................................................................3 7
7. 4. 1.
St u d y  Dr u gs.........................................................................................................3 7
7. 4. 2.
I nitiat i on of Ne w A nt i h y per gl yce mic Me dicati on .................................................3 7
7. 5.
Pre parati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y ...............................................................3 7

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 3
L Y 3 2 9 8 1 7 6
7. 6.
Treat me nt C o m plia nce ................................................................................................. 3 8
7. 7.
C o nc o mita nt T hera p y ...................................................................................................3 8
7. 8.
Treat me nt after t he E n d of t he St u d y ............................................................................3 9
7. 8. 1.
Treat me nt after St u d y  C o mplet i on ........................................................................3 9
7. 8. 2.
S peci al Treat me nt C o nsiderat i ons ........................................................................3 9
7. 8. 2. 1.
Sta n dar ds of Me dical Care ..............................................................................3 9
7. 8. 2. 2.
Ma na ge me nt of H y p o gl yce mia Ris k ...............................................................4 0
7. 8. 2. 3.
Ma na ge me nt of Patie nts wit h Se vere, Persiste nt 
H y per gl yce mia d uri n g t he Treat me nt Peri o d ...................................................4 0
7. 8. 2. 4.
Ma na ge me nt of Patie nts Per ma ne nt l y Disc o nti n ui n g 
St u d y  Dr u gs....................................................................................................4 0
7. 8. 2. 5.
Ma na ge me nt of Patie nts wit h Gastr oi ntesti nal S y m pt o ms ...............................4 1
8.
Di sc o nti n uatio n Cri t eri a....................................................................................................4 2
8. 1.
D isc o nti n uati o n fr o m St u d y  Treat me nt .........................................................................4 2
8. 1. 1.
P er m a ne nt Disc o nt i n uati on fr o m St u d y Treat me nt ...............................................4 2
8. 1. 2.
T e m p orar y  Disc o nti n uati on fr om St u d y  Treat me nt ...............................................4 3
8. 1. 3.
Di sc o nti n uatio n of  I na d verte ntl y Enr olle d Patie nts ...............................................4 3
8. 2.
Di sc o nti n uatio n f r o m t he St u d y....................................................................................4 4
8. 3.
L ost t o F oll o w -U p ........................................................................................................4 5
9.
St u d y  Assess me nts a n d Pr oce d ures...................................................................................4 6
9. 1.
Efficac y Assess me nts ...................................................................................................4 6
9. 1. 1.
Pri mar y Efficac y  Assess me nts .............................................................................4 6
9. 1. 2.
Sec o n dar y  Efficac y Assess me nts..........................................................................4 6
9. 1. 3.
E x pl or at or y  Assess me nts a n d Pr oce d ures.............................................................4 6
9. 1. 4.
B o d y  Wei g ht, Heig ht, Waist Ci rc u mfere nce a n d B o d y Mass 
I n de x....................................................................................................................4 7
9. 1. 5.
A p pr o priate ness of Assess me nts ..........................................................................4 7
9. 2.
A d verse E ve nts ............................................................................................................4 7
9. 2. 1.
S eri o us A d verse E ve nts ........................................................................................4 8
9. 2. 1. 1.
S us pecte d U ne x pecte d Seri o us A d verse React i ons ..........................................4 9
9. 2. 2.
A d verse E ve nt of S pecial I nterest .........................................................................4 9
9. 2. 2. 1.
H y p o gl yce mia ................................................................................................4 9
9. 2. 2. 2.
Se vere, Persiste nt H y per gl yce mia ...................................................................5 0
9. 2. 2. 3.
Pa ncreat itis.....................................................................................................5 1
9. 2. 2. 4.
T h y r oid Mali g na ncies a n d C -Cell H y per plasia ................................................5 2
9. 2. 2. 5.
Maj or A d verse Car di o vasc ular E ve nts ............................................................5 2
9. 2. 2. 6.
S u pra ve ntric ular Arr h yt h mias a n d Car diac C o n d ucti o n 
Di s or ders ........................................................................................................5 2
9. 2. 2. 7.
H y perse nsi tivi t y E ve nts..................................................................................5 3

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 4
L Y 3 2 9 8 1 7 6
9. 2. 2. 7. 1.
I njecti on Si te Reactio ns ............................................................................ 5 3
9. 2. 2. 7. 2.
A nt i-Dr u g A nt i b o dies ...............................................................................5 3
9. 2. 2. 8.
Di a bet ic Reti n o pat h y C o mplicat i ons ...............................................................5 3
9. 2. 2. 9.
He pat o biliar y  Dis or ders..................................................................................5 3
9. 2. 2. 1 0.
Se vere Gastr oi ntesti nal A d verse E ve nts ..........................................................5 3
9. 2. 2. 1 1.
Ac ute Re nal E ve nts ........................................................................................5 3
9. 2. 2. 1 2.
Meta b o lic Aci d osis, I ncl u di n g Dia betic Ket oaci d osis .....................................5 4
9. 2. 2. 1 3.
A m p utati o n/ Peri p heral Re vasc ularizat i on .......................................................5 4
9. 2. 2. 1 4.
Maj or De pressi ve Dis or der/ S uici dal I deati on ..................................................5 4
9. 2. 3.
C o m plai nt Ha n dli n g .............................................................................................5 4
9. 3.
Treat me nt of O ver d ose ................................................................................................. 5 4
9. 4.
S af et y ...........................................................................................................................5 4
9. 4. 1.
Electr ocar di o gra ms ..............................................................................................5 4
9. 4. 2.
Vi t al Si g ns........................................................................................................... 5 5
9. 4. 3.
La b orat or y  Tests..................................................................................................5 5
9. 4. 4.
I mm u n o ge nicit y Assess me nts ..............................................................................5 5
9. 4. 5.
S af et y M o ni t ori n g ................................................................................................5 6
9. 4. 5. 1.
He pati c Safet y M o ni t ori n g..............................................................................5 6
9. 5.
P har mac o ki net ics .........................................................................................................5 7
9. 6.
P har mac o d y na mics ......................................................................................................5 7
9. 7.
P har mac o ge n o mics ......................................................................................................5 7
9. 7. 1.
W h o le Bl o o d Sa m ple(s) f or P har mac o ge netic Researc h .......................................5 7
9. 8.
Bi o m ar kers ...................................................................................................................5 8
9. 9.
Heal t h Ec o n o mics........................................................................................................5 8
9. 9. 1.
I mpac t of Wei g ht o n Self-Perce pt i on Q uest i on naire .............................................5 9
9. 9. 2.
A bilit y t o Perf or m P h ysical Acti vities of Dail y Li vi n g .........................................5 9
9. 9. 3.
E ur o pea n Q ualit y of  Life......................................................................................5 9
1 0.
Stati stical C o nsi derati o ns ..................................................................................................6 0
1 0. 1.
S a m ple Si ze Deter mi nat i on ..........................................................................................6 0
1 0. 2.
P o p ul at i ons f or A nal yses..............................................................................................6 1
1 0 . 3. Stati stical A nal yses ......................................................................................................6 1
1 0. 3. 1.
Ge neral Statist ical C o nsi derat i ons ........................................................................6 1
1 0. 3. 2.
Treat me nt Gr o u p C o m para bilit y ...........................................................................6 2
1 0. 3. 2. 1.
P ati e nt Dis p ositio n ..........................................................................................6 2
1 0. 3 . 2. 2.
P ati e nt C haracteristics ....................................................................................6 3
1 0. 3. 2. 3.
C o nc o mita nt T hera p y .....................................................................................6 3
1 0. 3. 2. 4.
Treat me nt C o m plia nce ....................................................................................6 3
1 0. 3. 3.
Efficac y A nal yses ................................................................................................6 3

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 5
L Y 3 2 9 8 1 7 6
1 0. 3. 3. 1 .
Pri mar y A nal yses ...........................................................................................6 3
1 0. 3. 3. 2.
Sec o n dar y  A nal yses........................................................................................6 4
1 0. 3. 3. 3.
Terti ar y/ E x pl orat or y A nal yses........................................................................6 5
1 0. 3. 4.
S af et y A nal yses ....................................................................................................6 5
1 0. 3. 4. 1.
H y p o gl yce mic E ve nts .....................................................................................6 5
1 0. 3. 4. 2.
Gastr oi ntesti nal E ve nts ...................................................................................6 5
1 0. 3. 4. 3.
A d j u dicate d Car di o vasc ular E ve nts ................................................................6 5
1 0. 3. 4. 4.
Ce ntral  La b orat or y Meas ures, Vit al Sig ns, a n d 
Electr ocar di o gra ms .........................................................................................6 5
1 0. 3. 5.
P har mac o ki net ic/ P har mac o d y na mic A nal yses ......................................................6 6
1 0. 3. 6.
E val uat i on of I m m u n o ge nicit y .............................................................................6 6
1 0. 3. 7.
Ot her A nal yses .....................................................................................................6 6
1 0. 3. 7. 1.
Heal t h Ec o n o mics...........................................................................................6 6
1 0. 3. 7. 2.
S u b gr o u p A nal yses .........................................................................................6 6
1 0. 3. 8.
I nteri m A nal yses ..................................................................................................6 7
1 1.
Refere nces ........................................................................................................................6 8
1 2.
A p pe n dices .......................................................................................................................7 0

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 6
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 K. 1.
Sc he d ule of Act i vities....................................................................................1 4
Ta ble G P G K. 2.
O bject i ves a n d E n d p oi nts...............................................................................2 3
Ta ble G P G K. 3.
Treat me nt Re gi me ns ......................................................................................3 5
Ta ble G P G K. 4.
Descri pt i on of A nal ysis P o p ulat i on a n d Data Sets ..........................................6 1

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 7
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 K. 1.
Ill ustratio n of  st u d y desi g n f or Cli nical Pr ot oc ol I 8 F-M C -G P G K. ..................2 5

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 8
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 ........................................................................7 1
A p pe n di x 2.
Cli nical La b orat or y  Tests...............................................................................7 5
A p pe n di x 3.
St u d y  G o ver na nce C o nsi derati ons ..................................................................7 7
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 ....................8 2
A p pe n di x 5.
W o rld Heal t h Or ga nizati on Classificati o n of Dia betes a n d Dia g n ostic 
Cri teria ..........................................................................................................8 3
A p pe n di x 6.
Cl assificat i on of C o ntrace pti ve Met h o ds ........................................................8 4
A p pe n di x 7.
Pr ot oc ol  G P G K Sta n dar dize d Pr ot oc ols f or t he Meas ure me nt of Hei g ht, 
Wei g ht, a n d Waist Circ u mfere nce
................................................................. 8 5
A p pe n di x 8.
C ha n ges t o St u d y  Pr oce d ures d ue t o t he C O VI D-1 9 Pa n de mic ......................8 7
A p pe n di x 9.
Pr ot oc ol  A me n d me nt I 8 F-M C -G P G K( b)
A Ra n d o mize d, D o u ble -bli n d, Pl ace b o C o ntr olle d Trial C o m par i n g t he 
Efficac y a n d Safet y of  T hree Tirze patide D ose s vers us Place b o i n 
P ati e nts wit h T ype 2 Di a betes, I na de q uatel y C o ntr olle d wit h Diet a n d 
E xercise Al o ne ( S U R P A S S - 1) .......................................................................8 8

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 9
L Y 3 2 9 8 1 7 6
1. S y n o p si s
Title of St u d y:
A Ra n d o mize d, D o u ble -bli n d, Pl ace b o -C o ntr olle d Trial C o m par i n g t he Efficac y a n d Safet y of  
T hree Ti rze patid e D oses vers us Pl ace b o i n Patie nts wit h T ype 2 Di a betes, I na de q uatel y
C o ntr ol le d wi t h Diet a n d E xercise Al one ( S U R P A S S - 1)
R ati o n ale:
T y pe 2 di a betes mellit us ( T 2 D M) is a meta b o lic c o n diti on c haracterize d b y i m paire d gl yce mic 
c o ntr ol ca use d b y increase d i ns uli n resista nce a n d pr o gressi ve beta -cell fail ure a n d c o nse q ue nt l y 
i na de q uate i ns uli n secreti on.  I n a d diti on t o lifest yle i nter ve nt io n i ncl u di n g m e dical n utritio n 
t hera p y a n d p h ysical t hera p y, gl uc ose-l oweri n g me di cat i ons are us uall y  re q uire d f or i m pr o vi n g 
gl y ce mic c o ntr ol in pat ient s wit h T 2 D M ( A D A 2 0 18; Da vies et al. 2 0 1 8).
Ti rze patid e is a 3 9-a mi n o aci d s y nt het ic pe pti de wit h a g o nist a ctivit y at b ot h t he 
gl uc ose - de pe n de nt i ns uli n otr o pic p ol y pe pti de ( GI P) a n d gl uca g o n -li ke pe pti de- 1( G L P) rece pt ors.  
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 
 
It is a d mi nistere d o nce wee kl y ( Q W) b y s u bc uta ne o us i nject i on. 
St u d y  I 8 F-M C -G P G K ( St u d y  G P G K ) is a P hase 3, m ul tice nter, ra n d o mize d, d o u ble- bli n d , 
parallel , i nter natio n al , place b o-c o ntr olle d, 4 0-wee k st u d y t hat will assess t he efficac y a n d safety
of  3 d oses of tirze pati de vers u s pl ace b o i n patie nts wit h T 2 D M na i ve t o dia betes i njecta ble 
t hera p y, i na de q uatel y c o ntr olle d with di et a n d e xercise alo ne, a n d ha ve n ot bee n treate d wit h a n y 
or al  a nti dia betic me dicat i on d uri n g t he 3 m o nt hs prece di n g t o t he start of t he st u d y.
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 de m o nstrate t hat tirze pati de Q W 5 m g , 
a n d/ or 1 0 m g, a n d / or 1 5 m g are s u peri or t o 
place b o i n H b A 1c c ha n ge fr o m baseli ne t o 4 0 
wee ks

Mea n c ha n ge i n H b A 1c
Ke y Sec o n d ar y (c o ntr olle d f or t y pe 1 err or)

T o de m o nstrate s u peri orit y of tirze pati de Q W 
5 m g, a n d/ or 1 0 m g, a n d / or 1 5 m g t o place b o 
at 4 0 wee ks f or:

Mea n c ha n ge i n b o d y wei g ht

Pr o p orti o n of patie nts wit h H b A 1c tar get 
val ues of < 7. 0 % ( < 5 3 m m ol/ m ol)

Mea n c ha n ge i n fasti n g ser u m gl uc ose (ce ntral 
la b orat or y) 

Pr o p orti o n of patie nts wit h H b A 1c tar get 
val ues of < 5. 7 % ( < 3 9 m m ol/ m ol)
C CI

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 1 0
L Y 3 2 9 8 1 7 6
O bjecti ves
E n d p oi nts
A d diti o n al Sec o n d ar y ( n ot c o ntr olle d f or t y pe 1 
err or)

T o c o m pare tirze pati de Q W 5 m g, 1 0 m g, a n d 
1 5 m g t o place b o at 4 0 wee ks f or:

Pr o p orti o n of patie nts wit h H b A 1c tar get of 
≤6. 5 % ( ≤4 8 m m ol/ m ol)

Mea n c ha n ge i n dail y a vera ge 7 -p oi nt self -
m o nit ore d bl o o d gl uc ose pr ofiles fr o m 
baseli ne 

Pr o p orti o n of patie nts w h o ac hie ve d wei g ht 
l oss of ≥5 % , ≥1 0 % , a n d ≥1 5 %
S afet y

T o c o m pare t he safet y of tirze pati de Q W
5 m g, 1 0 m g, a n d 1 5 m g t o place b o f or:

Treat me nt -e mer ge nt a d verse e ve nts ( T E A Es) 

Earl y  disc o nti n uati on of st u d y dr u g d ue t o 
a d verse e ve nts ( A Es )

A dj u dicate d pa ncreatic A Es

S er u m calcit o ni n

Inci de nce of aller gic a n d h y perse nsiti vit y 
reacti o ns

I nci de nce of treat me nt-e mer ge nt a nti -dr u g 
a nti b o dies t o tirze pati de

Mea n c ha n ge i n s yst olic a n d diast olic bl o o d 
press ure a n d heart rate fr o m baseli ne 

Occ urre nce of h y p o gl yce mic e pis o des

Ti me t o i nitiati o n of resc ue t hera p y f or se vere 
persiste nt h y per gl yce mia
P h ar m ac o ki netics

T o c haracterize t he p har mac o ki netics of 
tirze pati de Q W 5 m g, 1 0 m g, a n d 1 5 m g a n d 
t he relati o ns hi ps bet wee n tirze pati de e x p os ure 
a n d safet y, t olera bilit y, a n d efficac y meas ures

P o p ulati o n p har mac o ki netic a n d 
p har mac o d y na mic para meters

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 1 1
L Y 3 2 9 8 1 7 6
S u m m ar y of St u d y Desi g n:   
St u d y  G P G K is a mul tice nter, ra n d o mize d, d o u ble- bli n d, parallel, i nter nat i onal, 
pl ace b o -c o ntr olle d, 4 0 -wee k st u d y  w hic h will assess t he efficac y a n d safet y of  3 d oses of 
tirze pati de vers u s place b o i n a p pr o xi matel y  4 7 2 ra n d o mize d patient s wit h T 2 D M w h o are n ot 
c o ntr olle d o n diet a n d e xercise al o ne , naï ve t o dia betes i njecta ble t hera p y, a n d ha ve n ot bee n 
treate d wit h a n y oral a nti dia betic me dicat i on d uri n g t he 3 m o nt hs prece di n g t o t he start of t he 
st u d y.
Tre at me nt Ar ms a n d D ur ati o n:   
St u d y  G P G K will c o nsist of 3 peri o ds:  a n a p pr o xi matel y 3-wee k scree ni n g/lea d -i n peri o d, 
f oll owe d b y a 4 0 -wee k treat m e nt perio d , a n d a 4-wee k safet y f oll ow- u p peri o d .  Patie nts will be 
ra n d omize d i n a 1: 1: 1: 1 rati o (tirze pat i de 5 m g Q W , 1 0 mg Q W , 1 5 mg Q W , a n d i njecta ble 
pl ace b o).  Patie nts will be stratifie d base d o n c o u ntr y, baseli ne H b A 1c [ ≤8. 5 % ( ≤6 9 m m o l/ m ol)
or > 8. 5 % ( > 6 9 m m o l/ m ol)], a n d a n y past prior us e ( Yes or N o) of a n y oral a nt i dia betic 
me dicat i on ). 
N u m ber of P atie nts :
A t otal o f a p pr o xi matel y 4 7 2 p atie nts ( 1 1 8 patie nts per treat me nt gr o u p) will be ra n d o mize d .
St atistic al A n al ysis:
E ffic ac y A n al yses
Efficac y will be assesse d usi n g t he m o difie d i nte nt -t o-treat p o p ulati o n, w hic h c o nsists of all 
ra n d oml y assi g ne d partici pa nts w h o are e x p ose d t o at least 1 d ose of st u d y dr u g.  T here will be 2 
esti ma n ds of i nterest i n c o m par i n g efficac y of Q W tirze pati de doses wi t h place b o relat i ve t o t he 
pri mar y  meas ure of mea n c ha n ge i n H b A 1c val ues fr om baseli ne t o 4 0- wee k visit.  T he 
“efficac y” est i ma n d, re prese nts efficac y pri or t o disc o nti n uati o n of st u d y dr u g wit ho ut 
c o nf o u n di n g effects of resc ue t hera p y for persi stent se vere h y per gl yce mia.  T he “treat me nt -
re gi me n” esti ma n d, re prese nts t he efficac y irres pecti ve of a d here nce t o i n vesti gati onal pr o d uct or 
i ntr o d uctio n of  resc ue t hera p y for p ersi ste nt se vere h yper gl yce mia.  
F or t he F D A a n d p ossi bl y ot her re g ulat or y  a ge ncies, t he pri mar y efficac y assess me nt will be 
g ui de d b y  t he “treat me nt -re gi me n” esti ma n d.  T his assess me nt will a nal yze c ha n ge i n H b A 1c 
val ues fr o m baseli ne t o 4 0- wee k visit usi n g a n a nal ysis o f c o varia nce ( A N C O V A ) wi t h t er ms:
treat me nt, c o u ntr y, a n y past pri or use ( Yes or N o) of a n y oral a nt i dia betic me dicat i on, a n d 
baseli ne H b A 1c as a c o variate .  T he A N C O V A a nal ysis will be c o n d ucte d usi n g t he full a nal ysis 
set at 4 0- wee k visit, w hic h c o nsists of all a vaila ble c ha n ge fr o m baseli ne i n H b A 1c data at t he 
4 0 -wee k visit, irres pect i ve of w het her t he y were o btai ne d w hile t he partici pa nts ha d disc o nti n ue d 
t he st u d y dr u g or w het her t he partici pa nt ha d bee n gi ve n resc ue me dicati on.   A d dit i onall y, data 
f or patie nts wi t h missi n g val ues will be i m p uted base d o n o bser ve d data i n t he sa me treat me nt 
ar m fr o m pat ient s w h o ha d t heir efficac y meas ure at t he Wee k 4 0 visit assesse d after earl y 
di sc o nti n uati on of st u d y  dr u g a n d/ or i nitiati on of resc ue me dicat i on (retrie ve d dr o p o uts).  

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 1 2
L Y 3 2 9 8 1 7 6
A nal ysis will be c o n d ucte d wit h m ult i ple i m p utatio ns, a n d st atistical i nfere nce o ver m ulti ple 
i m p utatio ns will be g ui de d b y t he met h o d pr o p ose d b y  R u bi n ( 1 9 8 7).
F or all ot her p ur p oses, t he pri mar y efficac y assess me nt, g ui de d b y t he “efficac y” est i ma n d, will 
use efficac y a nal ysis se t w hic h c o nsists of data o btai ne d bef ore t he i nitiati on of a n y  resc ue 
t hera p y a n d bef ore pre mat ure treat me nt disc o nti n uati o n.  T he a nal ysis m o del f or c ha n ge i n 
H b A 1c val ues fr o m baseli ne assesse d o ver ti me will  be a mi xe d mo d el  for re peate d m eas ures 
( M M R M) wi t h ter ms:  treat me nt, visit, treat me nt -b y -visit i nteracti o n , c o u ntr y, a n y past pri or use 
( Yes or N o) of a n y or al a ntidia betic m e dicat i on as fi xe d effects, baseli ne H b A 1c as a c o variate, 
a n d pat ient as a ra n d o m effect.   A n u nstr uct ure d c o varia nce str uct ure will m o del relat i ons hi p of 
wi t hi n-patie nt err ors.  
Si nce t he y  are i nte n de d f or differe nt p ur p oses, eac h of t he 2 pri mar y efficac y assess me nts
r elat i ve t o t w o esti ma n ds will be c o n d ucte d at 2 -si de d al p ha of 0. 0 5.  A d d iti on al  details, 
i ncl u di n g a nal ysis met h o ds f or ke y sec o n dar y e nd p oi nts a n d a strate g y  for c o ntr olli n g o verall 
t ype 1 err or rate at a 2 -si de d alp ha of 0. 0 5 of pri mar y  a n d ke y sec o n dar y e n d p oi nt e valu ati o n, 
will be pr o vi de d i n t he statist ical a nal ysis pla n ( S A P).
S afet y A n al yses
S af et y assess me nt will be base d o n all a vaila ble data t hr o u g h safety f oll ow u p visit , irres pecti ve 
of  w het her t he y were o btai ne d aft er st u d y dr u g disc o nti n uat i on or w het her t he partici pa nt 
recei ve d resc ue me dicati on. S u m mar y statis tics will be pr o vid e d f or i nci de nce o f T E A Es, 
serio us A E s, a n d st u d y disc o nti n uati on d ue t o A Es or deat hs fr o m first d ose t o e n d of safet y 
f oll ow- u p.  C o u nts a n d pr o p orti o ns of pat ient s e x perie nci n g A Es will be re p orte d f or eac h 
treat me nt gr o u p, a n d Fis her’s e xact test will be use d t o c o m pare t he treat me nt gr o u ps.  F or 
c o nti n u o us la b orat or y a nal ytes, s u m mar y st atistics will be pr o vi de d b y visit, wit h statist ical 
c o mparis o ns a m o n g treat m e nt at eac h visit c o n d ucte d usi n g a n M M R M a nal ysis. A d dit i onal 
details, i ncl u di n g a nal ysis o f A Es of s pecial i nterest, will be pr o vi de d i n t he S A P .

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 1 3
L Y 3 2 9 8 1 7 6
2. S c h e d ul e of A cti viti e s
T he Sc he d ule o f Act i vities descri be d bel o w s h o ul d be f oll owe d f or all pat ient s e nr olle d i n 
St u d y G P G K .  H o we ver, f or t h ose patie nts w h ose partici pati on i n t his st u d y is affecte d b y se vere 
ac ute res pirat or y s y n dr o me c or o na vir us 2 ( S A R S-C o V -2), t he vir us t hat ca uses t he n o vel 
C or o na vir us Disease 2 0 1 9 ( C O VI D- 1 9), please refer t o A p pe n di x 8 f or a d ditio nal  instr ucti o ns.
   

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 1 4
L Y 3 2 9 8 1 7 6
T a bl e G P G K . 1.
S c h e d ul e of A cti viti e s
St u d y P eri o d 
I
St u d y P eri o d II
St u d y 
P eri o d III
Scr e e ni n g/
Le a d i n
Tr e at m e nt P eri o d
S af et y 
F/ U
Visit
1
2
3 a
4
5
6
7
8
9
1 0
1 1
1 2
1 3
1 4
E T b
8 0 1
W e e k of Tr e at m e nt
- 3
- 2
0
4
7
8
1 2
1 5
1 6
2 0
2 3
2 4
3 2
4 0
4 w e e ks 
p ost e n d 
of t x
All o w a bl e 
D e vi ati o n ( d a ys) c
± 3
± 7
± 3
-
± 3
± 3
-
± 3
± 3
-
± 3
± 7
± 7
± 7
F asti n g Visit d
X
X
X
X
X
X
X
X
X
X
X
P K s p ecific Visit e
X
X
X
I nf or m e d c o ns e nt
X
R a n d o miz ati o n
X
Cli nic al Ass ess m e nts
M e dic al h ist oryf
X
P h ysic al
X
X 
X 
X
H ei g ht
X
W ei g ht
g
X
X 
X
X 
X
X 
X
X 
X 
X 
X 
X
W aist 
circ u mf er e nc e
X 
X
X 
X
X 
X
X 
X 
X 
X 
X
El ectr oc ar di o gr a m h
X
X 
X 
X
Vit al si g ns ( 2 sitti n g 
B P a n d H R) i
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Dil at e d fu n d o sc o pic 
E x a mi n ati o nj
X
A d v ers e e v e nts
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
C o nc o mit a nt 
m e dic ati o ns
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
R e vi e w 
hy p o glyc e mic 
ev e nts c oll ect e d i n 
t h e di ari es
X 
X
X 
X
X 
X
X 
X 
X 
X 
X

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 1 5
L Y 3 2 9 8 1 7 6
St u d y P eri o d 
I
St u d y P eri o d II
St u d y 
P eri o d III
Scr e e ni n g/
Le a d i n
Tr e at m e nt P eri o d
S af et y 
F/ U
Visit
1
2
3 a
4
5
6
7
8
9
1 0
1 1
1 2
1 3
1 4
E T b
8 0 1
W e e k of Tr e at m e nt
- 3
- 2
0
4
7
8
1 2
1 5
1 6
2 0
2 3
2 4
3 2
4 0
4 w e e ks 
p ost e n d 
of t x
All o w a bl e 
D e vi ati o n ( d a ys) c
± 3
± 7
± 3
-
± 3
± 3
-
± 3
± 3
-
± 3
± 7
± 7
± 7
F asti n g Visit d
X
X
X
X
X
X
X
X
X
X
X
P K s p ecific Visit e
X
X
X
Di a b et es 
e d uc ati o n k,l
X
B G m et er, S M B G 
tr ai ni n gm
X
Dis p e ns e B G 
m et er/s u p pli es as 
n e e d e d
X 
X 
X
X 
X
X 
X
X 
X 
X 
X
St u dy dr u g i nj ecti o n 
tr ai ni n g wit h d e m o 
d evic e l
X
H a n d o ut di ari es , 
i nstr uct i n us el
X 
X
X 
X
R e mi n d p ati e nts 
a b o ut 7 -p oi n t 
S M B G m
X
X
X 
X 
X
R e vi e w 7 -p oi nt 
S M B G v al u es 
c oll ect e d i n t h e 
di ari es
X
X
X
X

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 1 6
L Y 3 2 9 8 1 7 6
St u d y P eri o d 
I
St u d y P eri o d II
St u d y P eri o d 
III
Scr e e ni n g/
Le a d i n
Tr e at m e nt P e ri o d
S af et y F/ U
Visit
1
2
3 a
4
5
6
7
8
9
1 0
1 1
1 2
1 3
1 4
E T b
8 0 1
W e e k of Tr e at m e nt
- 3
- 2
0
4
7
8
1 2
1 5
1 6
2 0
2 3
2 4
3 2
4 0
4 w e e ks p ost 
e n d of t x
All o w a bl e D e vi ati o n 
( d a ys)c
± 3
± 7
± 3
-
± 3
± 3
-
± 3
± 3
-
± 3
± 7
± 7
± 7
F asti n g Visit d
X
X
X
X
X
X
X
X
X
X
X
P K s p ecific Visit e
X
X
X
Dis p e ns e st u dy dr u g
X 
X
X 
X
X 
X
X 
X
O bs erv e p ati e nt 
a d mi nist er st u dy 
dr u g n
X
P ati e nt r et ur ns 
st u dy dr u gs a n d 
i nj ecti o n s u p pli es
X
X 
X
X 
X
X 
X 
X 
X
Ass ess st u dy dr u g 
c o m pli a nc e
X
X 
X
X 
X
X 
X 
X 
X

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 1 7
L Y 3 2 9 8 1 7 6
St u d y P eri o d I
St u d y P eri o d II
St u d y 
P eri o d III
Scr e e ni n g/ 
L e a d i n
Tr e at m e nt P eri o d
S af et y F/ U
Visit
1
2
3 a
4
5
6
7
8
9
1 0
1 1
1 2
1 3
1 4
E T b
8 0 1
W e e k of Tr e at m e nt
- 3
- 2
0
4
7
8
1 2
1 5
1 6
2 0
2 3
2 4
3 2
4 0
4 w e e ks 
p ost e n d of 
t x
All o w a bl e D e vi ati o n 
( d a ys)c
-
± 3
± 7
± 3
-
± 3
± 3
-
± 3
± 3
-
± 3
± 7
± 7
± 7
F asti n g Visit d
X
X
X
X
X
X
X
X
X
X
X
P K s p ecific Visit e
X
X
X
L a b or at ory T ests
S er u m pr e g n a ncy t est o
X
Uri n e pr e g n a ncy t est p
X
X
X
X
F ollicl e-sti m ul ati n g 
h or m o n e t est , estr a di ol q
X
C h e mistry p a n el 
X r
X
X
X 
X 
X
F asti n g s er u m gl uc os e
X 
X
X 
X
X 
X
X 
X 
X 
X 
X
F asti n g i ns uli n
X
X
X
X
X
X
F asti n g gl uc a g o n
X
X
X
X
X
X
F asti n g C -p e pti d e
X
X
X
X
X
X
Li pi d p a n el
X
X
X
X
X 
X 
X
Uri n ary al b u mi n/cr e ati ni n e 
r ati o
X r
X 
X 
X
S er u m cr e ati ni n e, e G F R 
( C K D-E PI) s
X r
X
X
X 
X 
X
C alcit o ni n
X r
X
X
X 
X 
X
H e m at ol o g y
X r
X
X
X 
X 
X
H b A 1c
X
X 
X
X 
X
X 
X
X 
X 
X 
X 
X
P a ncr e atic a myl as e, li p as e
X r
X
X
X 
X 
X
I m m u n o g e nicityt
X 
X
X
X
X 
X 
X
P K s a m pl e f or 
i m m u n o g e nicityu
X 
X
X
X
X 
X 
X

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 1 8
L Y 3 2 9 8 1 7 6
St u d y P eri o d I
St u d y P eri o d II
St u d y 
P eri o d III
Scr e e ni n g/ 
L e a d i n
Tr e at m e nt P eri o d
S af et y F/ U
Visit
1
2
3 a
4
5
6
7
8
9
1 0
1 1
1 2
1 3
1 4
E T b
8 0 1
W e e k of Tr e at m e nt
- 3
- 2
0
4
7
8
1 2
1 5
1 6
2 0
2 3
2 4
3 2
4 0
4 w e e ks 
p ost e n d of 
t x
All o w a bl e D e vi ati o n 
( d a ys)c
-
± 3
± 7
± 3
-
± 3
± 3
-
± 3
± 3
-
± 3
± 7
± 7
± 7
F asti n g Visit d
X
X
X
X
X
X
X
X
X
X
X
P K s p ecific Visit e
X
X
X
St or e d s a m pl es
Tirz e p ati d e P K v
X w
X
X
X
X x
X
P h ar m ac o g e n etic st or e d 
s a m pl e
X
N o n p h ar m ac o g e n etic 
st or e d s a m pl e
E D T A pl as m a, s er u m, P 8 0 0 
pl as m a -2. 0 mL
X
X
X
X 
X
P ati e nt -R e p ort e d O utc o m es y
A P P A DL 
X
X 
X
E Q -5 D -5L 
X
X 
X
I W-S P
X
X 
X

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 1 9
L Y 3 2 9 8 1 7 6
A b bre viati o ns:  A D A = a nti -dr u g a nti b o d y ; A P P A D L = A bilit y t o Perf or m P h ysical Acti vities of Dail y Li vi n g; B G = bl o o d gl uc ose; B P = bl o o d press ure; C K D-
E PI = C hr o ni c  Ki d ne y Disease-E pi de mi ol o g y; E C G = electr ocar di o gra m; e C R F = electr o nic case re p ort f or m; e G F R = esti mate d gl o mer ular filtrati o n r ate; 
E Q - 5 D-5 L = E ur o pea n Q ual it y of Life-di me nsi o ns; E T = earl y ter mi nati o n; F/ U = f oll o w - u p; H b A 1c = he m o gl o bi n A 1c; H R = heart rate; I W -S P = I m pact of 
Wei g ht o n Self -Perce pti o n; P K = p har mac o ki netics; P R O = patie nt -re p orte d o utc o me; S M B G = self -m o nit o ri n g of bl o o d gl uc ose ; T x = treat me nt .
a
Baseli ne assess me nts m ust be c o m plete d bef ore pr ocessi n g i n t he i nteracti ve we b -res p o nse s yste m (I W R S).
b
Patie nts w h o are u na ble or u n willi n g t o c o nti n ue i n t he st u d y f or a n y reas o n will perf or m a n E T visit.  If t he p atie nt is disc o nti n ui n g d uri n g a n u nsc he d ule d 
visit, t hat visit s h o ul d be perf or me d as t he E T visit.  If t he patie nt is disc o nti n ui n g d uri n g a sc he d ule d visit, t hat visit s ho ul d be perf or me d as a n E T visit.  
Visit 8 0 1 ( safet y foll o w - u p visit) s h o ul d be perf orme d 4 wee ks after t he E T visit as t he fi nal st u d y visit.
c
T he visit date is deter mi ne d i n relati o n t o t he date of t he ra n d o mizati o n visit ( ± t he all o we d visit wi n d o w).
d
O n visits 3, 4, 6, 7, 9, 1 0, 1 2, 1 3, 1 4 , E T, a n d at f oll o w-u p, patie nts s h o ul d be re mi n de d t o re p ort t o t he site i n a fasti n g c o n diti o n, after a peri o d of 
a p pr o xi matel y 8 h o urs wit h o ut eati n g, dri n ki n g (e xce pt water), or a n y si g nifica nt p h ysical acti vit y a n d bef ore ta ki n g st u d y d r u g.
e
Visit is f or tirze pati de P K bl o o d dra ws 
f
Me dical hist or y  i ncl u des assess me nt of pree xisti n g c o n diti o ns (i ncl u di n g hist or y of gall bla d der disease, car di o vasc ular disease, a n d me d ullar y t h yr oi d 
carci n o ma) a n d s u bsta nce usa ge (s uc h as alc o h ol a n d t o bacc o) .
g
Wei g ht meas ure me nts m ust be i n kil o gra ms.
h
Elec tr ocar di o gra ms occ urri n g o n visits wit h tirze pati de P K c ollecti o n s h o ul d be c ollecte d at least 3 0 mi n utes pri or t o o btai ni n g t he sa m ple f or tirze pati de P K 
meas ure me nt.
i
Vital si g n meas ure me nts s h o ul d be ta ke n bef ore o btai ni n g a n E C G traci n g a n d bef ore c ol lecti o n of bl o o d sa m ples f or la b orat or y testi n g, at visits w here 
re q uire d.  T he partici pa nt s h o ul d sit q uietl y f or 5 mi n utes bef ore vital si g n meas ure me nts are ta ke n.  F or eac h para meter, 2 meas ure me nts will be ta ke n usi n g 
t he sa me ar m; t he rec or di n gs s h o ul d be ta ke n at least 1 mi n ute a part.  B P m ust be ta ke n wit h a n a ut o mate d bl o o d press ure mac hi ne.
j
Dilate d f u n d osc o pic e xa m i nati o n will be perf or me d b y a n e ye care pr ofessi o nal ( o p ht hal m ol o gist or o pt o metrist) f or all patie nts bet wee n Visit 2 a n d Visit 3 t o 
e xcl u de patie nts wit h pr oliferati ve dia betic reti n o pat h y, dia betic mac ul o pat h y , or  n on pr oliferati ve dia betic reti n o pat h y t hat re q uires ac ute treat me nt.  T he 
res ults fr o m t his e xa mi nati o n will be rec or de d o n a s pecific reti n o pat h y e C R F as a baseli ne meas ure of reti n o pat h y.  F oll o w -u p dilate d f u n dosc o pic
e xa mi nati o n s ho ul d be perf or me d w he n cli nicall y i n dicate d, a n d t he res ults were rec or de d o n t he reti n o pat h y e C R F.
k
I ncl u des c o u nseli n g o n diet a n d e xercise, s y m pt o ms a n d ma na ge me nt of h y p o gl yce mia an d h y per gl y ce mia, etc.
l
All trai ni n g s h o ul d be re peate d as nee de d t o e ns ure patie nt c o m plia nce. 
m
Patie nt is re q uire d t o c ollect t w o 7 -p oi nt S M B Gs o n n o nc o nsec uti ve da ys pri or t o t he ne xt visit.  A 7 -p oi nt S M B G c o nsists of meas ure me nts bef ore a n d 
2 h o urs after eac h of 3 mai n meals wit hi n t he sa me da y a n d at be dti me.  T hese S M B G pr ofiles will be c ollecte d b y t he patie nt wit hi n 2 wee ks pri or t o t he 
assi g ne d visits.  If m ore t ha n 2 S M B G pr ofiles are a vaila ble, t he 2 m ost rece nt n o nc o nsec uti ve pr ofiles s h o ul d be use d.
n
Patie nts s h o ul d a d mi nister t heir first d ose of st u d y dr u g at t he e n d of t his visit, after ot her st u d y pr oce d ures a n d ra n d o miz ati on.
o
A ser u m pre g na nc y test will be perf or me d at Visit 1 f or w o me n of c hil d beari n g p ote ntial o nl y.
p
A l ocal uri ne pr e g na nc y test m ust be perf or me d at Visit 3 wit h t he res ult a vaila ble pri or t o ra n d o mizati o n a n d first i njecti o n of st u d y dr u g(s) f or w o me n of 
c hil d beari n g p ote ntial o nl y.  A d diti o nal pre g na nc y tests will be perf or me d at Visits 7, 1 2, a n d 1 4. P re g na nc y t ests ma y be perf or me d at t he i n vesti gat or’s 
discreti o n d uri n g t he st u d y.  If re q uire d per l ocal re g ulati o ns a n d/ or i nstit uti o nal g ui deli nes, pre g na nc y testi n g ca n als o o cc ur at ot her ti mes d uri n g t he st u d y 
treat me nt peri o d.

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 2 0
L Y 3 2 9 8 1 7 6
q
F ollicle -sti m ulati n g h or m o ne ( FS H) test perf or me d at Visit 1 f or p ost me n o pa usal w o me n at least 4 5 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, a n d w h o ha ve ha d s p o nta ne o us a me n orr hea f or m ore t ha n 6 m o nt hs a n d less t ha n 1 2 m o nt hs a n d estra di ol le vels c o nsistent wit h a p os t me n o pa usal 
state ( F S H ≥4 0 mI U/ m L a n d estra d i ol < 3 0 p g/ m L).
r
Scree ni n g visit assess me nt will ser ve as baseli ne .
s
T he C K D -E PI e q uati o n will be use d b y t he ce ntral la b t o esti mate a n d re p ort e G F R. 
t
I n t he e ve nt of s yste mic dr u g h y perse nsiti vit y reacti o ns (i m me diate or n o ni m me diate), a d diti o nal bl o o d sa m ples will be c ollecte d i ncl u di n g A D A , P K, a n d 
e x pl orat or y i m m u ne safet y sa m ple.
u
P K sa m ples f or i m m u n o ge nicit y m ust be ta ke n pri or t o dr u g a d mi nistra ti o n.
v
P K sa m ples will be c ollecte d at t hese visits e xce pt f or Visit 3 a n d Visit 1 4 at ti me wi n d o ws of 1 t o 2 4 h o urs, 2 4 t o 9 6 h o urs, O R 1 2 0 t o 1 6 8 h o urs p ost d ose, 
as assi g ne d b y I W R S.  De pe n de nt o n t he ti me wi n d o ws t o w hic h a patie nt gets assi g ne d, t he y m a y  be re q uire d t o c o me t o site f or P K-s pecific visits.  
w
T he P K sa m ple after t he first d ose at Visit 3 s ho ul d be c ollecte d a n yti me o n t he sa me da y after a d mi nistrati o n of t he first d ose at t he site.  
x   T he P K sa m ple after t he last d ose a d mi nistere d a t Wee k 3 9 will be c ollecte d at Visit 1 4 ( Wee k 4 0). 
y
All P R Os s h o ul d be c o m plete d bef ore a n y ot her st u d y pr oce d ures if t he patie nt is n ot a d versel y affecte d b y t he fasti n g c o n dit i o n or c o m plete d after t he patie nt 
has s ufficie ntl y rec o vere d fr o m t he pr ece di n g visit pr oce d ures.

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 2 1
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 y pe 2 di a betes mellit us ( T 2 D M) is a meta b o lic c o n diti on c haracterize d b y i m paire d gl yce mic 
c o ntr ol ca use d b y i ncrease d i ns uli n resista nce a n d pr o gressi ve beta-cell fail ure a n d c o nse q ue nt l y 
i na de q uate i ns uli n secreti on.  T y pe 2 di a betes mellit us is ass ociate d wit h c o m o r bidi ties s uc h as 
i ncrease d wei g ht or o besity,  h y perte nsi on, i ncrease d bl o o d li p o pr otei n c o nce ntr atio ns, a n d a 
hi g her ri s k f or macr o- a n d micr o vasc ular c o m plicati o ns.  T o pre ve nt t hese c o m plicati o ns, ti g ht 
gl yce mic c o ntr ol is rec o m me n de d ( A D A 2 0 1 8 ; Da vies et al. 2 0 1 8 ).
I njecta ble i ncreti n-base d treat me nts ( f or e xa m ple, gl uca g o n -li ke pe pti de- 1 [G L P - 1] rece pt or 
a g o nists) are c o m m o nl y use d i n c o m bi nat i on wi t h or al  a nti h y per gl yce mic me dicati on ( O A Ms ) t o 
ac hie ve a n d mai ntai n gl uc ose c o ntr ol ( I nz ucc hi et al. 2 0 1 5 ; A D A 2 0 1 8 ).  W hile ass ociate d wit h 
l ow er ri s k f or h y p o gl yce mia a n d either wei g ht ne utral or wei g ht l oss effects, c urre nt pre parati o ns 
are directe d at a si n gle m o lec ular tar get ( G L P-1 rece pt ors) a n d pr o vi de d ose -de pe n de nt 
gl uc ose -l oweri n g effects, w hic h ca n be li mite d b y gastr oi ntesti nal ( GI) t olera bilit y ( Na uc k 2 0 1 6).
T he m eta b o lic effects of G L P- 1 rece pt or a g o nists ca n be e n ha nce d b y c om bi ni n g t he m wit h t he 
actio ns of  ot her e nter o pa ncreatic h or m o nes.  Gl uc ose-de pe n de nt i ns uli n otr o pic p ol y pe pti de 
( GI P) sti m ulates i ns uli n secreti on i n a gl uc ose-de pe n de nt m a n ner a n d ma y e xert s o me ot her 
actio ns be y o n d its r ole as a n i ncreti n t hat c o ul d p ote nt iall y i m pr o ve t hera pe utic efficac y i n 
c o m bi nat i on wi t h G L P-1 rece pt or a g o ni sts alo ne (f or e xa m ple, i m pr o ve d li pi d h o m e ostasis a n d 
w h o le-b o d y  e ner g y meta b o lis m) ( As mar et al. 2 0 1 6; Na uc k a n d Meier 2 0 1 8 ).
Ti rze patid e (L Y 3 2 9 8 1 7 6 ) is a 3 9 -a mi n o aci d s y nt heti c pe pt i de wit h a g o nist acti vity at b ot h t he 
GI P a n d G L P -1 rece pt ors.  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 -aci d moi et y t hat 
  It is a d mi nistere d as o nce- wee kl y ( Q W) 
s u bc uta ne o us ( S C) i njecti on ( C os k u n et al. 2 0 1 8).  
St u d y  I 8 F-M C -G P G K ( St u d y  G P G K ) is a P hase 3, m ul tice nter, ra n d o mize d, d o u ble- bli n d , 
parallel , i nter natio n al , place b o-c o ntr olle d, 4 0-wee k st u d y t hat will assess t he efficac y a n d safet y
of  3 d oses of tirze pati de vers us place b o i n patie nts wit h T 2 D M nai ve t o dia betes i njecta ble 
t hera p y, i na de q uatel y c o ntr olle d with di et a n d e xercise alo ne, a n d ha ve n ot bee n treate d wit h a n y 
or al  a nti dia betic me dicat i on d uri n g t he 3 m o nt hs prece di n g t o t he start of t he st u d y.
3. 2.
B a c k gr o u n d
T hree tirze pati de cli nical st u dies ha ve c o m plete d d osi n g a n d a nal ysis:  a P hase 1 st u d y , 
St u d y I 8 F-M C -G P G A ( St u d y  G P G A), a n d t w o P hase 2 st u dies, St u d ies I 8 F-M C -G P G B ( St u d y  
G P G B) a n d I 8 F -M C -G P G F (St u d y  G P G F).   
P hase 1 St u d y  G P G A was a c o m bi nati on of si n gle asce n di n g d ose ( S A D) a n d m ult i ple asce n di n g 
d ose st u d y  in heal t h y s u bjects f oll owe d b y  a m ultipl e d ose st u d y in pat ient s wit h T 2 D M.  
St u d y G P G A i n vesti gate d safety,  t olera bilit y, p har mac o ki net ics ( P K), a n d p har mac o d y na mics 
( P D) of tirze pati de a d mi nistere d as S C i nject i ons.  A t otal o f 1 4 2 s u bjects ( 8 9 healt h y s u bjects 
a n d 5 3 pati e nts wit h T 2 D M) recei ve d at least 1 d ose of treat me nt.  D o ses of tirze pati de ra n ge d 
C CI

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 2 2
L Y 3 2 9 8 1 7 6
fr om 0. 2 5 m g t o 8 m g i n t he S A D (wi t h ma xi m u m t olerate d d ose ac hie ve d at 5 m g) i n health y 
s u bjects; m ult i ple d oses fr o m 0. 5 m g t o 4. 5 m g Q W a n d titrate d d oses u p t o 1 0 m g Q W  for 4 
wee ks i n healt h y s u bjects; a n d mul tiples d oses ra n ge d fr om 0. 5 m g t o 5 m g Q W a n d titrate d 
d oses u p t o 1 5 mg Q W f or 4 wee ks i n patie nts wit h T 2 D M.  T he safet y,  t olera bilit y, a n d P K/ P D 
pr ofiles of tirze pati de at d oses a n d escalat i on re gi me ns a d mi nistere d i n t his P hase 1 st u d y  
s u p p orte d f urt her de vel o p me nt of tirze pati de f or Q W d osi n g i n patient s wit h T 2 D M.
A 2 6 -wee k P hase 2 st u d y  (St u d y  G P G B) assesse d t he efficac y , t olera bilit y, a n d safety of  4 d oses 
( 1 m g , 5 m g , 1 0 mg , a n d 1 5 mg) of  tirze pati de vers us place b o a n d a n acti ve c o m parat or 
( d ula gl utid e 1. 5 m g) i n 3 1 8 pati e nts wi t h T 2 D M with i na 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 metf or mi n m o n ot hera p y .  T he d oses of 1 0 m g a n d 1 5 m g 
were attai ne d b y t itrati o n ( Frias et al. 2 0 1 8).  
St u d y  G P G B de mo nstrate d t hat tirze pati de 5 -m g , 1 0-m g , a n d 1 5-m g d oses si g nifica nt l y l owere d 
he m o gl o bi n A 1 c ( H b A 1c) a n d b o d y  wei g ht i n a d ose-de pe n de nt ma n ner i n patient s wit h T 2 D M 
i n c o mparis o n t o place b o .  I n a d diti on, re d ucti o ns i n H b A 1c i n t he tirze pat i de 5 -m g , 1 0-m g , a n d 
1 5 -m g d oses were greater t ha n wit h d ul a gl ut i de 1. 5 m g Q W.  Si milar t o t he G L P -1 rece pt or 
a g o nist class a n d t he P hase 1 St u d y, most of  t he tirze patid e a d verse e ve nts ( A Es ) were GI
r elate d, c o nsist i 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.  T he GI 
A Es were us uall y  mil d t o mo derate i n i nte nsit y.   S erio us A Es ( S A Es) were bala nce d acr oss t he 
treat me nt gr o u ps, a n d n o ne of t he gr o u ps i n eit her st u d y re p orte d se vere h y p o gl yce mia
( Frias et al. 2 0 1 8) . 
As i t was rec o g nize d t hat t he titrati o n sc he me e m pl oye d i n St u d y  G P G B was u nli kel y t o be 
o pti mal f or t he re d ucti o n of  GI-relate d A Es e x pecte d wit h tirzepat i de, St u d y G P G F was desi g ne d 
t o e x pl ore alter nati ve titrati o n sc he mes (l o n ger ti me i nter vals bet wee n d ose escalati o ns a n d 
differe nt d ose escalat i ons) t o s u p p ort e val uati o n of o pti mize d d osi n g re gi me n(s) i n P hase 3. T his 
was a 1 2 -wee k, place b o -c o ntr olled st u d y  t o assess t he efficac y a n d 3 differe nt titrati o n sc he mes 
t o attai n d oses as hi g h as 1 5 m g of tirze pati de i n patie nts wit h T 2 D M.
T hese data s u p p ort c o nti n ue d de vel o p me nt of tirze patide as a t hera p y for T 2 D M.  
3. 3.
B e n e fit/ Ri s k A s s e s s m e nt
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, S A Es , a n d reas o na bl y 
a nt ici pate d A Es of tirze patide are t o be f o u n d i n t he I n vest i gat or’s Br oc h ure (I B).

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 2 3
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
Ta ble G P G K . 2 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 K . 2.
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 de m o nstrate t hat tirze pati de Q W 5 m g ,
a n d/ or 1 0 m g, a n d/ or 1 5 m g are s u peri or t o 
place b o i n H b A 1c c ha n ge fr o m baseli ne t o 4 0
wee ks

Mea n c ha n ge i n H b A 1c 
Ke y Sec o n d ar y (c o ntr olle d f or t y pe 1 err or)

T o de m o nstrate s u peri orit y of tirze pati de Q W 
5 m g , a n d/ or 1 0 m g, a n d/ or 1 5 m g t o place b o 
at 4 0 wee ks f or:

Mea n c ha n ge i n b o d y wei g ht 

Pr o p orti o n of patie nts wit h H b A 1c tar get 
val ues of < 7. 0 % ( < 5 3 m m ol/ m ol)

Mea n c ha n ge i n fasti n g ser u m gl uc ose ( F S G) 
(ce ntral la b orat or y) 

Pr o p orti o n of patie nts wit h H b A 1c tar get 
val ues of < 5. 7 % ( < 3 9 m m ol/ m ol)
A d diti o n al Sec o n d ar y ( n ot c o ntr olle d f or t y pe 1 
err or)

T o c o m pare tirze pati de Q W 5 m g, 1 0 m g, a n d 
1 5 m g t o place b o at 4 0 wee ks f or:

Pr o p orti o n of patie nts wit h H b A 1c tar get of 
≤6. 5 % ( ≤4 8 m m ol/ m ol)

Mea n c ha n ge i n dail y a vera ge 7 -p oi nt self -
m o nit ore d bl o o d gl uc ose pr ofiles fr o m 
baseli ne

Pr o p orti o n of patie nts w h o ac hie ve d wei g ht 
l oss of ≥5 % , ≥1 0 % , a n d ≥1 5 %
S afet y

T o c o m pare t he safet y of tirze pati de Q W
5 m g, 1 0 m g, a n d 1 5 m g t o place b o f or:

Treat me nt -e mer ge nt a d verse e ve nts ( T E A Es)

Earl y  disc o nti n uati o n of st u d y dr u g d ue t o 
a d verse e ve nts ( A Es)

A dj u dicate d pa ncreatic A Es

S er u m calcit o ni n

Inci de nce of aller gic a n d h y perse nsiti vit y 
reacti o ns

I nci de nce of treat me nt-e mer ge nt a nti -dr u g 
a nti b o dies t o tirze pati de

Mea n c ha n ge i n s yst olic a n d diast olic bl o o d 
press ure a n d heart rate fr o m baseli ne 

Occ urre nce of h y p o gl yce mic e pis o des

Ti me t o i nitiati o n of resc ue t hera p y f or se vere 
persiste nt h y per gl yce mia

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 2 4
L Y 3 2 9 8 1 7 6
O bjecti ves
E n d p oi nts
P h ar m ac o ki netics

T o c haracterize t he p har mac o ki netics ( P K) of 
tirze pati de Q W 5 m g, 1 0 m g, a n d 1 5 m g a n d 
t he relati o ns hi ps bet wee n tirze pati de e x p os ure 
a n d safet y, t olera bilit y, a n d efficac y meas ures

P o p ulati o n P K a n d P D para meters
Terti ar y / E x pl or at or y

T o c o m pare tirze pati de Q W 5 m g, 1 0 m g, a n d 
1 5 m g wit h place b o wit h res pect f or t he 
f oll o wi n g:

C ha n ge i n fasti n g gl uca g o n, C- pe pti de, a n d 
i ns uli n le vel

Mea n c ha n ge i n li pi ds (t otal c h olester ol, H D L, 
L D L, V L D L, a n d T G )

Mea n c ha n ge i n waist circ u mfere nce

C ha n ges fr o m baseli ne i n mea n b o d y mass 
i n de x

Bi o mar kers

Patie nt- re p orte d o utc o mes
o
A bilit y t o Perf or m P h ysical 
Acti vities of Dail y Li vi n g
o
E ur o pea n Q ualit y of 
Life - Di me nsi o ns ( E Q- 5 D-5 L) sc ores
o
I m pact of Wei g ht o n Self -Perce pti o n
A b bre viati o ns:  H D L = hi g h -de nsit y li p o pr otei n; L D L = l o w -de nsit y li p o pr otei n; P D = p har mac o d y na mics; Q W = 
o nce wee kl y; T G = tri gl yceri des; V L D L = ver y l o w -de nsit y  li p o pr otei n.

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 2 5
L Y 3 2 9 8 1 7 6
5. St u d y  D e si g n
5. 1.
O v er all D e si g n
St u d y  G P G K is a m ult ice nter, ra n d o mize d, d o u ble-bli n d, parallel, pl ace b o -c o ntr olle d, P hase 3
st u d y wi t h 3 st u d y p erio ds i n pat ient s wit h T 2 D M, nai ve t o dia betes i njecta ble t hera p y, 
i na de q uatel y c o ntr olle d wit h diet a n d e xercise al one, a n d ha ve n ot bee n treate d wit h a n y oral  
a nt i dia betic me dicat i on d uri n g t he 3 m o nt hs prec e di n g t o t he start of t he st u d y.  
St u d y  G P G K will c o nsist of 3 peri o ds:  a n a p pr o xi matel y 3-wee k scree ni n g/lea d -i n peri o d,
f oll owe d b y a 4 0 -wee k treat m e nt perio d , a n d a 4-wee k safet y f oll ow- u p peri o d .  Patie nts will be 
ra n d omize d i n a 1: 1: 1: 1 rati o ( tirze pati de 5 m g Q W , 1 0 mg Q W , 1 5 mg Q W , a n d i njecta ble 
pl ace b o).  Patie nts will be stratifie d base d o n c o u ntr y, baseli ne H b A 1c [ ≤8. 5 % ( ≤6 9 m m o l/ m ol) 
or > 8. 5 % ( > 6 9 m m o l/ m ol)], a n d a n y past prior use ( Yes or N o) of a n y O A M .
St u d y  g o ver na nce c o nsi derati o ns are descri be d i n detail i n A p pe n di x 3 .
Fi g ure G P G K . 1 ill ustrates t he st u d y desi g n.
A b bre viati o n :  Q W = o nce wee kl y .
Fi g ur e G P G K . 1.
Ill u str ati o n of st u d y d e si g n f or Cli ni c al Pr ot o c ol I 8 F-M C -G P G K .

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 2 6
L Y 3 2 9 8 1 7 6
St u d y Peri o d I ( scree ni n g a n d le a d-in)
Scree ni n g ( Visit 1)
T he p ur p ose of scree ni n g pr oce d ures at Visit 1 is t o esta blis h i nit ial eli gi bility a n d t o o btai n 
bl o o d sa m ples f or l a b orat or y assess me nts nee de d t o c o nfir m eli gi bility at Visit 2. T he patie nt 
will si g n t he i nf or me d c o nse nt f or m (I C F) bef ore a n y st u d y pr oce d ures are perf or me d. 
Pr oce d ures at t his visit will be perf or me d as s h o w n i n t he Sc he d ule of Acti vit ies (Secti o n 2 ). 
Le a d -i n ( Visit 2 t o Visit 3)
At  Visit 2, t he scree ni n g la b orat or y res ults will be re vie we d. F or t h ose patie nts meet i n g all ot her 
eli gi bilit y re q uire me nts, a dilate d f u n d osc o pic e xa mi nati on, perf or m e d b y a n o p ht hal m o l ogist or 
o pt o m etrist, must be c o m plete d bet wee n Visit 2 a n d Visit 3 t o e ns ure t hat patie nts wit h 
pr oliferat i ve dia betic reti n o pat h y, dia betic mac ul o pat h y , or n o n pr oliferat i ve dia betic reti n o pat h y
w h o re q uire ac ute treat me nt, are i de ntifie d a n d e xcl u de d. A d dit i onall y, at Visit 2, pati e nts a n d 
t heir care gi ver(s), if a p plica ble, will recei ve a gl uc o meter a n d trai ni n g o n h o w t o perf or m self-
m o nit ori n g of bl o o d gl uc ose ( S M B G).  Patie nts will be as ke d t o m o nit or fasti n g bl o o d gl uc ose 
(F B G) 4 ti mes a wee k a n d t w o 7-p oi nt S M B G pr ofiles d o ne o n 2 n o nc o nsec uti ve da ys i n t he 2 -
wee k peri o d pri or t o Visit 3 (ra n d o mizat i on), Visit 7 ( Wee k 1 2), Visit 1 4 ( Wee k 4 0), a n d Visit 
8 0 1 ( Wee k 4 4) .  Patie nts will be pr o vi de d diaries a n d will be trai ne d as a p pr o priate t o rec or d 
bl o o d gl uc ose ( B G ) val ues a n d h y p o gl yce mic e ve nts .  D uri n g t his peri o d, patie nts will als o be 
trai ne d o n disease ma na ge me nt (s y m pt o ms of h y p o gl yce mia a n d h y per gl yce mia) a n d st u d y 
pr oce d ures; t his trai ni n g ca n be re peate d at s u bse q ue n t visits as dee me d a p pr o priate. Patie nts 
s h o uld m o ni t or B G a n y ti me a h y p o gl yce mic e ve nt is s us pecte d. D uri n g t he lea d-i n p eri o d, 
pati e nts s h o uld c o nt i n ue t heir diet a n d e xercise r o uti ne a n d m ust n ot a d d a n y O A Ms i n or der t o 
all o w relia ble assess me nt of H b A 1c at baseli ne ( Visit 3).  
St u d y Peri o d II ( 4 0 -wee k tre at me nt peri o d)
R a n d o miz ati o n ( Visit 3)
At  Visit 3, eli gi ble patient s will perf or m all re q uire d baseli ne st u d y pr oce d ures (i ncl u di n g t he 
c ollect i on of all baseli ne la b orat or y meas ures a n d electr ocar dio gr a m  [E C G ]) pri or t o 
ra n d omizat i on a n d pri or t o ta ki n g t he first d ose of st u d y dr u g e xce pt f or P K sa m ple c ollecti o n
w hic h will be c o llecte d a n yti me o n t he sa me da y after a d mi nistrati o n at t he site (see Sect i on 2 ).  
P ati e nt s h o uld arri ve t o t he cli nic i n t he fast i n g state; t he fasti n g state s h o ul d ha ve laste d at least 
8 h o urs . T he q uesti o n naires ( E ur o pea n Q ualit y of Life - Di me nsi ons [ E Q - 5 D- 5 L], A bilit y t o 
Perf or m  P h ysical Acti vities of Dail y Li vi n g [A P P A D L ], I mpact of  Wei g ht o n Self-Perce pt i on
[I W-S P ]) s h o ul d be c o m plete d bef ore a n y ot her st u d y pr oce d ures if t he patient  is n ot a d versel y 
affecte d b y t he fasti n g c o n ditio n or c o m plete d after t he patie nt has s ufficie nt l y rec o vere d fr o m 
t he prece di n g visit pr oce d ures.  

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 2 7
L Y 3 2 9 8 1 7 6
P ati e nts will be i nstr ucte d o n h o w t o use t he si n gle- dose p e n ( S D P) a n d will i nject t heir first d ose 
of  st u d y dr u g w hile i n t he cli nic for Vi sit 3.  T he date a n d ti me of t he first d ose of st u d y dr u g 
s h o uld be rec or de d o n t he ele ctr o nic case re p ort f or m (e C R F).
F o ll owi n g ra n d o mizat i on, p atie nts will p artici pate i n a 4 0- wee k treat me nt peri o d.  
P ostr a n d o miz ati o n peri o d (e n d of Visit 3 t o Visit 1 4 ):
T he starti n g d ose of st u d y dr u g will be 2. 5 m g Q W f or 4 wee ks, f oll o we d b y a n increase t o 5 m g 
Q W , for t he d urati o n of  t he st u d y in t he 5 -m g gr o u p.  F or t he 1 0 -m g gr o u p , t he starti n g d ose of 
st u d y dr u g will be 2. 5 m g Q W f or 4 wee ks, t he n t he d ose will be i ncrease d b y 2. 5 m g e ver y 4 
wee ks ( 2. 5 m g t o 5 m g t o 7. 5 m g t o 1 0 mg) u nt il t he 1 0-m g d ose is reac he d a n d mai ntai ne d f or 
t he d urati o n of  t he st u d y.  F or t he 1 5-m g gr o u p , t he starti n g d ose of st u d y dr u g will be 2. 5 m g 
Q W f or 4 wee ks, t he n t he d ose will be i ncrease d b y 2. 5 m g e ver y 4 wee ks ( 2. 5 m g t o 5 m g t o 
7. 5 m g t o 1 0 m g t o 1 2. 5 m g t o 1 5 mg) u nt il t he 1 5-m g d ose is reac he d a n d mai ntai ne d f or t he 
d urati o n of  t he st u d y.  F or t he place b o gr o u p, patie nts will i nject matc he d Q W place b o f or t he 
d urati o n of t he st u d y .
St u d y Peri o d I II (safet y f oll o w -u p p eri o d)
S afety foll o w - up ( Visit 8 0 1) v isits:
All patie nts w h o c o m plete t he treat me nt peri o d are re q uire d t o c o m plete Visit 8 0 1, a safet y  
f oll ow- u p visit a p pr o xi matel y 4 wee ks after t heir last treat me nt visit.  Patie nts disc o nt i n ui n g t he 
st u d y earl y a n d perf or mi n g a n earl y ter mi nati on ( E T) vi sit will als o be as ke d t o perf or m t he 
safety f oll ow- u p visi t, s o t hat t he safety f oll ow- u p visit will be t heir fi nal visit.  D uri n g t he safet y 
f oll ow- u p peri o d, patie nt s will n ot recei ve st u d y dr u g or i ni tiate a n y ne w a nti h y per gl yce mic 
t hera p y.  I n t he e ve nt a patie nt has persiste nt , se vere h y per gl yce mia, defi ne d as a n y F B G val ues 
wi t hi n 1 wee k f or 2 c o nsec uti ve wee ks is >2 0 0 m g/ d L ( > 1 1. 1 m m o l/L) or H b A 1c ≥8. 5 %
(≥6 9 m m o l/ m ol), ne w a nt i h y per gl yce mic me dicati o n ca n be i nit iate d at t he discreti on of t he 
i n vesti gat or as descri be d i n Sect i on 7. 4. 2 . If a n y ne w a nt i h y per gl yce mic me dicati o n is i nitiate d 
d uri n g t he safet y f oll ow- u p peri o d , it will n ot be classifie d as resc ue t hera p y . Pati e nts are als o 
re q uire d t o ret ur n a n y re mai ni n g st u d y diaries t o t he st u d y site at t he e n d of t his peri o d.
St u d y Pr oce d ures
P ati e nt s will perf or m st u d y pr oce d ures liste d i n t he Sc he d ule of Acti vities ( Sectio n 2 ).
P ati e nts will be per mitte d t o use c o nc o mita nt me dicati o ns t hat t he y re q uire d uri n g t he st u d y, 
e xce pt certai n me dicat i ons t hat ma y i nterfere wit h t he assess me nt of efficac y a n d safet y 
c haracterist ics of t he st u d y tr e at me nts.  A nt i h y per gl yce mic me dicati ons ot her t ha n st u d y  dr u gs
are n ot all o we d at a n y time d uri n g t he st u d y e xce pt as all o we d f or resc ue t hera p y, after earl y 
st u d y dr u g disc o nti n uati on, or s h ort -t er m ins uli n use.  Resc ue t hera p y  wit h ot her 
gl uc ose -l oweri n g a ge nts ma y  b e me dicall y i n dicate d i n certai n sit uat i ons after ra n d o mizat i on d ue 
t o se vere, persiste nt hy per gl yce mia or earl y disc o nti n uat i on of st u d y  treat me nt .  Metf or mi n will 
be t he first c h oice of t hera p y u nless c o ntrai n dicate d.  Gl uca g o n-li ke pe pti de-1 rece pt or a g o ni sts, 
di pe pt i dyl pe pt i dase-4 ( D P P -4) i n hi bit ors, a n d pra mli nt i de are pr o hi bite d me dicat i ons a n d are n ot 

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 2 8
L Y 3 2 9 8 1 7 6
all o we d as resc ue t hera pies.  S h ort -t er m ins uli n use f or u p t o 1 4 da y s is allo w e d f or certai n 
cli nical sit uat i ons (f or e xa m p le, electi ve s ur ger y, d uri n g h os pitalizati o n, h y per os m olar states).  If 
i ns uli n is prescri be d as a resc ue t hera p y, it must be differe ntiate d fr o m s h ort -t er m use of i ns uli n 
t hera p y for m e dical e mer ge ncies w he n re p orte d i n t he e C R F.
P ati e nts w h o de vel o p se ve re, persiste nt h yper gl yce mia base d o n pre s pecifie d t hres h ol ds (see 
Secti o n s 7. 8. 2. 3 a n d 9. 2. 2. 2 ) will recei ve a ne w gl uc ose-l oweri n g i nter ve nt i on (“resc ue t hera p y”) 
a n d will als o c o nti n ue t o a d mi nister st u d y dr u g.  Patie nts w h o nee d h y per gl yce mic resc ue 
t hera p y will c o nti n ue i n t he trial u ntil t h e y c o mplete all  st u d y visits.  
St u d y  g o ver na nce c o nsi derati o ns are descri be d i n detail i n A p pe n di x 3 .
5. 2.
N u m b er of P arti ci p a nt s
A t otal o f a p pr o xi matel y 4 7 2 p atie nts ( 1 1 8 patie nts per treat me nt gr o u p) will be ra n d o mize d.
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 last 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 ( Sectio n 2 ) f or t he last patie nt .
5. 4.
S ci e ntifi c R ati o n a l e f or St u d y D e si g n
St u d y  G P G K is desi g ne d t o assess t he efficac y, safet y, a n d P K of  tirze pati de Q W (5 m g, 1 0 m g, 
a n d 1 5 m g ) as mo n ot hera p y vers us place b o i n patie nts wit h T 2 D M w h o ha ve i na de q uate 
gl yce mic c o ntr ol wi t h diet a n d e xercise al o ne a n d ha ve n ot bee n treate d wit h a n y O A M d uri n g 
t he 3 m o nt hs prece di n g t o t he start of t he st u d y.  Patie nts m ust be naï ve t o a nti h y per gl yce mic 
i njecta ble t hera p y.
Pl ace b o was c h ose n as t he c o m parat or t o meet t he F D A re q uire me nt t o c o m pare t he st u d y  dr u g 
ver s us a place b o i n at least 1 st u d y. T he pla n ne d treat me nt d urati o n of  4 0 wee ks is c o nsi dere d 
a p pr o priate t o assess t he f ull effects a n d be nefit/ris k of eac h mai nte na nce d ose of tirze pat i de o n 
b ot h gl yce mic c o ntr ol a n d b o d y  wei g ht as re q ueste d b y t he F D A .
T he parallel -gr o u p desi g n f or treat me nt c o m paris o n was c h ose n t o a v oi d a n y i nteracti o n bet wee n 
treat me nts t hat ma y i nterfere wit h t he i nter pretati o n of t he trial o utc o me.  T o mi ni mize t he 
p ote nti al c o nfo u n di n g effect of c ha n ges t o c o nc o mita nt me dicati o ns, pati e nts will be per mitte d t o 
use c o nc o mita nt me dicat i ons t hat t he y  re q uire d uri n g t he st u d y.  Me dicati ons t hat ma y i nterfere 
wi t h t he assess me nt of efficac y a n d safety c haracteristics of t he st u d y treat me nts will not be 
all o we d (see Sect i on 7. 7 ).
5. 5.
J u stifi c ati o n f or D o s e
Ti rze patid e d oses of  5 mg, 1 0 m g , a n d 1 5 mg a d mi nistere d s u bc uta ne o usl y  Q W will be e val uate d 
i n t his st u d y. 
T hese d oses a n d ass ociate d escalat i on sc he mes were selecte d base d o n assess me nt of safet y,  
efficac y ( gl yce mic a n d wei g ht loss be nefit), a n d GI t olera bilit y data f o ll owe d b y  e xp os ure -
res p o nse m o deli n g of data i n pati e nts wit h T 2 D M i n P hase 1 a n d 2 st u dies.
D osi n g al g orit h ms 

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 2 9
L Y 3 2 9 8 1 7 6
starti n g at a l o w d ose of 2. 5 m g acc o m pa nie d b y d ose escalat i on of 2. 5 m g i ncre me nts e ver y  4-
wee k w o ul d per mit 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 ol era bilit y c o ncer ns.
T he m a xi m u m pr o p ose d d ose of 1 5 mg m ai ntai ns a n e x p os ure mul tiple o f 1. 6 t o 2. 4 t o t he n o -
o bser ve d -a d verse-effect le vel d oses i n 6-m o nt h m o n ke y a n d rat t o xic ol o g y  st u dies.
T he selecte d d ose a n d escalati o n sc he me w o ul d e na ble f urt her e val uat i on of be nefit/ris k 
c o nsi derati o ns f or 5 -m g, 1 0 -m g, a n d 1 5 -m g d oses of tirze pati de.

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 3 0
L Y 3 2 9 8 1 7 6
6.
St u d y  P o p ul ati o n
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
P ati e nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if t he y meet all of t h e foll o wi n g criteria at 
scree ni n g:
T y pe of P atie nt a n d Dise ase C h ar acteristics
[ 1] Ha ve bee n dia g n ose d wit h T 2 D M base d o n t he W orl d H ealt h Or ga nizati on
classificat i on or ot her l ocall y a p p lica ble dia g n ostic sta n dar ds, are naï ve of 
di a betes i njecta ble t hera pies , a n d ha ve n ot use d a n y O A M d uri n g t he 3 m o nt hs 
prece di n g Visi t 1
P atie nt C h ar acteristics
[ 2] Ha ve H b A 1c ≥7. 0 % ( ≥5 3 m m o l/ m ol) t o ≤9. 5 % ( ≤8 0 m m o l/ m ol) des pi t e diet a n d 
e xercise treat me nt , as deter mi ne d b y t he ce ntral la b orat or y at Visit 1 ( N ote: 
H b A 1c val ue as deter mi ne d b y t he ce ntral la b at Visit 1)
[ 3] Are of sta ble wei g ht ( ± 5 %) d uri n g t he 3 m o nt hs pr ece di n g Visi t 1 a n d a gree t o 
n ot i nit iate a diet a n d/ or e xercise pr o gra m d u rin g t he st u d y  wit h t he i nte nt of 
re d uci n g b o d y wei g ht ot her t ha n t he lifestyle a n d dietar y meas ures f or dia betes 
treat me nt
[ 4] Ha ve b o d y  mass i n de x ( B MI) ≥2 3 k g/ m 2 at Visit 1 
[ 5] Are 1 8 y e ars old or of a n acce pta ble a ge t o pr o vi de i nf or me d c o nse nt acc or d i n g t o 
l ocal re g ulatio ns, w hic he ver is ol der
Male patie nts
( See A p pe n di x 6 f or more details) :
o
Male patie nts s h o ul d be willi n g t o use relia ble c o ntrace pti ve met h o ds t hr o u g h o ut 
t he st u d y a n d for at least 3 m o nt hs after l ast i nject i o n 
Fe male pat ient s:
o
Fe male pat ient s n ot of c hil d beari n g p ote ntial d ue t o s ur gical sterilizat i on 
( h ysterect o m y or bilateral o o p h orect o m y or t u bal li gati on) , c o n ge nital a n oma l y
(t hat is, M ulleria n a ge nesis) , or m e n o pa use
o
W o me n wi t h a n i ntact uter us are dee me d p ost me n o pa usal if t he y are at 
least 4 5 years ol d a n d

ha ve n ot ta ke n h or m o nes or oral c o ntrace pti ves wit hi n t he last 
ye ar a n d ha d cessat i on of me nses f or at least 1 year
O R

ha ve ha d at least 6 m o nt hs a n d less t ha n 1 2 mo nt hs of  
s p o nta ne o us a me n orr hea wit h fol licle-sti m ulati n g h or m o ne 

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 3 1
L Y 3 2 9 8 1 7 6
( F S H) a n d estra di ol le vels c o nsiste nt wit h a p ost me n o pa usal 
state ( F S H ≥4 0 m I U/ m L a n d estra di ol < 3 0 p g/ m L).
o
Fe male pat ient s of c hil d beari n g p ote ntial ( n ot s ur gicall y sterilize d a n d
bet wee n m e narc he a n d 1-ye ar p ost me n o pa usal) m ust

test ne gati ve f or pre g na nc y at Visit 1 base d o n a ser u m 
pre g na nc y test ,

if se x uall y acti ve, a gree t o use 2 f or ms of effecti ve 
c o ntrace pti o n, w here at least 1 f or m is hi g hl y effecti ve f or t he 
d urati o n of  t he trial a n d f or 3 0 da ys t hereafter,
A N D

n ot be breastfee di n g
[ 6] I n t he i n vesti gat or’s o pi ni on, are well m o tivate d, ca pa ble, a n d willi n g t o
(a)
perf or m  fi n ger-stic k B G m o nit ori n g, i ncl u di n g sc he d ule d B G pr ofiles with u p t o 7 
meas ure me nts i n 1 da y  
( b)
lear n h o w t o self-i nject st u d y dr u gs, as re q uir e d for t his pr ot oc ol ( vis uall y i m paire d 
pers o ns w h o are n ot a ble t o perf or m t he i nject i ons m ust ha ve t he assista nce of a 
sig hte d i n di vi d ual trai ne d t o i nject t he st u d y  dr u g; pers o ns wit h p h ysical li mitati ons 
w h o are n ot a ble t o perf or m t he i nject i ons m u st ha ve t he assista nce of a n i n di vi d ual 
trai ne d t o i nject t he st u d y dr u g) 
(c)
are willi n g a n d a ble t o i nject stu d y dr u gs
( d)
mai ntai n st u d y diaries, as re q uire d f or t his pr ot oc ol
(e)
ha ve a s ufficie nt u n dersta n di n g of o ne of t he pr o vi de d la n g ua ges of t he c o u ntr y  
s uc h t hat t he y will be a ble t o c o mplete t he pati e nt q uesti o n naires
I nf or me d C o nse nt
[ 7]
Ha ve gi ve n writte n i nf or me d c o nse nt t o partici pate i n t his st u d y  in acc or da nce 
wi t h lo c al  re g ulati ons a n d t he et hical revie w b oar d ( E R B) g o ver ni n g t he st u d y  
sit e
6. 2.
E x cl u si o n Crit eri a
P ati e nts will be e xcl u de 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 t eria at
scree ni n g:
Me dic al C o n diti o ns
[ 8]
Ha ve t y pe 1 dia betes mellit us ( T 1 D M)
[ 9]
Ha ve a hist or y  of c hr o nic or ac ute pa ncreatit is a n y ti me prior t o st u d y  e ntr y 
( Visit 1)

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 3 2
L Y 3 2 9 8 1 7 6
[ 10 ] Ha ve hist or y  of

pr oliferat i ve dia bet ic reti n o pat h y,
or

di a bet ic mac ul o pat h y ,
or

n o n pr o liferati ve dia betic reti n o pat h y t hat re q uires ac ute treat me nt
( a dilate d f u n d osc o pic e xa mi nat i on perf or me d b y a n o p ht hal m o l ogist or 
o pt o m etrist bet wee n Visit 2 a n d Visit 3 is re q uire d t o c o nfir m eli gi bilit y)  
[ 11 ] Ha ve a hist or y  of ket oaci d osi s or h yper os m ol ar state/c o ma
[ 12 ] Ha ve a k n o w n cli nicall y si g nifica nt gastric e m pt yi n g a b n or malit y (f or 
e xa m ple, se vere dia bet ic gastr o paresis or gastric o utlet o bstr ucti o n), ha ve 
u n der g o ne or pla n t o ha ve d uri n g t he c o urse of t he st u d y :  gastric b y pass 
( bariatric) s ur ger y or restrict i ve bariatric s ur ger y (f or e xa m ple, La p-Ba n d ® ), 
or c hr o ni call y ta ke dr u gs t hat direct l y affect GI m o tility
[ 13 ] Ha ve a n y of t he f o ll owi n g car dio vasc ular ( C V ) c o n dit i ons wit hi n 2 m o nt hs 
pri or t o Visit 1:  ac ute m y ocar dial  infarcti o n, cere br o vasc ular acci de nt 
(str o ke), or h os pitalizati on d ue t o c o n gesti ve heart fail ure ( C H F)
[ 14 ] Ha ve a hist or y  of Ne w Y or k Heart Ass ociat i on F u nct i onal Classificati o n I V
C H F
[ 15 ] Ha ve ac ute or c hr o nic he pat itis, si g ns a n d s y m pt o ms of a n y li ver disease 
ot her t ha n n o nalc o h o lic fatt y li ver disease ( N A F L D), or ala ni ne 
a mi n otra nsferase ( AL T) level > 3. 0 ti mes t he u p per li mit of n or mal ( U L N) f or 
t he refere nce ra n ge, as deter mi ne d b y t he ce ntral la b orat or y at st u d y e ntr y.  
P ati e nts wit h N A F L D are eli gi ble t o partici pate i n t his trial if t heir A L T le vel 
is ≤3. 0 ti mes t he U L N f or t he refere nce ra n ge
[ 16 ] Ha ve a n est i mate d gl o mer ular filtrati o n rate < 3 0 m L/ mi n/ 1. 7 3 m2, c alc ulate d 
b y C hr o nic Ki d ne y Disease -E pi de mi ol o g y as deter mi ne d b y ce ntral  
la b orat or y at Visit 1
[ 17 ] Ha ve e vi de nce of a si g nifica nt, u nc o ntr olle d e n d ocri ne a b n or malit y (for 
e xa m ple, t h yr ot o xic osis or a dre nal crises), i n t he o pi ni o n of t he i n vesti gat or
[ 18 ] Ha ve fa mil y or pers o nal hist or y  of me d ullar y t h yr oi d carci n o ma ( M T C) or 
M ul tiple E n d ocri ne Ne o pl asia t y pe 2 ( M E N 2)
[ 1 9] Ha ve a ser u m  c al cit o ni n le vel of ≥3 5 n g/ L , as deter mi ne d b y ce ntral 
la b orat or y at Visit 1
[ 20 ] K n o w n or s us pecte d h y perse nsi tivit y t o trial pr o d uct(s) or relate d pr o d ucts
[ 21 ] Ha ve e vi de nce of a si g nifica nt, a ct i ve a ut oi m m u ne a b n or mality (f or e xa m ple, 
l u p us or r he u mat oi d art hritis) t hat, i n t he o pi ni o n of t he i n vesti gat or, is li kel y 
t o re q uire c o nc urre nt treat me nt wit h s yste mic gl uc oc ortic oi ds i n t he ne xt 1 2 
m o nt hs

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 3 3
L Y 3 2 9 8 1 7 6
[ 22 ] Ha ve ha d a tra ns pla nte d or ga n (c or neal tr a ns pla nts [ kerat o plast y] all o we d) or 
a waitin g a n or ga n tra ns pla nt
[ 23 ] Ha ve a hist or y  of a n acti ve or u ntreate d mali g na nc y or are i n re missi on fr om 
a cli nicall y si g nifica nt mali g na nc y ( ot her t ha n basal or s q ua mo us cell s ki n 
ca ncer, i n sit u carci n o mas of t h e cer vi x, or i n sit u pr ostate ca ncer) f or less 
t ha n 5 years
[ 24 ] Ha ve a hist or y  of a n y ot her c o n diti on (s uc h as k n o w n dr u g, alc o h o l a b use, or 
ps yc hiatric dis or der) t hat, i n t he o pi ni o n o f t he i n vesti gat or, ma y precl u de t he 
pati e nt fr o m fol l owi n g a n d c o m p letin g t he pr ot oc ol
[ 25 ] Ha ve a n y he mat ol o gical c o n dit i on t hat m a y i nterfere wit h H b A 1c 
meas ure me nt (f or e xa m ple, he m o l ytic a ne mias, sic kle cell disease)
Pri or/ C o nc o mit a nt T her a p y
[ 2 6] Use of a n y  O A M d uri n g t he 3 m o nt hs prece di n g t o Visit 1
[ 27 ] Ha ve a hist or y  of use of a n y injecta ble t hera p y  for T 2 D M treat m e nt e xce pt 
f or t he use of i ns uli n f or treat me nt of gestati o nal dia betes, or s h ort-t er m use 
(1 4 da y s) for ac ute c o n di tio ns s uc h as ac ute ill ness, h os pitalizat i on, or 
elect i ve s ur ger y
[ 28 ] Ha ve bee n tr eate d wit h prescri pti o n dr u gs t hat pr o m ote wei g ht l oss (for 
e xa m ple, Sa xe n da [lira gl ut i de 3. 0 m g], Xe nical® [ orlistat], Meri dia®
[si b utra mi ne], Ac utri m® [ p he n yl pr o pa n olami ne], Sa n ore x ® [ mazi n d o l], 
A di p e x ® [ p he nter mi ne], B E L VI Q® [lorcaseri n], Qs y mia ™
[ p he nter mi ne/t o pira mate c o m bi nat i on], C o n tra ve® [ naltre x o ne/ b u pr o pi o n], or 
si milar ot her b o d y w ei g ht l oss me dicat i ons i ncl u di n g o ver-t he- c o u nter [ O T C]
me dicat i ons [f or e xa m ple, allī ® ]) wit hi n 3 mo nt hs pri or t o Visit 1 a n d/ or 
bet wee n st u d y  e ntr y ( Visit 1) a n d ra nd o mizat i on ( Vi sit 3)
[ 29 ] Are recei vi n g c hr o nic ( > 2 wee ks or 1 4 da y s) s yste mic gl uc oc ortic oi d t hera p y 
(e xcl u di n g t o pical, i ntra oc ular, i ntra nasal, or i n hale d pre parati o ns) or ha ve 
recei ve d s uc h t hera p y wit hi n 1 mo nt h of Visit 1 or bet wee n Visit s 1 a n d 3
P ri or/ C o nc urre nt Cli nic al Tri al E x perie nce
[ 3 0]
Are c urre ntl y e nr olle d 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 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 m e dicall y c o mpat i ble wit h t his st u d y
[ 3 1]
Ha ve part ici pate d, wit hi n t he last 3 0 da ys 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.  If t he pre vi o us i n vesti gati o nal pr o d uct has 5 half-
li ves or 3 0 da y s ( w hic he ver is lo n ger) , s h o uld ha ve passe d pri or t o scree ni n g
[ 3 2]
Ha ve pre vi o usl y c o m p lete d or wi t hdra 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 pati de

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 3 4
L Y 3 2 9 8 1 7 6
Ot her E xcl usi o ns
[ 3 3]
Are i n vesti gat or site pers o n nel directl y affiliate d with t his st u d y  a n d/ or 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, pare nt, c hil d, 
or si bli n g, w het her bi o l ogical  or le gall y a d o pte d
[ 34 ]
Are Lill y e m plo y ees 
[ 35 ]
Are u n willi n g or u na ble t o c o m pl y wit h t he use of a data c ollecti on de vice t o 
di rectl y rec or d dat a fr o m t he patie nt
6. 3.
Lif e st yl e R e stri cti o n s
Per t he Sc he d ule of Act i vities ( Secti on 2 ), q ualifie d me dical staff will pr o vi de dia betes 
ma na ge me nt c o u nseli n g, w hic h will i ncl u de i nstr ucti o ns o n diet a n d e xercise a n d e d ucat i on 
a b o ut t he si g ns, s y m pt o ms, a n d treat me nt of h y p o gl yce mia , s h o uld i t occ ur.  
P ati e nts s h o uld c o nt i n ue t heir us ual e xercise ha bits a n d ge nerall y f oll ow a heal t hy meal pla n 
( wit h c o nsiste nt meal size a n d ti me of da y) t hr o u g h o ut t he c o urse of t he st u d y.  Dietar y 
c o u nseli n g ma y be re vie we d t hr o u g h o ut t he st u d y , as nee de d.  Per Incl usi o n C rit erio n [ 4 ] 
(Secti o n 6. 1 ), patie nts s h o uld n ot i nit iate a n or ga nize d diet a n d/ or e xercise (wei g ht re d ucti o n )
pr o gra m d uri n g t he st u d y  ot her t ha n t he lifest yle a n d dietar y meas ures f or dia betes treat me nt.
St u d y  p artic i pa nts s h o ul d be i nstr ucte d n ot t o d o nate bl o o d or bl o o d pr o d ucts d uri n g t he st u d y.
6. 4.
S cr e e n F ail ur e s
I n di vi d uals w h o d o n ot meet t he criteria f or partici pati o n i n t his st u d y (scree n fail ure) m ust n ot 
be rescree ne d .

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 3 5
L Y 3 2 9 8 1 7 6
7. Tr e at m e nt s
7. 1.
Tr e at m e nt s A d mi ni st er e d
P ati e nt s will be ra n d o mize d i n a 1: 1: 1: 1 rati o t o recei ve tirze pat i de 5 m g, 1 0 m g, 1 5 m g, or 
pl ace b o .  St u d y  dr u g will be a d mi nistere d Q W as S C i njecti on i n patie nts wit h T 2 DM
w h o are 
nä i ve t o i njecta ble t hera p y, i na de q uatel y c o ntr olle d wit h diet a n d e xercise alo n e , a n d ha ve n ot 
bee n treate d wit h a n y or al  a nti dia betic me dicatio n d uri n g t he 3 m o nt hs prece di n g t o t he start of 
t he st u d y.  
Ta ble G P G K . 3 s h o ws the ra n d o mize d tr e at me nts f or t he e ntire treat me nt perio d.
T he starti n g d ose of tirze pati de will be 2. 5 m g Q W f or 4 wee ks, f oll o we d b y  a n increase t o 5 m g 
Q W, f or t he d urati o n of t he st u d y  for t he 5 -m g gr o u p.  F or t he 1 0 -m g gr o u p, t he starti n g d ose of 
tirze pati de will be 2. 5 m g Q W f or 4 wee ks, t he n t he d ose will be i ncrease d b y 2. 5 m g e ver y 4 
wee ks ( 2. 5 m g t o 5 m g t o 7. 5 m g t o 1 0 mg) u nt il t he 1 0-m g d ose is reac he d a n d mai ntai ne d f or 
t he d urati o n of t he st u d y.  F or t he 1 5-m g ar m, t he starti n g d ose of tirze pati de will be 2. 5 m g Q W 
f or 4 wee ks, t he n t he d ose will be i ncrease d b y 2. 5 m g e ver y 4 wee ks ( 2. 5 m g t o 5 m g t o 7. 5 m g 
t o 1 0 m g t o 1 2. 5 m g t o 1 5 mg) u nt il t he 1 5-m g d ose is reac he d a n d mai ntai ne d f or t he d urati o n of 
t he st u d y.  
P ati e nts ra n d o mize d t o t he place b o gr o u p will i nject mat c he d place b o s u bc uta ne o usl y Q W f or 
t he e nt ire treat me nt perio d.
It will n ot be p ossi ble f or i n vesti gat ors a n d patie nts t o k n o w w hic h treat me nt t he y are recei vi n g.
T a bl e G P G K . 3.
Tr e at m e nt R e gi m e n s
N a me of Dr u g
D os a ge
Fre q ue nc y
Dr u g F or m ul ati o n
R o ute of 
A d mi nistr ati o n
I n vesti g ati o n al C o m p o u n d
tirze pati de
5 m g
Q W
Si n gle -d ose pe n
S C
1 0 m g
Q W
Si n gle -d ose pe n
S C
1 5 m g
Q W
Si n gle -d ose pe n
S C
C o m p ar at ors
place b o
Q W
Si n gle -d ose pe n
S C
A b bre viati o ns: Q W = o nce wee kl y; S C = s u bc uta ne o us.
T he i n vest igat or or his or her desi g nee is res p o nsi ble f or t he f oll o wi n g:

e x plai ni n g t he c orrect use of t he i n vesti gati o nal a ge nt(s) t o t he patie nt . F or S D P, 
a de mo nstrati o n de vice will be use d

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

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 3 6
L Y 3 2 9 8 1 7 6
P ati e nts s h o uld ret ur n all  st u d y dr u gs t o t he site acc or di n g t o t he Sc he d ule of Acti vities 
(Secti o n 2 ).  Patie nts s h o ul d be i nstr ucte d t o discar d all use d S D Ps i n a cl osea ble, 
p u nct ure -resista nt c o ntai ner acc or di n g t o l ocal r e g ulat i ons.
7. 1. 1.
P a c k a gi n g a n d L a b elli n g
T he s p o ns o r will pr o vi de t irze pat i de a n d place b o i n S D Ps.   T hese will be dis pe nse d via a n 
i nteract i ve we b-res p o nse s yste m (I W R S).  Si n gle-d ose pe ns will be pac ka ge d i n cart o ns t o be 
di s pe nse d.  Cli nical st u d y  mat erials 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. 1. 2.
M e di c al D e vi c e s 
T he c o m bi nat i on pr o d ucts pr o vi de d f or use i n t he st u d y are tirze pati de i n vesti gati onal S D P a n d
pl ace b o S D P .
7. 2.
M et h o d of Tr e at m e nt A s si g n m e nt
P ati e nts w h o meet all crit eria for e nr oll me nt will be ra n d o mize d t o 1 of t h e st u d y treat me nt 
gr o u ps at Visit 3.  Assi g n me nt t o treat me nt gr o u ps will be deter mi ne d b y a c o m p uter -ge nerate d 
ra n d om se q ue nce usi n g a n I W R S.  Patie nts will be ra n d o mize d i n a 1: 1: 1: 1 rati o t o recei ve 
tirze pati de 5 m g , 1 0 m g, 1 5 m g, or pl ace b o .
7. 2. 1.
S el e cti o n a n d Ti mi n g of D o s e s of St u d y Dr u g s
Assi g n me nt t o tirze pati de ( 3 d oses) or place b o will occ ur at ra n d o mizati o n.  
T here are n o restrict i ons o n t he ti me of da y eac h wee kl y d ose of st u d y dr u g is gi ve n, b ut it is 
a d visa ble t o a d mi nister t he S C i njecti o ns o n t he sa me da y a n d sa me ti me eac h wee k, wit h or 
wi t ho ut m eals.  T he act ual date a n d ti me of all d ose a d mi nistrati o ns will be rec or de d b y t he 
pati e nt .  If a d ose of st u d y dr u g is misse d, t he patie nt s h o ul d ta ke it as s o o n as p ossi ble u nless it 
is withi n 7 2 h o urs of t he ne xt d ose, i n w hic h case, t hat d ose s h o ul d be s ki p pe d a n d t he ne xt d ose 
s h o uld be ta ke n at t he a p pr o priate ti me.  T he da y  of wee kl y a d mi nistratio n ca n be c ha n ge d if 
necessar y , as lo n g as t he last d ose was a d mi nistere d 7 2 or m ore h o urs bef ore.   
All patie nts will i nject st u d y  dr u g s u bc uta ne o usl y i n t he a b d ome n or t hi g h usi n g t he i nject i on 
s u p plies pr o vi de d; a care gi ver ma y a d mi nister t he i njecti on i n t he patie nt’s u p per ar m. A ne w
S D P will be use d f or eac h i nject i on. If st u d y dr u g is t o al wa ys be i njecte d i n t he sa me b o d y 
r e gio n, pati e nts s h o uld be a d vise d t o use a differe nt i njecti o n site eac h wee k.
7. 3.
Bli n di n g
T his is a d o u ble -bli n d st u d y . I n vesti gat ors, site staff, cli nical m onit ors , a n d patie nts will re mai n 
bli n de d t o t he treat me nt  assi g n me nts u ntil t he st u d y is c o mplete.
E mer ge nc y  u n blin di n g f or A Es m a y be perf or me d t hr o u g h t he I W R S, w hic h ma y s u p ple me nt or 
ta ke t he place of e mer ge nc y c o des ge nerate d b y a c o mp uter dr u g -labeli n g s yste m. T hi s o ptio n
ma y be use d O N L Y if t he pati e nt ’s well-bei n g re q uires k n o wle d ge of t he patie nt ’s treat me nt
assi g n me nt. All act i ons res ult i n g i n a n u n bli n di n g e ve nt are rec or de d a n d re p orte d b y t he I W R S.

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 3 7
L Y 3 2 9 8 1 7 6
I n case of a n e mer ge nc y, t he i n vesti gat or has t he s ole res p o nsi bility f or deter mi ni n g if u n bli n di n g
of  a patie nt ’s treat me nt assi g n me nt is warra nte d f or me dical ma na ge me nt of t he e ve nt.  T he 
pati e nt’s safet y m u st alwa ys be t he first c o nsi derati o n i n ma ki n g s uc h a deter mi nat i on.  If a 
pati e nt’s treat me nt assi g n me nt is u n bli n de d, Lill y m ust be n otifie d i m me diatel y. If t he 
i n vesti gat or deci des t hat u n bli n di n g is warra nte d, it is t he res p o nsi bility of  t he i n vestigat or t o 
pr o m ptl y d oc u m e nt t he decisi o n a n d rati o nale a n d n otif y Lill y as s o o n as p ossi ble.
If a n i n vesti gat or, site pers o n nel perf or mi n g assess me nts, or patie nt is u n bli n de d, t he patie nt will 
c o nti n ue o n t he assi g ne d t hera p y t hr o u g h t he e n d of t he st u d y, if me dicall y a p pr o priate. St u d y
site pers o n nel a n d t he s p o ns or will d oc u me nt a n y u n bli n di n g e ve nts.
7. 4.
D o s a g e M o difi c ati o n
7. 4. 1.
St u d y Dr u g s
N o a dj ust me nt  i n st u d y dr u g d oses will be all o we d. Details a b o ut d ose a d mi nistrati o n of 
tirze pati de d uri n g t he st u d y  are descri be d i n Secti ons 7. 2. 1 a n d 8. 1. 2 .
7. 4. 2.
I niti ati o n of N e w A nti h y p er gl y c e mi c M e di c ati o n
T he i ntr o d ucti o n of ne w a nt i h y per gl yce mic me dicati o n is e x pecte d d uri n g t he st u d y o nl y i n t he
f oll owi n g sit uat i ons:

As a n a nt i h y per gl yce mic i nter ve nti on f or se vere, persiste nt h yper gl yce mia ( “resc ue
t hera p y”), as defi ne d i n Secti on 9. 2. 2. 2 .

I n t h ose patie nts w h o re q uire per ma ne nt disc o nti n uati o n of st u d y dr u g, b ut re mai n i n t he
st u d y ( Sectio n 8. 1. 1 )

D uri n g t he safet y fol l ow- u p p erio d ( bet wee n Visi t 14 [ Wee k 4 0 ] or E T a n d Visit 8 0 1),
o nl y  if t he patient  nee ds a d dit i onal gl yce mic c o ntr ol as o utli ne d i n Secti on 5. 1 u n der 
st u d y P erio d III (safet y f oll ow- u p peri o d) disc ussi o n .
If a ne w a nti h y per gl yce mic me dicat i on is i ntr o d uce d, m et f or mi n will be t he first c h oice of
t hera p y u nless c o ntrai n dicate d. Gl uca g o n -li ke p e pti de- 1 rece pt or a g o nists, D P P -4 i n hi bit ors, a n d 
pra mli nt i de are n ot all o we d. I nitiat i on of i ns uli n as first resc ue i nter ve nt i on f or h yper gl yce mia 
s h o uld be reser ve d f or patie nts wit h se vere, persiste nt h y per gl yce mia wit h a n a vera ge F S G ≥3 0 0 
m g/ d L ( ≥1 6. 7 m m ol / L) or i n ot her cli nical sit uati ons w here t he i n vesti gat or belie ves m ore ra pi d 
gl yce mic c o ntr ol is warra nte d.
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 bilit y
T he i n vest i gat or or his or her desi g nee is res p o nsi ble f or t he f oll o wi n g:

c o nfir mi n g a p pr o priate t e mperat ure c o n di tio ns ha ve bee n mai ntai ne d d uri n g 
tra nsit for all st u d y  treat me nt 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 tr e at me nt.

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 3 8
L Y 3 2 9 8 1 7 6

e ns uri n g t hat o nl y partici pa nts e nr o lle d i n t he st u d y ma y recei ve st u d y treat me nt 
a n d o nl y a ut h orize d site staff ma y s u p pl y or a d mi nister st u d y treat me nt. All st u d y 
treat me nts must be st ore d i n a sec ure, e n vir o n me ntall y  c o ntr olle d, a n d mo ni t or e d 
( ma n ual or a ut o mate d) area in acc or da nce wit h t he la bele d st ora ge c o n dit i ons 
wi t h access li mite d t o t he i n vesti gat or a n d a ut h orize d site staff.

the i n vest i gat or, i nstitut i on, or t he hea d of t he me dical i nst ituti o n ( w here 
a p plica ble) is res p o nsi ble f or st u d y treat me nt acc o u nta bilit y,  rec o nciliati on, a n d 
rec or d mai nte na nce (s uc h as recei pt, rec o nciliat i on , a n d fi nal dis p osit i on rec or ds).
T he st u d y  sit e must st ore t he st u d y  dr u g i n a loc ke d a n d sec ure e n vir o n me nt. Pl ease refer t o t he 
st u d y dr u g la bel f or s pecific st ora ge c o n dit i ons.  Pati e nts will recei ve i ns ulate d ba gs wit h c o oli n g 
g el  pac ks f or use i n tra ns p orti n g t he st u d y  dr u g cart o n fr o m t he site t o h o me. 
St u d y  site staff m ust re g ularl y assess w het her t he patie nt is c orrectl y a d mi nisteri n g t he assi g ne d 
st u d y dr u g a n d st ori n g t he st u d y dr u g acc or di n g t o t he pr o vi de d i nstr ucti o ns. 
7. 6.
Tr e at m e nt C o m pli a n c e
St u d y  dr u g c o mplia nce will  be deter mi ne d b y t he f ollo wi n g: 

St u d y  dr u g a d mi nistrati o n data will be rec or de d b y t he patie nt a n d re vie we d b y 
t he i n vest i gat or at eac h st u d y visit.

T h e patie nts will be i nstr ucte d t o ret ur n a n y u n use d st u d y dr u g a n d/or e m pt y 
cart o ns at t he ne xt visit t o t he st u d y sit e for t he p ur p ose of perf or mi n g dr u g 
acc o u nta bilit y.
I n t he 3 ti rze pati de treat me nt gr o u ps, as well as t he place b o gr o u p , treat me nt c o m plia nce f or eac h 
visit i nter val is defi ne d as ta ki n g at least 7 5 % of t he re q uire d d oses of st u d y  dr u g.  Si milarl y, a 
pati e nt will be c o nsi dere d si g nifica ntl y n o nc o m p lia nt if he or s he is j u d ge d b y t he i n vestigat or t o 
ha ve i nte nt i onall y  or re peate dl y ta ke n m ore t ha n t he prescri be d a m o u nt of me dicati on.  
I n a d diti on t o t he as sess me nt of a patie nt’s c o m p lia nce wit h t he st u d y dr u g a d mi nistrati o n, ot her 
as pects of c o m plia nce wit h t he st u d y  treat me nts will be assesse d at eac h visit base d o n t he 
pati e nt’s a d here nce t o t he visit sc he d ule, c o m plet i on of st u d y  diaries, t he res ults of h o me B G 
m o nit ori n g, a n d a n y ot her para meters t he i n vesti gat or c o nsi ders necessar y .
P ati e nts c o nsidere d t o be p o orl y  c o mplia nt wi t h t h eir me dicatio n a n d/ or t he st u d y  pr oce d ures 
will recei ve a d dit i onal trai ni n g a n d i nstr ucti o n, as re q uire d, a n d will be re mi n de d of t he 
i m p orta nce of c om p l yi n g with t he pr ot oc ol. 
7. 7.
C o n c o mit a nt T h er a p y
P ati e nts will be per mitte d t o use c o nc o mita nt me dicati o ns t hat t he y re q uire d uri n g t he st u d y, 
e xce pt certai n me dicat i ons t hat ma y i nterfere wit h t he assess me nt of efficac y a n d safet y 
c haracterist ics of t he st u d y tr e at me nts.
I n vesti gati ve site staff will i nf or m patient s t hat t he y m ust c o ns ult wit h t he i n vesti gat or or a 
desi g nate d site staff me m ber u p o n bei n g prescri be d a n y ne w me dicat i ons d uri n g t he st u d y .  T his 

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 3 9
L Y 3 2 9 8 1 7 6
ma y n ot be p ossi ble w he n i ni tiate d f or treat me nt of me dical e mer ge ncies, i n w hic h case , t he 
pati e nt will i nf or m t he i n vest i gat or or a desi g nate d site staff me m ber as s o o n as p ossi ble.  A n y 
a d ditio nal  me dicat i on i nitiate d d uri n g t he c o urse of t he st u d y (i ncl u di n g O T C dr u gs, s uc h as 
paraceta m o l or as pi rin) m ust be d oc u m e nte d, a n d t he na me of t he dr u g a n d t he date(s) of 
a d mi nistrati o n m ust be rec or de d o n t he “ C o nc o mit a nt Me dicat i ons” sect i on of t he e C R F. 
A nt i h y per gl yce mic me dicati ons ot her t ha n st u d y  dr u gs are n ot all o we d at a n y ti me d uri n g t he 
st u d y e xce pt as all o we d f or t hose pati e nts w h o re q uire per ma ne nt disc o nti n uati on of st u d y  dr u g, 
b ut re m ai n i n t he st u d y; resc ue t hera p y after ra n d o mizati on d ue t o se vere, persiste nt 
h y per gl yce mia ; or d uri n g t he safet y f oll ow- u p peri o d (see S ectio n 7. 4. 2 ).  S h ort -t er m i ns uli n use 
f or u p t o 1 4 da ys is all o we d f or certai n cli nical sit uati o ns (f or e xa m ple, electi ve s ur ger y, d uri n g 
h os pi talizatio n, h y per os m ol ar states) a n d m ust be differe nt iate d fr o m i ns uli n use as resc ue 
t hera p y w he n re p orte d i n t he e C R F .  
All n o n st u d y me dicatio ns will be rec or de d o n t he e C R F at all visits.
N o nst u d y me dicat i ons ta ke n b y  patient s w h o are scree ne d b ut n ot ra n d o mize d will n ot be 
re p orte d t o Lill y u nless a n S A E or A E occ urs t hat t he i n vest i gat or belie ves ma y ha ve bee n 
ca use d b y a st u d y pr oce d ure.
7. 8.
Tr e at m e nt aft er t h e E n d of t h e St u d y
7. 8. 1.
Tr e at m e nt aft er St u d y C o m pl eti o n 
St u d y  c o mpl et i on will occ ur after all pat ient s c o m plete t he f oll o w -u p visit.   I n vesti gat ors will 
c o nti n ue t o f o ll ow Sc he d ule of Act i vities ( Secti o n 2 ) for all  patie nts u ntil n otifie d b y Lill y t hat 
st u d y c o mplet i on ha s occ urre d.
Ti rze patid e will n ot be ma de a vaila ble after c o nc l usio n of  t he st u d y t o patie nts.
7. 8. 2.
S p e ci al Tr e at m e nt C o n si d er ati o n s 
T his sect i on pr o vi des g ui da nce o n ma na ge me nt of e pis o des of h y p o gl yc e mic e ve nts; se vere, 
persiste nt h y per gl yce mia d uri n g t he treat me nt peri o d ; patie nts w h o per ma ne nt l y disc o nti n ue 
st u d y dr u g prior t o Vi sit 1 4; a n d pat ient s wit h GI s y m pt o ms.  F or effect i ve i m ple me ntati o n of 
meas ures descri b e d here, it is i m p orta nt t hat patie nts, a n d t heir care gi vers, if a p plica ble, be well
e d ucate d a b o ut t he si g ns a n d s y m pt o ms of h y per gl yce mia ( f or e xa m ple, se vere t hirst, dr y mo ut h, 
fre q ue nt mict uriti on, or dr y  s ki n) a n d h y p o gl yce mia (f or e xa m ple, i nte nse h un ger, s weati n g, 
tr e mor, restless ness, irrita bilit y, de pressio n , hea dac hes, dist ur be d slee p, or tra nsie nt ne ur ol o gical 
di s or ders).  Patie nts s h o ul d be i nstr ucte d t o c o ntact t he i n vesti gati ve site i n t he e ve nt of se vere, 
persiste nt h y per gl yce mia or se vere h y p o gl yce mia bet wee n st u d y  visits or i n t he e ve nt w he n a 
pati e nt i nte n ds t o per ma ne nt l y disc o nti n ue st u d y dr u g.
7. 8. 2. 1.
St a n d ar d s of M e di c al C ar e
I n vesti gat ors a n d ot her st u d y t e a m me m bers are e x pecte d t o treat patie nts acc or di n g t o t he
nat i onall y  esta blis he d sta n dar ds of care f or dia betes ma na ge me nt i n res pecti ve partici pati n g
c o u ntries, e xce pt w here t hat treat me nt w o ul d be i n c o nflict wit h t he pr ot oc ol-pr o vi de d treat m e nt 

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 4 0
L Y 3 2 9 8 1 7 6
re q uire me nts. If t here are n o l ocal sta n dar ds of care f or dia betes, t he i n vesti gat ors s h o ul d fol l ow 
c urre nt p u blis he d sta n dar ds of care fr o m t he A merica n Dia betes Ass ociati o n a n d t he E ur o pea n 
As s o ciat i on f or St u d y of Dia betes ( Da vies et al. 2 0 1 8) d uri n g t heir patie nts ’ part ici pati on i n t his 
st u d y.
7. 8. 2. 2.
M a n a g e m e nt of H y p o gl y c e mi a Ri s k
I n t his st u d y, i ncrease d ris k of h y p o gl yce mia is defi ne d as ha vi n g a si n gle e pis o de of se vere 
h y p o gl yce mia or ha vi n g m ore t ha n 1 e pis o de of d oc u me nte d s y m pt o mat ic h y p o gl yce mia wit hi n
a 1-wee k peri o d at a n y t i me d uri n g t he treat me nt perio d.   I n cases w here a patie nt e x periences
h y p o gl yce mia as descri be d a b o ve, t o c o nfir m t he i ncrease d ris k, t he st u d y sit es must e ns ure t hat
t he patie nt has bee n f ull y c o mplia nt wi t h t he assi g ne d t hera pe ut ic re gi me n a n d als o t hat t here is
n o e vi de nce of ot her p ossi ble ca uses of h y p o gl yce mia (f or e xa m ple, o missio n  of meal, 
u ne x pecte d i ncrease i n e xercise). If t he patie nts fulfill t he defi nit i on of i ncrease d ris k of 
h y p o gl yce mia, t he i n vest i gat or s h o ul d di sc o nti n ue t he patie nt fr o m st u d y treat me nt a n d f o ll ow 
t he g ui da nce f or m a na ge me nt of pati e nt s t o per ma ne nt l y disc o nti n ue t he st u d y dr u gs as o utli ne d 
i n S e cti o n 8. 1. 1 .
7. 8. 2. 3.
M a n a g e m e nt of P ati e nt s wit h S e v er e, P er si st e nt H y p er gl y c e mi a d uri n g 
t h e Tr e at m e nt P eri o d
Se vere, persiste nt h y per gl yce mia will be c ollecte d d uri n g t he trial t o assess t he ris k of e xtre me 
i mbala nce i n gl yce mic c o ntr ol.
I n vesti gat ors will be trai ne d o n t he a p plicati on of cri t eria for d e ci di n g w he n a n d h o w t o i nter ve ne 
wi t h patie nts w h o d o n ot reac h gl yce mic tar gets.  If a n y of t he F B G val ues wi t hi n 1 wee k f or 2 
c o nsec ut i ve wee ks e xcee d t he li m its o utli ne d bel ow a n d n o i nterc urre nt ca use of t he 
h y per gl yce mia c o ul d be i de nt ifie d (i n vesti gat ors s h o ul d first c o nfir m t hat t he patie nt is f ull y 
c o mplia nt wi t h t he assi g ne d t hera pe utic re gi me n a n d t hat he or s he d oes n ot ha ve a n ac ute 
c o n ditio n ca usi n g se vere h y per gl yce mia), resc ue me dicat i on will be prescri be d as a n a d d-o n t o 
ra n d omize d treat me nt . Pat ient s will c o nti n ue t o foll o w t he pr ot oc ol -s pecifie d visit sc he d ule as 
descri be d i n S ectio n 7. 4. 2 .

> 2 7 0 m g/ d L ( > 1 5. 0 m m o l/ L) fr om baseli ne t o Wee k 6 ( 4 val ues/ wee k) 

> 2 4 0 m g/ d L ( > 1 3. 3 m m o l/ L) fr om Wee k 6 t o Wee k 1 2 ( 4 val ues/ wee k)

> 2 0 0 m g/ d L ( > 1 1. 1 m m o l/ L) fr om Wee k 1 2 t o e n d of trial ( 4 val ues/ wee k)
O R

H b A 1c ≥8. 5 % ( ≥6 9 m m o l/m ol)  b y a n d after Wee k 2 4
7. 8. 2. 4.
M a n a g e m e nt of P ati e nt s P er m a n e ntl y Di s c o nti n ui n g St u d y Dr u g s
Ci rc u msta nces u n der w hic h patient s ma y be re q uire d t o pre mat urel y disc o nti n ue st u d y dr u g are 
o utli ne d i n Sect i on 8. 1 . Patie nts w h o st o p t he st u d y dr u g per ma ne n tl y will c o nti n ue partici pati n g 
i n t he trial acc or di n g t o t he pr ot oc ol t o c ollect all pla n ne d efficac y a n d safety meas ure me nts a n d
s h o uld recei ve a n ot her gl uc ose -l oweri n g i nter ve nt i o n ( Secti o n 7. 4. 2 ). T he ne w gl uc ose -l oweri n g
i nter ve nt i on will be rec or de d o n t he e C R F s pecifie d f or c ollecti n g a nt i h y per gl yce mic
me dicat i ons.
T o ass ure ti mel y i nit iati on of a n ot her a nti h y per gl yce mic me dicat io n after per m a ne nt
di sc o nti n uati on of st u d y  dr u g, patie nts s h o uld be a d vise d t o pr o m pt l y n otif y  t he site w he n t his 

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 4 1
L Y 3 2 9 8 1 7 6
sit u atio n occ urs. T he i n vest i gat or s h o ul d e val uate t he nee d for a d di tio nal a nt i h y per gl yce mic 
me dicat i on at t hi s ti me (as o utli ne d i n Secti on 7. 4. 2 ) a n d i nitiate t he a d diti onal i nter ve nt i on
acc or di n gl y. A n u nsc he d ule d visit s h o ul d be use d as nee de d f or m ore ti mel y  ini tiat i on if 
warra nte d base d o n t he i n vest i gat or’s cli nical j u d g me nt.
7. 8. 2. 5.
M a n a g e m e nt of P ati e nt s wit h G a str oi nt e sti n al S y m p t o m s
I n t he P hase 2 pr o gra m, t he m ost c o m m onl y  re p orte d treat me nt-e mer ge nt A Es ( T E A Es) f or 
pati e nts recei vi n g tirze pat i de were na usea, v o miti n g, a n d diarr hea.
T he ti rze pati de d ose escalat i on sc he me has bee n desi g ne d t o mi ni mize t he de vel o p me nt of 
i ntol era ble GI s y m pt o ms.  T he escalati on peri o d is c o nsi dere d t o be 2 4 wee ks, w hic h all o ws 
2 0 wee ks t o escalate t o 1 5 m g a n d a d dit i onal 4 wee ks t o reac h stea d y  state.  D uri n g t he d ose
escalat i on peri o d, e ver y  eff ort s h o uld be ma de b y t he i n vest i gat or t o be a ble t o escalate a n d 
mai ntai n patie nts o n t he c orres p o n di n g st u d y  dr u g d osa ge. 
T o mit i gate GI s y m pt o ms a n d ma na ge patie nts wit h i nt olera ble GI A Es d uri n g t he escalat i o n 
p eri o d ( Wee k 0 t o 2 4) , t he i n vesti gat or s h o ul d

ad vise patie nts t o eat s maller meals, f or e xa m ple, s plitti n g 3 dail y meals i nt o 4 or 
m o re s maller meals, a n d t o st o p eati n g w he n t he y f e el full.

p rescri be s y m pt o matic me dicat i on (f or e xa m ple, a nt iemet ic or a ntidiarr heal 
me dicat i on) per l ocal c o u ntr y  a vaila bility a n d i n di vi d ual patie nt nee ds. Use of 
s y m pt o mat ic me dicat i on s h o ul d be ca pt ure d as c o nc o mita nt me dicat i on i n t he 
e C R F.

te m p oraril y i nterr u pt tirze pat i de ( o mit 1 d ose, t he patie nt will ta ke 3 of 4 d oses at 
t hat d ose le vel).  After t he i nterr u pti o n, restart at t he sa me d ose wit h t he patie nt 
ta ki n g me dicati on t o alle viate t heir GI s y m pt o ms . T he data relate d t o te m p orar y  
i nterr u ptio n of  st u d y treat me nt s h o uld be d oc u me nte d i n s o urce d oc u me nts a n d 
e ntere d o n t he e C R F.  

If i ntolera ble GI s y m pt o ms or e ve nts persist des pite t he a b o ve meas ures, t he 
i n vesti gat or ma y deci de t o disc o nti n ue st u d y dr u gs.
De-escalati o n of st u d y dr u gs 
will n ot be all o we d . Patie nts w h o st o p t he st u d y dr u g per ma ne ntl y will recei ve 
an ot her gl uc ose -l oweri n g i nter ve nt i on ( Sectio n 7. 4. 2 ) a n d will c o nti n ue 
parti ci pat i n g i n t he st u d y acc or di n g t o t he pr ot oc ol t o c ollect all pla n ne d efficac y 
a n d safet y meas ure me nts.
T he ne w gl uc ose -l oweri n g i nter ve nt i on will be 
rec or de d o n t he e C R F s pecifie d f or c ollecti n g a nti h y per gl yce mic me dicat i ons .
I n t he e ve nt of i ntol era ble persiste nt GI s y m pt o ms t hat occ ur after t h e escalati o n peri o d ( aft er 
Wee k 2 4) , t he i n vesti gat or s h o ul d ta ke t he a b o ve meas ures t o kee p t he patie nt o n st u d y treat me nt 
bef ore st o p pi n g t he st u d y  dr u g per ma ne ntl y a n d i nitiate a n ot her gluc ose -l oweri n g i nter ve nt i on. 

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 4 2
L Y 3 2 9 8 1 7 6
8.
Di s c o nti n u ati o n Crit eri a
8. 1.
Di s c o nti n u ati o n fr o m St u d y Tr e at m e nt
8. 1. 1.
P er m a n e nt Di s c o nti n u ati o n fr o m St u d y Tr e at m e nt
P ossi ble r eas o ns lea di n g t o per ma ne nt disc o nti n uati o n of i n vesti gati onal pr o d uct :

P atie nt Decisi o n
o
T he patie nt re q uests t o disc o nti n ue i n vesti gati onal pr o d uct.

Disc o nti n u ati o n d ue t o i ncre ase d ris k of h y p o gl yce mi a
Pl ease refer t o S ecti o n 7. 8. 2. 2 f or details.

Disc o nti n u ati o n d ue t o a he p atic e ve nt or li ver test a b n or m alit y
P ati e nts w h o are disc o nt in ue d fr o m i n vesti gati onal pr o d uct d ue t o a he pat ic e ve nt or li ver 
test a b n or malit y s h o uld ha ve a d di tio n al he pat ic safet y data c ollecte d via a n eC R F.
Di sc o nti n uatio n of  t he i n vesti gati onal pr o d uct f or a b n or mal li ver tests s h o ul d be
c o nsi dere d b y t he i n vestigat or w he n a patie nt meets o ne of t he f o ll owi n g c o n di tio ns af t er 
c o ns ultati o n wit h t he Lill y -desi g nate d m e dical mo ni t or:

A L T or as partate a mi n otra nsferase ( A S T) > 8 X U L N

A L T or A S T > 5 X U L N f or m ore t ha n 2 wee ks

A L T or A S T > 3 X U L N a n d t otal bilir u bi n le vel ( T B L) >2 X U L N or 
i nter nat i onal n or m alize d ratio > 1. 5

A L T or A S T > 3 X U L N wit h t he a p peara nce of fat i g ue, na usea, v omit i n g, 
rig ht u p per q ua dra nt pai n or te n der ness, fe ver, ras h, a n d/ or e osi n o p hilia 
( > 5 %)

alkali ne p h os p hatase ( A L P) > 3 X U L N

A L P > 2. 5 X U L N a n d T B L > 2 X U L N

A L P > 2. 5 X U L N wit h t he a p peara nce of fati g ue, na usea, v o mit i n g, ri g ht 
q ua dra nt pai n or te n der ness, fe ver, ras h, a n d/ or e osi n o p hilia ( > 5 %)
I n a d diti on, patie nts will be disc o nt i n ue d fr om t he i n vesti gat i onal pr o d uct i n t he 
f oll owi n g circ u msta nces :

If a patie nt is i na d verte ntl y e nr olle d a n d it is deter mi ne d t hat c o nti n ue d treat me nt 
wi t h st u d y dr u g w o uld n ot be m e dicall y a p pr o priate, see Sectio n 8. 1. 3

Ac ute or c hr o nic p a ncreat itis 

If a patie nt is dia g n ose d wit h M T C after ra n d o mizati o n or has a p ostra n d o mizat i on 
calcit o ni n val ue ≥3 5 n g/ L t hat has i ncrease d at least 5 0 % o ver baseli ne

If a patie nt i s dia g n ose d wit h a n acti ve or u ntreate d mali g na nc y ( ot her t ha n basal or 
s q ua m o us cell s ki n ca ncer, i n sit u carci n o mas of t he cer vi x, or i n sit u pr ostate ca ncer) 
after ra n d o mizati on

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 4 3
L Y 3 2 9 8 1 7 6

A n y si g nifica nt st u d y  dr u g-r elate d h y perse nsit i vity reacti o n

A n y o t her T E A E, S A E, or cli nicall y si g nifica nt la b orat or y val ue f or w hic h t he 
i n vesti gat or belie ves t hat per ma ne nt st u d y dr u g disc o nti n uati on is t he a p pr o priate 
meas ure t o be ta ke n

If fe male patie nt bec ome s pre g na nt

If a patie nt is dia g n ose d wit h T 1 D M
P ati e nts w h o st o p t he st u d y  dr u g per ma ne ntl y will recei ve a n ot her gl uc ose-l oweri n g i nter ve nti o n
a n d will c o nt i n ue partici pati n g i n t he trial acc or di n g t o t he pr ot oc ol t o c ollect all pla n ne d efficac y  
a n d safet y meas ure me nts.
T he ne w gl uc ose -l oweri n g i nter ve nt i on will be rec or de d o n t he e C R F 
s pecifie d f or c ollecti n g a nti h y per gl yce mic me dicati o ns.
P ati e nts di sc o nti n ui n g fr om t he i n vesti gati onal pr o d uct pre mat urel y f or a n y reas o n s h o ul d 
c o mplete a d verse e ve nt a n d ot her f oll ow- u p pr oce d ures per Secti o n 2 ( Sc he d ule of Acti vities),
Secti o n 9. 2 ( A d verse E ve nts), a n d Secti o n 9. 4 ( Safet y) of t his pr ot oc ol.
8. 1. 2.
T e m p or ar y Di s c o nti n u ati o n fr o m St u d y Tr e at m e nt
I n certai n sit uati ons after ra n d o mizat i on, t he i n vesti gat or ma y nee d t o te m p oraril y i nterr u pt st u d y  
dr u g (f or e xa m ple, A E) .  If st u d y dr u g i nterr u ptio n is d ue t o a n A E, t he e ve nt is t o be 
d oc u m e nte d a n d f o ll owe d acc or di n g t o t he pr oce d ures i n Secti o n 9. 2 of  t his pr ot oc ol.  E ver y  
eff ort s h o ul d be ma de b y t he i n vesti gat or t o mai ntai n patie nts o n st u d y dr u g a n d t o restart st u d y 
dr u g after a n y  t e mp orar y  int err u ptio n, as s o o n as i t is safe t o d o s o. 

If t he n u m ber of c o nsec ut i ve misse d d oses i s ≤2, t he treat me nt ca n be restarte d at t he 
sa me d ose, if t he dr u g was well t olerate d prior t o disc o nti n uat i on,

If t he n u m ber of c o nsec ut i ve misse d d oses is ≥3, t he n t he treat me nt s h o ul d be restarte d at 
5 m g or m atc he d place b o irres pecti ve of t he d ose t he patient  was recei vi n g bef ore t he 
i nterr u ptio n a n d s u bse q ue nt l y escalate d as re q uire d b y pr ot oc ol.

If t he a b o ve sit uati o ns occ ur a gai n d uri n g t he c o urse of t he st u d y, t he i n vest i gat or i n 
c o ns ultati o n wit h s p o ns or or desi g nee w ill disc uss t he ne xt treat me nt o pti o n.

T he i n vesti gat or will use t he I W R S t o recei ve t he a p pr o priate st u d y dr u g dis pe nsi n g 
i nf or mat i on t o preser ve bli n di n g o f t he st u d y dr u g
If t he st u d y dr u g i nterr u pti o n is d ue t o i nt olera ble persiste nt GI A E (f or e xa m ple, na usea, 
v o mit i n g, or diarr hea), t he patie nts s h o ul d be treate d as s u g geste d i n Sect i on 7. 8. 2. 5 .  
T he data relate d t o te m p orar y  int err u ptio n of  st u d y treat me nt will be d oc u me nte d i n s o urce 
d oc u m e nts a n d e ntere d o n t he e C R F.
8. 1. 3.
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 P ati e nt s
If t he s p o ns or or i n vesti gat or i de ntifies a patie nt w h o di d n ot meet e nr oll me nt criteria a n d was 
i na d verte ntl y e nr olle d, t he n t he patie nt s h o ul d be disc o nti n ue d fr om st u d y treat me nt u nless t here 
are e xte n uat i n g circ u msta nces t hat ma ke it me dicall y necessar y f or t he patie nt t o c o nti n ue o n 

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 4 4
L Y 3 2 9 8 1 7 6
st u d y tr e at me nt.  I f t he i n vest i gat or a n d t he s p o ns or C R P a gree t hat 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 s p o ns or C R P t o all o w t he 
i na d verte ntl y e nr olle d pat ient t o c o ntin ue i n t he st u d y  wit h or wit ho ut treat m e nt wi t h 
i n vesti gati onal pr o d uct. Safet y f oll ow- u p s h o uld be perf or m e d as o utli ne d i n Sect i on 2
( Sc he d ule of Acti vities), Sectio n 9. 2 ( A d verse E ve nts), a n d Secti o n 9. 4 ( Safet y) of t he pr ot oc ol.
8. 2.
Di s c o nti n u ati o n fr o m t h e St u d y
I n or der t o mi ni mize t he a m o u nt of missi n g data a n d t o e na ble assess me nt of st u d y o bjecti ves as 
pl a n ne d i n t he st u d y pr ot oc ol, e ver y att e mpt will  b e ma de t o kee p patie nts i n t he st u d y 
irres pecti ve of t he fol l owi n g:

a d here nce t o st u d y dr u g,

a d here nce t o visit sc he d ule ,

missi n g assess me nts ,

st u d y dr u g disc o nti n uati on d ue t o a n A E ,

de vel o p me nt of c o m or bi dit ies, a n d

de vel o p me nt of cli nical o utc o mes .
T he ci rc u msta nces liste d a b o ve are n ot vali d reas o ns f or disc o nti n uati on fr om t he st u d y. 
P ati e nts will be disc o nt i n ue d i n t he f oll owi n g ci rc 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 o ll me nt i n a n y ot her t yp e of  me dical researc h j u d ge d n ot t o be 
scie ntificall y or me dicall y c om pati ble wit h t his st u d y

P articip 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 ulat i ons, a n d g o o d cli nica l 
practi ce 

If a fe male patient  bec omes pre g na nt

If a patie nt is dia g n ose d wit h T 1 D M

P atie nt re q uests t o be wit h dra w n fr o m t he st u d y
P ati e nts w h o a gree t o pr o vi de i nf or mat i on rel e va nt t o a n y st u d y e n d p oi nt at t he e n d of t he st u d y 
are n ot c o nsi dere d t o ha ve disc o nti n ue d fr o m t he st u d y .
A pat ient  w h o wit hdra ws c o nse nt a n d clearl y i n dicates t hat t here will be n o f urt her c o ntact of a n y 
ki n d wit h t he site will be c o nsi dere d t o ha ve disc o nt i n ue d fr om t he st u d y.
Pri or t o earl y  st u d y disc o nti n uatio n, t he pati e nt ma y disc o nt i n ue st u d y dr u g a n d will ha ve 
e n d-of -st u d y pr oce d ures ( E T visit) p erfor m e d as s h o w n i n t he Sc he d ule of Act i vities ( Sectio n 2 ).  
D uri n g t he E T visit, t he patie nt will n ot i nit iate a n y ne w gl uc ose -l oweri n g t hera p y.  Visi t 8 0 1 
(safety f oll ow- u p visit) s h o ul d be perf or m e d a p pr o xi matel y 4 wee ks after t he E T visit as t he fi nal 
st u d y visit.

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 4 5
L Y 3 2 9 8 1 7 6
P ati e nts di sc o nti n ui n g fr om t he st u d y pr e mat urel y f or a n y reas o n s h o uld c o m plete a d verse e ve nt
a n d ot her safet y f oll ow- u p per Secti o n 2 ( Sc he d ule of Acti vities), Secti o n 9. 2 ( A d verse E ve nts),
a n d Sect i on 9. 4 ( Safet y) of t his pr ot oc ol.
8. 3.
L o st t o F oll o w - U p
A pat ient will be c o nsi dere d l ost t o f o ll ow- 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.  E ver y  att e mpt will  be ma de t o mi ni mize 
t he n u m ber of patie nts c o nsi dere d l ost t o f o ll ow- u p at t he e n d of t he st u d y .  P atie nts will be 
i nf or me d a b o ut t he i m p orta nce of c o m plet i n g t he st u d y a n d pr o vidi n g u p date d c o ntact 
i nf or mat i on t o t he st u d y  site w he n necessar y.

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 4 6
L Y 3 2 9 8 1 7 6
9.
St 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, wit h t he st u d y pr oce d ures a n d t heir ti mi n g (i ncl u di n g 
t olera nce li mits for ti mi n g).
A p pe n di x 2 lists t he la b orat or y tests t hat will be perf or me d f or t his st u d y.
U nless ot her wise state d i n t he s u bsect i ons bel o w, a ll sa m ples c ollecte d f or s pecifie d la b orat or y 
tests will be destr o ye d wit hi n 6 0 da ys of recei pt of c o nfir me d test res ults.  Certai n sa m ples ma y 
be retai ne d f or a l o n ger peri o d, if necessar y, t o c o m pl y wit h a p plica ble la ws, re g ulat i 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
9. 1. 1.
Pri m ar y Effi c a c y A s s e s s m e nt s
T he pri mar y  efficac y meas ure me nt i n t his st u d y is mea n c ha n ge i n H b A 1c val ues fr o m baseli ne 
t o 4 0 wee ks, as deter mi ne d b y t he ce ntral la b orat or y.  Bl o o d sa m ples f or H b A 1c meas ure me nts 
wil l be c o llecte d at s pecific cli nic visits as s u m marize d i n t he St u d y Sc he d ule, Secti o n 2 . 
9. 1. 2.
S e c o n d ar y Effi c a c y A s s e s s m e nt s
T he f o ll owi n g sec o n da r y efficac y meas ures will be assesse d at 4 0 wee ks base d o n data c ollecte d 
at t he ti mes s h o w n i n t he St u d y Sc he d ule (see Secti on 2 ).

Mea n c ha n ge i n b o d y w ei g ht

Pr o p orti o n of  patie nts ac hie vi n g a tar get H b A 1c < 7. 0% ( 5 3 m m o l/ m ol), ≤6. 5 % ( 4 8 
m m o l/ m ol), a n d < 5. 7 % ( 3 9 m m o l/ m ol)

Mea n c ha n ge i n F S G val ues meas ure d i n t he ce ntral la b orat or y

Mea n c h a n ge i n dail y  a vera ge 7 -p oi nt S M B G pr ofiles 

Pr o p orti o n of  patie nts w h o ac hie ve d wei g ht l oss ≥5 %, ≥1 0 %, a n d ≥1 5 % 
9. 1. 3.
E x pl or at or y A s s e s s m e nt s a n d Pr o c e d ur e s
T he f o ll owi n g sec o n dar y  efficac y meas ures will be calc ulate d base d o n data c o llecte d at t he 
ti mes s h o w n i n t he St u d y Sc he d ule (see Secti on 2 ).

Mea n c ha n ge i n wa ist circ u mfere nce

C ha n ge s fr o m baseli ne i n mea n B MI

Mea n c ha n ge i n li pi ds (t otal c h olester ol, hi g h -de nsit y li p o pr otei n, l ow- de nsit y 
li p o pr otei n, v er y  lo w -de nsit y li p o pr otei n, a n d trigl yceri des )

Bi o m ar kers

A P P A D L sc ores

E Q - 5 D-5 L sc ores

I W-S P sc ores

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 4 7
L Y 3 2 9 8 1 7 6
9. 1. 4.
B o d y W ei g ht, H ei g ht, W ai st Cir c u mf er e n c e
a n d B o d y M a s s 
I n d e x
B o d y  wei g ht a n d waist circ u mfere nce will be m eas ure d at pre s pecifie d ti me p oi nts (see Sc he d ule 
of  Acti vities [Secti o n 2 ].
Eac h patie nt’s wei g ht s h o ul d be meas ure d acc or di n g t o a sta n dar dize d pr ot oc ol a n d rec or de d o n
t he e C R F t o t he nearest o ne- te nt h k g . Waist circ u mfere nce s h o ul d be meas ure d at mi d p o i nt, 
bet wee n l o wer m ar gi n o f least p al pa ble ri b a n d t o p of iliac crest (a p pr o xi matel y 1 i nc h ( 2. 5 4 c m) 
a b o ve t he na vel) , (A p pe n di x 7 ).
B o d y  mass i n de x will be c o m p ute d fr o m t he patie nt’s weig ht a n d hei g ht. B o d y  mass i n de x
s h o uld be r o u n de d t o t he nearest w h ole n u m ber f or p ur p oses of I ncl usi on C rit erio n [ 4 ]
( Sectio n 6. 1 ).
9. 1. 5.
A p pr o pri at e n e s s of A s s e s s m e nt s
Efficac y a n d safet y assess me nts i ncl u de d i n t his st u d y are ge nerall y re gar de d as relia ble a n d 
acc urate wit h res pect t o t he efficac y a n d safet y assess me nts i n i n di vi d uals a n d p o p ulat i ons wit h 
T 2 D M.
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 pat ient s 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 pati e nt .
T he i n vest i gat or is res p o nsi ble f or t he a p pr o priate me dical care of pat ient s 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 us or ot her wise me dicall y i m p orta nt, c o nsi dere d r elate d t o t he i n vest i gati onal 
pr o d uct or t he st u d y, or t hat ca use d t he pati e nt 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 pati e nt s h o uld be f ol l owe d u nt il t he e ve nt res ol ves a n d sta bilizes with 
a p pr o priate dia g n ostic e val u atio n . T he fre q ue nc y of f o ll ow- u p e val uat i ons o f t he A E is left t o 
t he discret i on of t he i n vest i gat or.
Lac k of dr u g effect is n ot a n A E i n cli nical st u dies, beca use t he p ur p ose of t he cli nical st u d y is t o 
esta blis h treat me nt effect.
After t he I C F is si g ne d, st 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 pati e nt ’s pree xisti n g c o n diti ons, i ncl u di n g cli nicall y si g nifica nt si g ns a n d s y m pt o ms of t he 
di sease u n der treat me nt i n t he st u d y.  I n a d diti on, 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 a n y  ne w c o n ditio ns as A Es . F or eac h A E, t he o nset a n d d urati o n, t he 
serio us ness a n d se verit y,  a n d t he acti ons ta ke n wit h res pect t o st u d y treat me nt will be rec or de d.
I n vesti gat ors s h o ul d rec or d t heir assess me nt of t he p ote ntial relate d ness of eac h A E t o pr ot oc ol 
pr oce d ure a n d i n vesti gati o nal pr o d uct via a n e C R F .

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 4 8
L Y 3 2 9 8 1 7 6
Pr oce d ures a n d assess me nts perf or me d pri or t o Visit 3 are c o nsi dere d scree ni n g pr oce d ures .  T he 
res ults of t hese pr oce d ures a n d assess me nts s h o ul d be c o nsi dere d pree xist i n g c o n diti ons a n d 
s h o uld be re p orte d as m e dical hist or y or c o nc o mita nt ill ness.  
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 bility 
of  bei n g relate d t o st u d y treat me nt, st u d y de vice, or a st u d y pr oce d ure, ta kin g i nt o acc o u nt t he 
di sease, c o nc o mita nt treat me nt, or pat h ol o gies.
A “reas o na ble p ossi bilit y” mea ns t hat t here is a ca use a n d effect relat i ons hi p bet wee n t he 
i n vesti gati onal pr o d uct, st u d y  de vice a n d/ or st u d y pr oce d ure, a n d t he A E.
T he i n vest i gat or a ns wers yes/ n o w he n ma ki n g t his assess me nt.
Pl a n ne d s ur geries a n d n o ns ur gical i nter ve nt i ons 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 orse ne d d uri n g t he c o urse of t he st u d y .
If a patie nt ’s i n vesti gati o nal 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 a n e C R F, clarif yi n g, if p ossi ble, t he circ u msta nces 
lea di n g t o a n y d osa ge m o dificati o ns or disc o nt i n uati o ns of treat me nt.
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 o utc o m es:

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 pitali zat i on b ut m a y je o par dize t he patie nt or ma y re q uire i nter ve nti on 
t o pre ve nt o ne of t he ot her o utc o mes liste d i n t he defi niti on a b o ve.   E xa m ples of 
s uc h me dical e ve nts i ncl u de aller gic br o nc h os pas m re q uiri n g i nte nsi ve treat me nt 
i n a n e mer ge nc y r o o m or at h o me, blo o d d y scrasias or c o n v ulsi o ns t hat d o n ot 
res ult i n i n patient  h os pitalizati on, or t he de vel o p me nt of dr u g de pe n de nc y  or dr u g 
a buse.
All A Es occ urri n g after si g ni n g t he I C F are rec or de d i n t he e C R F a n d assesse d f or seri o us 
criteria.  T he S A E re p orti n g t o t he s p o ns or be gi ns after t he pati e nt has si g ne d t he I C F a n d has 
recei ve d i n vesti gati onal pr o d uct.  H o we ver, if a n S A E occ urs afte r sig ni n g t he I C F, b ut pri or t o 
recei vi n g i n vesti gati onal pr o d uct, t he S A E s h o ul d be re p orte d t o t he s p o ns or as per S A E -
re p orti n g re q uire me nts a n d ti meli nes (see Secti on 9. 2 ) if it is c o nsi dere d reas o na bl y p ossi bl y 
r elate d t o st u d y pr oce d ure.
St u d y  site pers o n nel must al ert Lill y or its desig nee of  a n y S A E wit hi n 2 4 h o urs of i n vesti gat or 
a ware ness o f 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 

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 4 9
L Y 3 2 9 8 1 7 6
are t o be i m me diatel y f o ll ow e d wi t h official notificati 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 on re q uire me nt refers t o t he i nit ial S A E i nf or mati on a n d all f o ll ow- u p S A E 
i nf or mat i on. Patie nts wi t h a serio us he pat ic A E s h o uld ha ve a d di tio nal data c ollecte d usi n g t he 
e C R F.
Pre g na nc y ( d uri n g mat er nal or pater nal e x p os ure t o i n vest i gati onal pr o d uct) d oes n ot meet t he 
defi nit i on o f 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 h o ul d be 
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.
I n vesti gat ors are n ot o bli gate d t o activ el y see k A Es or S A Es i n pat ient s o nce t he y  ha ve 
di sc o nti n ue d a n d/ or c o m plete d t he st u d y (t he pati e nt dis p osit i on C R F has bee n c o m plete 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 pati e nt has 
bee n disc har ge d fr o m t he st u d y  a n d he/s he c o nsiders 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 .
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 i de ntifies as relate d t o i n vesti gati o nal pr o d uct or pr oce d ure.  
U nite d States 2 1 C F R 3 1 2. 3 2 a n d E ur o pea n U ni o n Cli nical Trial Direct i ve 2 0 0 1/ 2 0/ E C a n d t he 
ass ociate d detaile d g ui da nces or nati o nal re g ulat or y  re q uire me nts i n partici pat i n g c o u ntries 
re q uire t he re porti n g of S U S A Rs.  Lill y has pr oce d ures t hat will be f oll o we d f or t he 
i de ntificati on, 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 ulat i ons a n d t he ass ociate d detaile d g ui da nces.
9. 2. 2.
A d v er s e E v e nt of S p e ci al I nt er e st
9. 2. 2. 1.
H y p o gl y c e mi a
P ati e nts will c ollect i nf or mat i on o n e pi s o des of h y p o gl yce mia starti n g fr o m Visit 3 u nt il t he last 
st u d y visit ( F ollo w -u p Vi sit or E T Visit).  F or t hat p ur p ose, patie nts will be trai ne d a b o ut si g ns 
a n d s y m pt o ms of h y p o gl yce mia, h o w t o treat h yp o gl yce mia, a n d h o w t o c ollect a p pr o priate 
i nf or mat i on f or eac h e pis o de of h y p o gl yce mia i n t he st u d y acc or di n g t o t he Sc he d ule of 
Act i vities ( Secti on 2 ).  Site pers o n nel will e nter t his i nf or mati on i nto t he e C R F at eac h visit. 
I n vesti gat ors s h o ul d use t he f oll owi n g defi nit i ons a n d criteria w he n dia g n osi n g a n d cate g orizi n g 
a n e pis o de c o nsi dere d t o be relate d t o h yp o gl yce mia (t he pl as ma gl uc ose [P G ] val ues i n t his 
secti on refer t o val ues deter mi ne d b y a la b orat or y  or I nter natio nal  Fe derat i on of Cli nical 
C he mistr y  a n d La b orat or y Me dici ne plas ma-e q ui vale nt gluc ose m eters a n d stri ps) ( A D A 2 0 1 7, 
A D A 2 0 1 8 ):
Gl uc ose Alert V al ue ( Level 1):

D oc u me nte d s y m pt o m atic h y p o gl yce mi a is defi ne d as a n y ti me a patient  feels 
t hat he or s he is e x perie nci n g s y m pt o ms a n d/ or si g ns ass ociate d wit h 
h y p o gl yce mia, a n d has a P G le vel of ≤7 0 m g/ d L ( ≤3. 9 m m o l/ L).

D oc u me nte d as y m pt o m atic h y p o gl yce mi a is defi ne d as a n y 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 a meas ure d P G 
≤7 0 m g/ d L (≤3. 9 m m o l/L) .

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 5 0
L Y 3 2 9 8 1 7 6

D oc u me nte d u ns pecifie d h y p o gl yce mi a is defi ned as a n y  e ve nt wit h n o 
i nf or mat i on a b o ut s y mpt o ms of h y p o gl yce mia a vaila ble, b ut wit h a meas ure d P G 
≤7 0 m g/ d L (≤3. 9 m m o l/L) .
Cli nic ally Si g nific a nt Hy p o glyce mi a ( Level 2):

D oc u me nte d s y m pt o m atic h y p o gl yce mi a
is defi ne d as a n y ti me a patient  feels 
t hat he or s he is e x perie nci n g s y m pt o ms a n d/ or si g ns ass ociate d wit h 
h y p o gl yce mia, a n d has a P G le vel of < 5 4 m g/ d L ( < 3. 0 m m o l/ L).

D oc u me nte d as y m pt o m atic h y p o gl yce mi a is defi ne d as a n y 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 a meas ure d P G 
< 5 4 m g/ d L ( < 3. 0 m m ol/ L).

D oc u me nte d u ns pecifie d h y p o gl yce mi a is defi ne d as a n y e ve nt wit h n o 
i nf or mat i on a b o ut s y mpt o ms of h y p o gl yce mia a vaila ble, b ut wit h a meas ure d P G 
< 5 4 m g/ d L ( < 3.0 m m o l/ L).
Severe hy p o glyce mi a ( Level 3):

Se vere h y p o gl yce mi a is defi ne d as a n e pis o de wit h se vere c o g nit i ve i m pair me nt 
re q uirin g t he assista nce of a n ot her pers o n t o acti vel y  a d mi nister car b o h y drate, 
gl uca g o n, or ot her res uscitati ve act i ons.  T hese e pis o de s ma y be ass ociate d wit h 
s ufficie nt ne ur o gl yc o pe nia t o i n d uce seiz ure or c o ma. Bl o o d gl uc ose 
meas ure me nts ma y  not 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 B G t o n or mal is c o nsi dere d s ufficie nt 
e vi de nc e t hat t he e ve nt was i n d uce d b y a lo w B G c o nce ntrati o n.
Ot her hy p o glyce mi a c ate g ories:

N oct ur n al h y p o gl yce mi a is defi ne d as a n y h y p o gl yce mic e ve nt t hat occ urs 
bet wee n be dt i me a n d wa ki n g.
If a h y p o gl yce mic e ve nt meets t he criteria of se vere, it nee ds t o be rec or de d as seri o us o n t he A E 
C R F a n d re p orte d t o Lill y as a n S A E.
T o a v oi d d u plicate re p orti n g, all c o nsec uti ve B G val ues ≤7 0 m g/ d L ( 3. 9 m m o l/ L) occ urri n g 
wi t hi n 1-h o ur peri o d ma y be c o n sidere d t o be a si n gle h y p o gl yce mic e ve nt ( Wei n ber g et al. 2 0 1 0; 
Da n ne et al. 2 0 1 3).  
I n eac h case of s us pecte d or c o nfir me d h y p o gl yce mia, it is i m p orta nt t hat t he e ve nt be pr o perl y 
cate g orize d, t he effect of t he i nter ve nti o n be assesse d, a n d t he fre q ue nc y of h y p o gl yce mia be 
e val uate d.  T he r ole of dietar y c ha n ges a n d p h ysical e xercise ( or a n y ot her c o ntri b uti n g fact or) i n 
t he de vel o p me nt of a n e ve nt s h o ul d be esta blis he d.  T he patie nt s h o ul d recei ve a d dit i onal 
e d ucati o n, if dee me d a p pr o priate.  Pl ease refer t o Sectio n 7. 8. 2. 2 f or g ui da nce o n ma na ge me nt of 
i ncrease d h y p o gl yce mia ris ks.  
9. 2. 2. 2.
S e v er e, P er si st e nt H y p er gl y c e mi a
Se vere, persiste nt h y per gl yce mia will be c ollecte d d uri n g t he trial t o assess t he ris k of e xtre m e 
i m bala nce i n gl yce mic c o ntr ol.

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 5 1
L Y 3 2 9 8 1 7 6
I n vesti gat ors will be trai ne d o n t he a p plicati on of cri t eria for d e ci di n g w he n a n d h o w t o i nter ve ne 
wi t h patie nts w h o d o n ot reac h gl yce mic tar gets.  A n a d diti on al  t hera pe utic i nter ve nt i on s h o ul d 
be c o nsi dere d i n pat ient s wh o de vel o p se vere, persiste nt h y per gl yce mia after ra n d o mizat i on .  
Resc ue me dicat i on will be prescri be d as a n a d d-o n t o ra n d o mize d treat me nt, a n d patie nts will 
c o nti n ue t o fol l ow t he pr ot oc ol -s pecifie d visit sc he d ule as descri be d i n S ect i on 7. 8. 2. 3 .
9. 2. 2. 3.
P a n cr e atiti s
Ac ute pa ncreat itis is defi ne d as a n A E of i nterest i n all trials wit h tirze pati de i ncl u di n g t his trial.  
Ac ute pa ncreat itis is 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 ol ve 
p eri pa ncreat ic tiss ues a n d/ or re m ote or ga n s yste ms ( Ba n ks a n d Free ma n 2 0 0 6).  T he dia g n osis of 
ac ute pa ncreatit is re q uires 2 of t he f oll owi n g 3 feat ures:

a b d o mi nal pa i n, c haracteristic of ac ute pa ncreatitis ( ge nerall y l ocate d i n t he 
e pig astri u m a n d ra di ates t o t he bac k i n a p pr o xi matel y half t he cases 
[Ba n ks a n d Free ma n 2 0 0 6; K o iz umi et al . 2 0 0 6]; t he pai n is ofte n ass ociate d wit h 
na usea a n d v o mit i n g)

ser u m a m ylase (t otal a n d/ or pa ncreatic) a n d/ or li pase ≥3 X 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 ( C T) sca n or 
ma g net ic res o na nce i ma gi n g ( M RI)
If ac ute pa ncreatitis is s us pecte d, a p pr o priate la b orat or y tests (i ncl u di n g le vels of pa ncreatic 
a m ylase [ p-a m ylase] a n d li pase) s h o ul d be o btai ne d via t he ce ntral la b orat or y (a n d locall y, if 
nee de d).  I ma gi n g st u dies, s uc h as a b d o mi nal C T sca n wit h or wit h o ut c o ntrast, M RI, or 
gall bla d der ultras o u n d, s h o ul d be perf or me d.  If la b orat or y val ues a n d/ or a b d o mi nal i ma gi n g 
s u p p ort t he dia g n osis of ac ute pa ncreat itis, t he patie nt m ust disc o nti n ue t hera p y with 
i n vesti gati onal pr o d uct(s) , b ut will c o nt i n ue i n t he st u d y o n a n ot her gluc ose -l oweri n g re gi me n 
( details o n resc ue i nter ve nti on will be pr o vi de d).  T he m o st a p pr o priate dia betes t hera pe utic 
re gi me n will be deci de d b y t he i n vesti gat or, base d o n t he patie nt’s cli nical stat us.  A re vie w of 
t he patie nt’s c o nc o mita nt me dicat i ons s h o ul d be c o n d ucte d t o assess a n y p ote ntial ca usal 
r elat i ons hi p wit h pa ncreat itis.
Eac h case o f a n A E of pa ncreat itis m ust be re p orte d.  If t y pical si g ns a n d/ or s y m pt o ms of 
pa ncreat itis are prese nt a n d c o nfir me d b y la b orat or y val ues (li pase or a m ylase [t otal a n d/ or 
pa ncreat ic]) a n d i ma gi n g st u dies, t he e ve nt m ust be re p orte d as a n S A E. F or a p ote ntial case t hat 
d oes n ot m eet all of t hese criteria, it is u p t o t he i n vesti gat or t o deter mi ne t he seri o us ness of t he 
case ( A E or S A E) a n d t he relate d ness o f t he e ve nt t o st u d y dr u g(s).
Eac h patie nt will ha ve meas ure me nts of  p-a m ylase a n d li pase (assesse d at t he ce ntral la b orat or y) 
as s h o w n o n t he Sc he d ule o f Act i vities ( Sectio n 2 ) t o assess t he effects of  t he i n vestig ati o n al  
d oses of ti rze patid e o n pa ncreat ic e nz y me le vels. S eri al meas ures of pa ncreat ic e nz y mes ha ve 
li mite d cli nical val ue f or pre dicti n g e pis o des of ac ute pa ncreatitis i n as y m pt o matic patient s 
( Na uc k et al. 2 0 1 7; Stei n ber g et al. 2 0 1 7a, 20 1 7 b). T h us, f urt her dia g n ostic f o ll ow- u p of  cases 
of  as y m pt o matic pa ncreat ic h y pere nz y me mia (li pase a n d/ or p -a m ylase ≥3 X U L N) is n ot 
ma n date d b ut ma y be perf or me d base d o n t he i n vesti gat or’s cli nical j u d g me nt a n d assess me nt of 
t he patie nt’s o verall cli nic al c o n ditio n . O nl y cases of pa ncreat ic h y pere nz y me mia t hat u n der g o 

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 5 2
L Y 3 2 9 8 1 7 6
a d ditio nal  di a g n ostic fol l ow- u p a n d/ or are acc o m pa nie d b y s y m pt o ms s u g gest i ve of pa ncreatitis 
will be s u b mitte d f or a dj u dicat i on.
All s us pecte d cases of ac ute or c hr o nic pa ncreatitis will be a dj u dicate d b y  a n i n de pe n de nt 
cli nical e n d p o i nt c o m mittee ( C E C).  I n ad di tio n, A Es of se vere or seri o us a b d o mi nal pai n o f 
u n k n o w n et i ol og y  will  als o be s u b mitte d t o t he a dj u dicati on c o m mit tee t o assess f or p ossi ble 
pa ncreat itis or ot her pa ncreatic disease. Rele va nt data fr o m patie nts wit h ac ute or c hr o nic 
pa ncreat itis a n d t h ose wit h se vere or seri o us a b d o mi nal pai n will be e ntere d i nt o a s pecificall y 
desi g ne d e C R F pa ge b y st u d y  site or Lill y st aff. T he a dj u dicat i on c o m mittee re prese ntati ve will 
e nter t he res ults of a dju dicat i on i n a c orres p o n di n g e C R F pa ge.
9. 2. 2. 4.
T h yr oi d M ali g n a n ci e s a n d C -C ell H y p er pl a si a
I n di vi d uals wit h pers o nal or fa mil y hist or y of M T C a n d/ or
M E N- 2
will be e xcl u de d fr o m t he 
st u d y.  T he assess me nt of t h yr oid safet y d uri n g t he st u d y will i ncl u de re p orti n g of  a n y case of 
t h yr oid mali g na nc y i ncl u di n g M T C
a n d pa pillar y carci n o ma a n d meas ure me nts of calcit o ni n.
T his data will be ca pt ure d i n s pecific e C R Fs. T he p ur p ose of calcit o ni n meas ure me nts is t o 
assess t he p ote ntial of tirze pati de t o affect t h yr oid C -cell f u nct i on, w hic h ma y  in dicate 
de vel o p me nt of C -cell h y per pl asia a n d ne o plas ms.
T irze patid e s h o uld be disc o nt i n ue d (after first c o nfir mi n g t he val ue) if p os tra n d o mizati on 
calcit o ni n val ue is ≥3 5 n g/ L a n d has i ncrease d at least 5 0 % over baseli ne.  A c o ns ultat i on wi t h a 
t h yr oid s pecialist (if n ot a vaila ble, a n e n d ocri n o l ogist) s h o ul d be o btai ne d. If t he i ncrease d 
calcit o ni n val ue (≥3 5 n g/ L a n d i ncreases b y ≥5 0 % c o m pare d wi t h baseli ne) is o bser ve d i n a 
pati e nt w h o has a d mi nistere d a me dicat i on t hat i s k n ow n t o i ncrease ser u m calcit o ni n, t his 
me dicat i on s h o ul d be st o p pe d a n d calcit o ni n le vels s h o uld be m eas ure d after a n a p pr o priate 
was h o ut peri o d.  If t he c o nfir me d calcit o ni n val ue is < 3 5 n g/ L, tirze pati de s h o uld be restarte d 
w he n it i s s afe t o d o s o.  
9. 2. 2. 5.
M aj or A d v er s e C ar di o v a s c ul ar E v e nt s
Deat hs a n d n o nfatal C V A Es will be a dj u dicate d b y a c o m mittee of p h ysicia ns e xter nal t o Lill y 
wi t h car diol o g y  e x pertise.  T he n on fatal CV A Es t o be a dj u dicate d i ncl u de t he fol l owi n g:   

m y ocar dial  infarct i on

h os pi talizatio n f or u nsta ble a n gi na

h os pi talizatio n f or heart fail ure

c or o nar y int er ve nt i ons (s uc h as c or o nar y  arter y b y pass graft or perc uta ne o us c or o nar y 
i nter ve nt i on)

cere br o vasc ular e ve nts, i ncl u di n g cere br o vasc u lar acci de nt (str o ke) a n d tra nsie nt 
isc he mic attac k
9. 2. 2. 6.
S u pr a v e ntri c ul ar Arr h yt h mi a s a n d C ar di a c C o n d u cti o n Di s or d er s
Treat me nt -e mer ge nt car diac c o n d ucti o n dis or ders will be f urt her e val uate d.  Patie nts w h o 
de vel o p a n y e ve nt fr o m t h is gr o u p of di s or ders s h o uld u n der g o a n E C G w hic h s h o ul d be 
s u b mitte d t o t he ce ntral rea di n g ce nter. A d dit i onal dia g n ostic tests t o deter mi ne e xact dia g n osis 
s h o uld be perf or m e d, as nee de d. T he s pecific dia g n osis will be rec or de d as a n A E. E ve nts t hat 
meet criteria f or seri o us c o n di tio ns as descri be d i n Secti o n 9. 2. 1 m ust be re p orte d as S A Es .

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 5 3
L Y 3 2 9 8 1 7 6
9. 2. 2. 7.
H y p er s e n siti vit y E v e nt s
All aller gic or h yperse nsi tivit y react i ons will be re p orte d b y t he i n vest i gat or as eit her A Es or, if 
a n y seri o us criteri o n is met, S A Es.  A d dit i onal data, s uc h as t y pe of reacti o n a n d treat me nt 
recei ve d, will be c ollected o n a n y A Es or S A Es t hat t he i n vest i gat or dee ms relate d t o st u d y 
dr u g(s) vi a a C R F create d f or t his p ur p ose.  A d dit i o nal sa m ples s h o ul d als o be c ollecte d as 
o utli ne d i n Sect i on 9. 4. 4 .  St u d y  dr u g(s) s h o uld be te m p oraril y i nterr u pte d i n a n y i n di vi d ual 
s us pecte d of ha vi n g a se vere or seri o us aller gic reacti o n t o t he st u d y dr u g(s).  St u d y dr u g(s) ma y 
be restarte d w he n/if it is safe t o d o s o, i n t he o pi ni o n of t he i n vest i gat or.  If st u d y dr u g(s) is 
p er m a ne nt l y disc o nti n ue d, t he patie nt will recei ve a n ot her gl uc ose-l oweri n g treat m e nt, ju d ge d b y 
t he i n vest i gat or t o be a p pr o priate base d o n t he patie nt’s cli nical stat us, a n d will c o nti n ue i n t he 
trial t o c ollect all pla nn e d efficac y a n d safety me as ure me nts. 
9. 2. 2. 7. 1.
I nj e cti o n Sit e R e a cti o n s
I njecti on site reacti o ns will be c o llecte d o n t he e C R F se parate fr o m t he h y perse nsiti vity reacti on 
e C R F.  At t he ti me o f A E occ urre nce i n t he tirze pati de gr o u p, sa m ples will be c o llecte d f or 
meas ure me nt of tirze pat i de a nt i-dr u g b o dies ( A D A s) a n d tirze pat i de c o nce ntratio n.
9. 2. 2. 7. 2.
A nti -Dr u g A nti b o di e s
T he occ urre nce of A D A f or mat i on will be assesse d as o utli ne d i n Secti o n 9. 4. 4 .
9. 2. 2. 8.
Di a b eti c R eti n o p at h y C o m pli c ati o n s
Dilate d reti nal f u n d os c o pi c e xa mi nat i on will be perf or me d b y  a q ualifie d e ye care pr ofessi onal 
( o p ht hal m ol ogist or o pt o metrist) f or all patie nts bet wee n Visit 2 a n d Visit 3 t o e xcl u de patie nts 
wi t h pr oliferati ve reti n o pat h y a n d/ or ma c ulo p at h y .  T he res ults fr o m t his e xa mi nat i on will be 
rec or de d o n a s pecific reti n o pat h y e C R F as a baseli ne meas ure of reti n o pat h y.  
A f oll ow- u p dilate d f u n d os c o pi c e xa mi nat i on s h o ul d be perf o r me d w he n cli nicall y  in dicate d b y  
a n y A E s us pecte d of w orse ni n g reti n o pat h y, a n d t he fi n di n gs s h o ul d be rec or de d o n t he 
reti n o pat h y e C R F.  
9. 2. 2. 9.
H e p at o bili ar y Di s or d er s
All e ve nts of T E biliar y c olic, c h olec yst itis, or ot her s us pecte d e ve nts relate d t o gall bla d der 
d isease s h o ul d be e val uate d a n d a d dit i onal dia g n ostic tests perf or me d, as nee de d. I n cases of 
ele vate d li ver mar kers, he patic mo ni t ori n g s h o uld be i nit iate d as o utli ne d i n Secti on 9. 4. 5. 1 a n d 
A p pe n di x 4 .
9. 2. 2. 1 0. S e v er e G a str oi nt e sti n al A d v er s e E v e nt s
Ti rze patid e ma y ca use se ver e GI A Es, s uc h as na usea, v o mit i n g, a n d diarr hea.  I nf or mati on 
a b o ut se vere GI A Es as well as a ntie metic/a nti diarr heal use will be c o llecte d i n t he e C R F/ A E 
f or m.  F or detaile d i nf or mati o n c o ncer ni n g t he ma na ge me nt  of GI A Es, please refer t o 
Secti o n 7. 8. 2. 5 .
9. 2. 2. 1 1. A c ut e R e n al E v e nt s
Re nal safet y  will be assesse d base d o n re peate d re nal f u nct i onal assess me nt as well as 
asse ss me nt of A Es s u g gesti ve of ac ute or w o rse ni n g of c hr o nic re nal fail ure. Gastr oi n testi nal 
A Es ha ve bee n re p orte d wit h tirze pati de, i ncl u di n g na usea, diarr hea, a n d v o miti n g.  T hese are 

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 5 4
L Y 3 2 9 8 1 7 6
c o nsiste nt wit h ot her G L P -1 rece pt or a g o nists ( Ar o da a n d Rat ner 2 0 1 1).  T he e ve nts ma y lea d t o 
de h y drat i on, w hic h c o ul d ca use a deteri orati o n i n re nal f u ncti o n, i ncl u di n g ac ute re nal fail ure.  
P ati e nts s h o uld be a d vise d t o n otif y i n vest i gat ors i n case of se vere na usea, fre q ue nt v o miti n g, or 
s y m pt o ms of de h y drati on.
9. 2. 2. 1 2. M et a b oli c A ci d o si s,
In cl u di n g Di a b eti c K et o a ci d o si s
Ket oaci d osis, a seri o us life -t hreate ni n g c o n diti on re q uiri n g ur ge nt h os pitalizat i on, has bee n 
re p orte d rarel y in patie nts wi t h T 2 D M.  Patie nts w h o prese nt wit h si g ns a n d s y m pt o ms c o nsiste nt 
wi t h se vere meta b olic aci d osis s h o ul d be assesse d f or ket oaci d osis re gar dless of prese nti n g B G 
le vels, as ket oaci d osis ma y be prese nt e ve n if B G le vels are less t ha n 2 5 0 m g/ d L.  Treat me nt of 
ket oaci d osis ma y  re q uire i ns uli n, fl ui d, a n d car b o h y drate re place me nt.   R o ut i ne bicar b o nate 
assess me nt will be perf or me d d urin g t he c o urse of t he st u d y .  If lact ic aci d osis is s us pecte d, 
met f or mi n s h o ul d be te m p oraril y disc o nti n ue d u ntil t he res ol uti on of t he e ve nt.
9. 2. 2. 1 3. A m p ut ati o n/ P eri p h er al R e v a s c ul ari z ati o n
All cases of a m p utati o n a n d peri p heral re vasc ularizati o n s h o ul d be re p orte d as a n A E.
9. 2. 2. 1 4. M aj or D e pr e s si v e Di s or d er/ S ui ci d al I d e ati o n
T he pre vale nce of de pressi ve s y m pt o ms a n d dis o r ders is i ncrease d i n patie nts wi t h T1 D M or T 2 D M 
( A D A 2 0 17 ).  A n y A E of maj or de pressi ve dis or der or s uici dal i deati o n s h o ul d be re p orte d.
9. 2. 3.
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 st u dies i n or der t o e ns ure t he safet y of  st u d y p artici pa nts, t o m o nit or q ualit y,  a n d t o 
facilitate pr ocess a n d pr o d uct i m pr o ve me nts.
P ati e nts will be i nstr ucte d t o c o ntact t he i n vesti gat or as s o o n as p ossi ble if he or s he has a 
c o 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
St u d y  dr u g o ver d ose ( m ore t ha n t he s pecifie d n u m ber of i njecti o ns) will be re p orte d as a n A E.  
I n t he e ve nt of o ver d ose, refer t o t he I B f or tirze pati de.
9. 4.
S af et y
9. 4. 1.
El e ctr o c ar di o gr a m s
F or eac h patie nt, E C Gs s h o ul d be c o llecte d acc or di n g t o t he Sc he d ule of Acti vities ( Sectio n 2 ).  
E C G s s h o uld be p erf or me d aft er vit al si g ns are c ollecte d a n d pri or t o t he c o llecti on of bl o o d 
sa m ples f or la b orat or y testi n g if t he patient  is n ot a d versel y affecte d b y t h e fasti n g c o n dit i on .  
P ati e nts s h o uld be s u pi ne f or a p pr o xi matel y  5 t o 1 0 mi n utes bef ore E C G c ollect i on a n d re m ai n 
s u pi ne, b ut a wa ke, d uri n g E C G c ollecti on .  El ectr ocar dio gr a m s s h o uld be rec or de d acc or di n g t o 
t he st u d y-s pecific rec o m me n dati o ns.  
Electr ocar di o gra ms will i nit iall y be i nter prete d b y a q ualifie d p h ysicia n (t he i n vesti gat or or 
q ualifie d desi g nee) at t he site as s o o n after t he ti me of E C G c ollecti o n as p ossi ble, a n d i deall y  
w hile t he pati e nt is still prese nt, f or i m me diate patie nt ma na ge me nt, s h o ul d a n y cli nicall y 

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 5 5
L Y 3 2 9 8 1 7 6
r ele va nt fi n di n gs be i de ntifie d.  A n y cli nicall y si g nifica nt fi n di n gs fr o m E C Gs t hat res ult i n a 
di a g n osis a n d t hat occ ur after t he patie nt recei ves t he first d ose of t he i n vest i gati onal tr eat me nt 
s h o uld be re p orte d t o Lill y or its desi g nee as a n A E via t he e C R F.
All di gital E C Gs will be o btai ne d usi n g ce ntrall y pr o vi de d E C G mac hi nes a n d will be 
ele ctr o nicall y tra ns mitte d t o a desi g nate d ce ntral E C G la b orat or y . T he ce ntral E C G la b orat or y  
wi ll perf or m a basic q uality c o ntr ol c hec k (f or e xa m ple, d e mo gra p hics a n d st u d y  details) a n d 
t he n st ore t he E C Gs i n a data base. At  a f ut ure ti me, t he st ore d E C G data ma y be o verrea d b y a 
car diol o gi st at t he ce ntral E C G la b orat or y for f urt her e val uat i on of m ac hi ne-rea d meas ure me nts 
or t o m eet re g ulat or y r e q uire me nts. T he m ac hi ne-rea d E C G i nter vals a n d heart rate ma y be use d 
f or data a nal ysis a n d re p ort writ i n g p ur p oses, u nless a car di ol o gist o verrea di n g of t he E C Gs is 
c o n d ucte d prior t o c o m plet i on of t he fi n al st u d y re p ort (i n w hic h case, t he o verrea d data w o ul d 
be use d).
9. 4. 2.
Vit al Si g n s
Vi t al si g n meas ure me nts s h o uld be ta ke n bef ore o btai ni n g a n E C G traci n g a n d bef ore c ollect i on 
of  blo o d s a m pl es f or l a b orat or y testi n g, at visits w here re q uire d.  T he participa nt s h o ul d si t 
q ui et l y f or 5 mi n utes bef ore vital si g n meas ure me nts are ta ke n.  F o r eac h patie nt, vital si g n 
meas ure me nts s h o ul d be c o n d ucte d acc or di n g t o t he Sc he d ule of Act i vities ( Sectio n 2 ) a n d 
f oll owi n g t he st u d y -s pecific rec o m me n dati o ns.
A n y cli nicall y  sig nifica nt fi n di n gs fr o m vital si g n meas ure me nt s t hat res ult i n a dia g n osis a n d 
t hat occ ur after t he patie nt recei ves t he first d ose of st u d y tr e at me nt s h o uld 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. 3.
L a b or at or y T e st s
F or eac h patie nt, lab orat or y  tests 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 ). 
W ith t he e xce pti o n o f lab orat or y  test res ults t hat ma y u n bli n d t he st u d y, Lill y or i ts desig nee will  
pr o vi de t he i n vest i gat or wit h t he res ults of la b orat or y tests a nal yze d b y a ce ntral ve n d or if a 
ce ntral ve n d or i s use d f or t he cli nical trial.  
A n y cli nicall y  sig nifica nt fi n di n gs fr o m la b orat or y tests t hat res ult i n a dia g n osis a n d t hat occ ur 
after t he pati e nt recei ves t he first d ose of 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. 4.
I m m u n o g e ni cit y A s s e s s m e nt s 
W here l ocal re g ulati ons a n d E R Bs all o w, bl o o d sa m ples f or i m m u n o ge nicit y testi n g will be 
c ollecte d t o deter mi ne a nt i b o d y pr o d uctio n a gai nst tirze pati de as s pecifie d i n t he Sc he d ule of 
Act i vities ( Secti o n 2 ).
At  t he visits a n d ti mes s pecifie d i n t he Sc he d ule of Acti vities ( Sectio n 2 ), ve n o us bl o o d sa m ples 
will be c o llecte d t o deter mi ne a nti b o d y pr o d uctio n a gai nst tirze pati de.  T o int er pret t he res ults of 
i m m u n o ge nicity,  a P K sa m ple will be c ollecte d at t he sa me t i me p oi nts as t he i m m u n o ge nicit y 
sa m ple.  All sa m ples f or i m m u n o ge nicity s h o uld be ta ke n bef or e d ose w he n a p plica ble a n d 

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 5 6
L Y 3 2 9 8 1 7 6
p ossi ble.  I n t he e ve nt of dr u g h y perse nsi tivi t y r e a ctio ns (i m me diate or n o n i m me diate), 
a d ditio nal  sa m ples will be c ollecte d (i ncl u di n g A D A, P K, a n d e x pl orat or y im m u ne safet y 
sa m ple) as cl ose t o t he o nset of t he e ve nt as p ossi ble, at t he res oluti o n of  t he e ve nt, a n d 3 0 da ys 
f oll owi n g t he o nset of t he e ve nt.  I nstr ucti o ns f or t he c o llecti 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.  Sa m ple c o llecte d at Visit 8 0 1 will assess i m m u n o ge nicity at 
was h o ut of tirze pati de ( 5 half-li ves p ost e n d of treat me nt).
Treat me nt -e mer ge nt A D As are defi ne d i n Sect i on 1 0. 3. 6 .
S a m ples wi t h tirze pati de A D A detecte d will be titere d a n d e val uate d f or t heir a bilit y t o ne utralize 
t he acti vit y of  assi g ne d treat me nt (tirze patid e -ne utralizi n g a nt i b odies).  Sa m ples wi t h tirze pati de 
A D A detecte d will als o be teste d f or cr oss -reacti ve bi n di n g t o nati ve GI P a n d G L P-1, a n d, if 
s uc h is detecte d, t he n f or ne utralizi n g a nti b o dies a gai nst nati ve GI P a n d G L P- 1.
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 patie nt visit or f or a s h orter 
p eri o d if l ocal  re g ulati ons a n d E R Bs all o w at a facilit y selecte d b y t he s p o ns or.  T he d uratio 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. 4. 5.
S af et y M o nit ori n g 
Lill y will peri o dicall y  re vie w e v ol vi n g a g gre gate safety data wi t hi n t he st u d y b y a p pr o priate 
met h o ds.   T he st u d y t e a m will re vie w safety re p orts i n a bli n de d fas hi on acc or di n g t o t he 
sc he d ule pr o vi de d i n t he Trial-Le vel Safet y Re vie w pla n. Lill y will als o re vie w S A Es wit hi n 
ti me fra mes ma n date d b y c o mpa n y pr oce d ures. T he Lill y C R P will, as a p pr o priate, c o ns u lt wit h 
t he f u nct i onall y i n de pe n de nt Gl o bal Pat ient  Safety t hera pe utic area p h ysicia n or cli nical scie nt ist.
9. 4. 5. 1.
H e p ati c S af et y M o nit ori n g
If a st u d y pati e nt e x perie nces ele vate d A L T ≥3 X U L N, A L P ≥2 X U L N, or el e vate d T B L ≥2 X
U L N, li ver testi n g ( 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 B L, direct bilir u bi n , ga m ma -gl uta m yl  tra nsferase, a n d creat i ne ki nase t o c o nfir m t he 
ab n or m alit y a n d t o deter mi ne if it is i ncreasi n g or decreasi n g.  If 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 a n d i n 
c o ns ultati o n wit h t he st u d y  me dical m o nit or. M o nit ori n g of A L T, A S T, T B L , a n d A L P s h o ul d 
c o nti n ue u ntil le vels n or malize or ret ur n t o a p pr o xi mate baseli ne le vels.
He p atic S afet y D at a C ollecti o n
A d dit i onal safety data s h o ul d be c o llecte d via t he e C R F if 1 or m ore of t he f oll owi n g c o n di tio ns 
occ ur: 

E le vati on of ser u m A L T t o ≥5 X U L N o n 2 or m ore c o nsec uti ve bl o o d tests

E le vati on of ser u m T B L t o ≥2 X U L N (e xce pt f or cases of k n o w n Gil bert’s 
s y n dr ome )

E le vati on of ser u m A L P t o ≥2 X U L N o n 2 or m ore c o nsec uti ve bl o o d tests

P atie nt disc o nt i n ue d fr o m treat me nt d ue t o a he patic e ve nt or a b n or m alit y of 
li ver tests

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 5 7
L Y 3 2 9 8 1 7 6

H e patic e ve nt c o nsidere d t o be a n S A E
9. 5.
P h ar m a c o ki n eti c s
P har mac o ki net ic sa m ples will be c ollecte d fr o m all patie nts. Pl as ma tirze pati de c o nce ntratio ns 
will be deter mi ne d fr o m bl o o d sa m ples o btai ne d fr o m patie nts recei vi n g tirze pati de treat me nt.
Bl o o d sa m pl es f or P K assess me nt will be c ollecte d at Wee k 0, 7, 1 5, 2 3, a n d 4 0 of st u d y dr u g
treat me nt per t he St u d y  Sc he d ule or at E T (see Secti o n 2 ).
All patie nts will ha ve a si n gle P K sa m ple c o llecte d f oll owi n g t he fi rst d ose at Wee k 0. T hi s P K 
sa m ple ca n be c ollecte d a n y t i me after t his first d ose o n t he da y of dr u g a d mi nistrati o n.
A d dit i onall y , eac h patient  will be assig ne d via I W R S t o o ne of t he sa m pli n g P K ti me wi n d o ws of 
1 t o 2 4 h o urs, 2 4 t o 9 6 h o urs, or 1 2 0 t o 1 6 8 h o urs p ost d ose at Wee ks 7, 1 5, a n d 2 3 of  st u d y dr u g 
treat me nt per t he St u d y Sc he d ule or at E T (see Secti o n 2 ).  T he P K sa m ple after t he last d ose of  
st u d y dr u g a d mi nistere d at Wee k 3 9 will be c ollecte d at Visit 1 4 ( Wee k 4 0).
T he date a n d ti me of t he m ost rece nt S C i nject i on a d mi nistere d pri or t o c ol lecti n g t he sa m ple 
m ust be rec or de d o n t he e C R F fr o m t he st u d y diaries. T he act ual date a n d ti me at w hic h eac h 
sa m ple was dra w n m ust be rec or de d o n t he la b orat or y re q uisitio n  for m . I nstr ucti o 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 .  
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 c hr o mat o gra p h y  mass 
s pectr o metr y met h o d. Bi o a nal yt ical s a mples c ollecte d t o m eas ure tirze pati de c o nce ntratio ns will 
be retai ne d f or a ma xi m u m o f 1 y e ar fol l owi n g last pati e nt visit for t he st u d y .
Dr u g c o nce ntrati o n i nf or mat i on t hat w o ul d u n bli n d t he st u d y  will not be re p orte d t o i n vest i gati ve 
sites or bli n de d pers o n nel ( u ntil t he st u d y has bee n u n bli n de d).
9. 6.
P h ar m a c o d y n a mi c s
S a m ple s t o assess t he P D pr o perties of tirze pati de are i ncl u de d i n t he efficac y meas ures a n d n ot 
a p plica ble i n t his sect i on.
9. 7.
P h ar m a c o g e n o mi c s
9. 7. 1.
W h ol e Bl o o d S a m pl e ( s) f or P h ar m a c o g e n eti c R e s e ar c h
A w h o le bl o o d sa mple will  be c ollecte d f or p har mac o ge net ic a nal ysis as s pecifie d i n t he 
Sc he d ule of Ac tivit ies ( Sectio n 2 ) w here l ocal re g ulati ons all o w .  
S a m ples will  not 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 res p o nse t o tirze pati de a n d t o 
i n vesti gate ge netic varia nts t h o u g h t 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 u atio n of  A Es or differe nces i n efficac y.  
All sa m ples will be c o de d wit h t he pati e nt n u m ber.  T hese sa m ples a n d a n y data ge ne rate d ca n 
be li n ke d bac k t o t he pati e nt o nl y b y  t he i n vesti gat or site pers o n nel.  

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 5 8
L Y 3 2 9 8 1 7 6
S a m ples will  be retai ne d at a facilit y selecte d b y  Lill y  or its desi g nee f or a ma xi m u m of 1 5 years 
after t he last patie nt visit f or t he st u d y or f or a s h orter peri o d if l o cal re g ulati ons a n d/ or 
E R Bs /I R Bs i m p ose s h orter ti me li mits.  T his rete nti on peri 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 n ot be o bser ve d 
u nt il later i n t he de velo p me nt of tirze pati de or af t er tirze pati de bec o me(s) c o m merciall y 
a vaila ble.
M olec ular tec h n o l ogi es ar e 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 xisti 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 oci at i on st u dies, a n d ca n di date ge ne st u dies.  Re gar dless of 
tec h n ol og y  utilize d, ge n ot y pi n g data ge nerate d will be use d o nl y f or 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
Bi o m ar ker researc h is perf or me d t o a d dress q uesti o ns of rele va nce t o dr u g di s p ositio n, tar get 
e n ga ge me nt, P D , mec ha nis m of acti on, varia bilit y of  patie nt res p o nse (i ncl u di n g safet y), a n d 
cli nical o utc o me.  Sa m ple c o llecti on is i nc or p orate d i nt o cli nical st u dies t o e na ble e xa mi nati on of 
t hese q uest i ons t hr o u g h meas ure me nt of bi o m o lec ules, i ncl u di n g D N A, R N A, pr otei ns, li pi ds, 
a n d ot her cell ular ele me nts.
S er u m  a n d plas ma sa m ples f or bio m ar ker researc h will be c o llecte d at t he ti mes s pecifie d i n t he 
Sc he d ule of Act i vities ( Sectio n 2 ) w here l ocal re g ulat i ons all o w.
S a m ples will  be use d f or researc h o n t he dr u g tar get, disease pr ocess, varia ble res p o nse t o 
tirze pati de, pat h wa ys ass ociate d wit h T 2 D M , mec ha nis m o f actio n of tirze pati de, a n d/ or researc h 
met h o d or i n vali dat i n g dia g n ostic t o ols or assa y(s) relate d t o T 2 D M .  
All sa m ples will be c o de d wit h t he pati e nt 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 pati e nt o nl y b y  t he i n vesti gat or site pers o n nel.  
S a m ples will  be retai ne d at a facilit y selecte d b y  Lill y  or its desi g nee f or a ma xi m u m 1 5 years 
after t he last pati e nt visit f or t he st u d y or f or a s h orter peri o d if l ocal re g ulati ons a n d E R Bs 
i m p ose s h orter ti me li mits.  T his rete nti o n peri o d e na bles use of ne w tec h n ol o gies, res p o nse t o 
re g ulat or y q uestio ns, a n d i n vest i gati on of varia ble res p o nse t hat ma y n ot be o bser ve d u nt il later 
i n t he c o urse of t he de vel o p me nt a n d c o m mercializati o n of b ot h st u d y dr u gs. 
9. 9.
H e alt h E c o n o mi c s
T he f oll owi n g q uest io n nai res will be c o mplete d b y t he pati e nts at s pecific cli nic visit s acc or di n g 
t o t he Sc he d ule of E ve nts ( Secti o n 2 ). At t hese visits, t he q uesti o n naires s h o ul d be c o m p lete d 
bef ore t he patie nt has disc usse d t heir me dical c o n dit i on or pr o gress i n t he st u d y  wit h t he 
i n vesti gat or a n d/ or site staff a n d bef ore a n y ot her st u d y pr oce d ures if t he patient  is n ot a d versel y 
affecte d b y t heir fasti n g c o n diti on.

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 5 9
L Y 3 2 9 8 1 7 6
9. 9. 1.
I m p a ct of W ei g ht o n S elf-P er c e pti o n Q u e sti o n n air e
T he I W -S P q uesti o n naire c o ntai ns 3 ite ms t hat assess h o w ofte n t he patie nts’ b o d y  w eig ht affects 
h o w ha p p y  t he y are wit h t h eir a p peara nce a n d h o w ofte n t he y feel self-c o nsci o us w he n o ut i n 
p u blic ( Ha yes a n d De L ozier 2 0 1 5).  Eac h ite m is rate d o n a 5 -p oi nt scale ra n gi n g fr o m “al wa ys” 
t o “ ne ver.”  T otal sc ores f or t he I W-S P are deri ve d b y  s u m mi n g t he it e m sc ores a nd di vi di n g b y  
t he n u m ber of ite ms.  T he sc ore ca n als o be tra nsf or me d t o a ra n ge fr o m 0 t o 1 0 0.  Hi g her I W -S P 
sc ores c orres p o n d t o better self-perce pt i on ( Ha y es a n d De L ozier 2 0 1 5).
9. 9. 2.
A bilit y t o P erf or m P h y si c al A cti viti e s of D ail y Li vi n g
T he A P P A D L q uest i on naire c o ntai ns 7 ite ms t hat assess h o w diffic ult it is f or patie nts t o e n ga ge 
i n certai n act i vities c o nsi dere d t o be i nte gral t o n or mal dail y life, s uc h as wal ki n g, sta n di n g, a n d 
cli m bi n g stairs ( H a yes et al. 2 0 1 2).  Ite ms are sc ore d o n a 5-p oi nt n u meric r ati n g scale, w here 
5 = “ n o t at all diffic ult” a n d 1 = “ u na ble t o d o.”  A ra w o verall sc ore is calc ulate d b y si m pl y 
s u m mi n g t he sc ores of t he 7 ite ms, a n d a tra nsf or me d o verall sc ore is o btai ne d b y li nearl y 
tra nsf or mi n g t he ra w o verall sc ore t o a 0 t o 1 0 0 scale.  A hi g her ra w o verall sc ore a n d a hi g her 
tra nsf or me d o verall sc ore are i n dicati ve of better a bility t o perf or m acti vities of dail y li vi n g.  
9. 9. 3.
E ur o p e a n Q u alit y of Lif e 
Ge neric h ealt h-r elate d q ualit y of life will be assesse d usi n g t he E Q - 5 D-5 L 
(E ur o Q o L Gr o u p 2 0 1 5).  T he E Q - 5 D-5 L is a sta n dar dize d 5 -ite m instr u me nt f or use as a 
meas ure of healt h o utc o me.  It pr o vi des a si m ple descri pt i ve pr ofile a n d a si n gle i n de x val ue f or 
healt h stat us t hat ca n be use d i n t he cli nical a n d ec o n o mic e val uat i on of healt h care as well as 
p o p ul at i on healt h s ur ve ys.  T he E Q - 5 D-5 L c o m prises 5 di me nsi o ns of healt h ( m o bilit y, self -care, 
us ual act i vities, pai n/ disc omf o rt, a n d a n xiety/ de pressi o n ).  T he 5 L versi on, i ntr o d uce d i n 2 0 0 5, 
sc ores eac h di me nsi on at 5 le vels ( n o pr o ble ms, sli g ht pr o ble ms, mo derate pr o ble ms, se vere 
pr o bl e ms, a n d u na ble t o perf or m/e xtre me pr o ble ms), f or a t otal of 3 1 2 5 p ossi ble healt h states.  I n 
a d ditio n t o t he healt h pr ofile, a si n gle healt h state i n de x val ue ca n be deri ve d base d o n a f or m ula 
t hat attac hes w ei g hts t o eac h of t he le vels i n eac h di me nsi on. T his i n de x val ue ra n ges bet wee n 
less t ha n 0 ( w here 0 is a health state e q ui vale nt t o deat h; ne gati ve val ues are val ue d as w orse 
t ha n dea d) a n d 1 ( perfect healt h).   I n a d diti o n, t he E Q Vis ual A nal o g Scale rec or ds t he 
res p o n de nt’s self-rate d healt h stat us o n a vertical gra d uate d ( 0 t o 1 0 0) vis ual a n alo g scale.  I n 
c o nju nct i on wi t h t he healt h state data, it pr o vides a c o m p osi te pict ure of t he res p o n de nt’s health 
stat us.
T he E Q - 5 D-5 L is use d w orl d wi de a n d is a v aila ble i n m ore t ha n 1 2 0 differe nt la n g ua ges.  Details 
o n t he i nstr u me nt, a n d sc ori n g, or ga nizi n g, a n d prese nti n g t he data c ollecte d ca n be f o u n d i n t he 
E Q - 5 D-5 L User G ui de ( E ur o Q o L Gr o u p 2 0 1 5). 

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 6 0
L Y 3 2 9 8 1 7 6
1 0. St ati sti c al C o n si d er ati o n s
1 0. 1. S a m pl e Si z e D et er mi n ati o n
P ati e nts will be ra n d o mize d i n a 1: 1: 1: 1 rati o t o tirze pati de 5 m g , 1 0 m g, 1 5 m g, or place b o .  
T he tri al is p o were d t o assess s u peri ority of  tirze patide 5 m g, 1 0 m g , or 1 5 m g vers us place b o i n 
parallel relati ve t o mea n c ha n ge fr om baseli ne i n H b A 1c at 4 0 wee ks u n der t he f o ll owi n g 
ass u m pt i ons: 

use of 2 -sa mple t -test t o c o mpare treat m e nt mea ns utilizi n g H b A 1c data c ollecte d bef ore 
i nitiati on of a n y resc ue me dicat i on a n d pre mat ure tre at me nt disc o nt i n uati on ; 

u p t o 2 5 % patie nts i n tirze pati de ar ms a n d u p t o 3 5 % patie nts i n place b o ar m i nitiati n g 
a n y resc ue me dicat i on or pre mat ure treat me n t disc o nti n uati on; 

at least 0. 6 5% ( place b o a dj uste d) mea n re d uctio n i n H b A 1c f or t he ti rze pati de d oses; a n d

a c o m m o n sta n dar d de viat i on ( S D) of 1. 1 %. 
O n t he basis of t hese ass u m pt i ons, ra n d o mizi n g 4 7 2 patie nts usi n g a 1: 1: 1: 1 ra n d o mizat i on rati o 
t o tirze pati de 5 m g ( 1 1 8 patie nts), tirze pati de 1 0 m g ( 1 1 8 patie nts), tirze pati de 1 5 m g ( 1 1 8 
pati e nts), a n d place b o ( 1 1 8 patie nts) will pr o vi de at least 9 0 % p o wer t o esta blis h s u peri orit y for a 
tirze pati de d ose c o mpare d t o pl ace b o at a 2-side d si g nifica nce le vel of 0. 0 1 7 . F urt her m ore, t his 
sa m ple size will e ns ure at least 9 0 % p o wer f or t he H b A 1c s u peri orit y  e val uati on utilizi n g all 
a vaila ble H b A 1c data at 4 0 wee ks wit h missi n g data i m p ute d wit h a c o nser vati ve m ult i ple 
i m p utatio n m et h o d (as descri be d i n t he E fficac y A nal yses [ Sectio n 1 0. 3. 3 ] bel o w ), pr o vi de d t hat 
t he mea n re d ucti o n i n H b A 1c f or t he tirze pati de d oses is at least 0. 6 5% ( place b o a dj uste d) a n d 
S D i ncreases t o n o m ore t ha n 1. 3 % d ue t o t he i ncl usi o n of data o n resc ue me d icati ons, i ncl usi o n 
of  data after pre mat ure treat me nt disc o nt i n uati on, a n d missi n g data i m p utati o n.

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 6 1
L Y 3 2 9 8 1 7 6
1 0. 2. P o p ul ati o n s f or A n al y s e s
F or p ur p oses of a nal ysis, t he f oll o wi n g a nal ysis sets are defi ne d i n Ta ble G P G K . 4.
T a bl e G P G K . 4.
D e s cri pti o n of A n al y si s P o p ul ati o n a n d D at a S et s
A n al ysis Set
Descri pti o n
Scree ne d patie nts
All partici pa nts w h o si g n i nf or me d c o nse nt
Ra n d o mize d patie nts
All patie nts w h o are ra n d o ml y assi g ne d a treat me nt ar m
m o difie d i nte nt -t o-treat ( mI T T) 
p o p ulati o n
All ra n d o ml y assi g ne d partici pa nts w h o are e x p ose d t o at least 1 d ose of st u d y 
dr u g.  I n t he e ve nt of a treat me nt err or, partici pa nts will be a nal yze d acc or di n g 
t o t he treat me nt t he y were ra n d o mize d.
Efficac y a nal ysis set ( E A S)
Data o btai ne d d uri n g St u d y Peri o d II fr o m t he mI T T p o p ulati o n , e xcl u di n g 
data after i nitiati n g resc ue a nti h y per gl yce mic me dicati o n or st o p pi n g st u d y 
dr u g.
F ull a nal ysis set ( F A S)  
Data o btai ne d d uri n g St u d y Peri o d II fr o m t he mI T T p o p ulati o n , re gar dless of 
a d here nce t o st u d y dr u g or i nitiati o n of resc ue a nti h y per gl yce mic me dicati o n
Safet y a nal ysis set ( S S)
Data o btai ne d d uri n g St u d y Peri o d II or III fr o m t he mI T T p o p ulati o n , 
re gar dless of a d here nce t o st u d y dr u g or i nitiati o n of resc ue a nti h y per gl yce mic 
me dicati o n.
1 0. 3. St ati sti c al A n al y s e s
1 0. 3. 1. G e n er al St ati sti c al C o n si d er ati o n s
Stati stical a nal ysis of t his st u d y will be t he res p o nsi bilit y of Lill y o r its desig nee.   A n y c ha n ge t o 
t he data anal ysis met h o ds descri be d i n t he pr ot oc ol will re q uire a n a me n d me nt O N L Y if it 
c ha n ges a pri nci pal feat ure of t he pr ot oc ol.  A n y ot her c ha n ge t o t he data a nal ysis met h o ds 
descri be d i n t he pr ot oc ol, a n d t he j ust ificati on f or ma ki n g t he c ha n ge, will be descri be d i n t he
statistical a nal ysis pla n ( S A P) or t he cli nical st u d y re p ort.  A d ditio nal  e x plor at or y  a nal yses of t he 
data ma y be c o n d ucte d as dee me d a p pr o priate.
U nless ot her wise n ote d, all tests of treat me nt effects will be c o n d ucte d at a 2 -si de d al p ha le vel of  
0. 0 5, a n d t he c o nfi de nce i nter val will be calc ulate d at 9 5 %, 2 -side d.  I n stati stical s u m maries a n d 
a nal yses, patie nts will be a nal yze d as ra n d o mize d.
T here will be 2 esti ma n ds o f i nterest i n c o m pari n g efficac y o f tirze patid e d oses wi t h pl ace b o .  
Fi rst esti ma n d, t he “efficac y” esti ma n d, re prese nts efficac y pri or t o disc o nt i n uati on of st u d y  dr u g 
wi t ho ut c o nf o u n di n g effects of a nt i h y per gl yce mic resc ue t hera p y.  Sec o n d esti ma n d, t he 
“t reat me nt -re gi me n” esti ma n d, re prese nts t he efficac y irres pecti ve of a d here nce t o st u d y dr u g or 
i nitiati on of resc ue a nti dia betic dr u gs.
T he pri mar y  efficac y assess me nt, g uide d b y t he “efficac y” est i ma n d, will be c o n d ucte d usi n g t he 
efficac y a nal ysis set ( E A S).  T he pri mar y efficac y assess me nt, g uide d b y  t he 
“t reat me nt -re gi me n” est i ma n d, will be c o n d ucte d usi n g t he f ull a nal ysis set.  As t he y are 
i nte n de d f or differe nt p ur p oses, n o m ult i plicity a dj ust me nts will be ma de f or c o n d ucti n g 2 
pri mar y  efficac y assess me nts r elat i ve t o efficac y a n d treat me nt-re gi me n esti ma n ds.

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 6 2
L Y 3 2 9 8 1 7 6
U nless s pec ifie d ot her wise, safety assess me nts will be g ui de d b y a n esti ma n d c om par i n g safet y 
of  tirze pati de d oses wi t h place b o irres pecti ve of a d here nce t o st u d y dr u g or i nitiati on of 
a nt i h y per gl yce mic resc ue t hera p y.  T h us, safet y a nal ysis will be c o n d ucte d usi n g t he safety 
a nal ysis set ( S S ).  Selecte d safet y a nal yses ma y be c o n d ucte d after e xcl u di n g data o n resc ue 
t hera p y or data after starti n g a n ot her a nti h y per gl yce mic me dicat i on.
S u m mar y  statistics f or c o nti n u o us meas ures will in cl u de sa m ple size, mea n, S D, me dia n, 
mi ni m u m, a n d ma xi m u m.  T he a nal ysis m o del t o ma ke c o m par is o ns a m on g treat me nt gr o u ps 
r elat i ve t o c o nti n u o us meas ure me nts assesse d o ver ti me will be a mi xe d m o del f or re peate d 
meas ures ( M M R M) wit h ter ms: 

treat me nt, 

visit,

treat me nt - b y-visit i nteracti o n, 

c o u ntr y, 

a n y past pri or use ( yes or n o) of a n y or al a nti dia betic me dicati on,

b aseli ne H b A 1c cate g or y [ ≤8. 5 % ( ≤6 9 m m o l/ m ol) or > 8. 5 % ( > 6 9 m m o l/ m ol)], 

a n d baseli ne meas ure me nt as a c o variate.  
F or a nal yses wi t h H b A 1c, t he baseli ne H b A 1c cate g or y will not be i ncl u de d i n t he m o d el . A n 
u nstr uct ure d c o varia nce str uct ure will m o del t he relat i ons hi p of wit hi n -pat ient  err ors.
T he Ka pla n -Meier m et h o d will be use d f or esti mati o n of c u m ulati ve e ve nt -free s ur vi val rates 
o ver ti me, a n d c o x pr o p orti o nal hazar ds re gressi o n a nal ysis will be use d t o c o m pare hazar d rates 
a mo n g treat m e nts.
S u m mar y  statistics f or cate g orical meas ures (i ncl u di n g cate g orize d c o nti n u o us meas ures) will 
i ncl u de sa m ple size, fre q ue nc y, a n d perce nta ges. Fis her’s e xact test will be use d t o e xa mi ne t he 
treat me nt differe nce i n cate g orical o utc o mes.  L o gistic re gressio n ma y  be use d t o e xa mi ne t he 
treat me nt differe nce i n bi nar y efficac y o utc o mes.  T he ne gati ve bi n o mial re gressi o n m o d el  will 
be use d f or t he tr eat me nt c o m paris o n of discrete c o u nt meas ures if dee me d a p pr o priate.
Ot her stati stical met h o ds ma y be use d, as a p pr o priate, a n d details will be d oc u me nte d i n t he 
S A P.
1 0. 3. 2. Tr e at m e nt Gr o u p C o m p ar a bilit y
1 0. 3. 2. 1. P ati e nt Di s p o siti o n
Fre q ue nc y c o u nts a n d perce nta ges of all pat ient s scree ne d, ra n d omize d, a n d recei vi n g at least 1 
d ose of st u d y  dr u g will be prese nte d b y tr e at me nt gr o u ps.  A list i n g of ra n d omize d patie nts n ot 
recei vi n g st u d y dr u g will be pr o vi de d.  Of t he patie nts i n t he mI T T set, fre q ue nc y, c o u nts, a n d 
perce nt a ges of pat ient s c o mpleti n g t he st u d y ; pre mat urel y  disc o nti n ui n g t he st u d y i ncl u di n g t he 
reas o n f or pre mat ure disc o nti n uati on ; a n d pr e m at urel y disc o nti n ui n g st u d y dr u g i ncl u di n g t he 
reas o n f or pre mat ure disc o nti n uati on of  st u d y dr u g will be prese nte d b y tr eat me nt gr o u ps.  A 
Ka pla n -Meier a nal yse s of time fr o m ra n d omizat i on t o pre m at ure disc o nti n uati on fr om st u d y a n d 
pr e m at ure disc o nti n uatio n f r o m st u d y dr u g b y treat me nt gr o u p will be pr o vi de d.

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 6 3
L Y 3 2 9 8 1 7 6
1 0. 3. 2. 2. P ati e nt C h ar a ct eri sti c s
D e m o gra p hics, me dical hist or y , a n d c o nc o mit a nt ill ness will be s u m marize d b y treat me nt gr o u p 
usi n g t he mI T T set.
1 0. 3. 2. 3. C o n c o mit a nt T h er a p y 
C o nc o mita nt me dicat i ons will be s u m marize d b y  a nat o mical t hera pe utic c he mical classificati on 
a n d treat me nt gr o u p usi n g t he mI T T p o p ul atio n .  I n partic ular, t he ti me t o i nitiati on of  resc ue 
t hera p y for se vere, persi ste nt h yper gl yce mia will be a nal yze d a n d s u m marize d .  
1 0. 3. 2. 4. Tr e at m e nt C o m pli a n c e
Treat me nt c o m plia nce f or eac h visit i nter val is defi ne d as ta ki n g at least 7 5 % of re q uire d 
i njecti ons o f st u d y dr u gs.  Fre q ue nc y c o u nts a n d perce nta ges of pat ient s c o mplia nt t o st u d y  dr u g 
will be s u m marize d b y  tr e at me nt ar ms usi n g t he mI T T p o p ulat i on . 
1 0. 3. 3. Effi c a c y A n al y s e s
1 0. 3. 3. 1. Pri m ar y A n al y s e s
As i n dicate d i n Secti o n 1 0. 3. 1 , t here will be 2 pri mar y efficac y a nal yses c o n d ucte d t o esta blis h 
s u periori t y of  tirze pati de 5 m g, a n d/ or 1 0 m g , a n d/ or 1 5 m g t o place b o relati ve t o mea n c ha n ge 
i n H b A 1c val ues fr om baseli ne t o t he 4 0-wee k visit.
F or t he F D A a n d p ossi bl y ot her re g ulat or y  a ge ncies, t he pri mar y efficac y a nal ysis will be g ui de d 
b y t he “treat me nt -re gi me n” esti ma n d defi ne d i n Secti o n 1 0. 3. 1 .  T his assess me nt will a nal yze 
c ha n ge i n H b A 1c val ues fr om baseli ne o btai ne d at t he 4 0 -wee k visit usi n g a nal ysis o f c o varia nce 
wi t h t er ms:

treat me nt, 

c o u ntr y, 

a n y past pri or use ( yes or n o) of a n y or al a nti dia betic me dicat i on , a n d

baseli ne H b A 1c as a c o variat e.  
Missi n g c ha n ge i n H b A 1 c val ues fr o m baseli ne val ues at t he 4 0 -wee k visit will be i m p ute d base d 
o n o bser ve d c ha n ges i n H b A 1c fr o m baseli ne val ues at t he visit fr o m pat ient s i n t he sa me 
treat me nt gr o u p w h o ha d t heir efficac y assesse d after earl y disc o nti n uati on of st u d y  dr u g a n d/ or 
i nitiati on of resc ue a nti h y per gl yce mic me dicat i on.  A nal ysis will be c o n d ucte d wit h m ult i ple 
i m p utatio ns, a n d statistical i nfere nce o ver m ult i ple i m p utati o ns will be g ui de d b y t he met ho d 
pr o p ose d b y  R u bi n ( 1 9 8 7).
F or t he P har mace uticals a n d Me dical De vices A ge nc y ( P M D A), t he pri mar y efficac y assess me nt 
will be g ui de d b y  t he “efficac y” esti ma n d, wit h c o ntr olli n g o verall fa mil y-wise t y pe 1 err or rate 
at a 2-si de d al p ha of 0. 0 5 o nl y f or pri mar y  e n d p oi nt e val uati on t hat ti rze patide Q W  is s u perior t o 
pl ace b o i n H b A 1c c ha n ge fr o m baseli ne t o 4 0 wee ks.
A d dit i onal details will be pr o vi de d i n t he 
S A P.
F or all ot her p ur p oses, t he pri mar y efficac y  a nal ysis will be g ui de d b y t he “efficac y” est i ma n d 
defi ne d i n Sect i on 1 0. 3. 1 .  T his assess me nt will be c o n d ucte d usi n g E A S.  T he pri mar y a nal ysis 
m o d el  for H b A 1c m eas ure me nts o ver ti me will be a M M R M.  T he res p o nse varia ble o f M M R M 

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 6 4
L Y 3 2 9 8 1 7 6
will be c ha n ge i n H b A 1c val ues fr om baseli ne o btai ne d at eac h sc he d ule d p ost baseli ne visit.  T he 
i n de pe n de nt varia bles of t he M M R M m o del are treat me nt, visit, a n d treat me nt- b y-visit 
i nteract i on, c o u ntr y , a n y p ast pri or use ( y es or n o) of a n y oral a nt i dia betic me dicat i on as fi xe d 
effects, a n d baseli ne H b A 1c as a c o variate.
Si nce t he y  are i nte n de d f or differe nt p ur p oses, eac h of t he 2 pri mar y efficac y assess me nts 
r elat i ve t o efficac y a n d treat me nt re gi me n esti ma n ds will be c o n d ucte d at a fa mil y -wise t y pe 1 
err or rate of 0. 0 5.  A d dit i onal details, i ncl u di n g a nal ysis met h o ds f or ke y  sec o n dar y e n d p oi nts 
a n d a strate g y for c o ntr olli n g t he o verall fa mil y -wise t y pe 1 err or rate at a n al p ha of 0. 0 5 f or 
pri mar y  a n d ke y sec o n dar y e n d p o i nt e val uati on will be pr o vi de d i n t he S A P.
1 0. 3. 3. 2. S e c o n d ar y A n al y s e s
T he sec o n dar y  st u d y o bject i ves s u bject t o t ype 1 err or rate c o ntr ol are as f oll o ws:

S u peri ori t y of  tirze pati de d ose (s) t o place b o relati ve t o mea n c ha n ge i n b o d y wei g ht 
fr om baseli ne t o t he 4 0 -wee k visit

S u peri ori t y of  tirze pati de d ose (s) t o place b o relati ve t o pr o p orti o n of patient s ac hie vi n g 
t he tar get val ue of H b A 1c < 7 % ( <5 3 m m o l/ m ol) at t he 4 0 -wee k visit

S u peri ori t y of  tirze patide d ose (s) t o place b o relati ve t o mea n c ha n ge i n F S G (ce ntral 
la b orat or y) at t he 4 0-wee k visit

S u peri ori t y of  tirze pati de d ose(s) t o place b o relati ve t o pr o p orti o n of pat ient s ac hie vi n g 
t he tar get val ue of H b A 1c < 5. 7 % ( < 3 9 m m o l/ m ol)  at t he 4 0-wee k visi t
T he t y pe 1 err or -c o nt r olle d strate g y f or t he pri mar y a n d sec o n dar y e n d p oi nts will be descri be d i n 
t he S A P.  All t y pe I err or -c o ntr olle d sec o n dar y efficac y a nal yses will be c o n d ucte d relati ve t o 
b ot h esti ma n ds, t he “efficac y” est i ma n d a n d t he “treat me nt-re gi me n” esti ma n d se paratel y.
A nal ysis of c ha n ge fr o m b aseli ne i n b o d y wei g ht a n d F S G at t he 4 0- wee k visit will be c o n d ucte d 
i n a ma n ner si milar t o t he pri mar y efficac y a nal yses wit h baseli ne H b A 1 C cate g or y  [ ≤8. 5 % ( ≤6 9 
m m o l/ m ol) or > 8. 5 % ( >6 9 m m o l/ m ol)] a d de d i n t he m o del, a n d baseli ne of  t he c orres p o n di n g 
varia ble as a c o variate . T he M M R M a nal yses were descri be d i n S ect i on 1 0. 3. 1 . 
C o m paris o ns a m o n g treat m e nts relati ve t o t he pr o p orti o n of patie nts ac hie vi n g t he H b A 1c tar get 
val ue of  < 7. 0 % (< 5 3 m m o l/ m ol) a n d < 5. 7 % ( < 3 9 m m o l/ m ol) at t he 4 0-wee k visit will be 
c o n d ucte d usi n g a l o gistic re gressi o n a nal ysis wit h ter ms : treat me nt , c o u ntr y, a n d baseline 
H b A 1c as a c o variate.  I n t he a nal ysis of pat ient s ac hie vi n g t he H b A 1c tar get val ue relat i ve t o t he 
“efficac y” est i ma n d, patie nts wi t h missi n g val ues at t he 4 0-wee k visit will be e xcl u de d.  I n t he 
a nal ysis of pat ient s ac hie vi n g t he H b A 1c tar get val ue relati ve t o t he “treat me nt-re gi me n” 
esti ma n d, missi n g val ues at t he 4 0 -wee k visit will be i m p ute d base d o n o bser ve d data at 
res pecti ve visits fr o m patient s i n t he sa me treat me nt gr o u p w h o ha d t heir efficac y assesse d after 
earl y disc o nti n uati on of st u d y  dr u g a n d/ or i nit iati on of resc ue me dicat i on.  T he a nal ysis will be 
c o n d ucte d wit h m ult i ple i m p utati o ns a n d statistical i nfere nce o ver m ult i ple i m p utati o ns will be 
g ui de d b y  t he met h o d pr o p ose d b y R u bi n ( 1 9 8 7).

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 6 5
L Y 3 2 9 8 1 7 6
1 0. 3. 3. 3. T erti ar y/ E x pl or at or y A n al y s e s
All e x plor at or y  efficac y a nal yses will be g ui de d b y t he “efficac y” esti ma n d a n d will be 
c o n d ucte d usi n g t he E A S.  Details will be pr o vi de d i n t he S A P.
1 0. 3. 4. S af et y A n al y s e s
U nless s pecifie d ot her wise, safet y assess me nts will be g ui de d b y a n esti ma n d c om par i n g safet y 
of  tirze pati de d oses wi t h place b o irres pecti ve of a d here nce t o st u d y dr u g or i nitiati on of resc ue 
t hera p y.  T h us, safety a nal yses will be c o n d ucte d usi n g t he S S.  Selecte d safet y a nal yses ma y be 
c o n d ucte d after e xcl u di n g data o n resc ue t hera p y or data after starti n g a n ot h er a nt i h y per gl yce mic 
me dicat i on.
A d verse e ve nts will be c o de d fr o m t he act ual ter m usi n g t he Me dical Dict i onar y  for Re g ul at or y 
Act i vities ( Me d D R A) a n d re p orte d wit h preferre d ter ms a n d s yste m or ga n class.  Selected
n ota bl e A Es of i nterest ma y be re p orte d u si n g hi g h-level ter ms or Sta n dar dize d Me d D R A 
Q ueri es.  S u m mar y statistics will be pr o vi de d f or i nci de nce of T E A Es, S A Es, st u d y 
di sc o nti n uati on d ue t o A Es, st u d y  dr u g disc o nti n uatio n d ue t o A Es, deat hs, a n d ot her C V 
e n d p o i nts.  C o u nts a n d pr o p orti o ns of pat ient s e x p erie nci n g A Es will be re p orte d f or eac h 
treat me nt gr o u p, a n d Fis her’s e xact test will be use d t o c o m pare t he treat me nt gr o u ps.
1 0. 3. 4. 1. H y p o gl y c e mi c E v e nt s
I nci de nce of d oc u me nte d s y m pt o matic h y p o gl yce mia e ve nts a n d se vere h y p o gl yce mia will be
s u m marize d a n d c o m pare d bet wee n tirze pati de d oses a n d place b o . Rate of  h y p o gl yce mic 
e pis o des will be a nal yze d usi n g a ge neralize d li near mi xe d -effects mo d el  ass u mi n g ne gati ve 
bi n o mial distri b ut i on f or h yp o gl yce mic e pis o des if data warra nt. S o me a nal ys es ma y be 
c o n d ucte d e xcl u di n g data after i ntr o d uci n g a n ot her a nti h y per gl yce mic t hera p y.
1 0. 3. 4. 2. G a str oi nt e sti n al E v e nt s
S u m maries a n d a nal yses f or i nci de nce a n d se verit y of na usea, v o mit i n g, a n d diarr hea will be 
pr o vi de d b y eac h treat me nt.
1 0. 3. 4. 3. A dj u di c at e d C ar di o v a s c ul ar E v e nt s
List i n gs of deat hs, m y ocar dial i nfarct i ons, str o kes, a n d h os pitalizat i on f or u nsta ble a n gi na 
c o nfir me d b y a n i n de pe n de nt C E C will be pr o vi de d.  T he e ve nt, first d ose a n d last d ose of st u d y 
dr u g, a n d ti me fr o m ra n d omizat i on t o t he e ve n t will be liste d.
1 0. 3. 4. 4. C e ntr al L a b or at or y M e a s ur e s, Vit al Si g n s, a n d El e ctr o c ar di o gr a m s
V al ues a n d c ha n ge fr o m baseli ne t o p ost baseli ne val ues of ce ntral la b orat or y  meas ures, vital 
sig ns, a n d selecte d E C G para meters will be s u m marize d at eac h sc he d ule d visit.  T he a nal ysis 
m o d el  t o ma ke c o m par is o ns a m on g treat me nt gr o u ps relat i ve t o c o nti n u o us c ha n ge fr om baseli ne 
val ues assesse d o ver ti me will be a n M M R M si milar t o t he pri mar y  efficac y a nal ysis a n d wit h 
baseli ne meas ure me nt as a c o variate.  A n u nstr uct ure d c o va ria nce str uct ure will m o del 
r elat i ons hi p of wit hi n -pat ient  err ors.
T he perce nta ges of pat ient s wit h T E a b n or mal, hi g h, or l o w la b orat or y  meas ures at a n y ti me will 
be s u m marize d a n d c o m pare d bet wee n treat me nt gr o u ps b y  usi n g Fis her’s e xact test.  A T E 
a b n or mal val ue i s defi ne d as a c ha n ge fr o m n or mal val ue at base li ne t o a val ue greater t ha n t he 

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 6 6
L Y 3 2 9 8 1 7 6
hi g h li mit at a n y  ti me d uri n g St u d y  Perio ds I I a n d III.  A T E l ow res ult is defi ne d as a c ha n ge 
fr om a value greater t ha n or e q ual t o t he l o w li mit at baseli ne t o a val ue less t ha n t he l o w li mit at 
a n y ti me d uri n g St u d y  P eri o ds II a n d III.   T he hi g h a n d l o w li mit s will be pr o vi de d i n t he S A P.
1 0. 3. 5. P h ar m a c o ki n eti c/ P h ar m a c o d y n a mi c A n al y s e s
Ti rze patid e c o nce ntrati o n data will be a nal yze d usi n g a p o p ulat i on P K a p pr oac h via n o n li near
mi xe d -effects mo deli n g wi t h t he N O N M E M s oft ware. T he relati o ns hi ps bet wee n tirze pati de
d ose a n d/ or c o nce ntrati o n a n d efficac y , t olera bilit y, a n d safety e n d p o i nts will be c haracterize d.  
A d dit i onall y , t he i m pact of i ntri nsic a n d e xtri nsic patie nt fact ors s uc h as a ge, wei g ht, ge n der, a n d
re nal f u ncti on o n P K a n d/ or P D para meters ma y be e xa mi ne d as nee de d. If A D A titers are 
detecte d fr o m i m m u n o ge nicit y testi n g, t he n t he i m pact of i m m u n o ge nicity tit ers o n tirze pati de
P K or a n y  r ele va nt P D para met ers ma y als o be e xa mi ne d.
1 0. 3. 6. 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 patie nts wit h pree xist i n g A D A, wit h T E A D A, a n d wit h 
ne utralizi n g T E A D A t o tirze pati de will be ta b ulate d b y tirze pati de d ose . Treat me nt -e mer ge nt 
A D As are defi ne d as t h ose wit h a ti t 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 ut i on 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 ut i 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 
(treat me nt-b o oste d A D A).  F or t he pati e nts wit h T E A D A , t he distri b utio n of  ma xi m u m titers 
will be descri be d.  T he fre q ue nc y of ne utralizi n g a nt i b o dies t o tirze pati de a n d/ or cr oss-reacti ve 
a n d ne utralizi n g a nt i b o dies t o e n d o ge n o us c o un ter parts will be ta b ulate d i n pat ient s wit h T E 
A D A .
T he relat i ons hi p bet wee n t he prese nce of a nt i b o dies a n d tirze patid e P K a n d P D res p o nse
i ncl u di n g safety a n d efficac y t o tirze patid e ma y be assesse d.
1 0. 3. 7. Ot h er A n al y s e s
1 0. 3. 7. 1. H e alt h E c o n o mi c s
A nal yses of act ual a n d c ha n ge fr o m baseli ne i n patie nt -re p orte d o utc o me ( P R O) sc ores will be 
c o n d ucte d usi n g li near mo d el s wit h baseli ne P R O sc ores, treat me nt, a n d ot her fact ors t hat ma y 
be c o nsi dere d rele va nt.  T hese varia bles will be s pecifie d i n t he S A P.
1 0. 3. 7. 2. S u b gr o u p A n al y s e s
S u b gr o u p a nal yses of mea n c ha n ge i n H b A 1c val ues fr o m baseli ne t o Visit 1 4 will be pr o vi de d 
b y

a ge, 

race,

et h nicit y,  

ge n der, 

d urati o n of  dia betes, a n d

baseli ne H b A 1c [( ≤8. 5 % ( ≤6 9 m m o l/ m ol) a n d > 8. 5 % ( > 6 9 m m o l/ m ol)].

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 6 7
L Y 3 2 9 8 1 7 6
1 0. 3. 8. I nt eri m A n al y s e s
N o i nt eri m a nal yses of efficac y are pla n ne d f or t his st u d y.  If a n u n pla n ne d i nteri m a nal ysis is 
dee m e d necessar y, t he a p pr o priate Lill y me dical direct or, or desi g nee, will be c o ns ulte d t o 
deter mi ne w het her it is necessar y  t o a me n d t he pr ot oc ol ( o nl y for u n pla n ne d efficac y  re vie w).

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 6 8
L Y 3 2 9 8 1 7 6
1 1. R ef er e n c e s
[ A D A] A merica n Dia betes Ass ociati on. 3 3. C o m pre he nsi ve Me dical E val uat i on a n d 
Assess me nt of C o m or bi dit ies: sta n dar ds of me dical Care i n dia betes 2 0 1 7. Di a betes C are.
2 0 1 7; 4 0(s u p pl 1): S 2 5 -S 3 2 .
[ A D A] A merica n Dia betes Ass ociat i on. 6. Gl yce mic tar gets: sta n dards of m e dical Care i n 
d iabetes — 2 0 1 8 . Di a betes C are . 2 0 1 8; 4 1(s u p pl 1): S 5 5-S 6 4.
Al bert i K G, Zi m met P Z. Defi nit i on, di a g n osis a n d classificat i on of dia betes mellit us a n d its 
c o mplicat i ons. Part 1: dia g n osis a n d classificat i on of dia betes mellit us pr o visi o nal re p ort of a 
W H O c o ns ultati o n. Di a bet Me d. 1 9 9 8; 1 5( 7): 5 3 9 -5 5 3.
Ar o da V R, Rat ner R. T he safet y a n d t olera bilit y of G L P -1 rece pt or a g o nists i n t he treat me nt of 
t ype 2 di a betes: a re vie w. Di a betes Met a b Res Rev 2 0 1 1 ;2 7( 6): 5 2 8 - 5 4 2.
As mar M, Si m o nse n L, As mar A, H olst JJ, Dela F, B ul o w J. I ns uli n pla ys a per missi ve r ole f or 
t he vas oacti ve effect of GI P re g ulati n g a di p ose tiss ue meta b o lis m i n h u ma ns. J Cli n 
E n d ocri n ol Met a b 2 0 1 6; 1 0 1: 3 1 5 5 - 3 1 6 2.
Ba n ks P A, Free ma n M L. Practice g ui deli nes i n ac ute pa ncreatitis. A m J G astr oe nter ol.
2 0 0 6; 1 0 1( 1 0): 2 3 7 9 - 2 4 0 0.
C os k u n T, Sl o o p K W, L o g hi n C, Alsi na -Fer na n dez J, Ur va S, B o k vist K B, C ui X, Briere D A, 
Ca brera O, R oell W C, K uc hi b h ot la U, M o yers J S, Be ns o n C T, Gi me n o R E, D’ Alessi o D A, 
Ha u pt A. L Y 3 2 9 8 1 7 6 , a n o vel d ual GI P a n d G L P-1 rece pt or a g o nist f or t h e treat me nt of t ype 2 
di a betes mellit us: fr o m disc o ver y t o cli nical pr o of of c o nce pt. M olec ul ar Met a b . 2 0 1 8; 1 8: 3- 1 4.
Da n ne T, P hil ot he o u A, G ol d ma n D, G u o X, Pi n g L, Cali A, J o h nst o n P. A ra n d o mize d trial
c o mpari n g t he rate of h y p o gl yce mia – assesse d usi n g c o nti n u o us gl uc ose m o nit ori n g – i n 1 2 5 
presc h o ol c hil dre n wit h t y pe 1 dia betes treate d wit h i ns uli n glar gi ne or N P H i ns uli n (t he
P R E S C H O O L st u d y ). Pe di atr Di a betes . 2 0 1 3; 1 4( 8): 5 9 3-6 0 1. 
Da vies MJ, D ’Alessi o D A, Fra d ki n J, Ker na n W N , Mat hi e u C, Mi n gr o ne G, R ossi n g P, Tsa pas 
A, We xler DJ, B use J B. Ma na ge me nt of h y per gl yce mia i n ty pe 2 d iabetes, 2 0 1 8. A co nse ns us 
re p ort b y t he A merica n Dia betes Ass ociati on ( A D A) 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 ( E A S D). Di a betes C are . 2 0 1 8; 4 1( 1 2): 2 6 6 9-2 7 0 1.
E ur o Q o L Gr o u p. E Q - 5 D-5 L User g ui de: basic i nf o r mat i on o n h o w t o use t he E Q - 5 D-5 L 
i nstr u me nt. Versio n 2. 1. A vaila ble at: htt ps://e ur o q ol. or g/ w p -c o nt e nt/ u pl oa ds/ 2 0 1 6/ 0 9/ E Q - 5 D-
5 L _ User G ui de _ 2 0 1 5. p df. P u blis he d A pril 2 0 1 5. Accesse d A u g ust 0 6, 2 0 1 8.
Fr ias J P, Na uc k M A, Va n J, K ut ner M E, C ui X, Be ns o n C, Ur va S, Gi me n o R E, Milice vic Z, 
R o bi ns D , Ha u pt A . Efficac y a n d safet y of  L Y 3 2 9 8 1 7 6, a n o vel d ual GI P a n d G L P-1 rece pt or 
a g o nist, i n pat ient s wit h t ype 2 di a betes: a ra n d o mise d, place b o -c o ntr olle d a n d act i ve 
c o mp ar at or -c o nt r olle d p hase 2 trial. L a ncet. 2 0 1 8; 3 9 2( 1 0 1 6 0): 2 1 8 0 -2 1 9 3.
H a y es R P, De L ozier A M. Relia bilit y,  vali dity, a n d res p o nsi ve ness o f t he I mpact of  Wei g ht o n 
Self -Perce pt i ons Q uesti o n naire (I W -S P) i n i n di vi d uals wit h t y pe 2 dia betes a n d o besit y.  
Di a betes Tec h n ol T her . 2 0 1 5; 1 7( 3): 2 1 0-2 1 4.
H a y es R P, Nels o n D R, Mel da hl M L, C urtis B H. A bilit y t o perf or m dail y p h ysical a cti vities i n 
i n di vi d uals with t y pe 2 di a betes a n d mo derate o besit y: a preli mi nar y vali dati o n o f t he I mp a ct 

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 6 9
L Y 3 2 9 8 1 7 6
of  W eig ht o n Acti vit ies of Dail y Li vi n g Q uesti on nai re. Di a betes Tec h n ol T her . 
2 0 1 1; 1 3( 7): 7 0 5 - 7 1 2.
H a y es R P, Sc h ultz E M, Nae geli AN, C urti s B H. Test-retest, res p o nsi ve ness, a n d mi ni mal 
i m p orta nt c ha n ge of t he a bilit y t o perf or m p h y sical acti vities of dail y li vi n g q uesti on naire i n 
i n di vi d uals with t y pe 2 di a betes a n d o besit y.  Di a betes Tec h n ol T her . 2 0 1 2; 1 4( 1 2): 1 1 1 8-1 1 2 5.
I nz ucc hi S E, Ber ge nstal R M, B use J B, Dia ma nt M, Ferra n ni ni E, Na uc k M, Peters A L, Tsa pas 
A, We n der R, Matt he ws D R. Ma na ge me nt of h y per gl yce mia i n t y pe 2 dia betes, 2 0 1 5: a 
pati e nt -ce ntere d a p pr oac h: u p date t o a p osit i on state m e nt of t he A merica n Dia betes 
Ass oci at 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 5; 3 8( 1): 1 4 0 - 1 4 9.
K o iz umi M, Ta ka da T, Ka wara da Y, Hirata K, Ma y u mi T, Y os hi da M, Se ki m ot o M, Hir ota M, 
Ki m ura Y, Ta ke da K, Isaji S, Ots u ki M, Mats u n o S; J P N. J P N G ui deli nes f or t he ma na ge me nt 
of  ac ute pa ncreatitis: dia g n ostic criteria f or ac ute pa ncreatitis. J He p at o bili ary P a ncre at S u r g.
2 0 0 6; 1 3( 1): 2 5 - 3 2.
Na uc k M. I ncreti n t hera pies: hi g hli g ht i n g c o m m on feat ures a n d differe nces i n t he m o des of 
actio n of  gl uca g o n-li ke pe pti de-1 a g o nists a n d di pe pti d yl pe pti dase -4 i n hi bit ors. Di a betes 
O bes Met a b. 2 0 1 6; 1 8( 3): 2 0 3 -2 1 6.
Na uc k M A, Meier JJ. I ncret i n h or m o nes: their r ole i n healt h a n d disease. Di a betes O bes Met a b.
2 0 1 8: 2 0( su p pl 1): 5 - 2 1.
Na uc k M A, Meier JJ, Sc h mi dt W E. I ncreti n -base d gl uc ose -l oweri n g me dicat i ons a n d t he ris k o f 
ac urte pa ncreatit is a n/ or pa ncreatic ca ncer: reass uri n g data fr o m car di o -vasc ular o utc o m e 
trials. Di a betes O bes Met a b . 2 0 1 7; 1 9( 9): 1 3 2 7-1 3 2 8.
R u bi n D B. M ulti ple Im p ut ati o n f or N o nres p o nse i n S urveys . Ne w Y or k: J o h n Wile y & S o ns I nc.; 
1 9 8 7.
Stei n ber g W M, B use J B, G h or ba ni M L M, Ørste d D D , Na uc k M A; L E A D E R Steeri n g 
C o m mittee; L E A D E R Tri al I n vest i gat ors. A m ylase, li pase, a n d ac ute pa ncreatitis i n pe o ple 
wi t h t ype 2 dia betes treate d wit h lira gl ut i de: res ults fr o m t he L E A D E R ra n d o mize d trial. 
Di a betes C are. 2 0 1 7a; 4 0( 7): 9 6 6 - 9 7 2.
Stei n ber g W M, R ose nst oc k J, Wa d d e n T A, D o ns mar k M, Je nse n C B, De Vries J H. I m pact of 
lira glut i de o n a m ylase, li pase, a n d ac ute pa ncreatitis i n partici pa nts wit h o ver weig ht/ o besi t y 
a n d n or m o gl yce mia, pre dia betes, or t ype 2 di a betes: sec o n dar y a nal yses of p o ole d data fr o m 
t he S C A L E cli nical de vel o p me nt pr o gra m . Di a betes C are. 2 0 1 7 b; 4 0( 7): 8 3 9 - 8 4 8.
Wei n ber g M E, Bacc hetti P, R us ha k off RJ. Fre q ue nt l y re peate d gluc ose m eas ure me nts 
o veresti mate t he i nci de nce of i n patie nt h y p o gl yce mia a n d se vere h y per gl yce mia. J Di a betes 
Sci Tec h n ol . 2 0 1 0; 4( 3): 5 7 7- 5 8 2.

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 7 0
L Y 3 2 9 8 1 7 6
1 2.
A p p e n di c e s

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 7 1
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 
patie nt 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 d verse e ve nt 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 o varia nce
A P P A D L
A bilit y t o Perf or m P h ysical Acti vities of Dail y Li vi n g
A S T
as partate a mi n otra nsferase
B G
bl o o d gl uc ose
bli n di n g/ m a s ki n g
A d o u ble -bli n d st u d y is o ne i n w hi c h neit her t he patie nt n or a n y of t he i n vesti gat or or 
s p o ns or staff w h o are i n v ol ve d i n t he treat me nt or cli nical e valuati o n of t he patie nts are 
a ware of t he treat me nt recei ve d.
B M I
b o d y mass i n de x
C E C
cli nical e n d p oi nt c o m mittee
C H F
c o n gesti ve heart fail ure
c o m pl ai nt
A c o m plai nt is a n y writte n, electr o nic, or oral c o m m u nicati o n t hat alle ges deficie ncies 
relate d t o t he i de ntit y, q ualit y, p urit y, d ura bilit y, relia bilit y, safet y or effecti ve ness, or 
perf or ma nce of a dr u g or dr u g deli ver y s yste m.
c o m pli a n c e
A d here nce t o all st u d y -relate d g o o d cli nical practice ( G C P) a n d a p plica ble re g ulat or y 
re q uire me nts.
C O VI D -1 9
C or o na vir us Disease 2 0 1 9
C R P
cli nical researc h p h ysicia n: I n di vi d ual res p o nsi ble f or t he me dical c o n d uct of t he st u d y.  
Res p o nsi bilities of t he C R P ma y be perf or me d b y a p h ysicia n, cli nical researc h 
scie ntist, gl o bal safet y p h ysicia n or ot her me dical officer.
C T
c o m p ute d t o m o gra p h y

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 7 2
L Y 3 2 9 8 1 7 6
C V
car di o vasc ular
D P P - 4
di pe pti d y l pe pti dase- 4
E A S
efficac y a nal ysis set
E C G
electr ocar di o gra m
e C R F
electr o nic case re p ort f or m
e nr oll
T he act of assi g ni n g a patie nt t o a treat me nt.  Patie nts w h o are e nr olle d i n t he st u d y are 
t h ose w h o ha ve bee n assi g ne d t o a treat me nt.
E Q -5 D -5 L
E ur o pea n Q ualit y of Life -Di me nsi o ns
E R B
et hical re vie w b oar d
E T
earl y ter mi nati o n
F B G
fasti n g bl o o d gl uc ose
F S G
fasti n g ser u m gl uc ose
F S H
f ollicle-sti m ulati n g h or m o ne
GI
gastr oi ntesti nal
GI P
gl uc ose -de pe n de nt i ns uli n otr o pic p ol y pe pti de
G L P - 1
gl uca g o n -li ke pe pti de- 1
H b A 1 c
he m o gl o bi n A 1c
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 nf or m e d c o n s e nt
A pr ocess b y w h ic h a patie nt v ol u ntaril y c o nfir ms his or her willi n g ness t o partici pate 
i n a partic ular st u d y, after ha vi n g bee n i nf or me d of all as pects of t he st u d y t hat are 
rele va nt t o t he patie nt’s decisi o n t o partici pate.  I nf or me d c o nse nt is d oc u me nte d b y 
mea ns of a writte n, si g ne d, a n d date d i nf or me d c o nse nt f or m.
i n 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 trial, i ncl u di n g pr o d ucts alrea d y o n t he mar ket w he n use d or
asse m ble d (f or m ulate d or pac ka ge d) i n a wa y differe nt fr o m t he a ut h orize d f or m, or 
mar kete d pr o d ucts use d f or a n u na ut h orize d i n dicati o n, or mar kete d pr o d ucts use d t o 
gai n f urt her i nf or mati o n a b o ut t he a ut h orize d f or m.
I T T
i nte nt t o treat:  T he pri nci ple t hat asserts t hat t he effect of a treat me nt p olic y ca n be best 
assesse d b y e val uati n g o n t he ba sis of t he i nte nt t o treat a patie nt (t hat is, t he pla n ne d 
treat me nt re gi me n) rat her t ha n t he act ual treat me nt gi ve n.  It has t he c o nse q ue nce t hat 
patie nts all o cate d t o a treat me nt gr o u p s h o ul d be f oll o we d u p, assesse d, a n d a nal yze d as 
me m bers of t hat gr o u p irres pecti ve of t heir c o m plia nce t o t he pla n ne d c o urse of 
treat me nt.

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 7 3
L Y 3 2 9 8 1 7 6
I W R S
i nteracti ve we b-res p o nse s yste m
I W-S P
I m pact of Wei g ht o n Self-Perce pti o n
M e d D R A
Me dical Dicti o nar y f or Re g ulat or y Acti vities
M E N 2
m ulti ple e n d ocri ne ne o plasia t y pe 2
mI T T
m o difie d i nte nt -t o-treat
M M R M
mi xe d m o del f or re peate d meas ures
M RI
ma g netic res o na nce i ma gi n g
M T C
me d ullar y t h yr oi d carci n o ma
N A F L D
n o nalc o h olic fatt y li ver disease
O A M
or al a nti h yper gl y ce mic me dicati o ns 
O T C
o ver t he c o u nter
p- a m yl a s e
pa ncreatic a m ylase
P G
plas ma gl uc ose
P K/ P D
p har mac o ki netics/ p har mac o d y na mics
P R O/ e P R O
patie nt -re p orte d o utc o mes/electr o nic patie nt-re p orte d o utc o mes
Q W
o nce wee kl y
S A D
si n gle asce n di n g d ose
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
S A R S -C o V - 2
se vere ac ute res pirat or y s y n dr o me c or o na vir us 2
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 D
sta n dar d de viati o n
S D P
si n gle-d ose pe n
S M B G
self-m o nit ori n g of bl o o d gl uc ose
S S
safet y a nal ysis set
S U S A R s
s us pecte d u ne x pecte d seri o us a d verse reacti o ns

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 7 4
L Y 3 2 9 8 1 7 6
T 1 D M
t ype 1 dia betes mellit us
T 2 D M
t ype 2 dia betes mellit us
T B L
t otal bilir u bi n le vel
T E A E
Treat me nt -e mer ge nt a d verse e ve nt:  A n u nt o war d me dical occ urre nce t hat e mer ges 
d uri n g a defi ne d treat me nt peri o d, ha vi n g bee n a bse nt pretreat me nt, or w orse ns relati ve 
t o t he pretreat me nt state, a n d d oes n ot necessaril y ha ve t o ha ve a ca usal relati o ns hi p 
wit h t his treat me nt.
U L N
u p per li mit of n or mal

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 7 5
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 
Cli nic al L a b or at or y Te stsa
He m at ol o g y
Cli nic al C he mistr y
He m o gl o bi n
Ser u m C o nce ntr ati o ns of
He mat ocrit
S o di u m
Er y t hr oc yte c o u nt (R B C )
Mea n cell v ol u me
P otassi u m
Bicar b o nate
Mea n cell he m o gl o bi n c o nce ntrati o n
T otal bilir u bi n
Le u k oc ytes ( W B C)
Direct bilir u bi n
Ne utr o p hils, se g me nte d
Al kali ne p h os p hatase
L y m p h oc y t es
Ala ni ne a mi n otra nsferase ( A L T)
M o n oc ytes
As partate a mi n otra nsferase ( A S T)
E osi n o p hils
Bl o o d urea nitr o ge n ( B U N)
Bas o p hils
Creati ni ne
Platelets
Ur ic aci d
Calci u m
Gl uc ose , fasti n gb
Uri n al ysis
Al b u mi n
Creati ni ne
Pre g n a nc y Test (fe males o nl y)c
F ollicle -sti m ulati n g h or m o ne ( F S H) d
Estra di ol c
H b A 1c
E n d ocri ne
e G F R (calc ulate d b y C K D-E PI e q uati o n) e
Fasti n g plas ma gl uca g o n
Fasti n g ser u m Ins uli n
Calcit o ni n
Fasti n g C- pe pti de
I m m u n o ge nicit y
Tirze pati de a nti-dr u g a nti b o d y
P K sa m ple f or i m m u n o ge nicit y
P a ncre as (e x ocri ne)
Ser u m pa ncreatic a m ylase
Ser u m li pase
N o n p h ar m ac o ge netic St ore d S a m ples
E D T A plas ma
Ser u m
P 8 0 0 plas ma
P h ar m ac o ge netic St ore d S a m ples
S a m ples f or P h ar m ac o ki netic A n a l ysis
Li pi d P a nel (f asti n g)
T otal c h olester ol
L D L
H D L
V L D L
Tri gl yceri d es
A b bre viati o ns :  C K D -E PI = C hr o nic Ki d ne y Disease -E pi de mi ol o g y; E D T A = et h yle ne dia mi netetraacetic aci d; 
e G F R = esti mate d gl o mer ular filtrati o n rate; H b A 1c = he m o gl o bi n A 1c; H D L = hi g h -de nsit y li p o pr otei n; 
L D L = l o w-de nsit y  li p o pr otei n; R B C = re d bl o o d cells; V L D L = ver y l o w -de nsit y  li p o pr otei n; W B C = w h ite 
bl o o d cells.

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 7 6
L Y 3 2 9 8 1 7 6
a
All tests will be perf or me d b y a Lill y -desi g nate d ce ntral la b orat or y, u nless ot her wise n ote d .
b
Gl uc ose as part of t he c he mistr y pa nel at Visit 1 ca n be c ollecte d irres pecti ve of t h e fasti n g stat us of t he patie nt.
c     Ser u m pre g na nc y test will be perf or me d b y ce ntral la b orat or y at Visit 1 f or w o me n of c hil d beari n g p ote ntial.  A 
l ocal uri ne pre g na nc y test m ust be perf or me d at Visit 3 wit h t he res ult a vaila ble pri or t o ra n d o mizati o n a n d first 
i njecti o n of st u d y dr u g(s) f or wo me n of c hil d beari n g p ote ntial o nl y.  A d diti o nal pre g na nc y tests will be perf or me d at 
Visits 7, 1 2, a n d 1 4. Pr e g na nc y tests ma y be perf or me d at t he i n vesti gat or’s discreti o n d uri n g t he st u d y.  If re q uire d 
per l ocal re g ulati o ns a n d/ or i nstit uti o nal g ui d eli nes, pre g na nc y testi n g ca n als o occ ur at ot her ti mes d uri n g t he st u d y 
treat me nt peri o d
d
F ollicle -sti m ulati n g h or m o ne test perf or me d at Visit 1 f or p ost me n o pa usal w o me n at least 4 5 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, a n d w h o ha ve ha d s p o nta ne o us a me n orr hea f or m ore t ha n 6 m o nt hs a n d 
less t ha n 1 2 m o nt hs a n d estra di ol le vels c o nsiste nt wit h a p ost me n o pa usal state ( F S H ≥4 0 mI U/ m L a n d estra di ol 
< 3 0 p g/ m L).
e
Esti mate d gl o mer ular filtrati o n rate will be calc ulate d b y t he ce ntral la b ora t or y a n d i ncl u de d i n la bor at or y res ult 
re p orts.

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 7 7
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 C o n si d er ati o n s

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 7 8
L Y 3 2 9 8 1 7 6
A p p e n di x 3. 1 . 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 n cl u di n g t h e 
I nf or m e d C o n s e nt Pr o c e s s
A p p e n di x 3. 1. 1 .
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 pati e nt 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 partici pat i n g i n t he st u d y, a n d t hat t heir partici pat i on is 
v o l 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 pati e nt 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 nf or me d c o nse nt f or m (I C F) pri or t o t he perf or ma nce o f 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 gat i onal pr o d uct.

a ns weri n g a n y q uest i ons t he pati e nt  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 
pati e nt ’s willi n g ness t o c o nti n ue his or her partici pati o n i n t he st u d y.

e ns uri n g t hat a c o p y of t he I C F is pr o vide d t o t he partici pa nt or t he 
part ici pa nt’s le gal re prese ntati ve a n d is ke pt o n file.

e ns uri n g t hat t he me dical rec or d i ncl u des a state me nt t hat writte n i nf or me d 
c o nse nt was o btai ne d bef ore t he partici pa nt was e nr olle d i n t he st u d y  a n d t he 
date t he writte n c o nse nt was o btai ne d. T he a ut h or ize d pers o n o btai ni n g t he 
i nf or me d c o nse nt must al s o sig n t he I C F.
A p p e n di x 3. 1. 2 .
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 uitme nt  strate g y for pati e nts.  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.
A p p e n di x 3. 1. 3.
Et hi c al R e vi e w
T he i n vest i gat or (or a n a p pr o pri ate lo c al  re prese ntati ve) m u st gi ve ass ura nce t hat t he et hical 
re vie w b oar d ( E R 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 H ar mo nisat i on (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  E R B a p pr o val of t he pr ot oc ol a n d t he I C F m u st 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 vestigati ve si te(s).  Lill y or its re prese ntati ves m ust a p pr o ve t he I C F, 
i ncl u di n g a n y c ha n ges ma de b y t he E R Bs, bef ore it is use d at t he i n vesti gati ve site(s).  All I C Fs 
m ust be c o m plia nt wi t h t he I C H g uideli ne o n G o o d Cli nical Pract ice (G C P ).
T he st u d y  site’s E R 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 pr ot oc ol a n d relate d a me n d me nts a n d a d de n da , c urre nt I n vesti gat or 
Br oc h ure ( 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 nf or me d c o nse nt f or m 

ot her rele va nt d oc u m e nts ( f or e xa m ple, c urric ula vit a e, a d vertise me nts)

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 7 9
L Y 3 2 9 8 1 7 6
A p p e n di x 3. 1. 4.
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 t he

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 Declarat i on of Helsi n ki a n d C o u ncil f or I nter nati o nal Or ga nizati o ns of
Me dical
Scie nces (CI O M S ) I nter natio nal Et hi cal G uideli nes

a p plica ble I C H G C P g ui deli nes

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 .
A p p e n di x 3. 1 . 5.
I n v e sti g at or I nf or m ati o n
P h ysicia ns wit h a s pecialt y i n dia betes/e n d ocri n ol o g y , i nter nal me dici ne, fa mil y me dici ne, 
ge neral me dici ne , or a n y  ot her s pecialt y p h ysicia n w h o have e x perie nce tre at i n g T 2 D M a n d 
cli nical researc h i n T 2 D M will partici pate as i n vesti gat ors i n t his cli nical st u d y.
A p p e n di x 3. 1. 6.
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, t he 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.
A p p e n di x 3 . 1.7.
Fi n al R e p ort Si g n at ur e
T he C li nical S t u d y Re p ort ( C S R) c o or di nat i n g i n vesti gat or will si g n t he fi nal C S R 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.
A q ualifie d i n vest i gat or will ser ve as t he C S R c o or di nati 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 nct i on, a n ot her i n vest i gat or will be c h ose n b y Lill y t o ser ve as t he C S R 
c o or di nat i n g i n vesti gat or.
T he s p o ns or’s res p o nsi ble me dical o fficer a n d statisticia n will  a p pr o ve t he fi nal C S R 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.
A p p e n di x 3. 2.
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 s p o ns or start-u p trai ni n g t o i nstr uct t he i n vesti 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 pleti on 
of  t he C R Fs, a n d st u d y pr oce d ures.

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 8 0
L Y 3 2 9 8 1 7 6

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, tel e p h o ne, a n d/ or f a x

re vie w a n d verif y  data re p orte d t o detect p ote ntial err ors 
I n a d diti on, Lill y or its re prese ntati ves will peri o dicall y c hec k a sa m ple of t he patie nt 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 or its
re prese ntati ves a n d/ or re g ulat or y a ge ncies at a n y ti me.  I n vesti gat ors will be gi ve n n otice bef ore 
a n a u dit occ urs.
T 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 vesti 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 E R Bs wit h direct access t o ori gi nal s o urce 
d oc u m e nts.
A p p e n di x 3. 2. 1.
D at a C a pt ur e S y st e m
T he i n vest i gat or is res p o nsi ble f or e ns uri n g t he acc urac y, c om p lete ness, le gi bility,  a n d ti meli ness 
of  t he data re p orte d t o t he s p o ns or.
A n electr o nic data ca pt ure s y st e m ( E D C) will be use d i n t his st u d y for t he c ollect i on of C R F 
data.  T he i n vesti gat or mai ntai ns a se parate s o urce f or t he data e ntere d b y  t he i n vesti gat or or 
desi g nee i nt o t he s p o ns or -pr o vi de d E D C s yste m.  T he i n vest i gat or is res p o nsi ble f or t he 
i de ntificati on of a n y data t o be c o nsi dere d s o urce a n d f or t he c o nfir mat i on t hat data re p orte d are 
acc urate a n d c o m plete b y si g ni n g t he C R F.
A d dit i onall y , clinical  o ut c o me assess me nt data (scales, self-re p orte d diar y data) will be c ollecte d 
b y t he patie nt/i n vesti gat or site pers o n nel, via a pa per s o urce d oc u me nt , a n d will be tra nscri be d 
b y t he i n vesti gat or site pers o n nel i nt o t he E D C s yste m.
Data c ollecte d via t he s p o ns or -pr o vi de d data ca pt ure s yste m (s) will be st ore d at t hir d parties. 
T he i n vest i gat or will ha ve c o nti n u o us access t o t he data d uri n g t he st u d y a n d u ntil 
dec o m missi o ni n g of t he data ca pt ure s y st e ms.  Prior t o dec o m missi o ni n g, t he i n vest i gat or will 
recei ve a n arc hi val c o p y of perti ne nt data f or rete nti o n.
Data m a na ge d b y a ce ntral ve n d or, s uc h as la b orat or y test data, will be st ore d electr o nicall y in 
t he ce ntral ve n d or’s data base s yste m, a n d electr o nic tra nsfers will be pr o vi de d t o t he i n vest i gat or 
for re vie w a n d rete nt i on.  Data will s u bse q ue ntl y be tra nsferre d fr o m t he ce ntral ve n d or t o t he 
Lill y data ware h o use.
Data fr o m c o m p lai nt f or ms s u b mitte d t o Lill y will be e nc o de d a n d st ore d i n t he gl o bal pr o d uct 
c o mplai nt m a na ge me nt s yst e m.
A p p e n di x 3. 3.
S t u d y a n d Sit e Cl o s ur e
A p p e n di x 3. 3. 1.
Di s c o nti n u ati o n of St u d y Sit e s

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 8 1
L Y 3 2 9 8 1 7 6
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 E R 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.
A p p e n di x 3. 3. 2.
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 i ts desig 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 a p plica ble la ws, re g ulati ons, a n d G C P.
A p p e n di x 3. 4.
P u bli c ati o n P oli c y
T h e p u blicat i on p o lic y f or St u d y I 8 R-M C -G P G K is descri be d i n t he Cli nical Trial A gree me nt.

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 8 2
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 p atie nts i n c o ns ultat i o n wit h t he Lill y, or its desig nee, cli nical 
researc h p hysicia n.
He p atic M o nit ori n g Tests
He p atic h e 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 m e
W B C
Pr ot hr o m bi n ti m e, 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 cor e 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
Direct bilir u bi n
He patitis E a nti b o d y, I g M
Al kali ne p h os p hatase
A L T
A nti -n ucle ar a nti b o d y a
A S T
G G T
Al k ali ne p h os p h at ase is oe nz y mesa
C P K
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 pirate a mi n otra nsferase; C P K = creati ni 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 mali z e 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 K( b) Cli ni c al Pr ot o c ol
P a g e 8 3
L Y 3 2 9 8 1 7 6
A p p e n di x 5.
W orl d H e alt h Or g a ni z ati o n 
Cl a s sifi c ati o n of Di a b et e s a n d Di a g n o sti c Crit eri a
T y pe 1 Di a betes:   T y pe 1 di a betes is ju d ge d t o be prese nt w he n t he classical s y m pt o ms of 
di a betes (t hi rst, p ol y uria, wast i n g a n d st u p or, or c o ma) are ass ociate d wit h rea dil y detecta ble 
c o nce ntrati o ns of gl uc ose a n d ket o ne b o dies i n t he bl o o d a n d uri ne.  I ns uli n treat me nt is 
necessar y  not o nl y t o c o ntr ol  h y per gl yce mia b ut als o t o pre ve nt s p o nta ne ous ket osis a n d deat h.
T y pe 2 Di a betes:   T y pe 2 di a betes, alt ho u g h ofte n as y m pt o mat ic, ma y als o prese nt wit h 
classical h y per gl yce mic s y m pt o ms (t hirst, p ol y uria, wei g ht l oss), b ut des pite h y per gl yce mia, 
ket o ne b o di es are prese nt i n o nl y l o w c o nce ntrati o ns i n t he blo o d a n d uri ne.  C o m a is rare i n t yp e 
2 dia betes , b ut m a y r es ult fr o m e xtre me h y per gl yce mia a n d h y per os m o larity; lactic acid osis or 
ket oaci d osis ca n als o occ ur i n f ul mi nat i n g ill ness (f or e xa m ple, se vere i nfecti on or m ese nteric 
arter y t hr o mb osis) d ue t o a n ac ute i ncrease i n i ns uli n re q uire me nts, b ut s p o nta ne o us ket osis d oes 
n ot occ ur.  S o me patie nts wit h t y pe 2 dia betes later pr o gress t o a state of a bs o l ute i ns uli n 
deficie nc y ( Al bert i a n d Zi m met 1 9 9 8). 

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 8 4
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 (if t his is t heir preferre d a n d us ual lifest yle) or i n a sa me-se x relat i ons hi p 
wi t h n o se x ual r el atio ns hi p wi t h males (as part of t heir preferre d a n d us ual lifest yle).  
N ote:  peri o dic a bst i ne nce (f or e xa m ple, c ale n dar, o v ul at i on, s y m pt ot her mal, 
p ost o v ulat i on met h o ds), declarat 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 st u dies
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 wit h 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
Me n, re gar dless of t heir fertilit y stat us, wit h n o n pre g na nt w o me n of c hil d beari n g p ote ntial 
part ners m ust a gree t o eit 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 1 a d ditio nal hi g hl y  effecti ve (less t ha n 1 % failure rate) m et h o d of c o ntrace pti o n 
(s uc h as c om bi nat i on oral  c o ntrace pti ves, i m pla nte d c o ntrace pti ves, or i ntra uteri ne de vice) or 
effect i 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 urati o n of t he st u d y a n d f or at least 3 mo nt hs after t he l ast i njecti 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 ntil t he e n d of est i mate d rele va nt p ote ntial e x p os ure i n w o me n of c hil d beari n g p ote ntial. 
Me n w h o are i n e xcl u si vel y sa me se x relati ons hi ps (as t heir preferre d a n d us ual lifest yle) are n ot 
re q uire d t o use c o ntrace pti o n. 

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 8 5
L Y 3 2 9 8 1 7 6
A p p e n di x 7.
Pr ot o c ol G P G K St a n d ar di z e d 
Pr ot o c ol s f or t h e M e a s ur e m e nt of H ei g ht , W e i g ht, 
a n d W ai st Cir c u mf er e n c e
T he f o ll owi n g i nf or m at i on has bee n a da pte d fr om sta n dar dize d p h ysical meas ure me nt pr ot oc ols 
f or t he W orl d Healt h Or ga nizati o n’s S T E P wise a p pr oac h t o S ur veilla nce ( S T E P S) ( W H O 2 0 0 8) 
(A vaila ble at: htt p:// w w w. w h o.i nt/c h p/ste ps/ Part 3 _ Secti o n 3. p df ) A ccesse d N o ve m ber 0 5 , 2 0 1 8.
Me as uri n g Hei g ht
Ste p 1 .As k t he pati e nt t o re mo ve t heir f o ot wear a n d a n y hea d gear (li g ht hea d gear w or n f or 
reli gi o us reas o ns ca n re mai n, b ut t his s h o ul d be w or n b y t he patie nt at e ver y cli nic visit w he n 
t heir hei g ht is meas ure d).
Ste p 2 .As k t he pati e nt t o sta n d o n t he cali brated hei g ht meas uri n g b oar d (sta di o met er) or a gai nst 
a wall wit h t heir feet t o get her a n d t heir k nees strai g ht wit h t heir heels a gai nst t he bac k b oar d , t he 
sta dio m eter or t he wall.
Ste p 3 .As k t he pati e nt t o lo o k strai g ht a hea d wi t ho ut til tin g t heir hea d u p.
Ste p 4 .As k t he pati e nt t o breat he i n a n d sta n d tall.  If usi n g a sta di o meter or fi xe d meas uri n g 
de vice, m o ve t he de vice’s meas ure me nt ar m ge nt l y d o w n o nt o t he t o p of t he patie nt’s hea d. 
Rec or d t he patie nt’s hei g ht i n ce nt i meters (c m).
Me as uri n g Wei g ht

B o d y wei g ht meas ure me nts s h o ul d be d o ne i n a c o nsiste nt ma n ner usi n g a cali brate d 
ele ctr o nic scale ca pa ble of meas uri n g wei g ht i n kil o gra ms.

All wei g hts f or a gi ve n patie nt s h o ul d be meas ure d usi n g t he sa me scale, w he ne ver p ossi ble, 
at a p pr o xi matel y t he sa me ti me i n t he m or ni n g after e vac uati on of bla d der c o nte nts .  

P ati e nts s h o uld be li g ht l y clot h e d b ut n ot weari n g s h oes w hile t heir wei g ht is meas ure d.
Ste p 1 .As k t he pati e nt t o re mo ve t heir f o ot wear, o uter wear (c oat, jac ket, etc), a n d a n y hea d gear 
(li ght  hea d gear w or n f or reli gi o us reas o ns ca n re mai n, b ut t his s h o ul d be w or n b y  t he patient  at 
e ver y cli nic visit w he n wei g ht is meas ure d).
Ste p 2 .Ma ke s ure t he scale is place d o n a fir m, flat, e ve n s urface ( n ot o n car pet , o n a sl o pi n g 
s urface, or a r o u g h, u ne v e n s urface).
Ste p 3 .As k t he pati e nt t o ste p o nt o t he scale wit h 1 f oot o n eac h si de of t he scale.
Ste p 4 .As k t he pati e nt t o sta n d still wit h ar ms b y si des a n d t he n rec or d wei g ht i n kil o gra ms ( k g) 
t o t he nearest o ne- te nt h k g.
Me as uri n g W aist Circ u mfere nce

Waist circ u mfere nce s h o ul d be meas ure d at mi d p oi nt, bet wee n l o wer mar gi n o f least

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 8 6
L Y 3 2 9 8 1 7 6
p al pa ble ri b a n d t o p of iliac crest (a p pr o xi matel y  1 i nc h ( 2. 5 4 c m) a b o ve t he na vel).

P ati e nts s h o uld be li g ht l y clot h e d.
Ste p 1 . As k t he patie nt t o sta n d wit h t heir feet close t o get her, a n d ar m s at t heir si de wit h t heir
b o d y  wei g ht e ve nl y distri b ute d.
Ste p 2 . As k patie nt t o rela x
Ste p 3 . Meas ure me nts s h o ul d be rec or de d at t he e n d of a n or mal e x pirati on.

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 8 7
L Y 3 2 9 8 1 7 6
A p p e n di x 8.
C h a n g e s t o St u d y  Pr o c e d ur e s d u e t o t h e 
C O VI D -1 9 P a n d e mi c
Se vere ac ute res pirat or y s y n dr o me c or o na vir us 2 (S A R S -C o V - 2), t he vir us t hat ca uses t he n o vel
C O VI D -1 9 pa n de mic , has ca use d n u mer o us gl o bal restricti ons t o be e nacte d t hat ma y i m pact a 
pati e nt’s a bilit y a n d/ or willi n g ness t o atte n d t heir o nsite st u d y  visit as origi nall y  sc he d ule d.  I n 
s uc h a sit uati o n, pl ease f o ll ow t he g ui da nce bel o w:
1)
P ati e nts s h o uld c o m e for t he pri mar y  e nd p oi nt visit ( Visit 1 4) at t he origi nall y pla n ne d 
4 0 - wee k ( ±7 da ys) sc he d ule w he ne ver p ossi ble a n d safe t o d o s o, at t he i n vest i gat or's 
di scretio n.  H o we ver, i n or der t o ma xi mize t he a bilit y f or o nsite visits for Vi sit 1 4, 
mi ni mize missi n g data , a n d preser ve t he i nte n de d c o n d uct of t he st u d y, t he visit wi n d o w 
f or Visit 1 4 ma y be br o u g ht f or war d n o s o o ner t ha n 1 4 da ys ( Wee k 3 8) or e xte n de d u p t o 
2 8 d a y s ( Wee k 4 4).  T he s u bse q ue nt safety f oll ow- u p visit ( Visit 8 0 1) s h o ul d ta ke place 
4 wee ks ± 7 da y s after Visit 1 4.  
2)
F or pati e nts re q uirin g a n e xte nsi o n f or Visit 1 4 u p t o Wee k 4 4, a d diti onal I P will be 
pr o vi de d t o all o w patie nts t o re mai n o n st u d y  dru g u ni nterr u pte d d uri n g t he e xte n de d 
treat me nt perio d, t o e ns ure patie nt safet y, a n d t o mai ntai n t he o verall i nte grit y of  t he trial. 
3)
A d dit i onal c o nse nt fr o m t he patie nt per lo c al  re g ulatio ns will  be o btai ne d f or t h ose 
pati e nts w h o will be dis pe nse d a d dit io nal I P d uri n g t he e xte n de d treat me nt peri o d.
4)
T he sites will nee d t o i de nt if y a n d d oc u me nt t he details of h o w all patient s a n d visits 
were affecte d b y C O VI D -1 9 pa n de mic restrict i ons.

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 8 8
L Y 3 2 9 8 1 7 6
A p p e n di x 9.
Pr ot o c ol A m e n d m e nt I 8 F -M C -G P G K( b)
A R a n d o mi z e d, D o u bl e -bli n d , Pl a c e b o C o ntr oll e d Tri al 
C o m p ari n g t h e Effi c a c y  a n d S af et y of T hr e e Tir z e p ati d e 
D o s e s v er s u s Pl a c e b o i n P ati e nt s wit h T y p e 2 Di a b et e s, 
I n a d e q u at el y C o ntr oll e d wit h Di et a n d E x er ci s e Al o n e
( S U R P AS S - 1)
O v er vi e w
Pr ot oc ol  I 8 F-M C -G P G K ti tle d “A Ra n d o mize d, D o u ble -bli n d, Pl ace b o -C o ntr olle d Trial 
C o m pari n g t he Efficac y a n d Safet y of  T hree Tirze patide D oses vers us Place b o i n Patie nts wit h 
T y pe 2 Di a betes, I na de q uatel y C o ntr olle d wit h Diet a n d E xercise Al one ( S U R P A S S - 1)” 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 ( b) a n d will be use d t o c o n d uct t he 
st u d y in 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 descri be d i n t he 
f oll owi n g ta ble.   

I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 8 9
L Y 3 2 9 8 1 7 6
A m e n d m e nt S u m m ar y f or Pr ot o c ol I 8 F -M C -G P G K A m e n d m e nt ( b)
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
Secti o n 2 Sc he d ule 
of Acti vities
A d de d la n g ua ge t o direct rea der s t o 
A p pe n di x 8 i n case of patie nts w h ose 
partici pati o n i n t his st u d y is affecte d b y 
restricti o ns d ue t o t he C O VI D - 1 9
pa n de mic .
T his e na bles patie nts a n d i n vesti gat ors t o 
a dj ust t he Visit 1 4 wi n d o w a n d t o e ns ure 
patie nt safet y a n d trial i nte grit y.
A p pe n di x 8 . 
C ha n ges t o St u d y 
Pr oce d ures d ue t o 
the C O VI D -1 9 
Pa n de mic 
A n a p pe n di x was a d de d t o pr o vi de 
g ui da nce f or Visit 1 4 o n:
1)
A dj usti n g t he Visit 1 4 wi n d o w t o 
be br o u g ht f or war d n o s o o ner 
t ha n 1 4 da ys ( Wee k 3 8) or 
e xte n de d u p t o 2 8 da ys ( Wee k 
4 4),
2)
A d diti o nal I P dis pe nse d f or Visit 
1 4, a n d
3)
C o nse nt fr o m t he patie nts f or t he 
a d diti o nal I P nee de d f or Visit 1 4 .
T his e na bles patie nts a n d i n vesti gat ors t o 
a dj ust t he ti mi n g of Visit 1 4 ( pri mar y 
e n d p oi nt) a n d t o e ns ure patie nt safet y a n d trial
i nte grit y.

L e o  D o c u m e n t  I D  =  8 8 3 3 f 2 4 f - 6 d a 0 - 4 8 f f - b c 6 4 - c c 8 d 1 2 c c 1 b b 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 5 - A p r - 2 0 2 0  2 0 : 1 6 : 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 5 - A p r - 2 0 2 0  2 2 : 0 4 : 0 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