Randomized, Phase 3, Double-blind Trial Comparing the Effect of the Addition of Tirzepatide Versus Placebo in Patients With Type 2 Diabetes Inadequately Controlled on Insulin Glargine With or Without Metformin
Phase: PHASE3
Conditions: Type 2 Diabetes
Sponsor: Eli Lilly and Company

Pr ot oc ol I 8 F- M C- G P GI( b)
A Ra n d o mize d, P hase 3, D o u ble- bli n d Trial C o m pari n g t he Effect of t he A d diti o n of Tirze pati de 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 o n I ns uli n Glar gi ne Wit h or Wit h o ut 
Metf or mi n 
N C T 0 4 0 3 9 5 0 3    
A p pr o val Date: 2 6-J u n- 2 0 2 0

I 8 F-M C -G P GI( 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 GI ( b)
A R a n d o mi z e d, P h a s e 3 , D o u bl e-bli n d Tri al C o m p ari n g t h e 
Eff e ct of th e A d diti o n of Tir z e p ati d e 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 o n 
I n s uli n Gl ar gi n e w it h or w it h o ut M etf or mi n
( S U R P AS S - 5)
2 0 1 9 -0 0 0 8 6 0 -9 9
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 Y3 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 ut t h e writt e n 
a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s.
Tir z e p ati d e ( L Y3 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 : 0 1 M ar c h 2 0 1 9 .
A m e n d m e nt ( a) El e ct r o ni c all y Si g n e d a n d A p pr o v e d b y Lill y: 3 0 A pril 2 0 2 0.
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: 2 6- J u n- 2 0 2 0 G M T

I 8 F-M C -G P GI( 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 GI( b) A Ra n d o mize d, P hase 3, D o u ble -bli n d Trial 
C o m pari n g t he Effect of t he A d dit i on of Ti rze pati de vers us Place b o 
i n Patient s wit h T ype 2 Di a betes I na de q uatel y C o ntr olle d o n I ns uli n 
Gl ar gi ne wit h or wit ho ut Metf or mi n ( S U R P A S S - 5) ............................................................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 5
3.
I ntr o d ucti o n ......................................................................................................................2 3
3. 1.
St u d y  Ratio n a le............................................................................................................2 3
3. 2.
Bac k gr o u n d ..................................................................................................................2 3
3. 3.
Be nefit/ Ris k Assess me nt ..............................................................................................2 4
4.
O bject i ves a n d E n d p oi nts ..................................................................................................2 5
5.
St u d y  Desi g n.....................................................................................................................2 7
5. 1.
O verall Desi g n .............................................................................................................2 7
5. 2.
N u m ber of P arti ci pa nts ................................................................................................. 3 4
5. 3.
E n d of St u d y  Defi niti on ...............................................................................................3 4
5. 4.
S ci e nt ific Rati o nale f or St u d y Desi g n...........................................................................3 4
5. 5.
J ustificati o n f or D ose ...................................................................................................3 4
6.
St u d y P o p ulat i on ...............................................................................................................3 6
6. 1.
I ncl usi on Cri t eria ..........................................................................................................3 6
6. 2.
E xcl usi o n Cri t eria ........................................................................................................3 8
6. 3.
Lifes t yle Restricti ons ....................................................................................................4 0
6. 4.
Scree n Fail ures .............................................................................................................4 0
7.
Treat me nts ........................................................................................................................4 1
7. 1.
Treat me nts A d mi nistere d .............................................................................................4 1
7. 1. 1.
Ti rze patide D osi n g ...............................................................................................4 1
7. 1. 2.
Pl ace b o D osi n g ....................................................................................................4 1
7. 1. 3.
I ns uli n Glar gi ne D osi n g .......................................................................................4 1
7. 1. 4.
Pac ka gi n g a n d La belli n g ......................................................................................4 3
7. 1. 5.
Me dical De vices ...................................................................................................4 4
7. 2.
Met h o d of Treat me nt Assi g n me nt
................................................................................4 4
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 g......................................................4 4
7. 3.
Bli n di n g .......................................................................................................................4 4
7. 4.
D osa ge M o dificati o n ....................................................................................................4 5

I 8 F-M C -G P GI( 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. 4. 1.
St u d y  Dr u gs.........................................................................................................4 5
7. 4. 2.
Re d ucti o n a n d/ or Disc o nt i n uati on of C o nc o mit a nt 
A nt i h y per gl yce mic Me dicati ons ...........................................................................4 5
7. 5.
Pre parati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y ...............................................................4 6
7. 6.
Treat me nt C o m plia nce ................................................................................................. 4 6
7. 7.
C o nc o mita nt T hera p y ...................................................................................................4 7
7. 7. 1.
Ma na ge me nt of Patie nts wit h Gastr oi ntesti nal S y m pt o ms .....................................4 7
7. 8.
Treat me nt after t he E n d of t he St u d y ............................................................................4 8
8.
Di sc o nti n uatio n Cri t eri a....................................................................................................4 9
8. 1.
D isc o nti n uati o n fr o m St u d y  Treat me nt .........................................................................4 9
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 9
8. 1. 2.
T e m p orar y  Disc o nti n uati on fr om St u d y  Treat me nt ...............................................5 0
8. 1. 3.
Di sc o nti n uatio n of  I na d verte ntl y Enr olle d Patie nts ...............................................5 0
8. 2.
Di sc o nti n uatio n f r o m t he St u d y....................................................................................5 1
8. 3.
L ost t o F oll o w -U p ........................................................................................................5 2
9.
St u d y  Assess me nts a n d Pr oce d ures...................................................................................5 3
9. 1.
Efficac y Assess me nts ...................................................................................................5 3
9. 1. 1.
Pri mar y Efficac y  Assess me nts .............................................................................5 3
9. 1. 2.
Sec o n dar y  Efficac y Assess me nts..........................................................................5 3
9. 1. 3.
E x pl or at or y  Assess me nts a n d Pr oce d ures.............................................................5 3
9. 1. 4.
A p pr o priate ness of Assess me nts ..........................................................................5 4
9. 2.
A d verse E ve nts ............................................................................................................5 4
9. 2. 1.
S eri o us A d verse E ve nts ........................................................................................5 5
9. 2. 1. 1.
S us pecte d U ne x pecte d Seri o us A d verse React i ons ..........................................5 6
9. 2. 2.
A d verse E ve nts of S pecial I nterest .......................................................................5 6
9. 2. 2. 1.
H y p o gl yce mia ................................................................................................5 6
9. 2. 2. 2.
Se vere, Persiste nt H y per gl yce mia ...................................................................5 7
9. 2. 2. 3.
Pa ncreat itis.....................................................................................................5 8
9. 2. 2. 4.
T h y r oid Mali g na ncies a n d C -Cell H y per plasia ................................................5 9
9. 2. 2. 5.
Maj or A d verse Car di o vasc ular E ve nts ............................................................6 0
9. 2. 2. 6.
S u pra ve ntric ular arr y t h mias a n d Car diac C o n d ucti o n 
Di s or ders ........................................................................................................6 0
9. 2. 2. 7.
H y perse nsi tivi t y E ve nts..................................................................................6 0
9. 2. 2. 8.
I njecti on Si te Reactio ns.................................................................................. 6 1
9. 2. 2. 9.
A nt i-Dr u g A nt i b o dies.....................................................................................6 1
9. 2. 2. 1 0.
Di a bet ic Reti n o pat h y C o mplicat i ons ...............................................................6 1
9. 2. 2. 1 1.
He pat o biliar y  Dis or ders..................................................................................6 1
9. 2. 2. 1 2.
Se vere Gastr oi ntesti nal A d verse E ve nts ..........................................................6 1

I 8 F-M C -G P GI( 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. 1 3.
Ac ute Re nal E ve nts ........................................................................................6 1
9. 2. 2. 1 4.
Meta b o lic Aci d osis, I ncl u di n g Dia betic Ket oaci d osis .....................................6 1
9. 2. 2. 1 5.
A m p utati o n/ Peri p heral Re vasc ularizat i on .......................................................6 2
9. 2. 2. 1 6.
Maj or De pressi ve Dis or der/ S uici dal I deati on ..................................................6 2
9. 2. 3.
C o m plai nt Ha n dli n g .............................................................................................6 2
9. 3.
Treat me nt of O ver d ose ................................................................................................. 6 2
9. 4.
S af et y ...........................................................................................................................6 2
9. 4. 1.
Electr ocar di o gra ms ..............................................................................................6 2
9. 4. 2.
Vi t al Si g ns........................................................................................................... 6 3
9. 4. 3.
La b orat or y  Tests..................................................................................................6 3
9. 4. 4.
I mm u n o ge nicit y Assess me nts ..............................................................................6 3
9. 4. 5.
S af et y M o ni t ori n g ................................................................................................6 4
9. 5.
P ha r mac o ki net ics .........................................................................................................6 4
9. 6.
P har mac o d y na mics ......................................................................................................6 5
9. 7.
P har mac o ge n o mics ......................................................................................................6 5
9. 7. 1.
W h o le Bl o o d Sa m ples f or P har mac o ge netic Researc h..........................................6 5
9. 8.
Bi o m ar kers ...................................................................................................................6 5
9. 9.
Heal t h Ec o n o mics........................................................................................................6 6
9. 9. 1.
A bilit y t o Perf or m P h ysical Acti vities of Dail y Li vi n g .........................................6 6
9. 9. 2.
I mpact of Wei g ht o n Self- Perce pt i on Q uest i on naire .............................................6 6
9. 9. 3.
Di a betes Treat me nt Satisfacti o n Q uesti o n n ai re.....................................................6 6
9. 9. 4.
E ur o pea n Q ualit y of  Life......................................................................................6 7
1 0.
Stati stical C o nsi derati o ns ..................................................................................................6 8
1 0. 1.
S a m ple Si ze Deter mi nat i on ..........................................................................................6 8
1 0. 2.
P o p ul at i ons f or A nal yses..............................................................................................6 9
1 0 . 3. Stati stical A nal yses ......................................................................................................6 9
1 0. 3. 1.
Ge neral Statist ical C o nsi derat i ons ........................................................................6 9
1 0. 3. 2.
Treat me nt Gr o u p C o m para bilit y ...........................................................................7 0
1 0. 3. 2. 1.
P ati e nt Dis p ositio n ..........................................................................................7 0
1 0. 3 . 2. 2.
P ati e nt C haracteristics ....................................................................................7 0
1 0. 3. 2. 3.
C o nc o mita nt T hera p y .....................................................................................7 0
1 0. 3. 2. 4.
Treat me nt C o m plia nce ....................................................................................7 1
1 0. 3. 3.
Efficac y A nal yses ................................................................................................7 1
1 0. 3. 3. 1 .
Pri mar y A nal yses ...........................................................................................7 1
1 0. 3. 3. 2.
Sec o n dar y  A nal yses........................................................................................7 2
1 0. 3. 3. 3.
Terti ar y/ E x pl orat or y A nal yses........................................................................7 3
1 0. 3. 4.
S af et y A nal yses ....................................................................................................7 3
1 0. 3. 4. 1.
H y p o gl yce mic E ve nts .....................................................................................7 3

I 8 F-M C -G P GI( 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. 4. 2.
Gastr oi ntesti nal E ve nts ...................................................................................7 3
1 0. 3. 4. 3.
A d j u dicate d Car di o vasc ular E ve nts ................................................................7 3
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 .........................................................................................7 4
1 0. 3. 5.
P har mac o ki net ic/ P har mac o d y na mic A nal yses ......................................................7 4
1 0. 3. 6.
E val uat i on of I m m u n o ge nicit y .............................................................................7 4
1 0. 3. 7.
Ot her A nal yses .....................................................................................................7 5
1 0. 3. 7. 1.
Heal t h Ec o n o mics...........................................................................................7 5
1 0. 3. 7. 2.
S u b gr o u p A nal yses .........................................................................................7 5
1 0. 3. 8.
I nteri m A nal yses ..................................................................................................7 5
1 1.
Refe re nces ........................................................................................................................7 6
1 2.
A p pe n dices .......................................................................................................................7 9

I 8 F-M C -G P GI( 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 GI. 1.
Sc he d ule of Act i vities....................................................................................1 6
Ta ble G P GI. 2.
O bject i ves a n d E n d p oi nts...............................................................................2 5
Ta ble G P GI. 3.
Treat -t o-Tar get Al g ori t h m .............................................................................4 2

I 8 F-M C -G P GI( 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 GI. 1.
Ill ustratio n of  st u d y desi g n f or Cli nical Pr ot oc ol I 8 R-M C -G P GI. ...................2 8

I 8 F-M C -G P GI( 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 ........................................................................8 0
A p pe n di x 2.
Cli nical La b orat or y  Tests...............................................................................8 4
A p pe n di x 3.
St u d y  G o ver na nce C o nsi derati ons ..................................................................8 6
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 ....................9 1
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 ..........................................................................................................9 2
A p pe n di x 6.
Cl assificat i on of C o ntrace pti ve Met h o ds ........................................................9 3
A p pe n di x 7.
Pr ot oc ol  G P GI Sta n dar dize d Pr ot oc ols for t he Meas ure m e nt of H eig ht, 
Wei g ht a n d Waist Circ u mfere nce
..................................................................9 4
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 ......................9 6
A p pe n di x 9.
Pr ot oc ol  A me n d me nt I 8 F-M G -G P GI( b)
A Ra n d o mize d, P hase 3, D o u ble -bli n d Tri al C o mpari n g t he Effect of 
t he A d dit i on of Ti rze patide 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 o n I ns uli n Glar gi ne wit h or wit ho ut 
Metf or mi n ( S U R P A S S - 5)..............................................................................9 7

I 8 F-M C -G P GI( 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, P hase 3, D o u ble -bli n d Tri al C o mpari n g t he Effect of t he A d dit i on of Ti rze pati de
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 o n I ns uli n Glar gi ne 
w ith or w ith o u t Met f or mi n ( S U R P A S S- 5).
R ati o n ale: 
C urre nt i ncret i n- base d i njecta ble treat me nt o pti o ns f or t y pe 2 dia betes mellit us ( T 2 D M) are 
di recte d at a si n gle i ncreti n m o lec ular tar get ( G L P-1 [ gl uca g o n -li ke pe pti de-1]) a n d t heref ore ,
c o uld ha ve t hera pe utic li mitati o ns.  T hese treat me nt o pti o ns offer i m pr o ve d gl yce mic c o ntr ol a n d 
a lo w ri s k of h y p o gl yce mia, a n d ha ve a p ote ntial f or cli nicall y rele va nt wei g ht l oss.  H o we ver, a 
lar ge pr o p orti o n of patie nts still d o n ot reac h t he treat me nt tar gets des pite a hi g h le vel of 
c o mplia nce wi t h t he treat me nt re gi me ns.  T heref ore, it is i m p orta nt t o pr o vi de a d dit i onal 
treat me nt o ptio ns f or pati e nts t hat all o w f or e n ha nce d gluc ose c o ntr ol  a n d wei g ht l oss w hile 
preser vi n g a n o verall acce pta ble be nefit/ris k pr ofile ( Star k Casa gra n de 2 0 1 3; Zaccar di et al. 
2 0 1 6).
Ti rze patide ( L Y 3 2 9 8 1 7 6) is a o nce -wee kl y d ual GI P ( gl uc ose -de pe n de nt i n s uli n otr o pic 
p ol y pe pt i de)/ G L P-1 rece pt or a g o nist .  It is a 3 9-a mi n o aci d s y nt hetic pe pti de wit h a g o nist 
acti vit y 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-a ci d moi et y t hat 
  It is a d mi nistere d 
s u bc uta ne o usl y. 
St u d y  I 8 F-M C -G P GI ( G P GI) will c o m pare tirze pati de ( 3 d oses) t o place b o, a d de d t o titrate d 
o nce -dail y  basal i ns uli n glar gi ne i n patient s wit h T 2 D M pre vi o usl y treate d wit h i ns uli n glar gi ne 
( wit h or wit ho ut m et f or mi n).  T here are n o a vaila ble p u blis he d re p orts o n t he effects of t he 
c o m bi nat i on of basal i ns uli n a n d a l o n g -acti n g, o nce-wee kl y ( Q W) d ual  GI P/ G L P-1 rece pt or 
a g o nist o n bl o o d gl uc ose ( B G) t o date.  T he c o m bi nat i on of i ns uli n glar gi ne wit h tirze pat i de is 
e x pecte d t o pr o vi de i m pr o ve d gl uc ose c o ntr ol a n d atte n uate t he wei g ht gai n a n d h y p o gl yce mi a 
ris k ass o ciate d wit h t he m o re i nte nsi ve titrati o n a n d hi g her dail y  d oses of i ns uli n glar gi ne.
C CI

I8F-MC-GPGI(b) Clinical Protocol
Page 10
LY3298176
Objective(s)/Endpoints:
Objectives
Endpoints
Primary

To demonstrate superiority of QW tirzepatide 
10 mg and/or 15 mg versus placebo when 
added to titrated basal insulin glargine, with or 
without metformin, with respect to glycemic 
control at 40 weeks for:

Mean change in HbA1c from baseline 
Key Secondary (controlled for type 1 error)
Efficacy

To demonstrate superiority of QW tirzepatide
5 mg versus placebo when added to titrated 
basal insulin glargine, with or without 
metformin, with respect to glycemic control at 
40 weeks for:

To demonstrate superiority of QW tirzepatide 
5 mg, 10 mg, and/or 15 mg versus placebo 
when added to titrated basal insulin glargine, 
with or without metformin, at 40 weeks for:

Mean change in HbA1c from baseline

Mean change in body weight from baseline 

Proportion of patients with HbA1c target 
values of <7.0% (53 mmol/mol) 

Mean change in fasting serum glucose (central 
laboratory) from baseline
Additional Secondary (not controlled for type 1 
error)
Efficacy

To compare QW tirzepatide 5 mg, 10 mg, and 
15 mg to placebo at 40 weeks for:

Proportion of patients achieving HbA1c target 
≤6.5% (48 mmol/mol), <5.7% (39 mmol/mol)

Mean change in daily average 7-point 
self-monitored blood glucose profiles from 
baseline

Proportion of patients who achieved weight 
loss of ≥5%, ≥10%, and ≥15% from baseline

Change from baseline in daily mean insulin 
glargine dose

I8F-MC-GPGI(b) Clinical Protocol
Page 11
LY3298176
Objectives
Endpoints
Safety

To compare QW tirzepatide 5 mg, 10 mg, 
and 15 mg to placebo to the end of safety 
follow-up for:

Treatment-emergent adverse events (TEAEs)

Early discontinuation of study drug due to 
adverse events (AEs)

Adjudicated pancreatic AEs

Serum calcitonin

Incidence of allergic and hypersensitivity 
reactions 

Incidence of treatment-emergent antidrug 
antibodies to tirzepatide

Mean change in systolic and diastolic blood 
pressure and heart rate from baseline 

Occurrence of hypoglycemic episodes

Incidence of initiation of rescue therapy for 
severe, persistent hyperglycemia 
Pharmacokinetics

To characterize the pharmacokinetics (PK) of 
QW tirzepatide 5 mg, 10 mg, and 15 mg and 
the relationships between tirzepatide exposure 
and safety, tolerability, and efficacy measures
for:

Population PK and pharmacodynamic 
parameters
Abbreviations: HbA1c = hemoglobin A1c; QW = once weekly.

I8F-MC-GPGI(b) Clinical Protocol
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LY3298176
Summary of Study Design:  
Study GPGI is a multicenter, randomized, double-blind, parallel, multinational, 
placebo-controlled Phase 3 study which will assess the safety and efficacy of the addition of 
5 mg, 10 mg, or 15 mg tirzepatide or placebo for change from baseline in hemoglobin A1c
(HbA1c) in patients with T2DM receiving titrated basal insulin glargine (with or without 
metformin) over a 40-week treatment.  Approximately, 472 patients with T2DM who have been 
treated with insulin glargine (U100), once daily with or without metformin ≥3 months prior to 
Visit 1, will be randomized.
Treatment Arms and Duration:  
Study GPGI will consist of 3 periods:  an approximately 3-week screening/lead-in period, 
followed by a 40-week treatment period and a 4-week safety follow-up period.  Patients will be 
randomized in a 1:1:1:1 ratio (tirzepatide 5 mg, tirzepatide 10 mg, tirzepatide 15 mg, and 
placebo).  Patients will be stratified based on country, baseline HbA1c (≤8.0% or >8.0% [≤64,
˃64 mmol/mol]), and baseline metformin use (Yes or No).
Number of Patients:
A total of approximately 472 patients (118 patients per treatment group or placebo) will be 
randomized.
Statistical Analysis:
Sample Size:
The trial is powered to evaluate superiority of tirzepatide 10 mg and tirzepatide 15 mg versus 
placebo in parallel relative to the primary endpoint (mean change from baseline in HbA1c at 
40 weeks) under the following assumptions:  

use of 2-sample t-test to make statistical comparisons among treatment means,

use of HbA1c data collected before initiation of any rescue medication or 
premature treatment discontinuation,

no more than 28% patients in tirzepatide groups and placebo initiating any 
rescue medication or prematurely discontinue study drug,

at least 0.60% (placebo adjusted) mean reduction in HbA1c from baseline to 
40 weeks for the tirzepatide doses, and 

a common standard deviation (SD) of 1.1%.  
Based on these assumptions, randomizing approximately 472 subjects using a 1:1:1:1 
randomization ratio to 5 mg tirzepatide, 10 mg tirzepatide, 15 mg tirzepatide, and placebo is 
required to ensure at least 90% power to establish superiority of tirzepatide 10 mg and/or 15 mg 
doses versus placebo, each evaluated at a 2-sided significance level of 0.025.  Furthermore, this 
sample size will ensure 90% power to establish superiority using an analysis of covariance 
(ANCOVA) utilizing all available HbA1c data at 40 weeks, irrespective of adherence to study 
drug or initiation of rescue therapy, and with missing data imputed with a conservative multiple 

I8F-MC-GPGI(b) Clinical Protocol
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LY3298176
imputation method (as described in the Efficacy Analyses section below).  It is assumed that 
efficacy (placebo adjusted) remains unchanged and SD increases to no more than 1.3% due to 
the inclusion of data on rescue medications, inclusion of data after premature treatment 
discontinuation, and imputation of missing data.  
Efficacy:
Efficacy and safety will be assessed using the modified intention-to-treat population, which 
consists of all randomly assigned participants who are exposed to at least one dose of study drug.  
There will be 2 estimands of interest in comparing efficacy of tirzepatide doses with placebo 
relative to the primary measure of mean change in HbA1c from baseline to 40-week visit.  The 
“efficacy” estimand represents efficacy prior to discontinuation of study drug without 
confounding effects of rescue therapy for persistent severe hyperglycemia.  The 
“treatment-regimen” estimand represents the efficacy irrespective of adherence to investigational 
product or introduction of rescue therapy for persistent severe hyperglycemia.
For the FDA, the primary efficacy assessment will be guided by the “treatment-regimen” 
estimand.  This assessment will analyze change from baseline in HbA1c to 40-week visit using 
an ANCOVA with terms, treatment, country, metformin use (Yes or No), and baseline HbA1c as 
a covariate.  The ANCOVA analysis will be conducted using full analysis set at 40-week visit, 
which consists of all available change from baseline in HbA1c data at the 40-week visit, 
irrespective of whether they were obtained while the participants had discontinued the study drug 
or whether the participant had been given rescue medication.  Additionally, data for subjects with 
missing values will be imputed based on observed data in the same treatment arm from subjects 
who had their efficacy measure at the Week 40 visit assessed after early discontinuation of study 
drug and/or initiation of rescue medication (retrieved dropouts).  Analysis will be conducted with 
multiple imputations, and statistical inference over multiple imputations will be guided by the 
method proposed by Rubin (1987).
For all other purposes, the primary efficacy assessment will be guided by the “efficacy” 
estimand.  This assessment will use efficacy analysis set which consists of data obtained before 
the initiation of any rescue therapy and before premature treatment discontinuation.  The analysis 
model for change from baseline in HbA1c assessed over time will be a mixed model for repeated 
measures (MMRM), with terms treatment, visit, treatment-by-visit interaction, country, 
metformin use (Yes or No), and baseline HbA1c as a covariate.  An unstructured covariance 
matrix will model relationship of within-patient errors.  
Since they are intended for different purposes, each of the 2 primary efficacy assessments will be 
conducted at 2-sided alpha of 0.05.  Additional details, including analysis methods for key 
secondary endpoints and a strategy for controlling overall type 1 error rate at a 2-sided alpha of 
0.05 of primary and key secondary endpoint evaluation, will be provided in the statistical 
analysis plan (SAP).

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Safety:
Safety assessment will be based on all available data, irrespective of whether they were obtained 
while the participants had discontinued the study drug or whether the participant had been given 
rescue medication.  Summary statistics will be provided for incidence of TEAEs, serious AEs, 
and study discontinuation due to AEs or deaths from first dose to end of safety follow-up.  
Counts and proportions of subjects experiencing AEs will be reported for each treatment group, 
and Fisher’s exact test will be used to compare the treatment groups.  For continuous laboratory 
analytes, summary statistics will be provided by visit, with statistical comparisons among 
treatment at each visit conducted using an MMRM analysis.  Additional details, including 
analysis of AEs of special interest, will be provided in the SAP.

I 8 F-M C -G P GI( 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
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 I.  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 D isease 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 GI( 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
T a bl e G P GI . 1.
S c h e d ul e of A cti viti e s
St u d y 
Peri o d I
St u d y Peri o d II
St u d y 
Peri o d 
III
Scree ni n g 
Le a d i n
Tre at me nt Peri o d
S afet y 
F/ U
Visit
1
2
3 a
4
5
6
7
8
9
1 0
1 1
1 2
1 3
1 4
1 5
1 6
1 7
1 8
1 9
2 0
2 1
2 2
E T b
8 0 1
Wee k of Tre at me nt
- 3
- 2
0
1
2
3
4
5
6
7
8
1 0
1 2
1 4
1 5
1 6
2 0
2 3
2 4
3 2
3 9
4 0
4 
wee ks 
p ost 
e n d of 
T x
All o w a ble De vi ati o n 
( d a ys)c
-
± 3
± 7
± 3
± 3
± 3
± 3
± 3
± 3
-
± 3
± 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 o nl y V isit
X
X
X
X
Tele p h o ne Visit
X
X
X
X
I nf or me d c o nse nt
X
Ra n d o mizati o n
X
Cli nic al Assess me nts
Me dical hist or y
e
X
P h ysical
E xa mi nati o n
X
X  
X
Hei g ht
X
Wei g ht
X  
X
X
X  
X
X  
X  
X  
X  
X  
X  
X
Waist circ u mfere nce
X
X
X  
X
X  
X  
X  
X  
X  
X
Electr ocar di o gra m f
X
X  
X  
X
Vital si g ns ( 2 sitti n g 
B P a n d H R) g
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
A d verse e ve nts
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Dilate d fu n d osc o pic 
exa m i nati o nh
X

I 8 F-M C -G P GI( 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 
Peri o d I
St u d y Peri o d II
St u d y 
Peri o d 
III
Scree ni n g 
Le a d i n
Tre at me nt Peri o d
S afet y 
F/ U
Visit
1
2
3 a
4
5
6
7
8
9
1 0
1 1
1 2
1 3
1 4
1 5
1 6
1 7
1 8
1 9
2 0
2 1
2 2
E T b
8 0 1
Wee k of Tre at me nt
- 3
- 2
0
1
2
3
4
5
6
7
8
1 0
1 2
1 4
1 5
1 6
2 0
2 3
2 4
3 2
3 9
4 0
4 
wee ks 
p ost 
e n d of 
T x
All o w a ble De vi ati o n 
( d a ys)c
-
± 3
± 7
± 3
± 3
± 3
± 3
± 3
± 3
-
± 3
± 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 o nl y V isit
X
X
X
X
Tele p h o ne Visit
X
X
X
X
C o nc o mita nt 
me dicati o ns
X  
X  
X  
X  
X  
X  
X  
X  
X
X 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Re vie w 
h y p o gl yce mic e ve nts 
c ollecte d i n t he diar y
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
P atie nt E d uc ati o n
Dia betes e d ucati o n i,j
X
B G meter, S M B G 
trai ni n gj
X
Dis pe nse B G 
meter/s u p plies, as 
nee de d
X  
X  
X  
X  
X  
X  
X  
X
X  
X  
X  
X
St u d y  dr u g i njecti o n 
trai ni n gj
X
Ha n d o ut diar y, 
i nstr uct i n usej
X  
X
X
X
X
Re mi n d patie nts 
a b o ut 7-p oi nt 
S M B G k
X
X

I 8 F-M C -G P GI( 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 
Peri o d I
St u d y Peri o d II
St u d y 
Peri o d 
III
Scree ni n g 
Le a d i n
Tre at me nt Peri o d
S afet y 
F/ U
Visit
1
2
3 a
4
5
6
7
8
9
1 0
1 1
1 2
1 3
1 4
1 5
1 6
1 7
1 8
1 9
2 0
2 1
2 2
E T b
8 0 1
Wee k of Tre at me nt
- 3
- 2
0
1
2
3
4
5
6
7
8
1 0
1 2
1 4
1 5
1 6
2 0
2 3
2 4
3 2
3 9
4 0
4 
wee ks 
p ost 
e n d of 
T x
All o w a ble De vi ati o n 
( d a ys)c
-
± 3
± 7
± 3
± 3
± 3
± 3
± 3
± 3
-
± 3
± 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 o nl y V isit
X
X
X
X
Tele p h o ne Visit
X
X
X
X
Re vie w 7 -p oi nt 
S M B G val ues 
c ollecte d i n t he diar y
X
X
Dis pe nse st u d y dr u g
X  
X  
X  
X  
X  
X  
X
X  
X  
X  
X
O bser ve patie nt 
a d mi nister st u d y 
dr u g l
X
Patie nt ret ur ns st u d y 
dr u gs a n d i njecti o n 
s u p plies
X  
X  
X  
X  
X  
X
X  
X  
X  
X  
X  
X
Assess st u d y dr u g 
c o m plia nce
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Re vie w i ns uli n d ose 
a n d a dj ust me nt per 
T T T al g orit h m
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Assess c o m plia nce 
wit h i ns uli n d ose 
a dj ust me nt T T T 
al g orit h m m
X  
X  
X  
X  
X  
X
X  
X  
X  
X  
X  
X
L a b or at or y Tests
Ser u m pre g na nc y 
testn
X

I 8 F-M C -G P GI( 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
St u d y 
Peri o d I
St u d y Peri o d II
St u d y 
Peri o d 
III
Scree ni n g 
Le a d i n
Tre at me nt Peri o d
S afet y 
F/ U
Visit
1
2
3 a
4
5
6
7
8
9
1 0
1 1
1 2
1 3
1 4
1 5
1 6
1 7
1 8
1 9
2 0
2 1
2 2
E T b
8 0 1
Wee k of Tre at me nt
- 3
- 2
0
1
2
3
4
5
6
7
8
1 0
1 2
1 4
1 5
1 6
2 0
2 3
2 4
3 2
3 9
4 0
4 
wee ks 
p ost 
e n d of 
T x
All o w a ble De vi ati o n 
( d a ys)c
-
± 3
± 7
± 3
± 3
± 3
± 3
± 3
± 3
-
± 3
± 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 o nl y V isit
X
X
X
X
Tele p h o ne Visit
X
X
X
X
Uri ne pre g na nc y test o
X
X
X
X
F ollicle -sti m ulati n g 
h or m o ne 
test/Estra di ol p
X
C he mistr y pa nel
X q
X
X
X  
X  
X
Fasti n g ser u m 
gl uc ose
(ce ntral la b orat or y)
X  
X  
X
X  
X
X  
X  
X
X  
X  
X
Li pi d pa nel
X
X  
X  
X
Uri nar y 
al b u mi n/creati ni ne 
rati o
X q
X  
X  
X
Ser u m creati ni ne, 
e G F R ( C K D-E PI) r
X q
X
X
X  
X  
X
Calcit o ni n
X q
X
X
X  
X  
X
He mat ol o g y
X q
X
X
X  
X  
X
H b A 1c
X  
X
X
X  
X
X  
X  
X
X  
X  
X
Pa ncreatic a m ylase, 
li pase
X q
X
X
X  
X  
X
I m m u n o ge nicit ys
X
X
X
X
X  
X  
X

I 8 F-M C -G P GI( 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
St u d y 
Peri o d I
St u d y Peri o d II
St u d y 
Peri o d 
III
Scree ni n g 
Le a d i n
Tre at me nt Peri o d
S afet y 
F/ U
Visit
1
2
3 a
4
5
6
7
8
9
1 0
1 1
1 2
1 3
1 4
1 5
1 6
1 7
1 8
1 9
2 0
2 1
2 2
E T b
8 0 1
Wee k of Tre at me nt
- 3
- 2
0
1
2
3
4
5
6
7
8
1 0
1 2
1 4
1 5
1 6
2 0
2 3
2 4
3 2
3 9
4 0
4 
wee ks 
p ost 
e n d of 
T x
All o w a ble De vi ati o n 
( d a ys)c
-
± 3
± 7
± 3
± 3
± 3
± 3
± 3
± 3
-
± 3
± 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 o nl y V isit
X
X
X
X
Tele p h o ne Visit
X
X
X
X
P K sa m ple f or 
I m m u n o ge nicit yt
X
X
X
X
X  
X  
X
A nti -G A D a nti b o d y
X
Tirze pa ti de P K u
X
X
X
X  
X
St ore d s a m ples
P har mac o ge netic 
st ore d sa m ple
X
N o n p har mac o ge netic 
st ore d sa m ple
X
X
X
X  
X
P atie nt Re p orte d O utc o mes -t o be c o m plete d b y p atie nt at sitev
A P P A D L
X
X  
X
I W-S P
X
X  
X
D T S Qs
X
D T S Qc
X  
X
E Q - 5 D- 5 L
X
X  
X

I8F-MC-GPGI(b) Clinical Protocol
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LY3298176
Abbreviations:  ADA = antidrug antibodies; APPADL = Ability to Perform Physical Activities of Daily Living; BG = blood glucose; BP = blood pressure; 
CKD-EPI = Chronic Kidney Disease-Epidemiology; DTSQc = Diabetes Treatment Satisfaction Questionnaire change; DTSQs = Diabetes Treatment 
Satisfaction Questionnaire status; ECG = electrocardiogram; eCRF =electronic case report form; eGFR = estimated glomerular filtration rate; 
EQ-5D-5L = European Qualtiy of Life- 5 dimensions-5 levels; ET = early termination; F/U = follow-up; GAD = glutamic acid decarboxylase; 
HbA1c = hemoglobin A1c; HR = heart rate; IW-SP = Impact of Weight on Self-Perception; PK = pharmacokinetics; PRO = patient-reported outcome;; 
SMBG = self-monitored blood glucose; TTT = treat to target; Tx = treatment.
a
Baseline assessments must be completed before processing in the interactive web-response system (IWRS).
b
Patients who are unable or unwilling to continue in the study for any reason will perform an ET visit.  If the patient is discontinuing during an unscheduled 
visit, that visit should be performed as the ET visit.  If the patient is discontinuing during a scheduled visit, that visit should be performed as an ET visit.  
Visit 801 (safety follow-up visit) should be performed 4 weeks after the ET visit as the final study visit.
c
The visit date is determined in relation to the date of the randomization visit (± the allowed visit window). 
d
On visits 3, 5, 7, 11, 13, 16, 17, 19, 22, ET, and at follow-up, patients should be reminded to report to the site in a fasting condition, after a period of 
approximately 8 hours without eating, drinking (except water), or any significant physical activity and before taking study drug(s), insulin glargine and 
metformin (if used).
e
Medical history includes assessment of preexisting conditions (including history of gall bladder disease, cardiovascular disease, and medullary thyroid 
carcinoma) and substance usage (such as; alcohol and tobacco).
f
Electrocardiograms (ECG) occurring on visits with PK collection should be collected at least 30 minutes prior to obtaining the sample for PK measurement.
g
Vital sign measurements should be taken before obtaining an ECG tracing and before collection of blood samples for laboratory testing, at visits where 
required.  The participant should sit quietly for 5 minutes before vital sign measurements are taken. For each parameter, 2 measurements will be taken using 
the same arm; the recordings should be taken at least 1 minute apart. Blood pressure must be taken with an automated blood pressure machine.
h
Dilated fundoscopic exam will be performed by a qualified eye care professional (ophthalmologist or optometrist) for all patients between Visit 2 and Visit 3 
to exclude patients with proliferative diabetic retinopathy and/or diabetic maculopathy (macular edema), or nonproliferative diabetic retinopathy that requires 
acute treatment.  The results from this exam will be recorded on a specific retinopathy eCRF as a baseline measure of retinopathy.  Follow up dilated 
fundoscopic exam should be performed when clinically indicated, and, the results recorded on the retinopathy eCRF.
i
Includes counseling on diet and exercise, management of hypoglycemia, etc.
j
All training should be repeated as needed to ensure patient compliance. 
k
Patient is required to collect two 7-point SMBGs on nonconsecutive days prior to the next visit.  A 7-point SMBG consists of measurements before and 2 
hours after each of 3 main meals within the same day and at bedtime.  These SMBG profiles will be collected by the patient within 2 weeks prior to the 
assigned visits.  If 7-point SMBG is not performed, then data from the most recent nonconsecutive 4-point SMBG profiles can be used.  If more than two 7-
point SMBG profiles are available, the two most recent nonconsecutive profiles should be used. Patients will be required to collect a daily fasting BG and a 
4-point SMBG once weekly between Visit 2 and 3, twice weekly from Visits 3-7 (Weeks 0-4) followed by weekly for the remainder of the study.
l
Patients should administer their first dose of study drug at the end of this visit, after other study procedures and randomization.
m Assessment of the patient’s compliance to the TTT algorithm will be collected in the eCRF at Visits 7, 9, 11, 13, 16, 19, and 22 for the period since the 
previous clinic visit.

I8F-MC-GPGI(b) Clinical Protocol
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LY3298176
n
A serum pregnancy test will be performed at Visit 1 for women of childbearing potential only.
o
A urine pregnancy test must be performed at Visit 3 with the result available prior to randomization and first injection of study drug(s) for women of 
childbearing potential only.  Additional pregnancy tests will be performed at Visits 13, 19, and 22. Pregnancy tests may be also performed at the 
investigator’s discretion during the study.  If required per local regulations and/or institutional guidelines, pregnancy testing can also occur at other times 
during the study treatment period.
p
Follicle-stimulating hormone test performed at Visit 1 for postmenopausal women at least 45 years of age with an intact uterus, not on hormone therapy, and 
who have had spontaneous amenorrhea for more than 6 months and less than 12 months and estradiol levels consistent with a postmenopausal state (FSH 
≥40 mIU/mL and estradiol <30 pg/mL).
q
Screening visit assessment will serve as baseline.
r
The CKD-EPI equation will be used by the central lab to estimate and report eGFR. 
s
In the event of systemic drug hypersensitivity reactions (immediate or nonimmediate), additional blood samples will be collected including ADA, PK, and an 
exploratory biomarker sample.
t
Pharmacokinetic samples for immunogenicity must be taken prior to drug administration.
u
Pharmacokinetic samples will be collected for all patients at these visits at time windows of 1 to 24 hours, 24 to 96 hours, OR 120 to 168 hours post dose, as 
assigned by IWRS for each PK sample.  Dependent on the time-windows to which a patient gets assigned, they may be required to come to site for 
PK-specific visits.
v
All PROs should be completed before any other study procedures if the patient is not adversely affected by the fasting condition or completed after the patient 
has sufficiently recovered from the preceding visit procedures.

I 8 F-M C -G P GI( 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
3. I ntr o d u cti o n
3. 1.
St u d y R ati o n al e
C urre nt i ncret i n- base d i njecta ble treat me nt o pti o ns f or t y pe 2 dia betes mellit us ( T 2 D M) are 
di recte d at a si n gle i ncreti n m o lec ular tar get ( G L P-1 [ gl uca g o n -li ke pe pti de-1]) a n d t heref ore 
c o uld ha ve t hera pe utic li mitati o ns.  T hese treat me nt o pti o ns offer i m pr o ve d gl yce mic c o ntr ol a n d 
a lo w ri s k of h y p o gl yce mia, a n d ha ve a p ote ntial f or cli nicall y rele va nt wei g ht l oss.  H o we ver, a 
lar ge pr o p orti o n of patie nts still d o n ot reac h t he treat me nt tar gets des pite a hi g h le vel of 
c o mplia nce wi t h t he treat me nt re gi me ns.  T heref ore, it is i m p orta nt t o pr o vi de a d dit i onal 
treat me nt o ptio ns f or pati e nts t hat all o w f or e n ha nce d gl uc ose c o ntr ol a n d wei g ht l oss w hile 
prese r vi n g a n o verall acce pta ble be nefit/ris k pr ofile ( Star k Casa gra n de et al. 2 0 1 3; Zaccar di et al. 
2 0 1 6).
Ti rze patide ( L Y 3 2 9 8 1 7 6) is a o nce -wee kl y d ual GI P ( gl uc ose -de pe n de nt i n s uli n otr o pic 
p ol y pe pt i de) a n d G L P -1 rece pt or a g o ni st.  It is a 3 9-a mi n o aci d s y nthet ic pe pti de wit h a g o nist 
acti vit y 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-a ci d moi et y t hat 
  It is a d mi nistere d 
s u bc uta ne o usl y.
St u d y  I 8 F-M C -G P GI ( G P GI) will c o m pare tirze pati de ( 3 d oses) t o place b o, a d de d t o titrate d 
o nce -dail y  basal i ns uli n glar gi ne i n patient s wit h T 2 D M pre vi o usl y treate d wit h basal i ns uli n 
( wit h or wit ho ut m et f or mi n). Des pite a n i na de q uate gl yce mic c o ntr ol, i ns uli n t hera p y is often 
n ot i nte nsifie d i n t hese patie nts, f or m ult i ple reas o ns, s uc h as c o ncer n f or h yp o gl yce mia or 
w ei g ht gai n ( K h u nti et al. 2 0 1 6). Se veral st u dies ha ve assesse d t he efficac y a n d safet y of  t he 
a d ditio n of  a o nce-wee kl y  G L P-1 rece pt or a g o nist t o basal i ns uli n i n t his t yp e of  patie nts 
( P ozzilli et al. 2 0 1 7; G uja et al. 2 0 1 8; R o d bar d et al. 2 0 1 8). H o we ver, there is n o a vaila ble 
e vi de nce o n t he effects of t he c o m bi nat i on of basal i ns uli n a n d a l o n g -act i n g, o nce-wee kl y  d ual 
GI P/ G L P -1 rece pt or a g o nist o n bl o o d gl u c ose ( B G) t o date.  T he c o m bi nati o n o f i ns uli n glar gi ne 
wi t h tirze pati de is e x pecte d t o pr o vi de i m pr o ve d gl uc ose c o ntr ol a n d atte n uate t he wei g ht gai n 
a n d h y p o gl yce mia ris k ass o ciat e d wit h t he m o re i nte nsi ve titrati o n a n d hi g her dail y  d oses of 
i ns uli n glargi ne .
3. 2.
B a c k gr o u n d
F o ur 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:  t wo P hase 1 st u d ies, 
St u d y I 8 F-M C -G P G A ( G P G A) a n d I 8 F-M C -G P G C ( G P G C) a n d t w o P hase 2 st u dies, St u d y 
I 8 F-M C -G P G B ( G P G B) a n d I 8 F -M C -G P G F ( 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 a n d m ult i ple asce n di n g d ose 
st u d y in 8 9 healt h y s u bjects a n d a m ulti ple d ose pr o of -of -c o nce pt st u d y in 5 3 pati e nts 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 netics ( 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 u bc uta ne o us (S C ) i njecti o ns.  T he 
C CI

I8F-MC-GPGI(b) Clinical Protocol
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LY3298176
results of this study supported further development of tirzepatide for once weekly (QW) dosing 
in patients with T2DM (Coskun et al. 2018).
Study GPGC was a Phase 1, multiple ascending dose study conducted in 48 Japanese patients 
with T2DM. Safety, tolerability, and PK/PD profiles of tirzepatide appeared comparable to 
previous studies in non-Japanese patients with T2DM, all of which supports the development of 
QW tirzepatide in this population.
A 26-week Phase 2 study (GPGB) assessed the efficacy, tolerability, and safety of QW 
administration of 4 doses (1 mg/5 mg/10 mg and 15 mg) of tirzepatide versus placebo and an 
active comparator (dulaglutide 1.5 mg QW) in 318 patients with T2DM with inadequate 
glycemic control on diet and exercise alone or on a stable dose of metformin monotherapy.  The 
doses of 10 mg and 15 mg were attained by titration (Frias et al. 2018).
Study GPGB demonstrated that tirzepatide 5 mg, 10 mg, and 15 mg doses significantly lowered 
hemoglobin A1c (HbA1c) and body weight in a dose-dependent manner in patients with T2DM 
in comparison to placebo .  In addition, reductions in HbA1c in the tirzepatide 5, 10, and 15 mg
doses were greater than with dulaglutide 1.5 mg QW.  Similar to the GLP-1 receptor agonist 
class and the Phase 1 Study, most of the tirzepatide adverse events (AEs) were gastrointestinal
(GI)-related, consisting mainly of nausea, vomiting, and diarrhea and were dose-dependent.  The 
GI AEs were usually mild to moderate in intensity.  Serious AEs (SAEs) were balanced across 
the treatment groups and none of the groups reported severe hypoglycemia (Frias et al. 2018). 
As it was recognized that the titration scheme employed in Study GPGB was unlikely to be 
optimal for the reduction of GI-related AEs expected with tirzepatide, Study GPGF was designed 
to explore alternative titration schemes (longer time intervals between dose escalations and 
different dose escalations) to support evaluation of optimized dosing regimen(s) in Phase 3
clinical studies. This was a 12-week, placebo-controlled study to assess the efficacy and safety 
of 3 different titration schemes to attain doses as high as 15 mg of tirzepatide in patients with 
T2DM.
These data support continued development of tirzepatide as a therapy for T2DM.  
3.3.
Benefit/Risk Assessment
More information about the known and expected benefits, risks, SAEs and reasonably 
anticipated AEs of tirzepatide are to be found in the Investigator’s Brochure (IB).
In addition, detailed information about the known and expected benefits and risks of insulin 
glargine may be found in the marketed insulin glargine package insert.

I 8 F-M C -G P GI( 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
4.
O bj e cti v e s a n d E n d p oi nt s
Ta ble G P GI . 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 GI . 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 s u peri orit y of Q W tirze pati de 
1 0 m g a n d / or 1 5 m g vers us place b o w he n 
a d de d t o titrate d basal i ns uli n glar gi ne, wit h 
or  wit h o ut metf or mi n, wit h res pect t o 
gl yce mic c o ntr ol at 4 0 wee ks f or:

Mea n c ha n ge i n H b A 1c fr o m baseli ne 
Ke y Sec o n d ar y (c o ntr olle d f or t y pe 1 err or)
Efficac y

T o de m o nstrate s u peri orit y of Q W tirze pati de
5 m g vers us place b o w h e n a d de d t o titrate d 
basal i ns uli n glar gi ne, wit h or wit h o ut 
metf or mi n, wit h res pect t o gl y ce mic c o ntr ol at 
4 0 wee ks f or:

T o de m o nstrate s u peri orit y of Q W tirze pati de 
5 m g, 1 0 m g, a n d / or 1 5 m g  vers us place b o  
w h e n a d de d t o titrate d basal i ns uli n glar gi ne, 
wit h or wit h o ut metf or mi n, at 4 0 wee ks f or :

Mea n c ha n ge i n H b A 1c fr o m baseli ne

Mea n c ha n ge i n b o d y wei g ht fr o m base li ne 

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) fr o m baseli ne
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)
Efficac y

T o c o m pare Q W tirze pati de 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 ac hie vi n g H b A 1c tar get 
≤6. 5 % ( 4 8 m m ol/ m ol) , < 5. 7 % ( 3 9 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 % fr o m baseli ne

C ha n ge f r om baseli ne i n dail y mea n i ns uli n 
glar gi ne d ose
Safet y

T o c o m pare Q W tirze pati de 5 m g, 1 0 m g, a n d 
1 5 m g t o place b o t o t he e n d of safet y 
f oll o w-u p 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

Ser u m calcit o ni n

I nci de nce of aller gic a n d h y perse nsiti vit y 
reacti o ns 

I8F-MC-GPGI(b) Clinical Protocol
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LY3298176
Objectives
Endpoints

Incidence of treatment-emergent antidrug 
antibodies to tirzepatide

Mean change in systolic and diastolic blood 
pressure and heart rate from baseline 

Occurrence of hypoglycemic episodes

Incidence of initiation of rescue therapy for 
severe, persistent hyperglycemia 
Pharmacokinetics

To characterize the pharmacokinetics (PK) of 
QW tirzepatide 5 mg, 10 mg, and 15 mg 
doses and the relationships between 
tirzepatide exposure and safety, tolerability, 
and efficacy measures for:

Population PK and PD parameters
Tertiary/Exploratory

To compare QW tirzepatide 5 mg, 10 mg, and 
15 mg to placebo at 40 weeks for:

Mean change in lipids (total cholesterol, HDL, 
LDL, VLDL, and TG)

Mean change in waist circumference

Changes from baseline in mean body mass 
index 

Biomarkers

Patient-reported outcomes
o
Ability to Perform Physical 
Activities of Daily Living
o
Impact of Weight on Self-Perception
o
Diabetes Treatment Satisfaction 
Questionnaire status/ Diabetes 
Treatment Satisfaction Questionnaire 
change
o
European Quality of Life-5 
Dimensions-5 level
Abbreviations: HbA1c = hemoglobin A1c; HDL= high-density lipoprotein; LDL = low-density lipoprotein; 
PD = pharmacodynamics; PK=pharmacokinetics; QW = once weekly; TG = triglycerides; VLDL = very 
low-density lipoprotein.

I 8 F-M C -G P GI( 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
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 GI is a mul tice nter, ran d o mize d, d o u ble -bli n d, parallel, m ult i nati onal, 
pl ace b o -c o ntr olle d P hase 3 st u d y w hic h will assess t he safet y a n d efficac y of t he a d ditio n of  
5 m g, 1 0 m g, or 1 5 m g t irze pat i de, or pl ace b o f or c ha n ge fr o m baseli ne i n H b A 1c i n patie nts 
wi t h T 2 D M recei vi n g titrate d basal i ns uli n glar gi ne ( wit h or wit ho ut m et f or mi n) o ver a 4 0 -wee k 
treat me nt.  A p pr o xi matel y, 4 7 2 patie nts wit h T 2 D M w h o ha ve bee n treate d wit h i ns uli n glar gi ne 
( U 1 0 0), once dail y wit h or wit h o ut metf or mi n ≥3 m o n t hs prior t o Vi sit 1, will be ra n d o mize d 
(see Secti o n 2 ).
St u d y  G P GI will c o nsist of 3 peri o ds:  a n a p pr oxi 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, tirze pati de 1 0 m g, tirze pati de 1 5 m g, a n d 
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. 0 % or > 8. 0 % [≤6 4 , 
˃ 6 4 m m o l/ m ol]), a n d baseli ne met f or mi n use ( Yes or N o).
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 GI . 1 ill ustrates t he st u d y desi g n.

I 8 F-M C -G P GI( 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
a
Sta bilizati o n Peri o d = first 4 wee ks after ra n d o mizati o n, wit h restricte d i ns uli n 
d ose a dj ust me nts.  I ns uli n Glar gi ne Titrati o n Peri o d Wee ks 4  t o 4 0 (e n d of 
treat me nt/e n d of st u d y), wit h u nrestricte d i ns uli n d ose a dj ust me nts.  Mai nte na nce 
Peri o d = Wee ks 2 4 t o 4 0 (e n d of treat me nt/e n d of st u d y), t he peri o d w he n i ns uli n 
glar gi ne d ose is e x pecte d t o be sta ble. 
Fi g ur e G P GI . 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 R-M C -G P GI .
St u d y Peri o d I ( S cree ni n g a n d L e 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 co nfir m eli gi bilit y 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) be f 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 p erf or me d as s h o w n i n t he St u d y Sc he d ule of 
Act i vities, Secti o n 2 .

P ati e nts w h o meet all a p plica ble i ncl usi o n cri t eria a n d n o ne of t he a p plica ble 
e xcl usi o n cri teria ( Sectio n 6 ) at Visit 1 will c o nti n ue o n t heir prest u d y t hera p y 
d oses bet wee n Visits 1 a n d 2.

I 8 F-M C -G P GI( 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
Le a d -i n ( Visit 2 t o Visit 3)
At  Visit 2:

Scree ni n g la b orat or y  res ults will be re vie we d.  F or t h ose patie nts meeti 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 me 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 oliferati ve dia betic reti n o pat h y, dia betic mac ul o pat h y, or 
n o n pr o liferati 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 n ot 
e nr o lle d.

P atie 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 n i n g o n 
h o w t o perf or m self -m o nit ori n g o f b l oo d gl uc ose ( S M B G).

P ati e nts will be pr o vide d diaries a n d will be trai ne d as a p pr o priate t o rec or d ;
o
B G val ues, 
o
h y p o gl yce mic e ve nts,
o
i ns uli n d ose assess me nts usi n g t he treat t o tar get (T T T ) al g orit h m, 
o
me dicat i on s, a n d 
o
a d verse e ve nts.  

P ati e nts will be trai ne d o n disease ma na ge me nt 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 nt visits as dee me d a p pr o priate.

P ati e nts will be trai ne d (if nee de d ) t o f oll ow i nstr ucti o ns f or use of t he i ns uli n gla r gi ne 
pr efille d pe n t hat t he y are usi n g.
After Vi sit 2:

P ati e nts will start i ns uli n d ose assess me nts o nce wee kl y f or t he re mai n der of t he lea d-i n 
p eri o d (t he use of t he al g orit h m is restricte d d uri n g t he lea d -i n a n d sta bilizati o n peri o ds, 
as descri be d bel o w). 

P ati e nts will be re q ueste d t o perf or m 4 -p oi nt S M B G pr ofiles at least o nce wee kl y , 
starti n g at Visit 2.

P ati e nts will nee d t o perf or m t w o 7-p oi nt S M B G pr ofiles d o ne o n 2 n o nc o nsec ut i ve da ys 
i n t he 2 - wee k perio d pri or t o Vi sit 3 (ra n d o mizatio n) a n d Visit 2 2 ( Wee k 4 0). 

D uri n g t he l ea d-i n peri o d, patie nts s h o ul d c o nti n ue t heir prest u d y t hera p y a n d s h o uld n ot 
c ha n ge t he d ose , i n or der t o all o w relia ble assess me nt of H b A 1c at baseli ne ( Visit 3).

I ns uli n d oses s h o ul d be a dj uste d o nl y f or t he safet y of t he st u d y partici pa nts ( occ urre nce 
of  h y p o gl yce mia d ue t o i na de q uate i ns uli n d ose or se vere h y per gl yce mia, defi ne d as 
mea n dail y  BG f r o m 4-p oi nt S M B G pr ofile > 2 7 0 m g/ d L [ > 1 5 m m o l/ L]. I n t hese 
sit u atio ns, t he pati e nt s h o uld c o ntact t he site i n or der t o a dj ust t he d ose per t he T T T 
alg ori t h m (see Secti on 7. 2 , Ta ble G P GI . 2). 

P ati e nts w h o are ta ki n g c o nc o mita nt met f or mi n a n d de velo p a n y c o n di tio n  t hat is a 
c o ntrai n dicat i on f or its use will be c o nsi dere d i neli gi ble a n d will be disc o nti n ue d fr o m 
t he trial bef ore ra n d o mizati o n.

I 8 F-M C -G P GI( 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
St u d y Peri o d II ( 4 0 - Wee k T re at me nt P eri o d)
R a n d o miz ati o n ( Visit 3)
At  Visit 3:

Eli gi ble pat ient 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 E C G) prior t o ra n d o mizat 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.  

P ati e nt s 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 wit h o ut ha vi n g ta ke n a n y d oses of  st u d y dr u g, i ns uli n glar gi ne a n d 
met for mi n (if use d).   

Res p o nsi ble st u d y -site pers o n nel will re vie w t he diar y a n d assess t he nee d t o a dj ust t he 
i ns uli n glar gi ne d ose per t he T T T alg ori t h m criteria (Ta ble G P GI. 3 ). O nl y patie nts w h o 
re q uir e furt her i ns uli n glar gi ne d ose i ncrease, as i n dicate d b y  FB G a b o ve t he tar get 
c o nce ntrati o n per t he T T T al g orit h m (see Secti o n 7. 1 ) d uri n g t he wee k pri or t o t he visit, 
will be eli gi ble f or f urt her partici pati o n i n t he st u d y.

T he q uest i on naires ( E ur o pea n Q ualit y of Life [ E Q - 5 D-5 L], A bilit y t o Perf or m P h ysical 
Act i 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], 
a n d Dia betes Treat m e nt Satisfacti on Q uest i on naire stat us [ D T S Qs]) s h o ul d be c om p lete 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 ng 
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.  

P ati e nts will be i nstr ucte d o n h o w t o use t he si n gle -d ose pe n ( S D P) wit h a de mo nstrati o n 
pe n .
Tre at me nt peri o d : Ge ner al C o nsi der ati o ns
T he treat me nt perio d will last 4 0 wee ks, starti n g wit h a 4 -wee k sta bilizat i on peri o d i m me diatel y  
after ra n d o mizati on a n d f o ll owe d b y a 3 6 -wee k gl ar gi ne titr atio n peri o d. T he mai nte na nce 
p eri o d is defi ne d as a part of t he titrati o n peri o d w he n i ns uli n glar gi ne d ose i s e x pecte d t o be 
sta ble a n d o pti mize d ( Wee ks 2 4 t o 4 0 [ Visits 1 9 t o 2 2 ]). Patie nts s h o ul d i nject t heir first d ose of 
st u d y dr u g u n der t he s u per visi o n o f t he staff at Visit 3 ( baseli ne) w hile st ill at t he st u d y sit e. 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 electr o nic case re p ort
f or m (e C R F) .
P ati e nts will:

perf or m  dail y B G meas ure me nts per t heir wee kl y S M B G pla n as o utli ne d i n t his secti on 
a n d i n Sect i on 2 . 

perf or m  ins uli n glar gi ne d ose assess me nts o nce or t wice per wee k, de pe n di n g o n t he 
st u d y p erio d, as descri be d i n t he secti o ns bel o w. 

di sc uss ot her rele va nt cli nical i nf or mati o n, f or e xa m ple, A Es a n d c o n c o mita nt 
me dicat i ons at eac h visit. Patie nts w h o are ta ki n g c o nc o mita nt metf or mi n d uri n g t he 
lea d-i n peri o d will be re q uire d t o c o nti n ue usi n g t he sa me d ose of metf or mi n t hr o u g h o ut 

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t he treat me nt peri o d. Disc o nti n uati o n o f met f or mi n or c ha n ges i n its d ose will n ot be 
per mitte d, e xce pt i n t he cases of de vel o p me nt of c o ntrai n dicat i ons ( per c o u ntr y -s pecific 
la bel) f or its use or i n t he case of i ncrease d ris k of h y p o gl yce mia (see Secti on 7. 4. 2 f or 
details).
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  in t he 5 m g gr o u p.  F or t he 1 0 m g gr o u p, t he star ti 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 t o 5 t o 7. 5 t o 1 0 m g) u ntil 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  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 t o 5 t o 7. 5 t o 1 0 t o 
1 2. 5 t o 1 5 m g) 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 w ill 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.
P ost r a n d o miz ati o n peri o d (e n d of Visit 3 t o Visit 22 ):
Sta bilizat i on Peri o d ( E n d of Vi sit 3 t hr o u g h Visit 7 [ Wee ks 0 t hr o u g h 4])
T he m ai n p ur p oses of t his perio d are t o i ntr o d uce ra n d o mize d st u d y dr u gs (Q W tirze patide or 
Q W place b o) i n a safe ma n ner, t o ass ure re g ular a n d c orrect use of t he self-m o nit ori n g a n d 
i ns uli n d ose a dj ustme nt  pr oce d ures, a n d t o stu d y diaries d uri n g t he e ntire st u d y . Patie nts will be 
re q uire d t o perf or m 4 -p oi nt S M B G pr ofiles a n d i ns uli n d ose assess me nt per t he T T T al g orit h m 
t wice wee kl y d uri n g t his peri o d. I n a n eff ort t o all o w a p pr o priate ti me f or tirze pati de t o reac h 
stea d y state, i ns uli n glar gi ne d ose a dj ust me nt s d uri n g t he 4-wee k sta bilizat i on peri o d s h o ul d be 
restricte d t o t h ose nee de d i n t he case of si g nifica nt safet y ris ks d ue t o i na de q uate i ns uli n d ose: 

occ urre nce of h y p o gl yce mia; (see Secti o ns 7. 4. 2 a n d 9. 2. 2. 1 ); i n t his case, t he i ns uli n 
gl ar gi ne d ose will be decrease d per t he T T T al g orit h m; or 

de vel o p me nt of se vere h y per gl yce mia, defi ne d as mea n dail y P G fr o m 4-p oi nt S M B G 
pr ofile > 2 7 0 m g/ d L ( > 1 5 m m o l/ L); i n t his case, i ns uli n d ose will be i ncrease d per t he 
T T T al g ori t h m. 
P ati e nts s h o uld be i nstr ucte d t o c o ntact t he sites if a n y of t he a b o ve sit uati o ns occ urre d, i n or der 
t o a dj ust t he i nsuli n glar g i ne d ose per t he T T T al g orit h m. I n a d diti on, f or patie nts wit h baseli ne 
H b A 1c ≤8. 0 %, t he i ns uli n glar gi ne d ose will be decrease d b y 2 0 % i m me diatel y  aft er 
ra n d omizat i on, n ot later t ha n 7 da ys after t he first d ose of st u d y  dr u g, a n d will t he n re mai n 
u nc ha n ge d d uri n g t he sta bilizat i on peri o d t o decrease t he ris k of h y p o gl yce mia. T he i ns uli n 
gl ar gi ne d ose will re mai n u nc ha n ge d if baseli ne H b A 1c is > 8. 0 %. If t he baseli ne H b A 1c val ue 
f or a patie nt is n ot a vaila ble withi n t he first 7 da y s after ra n d o mizati on, t he st u d y  site s h o uld 
i m me diatel y c o ns ult t he res p o nsi ble Lill y p h ysicia n ( n ot later t ha n t he date of Visit 4) t o disc uss 
if a n a dj ustme nt  i n i ns uli n d ose w o ul d be a p pr o priate base d o n t he a vaila ble cli nical data f or t he 
patie nt.
I n a d diti on t o t h e cli nic visit s, o ne tele p h o ne visit will be sc he d ule d d uri n g t his peri o d ( Visit 6, 
Wee k 3). 
At  t his visit, pr oce d ures will i ncl u de

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
assess me nts of S M B G, 

a djust m e nt of ins uli n d ose f or safet y reas o ns ( h y p o gl yce mia a n d/ or se vere 
h y per gl yce mia) , 

st u d y dr u g c o mplia nce ( will be re -assesse d at t he office visit), 

h y p o gl yce mic e ve nts, 

c o nc o mita nt me dicat i ons, a n d 

A Es. 
T he data o btai ne d at t hese tele p h o ne visit s will be e ntere d i nt o t he case re p ort f or ms (C R Fs ) at 
t he ne xt office visit.
Ti tr atio n Peri o d ( E n d of  Visit 7 t hr o u g h Visit 2 2 [ Wee ks 5 t hr o u g h 4 0])
T hr o u g h o ut t he treat me nt p eri o d, patie nts will c ollect t he f o ll owi n g data i n t he patie nt diar y  t o be 
re vie we d at t he ne xt office visit:

S M B G, 

i ns uli n d ose assess me nts, 

i ns uli n d oses a d mi nistere d, 

dates w he n st u d y dr u g was a d mi nistere d, a n d

h y p o gl yce mic e ve nts.
F or t hat p ur p ose, at eac h visit, st u d y  diaries for t he peri o d af ter t he pre vi o us office visit, will be 
c ollecte d, a n d i nstr ucti o ns will be re vie we d at eac h visit.  St u d y  dr u g a n d i njecti on s u p pli es will 
be ret ur ne d per t he Sc he d ule of Act i vities ( Sectio n 2 ) a n d acc or di n g t o l ocal re q uire me nts.  Ne w 
s u p plies will be dis pe nse d as nee de d.  
I n a d ditio n t o t he cli nic visit s, 3 tele p h o ne visits will be sc he d ule d d uri n g t his peri o d . At eac h of 
t hese visit s, pr oce d ures will i ncl u de 

assess me nts of S M B G, 

c o mplia nce wi t h ins uli n t itrati o n al g orit h m, 

i ns uli n d ose, 

st u d y dr u g c o mplia nce ( will be re -assesse d at t he office visit), 

h y p o gl yce mic e ve nts, 

c o nc o mita nt me dicat i ons, a n d 

A Es. 
T he data o btai ne d at t hese tele p h o ne visit s will be e ntere d i nt o t he C R Fs at t he ne xt office visit.
At  t he be gi n ni n g of t he titrati o n peri o d, t he patie nt will be i nstr ucte d t o start usi n g t he T T T 
alg ori t h m wit ho ut restri ct i ons i n or der t o reac h t he o pti mal d ose of i ns uli n glar gi ne as s o o n as 
p ossi ble. T he patie nt will be re q ueste d t o perf or m i ns uli n d os e assess me nt o nce wee kl y d uri n g 
t his perio d. Res ults of S M B G a n d h y p o gl yce mic e ve nts will be use d b y t he patie nt t o assess 
i ns uli n glar gi ne d oses per t he titrati o n al g orit h m. A d dit i onal assess me nts ma y be re q ueste d b y 

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t he i n vest i gat or base d o n his or her cli nical j u d g me nt.  O utc o me of t he assess me nt will be 
rec or de d i n patient  diaries.
C o m plia nce wi t h st u d y dr u g a d mi nistrati o n sc he d ule a n d c o mplia nce wi t h t he i ns uli n glar gi ne 
titr atio n al g ori t h m will be assesse d at e ver y office visit a n d c ollecte d i n t he e C R F at pres pecifie d 
visit s (Secti o n 2 ). Base d o n t he o utc o me of t hese re vie ws, t he site staff s h o ul d disc uss a d ditio nal 
i ns uli n glar gi ne d ose a dj ust me nts w hile t he patie nt is still at t he site a n d pr o vi de retrai ni n g, if 
nee de d.
P ati e nts s h o uld be i nstr ucte d t o c o n tact t he i n vesti gati ve site f or assista nce as s o o n as p ossi ble if 
t he y e x perie nce a n y diffic ulties a d mi nisteri n g t heir st u d y dr u gs or wi t h t he titratio n al g ori t h m at 
a n y ti me d uri n g t he st u d y.  Patie nts s h o uld als o be a d vise d a b o ut t he a p pr o priate c o urse of act i on 
i n t he e ve nt t hat st u d y dr u g is n ot ta ke n as i nstr ucte d (f or e xa m ple; missi n g d oses).
St u d y Peri o d I II ( Safet y F oll o w -u p P eri o d)
S afety f oll o w -u p ( Visit 8 0 1) visits:

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 
safety f oll ow- u p visi t, a p pr o xi matel y 4 wee ks after t heir last visit.  

P ati e nts disc o nti n ui n g t he st u d y earl y a n d perf or mi n g a n early ter mi nat i on ( E T) visit will 
als o be as ke d t o perf or m t he safet y f oll ow- u p visit, s o t hat t he safet y 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, pati e nt s will n ot recei ve st u d y dr u g.

P ati e nts will be treate d wit h a n ot her gluc ose -l oweri n g i nter ve nt i on deci de d u p o n b y t he 
i n vesti gat or.  I nitiati on of ne w a nt i h y per gl yce mic t hera p y f or t he safety f oll ow- u p peri o d 
will n ot be classifie d as “resc ue t hera p y . ”

P ati 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 perio d.
St u d y Pr oce d ures
P ati e nts will p erfor 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 h er 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 a n d/ or after 
earl y st u d y dr u g disc o nti n uati on.  Resc ue t hera p y  wit h ot her gluc ose -l oweri n g a ge nts, i ncl u di n g 
pra n dial i ns uli n, ma y be me dicall y  in dicat e d i n certai n sit uat i ons after ra n d o mizati o n d ue t o
se vere, persiste nt h y per gl yce mia or earl y disc o nt i n uati o n of st u d y treat me nt.  Gl uca g o n -li ke 
pe pti de- 1 rece pt or a g o nists, dipe pt i dyl pe pt i dase ( 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 on s a n d are n ot all o we d as resc ue t hera pies.  N o ot her basal i ns uli ns are 
all o we d d uri n g t he c o urse of t he st u d y.

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P ati e nts w h o de vel o p se vere, persiste nt h yper gl yce mia base d o n pres pecifie d t hres h o l ds (see 
Secti o n 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 st u d y u ntil t he y c om p lete 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 of a p pr o xi matel y 4 7 2 pat ient s ( 1 1 8 patie nts per treat me nt gr o u p or place b o) will be 
ra n d omize 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 al e f or St u d y D e si g n
St u d y  G P GI is desi g ne d t o deter mi ne t he c o m parati ve be nefits a n d ris ks of Q W tirze patide 
( 5 m g, 1 0 m g, or 1 5 m g ) vers us place b o i n patient s wit h T 2 D M w h o ha ve i na de q uate gl yce mic 
c o nt r ol o n sta ble d oses of i ns uli n glar gi ne wi t h or wit ho ut met f or mi n.
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
vers us a place b o i n at least o ne st u d y.  T he pl a 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. M ore o ver, t he d urati o n of t he 
st u d y is c o nsi dere d s ufficie nt a n d a p pr o priate f or patie nts t o o pti mize d osi n g of i ns uli n glar gi ne 
i n t he place b o gr o u p f or c o m paris o n wit h t he tirze pati de treat me nt gr o u ps wit h res pect t o c ha n ge 
i n H b A 1c.
T he parallel - gr o u p desig 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 st u d y 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, patie 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 ).  Metf or mi n was c h ose n as all o we d c o nc o mit a nt a nti h y per gl yce mic 
me dicat i on as it i s c om m o nl y  use d i n c o m bi nati on wi t h basal i ns uli n i n cli nical practice.
5. 5.
J u stifi c ati o n f or D o s e
Ti rze patid e d oses of 5 m g, 1 0 m g, a n d 1 5 m g 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 ole ra bilit y data f ollo we d b y  e xp os ure 
res p o nse m o deli n g of data i n patie nts wit h T 2 D M i n P hases 1 a n d 2 st u dies.  D osi n g al g orit h ms 
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  

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4-week would permit time for development of tolerance to GI events and are predicted to 
minimize GI tolerability concerns.
The maximum proposed dose of 15 mg maintains an exposure multiple of 1.6 to 2.4 to the 
no-observed adverse effect level doses in 6-month monkey and rat toxicology studies.
The selected dose and escalation scheme would enable further evaluation of benefit/risk 
considerations for 5 mg, 10 mg, and 15 mg doses of tirzepatide.

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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 b ee n dia g n ose d wit h T 2 D M base d o n t he Worl d H ealt h Or ga nizati on
classificat i on or ot her l ocall y a p plica ble dia g n ostic sta n dar ds a n d ha ve bee n 
treate d wit h i ns uli n glar gi ne ( U 1 0 0), o nce dail y wit h or wit ho ut m etfor m i n 
≥3 m o nt hs pri or t o Visit 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 ≤1 0. 5 % ( 9 1 m m ol/ m ol), as deter mi ne d b y 
t he ce ntral la b orat or y at Visit 1
[ 3] Ha ve bee n o n sta ble d oses of o nce -dail y i ns uli n glar gi ne ( > 0. 2 5 U/ k g/ da y or 
> 2 0 U/ da y ) a n d metf or mi n (if ta ke n) d uri n g t he 3-m o nt h peri o d pri or t o Vi sit 1.  
Ins uli n glar gi ne d os e i s c o nsi dere d sta ble w he n all d oses d uri n g t his peri o d are 
wi t hi n t he ra n ge defi ne d b y ± 2 0 % of t he most c o m m o nl y  use d i ns uli n d ose d uri n g 
t his sa me peri o d.  D oses of metf or mi n are c o nsi dere d sta ble if all prescri be d d oses 
d uri n g t hi s perio d are i n t he ra n ge bet wee n t he mi ni m u m re q uire d d ose 
(≥1 5 0 0 m g/ da y ) a n d t he ma xi m u m a p pr o ve d d ose per t he locall y  a p pr o ve d label
[ 4] Re q ui r e furt her i ns uli n glar gi ne d ose i ncrease at Visit 3 per t he T T T al g orit h m 
base d o n t he S M B G data c ollecte d d uri n g t he pri or wee k
[ 5] Are of sta ble wei g ht ( ± 5 %) ≥3 m o nt hs pri or t o Visit 1 a n d a gree t o n ot i nit iate a 
di et a n d/ or e xercise pr o gra m d uri n g t he st u d y wit h t he i nte nt of re d uci n g b o d y 
w ei g ht ot her t ha n t he lifest yle a n d dietar y me as ures f or dia betes treat me nt
[ 6] Ha ve b o d y  mass i n de x ( B MI) ≥2 3 k g/ m 2 at Visit 1
[ 7] 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 di n g t o 
l ocal re g ulatio ns, w hic he ver is ol der
(a) Mal e patie nts:

Male patie nts s h o ul d be wi lli 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 (A p pe n di x 6 )
( b) Fe male patie nts:

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
Female patients not of childbearing potential due to surgical sterilization 
(hysterectomy or bilateral oophorectomy or tubal ligation), congenital anomaly 
(i.e., Mullerian agenesis) or menopause.
o
Women with an intact uterus are deemed postmenopausal if they are 45 
years old, and

have not taken hormones or oral contraceptives within the last year 
and had cessation of menses for at least 1 year,
OR

have had at least 6 months and less than 12 months of spontaneous 
amenorrhea with follicle-stimulating hormone (FSH) and estradiol 
levels consistent with a postmenopausal state (FSH ≥40 mIU/mL 
and estradiol <30 pg/mL).
o
Female patients of childbearing potential (not surgically sterilized and
between menarche and 1-year postmenopausal) must:

test negative for pregnancy at Visit 1 based on a serum pregnancy 
test
AND

if sexually active, agree to use 2 forms of effective contraception, 
where at least one form is highly effective for the duration of the 
trial and for 30 days thereafter 

not be breastfeeding
[8] In the investigator’s opinion, are well-motivated, capable, and willing to: 
(a)
perform fingerstick BG monitoring, including scheduled BG profiles with up to 7 
measurements in 1 day 
(b)
learn how to self-inject study drugs as required for this protocol (visually impaired 
persons who are not able to perform the injections must have the assistance of a 
sighted individual trained to inject the study drug; persons with physical limitations 
who are not able to perform the injections must have the assistance of an individual 
trained to inject the study drug) 
(c)
are willing and able to inject study drugs
(d)
maintain a study diary, as required for this protocol
(e)
have a sufficient understanding of one of the provided languages of the country 
such that they will be able to complete the patient questionnaires
Informed Consent
[9] Have given written informed consent to participate in this study in accordance 
with local regulations and the ethical review board (ERB) governing the study site

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6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at 
screening:
Medical Conditions
[10] Have type 1 diabetes mellitus (T1DM)
[11] Had chronic or acute pancreatitis any time prior to study entry (Visit 1)
[12] Have history of:

proliferative diabetic retinopathy 
or 

diabetic maculopathy 
or

nonproliferative diabetic retinopathy that requires acute treatment
(a dilated fundoscopic examination performed by an ophthalmologist or 
optometrist between Visit 2 and Visit 3 is required to confirm eligibility) 
[13] Have a history of severe hypoglycemia and/or hypoglycemia unawareness within 
the 6 months prior to Visit 1
[14] Have a history of diabetic ketoacidosis or hyperosmolar state/coma 
[15] Have a known clinically significant gastric emptying abnormality (for example, 
severe diabetic gastroparesis or gastric outlet obstruction), have undergone or 
plan to have during the course of the study:  a gastric bypass (bariatric) surgery 
or restrictive bariatric surgery (for example, Lap-Band®), or chronically take 
drugs that directly affect GI motility
[16] Have any of the following cardiovascular (CV) conditions within 2 months prior 
to Visit 1:  acute myocardial infarction, or cerebrovascular accident (stroke) or 
hospitalization due to congestive heart failure (CHF)
[17] Have New York Heart Association Functional Classification III and IV CHF
[18] Have acute or chronic hepatitis, signs and symptoms of any other liver disease 
other than nonalcoholic fatty liver disease (NAFLD), or alanine aminotransferase 
(ALT) level >3.0 times the upper limit of the reference range, as determined by 
the central laboratory at study entry; patients with NAFLD are eligible for 
participation in this trial only if their ALT level is ≤3.0 times the upper limit of 
normal (ULN) for the reference range
[19] Have an estimated glomerular filtration rate <30 mL/min/1.73 m2, calculated by 
Chronic Kidney Disease-Epidemiology as determined by central laboratory at 
Visit 1; for patients on metformin, estimated glomerular filtration rate 
<45 mL/min/1.73 m2 (or lower than the country-specific threshold for using the 
protocol-required dose of metformin per local label)

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[20] Have evidence of a significant, uncontrolled endocrine abnormality (for 
example, thyrotoxicosis or adrenal crises), in the opinion of the investigator
[21] Have family or personal history of medullary thyroid carcinoma (MTC) or 
multiple endocrine neoplasia syndrome type 2
[22] Have a serum calcitonin level of ≥35 ng/L, as determined by central laboratory at 
Visit 1
[23] Known or suspected hypersensitivity to trial product(s) or related products
[24] Have evidence of a significant, active autoimmune abnormality (for example, 
lupus or rheumatoid arthritis) that, in the opinion of the investigator, is likely to 
require concurrent treatment with systemic glucocorticoids in the next 12 months
[25] Have had a transplanted organ (corneal transplants [keratoplasty] allowed) or 
awaiting an organ transplant
[26] Have a history of an active or untreated malignancy or are in remission from a 
clinically significant malignancy (other than basal or squamous cell skin cancer, 
in situ carcinomas of the cervix, or in situ prostate cancer) for less than 5 years
[27] Have a history of any other condition (such as known drug, alcohol abuse, or 
psychiatric disorder) that, in the opinion of the investigator, may preclude the 
patient from following and completing the protocol
[28] Have any hematological condition that may interfere with HbA1c measurement 
(for example, hemolytic anemias and sickle cell disease)
Prior/Concomitant Therapy
[29] Treatment with any glucose-lowering agent(s) other than stated in the inclusion 
criteria [4] in a period of 3 months prior to Visit 1 and between Visit 1 and 
Visit 3
[30] Have been treated with prescription drugs that promote weight loss (for example, 
Saxenda [liraglutide 3.0 mg], Xenical® [orlistat], Meridia® [sibutramine], 
Acutrim® [phenylpropanolamine], Sanorex® [mazindol], Apidex® [phentermine], 
BELVIQ® [lorcaserin], Qsymia™[phentermine/topiramate combination], 
Contrave® [naltrexone/bupropion], or similar other body weight loss medications 
including over-the-counter (OTC) medications [for example, allī®]) within 3 
months prior to Visit 1 and/or between study entry (Visit 1) and randomization 
(Visit 3)
[31] Are receiving chronic (>2 weeks or 14 days) systemic glucocorticoid therapy 
(excluding topical, intraocular, intranasal, or inhaled preparations) or have 
received such therapy within 1 month of Visit 1 or between Visits 1 and 3
Prior/Concurrent Clinical Trial Experience
[32] Are currently enrolled in any other clinical study involving an investigational 
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I 8 F-M C -G P GI( b ) Cli ni c al Pr ot o c ol
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me dicall y c o m pat i ble wit h t his st u d y
[ 3 3] 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 a l o n g 
half -life, 5 half-li ves or 3 0 da ys ( w hic he ver is lo n ger) s h o ul d ha ve passe d
[ 3 4] Ha ve pre vi o usl y c o m p lete d or wit h dra w n fr om 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
Ot her E xcl usi o ns
[ 3 5]
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 ol ogi c al or le gall y a d o pt e d
[ 3 6]
Are Lill y e m plo y ees 
[ 3 7]
Are u n willi n g or u na ble t o c o m pl y wit h t he use of a pa per diar y t o directl y 
rec or d data fr o m t he s u bject
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 o n 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 crit erio n [ 5 ] 
( Sectio n 6 ), patie nts s h o uld n ot i ni tiate d uri n g t he st u d y a n or ga nize d diet a n d/ or e xercise wei g ht 
re d uctio n pr o gra m 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 artici pa nts s h o uld 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 GI( b ) Cli ni c al Pr ot o c ol
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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
Eli gi bilit y f or t his st u d y will be deter mi ne d at t he i nitial scree ni n g visit ( Visit 1).  Scree ni n g 
pr oce d ures a n d patie nt trai ni n g will be perf or me d at Visits 1 a n d 2 (scre e ni n g a n d lea d -i n 
p eri o ds).  Pati e nt trai ni n g will i ncl u de disease m o nit ori n g a n d ma na ge me nt pr oce d ures, st u d y  
di aries, a n d st u d y pr oce d ures.  At Visit 3, p atie nts will p erfor 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 ollecti o n o f all baseli ne la b orat or y meas ures a n d E C G) prior 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.  F oll o wi n g ra n d o mizat i on, t he 
pati e nt will i nject t he first d ose of st u d y dr u g/ place b o at t he st u d y sit e.  T he date a n d ti me of all 
d ose s of  st u d y dr u g s h o uld be rec or de d o n t he electr o nic case re p ort f or m ( e C R F).  Be gi n ni n g at 
ra n d omizat i on, all pat ient s will recei ve st u d y dr u g acc or di n g t o t he ra n d o mize d treat me nt gr o u p
f or t he d uratio n of  t he 4 0 -wee k treat m e nt perio d.  A safet y f oll ow- u p visit will occ ur 
a p pr o xi matel y 4 wee ks f ollo wi n g t he l ast d ose of t he st u d y dr u g.
7. 1. 1.
Tir z e p ati d e D o si n g 
T he starti n g d ose of tirze pat i de will be 2. 5 m g o nce wee kl y f or 4 wee ks, f oll o we d b y a n i ncrease 
t o 5 mg o nce wee kl y, f or t he d urat i on of t he st u d y  i n 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 o nce wee kl y 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 t o 5 t o 7. 5 t o 1 0 m g) 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 tirze pati de 
will be 2. 5 m g o nce wee kl y  for 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 t o 5 t o 7. 5 t o 1 0 t o 1 2. 5 t o 1 5 m g) 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 o f t he st u d y.
7. 1. 2.
Pl a c e b o D o si n g
P ati e nts ra n d o mize d t o t he place b o gr o u p will i nject matc he d place b o s u bc uta ne o usl y  Q W for 
t he e nt ire treat me nt perio d. T hi s is a d o u ble- bli n d st u d y , a n d t heref ore it will not 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 .
7. 1. 3.
I n s uli n G l ar gi ne D o si n g
I ns uli n glar gi ne will be i njecte d o nce dail y, as a si n gle S C i njecti on, al wa ys at t he sa m e ti me of 
d a y , i deall y at be dti me.  P atie nts will be i nstr ucte d t o a dj ust i ns uli n glar gi ne d oses t o a tar g et 
F B G of  < 1 0 0 mg/ d L ( 5. 5 m m ol / L) acc or di n g t o t he sc he d ule bel o w (Ta ble G P GI. 3 ). F or t his 
p ur p ose, patie nts will be re q uire d t o meas ure t heir F B G eac h mor ni n g a n d t o c ollect 4 -p oi nt 
S M B G pr ofiles at least o nce a wee k . T he 4 -p oi nt S M B G pr ofile will c o nsist of fast i ng , pre -
mi d da y  me al, pr e-e ve ni n g meal, a n d be dt i me meas ures. Patie nts will c o llect t he 4- p oi nt S M B G 
pr ofiles o nce wee kl y bet wee n Visit 2 a n d Visit 3, t wice wee kl y fr o m Visi ts 3-7 ( Wee ks 0 -4) 
f oll owe d b y o nce wee kl y  for t h e r e m ai n der of t he st u d y.

I 8 F-M C -G P GI( b ) Cli ni c al Pr ot o c ol
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T a bl e G P GI. 3.
Tr e at -t o-T ar g et A l g orit h m 
Me di a n F asti n g Bl o o d Gl uc ose
a
A dj ust me nt of I ns uli n Gl ar gi ne if 
D ose is < 2 0 U nits
A dj ust me nt of I ns uli n Gl ar gi ne if 
D ose is ≥2 0 U nits
m g/ d L
m m ol/ L
≤7 0
≤3. 9
−1 o r −2 u nitsb, c
−2 t o 4 u nits b, c
7 1 t o 1 0 0
4. 0 t o 5. 5
N o a dj ust me nt
N o a dj ust me nt
1 0 1 t o 1 1 9 
5. 6 t o 6. 6
+ 1 u nits
+ 2 u nits
1 2 0 t o 1 3 9 
6. 7 t o 7. 7
+ 2 u nits
+ 4 u nits
1 4 0 t o 1 7 9
7. 8 t o 9. 9
+ 3 u nits
+ 6 u nits
≥1 8 0
≥1 0. 0
+ 4 u nits
+ 8 u nits
A b bre viati o n:  S M B G = self -m o nit ore d bl o o d gl uc ose.
a
Base d o n t he last 3 S M B G val ues.
b
D ose s h o ul d als o be decrease d b y 1 t o 2 u nits or 2 t o 4 u nits i n t he f oll o wi n g sit uati o ns:
If m ulti ple e pis o des of n o nse vere h y p o gl yce mia were rec or de d d uri n g t he assess me nt peri o d at a n y ti me d uri n g 
t he da y; a n d/ or
If at least 1 e pis o de t hat met t he criteria f or se vere h y p o gl yce mia (e ve nts re q uiri n g assista nce of a t hir d pers o n t o 
a d mi nister th e ra p y) or was ass ociate d wit h S M B G val ue < 5 4 m g/ d L ( < 3. 0 m m ol/ L) was rec or de d d uri n g t he 
assess me nt peri o d.
c
If o nl y 1 h y p o gl yce mic e pis o de wit h S M B G val ue ≥5 4 m g/ d L ( ≥3. 0 m m ol/ L) a n d ≤7 0 m g/ d L ( ≤3. 9 m m ol/ L) was 
rec or de d, i ns uli n d ose s h o ul d n ot be c ha n ge d.
S o urce:  A da pte d fr o m Ri d dle et al. 2 0 0 3.
T he site pers o n nel will i nstr uct t he patie nt, wit h t he patie nt i ns uli n d ose a djust me nt fr om t he 
pati e nt diar y a n d st u d y-s pecific trai ni n g materials pr o vi de d t o t he st u d y sites, w he n a n d h o w t o 
assess w het her a n i ns uli n d ose a dj ust me nt  is nee de d usi n g t he al g orit h m. T he i n vesti gat or or his
or her desi g nee is res p o nsi ble t o e ns ure t hat t he i ns uli n d ose titrati o n re gi me n use d b y st u d y 
parti ci pa nts f o ll ows t he sa m e re q uire me nts defi ne d i n t he T T T pla n t hro u g h o ut t he st u d y . T he 
pati e nt is res p o nsi ble f or c o m pleti n g t he i ns uli n d ose assess me nts a n d ma ki n g t he re q uire d d ose 
a djust m e nts (self-a dj ust me nt ). Assess me nt of i ns uli n d oses per t he T T T al g orit h m a n d 
a d mi nistere d i ns uli n d oses will be rec or de d b y t he pati e nt i n st u d y p erio d -s pecific diaries. 
P ati e nts s h o uld be i nstr ucte d t o c o n tact t he st u d y site if t he y are u na ble t o decide o n t he 
a p pr o priate d ose a dj ust me nt  at a n y ti me d uri n g t he trial. Si te pers o n nel will verif y at eac h office 
or tel e p h o ne visit t hat t he assess me nt(s) has bee n ma de a n d t hat t he i ns uli n a dj ust me nt was 
a p pr o priate. If nee de d, t he y will pr o p ose f urt her a dj ustme nt s base d u p o n t heir re vie w of data 
c ollecte d si nce t he pre vi o us visit. If assess me nts were n ot ma de or t he al g orit h m was not 
c orrectl y foll o we d, pati e nts will recei ve a d ditio n al trai ni n g a n d i nstr uctio ns. 
D uri n g t he l ea d-i n peri o d ( Visits 2 a n d 3 [ baseli ne]), i ns uli n d oses s h o ul d be a dj uste d per T T T 
alg ori t h m (Ta ble G P GI. 3 ) o nl y w he n nee de d t o pr otect t he safet y of  patie nts ( occ urre nce of 
h y p o gl yce mia or se vere persiste nt h y per gl yce mia). See Secti o n 5. 1 f or more details. I ns uli n 
d ose assess me nts d uri n g t his peri o d will occ ur o nce per wee k. 
D uri n g t he treat me nt peri o d, office visits will occ ur wee kl y or e ver y ot her wee k d uri n g t he first 2 
m o nt hs , a n d t hereafter e ver y 4 t o 8 wee ks t o e na ble t he site t o pr o perl y mo ni t or p atie nts’ usa ge
of  t he T T T alg ori t h m. After ra n d o mizati o n, d uri n g t he 4 -wee k sta bilizat i on peri o d, t he i ns uli n

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gl ar gi ne d ose will re mai n u nc ha n ge d if t he pat ient ’s baseli ne ( Visit 3) H b A 1c is > 8. 0 %. F or
pati e nts wit h baseli ne H b A 1c ≤8. 0 %, t he i ns uli n glar gi ne d ose will be decrease d b y 2 0 %
i m me diatel y ( wit hi n 7 da ys) after ra n d o mizati o n a n d will t he n re mai n u nc ha n ge d d uri n g t he
sta bilizati o n peri o d. A d dit i onal i ns uli n d ose a dj ust me nts d uri n g t he sta bilizati on peri o d will o nl y
be all o we d usi n g t he T T T al g orit h m ( Ta ble G P GI. 3 ) i n case of t he occ urre nce of h y p o gl yce mia 
or t he de vel o p me nt of se vere h y per gl yce mia. See Secti o n 5. 1 f or more details.   Patie nts will be 
re q ueste d t o perf or m i ns uli n d ose assess me nts t wice per wee k d uri n g t he sta bilizati on peri o d f or 
safety p ur p ose s. F oll o wi n g sta bilizat i on, pati e nts will be treate d f or a n a d dit i onal 3 6 wee ks, a n d 
t he y will be re q uire d t o assess t heir i ns uli n glar gi ne d ose o nce wee kl y, usi n g t he F B G val ues f or 
t hat wee k. D uri n g t his peri o d, t he i ns uli n d ose will be a dj uste d per t he T T T al g orit h m as 
descri be d i n Secti o n 5. 1 wi t h n o restrictio n. T he decisi o n t o a dj ust i ns uli n glar gi ne d oses will be 
base d u p o n t he me dia n o f t he last 3 dail y F B G ( S M B G) val ues c ollecte d aft er t he pre vi o us d ose 
assess me nt. If o nl y 2 val ues are a vaila ble f or assess me nt, t he n t he a vera ge val ue will be 
calc ulate d a n d use d t o a dj ust t he d ose. If o nl y o ne val ue is a vaila ble, t he patie nt s h o ul d c o ntact 
t he i n vest i gat or site f or i nstr ucti o ns o n a dj usti n g i ns uli n d ose. I n case of rec or de d h y p o gl yce mic 
e pis o des a n y time d uri n g t he peri o d i ncl u de d i n t he assess me nt, t he criteria pr o vi de d i n 
Ta ble G P GI. 3 s h o ul d be f oll owe d.
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, a n d after earl y 
st u d y dr u g disc o nti n uati on.  Resc ue t hera p y  wit h ot her gluc ose -l oweri n g a ge nts, i ncl u di n g 
pra n dial i ns uli n, ma y be me dicall y  in dicate d i n certai n sit uat i ons after ra n d o mizati o n d ue t o
se vere, persiste nt h y per gl yce mia or earl y disc o nt i n uati o n of st u d y treat me nt.  Resc ue treat me nt 
wi t h G L P -1 rece pt or a g o nis ts, pra mli nt i de, D P P-4 i n hi bit ors or ot her basal i ns uli ns will  not be 
all o we d.   S h ort -t er m tr e at me nt wit h a n o nst u d y ins uli n f or l ess t ha n 1 4 da ys is allo w e d f or 
certai n cli nical sit uati o ns (f or e xa m ple, elect i ve s ur ger y, d uri n g h os pitalizati on, h y per os m o lar 
states).  If i ns uli n is prescri be d as a resc ue t hera p y, it must be differe nt iate d fr o m s h ort-t er m use 
of  ins 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.
All n o nst u d y  me dicatio ns will be rec or de d o n s o urce d oc u me nts at all visit s.
N o n st 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 S A E or A E occ urs t hat t he i n vesti 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. 1. 4.
P a c k a gi n g a n d L a b elli n g
T he s p o ns or 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 
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7.1.5. Medical Devices
The combination products used in the study are tirzepatide investigational SDP and a marketed 
insulin glargine prefilled pen.
7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be randomized to one of the study treatment 
groups at Visit 3.  Assignment to treatment groups will be determined by a computer-generated 
random sequence using an IWRS.  Patients will be randomized in a 1:1:1:1 ratio to receive 
tirzepatide 5 mg, 10 mg, 15 mg, or placebo.
7.2.1. Selection and Timing of Doses of Study Drug
Assignment to tirzepatide (3 doses) or placebo will occur at randomization.  
There are no restrictions on the time of day each weekly dose of study drug is given, but it is 
advisable to administer the SC injections on the same day and same time each week.  The actual 
date and time of all dose administrations will be recorded by the patient.  If a dose of study drug 
is missed, the patient should take it as soon as possible unless it is within 72 hours of the next 
scheduled dose, in which case, that dose should be skipped and the next dose should be taken at 
the appropriate time.  
All patients will inject study drug subcutaneously in the abdomen or thigh using the SDP; a 
caregiver may administer the injection in the patient’s upper arm. A new SDP will be used for 
each injection. If study drug is to always be injected in the same body region, patients should be 
advised to use a different injection site each week.
7.3.
Blinding
This is a double-blind study.
To preserve the blinding of the study, a minimum number of Lilly personnel will see the 
randomization table and treatment assignments before the study is complete.
Emergency codes, generated by a computer drug-labeling system, will be available to the 
investigator.  These codes, which reveal the patient’s treatment group when opened, may be 
opened during the study ONLY if the patient’s well-being requires knowledge of the patient’s 
treatment assignment.
Emergency unblinding for AEs may be performed through the IWRS, which may supplement or 
take the place of emergency codes generated by a computer drug-labeling system.  This option 
may be used ONLY if the patient’s well-being requires knowledge of the patient’s treatment 
assignment.  All calls resulting in an unblinding event are recorded and reported by the IWRS.
If an investigator, site personnel performing assessments, or patient is unblinded, the patient
must be discontinued from the study.  In cases where there are ethical reasons to have the patient
remain in the study, the investigator must obtain specific approval from a Lilly clinical research 
physician (CRP) for the patient to continue in the study.

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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 pati e 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 
p atie nt safety m u st alwa ys be t he first c o nsi derat i on 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 gn 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.
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 on 7. 1 .
7. 4. 2.
R e d u cti o n a n d/ or Di s c o nti n u ati o n of C o n c o mit a nt 
A nti h y p er gl y c e mi c M e di c ati o n s
1)
If i ncrease d ris k of h y p o gl yce mia d uri n g t he peri o d bet wee n 2 i ns uli n d ose assess me nts is 
j u d ge d t o be relate d to t he treat me nt re gi me n, t he f oll o wi n g c ha n ges s h o ul d be ma de:

Decrease t he i ns uli n glar gi ne d ose b y  2 t o 4 U, per t he T T T al g orit h m, i n t he 
f oll owi n g cases:
o
If t he me dia n F P G val ue f or t he assess me nt peri o d is ≤7 0 m g/ d L ( ≤3. 9 
m m o l/ L); a n d/ or
o
If m ult i ple epis o des of n o nse vere h y p o gl yce mia were rec or de d at a n y  time 
d uri n g t he da y  for t he assess me nt peri o d; a n d/ or
o
If at least 1 e pis o de t hat met t he criteria f or se vere h y p o gl yce mia (e ve nts 
re q uirin g assista nce t o a d mi nister t hera p y ) or was ass ociate d wit h S MB G
val ue < 5 4 m g/ d L ( < 3. 0 m m o l/ L) was rec or de d d uri n g t he assess me nt 
p eri o d;

I n t he case of re peate d h yp o gl yce mic e ve nts, e ve n wit h a ver y  lo w glar gi ne d ose 
a n d des pite glar gi ne d ose decreases per t he T T T al g orit h m, a d mi nistrati o n of 
i ns uli n glar gi ne ma y be te m p oraril y or per ma ne nt l y disc o nti n ue d;

If i ncrease d ris k of h y p o gl yce mia persists des pite disc o nti n uati on of i ns uli n 
gl ar gi ne, t he n d ose re d ucti o n or disc o nt i n uati on of met f or mi n (f or patie nts w h o 
are ta ki n g it) s h o ul d be c o nsi dere d.
2)
I n certai n sit u atio ns s h ort -t er m disc o nti n uati on will be re q uire d i n li ne with t he pr o d uct(s) 
la beli n g f or eac h res pecti ve c o u ntr y (f or e xa m ple, f or metf or mi n:  se vere de h y drati on, 
elect i ve s ur ger y, or nee d f or ra di ol ogi c e xa mi nat i on i n v ol vi n g I V i o di nate d c o ntrast dye). 
O nce t he sit uat i on t hat l e d t o te mp orar y  disc o nti n uati o n of t he dr u g res ol ve d, treat me nt 
s h o uld be restarte d at i n vest i gat or discreti o n.

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3) If a patient develops contraindications to metformin (if used), such that the use of the 
drug is contraindicated according to the country-specific label, the drug should be 
discontinued; in this case, the insulin glargine dose may need to be further adjusted.
A patient will be considered noncompliant with the protocol (protocol deviation) if he or she 
changes the dose or discontinues metformin (if used) for reasons other than those described here.  
In the case of noncompliance that lasts >14 days during the treatment period, the patient will not 
be included in the per-protocol analyses.
7.5.
Preparation/Handling/Storage/Accountability
The investigator or his or her designee is responsible for the following:

confirming appropriate temperature conditions have been maintained during 
transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment.

ensuring that only participants enrolled in the study may receive study treatment 
and only authorized site staff may supply or administer study treatment. All study 
treatments must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions 
with access limited to the investigator and authorized site staff.

the investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (such as receipt, reconciliation and final disposition records).
The study site must store the study drug in a locked and secure environment. Please refer to the 
study drug label for specific storage conditions.  Patients will receive insulated bags with cooling 
gel packs for use in transporting the study drug carton from the site to home. 
Study site staff must regularly assess whether the patient is correctly administering the assigned 
study drug and storing the study drug according to the provided instructions. 
7.6.
Treatment Compliance
Study drug compliance will be determined by the following: 

Study drug administration data will be recorded by the patient and reviewed by 
the investigator at each study visit.

The patients will be instructed to return any unused study drug and/or empty 
cartons at the next visit to the study site for the purpose of performing drug 
accountability.
In the 3 tirzepatide treatment groups, as well as the placebo group, treatment compliance for each 
visit interval is defined as taking at least 75% of the required doses of study drug.  Patients will 
be considered to be noncompliant with their insulin glargine treatment if they miss their daily 
dose of insulin glargine for more than 7 consecutive days or for more than 7 days within a month 
(that is, a patient is considered to be compliant if they are ≥75% compliant with their required 

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insulin glargine therapy).  Similarly, a patient will be considered noncompliant if he or she is 
judged by the investigator to have intentionally or repeatedly taken more than the prescribed 
amount of medication.  
In addition to the assessment of a patient’s compliance with the study drug administration, other 
aspects of compliance with the study treatments will be assessed at each visit based on the 
patient’s adherence to the visit schedule, completion of study diaries, the results of home BG 
monitoring, and any other parameters the investigator considers necessary.
Patients considered not to be compliant with their medication and/or the study procedures will 
receive additional training and instruction, as required, and will be reminded of the importance of 
complying with the protocol. 
7.7.
Concomitant Therapy
Patients will be permitted to use concomitant medications that they require during the study, 
except certain medications that may interfere with the assessment of efficacy and safety 
characteristics of the study treatments.
Investigative site staff will inform patients that they must consult with the investigator or a 
designated site staff member upon being prescribed any new medications during the study.  This 
may not be possible when initiated for treatment of medical emergencies, in which case, the 
patient will inform the investigator or a designated site staff member as soon as possible.  Any 
additional medication initiated during the course of the study (including OTC drugs, such as 
paracetamol or aspirin) must be documented, and the name of the drug and the date(s) of 
administration must be recorded on the “Concomitant Medications” section of the eCRF. 
Antihyperglycemic medications other than study drugs are not allowed at any time during the 
study except as allowed for those patients who require permanent discontinuation of study drug, 
but remain in the study; rescue therapy after randomization due to severe, persistent 
hyperglycemia; or during the safety follow-up period.  Glucagon-like peptide-1 receptor 
agonists, DPP-4 inhibitors, pramlintide, and other basal insulins are prohibited medications and 
are not allowed as rescue therapies.
All nonstudy medications will be recorded on the eCRF at all visits.
Nonstudy medications taken by patients who are screened, but not randomized will not be 
reported to Lilly unless an SAE or AE occurs that the investigator believes may have been 
caused by a study procedure.
7.7.1. Management of Patients with Gastrointestinal Symptoms
In the Phase 2 program, the most commonly reported treatment-emergent AEs (TEAEs) for 
patients receiving tirzepatide were nausea, vomiting, and diarrhea.  
The tirzepatide dose escalation scheme has been designed to minimize the development of 
intolerable GI symptoms.  The escalation period is considered to be 24 weeks, which allows 

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2 0 wee ks t o escalate t o 1 5 m g a n d a d diti 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 escalate a n d mai ntai n 
pati e 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 mana ge pati e nts wit h int ol era ble GI A Es d uri n g t he escalat i on 
p eri o d ( Wee k s 0 t o 2 4) , t he i n vesti gat or s h o ul d:

A d vise patie nts t o eat s maller meals, f or e xa m ple, s plitt i n g 3 dail y meals i nt o 4 or m ore 
s maller meals, a n d t o st o p eati n g w he n t he y feel f ull.

Pr escri be s y m pt o mat ic me dicatio n (f or e xa m ple, a nt i-e metic or a nti diarr heal me dicat i on) 
per l o c al  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.

T e m p oraril y  int err u pt tirze pati de ( o mit 1 d ose, t he patie nt will ta ke 3 of 4 d oses at t hat 
d ose l e 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 dicat i 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  int err u ptio n of  
st u d y tr e at me nt s h o uld be d oc u m e 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 vest i gat or 
ma y deci de t o disc o nt i 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.  
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 nt i on ( Secti o n 8. 1. 1 ) a n d will c o nti n ue partici pati 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 safety 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 ollect i n g 
a nt i 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 he escalati o n peri o d 
(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 .  
7. 8.
Tr e at m e nt aft er t h e E n d of t h e St u d y
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 has 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.

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8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
8.1.1. Permanent Discontinuation from Study Treatment
Possible reasons leading to permanent discontinuation of investigational product:

Patient Decision
o
the patient requests to discontinue investigational product.

Discontinuation due to a hepatic event or liver test abnormality.  Patients who are 
discontinued from investigational product due to a hepatic event or liver test abnormality 
should have additional hepatic safety data collected via electronic case report form.
Discontinuation of the investigational product for abnormal liver tests should be
considered by the investigator when a patient meets one of the following conditions after 
consultation with the Lilly designated medical monitor:
o
ALT or aspartate aminotransferase (AST) >8X ULN
o
ALT or AST >5X ULN for more than 2 weeks
o
ALT or AST >3X ULN and total bilirubin level (TBL) >2X ULN or 
international normalized ratio (INR) >1.5
o
ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, 
right upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
o
alkaline phosphatase (ALP) >3X ULN
o
ALP >2.5X ULN and TBL >2X ULN
o
ALP >2.5X ULN with the appearance of fatigue, nausea, vomiting, right 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
In addition, patients will be discontinued from the investigational product in the 
following circumstances:
If a patient is inadvertently enrolled and it is determined that continued treatment 
with study drug would not be medically appropriate
Acute or chronic pancreatitis 
If a patient is diagnosed with MTC after randomization, or has postrandomization 
calcitonin value ≥35 ng/L that has increased at least 50% over baseline
If a patient is diagnosed with an active or untreated malignancy (other than basal 
or squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate 
cancer) after randomization
Any significant study drug-related hypersensitivity reaction

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
A n y ot 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.
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 o ll 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 at i 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.  E ver y  eff ort s h o uld b e m a de b y t he i n vesti gat or t o mai ntai n pat ient s 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 or ar y  int err u pti o n, as s o o n as it is safe t o d o s o.  

If t he n u m ber of d oses misse d is ≤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 pri or t o disc o nt i n uati on.

If t he n u m ber of misse d d oses is ≥3, t he n t he I W R S will dispe nse 5 m g/ matc he d pl ace b o
irres pecti ve of t he d ose t he patie nt was recei vi n g bef ore t he i nterr u pti o n a n d s u bse q ue ntl y 
escalate d as re q uire d b y pr ot oc ol.
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 me nte d a n d f o ll owe d acc or di n g 
t o the pr oce d ures i n Secti o n 9. 2 of  t his pr ot oc ol.  If t he st u d y dr u g i nterr u ptio n is d ue t o 
i ntol era 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 Secti on 7. 7. 1 .  
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 ide nt if y a pat ient 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 
st u d y tr e at me nt.  If t he i n vest i gat or a n d t he s p o ns or C R P a gree it is me dicall y a p pr o priate t o 
c o nti n ue, t he i n 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 h o ut treat me nt wit h 
i n vesti gati onal pr o d uct. Safet y f oll ow u p i s as o utli ne d i n Secti on 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 he pr ot oc ol.

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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 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 me s.
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:

enr o ll 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 h er 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 o mpati ble wit h t his st u d y

p artici pat i on i n t he st u d y nee ds t o be st o p pe d f or me dical, safety,  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 nical 
practi ce ( G C P),

if a fe male patie nt bec o mes pre g na nt

if a pat ient  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 nsidere 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 h dra 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 patie 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 be prescri be d a n a p pr o priate gl uc ose -l oweri n g re gi me n a n d 
gl uc ose self -m o nit ori n g pla n. Visit 8 0 1 ( safet y fol l ow- u p v isit) s h o uld 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.
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.

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8.3.
Lost to Follow-Up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Every attempt will be made to minimize 
the number of patients considered lost to follow-up at the end of the study.  Patients will be 
informed about the importance of completing the study and providing updated contact 
information to the study site when necessary.

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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 mit s 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, all sa m ples c ollecte d f or s pecifie d la b orat or y 
tests will be destr o ye d wit hi n 6 0 da ys of recei pt of c o nfir me d test res ults.  Certai n sa m ples ma y 
be retai ne d f or a l o n ger peri o d, if necessar y, t o c o 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 me as 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 
will 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 % ( 5 3 m m ol/ m ol), ≤6. 5 % ( 4 8 
m m o l/ m ol), or < 5. 7 % ( 3 9 m m o l/ m ol)

Mea n c ha n ge i n fasti n g ser u m gl uc ose (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 % 

C ha n ge i n dail y mea n i ns uli n glar gi ne d ose
9. 1. 3.
E x pl or a t 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 assesse 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 waist circ u mfere nce

C ha n ges 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

I W-S P sc ores

D T S Qs/ D T S Qc

E Q - 5 D-5 L sc ores

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9.1.4. Appropriateness of Assessments
Efficacy and safety assessments included in this study are generally regarded as reliable and 
accurate with respect to the efficacy and safety assessments in individuals and populations with 
T2DM.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the to discontinue the investigational product before 
completing the study.  The patient should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation.  The frequency of follow-up evaluations of the AE is left to 
the discretion of the investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.
After the informed consent form (ICF) is signed, study site personnel will record via electronic 
case report form (eCRF) the occurrence and nature of each patient’s preexisting conditions, 
including clinically significant signs and symptoms of the disease under treatment in the study.  
In addition, site personnel will record any change in the condition(s) and any new conditions as 
AEs. Investigators should record their assessment of the potential relatedness of each AE to 
protocol procedure, investigational product, via eCRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment or pathologies.
A “reasonable possibility” means that there is a cause and effect relationship between the
investigational product, study device and/or study procedure and the AE.
The investigator answers yes/no when making this assessment.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
If a patient’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via eCRF, clarifying if possible, the circumstances 
leading to any dosage modifications, or discontinuations of treatment.

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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 pa s 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 b use.
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 eC 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 after si g 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 alerts are iss ue d via tele p h o ne, t he y 
are t o be i m me diatel y f o ll 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 o n a n d all f oll ow- u p S A E
i nf or mat i on. Patie nts wi t h a serio us he pat ic a d verse e ve nt s h o ul d ha ve a d diti onal 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 u lat 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 acti vel y see k A Es or S A Es i n s u bjects o nce t he y ha ve 
di sc o nti n ue d a n d/ or c o m plete d the st u d y (t he pati e nt dis p osit i on case re p ort f or m (C R F ) has bee n 
c o mplete d).  H o we ver, if t he i n vesti gat or lear ns of a n y S A E, i ncl u di n g a deat h, at a n y  ti me after 
a s u bject has bee n disc har ge d fr o m t he st u d y, a n d he or s he c o nsi ders t hat t he e ve nt reas o na bl y 
p ossi bl y  relate d t o t he st u d y treat me nt or st u d y p artici pat i on, t he i n vest i gat or m ust pr o m ptl y 
n otif y Lill y.

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9.2.1.1.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to investigational product or procedure.  
United States 21 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the 
associated detailed guidances or national regulatory requirements in participating countries 
require the reporting of SUSARs.  Lilly has procedures that will be followed for the 
identification, recording and expedited reporting of SUSARs that are consistent with global 
regulations and the associated detailed guidances.
9.2.2. Adverse Events of Special Interest
9.2.2.1.
Hypoglycemia 
Patients will collect information on episodes of hypoglycemia starting from Visit 2 until the last 
study visit (Follow-up Visit or Early Termination Visit).  For that purpose, patients will be 
trained about signs and symptoms of hypoglycemia, how to treat hypoglycemia, and how to 
collect appropriate information for each episode of hypoglycemia in the study according to the 
Schedule of Activities.  Site personnel will enter this information into the eCRF at each visit. 
Investigators should use the following definitions and criteria when diagnosing and categorizing 
an episode considered to be related to hypoglycemia (the plasma glucose [PG] values in this 
section refer to values determined by a laboratory or International Federation of Clinical 
Chemistry and Laboratory Medicine plasma-equivalent glucose meters and strips) (ADA 2017, 
ADA 2018):
Glucose Alert Value (Level 1):

Documented symptomatic hypoglycemia is defined as any time a patient feels 
that he or she is experiencing symptoms and/or signs associated with 
hypoglycemia, and has a PG level of ≤70 mg/dL (≤3.9 mmol/L).

Documented asymptomatic hypoglycemia is defined as any event not 
accompanied by typical symptoms of hypoglycemia, but with a measured PG 
≤70 mg/dL (≤3.9 mmol/L).

Documented unspecified hypoglycemia is defined as any event with no 
information about symptoms of hypoglycemia available, but with a measured PG 
≤70 mg/dL (≤3.9 mmol/L).
Clinically Significant Hypoglycemia (Level 2):

Documented symptomatic hypoglycemia is defined as any time a patient feels 
that he/she is experiencing symptoms and/or signs associated with hypoglycemia, 
and has a PG level of <54 mg/dL (<3.0 mmol/L).

Documented asymptomatic hypoglycemia is defined as any event not 
accompanied by typical symptoms of hypoglycemia, but with a measured PG <54 
mg/dL (<3.0 mmol/L).

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
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 des 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 nce t hat t he e ve nt was i n d uce d b y a l o 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 a 1-h o ur peri o d ma y be c o nsi dere 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 ducati o n, if dee me d a p pr o pri ate.
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 me 
i m bala 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.  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 w h o de vel o p se vere, persiste nt h y per gl yce mia after ra n d o mizati on at 
t he discret i on of i n vest i gat or i n acc or da nce wit h A merica n Dia betes Ass ociati on/ E ur o pea n 
Ass oci at i on f or t he St u d y of Dia betes g ui da nce (I nz ucc hi et al. 2 0 1 5).  Resc ue me dicati on will 
be prescri be d as a d d -o n t o ra n d o mize d treat me nt, a n d patie nts will c o nt i n ue t o foll o w t he 
pr ot oc ol -s pecifie d visit sc he d ule.
Beca use i ns uli n glar gi ne d ose a dj ust me nts wit h o ut restrict i ons will be i nit iate d at t he e n d of t he 
sta bilizati o n peri o d (see Secti o n 5. 1 ), decisio n  o n t he prese nce of se vere, persiste nt 
h y per gl yce mia ca n be first c o nsi dere d 1 2 wee ks after t he i nit iati o n of t his peri o d (a p pr o xi matel y 
1 6 wee ks after ra n d o mizati on)..

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Add-on glycemic rescue therapy will be allowed for patients who met any one of the following 
prespecified criteria for severe, persistent hyperglycemia and no intercurrent cause of the 
hyperglycemia could be identified (investigators should first confirm that the patient is fully 
compliant with the assigned therapeutic regimen and that the patient does not have an acute 
condition causing severe hyperglycemia): 
(a) average daily BG from the once-weekly 4-point SMBG profile >270 mg/dL 
(>15.0 mmol/L) over at least a consecutive 2-week period at any time 16 to 24 weeks 
post randomization; 
OR 
(b) average daily BG from the once-weekly 4-point SMBG profile >240 mg/dL 
(>13.3 mmol/L) over a consecutive 2-week period at any time 25 to 32 weeks post 
randomization; 
OR
(c) average daily BG from the once-weekly 4-point SMBG profile >200 mg/dL 
(>11.1 mmol/L) over a consecutive 2-week period at any time beyond the first 32 weeks 
post randomization.
OR
(d) HbA1c ≥8.5% at 24 weeks, with inadequate response to the existing regimen defined as 
improvement in HbA1c over the last 3 months (Week 12 to Week 24) that is, <0.3%
Rescue therapy option:
The criteria described above for severe, persistent hyperglycemia will only be applicable after 
Week 16.  The first choice before initiating any rescue therapy for those patients during the 
initial 16 weeks will be to follow the TTT algorithm to increase the dose of insulin glargine. 
Rescue treatment with pramlintide, DPP-4 inhibitors, or GLP-1 receptor agonists will not be 
allowed.  Additionally, use of other basal insulins will not be allowed.
Investigators must use clinical judgment in the interest of safety of the patient at all times. In 
any situation that, in the investigator’s opinion, may require an intervention that is not consistent 
with the requirements provided in this section, he or she should also consult the Lilly physician 
before such intervention is implemented, except when an immediate adjustment of the treatment 
regimen is medically required.
9.2.2.3.
Pancreatitis
Acute pancreatitis is defined as an AE of interest in all trials with tirzepatide including this trial.  
Acute pancreatitis is an acute inflammatory process of the pancreas that may also involve 
peripancreatic tissues and/or remote organ systems (Banks and Freeman 2006).  The diagnosis of 
acute pancreatitis requires 2 of the following 3 features:

abdominal pain, characteristic of acute pancreatitis (generally located in the 
epigastrium and radiates to the back in approximately half the cases [Banks and 
Freeman 2006; Koizumi et al. 2006]; the pain is often associated with nausea and 
vomiting);

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
ser u m pa ncreat ic a m ylase 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 ncreat ic 
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 n trast, M RI, or gall bla d der 
ul tras 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 
di a 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 nt i on will be pr o vi de d).  T he m ost a p pr o priate di a betes t hera pe utic re gi me n will be 
deci de d b y  t he i n vestigat 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 el atio ns hi p wi t h 
pa ncreat itis.
Eac h case o f A E of pa ncreat itis m u st be re p orte d.  If ty p ical si g ns a n d/ or s y m pt o ms o f 
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 pa ncreatic a m ylase) 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 meet 
all o f t hese crit eria, 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 of 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 vesti gati o nal 
d oses of tirze 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; Stei n ber g et al. 2 0 1 7 b). T h us, f urt her dia g n ost ic 
f oll ow- u p of  cases of as y m pt o matic pa ncreatic h y pere nz y me mia (li pase a n d/ or pa ncreatic 
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 nical c o n diti on. O nl y cases of pa ncreat ic 
h y pere nz y me mia t hat u n der g o a d diti o nal dia g n ostic f o ll 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 gesti ve of pa ncreatitis will be s u b mitte d f or a dj u dicati o n.
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 
c li nical e n d p o i nt co m mittee ( C E C). I n a d diti on, 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 d ata 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 adj u 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 ult i ple e n d ocri ne ne opl asia t y pe 2 
( 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 c as e of t h yr oid m ali g na nc y i ncl u di n g M T C
a n d pa pillar y carci n oma

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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 ncti o n, 
w hic h ma y  in dicate de vel o p me nt of C -cell h y per plasia a n d ne o plas ms . Ti rze pati de s h o uld be 
di sc o nti n ue d (after first c o nfir mi n g t he val ue) if p ostra n d o mizat i on calcit o ni n val ue is ≥3 5 n g/ L
a n d has i ncrease d at least 5 0 % o ver baseli ne.  A c o ns ultati 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 ogi st) s h o uld 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 patie nt w h o has a d mi nistere d a me dicati o n t hat is k n o w n t o i ncrease ser u m 
calcit o ni n, t his me dicati 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 n firme 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 is safe 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 dju dicate d b y  a c o m mitt e e of p h ysicia ns e xter nal t o Lill y wit h car diol o g y  e x pertise.  
T he n o nfatal C V A Es t o be a dj u dicate d i ncl u de t he f oll o wi 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 gr af t or perc uta ne o us c or o nar y 
i nter ve nt i on) , a n d 

cere br o vasc ular e ve nts, i ncl u di n g cere br o vasc ular 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 a rr 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 d ers 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 neede 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 diti o ns as descri be d i n Secti o n 9. 2 m u st be re p orte d as S A Es.
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, as 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 ollecte d o n a n y AEs or S A Es t hat t he i n vesti 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. 5 .  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 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 opi 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 collect all pla n n e d efficac y a n d safety me as ure me nts. 

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9. 2. 2. 8.
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 of A E occ urre nce i n t he tir z e p atide gr o u p, sa m ples will be c o llecte d f or 
meas ure me nt of tirze pati de A D A a n d tirze pati de c o nce ntratio n.
9. 2. 2. 9.
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 1 0. 3. 6 .
9. 2. 2. 1 0. 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 opat h y  e C R F.  
9. 2. 2. 1 1. H e p at o bili ar y Di s or d er s
All e ve nts of treat me nt e mer ge nt biliar y c o lic, c h olec ystitis, or ot her s us pecte d e ve nts relate d t o 
gall bla d der disease s h o ul d be e val uate d a n d a d dit i o nal dia g n ostic tests perf or me d, as nee de d. I n 
cases o f ele vate d liv er m ar kers, he patic mo ni t ori n g s h o uld be i ni tiate d as o utli ne d i n 
Secti o n 9. 4. 5 a n d A p pe n di x 4 .
9. 2. 2. 1 2. 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 vere 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. 7. 1 .
9. 2. 2. 1 3. 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 
assess me nt of A Es s u g gest i ve of ac ute or w orse ni n g of c hr o nic re nal fail ure . Gastr oi ntesti 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 
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 deterior ati 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 4. 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 o n re q uiri n g ur ge nt h os pitalizati o n, has bee n re p orte d 
rarel y i n patie nts wit 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 wit 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.  If ket oaci d osis is s us pecte d, 
patie nt s h o ul d be e val uate d, a n d pr o m pt treat me nt s h o ul d be i nstit ute d.  Treat me nt of ket oaci d osis 
ma y  re q uire i nsuli n, fl ui d a n d car b o h y drate re place me nt.

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Lactic aci d osis has bee n re p orte d rarel y i n patie nts wit h T 2 D M ass ociate d wit h use of metf or mi n, 
e xcessi ve alc o h ol i nta ke a n d decrease re nal f u ncti o n.  R o uti ne bicar b o nate assess me nt will be 
perf or me d d uri n g t he c o urse of t he st u d y.  If lactic aci d osis is s us pecte d, metf 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 o n of t he e ve nt.
9. 2. 2. 1 5. 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 6. 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 or ders is i ncrease d i n patie nts wi t h T 1 D M or T 2 D M 
( A D A G ui deli ne, 2 0 1 7).  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, mo ni t or q ualit y, a n d t o 
facilitate pr ocess a n d pr o d uct i m pr o ve me nts.
P ati e nts wil l 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 nje ctio 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 a n d/ or Pr o d uct L a bel f or i ns uli n glar gi ne.
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 pati e nt , electr ocar dio gr a m s ( E C Gs) s h o ul d be c ollecte d acc or di n g t o t he Sc he d ule of
Act i vities ( Sectio n 2 ).  Electr ocar dio gra ms s h o ul d 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 ons i ncl u de d i n Ma n ual of O perati o ns f or t he st u d y.  
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 s u bject ma na ge me nt, s h o ul d a n y cli nicall y 
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 treat me nt 
s h o uld be re p ort e 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 l a b orat or y. T he ce ntral E C G la b orat or y  
will perf or m a basic q uali t y 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 mac hi ne -rea d meas ure me nts

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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-wri ti n g p ur p oses, u nless a car di ol ogi st 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 nal st u d y  re p ort (i n w hich case, t he o verrea d data w o ul d 
be use d).
9. 4. 2.
Vit al Si g n s
F or eac h pati e nt , vit al si g ns meas ure me nts s h o ul d be c o n d ucte d acc or di n g t o t he Sc he d ule o f 
Act i vities (Secti o n 2 ).
A n y cli nicall y  sig nifica nt fi n di n gs fr o m vital si g ns meas ure me nt 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 st u d y treat me nt 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. 3.
L a b or at or y T e st s
F or eac h pati e nt , la b 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 ( Sectio n 2 ). 
Wit h 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 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 ulat i 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 mples 
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 i nt 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 pre d ose w he n a p plica ble a n d p ossi ble. 
In t he e ve nt of dr u g h y perse nsit i vity react i ons (i m me diate or n o ni m me diate) , a d diti o nal sa m ples 
will be c o llecte 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 close t o t he 
o nset of t he e ve nt as p ossi ble, at t he res ol ut i on of t he e ve nt, a n d 3 0 da ys f o ll owi n g t he e ve nt .  
I nstr uctio ns f or t he c ollect i on a n d ha n dli n g of bl o o d sa m ples will be pr o vi de d b y t he s p o ns or.  
S a m ple c ollecte d at Visit 8 0 1 will assess i m m u n o ge nicit y 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 A D A detecte d will be titere d a n d e val uate d f or t heir a bility t o ne utralize t he 
acti vit y of  assi g ne d treat me nt (tirze pati de-ne utralizi n g a nti b o dies).  Sa m ples wit h tirze pati de

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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, res pecti vel y.
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 pat ient  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 tirze pati de.  A n y sa m ples 
r e mai ni n g after 1 5 years will be destr o y e 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 S af et 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 ult 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.
He p at ic S afet 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 ele 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 b e re peate d wit 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 
a b n or malit y a n d t o deter mi ne if it is i ncreasi n g or decreasi n g.  If t he a b n or mality persists or 
w orse ns, cli nical a n d l a 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 o ll owi n g c o n di tio ns 
occ ur: 

e levat i on of ser u m  AL 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 levate d 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 levat i on of ser u m  AL 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 om treat me nt d ue t o a he patic e ve nt or a b n or malit y of li ver tests

h e pat ic e ve nt c o nsi dere d t o be a 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 f r o m blo o d s a 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 aft er Wee k 7, 1 5 , 2 3, a n d 39 of  treat me nt per
t he St u d y Sc he d ule or at E T (Secti o n 2 ). Eac h patie nt will be assi g 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, 2 3, a n d 3 9 .  T he date a n d ti me of  t he most rece nt S C i nject i on a d mi nistere d pri or t o 
c ollect i n g t he sa m ple m u st 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 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  accessio n pa ge.

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C o nce ntrati o ns of tirze patide 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 ( L C/ M S) met h o d.   Bi o a nal yt ical sa m ples c ollecte d t o meas ure tirze pati de
c o nce ntrati o ns will be retai ne d f or a ma xi m u m o f 1 year f o ll 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 ples t o assess t he P D pr o perties of tirze pat i 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 m ple 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 Act i vities ( 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 dia betes .  Assess me nt of varia ble res p o nse 
ma y i ncl u de e val uati o n o f A Es or differe nces i n efficac y .  
All sa m ples will be c o de d wit h t he patie 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 patie 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 of 1 5 years 
after t he last patie nt visit for t he st u d y, or f or a s h orter peri o d if l ocal re g ulati o ns a n d/ or 
(E R Bs /i n vesti gati o nal re vie w b oar ds) i m p ose s h orter ti me li mits.  T his rete ntio n 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 uestio ns, a n d i n vest i gati on of varia ble res p o nse 
t hat ma y not be o bser ve d u nt il later i n t he de velo p me nt of tirze patid e or after 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 are e x pecte d t o i m pr o ve d uri n g t he 1 5 -ye ar st ora ge peri o d a n d t heref ore 
ca n n ot be s pecificall y na me d.  H o wever, e xist i n g a p pr oac hes i ncl u de w h ole ge n ome or e x o me 
se q ue nci n g, ge n ome wi de ass ociati o n st u dies, 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 ypi 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 porate d i nt o cli nical st u dies t o e na ble e xa mi nat i 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 de o x y rib o n ucleic aci d ( D N A ), 
rib o n ucleic aci d ( R N A ), pr otei ns, li pi ds, a n d ot her cell ular ele me nts.

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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 pl es 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 .  
A ll sa m ples will be c o de d wit h t he patie 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 patie 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 patie nt visit for t he st u d y , or for a s h orter peri o d if l ocal re g ulati o ns a n d E R Bs 
i m p ose s h orter ti me li mits.  T his rete ntio 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 de velo p m e nt of  tirze pati de or after tirze pati de bec o me(s) c o m merciall y a vaila ble .
9. 9.
H e alt h E c o n o mi c s
T he f oll owi n g q uest i on naires will be c o m plete d b y t he patie 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 o r pr o gress i n t he st u d y with 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.
9. 9. 1.
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 nt ai 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 1; 2 0 1 2).  Ite ms are sc ore d o n a 5-p oi nt n u meric rati n g scale, 
w here 5 = “ n ot 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. 2.
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 nt ’s 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 IW- S P are deri ve d b y  s u m mi n g t he it e m sc ores a n d 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. 3.
Di a b et e s Tr e at m e nt S ati sf a cti o n Q u e sti o n n air e 
T he stat us (s) a n d c ha n ge (c) versi o ns of t he D T S Q will be use d d uri n g t he st u d y  t o assess t he 
pati e nt ’s satisfacti o n with t heir dia betes treat me nt a n d t he percei ve d fre q ue nc y o f h y per gl yce mia 

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and hypoglycemia.  The questionnaire contains 8 items (Bradley 1994).  Each item is rated on a 
7-point Likert scale.  Six items (1 and 4 through 8) are summed to produce a measure of 
treatment satisfaction ranging from 0 “very dissatisfied” to 6 “very satisfied.”  The remaining 2 
items (2 and 3) are treated individually.  Item 2 measures the perceived frequency of 
hyperglycemia on a scale ranging from 0 “none of the time” to 6 “most of the time,” and Item 3 
measures the perceived frequency of hypoglycemia on the same scale.  The change version has 
the same 8 items as the status version with a small alteration of the wording of Item 7.  The 
DTSQ change response options differ from those of the DTSQ status to produce measures of 
relative change rather than absolute satisfaction (3 “much more satisfied now” to -3 “much less 
satisfied now”).
9.9.4. European Quality of Life 
Generic health-related quality of life will be assessed using the EQ-5D-5L (EuroQoL Group 
2015).  The EQ-5D-5L is a standardized 5-item instrument for use as a measure of health 
outcome.  It provides a simple descriptive profile and a single index value for health status that 
can be used in the clinical and economic evaluation of health care as well as population health 
surveys.  The EQ-5D-5L comprises 5 dimensions of health (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression).  The 5L version, introduced in 2005, scores each 
dimension at 5 levels (no problems, slight problems, moderate problems, severe problems, 
unable to perform/extreme problems), for a total of 3125 possible health states.  In addition to the 
health profile, a single health state index value can be derived based on a formula that attaches 
weights to each of the levels in each dimension. This index value ranges between less than 0 
(where 0 is a health state equivalent to death; negative values are valued as worse than dead) to 1 
(perfect health).  In addition, the EQ Visual Analog Scale records the respondent’s self-rated 
health status on a vertical graduated (0 to 100) visual analog scale.  In conjunction with the 
health state data, it provides a composite picture of the respondent’s health status.  
The EQ-5D-5L is used worldwide and is available in more than 130 different languages.  Details 
on the instrument, and scoring, organizing, and presenting the data collected can be found in the 
EQ-5D-5L User Guide (EuroQoL Group 2015). 

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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 a l is p o were d t o assess s u peri ority of  tirze patide 1 0 m g a n d 1 5 m g, eac h teste d i n parallel, 
a gai nst place b o at a 2-si de d si g nifica nce le vel of 0. 0 2 5, relati ve t o t he pri mar y e n d p oi nt ( mea n 
c ha n ge i n H b A 1c fr o m baseli ne t o 4 0 wee ks), u n der t he f oll o wi n g ass u m pt i ons:  use of a 
2 -sa mple t -test utilizi n g H b A 1c data c ollecte d bef ore i nitiati on of a n y  resc ue me dicatio n or 
pr e m at ure treat me nt disc o nt i n uati on wi t h no m ore t ha n 2 8 % of s u bjects i nit iati n g resc ue 
me dicat i on or pre mat urel y disc o nt i n ui n g treat me nt i n eac h treat me nt gr o u p; 0. 6 % greater mea n 
re d uctio n i n H b A 1c fr o m baseli ne f or 1 0 a n d 1 5 m g tirze pat i de c om pare d wit h place b o; 1: 1: 1: 1 
ra n d omizat i on; 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, a sa m ple size of 4 7 2 s u bject s is re q uire d t o e ns ure at least 9 0 % p o wer t o 
d e m o nstrate t hat ti rze pati de 1 0 m g a n d/ or 1 5 m g are s u peri or t o place b o relati ve t o t he pri mar y 
e n d p o i nt.
F urt her m ore, t hi s sa m ple size will e ns ure 9 0 % p o wer f or t he s u peri orit y e val uati on c o n d ucte d 
usi n g a n a n al ysis o f c o varia nce ( A N C O V A) 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 vat i ve m ult i ple i m p utati o n met h o d (as descri be d i n 
Secti o n 1 0. 3. 3 bel o w), pr o vi de d a 0. 6 % greater mea n re d ucti o n i n H b A 1c fr o m baseli ne f or 1 0 
a n d 1 5 mg ti rze patid e c o mpare d wi t h place b o 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 on of data o n resc ue me dicati o ns a n d after pre mat ure treat me nt disc o nt i n uati on a n d 
i m p utatio n of  missi n g data.

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10.2. Populations for Analyses
For purposes of analysis, the following populations are defined as follows:
Population
Description
Screened patients
All participants who sign informed consent
Randomized patients
All patients who are randomly assigned a treatment group.
modified intention-to-treat 
(mITT) population
All randomly assigned participants who are exposed to at least 1 dose of study 
drug.  In the event of a treatment error, participants will be analyzed according 
to the treatment then were randomized.
Efficacy analysis set (EAS)
Data obtained during Study Period II from the mITT population, excluding 
data after initiating rescue antihyperglycemic medication or stopping study 
drug.
Full analysis set
Data obtained during Study Period II from the mITT population, regardless of 
adherence to study drug or initiation of rescue antihyperglycemic medication.
Safety analysis set (SS)
Data obtained during Study Periods II or III from the mITT population, 
regardless of adherence to study drug or initiation of rescue antihyperglycemic 
medication.
10.3. Statistical Analyses
10.3.1. General Statistical Considerations
Statistical analysis of this study will be the responsibility of Lilly or its designee.
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the statistical analysis plan (SAP) or clinical study report (CSR).  Additional exploratory 
analyses of the data will be conducted as deemed appropriate.
Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 
0.05, and the confidence interval (CI) will be calculated at 95%, 2-sided.  In statistical 
summaries and analyses, patients will be analyzed as randomized.
There will be 2 estimands of interest in comparing efficacy of tirzepatide doses with placebo.  
The first estimand, the “efficacy” estimand, represents efficacy prior to discontinuation of study 
drug without the confounding effects of antihyperglycemic rescue therapy.  The second 
estimand, the “treatment-regimen” estimand, represents the efficacy irrespective of adherence to 
study drug or initiation of rescue antidiabetic drugs.
The primary efficacy assessment, guided by the “efficacy” estimand, will be conducted using the 
EAS.  The primary efficacy assessment, guided by the “treatment-regimen” estimand, will be 
conducted using the full analysis set.  As they are intended for different purposes, no multiplicity 
adjustments will be made for conducting 2 primary efficacy assessments.
Unless specified otherwise, safety assessments will be guided by an estimand comparing safety 
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antihyperglycemic rescue therapy.  Thus, the safety analysis will be conducted using the SS.  
Selected safety analysis (for example, hypoglycemia) may be conducted excluding data after 
introducing another antihyperglycemic  therapy.
Summary statistics for continuous measures will include sample size, mean, SD, median, 
minimum, and maximum.  The analysis model to make comparisons among treatment groups 
relative to continuous measurements assessed over time will be a mixed model for repeated 
measures (MMRM), with terms: treatment, visit, and treatment-by-visit interaction, country, 
metformin use (Yes or No), and baseline measurement as a covariate.  An unstructured 
covariance matrix will model the relationship of within-patient errors.
The Kaplan-Meier method will be used for estimation of cumulative event-free survival rates 
over time, and cox proportional hazards regression analysis will be used to compare hazard rates 
among treatments.
Summary statistics for categorical measures (including categorized continuous measures) will 
include sample size, frequency, and percentages.  Fisher’s exact test will be used to examine the 
treatment difference in categorical outcomes.  Logistic regression may be used to examine the 
treatment difference in binary efficacy outcomes.  Summary statistics for discrete count 
measures will include sample size, mean, SD, median, minimum, and maximum.  The negative 
binomial regression model will be used for the treatment comparison of discrete count measures.
Other statistical methods may be used, as appropriate, and details will be documented in the 
SAP.
10.3.2. Treatment Group Comparability
10.3.2.1. Patient Disposition
Frequency counts and percentages of all patients screened, randomized, and receiving at least 1 
dose of study drug will be presented by treatment groups.  A listing of randomized patients not 
receiving study drug will be provided.  Of the patients in the mITT population, frequency, counts 
and percentages of patients completing the study, prematurely discontinuing the study, including 
the reason for premature discontinuation, will be presented by treatment group.  A Kaplan-Meier 
analysis of time from randomization to premature discontinuation from study by treatment group 
will be provided.
10.3.2.2. Patient Characteristics
Demographics, medical history, and concomitant illness will be summarized by treatment group 
using the mITT population.
10.3.2.3. Concomitant Therapy
Concomitant medications, including previous therapy for diabetes, will be summarized by 
anatomical therapeutic chemical classification and treatment group using the mITT population.  
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a nal yze d as a n e x pl orat or y s afet y e n d p o i nt.  D ose m odificati o ns of  or al a nti h y per gl yce mic 
t hera p y will als o be c o m pare d bet wee n treat me nt gr o u ps.
1 0. 3. 2. 4. Tr e at m e nt C o m pli a n c e
Of  t he patie nts i n t he mI T T p o p ulat i on, fre q ue nc y  c o u nts a n d perce nta ges of patie nts 
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 reaso n f or pre mat ure disc o nt i n uati on, will 
be prese nte d b y  tr e at me nt gr o u p.  A Ka pla n-Meier a nal ysis of ti me fr o m ra n d o mizati o n t o 
pr e m at ure st u d y dr u g disc o nti n uatio n b y  tr e at me nt gr o u p will be pr o vi de d.  
Treat me nt c o m plia nce is defi ne d as ta ki n g at least 7 5 % of re q uire d i nject i ons of st u d y  dr u g.  
Fre q ue nc y c o u nts a n d perce nta ges of pat ient s c o m plia nt t o st u d y dr u g will be s u m marize d b y 
treat me nt ar m 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 1 0 mg a n d 1 5 m g of  tirze pati de t o place b o relati ve t o mea n cha n ge i n H b A 1c fr o m 
baseli ne t o t he 4 0 -wee k visit.
F or t he F D A, t he pri mar y  efficac y a nal ysis will be g uide d b y  t he “treat me nt -re gi me n” esti ma n d 
defi ne d i n Sect i on 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 o btai ne d at t he 
4 0 -wee k visit usi n g a n A N C O V A wit h ter ms, treat me nt, stratificat i on fact ors, a n d baseli ne 
H b A 1c as a c o variate.  Missi n g c ha n ge i n H b A 1c fr o m baseli ne val ues at t h e 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 patient s 
i n t he sa me treat me nt ar m w h o ha d t heir efficac y assesse d after earl y disc o nti n uatio n of  st u d y 
dr u g a n d/ or i nit iati on of resc ue a nt i 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 utati o ns, a n d statistical i nfere nce o ver m ulti 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).  
F or t he P har mace uticals a n d Me dical De vices A ge nc y, t he pri mar y efficac y as sess me nt will be 
g ui de d b y  t he “efficac y” esti ma n d, c o ntr olli n g t he o verall fa mil y-wise t y pe 1 err or rate at a 
2 -side d al p ha of 0. 0 5 o nl y f or t he pri mar y e n d p oi nt e val uat i on t hat Q W tirze pati de 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.
T he A N C O V A a nal ysis will re p ort L S Mea n a n d sta n dar d err or ( S E) val ues f or eac h d osi n g ar m 
as well as t he differe nce i n mea n c ha n ge i n H b A 1c fr o m baseli ne t o t he 4 0 -wee k visit.  
C o m paris o ns will be ma de bet wee n 1 0 m g t irze pati de a n d place b o as well as bet wee n 1 5 m g 
tirze pati de a n d place b o.  T he 9 7. 5 % CIs a n d bet wee n treat me nt p-val ues will als o be i ncl u de d f or 
t he differe nces.  If t he differe nce b et wee n eit her ti rze patide d ose a n d pl ace b o is dir e ctio nall y 
s u perior, a n d t he 2 -side d p -v al u e i s < 0. 0 2 5, t he tirze patide d ose will  be declare d s u peri or t o 
pl ace b o.  

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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 t he E A S.  T he pri mar y 
a nal ysis m o del f or H b A 1c meas ure me nts o ver ti me w ill be a n M M R M.  T he res p o nse varia ble of 
M M R M will be c ha n ge i n H b A 1c fr o m baseli ne val ues 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 gr o u p ( 1 0 m g tirze pat i de, 
1 5 m g ti rze pati de, a n d place b o), visit, a n d treat me nt - b y-visit i nteract i on, c o u ntr y , met f or mi n use 
( Yes or N o), a n d baseli ne H b A 1c as a c o variate.  A n u nstr uct ure d c o varia nce str uct ure will 
m o d el  t h e r elat i ons hi p of wit hi n -pat ient  err ors.  If t he a nal ysis fails t o c o n ver ge, t he f oll o wi n g
varia nce - c o varia nce matri x will be use d (i n or der) u ntil c o n ver ge nce is ac hie ve d:  heter o ge ne o us 
c o mp o u n d s y m metr y , c o mp o u n d s y m metr y , a n d first-or der a ut ore gressi ve.  T he Ke n war d -R o ger 
a p pr o xi mat i on will be use d t o esti mate de n o mi nat or de grees of free d o m .  
T he M M R M a nal ysis will re p ort L S Mea n a n d sta n dar d err or ( S E) val ues f or eac h d osi n g ar m as 
well as t he differe nce i n mea n c ha n ge i n H b A 1c fr o m baseli ne t o t he 4 0 -wee k visit.  
C o m paris o ns will be ma de bet wee n 1 0 m g t irze pati de a n d place b o as well as bet wee n 1 5 m g 
tirze pati de a n d place b o.  T he 9 7. 5 % CIs a n d bet wee n treat me nt p-val ues will als o be i ncl u de d f or 
t he differe nces.  If t he differe nce bet wee n eit her ti rze patide d ose a n d pl ace b o is dir e ctio nall y 
s u perior, a n d t he 2 -side d p -v al u e i s < 0. 0 2 5, t he tirze patide d ose will  be declare d s u peri or t o 
pl ace b o.
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 periori t y of t he 5 mg ti rze patid e d ose t o pl ace b o relat i ve t o mea n c ha n ge i n H b A 1c 
fr om baseli ne t o t he 4 0 -wee k visit

s u periori t y of eac h tirze pati de d ose 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 periori t y of eac h tirze pati de d ose t o place b o relati ve t o t he pr o p orti o n of patie nts 
ac hie vi n g t he tar get val ue of H b A 1c < 7 % at t he 4 0- wee k visit

s u periori t y of eac h tirze pati de d ose t o place b o relati ve t o mea n c ha n ge i n F S G fr om 
baseli ne t o t he 4 0 -wee k visit
T he t y pe I err or -c o ntr olle d strate g y f or t h e pri mar y a n d sec o n dar y e nd 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.
A nal ysis of c ha n ge fr o m bas eli ne i n H b A 1c f or t he 5 m g tirze pat i de d ose 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 as disc usse d i n 
Secti o n 1 0. 3. 3. 1 .
A nal ysis of c ha n ge fr o m baseli ne i n b o d y  wei g ht as well as 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, res pecti vel y, c ha n ge i n 
w ei g ht f r o m baseli ne a n d c ha n ge i n F S G fr om baseli n e as t he res p o nse varia bles a n d baseli ne 
b o d y  wei g ht a n d baseli ne F S G as c o variates.

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Comparisons among treatments relative to the proportion of patients achieving the HbA1c target 
value of <7.0% (53 mmol/mol) at the 40-week visit will be conducted using a logistic regression 
analysis with terms of treatment, country, metformin use (Yes or No), and baseline HbA1c as a 
covariate.  In the analysis of patients achieving the HbA1c target value relative to the “efficacy” 
estimand, subjects with missing values at the 40-week visit will be excluded.  In the analysis of 
patients achieving the HbA1c target value relative to the “treatment-regimen” estimand, missing 
values at the 40-week visit will be imputed based on observed data at respective visits from 
patients in the same treatment group who had their efficacy assessed after early discontinuation 
of study drug and/or initiation of rescue medication.  The analysis will be conducted with 
multiple imputations and statistical inference over multiple imputations will be guided by the 
method proposed by Rubin (1987).
10.3.3.3. Tertiary/Exploratory Analyses
All exploratory efficacy analyses will be guided by the “efficacy” estimand without imputation 
of missing data and will be conducted using the EAS.  Details will be provided in the SAP.
10.3.4. Safety Analyses
Unless specified otherwise, safety assessments will be guided by an estimand comparing safety 
of tirzepatide doses with placebo irrespective of adherence to study drug or initiation of rescue 
therapy.  Thus, safety analyses will be conducted using the SS.  Selected safety analyses may be 
conducted excluding data after the introduction of another antihyperglycemic therapy.
Adverse events will be coded from the actual term using the Medical Dictionary for Regulatory 
Activities (MedDRA) and reported with preferred terms and system organ class.  Selected 
notable AEs of interest may be reported using high-level terms or Standardized MedDRA 
Queries.  Summary statistics will be provided for incidence of TEAEs, SAEs, study 
discontinuation due to AEs, study drug discontinuation due to AEs, deaths, and other CV 
endpoints.  Counts and proportions of subjects experiencing AEs will be reported for each 
treatment group, and Fisher’s exact test will be used to compare the treatment groups.
10.3.4.1. Hypoglycemic Events
Incidence of documented symptomatic hypoglycemia events and severe hypoglycemia in each 
category (either total or nocturnal) will be compared between tirzepatide doses and placebo using 
negative binomial regression analysis.  Selected safety analyses may be conducted excluding 
data after introduction of another antihyperglycemic therapy (for example, rescue therapy).
10.3.4.2. Gastrointestinal Events
Summaries and analyses for incidence and severity of nausea, vomiting, and diarrhea will be 
provided by each treatment.
10.3.4.3. Adjudicated Cardiovascular Events
Listings of deaths, myocardial infarctions, strokes, and hospitalization for unstable angina 
confirmed by an independent CEC will be provided.  The dates of randomization, event, first 
dose and last dose of study drug, and time from randomization to the event will be listed.

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10.3.4.4. Central Laboratory Measures, Vital Signs, and Electrocardiograms
Values and change from baseline to postbaseline values of central laboratory measures, vital 
signs, and selected ECG parameters will be summarized at each scheduled visit.  The analysis 
model to make comparisons among treatment groups, relative to continuous change from 
baseline values assessed over time will be an MMRM similar to the primary efficacy analysis 
and with baseline measurement as a covariate.  An unstructured covariance structure will model 
the relationship of within-patient errors.
The percentages of patients with TE abnormal, high, or low laboratory measures at any time will 
be summarized and compared between treatment groups by using Fisher’s exact test.  A TE 
abnormal value is defined as a change from normal value at baseline to a value greater than the 
high limit at any time during Periods II and III.  A TE low result is defined as a change from a 
value greater than or equal to the low limit at baseline to a value less than the low limit at any 
time during Periods II and III.  High and low laboratory limits will be determined by the central 
laboratory reference ranges.
10.3.5. Pharmacokinetic/Pharmacodynamic Analyses
Tirzepatide concentration data will be analyzed using a population PK approach via nonlinear
mixed-effects modeling with the NONMEM software. The relationships between tirzepatide
dose and/or concentration and efficacy, tolerability, and safety endpoints will be characterized.  
Additionally, the impact of intrinsic and extrinsic patient factors such as age, weight, gender, and
renal function on PK and/or PD parameters may be examined as needed. If ADA titers are 
detected from immunogenicity testing, then the impact of immunogenicity titers on tirzepatide
PK or any relevant PD parameters may also be examined.
10.3.6. Evaluation of Immunogenicity 
The frequency and percentage of patients with preexisting ADA, with TE ADA and with 
neutralizing TE ADA to tirzepatide will be tabulated by tirzepatide dose. Treatment-emergent 
ADAs are defined as those with a titer 2-fold (1 dilution) greater than the minimum required 
dilution (MRD) if no ADAs were detected at baseline (treatment-induced ADA) or those with a 
4-fold (2 dilutions) increase in titer compared to baseline if ADAs were detected at baseline 
(treatment-boosted ADA). The MRD of the ADA assay is 1:10.  For TE ADA patients, the 
distribution of maximum titers will be described.  The frequency of neutralizing antibodies to 
tirzepatide and/or cross-reactive and neutralizing antibodies to endogenous counterparts will be
tabulated in patients with TE ADA.
The relationship between the presence of antibodies and tirzepatide PK and PD response
including safety and efficacy to tirzepatide may be assessed.

I 8 F-M C -G P GI( 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
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 m e ( P R O) sc ores will be 
c o n d ucte d usi n g li near m o dels 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 fr o m baseli ne t o Visit 1 8 will be pr o vi de d b y  a ge, 
race, et h nicity, ge n der, d urati o n of dia betes, baseli ne H b A 1c ( ≤8. 0% or > 8. 0 % [≤6 4 , 
˃ 6 4 m m o l/ m ol], a n d baseli ne metf or mi n use.
1 0. 3. 8. I nt eri m A n al y s e s
N o i nt eri m a nal yses are pla n ne d f or t his st u d y.  If a n u n pla n ned i nteri m  a nal ysis is dee me 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 .
U n bli n di n g details are s pecifie d i n t he u n bli n di n g pla n sect i on of t he statist ical a nal ysis pla n 
( S A P) or a se parate u n bli n di n g pla n d oc u me nt.

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11.
References
[ADA] American Diabetes Association. 33. Comprehensive Medical Evaluation and Assessment
of Comorbidities: standards of medical Care in diabetes 2017. Diabetes Care. 2017;40(suppl 
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[ADA] American Diabetes Association. 6. Glycemic targets: standards of medical Care in 
diabetes—2018. Diabetes Care. 2018;41(suppl 1):S55-S64.
Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its 
complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a 
WHO consultation. Diabet Med. 1998;15(7):539-553.
Aroda VR, Ratner R. The safety and tolerability of GLP-1 receptor agonists in the treatment of 
type 2 diabetes: a review. Diabetes Metab Res Rev 2011;27(6):528-542.
Banks PA, Freeman ML. Practice guidelines in acute pancreatitis. Am J Gastroenterol.
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Bradley C. The diabetes treatment satisfaction questionnaire: DTSQ. Handbook of Psychology 
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Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, Cui X, Briere DA, 
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Haupt A. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 
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EuroQoL Group. EQ-5D-5L User guide: basic information on how to use the EQ-5D-5L 
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Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, Urva S, Gimeno RE, Milicevic Z, 
Robins D, Haupt A. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor 
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Guja C, Frias JP, Somogyi A, Jabbour S, Wang H, Hardy E, Rosenstock J. Effect of exenatide 
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DURATION-7 randomized study. Diabetes Obes Metab. 2018;20(7):1602-1614.
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Self-Perceptions Questionnaire (IW-SP) in individuals with type 2 diabetes and obesity. 
Diabetes Technol Ther. 2015;17(3):210-214.

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Hayes RP, Nelson DR, Meldahl ML, Curtis BH. Ability to perform daily physical activities in 
individuals with type 2 diabetes and moderate obesity: a preliminary validation of the Impact 
of Weight on Activities of Daily Living Questionnaire. Diabetes Technol Ther. 
2011;13(7):705-712.
Hayes RP, Schultz EM, Naegeli AN, Curtis BH. Test-retest, responsiveness, and minimal 
important change of the ability to perform physical activities of daily living questionnaire in 
individuals with type 2 diabetes and obesity. Diabetes Technol Ther. 2012;14(12):1118-1125.
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas 
A, Wender R, Matthews DR. Management of hyperglycemia in type 2 diabetes, 2015: a 
patient-centered approach: update to a position statement of the American Diabetes 
Association and the European Association for the Study of Diabetes. Diabetes Care.
2015;38(1):140-149.
Khunti K, Nikolajsen A, Thorsted BL, Andersen M, Davies MJ, Paul SK. Clinical inertia with 
regard to intensifying therapy in people with type 2 diabetes treated with basal insulin. 
Diabetes Obes Metab. 2016;18(4):401-409.
Koizumi M, Takada T, Kawarada Y, Hirata K, Mayumi T, Yoshida M, Sekimoto M, Hirota M, 
Kimura Y, Takeda K, Isaji S, Otsuki M, Matsuno S; JPN. JPN Guidelines for the management 
of acute pancreatitis: diagnostic criteria for acute pancreatitis. J Hepatobiliary Pancreat Surg.
2006;13(1):25-32.
Nauck MA, Meier JJ, Schmidt WE. Incretin-based glucose-lowering medications and the risk of 
acute pancreatitis and/or pancreatic cancer: reassuring data from cardio-vascular outcome 
trials. Diabetes Obes Metab. 2017;19(9):1327-1328.
Pozzilli P, Norwood P, Jódar E, Davies MJ, Ivanyi T, Jiang H, Woodward B and Milicevic Z. 
Placebo-controlled, randomized trial on the addition of once weekly glucagon-like peptide-1 
receptor agonist dulaglutide to titrated daily insulin glargine in patients with type 2 diabetes 
(AWARD-9). Diabetes Obes Metab. 2017;19:1024-1031.
Riddle MC, Rosenstock J, Gerich J; Insulin Glargine 4002 Study Investigators. The 
treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of 
type 2 diabetic patients. Diabetes Care. 2003;26(11):3080-3086.
Rodbard HW, Lingvay I, Reed J, de la Rosa R, Rose L, Sugimoto D, Araki E, Chu PL, 
Wijayasinghe N, Norwood P. Semaglutide added to basal insulin in type 2 diabetes 
(SUSTAIN 5): A randomized, controlled trial. J Clin Endocrinol Metab. 
2018;103(6);2291-2301.
Rubin DB. Multiple Imputation for Nonresponse in Surveys. New York: John Wiley & Sons 
Inc.; 1987.
Stark Casagrande S, Fradkin JE, Saydah SH, Rust KF, Cowie CC. The prevalence of meeting
A1c, blood pressure, and LDL goals among people with diabetes, 1988-2010. Diabetes Care.
2013;36(8):2271-2279.
Steinberg WM, Buse JB, Ghorbani MLM, Ørsted DD, Nauck MA; LEADER Steering 
Committee; LEADER Trial Investigators. Amylase, lipase, and acute pancreatitis in people 

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with type 2 diabetes treated with liraglutide: results from the LEADER randomized trial. 
Diabetes Care. 2017a;40(7):966-972.
Steinberg WM, Rosenstock J, Wadden TA, Donsmark M, Jensen CB, DeVries JH. Impact of 
liraglutide on amylase, lipase, and acute pancreatitis in participants with overweight/obesity 
and normoglycemia, prediabetes, or type 2 diabetes: secondary analyses of pooled data from 
the SCALE clinical development program. Diabetes Care. 2017b;40(7):839-848.
Weinberg ME, Bacchetti P, Rushakoff RJ. Frequently repeated glucose measurements 
overestimate the incidence of inpatient hypoglycemia and severe hyperglycemia. J Diabetes 
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Zaccardi F, Htike ZZ, Webb DR, Khunti K, Davies MJ. Benefits and harms of once-weekly 
glucagon-like peptide-1 receptor agonist treatments: a systematic review and network 
meta-analysis. Ann Intern Med 2016;164:102-113.

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12.
Appendices

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Appendix 1.
Abbreviations and Definitions
Term
Definition
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
APPADL
Ability to Perform Physical Activities of Daily Living
AST
aspartate aminotransferase
BG
Blood glucose
blinding/masking
A double-blind study is one in which neither the patient/subject nor any of the 
investigator or sponsor staff who are involved in the treatment or clinical evaluation of 
the subjects are aware of the treatment received.
BMI
body mass index
CEC
clinical endpoint committee
CHF
congestive heart failure
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements.
COVID-19
Coronavirus Disease 2019
CRF
case report form
CRP
clinical research physician: Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician or other medical officer.
CSR
Clinical Study Report

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CV
cardiovascular
DPP-4
dipeptidyl peptidase-4
DTSQs
Diabetes Treatment Satisfaction Questionnaire status
EAS
efficacy analysis set
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture system
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the study are 
those who have been assigned to a treatment.
EQ-5D-5L
European Quality of Life-Dimensions
ERB
ethical review board
ET
early termination
FBG
fasting blood glucose
FDA
Food and Drug Administration
FSG
fasting serum glucose
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GI
gastrointestinal
GIP
glucose-dependent insulinotropic polypeptide
GLP-1
glucagon-like peptide-1
HbA1c
hemoglobin A1c
IB
Investigator’s Brochure
ICF
informed consent form
Informed consent
A process by which a patient voluntarily confirms his or her willingness to participate 
in a particular study, after having been informed of all aspects of the study that are 
relevant to the patient’s decision to participate.  Informed consent is documented by 
means of a written, signed and dated informed consent form.
ICH
International Council for Harmonisation

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investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
ITT
intention to treat:  The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a patient (that is, the 
planned treatment regimen) rather than the actual treatment given.  It has the 
consequence that patients allocated to a treatment group should be followed up, 
assessed, and analyzed as members of that group irrespective of their compliance to the 
planned course of treatment.
IWRS
interactive web-response system
IW-SP
Impact of Weight on Self-Perception
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intent-to-treat
MMRM
mixed model for repeated measures
MRI
magnetic resonance imaging
MTC
medullary thyroid carcinoma
NAFLD
nonalcoholic fatty liver disease
OTC
over the counter
p-amylase
pancreatic amylase
PK/PD
pharmacokinetics/pharmacodynamics
PRO/ePRO
patient-reported outcomes/electronic patient-reported outcomes
QW
once weekly
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SC
subcutaneous
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study. 
SD
standard deviation
SDP
single-dose pen

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SMBG
self-monitoring of blood glucose
SS
safety analysis set
SUSARs
suspected unexpected serious adverse reactions
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus
TBL
total bilirubin level
TEAE
Treatment-emergent adverse event:  An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment.
TTT
treat to target
ULN
upper limit of normal

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Appendix 2.
Clinical Laboratory Tests
Clinical Laboratory Testsa
Hematology
Clinical Chemistry
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Bicarbonate
Mean cell volume
Total bilirubin
Mean cell hemoglobin concentration
Direct bilirubin
Leukocytes (WBC)
Alkaline phosphatase
Neutrophils, segmented
Alanine aminotransferase (ALT)
Lymphocytes
Aspartate aminotransferase (AST)
Monocytes
Blood urea nitrogen (BUN)
Eosinophils
Creatinine
Basophils
Uric acid
Platelets
Calcium
Glucose, fasting
Urinalysisa,b
Albumin
Creatinine
Pregnancy Test (females only)b
Follicle-stimulating hormone (FSH)c
Estradiol
HbA1c
eGFR (calculated by CKD-EPI equation)d
Endocrine
Calcitonin 
Immunogenicity
Tirzepatide anti-drug antibody
Anti-GAD antibodies
Nonpharmacogenetic Stored Samples
EDTA plasma
Serum
P800 plasma
Pancreas (exocrine)
Serum pancreatic amylase
Serum lipase
Lipid Panel
Total cholesterol
LDL
HDL
VLDL
Triglycerides
Samples for PK Analysis

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Abbreviations:  CKD-EPI = Chronic Kidney Disease-Epidemiology; GAD = glutamic acid decarboxylase; 
EDTA = ethylenediaminetetraacetic acid; eGFR = estimated glomerular filtration rate; HbA1c = hemoglobin 
A1c; HDL = high-density lipoprotein; LDL = low-density lipoprotein; RBC = red blood cells; VLDL = very 
low-density lipoprotein; WBC = white blood cells.
a
All tests will be performed by a Lilly-designated central laboratory, unless otherwise noted.
b
Serum pregnancy test will be performed by central laboratory at Visit 1 for women of childbearing potential.  A 
local urine pregnancy test must be performed at Visit 3 with the result available prior to randomization and first 
injection of study drug(s) for women of childbearing potential only.  Additional pregnancy tests will be 
performed at Visits 13, 19 and 22. Pregnancy tests may be performed at the investigator’s discretion during the 
study.  If required per local regulations and/or institutional guidelines, pregnancy testing can also occur at other 
times during the study treatment period.
c
Follicle-stimulating hormone test performed at Visit 1 for postmenopausal women at least 45 years of age with 
an intact uterus, not on hormone therapy, and who have had spontaneous amenorrhea for more than 6 months and 
less than 12 months and estradiol levels consistent with a postmenopausal state (FSH ≥40 mIU/mL and estradiol 
<30 pg/mL).
d
Estimated glomerular filtration rate will be calculated by the central laboratory and included in laboratory result 
reports.

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Appendix 3.
Study Governance Considerations

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Appendix 3.1. Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Appendix 3.1.1.
Informed Consent
The investigator is responsible for:

ensuring that the patient understands the nature of the study, the potential 
risks and benefits of participating in the study, and that their participation is 
voluntary.

ensuring that informed consent is given by each patient or legal 
representative.  This includes obtaining the appropriate signatures and dates 
on the informed consent form (ICF) prior to the performance of any protocol 
procedures and prior to the administration of investigational product.

answering any questions the patient may have throughout the study and 
sharing in a timely manner any new information that may be relevant to the 
patient’s willingness to continue his or her participation in the study.

ensuring that a copy of the ICF is provided to the participant or the 
participant’s legal representative and is kept on file.

ensuring that the medical record includes a statement that written informed 
consent was obtained before the participant was enrolled in the study and the 
date the written consent was obtained. The authorized person obtaining the 
informed consent must also sign the ICF.
Appendix 3.1.2.
Recruitment
Lilly or its designee is responsible for the central recruitment strategy for patients.  Individual 
investigators may have additional local requirements or processes.
Appendix 3.1.3.
Ethical Review
The investigator or an appropriate local representative must give assurance that the ethical 
review board (ERB) was properly constituted and convened as required by International Council
for Harmonisation (ICH) guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the must be provided to Lilly before the 
study may begin at the investigative site(s).  Lilly or its representatives must approve the ICF, 
including any changes made by the ERBs, before it is used at the investigative site(s).  All ICFs 
must be compliant with the ICH guideline on Good Clinical Practice (GCP).
The study site’s ERB(s) should be provided with the following:

the protocol and related amendments and addenda, current Investigator 
Brochure (IB) and updates during the course of the study

informed consent form 

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
other relevant documents (for example, curricula vitae, advertisements)
Appendix 3.1.4.
Regulatory Considerations
This study will be conducted in accordance with the protocol and with the:

consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines

applicable ICH GCP Guidelines

applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third party.
Appendix 3.1.5.
Investigator Information
Physicians with a specialty in diabetes/endocrinology, internal medicine, family medicine, 
general medicine, or any other specialty physician who have experience treating type 2 diabetes 
mellitus (T2DM) and clinical research in T2DM will participate as investigators in this clinical 
study.
Appendix 3.1.6.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Appendix 3.1.7.
Final Report Signature
The Clinical Study Report (CSR coordinating investigator will sign the final CSR for this study, 
indicating agreement that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.
A qualified investigator will serve as the CSR coordinating investigator.  If this investigator is 
unable to fulfill this function, another investigator will be chosen by Lilly to serve as the CSR 
coordinating investigator.
The sponsor’s responsible medical officer and statistician will approve the final CSR for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.
Appendix 3.2.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

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
provide sponsor start-up training to instruct the investigators and study 
coordinators.  This training will give instruction on the protocol, the completion 
of the CRFs, and study procedures.

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax

review and verify data reported to detect potential errors 
In addition, Lilly or its representatives will periodically check a sample of the patient data
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives, and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents.
Appendix 3.2.1.
Data Capture System
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.
An electronic data capture system (EDC) will be used in this study for the collection of CRF 
data.  The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system.  The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF.
Additionally, clinical outcome assessment data (scales, self-reported diary data) will be collected 
by the patient/investigator site personnel, via a paper source document, and will be transcribed 
by the investigator site personnel into the EDC system.
Data collected via the sponsor-provided data capture system(s) will be stored at third parties. 
The investigator will have continuous access to the data during the study and until 
decommissioning of the data capture systems.  Prior to decommissioning, the investigator will 
receive an archival copy of pertinent data for retention.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system, and electronic transfers will be provided to the investigator 
for review and retention.  Data will subsequently be transferred from the central vendor to the 
Lilly data warehouse.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.

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Appendix 3.3.
Study and Site Closure
Appendix 3.3.1.
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.
Appendix 3.3.2.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.
Appendix 3.4.
Publication Policy
The publication policy for Study I8F-MC-GPGI is described in the Clinical Trial Agreement.

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Appendix 4.
Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with the Lilly, or its designee, clinical 
research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils, segmented
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
GGT
Alkaline Phosphatase Isoenzymesa
CPK
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspirate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalised 
ratio; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

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Appendix 5.
World Health Organization Classification 
of Diabetes and Diagnostic Criteria
Type 1 Diabetes:  Type 1 diabetes is judged to be present when the classical symptoms of 
diabetes (thirst, polyuria, wasting and stupor, or coma) are associated with readily detectable 
concentrations of glucose and ketone bodies in the blood and urine.  Insulin treatment is 
necessary not only to control hyperglycemia but also to prevent spontaneous ketosis and death.
Type 2 Diabetes:  Type 2 diabetes, although often asymptomatic, may also present with 
classical hyperglycemic symptoms (thirst, polyuria, weight loss), but despite hyperglycemia, 
ketone bodies are present in only low concentrations in the blood and urine.  Coma is rare in type 
2 diabetes, but may result from extreme hyperglycemia and hyperosmolarity; lactic acidosis or 
ketoacidosis can also occur in fulminating illness (for example, severe infection or mesenteric 
artery thrombosis) due to an acute increase in insulin requirements, but spontaneous ketosis does 
not occur.  Some patients with type 2 diabetes later progress to a state of absolute insulin 
deficiency (Alberti and Zimmet 1998). 

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Appendix 6.
Classification of Contraceptive Methods
Highly Effective Methods of Contraception:

Combined oral contraceptive pill and mini pill

NuvaRing

Implantable contraceptives

Injectable contraceptives (such as Depo-Provera®)

Intrauterine device (such as Mirena® and ParaGard®)

Contraceptive patch – ONLY women <198 pounds or 90 kg

Total abstinence (if this is their preferred and usual lifestyle) or in a same-sex relationship 
with no sexual relationship with males (as part of their preferred and usual lifestyle).  
Note:  periodic abstinence (for example, calendar, ovulation, symptothermal, 
postovulation methods), declaration of abstinence just for the duration of a trial, and 
withdrawal are not acceptable methods of contraception

Vasectomy – for men in clinical studies
Effective Methods of Contraception (must use combination of 2 methods):

Male condom with spermicide

Female condom with spermicide

Diaphragm with spermicide

Cervical sponge

Cervical cap with spermicide
Men, regardless of their fertility status, with nonpregnant women of childbearing potential 
partners must agree to either remain abstinent (if this is their preferred and usual lifestyle) or use 
condoms plus 1 additional highly effective (less than 1% failure rate) method of contraception 
(such as combination oral contraceptives, implanted contraceptives, or intrauterine device) or 
effective method of contraception (such as diaphragms with spermicide or cervical sponge) for 
the duration of the study and for at least 3 months after the last injection.
Men with pregnant partners should use condoms during intercourse for the duration of the study 
and until the end of estimated relevant potential exposure in women of childbearing potential. 
Men who are in exclusively same sex relationships (as their preferred and usual lifestyle) are not
required to use contraception.

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Appendix 7.
Protocol GPGI Standardized Protocols for 
the Measurement of Height, Weight and Waist 
Circumference
The following information has been adapted from standardized physical measurement protocols 
for the World Health Organization’s STEPwise approach to Surveillance (STEPS) (WHO 2017) 
(Available at:
https://www.who.int/ncds/surveillance/steps/Section%204%20Step%202%20Physical%20Measu
rements.pdf)) Accessed January 17, 2019.
Measuring Height
Step 1. Ask the patient to remove their footwear and any headgear (light headgear worn for 
religious reasons can remain, but this should be worn by the patient at every clinic visit 
when their height is measured).
Step 2. Ask the patient to stand on the calibrated height measuring board (stadiometer) or 
against a wall with their feet together and their knees straight with their heels against 
the backboard, the stadiometer or the wall.
Step 3. Ask the patient to look straight ahead without tilting their head up.
Step 4. Ask the patient to breathe in and stand tall.  If using a stadiometer or fixed measuring 
device, move the device’s measurement arm gently down onto the top of the patient’s 
head.  Record the patient’s height in centimeters (cm).
Measuring Weight

Body weight measurements should be done in a consistent manner using a calibrated 
electronic scale capable of measuring weight in kilograms.

All weights for a given patient should be measured using the same scale, whenever possible, 
at approximately the same time in the morning after evacuation of bladder contents.  

Patients should be lightly clothed but not wearing shoes while their weight is measured.
Step 1. Ask the patient to remove their footwear, outerwear (coat, jacket, etc.), and any 
headgear (light headgear worn for religious reasons can remain, but this should be worn 
by the patient at every clinic visit when weight is measured).
Step 2. Make sure the scale is placed on a firm, flat, even surface (not on carpet, on a sloping 
surface, or a rough, uneven surface).
Step 3. Ask the patient to step onto the scale with 1 foot on each side of the scale.
Step 4. Ask the patient to stand still with arms by sides and then record weight in kilograms 
(kg) to the nearest one-tenth kg.

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Measuring Waist Circumference

Waist circumference should be measured at midpoint, between lower margin of least 
palpable rib and top of iliac crest (approximately 1 inch (2.54 cm) above the navel).

Patients should be lightly clothed.
Step 1. Ask the patient to stand with their feet close together, and arms at their side with their 
body weight evenly distributed.
Step 2. Ask patient to relax
Step 3. Measurements should be recorded at the end of a normal expiration.

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Appendix 8.
Changes to Study Procedures due to the 
COVID-19 Pandemic
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes the novel
COVID-19 pandemic, has caused numerous global restrictions to be enacted that may impact a 
patient’s ability and/or willingness to attend their onsite study visit as originally scheduled.  In 
such a situation, please follow the guidance below:
1) Patients should come for the primary endpoint visit (Visit 22) at the originally planned 
40-week (±7 days) schedule whenever possible and safe to do so, at the investigator's 
discretion.  However, in order to maximize the ability for onsite visits for Visit 22, 
minimize missing data, and preserve the intended conduct of the study, the visit window 
for Visit 22 may be brought forward no sooner than 14 days (Week 38) or extended up to 
28 days (Week 44).  The subsequent safety follow-up visit (Visit 801) should take place 
4 weeks ±7 days after Visit 22.  
2) For patients requiring an extension for Visit 22 up to Week 44, additional investigational 
product (tirzepatide or placebo) will be provided to allow patients to remain on study 
drug uninterrupted during the extended treatment period, to ensure patient safety, and to 
maintain the overall integrity of the trial. 
3) Additional consent from the patient will be obtained per local regulations for those 
patients who will be dispensed additional investigational product (tirzepatide or placebo)
during the extended treatment period.
4) The sites will need to identify and document the details of how all patients and visits 
were affected by the COVID-19 pandemic restrictions.
5) Mobile (in-home) healthcare visits:

Mobile visits may be performed at participants’ homes when participants cannot 
travel to the site due to extenuating circumstances. These will be performed by a 
qualified home nursing service provider following sponsor approval, if permitted by 
local regulations. Procedures performed may include, but are not limited to, taking 
blood samples, conducting physical assessments, administering PROs, and collecting 
health information. Please note that requirements related to the reporting of SAEs 
remain unchanged. Every effort should be made for the participant to return to onsite 
visits as soon as reasonably possible, while ensuring the safety of the participant and 
investigational site staff. 

Additional consent from the participant will be obtained for those who participate in 
home health services.

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Appendix 9.
Protocol Amendment I8F-MG-GPGI(b)
A Randomized, Phase 3, Double-blind Trial Comparing 
the Effect of the Addition of Tirzepatide versus Placebo 
in Patients with Type 2 Diabetes Inadequately Controlled 
on Insulin Glargine with or without Metformin 
(SURPASS-5)
Overview
Protocol I8F-MC-GPGI titled “A Randomized, Phase 3, Double-Blind Trial Comparing the 
Effect of the Addition of Tirzepatide versus Placebo in Patients with Type 2 Diabetes 
Inadequately Controlled on Insulin Glargine with or without Metformin (SURPASS-5)” has been 
amended.  The new protocol is indicated by amendment (b) and will be used to conduct the study 
in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are described in the 
following table.

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Amendment Summary for Protocol I8F-MC-GPGI Amendment (b)
Section # and 
Name
Description of Change
Brief Rationale
Appendix 8 
Changes to Study 
Procedures due to 
the COVID-19 
Pandemic
Added language about the mobile (in-
home) healthcare visits.
This provides an option to conduct a clinical 
trial visit and all the applicable procedures in 
a mobile healthcare facility or at the home of 
a patient when the patient is not able or not 
willing to go to the site due to COVID-19 
restrictions.

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