A Phase 3, Randomized, Open-Label Trial Comparing Efficacy and Safety of Tirzepatide Versus Semaglutide Once Weekly as Add-on Therapy to Metformin in Patients With Type 2 Diabetes
Phase: PHASE3
Conditions: Type 2 Diabetes
Sponsor: Eli Lilly and Company

Pr ot oc ol I 8 F- M C- G P G L( b)
A P hase 3, Ra n d o mize d, O pe n- La bel Trial C o m pari n g Efficac y a n d Safet y of Tirze pati de Vers us 
Se ma gl uti de O nce Wee kl y as A d d- o n T hera p y t o Metf or mi n i n Patie nts Wit h T y pe 2 Dia betes  
( S U R P A S S- 2)
N C T 0 3 9 8 7 9 1 9
A p pr o val Date: 2 6-J u n- 2 0 2 0

I 8 F-M C -G P G L ( b) Cli ni c al Pr ot o c ol
P a g e 1
L Y 3 2 9 8 1 7 6
Pr ot o c ol I 8 F -M C -G P G L ( b)
A P h a s e 3, R a n d o mi z e d, O p e n -L a b el Tri al C o m p ari n g 
Effi c a c y  a n d S af et y of Tir z e p ati d e v er s u s S e m a gl uti d e 
O n c e W e e kl y  a s Ad d -o n T h er a p y  t o M etf or mi n i n 
P ati e nt s wit h T y p e 2 Di a b et e s ( S U R P AS S -2)
2 0 1 8 -0 0 4 4 2 2 -2 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 ar i es a n d 
s h o ul d n ot b e c o pi e d b y or di stri b ut e d t o p er s o n s n ot i n v ol v e d i n t h e cli ni c al i n v e sti g ati o n of 
tir z e p ati d e (L Y 3 2 9 8 1 7 6), u nl e s s s u c h p er s o n s ar e b o u n d b y a c o nfi d e nti alit y a gr e e m e nt 
wit h Eli Lill y a n d C o m p a n y or it s s u b si di ari e s .  
N ot e t o R e g ul at or y A ut h oriti e s:   T hi s d o c u m e nt m a y c o nt ai n pr ot e ct e d p er s o n al d at a 
a n d/ or c o m m er ci all y c o nfi d e nti al i nf or m ati o n e x e m pt fr o m p u bli c di s cl o s ur e. Eli Lill y a n d 
C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r el e a s e/r e d a cti o n pri or t o a n y p u bli c r el e a s e. 
I n
t h e U nit e d St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m ati o n A ct ( F OI A) 
E x e m pti o n 4 a n d m a y n ot b e r e pr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e writt e n 
a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s.
Tir z e p ati d e ( L Y 3 2 9 8 1 7 6)
Eli Lill y a n d C o m p a n y
I n di a n a p oli s, I n di a n a U S A 4 6 2 8 5
Pr ot o c ol El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y : 1 9 -M ar -2 0 1 9
A m e n d m e nt ( a) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y : 2 7-A pr -2 0 2 0 -2 0 1 9
A m e n d m e nt ( b) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n a p pr o v al d at e pr o vi d e d 
b el o w.
A p pr o v al D at e: 2 6- J u n- 2 0 2 0 G M T

I 8 F-M C -G P G L ( b) Cli ni c al Pr ot o c ol
P a g e 2
L Y 3 2 9 8 1 7 6
T a bl e of C o nt e nt s
S e cti o n
P a g e
Pr ot oc ol  I 8 F-M C -G P G L( b) A P hase 3, Ra n d o mize d, O pe n -La bel Trial 
C o m pari n g Efficac y  a n d Safety of  Tirze pati de vers us Se ma gl uti de 
O nce Wee kl y as A d d -o n T hera p y  t o Metfor mi n i n Pati e nts wit h T ype 
2 Dia betes ( S U R P A S S - 2)....................................................................................................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 4
3.
I ntr o d ucti o n ......................................................................................................................2 1
3. 1.
St u d y  Ratio nale ............................................................................................................2 1
3. 2.
Bac k gr o u n d ..................................................................................................................2 1
3. 3.
Be nefit/ Ris k Assess me nt ..............................................................................................2 2
4.
O bject i ves a n d E n d p oi nts ..................................................................................................2 4
5.
St u d y Desi g n .....................................................................................................................2 6
5. 1.
O verall Desi g n .............................................................................................................2 6
5. 2.
N u m ber of P arti ci pa nts ................................................................................................. 2 9
5. 3.
E n d of St u d y  Defi niti on ...............................................................................................2 9
5. 4.
S ci e nt ific Rati o nale f or St u d y Desi g n...........................................................................2 9
5. 5.
J ustificati o n f or D ose ...................................................................................................3 0
6.
St u d y P o p ulat i on ...............................................................................................................3 2
6. 1.
I ncl usi on Cri t eria ..........................................................................................................3 2
6. 2.
E xcl usi o n Cri t eria ........................................................................................................3 3
6. 3.
Lifes t yle Restricti ons ....................................................................................................3 6
6. 4.
Scree n Fail ures .............................................................................................................3 6
7.
Treat me nts ........................................................................................................................3 7
7. 1.
Treat me nts A d mi nistere d .............................................................................................3 7
7. 1. 1.
Pac ka gi n g a n d La belli n g ......................................................................................3 8
7. 1. 2.
Me dical De vices ...................................................................................................3 8
7. 2.
Met h o d of Treat me nt Assi g n me nt
................................................................................3 8
7. 2. 1.
S el ect i on a n d Ti mi n g o f D oses .............................................................................3 8
7. 3.
Bli n di n g .......................................................................................................................3 9
7. 4.
D osa ge M o dificati o n ....................................................................................................3 9
7. 4. 1.
St u d y  Dr u gs.........................................................................................................3 9
7. 4. 2.
S peci al Treat me nt C o nsiderat i ons ........................................................................4 0
7. 4. 2. 1.
Sta n dar ds of Me dical Care ..............................................................................4 0

I 8 F-M C -G P G L ( 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. 2. 2.
Ma na ge me nt of H y p o gl yce mia Ris k ...............................................................4 0
7. 4. 2. 3.
Ma na ge me nt of Patie nts wit h Se vere, Persiste nt 
H y per gl yce mia d uri n g t he Treat me nt Peri o d ...................................................4 0
7. 4. 2. 4.
Ma na ge me nt of Patie nts Per m a ne nt l y Disc o nti n ui n g 
St u d y  Dr u gs....................................................................................................4 1
7. 4. 2. 5.
Ma na ge me nt of Patie nts wit h Gastr oi ntesti nal S y m pt o ms ...............................4 2
7. 5.
Pre parati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y ...............................................................4 3
7. 6.
Treat me nt C o m plia nce ................................................................................................. 4 4
7. 7.
C o nc o mita nt T hera p y ...................................................................................................4 4
7. 7. 1.
Bac k gr o u n d T hera p y  wit h Metf or mi n ..................................................................4 4
7. 7. 2.
I nitiatio n of  Ne w A nti h y per gl yce mic Me dicati on .................................................4 5
7. 7. 3.
Ot her C o nc o mita nt Me dicat i ons ...........................................................................4 6
7. 8.
Treat me nt after t he E n d of t he St u d y ............................................................................4 7
8.
Di sc o nti n uatio n Cri t eri a....................................................................................................4 8
8. 1.
Di sc o nti n uatio n f r o m St u d y Treat me nt .........................................................................4 8
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 8
8. 1. 2.
T e m p orar y  Disc o nti n uati on fr om St u d y  Treat me nt ...............................................4 9
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 0
8. 3.
L ost t o F oll o w -U p ........................................................................................................5 1
9.
St u d y  Assess me nts a n d Pr oce d ures...................................................................................5 2
9. 1.
Efficac y Assess me nts ...................................................................................................5 2
9. 1. 1.
Pri mar y Efficac y  Assess me nt...............................................................................5 2
9. 1. 2.
Sec o n dar y  Efficac y Assess me nts..........................................................................5 2
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.
B o d y  Wei g ht, Heig ht, a n d B o d y  Mass I n de x........................................................5 3
9. 1. 5.
A p pr o priate ness of Assess me nts ..........................................................................5 3
9. 2.
A d verse E ve nts ............................................................................................................5 3
9. 2. 1.
S eri o us A d verse E ve nts ........................................................................................5 4
9. 2. 1. 1.
S us pecte d U ne x pecte d Seri o us A d verse React i ons ..........................................5 5
9. 2. 2.
A d verse E ve nts of S pecial I nterest .......................................................................5 5
9. 2. 2. 1.
H y p o gl yce mia ................................................................................................5 5
9. 2. 2. 2.
Se vere, Persiste nt H y per gl yce mia ...................................................................5 7
9. 2. 2. 3.
Pa ncreat itis.....................................................................................................5 7
9. 2. 2. 4.
T h y r oid Mali g na ncies a n d C -Cell H y per plasia ................................................5 8
9. 2. 2. 5.
Maj or A d verse Car di o vasc ular E ve nts ............................................................5 8
9. 2. 2. 6.
S u pra ve ntric ular Arr h yt h mias a n d Car diac C o n d ucti o n 
Di s or ders ........................................................................................................5 9

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

I 8 F-M C -G P G L ( 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. 2. 2.
P ati e nt C haracteristics ....................................................................................6 9
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 0
1 0. 3. 3.
Efficac y A nal yses ................................................................................................7 0
1 0. 3. 3. 1 .
Pri mar y A nal yses ...........................................................................................7 0
1 0. 3. 3. 2.
Sec o n dar y  A nal yses........................................................................................7 1
1 0. 3. 3. 3.
Terti ar y/ E x pl orat or y A nal yses........................................................................7 2
1 0. 3. 4.
S af et y A nal yses ....................................................................................................7 2
1 0. 3. 4. 1.
H y p o gl yce mic E ve nts .....................................................................................7 2
1 0. 3. 4. 2.
Gastr oi ntesti nal E ve nts ...................................................................................7 2
1 0. 3. 4. 3.
A d j u dicate d Car di o vasc ular E ve nts ................................................................7 2
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 2
1 0. 3. 5.
E val uat i on of I m m u n o ge nicit y .............................................................................7 3
1 0. 3. 6.
Ot her A nal yses .....................................................................................................7 3
1 0. 3. 6. 1.
Heal t h Ec o n o mics...........................................................................................7 3
1 0. 3. 6. 2.
S u b gr o u p A nal yses .........................................................................................7 3
1 0. 3. 7.
I nteri m A nal yses ..................................................................................................7 3
1 1.
Refere nces ........................................................................................................................7 4
1 2.
A p pe n dices .......................................................................................................................7 8

I 8 F-M C -G P G L ( b) Cli ni c al Pr ot o c ol
P a g e 6
L Y 3 2 9 8 1 7 6
Li st of T a bl e s
T a bl e
P a g e
Ta ble G P G L. 1.
Sc he d ule of Act i vities....................................................................................1 5
Ta ble G P G L. 2.
O bject i ves a n d E n d p oi nts...............................................................................2 4
Ta ble G P G L. 3.
Treat me nt Re gi me ns ......................................................................................3 7
Ta ble G P G L. 4.
Cri teria f or Use of C o nc o mita nt Me dicati ons t hat Ma y I nterfere wit h 
Efficac y a n d Safet y Assess me nts i n St u d y  G P G L..........................................4 7

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

I 8 F-M C -G P G L ( b) Cli ni c al Pr ot o c ol
P a g e 8
L Y 3 2 9 8 1 7 6
Li st of A p p e n di c e s
A p p e n di x
P a g e
A p pe n di x 1.
A b bre viat i ons a n d Defi nit i ons ........................................................................7 9
A p pe n di x 2.
Cli nical La b orat or y  Tests ...............................................................................8 3
A p pe n di x 3.
St u d y  G o ver na nce C o nsi derati ons ..................................................................8 5
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 0
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 1
A p pe n di x 6.
Cl assificat i on of C o ntrace pti ve Met h o ds ........................................................9 2
A p pe n di x 7.
Pr ot oc ol  G P G L Sta n dar dize d Pr ot oc ols for t he Meas ure me nt of Hei g ht, 
Wei g ht, a n d Waist Circ u mfere nce
................................................................. 9 3
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 5
A p pe n di x 9.
Pr ot oc ol  A me n d me nt I 8 F-M C -G P G L( b)
A P hase 3, Ra n d o mize d, O pe n -La bel Tri al C o mpari n g Efficac y a n d 
S af et y of  Tirze pati de vers us Se ma gl uti de O nce Wee kl y as A d d- o n 
T hera p y  t o M etfor m i n i n Patient s wit h T ype 2 Di a betes ( S U R P A S S - 2) .........9 6

I 8 F-M C -G P G L ( 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 P hase 3, Ra n d o mize d, O pe n -La bel Tri al C o mpari n g Efficac y a n d Safet y of  Tirze pati de vers us 
S e m a gl ut i de O nce Wee kl y as A d d-o n T hera p y  t o Metf or mi n i n Patient s wit h T ype 2 Dia betes
( S U R P A S S- 2)
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]) . T hese treat me nt 
o pti o ns offer i m pr o ve d gl yce mic c o ntr ol , l ow ri s k of h y p o gl yce mia, a n d t he p ote nti al for 
cli nicall y rele va nt wei g ht l oss. H o we ver , a pr o p orti o n of patie nts d o n ot reac h treat me nt tar get s 
des pite hi g h le vel s of  c o mplia nce wi t h t he treat me nt re gi me ns.   T her ef ore, t here is a n u n met 
nee d f or a d ditio nal  tr e at me nt o pti o ns t hat e n ha nce gl yce mic c o ntr ol, pr o mot e  wei g ht l oss , a n d 
preser ve a n 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 patid e is a 3 9-a mi n o aci d s y nt het ic pe pti de wit h a g o nist acti vity at b ot h t he 
gl uc ose -de pe n de nt i ns uli n otr o pic p ol y pe pti de ( GI P) a n d G L P - 1 rece pt ors.  Its str uct ure is base d 
o n t he GI P se q ue nce a n d i ncl u des a C 2 0 fatt y  di-aci d moi et y t hat 
  
It is a d mi nistere d o nce wee kl y ( Q W) b y s u bc uta ne o us ( S C) i njecti on.
St u d y  I 8 F-M C -G P G L ( G P G L) i s a P hase 3, ra n d o mize d, o pe n -label , acti ve-c o ntr olle d, parallel 
gr o u p, m ul tice nter, mul tinat i onal, 4 -gr o u p tri al t o assess t he safet y a n d efficac y of tirze pati de 
5 m g, 1 0 m g, a n d 1 5 m g Q W c o mpare d t o se m a gl utide 1 m g Q W  i n patie nts wit h ty pe 2 dia betes 
i na de quatel y c o ntr olle d wit h ≥1 5 0 0 m g / da y metf or mi n al o ne.  St u d y  G P G L will pr o vi de a 
c o mparat i ve assess me nt of tirze pati de vers us t he hi g hest a p pr o ve d d ose of se ma gl ut i de ( 1 mg) 
wi t h res pect t o gl yce mic c o ntr ol a n d ot her cli nicall y rele va nt o utc o mes, i ncl u di n g wei g ht c ha n ge, 
h y p o gl yce mia i nci de nce, a n d t olera bilit y pr ofile.
C CI

I8F-MC-GPGL(b) Clinical Protocol
Page 10
LY3298176
Objectives/Endpoints:
Objectives
Endpoints
Primary

To demonstrate that tirzepatide 10 mg 
and/or 15 mg QW are noninferior to 
semaglutide 1 mg QW for glycemic
control at 40 weeks

Mean change in HbA1c from baseline
Key Secondary (controlled for type 1 error)
Efficacy

To demonstrate that tirzepatide 5 mg 
QW is noninferior to semaglutide 1 mg 
QW for glycemic control at 40 weeks 
for:

To demonstrate that tirzepatide 5 mg, 
10 mg, and/or 15 mg QW is superior to
semaglutide 1 mg QW at 40 weeks for:

Mean change in HbA1c from baseline

Mean change in body weight from baseline

Mean change in HbA1c from baseline

Proportion of patients with HbA1c target values of 
<7.0% (53 mmol/mol)
Additional Secondary (not controlled for 
type 1 error)
Efficacy

To compare tirzepatide 5 mg, 10 mg, 
and/or 15 mg QW to semaglutide 1 mg 
QW at 40 weeks for:

Proportion of patients achieving an HbA1c target 
value of ≤6.5% (48 mmol/mol)

Proportion of patients achieving an HbA1c target 
value of <5.7% (39 mmol/mol)

Mean change in fasting serum glucose (central 
laboratory) from baseline 

Mean change in 7-point SMBG profiles from 
baseline

Proportion of patients who achieved weight loss of 
>5%, >10%, and >15% from baseline

Patient-reported outcomes:
o
DTSQs (baseline only)/DTSQc (end of 
treatment only)
o
IW-SP (baseline and end of treatment)
o
APPADL (baseline and end of treatment)
Safety

To compare the safety of tirzepatide 
5 mg, 10 mg, and 15 mg QW to that of 
semaglutide 1 mg QW to the end of 
safety follow-up for:

TEAEs

Early discontinuation of study drug due to AEs

Adjudicated pancreatic AEs

Serum calcitonin 

Incidence of allergic and hypersensitivity reactions

Incidence of treatment-emergent anti-drug 
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

I8F-MC-GPGL(b) Clinical Protocol
Page 11
LY3298176
Abbreviations:  AE = adverse event; APPADL = Ability to Perform Physical Activities of Daily Living;
DTSQc = Diabetes Treatment Satisfaction Questionnaire change; DTSQs = Diabetes Treatment Satisfaction 
Questionnaire status; HbA1c = hemoglobin A1c; IW-SP = Impact of Weight on Self-Perception; QW = once 
weekly; SMBG = self-monitored blood glucose; T2DM = type 2 diabetes mellitus; TEAEs = treatment-emergent 
adverse events.
Summary of Study Design:
Study I8F-MC-GPGL is a Phase 3, 40-week, randomized, open-label, active-controlled, parallel 
group, multicenter, multinational, 4-group trial to assess the safety and efficacy of tirzepatide 
compared to semaglutide 1 mg in patients with type 2 diabetes inadequately controlled with 
≥1500 mg/day metformin alone.
Treatment Groups and Duration:
Study GPGL will consist of 3 sequential periods:  

Study Period I: approximately 3-week screening/lead-in period

Study Period II: 40-week treatment period, and 

Study Period III: 4-week safety follow-up period.
Patients will be randomly assigned 1:1:1:1 to 1 of the 4 treatments:

Tirzepatide (doses will be double-blinded)
o
5 mg
o
10 mg 
o
15 mg, or

Semaglutide 1 mg (not blinded).
Patient randomization will be stratified based on country and baseline HbA1c (≤8.5% or >8.5% 
[69 mmol/mol]).
Tirzepatide treatment will follow a fixed dose escalation. It will be

initiated at 2.5 mg QW for 4 weeks, and 

increased by 2.5 mg every 4 weeks (2.5 mg to 5 mg to 7.5 mg to 10 mg to 12.5 mg to 
15 mg) until the desired dose is achieved and maintained for the duration of the study.
Semaglutide treatment will follow a fixed dose escalation. It will be

initiated at 0.25 mg QW for 4 weeks

increased to 0.5 mg QW for 4 weeks, and 

increased to and maintained at 1 mg QW for the duration of study.
Number of Patients:
Approximately 1872 patients will be randomly assigned to treatment groups, with 468 patients in 
each group.

I8F-MC-GPGL(b) Clinical Protocol
Page 12
LY3298176
Statistical Analysis:
Efficacy Analyses
Efficacy and safety will be assessed using the modified intention-to-treat (mITT) population, 
which consists of all randomly assigned patients who are exposed to at least 1 dose of study 
drug.  There will be 2 estimands of interest in comparing efficacy of tirzepatide doses with 
semaglutide relative to the primary measure of mean change in HbA1c from baseline to the 
40-week visit.  The “efficacy” estimand represents efficacy prior to discontinuation of study drug 
without confounding effects of antihyperglycemic rescue therapy.  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 and possibly other regulatory agencies, the primary efficacy assessment will be 
guided by the “treatment-regimen” estimand.  This assessment will analyze change in HbA1c 
values from baseline to the 40-week visit using an analysis of covariance (ANCOVA) with 
terms:  treatment, country, and baseline HbA1c as a covariate.  The ANCOVA analysis will be 
conducted using the full analysis set at the 40-week visit, which consists of all available changes
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, missing HbA1c values at the 40-week visit will be imputed 
based on observed data in the same treatment group from patients who had their efficacy 
assessed after early discontinuation of study drug and/or initiation of rescue antihyperglycemic 
medication. This 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 the efficacy analysis set that 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-effects model for 
repeated measures (MMRM) with terms:  treatment, visit, treatment-by-visit interaction, and 
country as fixed effects, and baseline HbA1c as a covariate.  An unstructured covariance 
structure will model relationship of within-patient errors.  
A 0.3% boundary will be used for noninferiority evaluations between tirzepatide and 
semaglutide relative to mean change in HbA1c from baseline.
Since they are intended for different purposes, each of the 2 primary efficacy assessments 
relative to the two estimands will be conducted at a family-wise type 1 error rate of 0.05.  
Additional details, including analysis methods for key secondary endpoints and a strategy for 
controlling overall family-wise 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).

I8F-MC-GPGL(b) Clinical Protocol
Page 13
LY3298176
Safety Analyses
Safety assessment will be based on all available data through safety follow-up visit, irrespective 
of whether they were obtained after study drug discontinuation or whether the participant 
received rescue medication.  Summary statistics will be provided for incidence of TEAEs, 
serious AEs, and study discontinuation due to AEs or deaths from the time of first dose through 
end of safety follow-up.  Counts and proportions of patients 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.  Selected safety 
analysis (for example, hypoglycemia) may be conducted excluding data after introducing another 
antihyperglycemic therapy.  Additional details, including analysis of AEs of special interest, will 
be provided in the SAP.

I 8 F-M C -G P G L ( b) Cli ni c al Pr ot o c ol
P a g e 1 4
L Y 3 2 9 8 1 7 6
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 o we d f or all pat ient s e nr olle d i n 
St u d y G P G L .  H o we ver, f or t h ose patie nts w h ose partici patio n i n t his st u d y  is affecte d b y se vere 
ac ute res pirat or y s y n dr o me c or o na vir us 2 ( S A R S-C o V -2), t he vir us t hat ca uses t he n o vel 
C or o na vir us Disease 2 0 1 9 ( C O VI D- 1 9), please refer t o A p pe n di x 8 f or a d ditio nal  instr ucti o ns.

I 8 F-M C -G P G L ( 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
T a bl e G P G L. 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
E T b
8 0 1
Wee k of Tre at me nt
- 3
- 2
0
4
8
1 2
1 6
2 0
2 4
3 2
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
± 7
± 7
± 7
F asti n g Visit d
X
X
X
X
X
X
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 y sical
e xa mi nati o n
X
X  
X
Hei g ht
X
Wei g ht
f
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
X
Electr ocar di o gra m
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
Dilate d f u n d osc o pic 
e xa mi nati o n h
X
A d verse e ve nts
X  
X  
X  
X  
X  
X  
X  
X  
X  
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
Re vie w 
h y p o gl yce mic 
e ve nts c ollecte d i n 
t he diar y i
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X

I 8 F-M C -G P G L ( b) Cli ni c al Pr ot o c ol
P a g e 1 6
L Y 3 2 9 8 1 7 6
St u d y 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
E T b
8 0 1
Wee k of Tre at me nt
- 3
- 2
0
4
8
1 2
1 6
2 0
2 4
3 2
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
± 7
± 7
± 7
F asti n g Visit d
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 gi
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
St u d y dr u g i njecti o n 
trai ni n g wit h de m o 
de vice i
X
Ha n d o ut diar y, 
i nstr uct i n use i
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
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
X
Dis pe nse st u d y dr u g
X  
X  
X  
X  
X  
X  
X  
X
St u d y Dr u g C o m pli a nce
O bser ve patie nt 
a d mi nister st u d y 
dr u g l
X

I 8 F-M C -G P G L ( 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
E T b
8 0 1
Wee k of Tre at me nt
- 3
- 2
0
4
8
1 2
1 6
2 0
2 4
3 2
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
± 7
± 7
± 7
F asti n g Visit d
X
X
X
X
X
X
X
X
X
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
Assess st u d y dr u g 
c o m plia nce
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
testm
X
Ur i ne pre g na nc y 
testn
X
X
X
X
F ollicle -sti m ulati n g 
h or m o ne o
X
Estra di ol o
X
C he mistr y pa nel
X p
X
X
X  
X
X
Fasti n g g l uc ose
X  
X  
X  
X  
X  
X  
X
X  
X
X
Fasti n g ins uli n
X
X
X
X
X  
X
X
Fasti n g g l uca g o n
X
X
X
X
X  
X
X
Fasti n g C- pe pti de
X
X
X
X
X  
X
X
Li pi d pa nel
X
X
X
X
X  
X
X
Ur i nar y
al b u mi n/creati ni ne 
rati o
X p
X
X  
X
X
e G F R ( C K D- E PI)q
X p
X
X
X  
X
X
Calcit o ni n
X p
X
X
X  
X
X
He mat ol o g y
X p
X
X
X  
X
X

I 8 F-M C -G P G L ( 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
E T b
8 0 1
Wee k of Tre at me nt
- 3
- 2
0
4
8
1 2
1 6
2 0
2 4
3 2
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
± 7
± 7
± 7
F asti n g Visit d
X
X
X
X
X
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 p
X
X
X  
X
X
I m m u n o ge nicit yr
X  
X
X
X
X  
X
X
P K sa m ple f or 
im m u n o ge nicit y s
X  
X
X
X
X  
X
X
A nti- G A D 
a nti b o dies
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 neti
c st ore d sa m ple
E D T A plas ma, 
ser u m, P 8 0 0 plas ma
X
X
X
X  
X
X
P atie nt -Re p orte d O utc o mes t
D T S Qs
X
D T S Qc
X  
X
I W-S P
X
X  
X
A P P A D L
X
X  
X
E Q - 5 D- 5 L
X
X  
X
I W QO L- Lite- C T
X
X  
X

I 8 F-M C -G P G L ( b) Cli ni c al Pr ot o c ol
P a g e 1 9
L Y 3 2 9 8 1 7 6
A b bre viati o ns:  A D A = a nti -dr u g a nti b o dies; A P P A D L = A bilit y t o Perf or m P h ysical Acti vities of Dail y Li vi n g; B G = bl o o d gl uc ose; B P = bl o o d press ure; 
C K D -E PI = C hr o nic Ki d ne y Disease -E pi de mi ol o g y; D T S Qc = Dia betes Treat me nt Satisfacti o n Q uesti o n naire c ha n ge; D T S Qs = Dia betes Treat me nt 
Satisfacti o n Q uesti o n naire stat us; E C G = electr ocar di o gra m; e C R F = electr o nic case re p ort f or m; E D T A = et h yle ne dia mi netetraacetic aci d; e G F R = esti mate d 
gl o mer ular filtrati o n rate; E Q - 5 D-5 L = E ur o pea n Q ualti y of Li fe: 5 di me nsi o ns , 5 le vels ; E T = earl y ter mi nati o n; F/ U = f oll o w-u p; F S H = f ollicle -sti m ulati n g 
h or m o ne; G A D = gl uta mic aci d decar b o x ylase; H b A 1c = he m o gl o bi n A 1c; H R = heart rate; I W Q O L- Lite- C T = I m pact of Wei g ht o n Q ualit y of Life - Lite
Cli nical Trials Versi o n ; I W-S P = I m pact of Wei g ht o n Self -Perce pti o n; P K = p har mac o ki netics; S M B G = self -m o nit ore d bl o o d gl uc ose; tx = treat me nt.
a
Baseli ne assess me nts m ust be c o m plete d bef ore pr ocessi n g i n t he i nteracti ve we b -res p o nse s yste m.
b
Patie nts w h o are u na ble or u n willi n g t o c o nti n ue i n t he st u d y f or a n y reas o n will perf or m a n E T visit.  If t he patie nt is disc o nti n ui n g d uri n g a n u ns c h e d ule d 
visit, t hat visit s h o ul d be perf or me d as t he E T visit.  If t he patie nt is disc o nti n ui n g d uri n g a sc he d ule d visit, t hat vis it s h o ul d be perf or me d as a n E T visit.  
Visit 8 0 1 (safet y f oll o w -u p visit) s h o ul d be perf or me d 4 wee ks after t he E T visit as t he fi nal st u d y visit.
c
T he visit date is deter mi ne d i n relati o n t o t he date of t he ra n d o mizati o n visit ( ± t he all o we d visit wi n d o w). 
d
F or all t he fasti n g visits ( Visits 3 - 9 a n d 1 1 ), E T, a n d at f oll o w -u p, patie nts s h o ul d be re mi n de d t o re p ort t o t he site i n a fasti n g c o n diti o n, after a peri o d of 
a p pr o xi matel y 8 h o urs wit h o ut eati n g, dri n ki n g (e xce pt water), or a n y si g nifica nt p h ysi cal acti vit y a n d bef ore ta ki n g st u d y dr u g(s) a n d metf or mi n.
e
Me dical hist or y i ncl u des assess me nt of pree xisti n g c o n diti o ns (i ncl u di n g hist or y of gall bla d der disease, car di o vasc ular disea se, a n d me d ullar y t h yr oi d 
carci n o ma) a n d s u bsta nce usa ge (s uc h as alc o h ol a n d t o bacc o).
f
Wei g ht meas ure me nts m ust be i n kil o gra ms
per i nstr ucti o ns s pecifie d i n A p pe n di x 7 .
g
Vital si g n meas ure me nts s h o ul d be ta ke n bef ore o btai ni n g a n E C G traci n g a n d bef ore c oll ecti o n of bl o o d sa m ples f or la b orat or y testi n g, at visits w here 
re q uire d.  T he partici pa nt s h o ul d sit quietl y f or 5 mi n utes bef ore vital si g n meas ure me nts are ta ke n.  F or eac h para meter, 2 meas ure me nts will be ta ke n usi n g 
t he sa me ar m; t he rec or di n gs s h o ul d be ta ke n at least 1 mi n ute a part.  B P m ust be ta ke n wit h a n a ut o mate d bl o o d press ure mac hi ne.
h
Dilat e d f u n d osc o pic e xa mi nati o n will be perf or me d b y a n e ye care pr ofessi o nal ( o p ht hal m ol o gist or o pt o metrist) f or all patie nts be t wee n Visit 2 a n d Visit 3 t o 
e xcl u de patie nts wit h pr oliferati ve dia betic reti n o pat h y, dia betic mac ul o pat h y, or n o n pr oliferati ve di a betic reti n o pat h y t hat re q uires ac ute treat me nt.  T he 
res ults fr o m t his e xa mi nati o n will be rec or de d o n a s pecific reti n o pat h y e C R F as a baseli ne meas ure of reti n o pat h y.  F oll o w-u p dilate d f u n d osc o pic 
e xa mi nati o n s h o ul d be perf or me d whe n cli nicall y i n dica te d, a n d t he res ults s ho ul d be rec or de d o n t he reti n o pat h y e C R F.
i
All trai ni n g s h o ul d be re peate d as nee de d t o e ns ure patie nt c o m plia nce. 

D iaries will be pr o vi de d t o eac h patie nt.  Patie nts will nee d t o fill o ut t heir diar y a n d bri n g it wit h t he m at eac h visit. 

T he f oll o wi n g deli ver y de vices will be use d: a si n gle-d ose pe n f or tirze pati de a n d a si n gle-patie nt -use pe n f or se ma gl uti de.
j
I ncl u des c o u nseli n g o n diet a n d e xercise, s y m pt o ms a n d ma na ge me nt of h y p o gl yce mia a n d h y per gl yce mia, etc.
k
Pat ie nt is re q uire d t o c ollect t w o 7-p oi nt S M B Gs o n 2 n o nc o nsec uti ve da ys pri or t o t he ne xt visit.  A 7 -p oi nt S M B G c o nsists of meas ure me nts bef ore a n d 
2 h o urs after eac h of 3 mai n meals wit hi n t he sa me da y a n d at be dti me.  T hese S M B G pr ofiles will be c ollecte d b y  t he patie nt wit hi n 2 wee ks pri or t o t he 
assi g ne d visits. Patie nts will als o be re q uire d t o c ollect a wee kl y 4 -p oi nt S M B G.   If 7-p oi nt S M B G is n ot perf or me d, t he n data fr o m t he m ost rece nt 
n o nc o nsec uti ve 4 -p oi nt S M B G pr ofiles ca n be use d.  If m ore t ha n t w o 7 -p oi nt S M B G pr ofiles are a vaila ble, t he 2 m ost rece nt n o nc o nsec uti ve pr ofiles s h o ul d 
be use d.
l
Patie nts s h o ul d a d mi nister t heir first d ose of st u d y dr u g at t he e n d of t his visit ( Visit 3), after all t he ot her st u d y pr oce d ures a n d ra n d o mizati o n.   Pa tie nts will 
t he n c o nti n ue self-a d mi nisteri n g t heir st u d y dr u g Q W, wit h t heir last d ose a d mi nistere d o n Wee k 3 9 ( or wee k of E T visit).

I8F-MC-GPGL(b) Clinical Protocol
Page 20
LY3298176
m A serum pregnancy test will be performed at Visit 1 for women of childbearing potential only.
n 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 6, 9, and 11.  Pregnancy tests may also 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.
o
FSH test will be performed at Visit 1 only 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).
p
Screening visit assessment will serve as baseline. If missed at Visit 1, results should be obtained and reviewed before Visit 3 (randomization).
q
The CKD-EPI equation will be used by the central laboratory to estimate and report eGFR. 
r
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.
s
PK samples for immunogenicity must be taken prior to drug administration.
t
All PROs should be completed before any other study procedures if the patient is not adversely affected by the fasting condition or completed after patient has 
sufficiently recovered from the preceding visit procedures.

I 8 F-M C -G P G L ( b) Cli ni c al Pr ot o c ol
P a g e 2 1
L Y 3 2 9 8 1 7 6
3. I ntr o d u cti o n
3. 1.
St u d y R ati o n al e
T y pe 2 di a betes mellit us ( T 2 D M) is a meta b o lic c o n diti on c haracterize d b y i m paire d gl yce mic 
c o ntr ol ca use d b y increase d i ns uli n resista nce, pr o gressi ve beta -cell fail ure a n d c o nse q ue ntl y,
i na de q uate i ns uli n secreti on.  T 2 D M is ass ociate d wit h c o m or bi dities s uc h as i ncrease d wei g ht or 
o besit y,  h y perte nsi on, d y sli pi de mia, a n d a hi g her ris k f or macr o- a n d micr o vasc ular 
c o mplicat i ons.  T o pre ve nt t hese c o m p licati ons, ti g ht gl yce mic c o ntr ol is rec o m me n de d ( A D A 
2 0 1 9 b ; Da vies et al. 2 0 1 8).
I njecta ble i ncreti n-base d treat me nts (f or e xa m ple, gl uca g o n -li ke pe pti de-1 [ G L P -1] rece pt or 
a g o nists) are c o m m o nl y use d i n c o m bi nat i on wi t h or al a nti h y per gl yce mic me dicat i on ( O A Ms)
a n d basal i ns uli n t o ac hie ve a n d mai ntai n gl uc ose c o ntr ol (I nz ucc hi et al. 2 0 1 5; A D A 2 0 1 9 b ).  
W hile ass ociate d wit h l o wer ris k f or h y p o gl yce mia a n d eit her wei g ht ne utral or wei g ht l oss 
effects, c urre nt pre parati o ns are directe d at a si n gle i ncreti n m o lec ular tar get (f or e xa m ple, 
G L P -1 rece pt ors) .  T hese treat m e nt o ptio ns offer i m pr o ve d gl yce mic c o ntr ol , l ow ri s k of 
h y p o gl yce mia, a n d t he p ote nti al for cli nicall y  rele va nt weig ht l oss. H o we ver, a pr o p orti o n of  
patie nts d o n ot reac h treat me nt tar gets des pite hi g h le vels of  c o mplia nce wi t h t he treat me nt 
re gi me ns.  T heref ore, t here is a n u n met nee d f or a d dit i onal treat me nt o pti o ns t hat e n ha nce
gl yce mic c o ntr ol, pr o m ot e  w ei g ht l oss , a n d preser ve a n 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).
T he m eta b o lic effects of G L P-1 rece pt or a g o nists ca n be e n ha nce d b y c o m bi ni n g t he m wit h t he 
actio ns of  ot her e nter o pa ncreatic h or m o nes.  Gl uc ose-de pe n de nt i ns uli n otr o pic p ol y pe pti de 
( GI P) sti m ulates i ns uli n secreti on i n a gluc ose -de pe n de nt m a n ner a n d ma y e xert actio ns be y o n d 
its r ole as a n i ncreti n t hat ma y i m pr o ve t hera pe utic efficac y w he n c o m bi ne d wit h G L P -1 rece pt or 
a g o nists (f or e xa m ple, i m pr o ve d li pi d h o me o stasis a n d w h ole-b o d y  e ner g y meta b olis m) (As mar 
et al. 2 0 1 6; Na uc k a n d Meier 2 0 1 8).
Ti rze patide ( L Y 3 2 9 8 1 7 6) is a 3 9-a mi n o aci d s y nt heti c pe pt i de wit h a g o nist acti vity at b ot h t he 
GI P a n d G L P -1 rece pt ors.  Its str uct ure is base d o n t he GI P se q ue nce a n d i ncl u des a C 2 0 fatt y  
di -aci d moi et y t hat 
  It is 
a d mi nistere d as o nce -wee kl y ( Q W) s u bc uta ne o us ( S C) i nject i on ( Cos k u n et al . 2 0 1 8).  
St u d y  I 8 F-M C -G P G L ( St u d y  G P G L) is a P hase 3, ra n d o mize d, o pe n -label , acti ve-c o ntr olle d, 
parallel- gr o u p, m ul tice nter, mul tinati o nal, 4 -gr o u p trial t o assess t he safety a n d efficac y of 
tirze pati de 5 m g, 1 0 m g, a n d 1 5 m g Q W c o m pare d t o se ma gl ut i de 1 m g Q W  i n patient s wit h 
t ype 2 di a betes i na de q uatel y c o ntr olle d wit h ≥1 5 0 0 m g / da y met f or mi n alo n e.  St u d y G P G L will 
pr o vi de a c o m parat i ve assess me nt of tirze pati de vers us t he hi g hest a p pr o ve d d ose of se ma gl uti de 
( 1 m g) wi t h res pect t o gl yce mic c o ntr ol a n d ot her cli nicall y rele va nt o utc o mes, i ncl u di n g wei g ht 
c ha n ge, h y p o gl yce mia i nci de nce, a n d t olera bilit y pr ofile.
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 ( St u d y  G P G A) a n d St u d y I 8 F-M C -G P G C ( St u d y G P GC ) i n Ja pa nese 
C CI

I8F-MC-GPGL(b) Clinical Protocol
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patients, two Phase 2 studies, Studies I8F-MC-GPGB (Study GPGB) and I8F-MC-GPGF (Study 
GPGF).  
Phase 1 Study GPGA was a combination of single ascending dose (SAD) and multiple ascending 
dose study in healthy subjects followed by a multiple dose proof-of-concept study in patients 
with T2DM.  Study GPGA investigated safety, tolerability, pharmacokinetics (PK), and 
pharmacodynamics (PD) of tirzepatide administered as weekly SC injections.  A total of 
142 subjects (89 healthy subjects and 53 patients with T2DM) received at least 1 dose of 
treatment.  Doses of tirzepatide ranged from 0.25 mg to 8 mg in the SAD (with maximum 
tolerated dose achieved at 5 mg) in healthy subjects; multiple doses from 0.5 mg to 4.5 mg QW 
and titrated doses up to 10 mg QW for 4 weeks in healthy subjects; and multiple doses ranged 
from 0.5 mg to 5 mg QW and titrated doses up to 15 mg QW for 4 weeks in patients with T2DM.  
The safety, tolerability, and PK/PD profiles of tirzepatide at doses and escalation regimens 
administered in this Phase 1 study supported further development of tirzepatide for QW dosing 
in patients with T2DM (Coskun et al. 2018) .
A 26-week Phase 2 study (Study GPGB) assessed the efficacy, tolerability, and safety of 4 doses 
(1 mg, 5 mg, 10 mg, and 15 mg) of tirzepatide versus placebo and an active comparator 
(dulaglutide 1.5 mg) 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-mg, 10-mg, and 
15-mg doses were significantly 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 severity.  Serious AEs (SAEs) 
were balanced across the treatment groups, and none of the groups in either study reported severe 
hypoglycemia (Frias et al. 2018 ). 
As it was recognized that the titration scheme employed in Study GPGB was not optimal, Study 
GPGF was designed to explore alternative titration schemes (longer time intervals between dose 
escalations and different dose increments) to support evaluation of optimized dosing regimen(s) 
in Phase 3. Data from the Phase 1 and Phase 2 studies were used to model the escalation scheme 
to be used in the Phase 3 program and to minimize GI-related AEs.
These data support continued development of tirzepatide as a therapy for T2DM.  
3.3.
Benefit/Risk Assessment
Information about the known and expected benefits, risks, SAEs and reasonably anticipated AEs 
of tirzepatide is to be found in the Investigator’s Brochure (IB).

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In addition, detailed information about the known and expected benefits and risks of semaglutide 
may be found in the semaglutide package insert (Ozempic® USPI [WWW]; Ozempic® SmPC
[WWW]).  

I 8 F-M C -G P G L ( b) Cli ni c al Pr ot o c ol
P a g e 2 4
L Y 3 2 9 8 1 7 6
4.
O bj e cti v e s a n d E n d p oi nt s
Ta ble G P G L . 2 s h o ws t he o bjecti ves a n d e n d p oi nts of t he st u d y.
T a bl e G P G L . 2.
O bj e cti v e s a n d E n d p oi nt s
O bjecti ves
E n d p oi nts
Pri m ar y

T o de m o nstrate t hat tirze pati de 1 0 m g a n d/ or 
1 5 m g Q W are n o n i nferi or t o se ma gl uti de 1 
m g Q W f or gl y ce mic c o ntr ol at 4 0 wee ks

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 t hat tirze pati de 5 m g Q W is 
n o ni nferi o r t o se ma gl uti de 1 m g Q W f or
gl yce mic c o ntr ol at 4 0 wee ks f or:

T o de m o nstrate t hat tirze pati de 5 m g, 1 0 m g,
a n d/ or 1 5 m g Q W is s u peri or t o se ma gl uti de 
1 m g Q W 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 baseli ne

Mea n c ha n ge i n H b A 1c fr o m baseli 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)
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 tirze pati de 5 m g, 1 0 m g, a n d / or 
1 5 m g Q W t o se ma gl uti de 1 m g Q W at 
4 0 wee ks f or:

Pr o p orti o n of patie nts ac hi e vi n g a n H b A 1c 
tar get val ue of ≤6. 5 % ( 4 8 m m ol/ m ol)

Pr o p orti o n of patie nts ac hi e vi n g a n H b A 1c 
tar get val ue of < 5. 7 % ( 3 9 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 

Mea n c ha n ge i n 7 -p oi nt S M B G 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

Patie nt- re p orte d o utc o mes:
o
D T S Qs ( baseli ne o nl y)/D T S Qc (e n d of 
treat me nt o nl y)
o
I W-S P ( baseli ne a n d e n d of treat me nt)
o
A P P A D L ( baseli ne a n d e n d of treat me nt)
Safet y

T o c o m pare t he safet y of tirze pati de 5 m g, 
1 0 m g, a n d 1 5 m g Q W t o t hat of se ma gl uti de 
1 m g Q W t o t he e n d of safet y f oll o w-u p f or:

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 Es

A dj u dicate d pa ncreatic A Es

S er 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

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Objectives
Endpoints

Incidence of treatment-emergent anti-drug 
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
Exploratory Objective
To compare tirzepatide 5 mg, 10 mg, and 15 mg QW to semaglutide 1 mg QW at 40 weeks for:

Patient-reported outcomes at baseline and end of treatment:
o
EQ-5D-5L
o
IWQOL-Lite-CT

Changes in fasting glucagon, C-peptide, and insulin levels

Changes in lipids (total cholesterol, HDL, VLDL, and triglycerides)

Changes from baseline in mean BMI

Mean change in waist circumference 

Biomarkers
Abbreviations:  AE = adverse event; APPADL = Ability to Perform Physical Activities of Daily Living;
BMI = body mass index; DTSQc = Diabetes Treatment Satisfaction Questionnaire change; DTSQs = Diabetes 
Treatment Satisfaction Questionnaire status; EQ-5D-5L = European Quality of Life: 5 dimensions, 5 levels;
HbA1c = hemoglobin A1c; HDL = high-density lipoprotein; IW-SP = Impact of Weight on Self-Perception;
IWQOL-Lite-CT = Impact of Weight on Quality of Life-Lite Clinical Trials Version; QW = once weekly;
SMBG = self-monitored blood glucose; T2DM = type 2 diabetes mellitus; TEAEs = treatment-emergent adverse 
events; VLDL = very low-density lipoprotein.

I 8 F-M C -G P G L ( b) Cli ni c al Pr ot o c ol
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L Y 3 2 9 8 1 7 6
5. St u d y  D e si g n
5. 1.
O v er all D e si g n
St u d y G P G L is a P hase 3, 4 0 -wee k , ra n d o mize d, o pe n -la bel, act i ve-c o ntr olle d, parallel-gr o u p, 
m ult ice nter, m ulti nati onal, 4 -gr o u p trial t o assess t he safety a n d efficac y of t irze pat i de c o m pare d 
t o se ma gl ut i de 1 m g i n patient s wit h t ype 2 di a betes i na de q uatel y c o ntr olle d wit h ≥1 5 0 0 m g / da y
met f or mi n al one.
St u d y peri o ds
St u d y  G P G L will c o nsist of 3 se q ue ntial p eri o ds:  

St u d y  P erio d I: a p pr o xi matel y 3 -wee k scree ni n g/lea d -i n peri o d

St u d y  P erio d II: 4 0 -wee k treat me nt peri o d , a n d 

St u d y  P erio d III: 4 -wee k safet y f oll ow- u p peri o d .  
R a n d o miz ati o n t o st u d y tre at me nt
P ati e nts will be ra n d o ml y assi g ne d 1: 1: 1: 1 t o 1 of 4 Q W treat me nts:

Ti rze patid e ( d oses will be d o u ble-bli n de d)
o
5 m g
o
1 0 m g 
o
1 5 m g, or

S e m a gl ut i de 1 m g (n ot bli n de d) .
P ati e nt ra n d o mizat i on will be stratifie d base d o n c o u ntr y a n d baseli ne H b A 1c ( ≤8. 5 % or > 8. 5 % 
[ 6 9 m m ol/ m ol]).
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 .

I 8 F-M C -G P G L ( 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
Fi g ure G P G L .1 ill ustrates t he st u d y desi g n.  
A b bre viati o n :  Q W = o nce wee kl y.
a
Sta ble d oses of metf or mi n ≥1 5 0 0 m g/ da y f or at least 3 m o nt hs pri or t o Visit 1 a n d 
d uri n g t he scree ni n g/lea d -i n peri o d.
b
All tirze pati de d oses will be d o u ble -bli n de d.
Fi g ur e G P G L .1.
Ill u str ati o n of st u d y d e si g n f or Cli ni c al Pr ot o c ol I 8 F-M C -G P G L .
St u d y Peri o d I (scree ni n g a n d le a d -i n)
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 a n d uri ne sa m ples f or la b orat or y assess me nts nee de d t o c o nfir m eli gi bility at Vi sit 2.  T he 
pati e nt will si g n t he i nf or me d c o nse nt f or m (I C F) bef ore a n y st u d y pr oce d ures are perf or me d.  
Pr oce d ures at t his visit will be perf or me d as s h o w n i n t he Sc he d ule of Acti vit ies ( Sectio n 2 ).
Le a d -i n ( Visit 2 t o Visit 3)
T he p ur p ose of Visi t 2 is t o re vie w t he res ults of t he scree ni n g la borat or y  meas ures t o furt her 
assess pat ient  eli gi bilit y.  F or t h ose patie nts meet i n g all ot her eli gi bilit y re q uire me nts, a dilate d 
f u n d osc o pic e xa mi nati on, perf or me d b y  a n o p ht hal mol o gist or o pt o m etrist, must be c o m plete d 
bet wee n Visit 2 a n d Visit 3. T he p ur p ose of t his e xa mi nat i on is t o e ns ure t hat patie nts w h o meet 
E xcl usi o n C rit erio n [1 1 ] are excl u de d fr o m t he st u d y ( Sectio n 6. 2 ).

P atie nts a n d t heir care gi ver(s), if a p plica ble, will recei ve a gl uc o met er a n d trai ni n g o n 
h o w t o perf or m self -m o nit ori n g o f bl o o d gl uc ose ( S M B G).
o
P ati e nts will be as ke d t o m o nit or 4- p oi nt S M B G pr ofiles wee kl y a n d 7-p oi nt 
S M B G pr ofiles t wice o n 2 n o nc o nsec ut i ve da ys i n t he 2- wee k peri o d pri or t o 
Vi sit 3 (ra n d o mizatio n), Visi t 9 ( Wee k 2 4 ), a n d Visit 1 1 ( Wee k 4 0).  

I 8 F-M C -G P G L ( 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

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 bl o o d 
gl uc ose ( B G) val ues a n d h y p o gl yce mic e ve nts.  

D uri n g t his peri o d, patie nts will als o be trai ne d o n disease ma na ge me nt (s y m pt o ms of 
h y p o gl yce mia a n d h y per gl yce mia) a n d st u d y  pr oce d ures; t his trai ni n g ca n be re peate d at 
s u bse q ue nt visits as dee me d a p pr opri ate.   
o
P ati e nts s h o uld m o ni t or B G a n y time a h y p o gl yce mic e ve nt is s us pecte d.  

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 diet a n d e xercise r o uti ne a n d 
m ust n ot use a n y O A Ms ot her t ha n met f or mi n, or c ha n ge t heir metf or mi n d ose or 
f or mula tio n , t o all o w relia ble assess me nt of H b A 1c at baseli ne ( Visit 3).  
St u d y Peri o d II ( 4 0 -wee k tre at me nt peri o d)
R a n d o miz ati o n ( Visit 3)

At  Visit 3, pri or 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, eli gi ble 
pati e nts will c o m p lete all re q uire d baseli ne st u d y pr oce d ures (i nclu di n g t he c ollecti o n of 
all baseli ne la b orat or y  meas ures a n d electr ocar di o gra m [ E C G]).  

P ati e nt s h o uld arri ve t o t he cli nic i n t he fast i n g state t hat 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 t hei r metfor mi n d uri n g t hat ti me . 

T he pati e nt -re p orte d o utc o mes q uesti o n naires s h o ul d be c o m plete d bef ore a n y ot her 
st u d y pr oce d ures if t he patie nt is n ot a d versel y affecte d b y t he fasti n g c o n diti on or 
c o mplete 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 ir deli ver y de vices:  a si n gle-d ose pe n f or 
pati e nts ra n d o mize d t o tirze pati de a n d a si n gle-pat ie nt-use pe n f or patie nts ra n d o mize d t o 
se ma gl uti de. T he y will i n ject t heir first d ose of st u d y dr u g w hile i n t he cli nic f or Visit 3. 

T he date a n d ti me of t he first d ose of st u d y  dr u g s h o uld be rec or de d o n t he electr o nic 
case re p ort f or m ( e C R F).
F o ll owi n g ra n d o mizat i on, pati e nts will p artici pate i n a 4 0-wee k treat me nt peri o d.
Tre at me nt peri o d (e n d of Visit 3 t o Visit 1 1 ):
See t he Sc he d ule o f Act i vities ( Sectio n 2 ) f or details a b o ut t he st u d y pr oce d ures a n d Treat m e nts 
A d mi nistere d ( Secti o n 7. 1 ) f or details a b o ut t he st u d y dr u g d oses.
St u d y Peri o d III (s afet y f oll o w - u p peri o d)
S afety f oll o w -u p ( fi n al tre at me nt visit t o Visit 8 0 1):
All patie nts w h o c o m plete t he treat me nt peri o d are re q uire d t o c o m plete Visit 8 0 1, a safet y  
f oll ow- u p visit , a p pr o xi matel y 4 wee ks after t heir last treat me nt visit.  Patie nts disc o nt i n ui n g t he 
st u d y earl y a n d perf or mi ng a n earl y ter mi nat i on ( E T) vi sit will als o be as ke d t o perf or m t he 
safety f oll ow- u p visi t, s o t hat t he safety f oll ow- u p visit will be t heir fi nal visit.  D uri n g t he safet y  
f oll ow- u p peri o d, patie nts will n ot recei ve st u d y  dr u g. Patie nts will be treate d w ith a n ot her 
gl uc ose -l oweri n g i nter ve nt i on deci de d u p o n b y t he i n vest i gat or.  If a n y ne w a nti h y per gl yce mic 
me dicat i on is i nitiate d d uri n g t he safety f oll ow- u p peri o d, i t will n ot be classifie d as resc ue 
t hera p y.  Patie nts are als o re q uire d t o ret ur n a n y r e mai ni n g st u d y diaries t o t he st u d y site at t he 
e n d of t his peri o d.

I 8 F-M C -G P G L ( 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
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 c o nti n ue t o use c o nc o mita nt metf or mi n t hr o u g h o ut t he treat me nt peri o d; 
di sc o nti n uati on or c ha n ges t o t he d ose or f or m ulat i o n are n ot per mitte d, e xce pt i n t he sit uati o ns 
w here d ose a djust me nt  or c o mplete disc o nt i n uati on is re q uire d per c o u ntr y-s pecific la bel or 
w he n all o we d per st u d y  pr ot oc ol (for f urt her details , see Secti o n 7. 7. 1 ).
P ati e nts will be i nstr ucte d t o perf or m 4 -p oi nt S M B G meas ure me nts (c o nsisti n g o f fasti n g, pre -
mi d da y  me al, pre -e ve ni n g meal, a n d be dti me BG meas ure me nts) o nce wee kl y a n d t o rec or d all 
res ults i n diaries.
These res ults will be use d f or gl uc ose ma na ge me nt o nl y. I n a d diti on, a 7-p oi nt
S M B G pr of ile ( prior t o a n d 2 h o urs after t he 3 mai n meals a n d at be dti me) o n 2 n o nc o nsec ut i ve 
da ys will be c ollecte d d uri n g t he 2 wee k s prece di n g pres pecifie d cli nic visits , as s h o w n i n t he 
Sc he d ule of Act i vities ( Sectio n 2 ), a n d will be use d f or efficac y a nal yses. D uri n g t he wee ks 
w he n t he 7 -p oi nt S M B G pr ofiles are t o be c ollecte d, patie nts will n ot be re q uire d t o c ollect 
4 -p oi nt S M B G pr ofiles, a n d t he 7-p oi nt p r ofiles will be use d f or gl uc ose ma na ge me nt i nstea d. 
Data fr o m t he 7 -p oi nt pr ofiles will be e ntere d i nt o t he e C R F as s h o w n in t he Sc he d ule of 
Act i vities ( Secti o n 2 ). If t he 7 -p oi nt S M B G is n ot perf or me d, t he n data fr o m t he most rece nt 
n o nc o nsec ut i ve 4-p oi nt S M B G pr ofiles ca n be use d.  If m ore t ha n t wo 7- p oi nt S M B G pr ofiles 
are a vaila ble, t he 2 m ost rece nt n o nc o nsec ut i ve pr ofiles s h o ul d be use d.
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 ns 7. 4. 2. 3 a n d 9. 2. 2. 2 ) will recei ve a ne w gl uc ose-l oweri n g i nter ve nt i on (“resc ue t hera p y”) 
a n d will als o c o nti n ue t o a d mi nister st u d y dr u g.  Patie nts w h o nee d h y per gl yce mic resc ue 
t hera p y will c o nti n ue i n t he trial u ntil t he y c om p lete all st u d y visits.
P ati e nts w h o per ma ne nt l y disc ont i n ue st u d y dr u g prior t o t he safet y f oll ow- u p p erio d s h o ul d 
c o nti n ue i n t he trial a n d s h o ul d recei ve a ne w gl uc ose- l oweri n g i nter ve nt i on ( Secti o n 7. 7. 2 ).
5. 2.
N u m b er of P arti ci p a nt s
A p pr o xi matel y  1 8 7 2 patient s will be ra n d o ml y assi g ne d t o treat me nt gr o u ps, wit h 4 6 8 patie nts i n 
eac h gr o u p.
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 G L will pr o vi de a c o m parati ve assess me nt of tirze pati de vers us se ma gl uti de 1 m g wi t h 
res pect t o gl yce mic c o ntr ol a n d ot her cli nicall y rele va nt o utc o mes, i ncl u di n g wei g ht c ha n ge, 
h y p o gl yce mia i nci de nce, a n d t olera bilit y pr ofile .
S e m a gl ut i de 1 m g was c h ose n as t he act i ve c o mparat or beca use it is t he hi g hest a p pr o ve d d ose of  
se ma gl uti de f or patie nts wit h T 2 D M
t hat has s h o w n s u peri orit y i n i m pr o vi n g gl yce mic c o ntr ol 

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a n d re d uci n g b o d y wei g ht c o mpare d t o 2 ot her G L P - 1 rece pt or a g o nists i n t he class, d ula gl uti de 
a n d e xe nat i de Q W, wit h a si milar safety pr ofile ( A h ma n n et al. 2 0 1 8 ; Pratl e y et al. 2 0 1 8).  
Metf or mi n was c h ose n as t he re q uire d c o nc o mit a nt a nti h y per gl yce mic me dicat i on beca use it is
c o m m o nl y  use d i n cli nical practice as first -li ne t hera p y a n d w he n use d i n c o m bi nati on, t he ris k 
of  h y p o gl yce mia is l o w. T he mi ni m u m d ose (at l east 1 5 0 0 m g/ da y) was c h ose n t o e ns ure 
ma xi mizi n g efficac y of m etfor m i n pri or t o a d di n g a d ditio nal  t hera p y (Nat ha n et al . 2 0 0 9). T o
m i ni mize t he p ote ntial c o nf o u n di n g effect of c ha n ges to c o nc o mita nt met f or mi n, patie nts will be 
e x pecte d t o mai ntai n met f or mi n t hr o u g h o ut t he treat me nt peri o d u ntil t he last d ose of 
ra n d o mize d treat me nt, ot her t ha n f or t he sit uati o ns descri be d i n Sect i on 7. 7. 1 .
T he parallel -gr o u p desi g n f or treat me nt c o m paris o n was c h ose n t o a v oi d a n y i nteracti o n bet wee n 
treat me nts t hat ma y i nterfere wit h t he i nter pretati o n of t he st u d y o utc o me.  P atie 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 .  Me dicati 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 treat me nts 
will n ot be all o we d ( Secti o n 7. 7 ). 
T he o pe n -label desi g n is use d f or t his st u d y beca use of t he differe nt de vices use d f or 
a d mi nisteri n g tirze pat i de a n d se ma gl uti de. T he ti rze patide d oses will be bl i n de d f or better 
assess me nt of efficac y a n d safety o ut c o m es of  in di vi d ual d oses. 
T he pl a n ne d treat me nt d uratio 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 pati de o n b ot h gl yce mic c o nt r ol a n d b o d y 
w ei g ht as re q ueste d b y t he F D A.
5. 5.
J u stifi c ati o n f or D o s e
Tirze p ati de D oses
Ti rze patid e d oses of  5 mg, 1 0 m g , a n d 1 5 mg a d mi nistere d s u bc uta ne o usl y  Q W will be e val uate d 
i n t his st u d y. 
T hese d oses a n d ass ociate d escalat i on sc he mes were selecte d base d o n t he assess me nt of safet y,  
efficac y ( gl yce mic a n d wei g ht loss be nefit), a n d GI t olera bilit y data f o ll owe d b y  e xp os ure -
res p o nse m o deli n g of data i n pati e nts wit h T 2 D M i n P hase 1 a n d 2 st u di es. 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  
4 wee k s w o ul d per mi t ti me f or de vel o p me nt of  t olera nce t o GI e ve nts a n d are pre dicte d t o 
i m pr o ve GI t ol era bilit y.
T he m a xi m u m pr o p ose d d ose of 1 5 m g m ai ntai ns a n e x p os ure m ult i ple of 1. 6 t o 2. 4 t o t he 
n o -o bser ve d -a d verse-effect le v el d oses i n 6-m o nt h m o n k e y  a n d rat t o xic o l og y  st u dies.
T he selecte d d ose a n d escalati o n sc he me w o ul d e na ble f urt her e val uat i on of be nefit/ris k 
c o nsi derati o ns f or 5 -m g, 1 0 -m g, a n d 1 5 -m g d oses of tirze pati de.

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Semaglutide Dose
To allow the most robust comparison of tirzepatide and semaglutide, the highest approved dose 
of semaglutide (1 mg) for T2DM was chosen to be studied. 
Semaglutide has 2 effective doses, 0.5 mg QW and 1 mg QW. Whereas the lower dose (0.5 mg) 
is recognized as an effective dose for glycemic control, the 1-mg dose provides some additional 
benefit in glycemic control and weight reduction, with relatively similar tolerability (Marso et al. 
2016; Ahrén et al. 2017; Aroda et al. 2017; Sorli et al. 2017; Pratley et al. 2018; Rodbard et al. 
2018). Semaglutide dose will be escalated to 1 mg as recommended in the prescribing 
information (Ozempic® USPI [WWW]). 

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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 viati o ns t o recr ui t me nt a n d e nr o ll me nt criteria, als o k n o w n as 
pr ot oc ol  wai vers or e xe m pti ons, are n ot per mitte d.
6. 1.
I n cl u si o n Crit eri a
P ati e nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if t he y meet all of t h e foll o wi n g criteria at 
scree ni n g:
T y pe of P atie nt a n d Dise ase C h ar acteristics
[ 1] Ha ve bee n dia g n ose d wit h T 2 D M base d o n t he W orl d Healt h Or ga nizat i on 
classificat i on or ot her l ocall y a p plica ble dia g n ostic sta n dar ds
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 o l/ m ol), as deter mi ne d 
b y t h e ce ntral la b orat or y at Visit 1
[ 3] Are of sta ble wei g ht ( ± 5 %) ≥3 m o nt hs prece di n g 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 lifes t yle a n d dietar y meas ures f or dia betes treat me nt
[ 4] Ha ve b o d y  mass i n de x ( B MI ) ≥2 5 k g/ m 2 at Visit 1
[ 5] Ha ve bee n o n sta ble dia betes treat me nt wit h met f or mi n ≥1 5 0 0 m g/ da y  d uri n g t he 
3 m o nt hs pri or t o Visit 1 a n d bet wee n Visits 1 a n d 3
[ 6] 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
Male patie nts ( See A p pe n di x 6 f or more details):

Male patie nts s h o ul d be willi n g t o use relia ble c o ntrace pti ve met h o ds t hr o u g h o ut 
t he st u d y a n d for at least 3 m o nt hs after l ast i nject i o n 
Fe male pat ient s:

Fe male pat ient s n ot of c hil d beari n g p ote ntial d ue t o s ur gical sterilizat i on 
( h ysterect o m y or bilateral o o p h orect o m y or t u bal li gati on), c o n ge nital a n o ma l y 
(t hat is, M ulleria n a ge nesis), or me n o pa use
o
W o me n wi t h a n i ntact uter us are dee me d p ost me n o pa usal if t he y are at 
least 4 5 years ol d a n d

ha ve n ot ta ke n h or m o nes or oral c o ntrace pti ves wit hi n t he last y ear 
a n d ha d cessat i on of me nses f or at least 1 y ear
O R

ha ve ha d at least 6 m o nt hs a n d less t ha n 1 2 mo nt hs of  s p o nta ne o us 
a me n orr hea wit h fol licle-sti m ulati n g h or m o ne ( F S H) a n d estra di o l 
le vels c o nsiste nt wit h a p ost me n o pa usal state ( F S H ≥4 0 mI U/ m L 
a n d estra di o l < 3 0 p g/ m L).

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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 1 form is highly effective for the duration of the trial 
and for 30 days thereafter).

not be breastfeeding
[7] In the investigator’s opinion, are well motivated, capable, and willing to
(a)
perform finger-stick BG monitoring, including scheduled BG profiles with up to 
7 measurements in 1 day
(b)
learn how to self-inject study drugs (tirzepatide or semaglutide), 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)
inject tirzepatide or semaglutide once weekly
(d)
maintain study diaries, as required for this protocol
(e)
sufficiently understand one of the provided languages of the country such that they 
will be able to complete the patient questionnaires
Informed Consent
[8] 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
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at
screening:
Medical Conditions
[9] Have type 1 diabetes mellitus (T1DM)
[10] Have a history of chronic or acute pancreatitis any time prior to study entry 
(Visit 1)
[11] Have a history of any of the following:

proliferative diabetic retinopathy,
OR

diabetic maculopathy,
OR

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
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) 
[12] Have a history of ketoacidosis or hyperosmolar state/coma
[13] Have a history of severe hypoglycemia and/or hypoglycemia unawareness within 
the 6 months prior to Visit 1
[14] 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:  gastric bypass (bariatric) surgery or 
restrictive bariatric surgery (for example, Lap-Band®), or chronically take drugs 
that directly affect GI motility
[15] Have any of the following cardiovascular (CV) conditions within 2 months prior
to Visit 1:  acute myocardial infarction, cerebrovascular accident (stroke), or 
hospitalization due to congestive heart failure (CHF)
[16] Have a history of New York Heart Association Functional Classification IV CHF
[17] Have acute or chronic hepatitis, signs and symptoms of any liver disease other 
than nonalcoholic fatty liver disease (NAFLD), or alanine aminotransferase 
(ALT) level >3.0 times the upper limit of normal (ULN) for the reference range, 
as determined by the central laboratory at study entry.  Patients with NAFLD are 
eligible to participate in this trial if their ALT level is ≤3.0 times the ULN for the 
reference range
[18] Have an estimated glomerular filtration rate <45 mL/min/1.73 m2 (or lower than 
the country-specific threshold for discontinuing metformin therapy per local 
label), calculated by Chronic Kidney Disease-Epidemiology as determined by 
central laboratory at Visit 1
[19] Have evidence of a significant, uncontrolled endocrine abnormality (for example, 
thyrotoxicosis or adrenal crises), in the opinion of the investigator
[20] Have family or personal history of medullary thyroid carcinoma (MTC) or 
multiple endocrine neoplasia syndrome type 2 (MEN2)
[21] Have a serum calcitonin level of ≥35 ng/L, as determined by central laboratory at 
Visit 1
[22] Have known or suspected hypersensitivity to trial product(s) or related products
[23] 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
[24] Have had a transplanted organ (corneal transplants [keratoplasty] allowed) or 
awaiting an organ transplant

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[25] 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
[26] 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
[27] Have any hematological condition that may interfere with HbA1c measurement 
(for example, hemolytic anemias, sickle cell disease)
Prior/Concomitant Therapy
[28] Have been treated with any antihyperglycemic medication (other than metformin) 
within the 3 months prior to Visit 1.  An exception is for the use of insulin for 
gestational diabetes or short-term use (<14 days) for acute conditions such as 
acute illness, hospitalization, or elective surgery
[29] 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], Adipex® [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) 
[30] 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
[31] Are currently enrolled in any other clinical study involving an investigational 
product or any other type of medical research judged not to be scientifically or 
medically compatible with this study
[32] Have participated, within the last 30 days, in a clinical study involving an 
investigational product.  If the previous investigational product has a long half-
life, 5 half-lives or 30 days (whichever is longer), should have passed prior to 
screening
[33] Have previously completed or withdrawn from this study or any other study 
investigating tirzepatide

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Ot her E xcl usi o ns
[ 3 4] Are i n vest i 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 pte d
[ 3 5] Are Lill y  e m plo y ees 
[ 3 6] Are u n willi n g or u na ble t o c o m pl y wit h t he use of a data c ollect i on de vice t o 
di rectl y rec or d data fr o m t he patie nt
6. 3.
Lif e st yl e R e stri cti o n s
Per t he Sc he d ule of Act i vities ( Secti 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 ul d it occ ur.  
P ati e nts s h o uld c o nt i n ue t heir us ual e xercise ha bits an d ge nerall y f o ll 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 I ncl usi o n Criteri o n [ 3] 
( Sectio n 6. 1 ), patie nts s h o ul d n ot i nitiate a n or ga nize d diet a n d/ or e xercise ( wei g ht re d ucti o n) 
pr o gra m d uri n g t he st u d y  ot her t ha n t he lifestyle 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) must n ot 
be rescree ne d .

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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
P ati e nts will be ra n d o mize d i n a 1: 1: 1: 1 rati o t o 1 of t he 4 st u d y treat me nts: 

Ti rze patid e ( d oses will be d o u ble-bli n de d)
o
5 m g
o
1 0 m g 
o
1 5 m g, or

S e m a gl ut i de 1 m g (n ot bli n de d) .
St u d y  dr u g will be a d mi nistere d Q W as S C i njecti o n i n patient s wit h T 2 DM
i na de q uatel y 
c o ntr olle d wit h ≥1 5 0 0 m g / da y met f or mi n alo n e.
Ta ble G P G L . 3 s h o ws t he ra n d omize d treat me nts f or t he e nt ire treat me nt perio d.
T he date a n d ti me of all d ose s of  st u d y dr u g s h o ul d be rec or de d o n t he e C R F.  
T a bl e G P G L . 3.
Tr e at m e nt R e gi m e n s
N a me of Dr u g
D os a ge
Fre q ue nc y
Dr u g F or m ul ati o n
R o ute o f 
A d mi nistr ati o n
I n vesti g ati o n al c o m p o u n d
T irze pati dea
5 m g
Q W
Si n gle -d ose pe n
S C
1 0 m g
Q W
Si n gle -d ose pe n
S C
1 5 m g
Q W
Si n gle -d ose pe n
S C
C o m p ar at or
S e ma gl uti de b
1 m g
Q W
Si n gle -patie nt -use pe n
S C
A b bre viati o ns:  S C = s u bc uta ne o us; Q W = o nce wee kl y .
a
Tirze pati de treat me nt will f oll o w a fi xe d d ose escalati o n. It will be

i nitiate d at 2. 5 m g Q W f or 4 wee ks, a n d 

i ncrease d b y 2. 5 m g e ver y 4 wee ks ( 2. 5 m g t o 5 m g t o 7. 5 m g t o 1 0 m g t o 1 2. 5 m g t o 1 5 m g ) u ntil t he 
desire d d ose is ac hie ve d a n d mai nt ai ne d f or t he d urati o n of t he st u d y.
b
Se ma gl uti de treat me nt will f oll o w a fi xe d d ose escalati o n. It will be

i nitiate d at 0. 2 5 m g Q W f or 4 wee ks

i ncrease d t o 0. 5 m g Q W f or 4 wee ks, a n d 

i ncrease d t o a n d mai ntai ne d at 1 m g Q W f or t he d urati o n of st u d y.

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T he i n vest i gat or or his/ her desi g nee is res p o nsi ble f or t he f oll owi n g:

e x plai ni n g t he c orrect use of t he st u d y dr u gs a n d deli ver y de vices (t hat is, si n gle-
d ose pe n f or tirze pati de a n d si n gle -pat ient -use pe n f or se ma gl ut i de) t o t he patie nt
or pati e nt re prese ntati ve.  F or si n gle-d ose pe ns , a de mo nstrati o n de vice will be 
use d

ex plai ni n g t he c orrect use of c o nc o mit a nt met f or mi n t o t he patie nt or patie nt 
re prese ntati ve, i ncl u di n g a n y c o ntrai n dicati ons a n d a p pr o priate d osi n g per c o u ntr y -
s pecific la beli n g

verif y i n g t hat i nstr ucti o ns are f oll owe d pr o perl y b y t he patie nt

mai ntai ni n g acc urate rec or ds of i n vesti gati o nal pr o d uct dis pe nsi n g a n d c o llecti on
P ati e nts s h o uld ret ur n all  u n use d st u d y dr u gs t o t he site acc or di n g t o t he Sc he d ule of Act i vities 
( Sectio n 2 ).  Patie nts s h o ul d be i nstr ucte d t o discar d all use d deli ver y  de vices i n a cl osea ble, 
p u nct ure -resista nt c o ntai ner acc or di n g t o l ocal r e g ulat i ons.
7. 1. 1.
P a c k a gi n g a n d L a b elli n g
T he s p o ns or will pr o vi de t irze pat i de i n si n gle-d ose pe ns a n d sema gl ut i de, i n si n gle-pati e nt -use 
pe ns .  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 a n d si n gle-pat ient -use pe ns will  be pac ka ge d i n cart o ns t o be dis pe nse d.  Cli nical st u d y  
materi als will be la bele d acc or di n g t o t he c o u ntr y’s re g ulat or y re q uire me nts.
7. 1. 2.
M e di c al D e vi c e s
T he c o m bi nat i on pr o d ucts pr o vi de d f or use i n t he st u d y are i n vesti gati onal prefille d si n gle-d ose 
pe n s f or tirze pati de a n d mar kete d prefille d si n gle-pati e nt -use pe n s for s e m a gl ut i de.
7. 2.
M et h o d of Tr e at m e nt A s si g n m e nt
P ati e nts w h o meet all crit eria for e nr oll me nt will be ra n d o m l y assi g ne d t o 1 of t he st u d y 
treat me nt gr o u ps at Visit 3 .  Assi g n me nt t o treat me nt gr o u ps will be deter mi ne d b y a 
c o mp uter -ge nerate d ra n d o m se q ue nce usi n g a n I W R S.  Patie nts will be ra n d o m l y assig ne d i n a 
1: 1: 1: 1 rati o t o recei ve tirze pati de 5 m g , 1 0 m g, 1 5 m g, or se m a gl ut i de 1 m g . Patie nt 
ra n d omizat i on will be stratifie d base d o n c o u ntr y  a n d baseli ne H b A 1c ( ≤8. 5 % or > 8. 5 % 
[ 6 9 m m o l/ m ol]).
7. 2. 1.
S el e cti o n a n d Ti mi n g of D o s e s
Assi g n me nt t o tirze pati de ( 3 d oses) or se ma gl uti de will occ ur at ra n d o mizat i on .  
Tirze p ati de
T here are n o restrict i ons o n t he ti me of da y eac h wee kl y d ose of st u d y dr u g is give n, b ut i t is 
a d visa ble t o a d mi nister t he S C i njecti o ns o n t he sa me da y a n d sa me ti me eac h wee k, wi t h or 
wi t ho ut m eals. T he act ual date a n d ti me of all d ose a d mi nistrati o ns will be rec or de d b y t he 
pati e nt i n t he patie nt diar y.  If a d ose of st u d y dr u g is misse d, t he patie nt s h o ul d ta ke it as s o o n as 
p ossi ble u nless it is wit hi n 7 2 h o urs of t he ne xt sc he d ule d d ose, i n w hic h case, t hat d ose s h o ul d 

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be s ki p pe d a n d t he ne xt d ose s h o ul d be ta ke n at t he a p pr o priate ti me.  T he da y  of wee kl y 
a d mi nistrati o n ca n be c ha n ge d if necessar y, as lo n g as t he l ast d ose was a d mi nistere d 7 2 or m ore 
h o urs bef ore.
All patie nts will i nject st u d y  dr u g S C i n t he a b d ome n or t hi g h; a care gi ver ma y a d mi nister t he 
i njecti on i n t he patie nt’s u p per ar m. A ne w si n gle-d ose pe n will be use d f or eac h i nject i on.
W he n
st u d y dr u g is al wa ys i njecte d i n t he sa me b o d y r e gio n, pati e nts s h o uld be a d vise d t o use a 
differe nt i nject i on site eac h wee k.
Se m a gl uti de 
S e m a gl ut i de s h o ul d be a d mi nistere d Q W o n t he sa me da y  eac h wee k, at a n y tim e of t he da y, 
wi t h or wit ho ut m eals. T he da y  of wee kl y a d mi nistratio n ca n be c ha n ge d if necessar y , as lo n g as 
t he ti me bet wee n 2 d oses is at least 2 da ys ( > 4 8 h o urs). If a d ose is misse d, se ma gl ut i de s h o ul d 
be a d mi nister e d as s o o n as p ossi ble wit hi n 5 da ys after t he misse d d ose. If m o re t ha n 5 da ys 
ha ve passe d, t he misse d d ose s h o ul d be s ki ppe d a n d t he ne xt d ose s h o ul d be a d mi nister e d o n t he 
re g ularl y sc he d ule d da y. I n eac h case, patie nts ca n t he n res u me t heir re g ular Q W d osi n g 
sc he d ule ( Oze mpic ® U S PI [ W W W] ).
P atie nts will i nject se ma gl ut i de S C i n t he a b d ome n or t hi gh usi n g t he si n gle -patie nt -use pe n
usi n g t he i njecti o n s u p plies pr o vi de d ; a care gi ver ma y a d mi nister t he i nject i on i n t he patie nt’s 
u p per ar m . W he n
st u d y dr u g is alwa ys i njecte d i n t he sa me b o d y  r e gio n, pati e nts s h o uld be 
a d vise d t o use a differe nt i nject i on site eac h wee k. A si n gle -pat ient -use pe n ma y be use d f or 
m ult i ple i njecti on s.
7. 3.
Bli n di n g
T his is a n o pe n -la bel st u d y wit h res pect t o assi g n me nt to se ma gl uti de vers us tirze pat i de.  Withi n 
t he tirze patid e ar ms, t he d ose of tirze pati de will be d o u ble -bli n de d.   I n vesti gat ors, site staff, 
cli nical m o nit ors, a n d patie nts will re mai n bli n de d t o t he tirze pati de d oses u nt il t he st u d y is 
c o mplete.  
If a n i nvest i gat or, site pers o n nel perf or mi n g assess me nts, or patie nt is u n bli n de d t o t he 
tirze pati de d ose, t he patie nt will c o nti n ue o n t he assi g ne d t hera p y t hr o u g h t he e n d of t he st u d y, if 
me dicall y a p pr o priate.  St u d y  site pers o n nel a n d t he s p o ns or will d oc u me nt a n y u n bli n di n g 
e ve nts.
7. 4.
D o s a g e M o difi c ati o n
7. 4. 1.
St u d y Dr u g s
N o a dj ust me nt  i n st u d y dr u g d oses will be all o we d u nless f or safety reas o ns.  Details a b o ut d ose 
a d mi nistrati o n of tirze pati de a n d se ma gl ut i de d uri n g t he st u d y  are descri be d i n Secti ons 7. 2. 1
a n d 8. 1. 2 .

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7. 4. 2.
S p e ci al Tr e at m e nt C o n si d er ati o n s
T his sect i on pr o vi des g ui da nce o n ma na ge me nt of e pis o des of h y p o gl yce mic e ve nts; se vere, 
persiste nt h y per gl yce mia d uri n g t he treat me nt peri o d; patie nts w h o per ma ne nt l y disc o nti n ue 
st u d y dr u g prior t o Vi sit 1 1 ; a n d patient s wit h GI s y m pt o ms. F or effect i ve i m ple me ntati o n of 
meas ures descri be d here, it is i m p orta nt t hat patie nts, a n d t heir care gi vers, if a p plica ble, be well 
e d ucate d a b o ut t he si g ns a n d s y m pt o ms of h y per gl yce mia (f or e xa m ple, se vere t hirst, dr y  mo ut h, 
fre q ue nt mict uriti on, or dr y s ki n) a n d h y p o gl yce mia (f or e xa m ple, i nte nse h u n ger, s weati n g, 
tr e mor, restless ness, irrita bilit y, de pressi o n, hea dac hes, dist ur be d slee p, or tra nsie nt ne ur ol o gical 
di s or ders).  Patie nts s h o ul d be i nstr ucte d t o c o ntact t he i n vesti gati ve site i n t he e ve nt of  se vere, 
persiste nt h y per gl yce mia or se vere h y p o gl yce mia bet wee n st u d y  visits or i n t he e ve nt w he n a 
pati e nt i nte n ds t o per ma ne nt l y disc o nti n ue st u d y dr u g.
7. 4. 2. 1.
St a n d ar d s of M e di c al C ar e
I n vesti gat ors a n d ot her st u d y t e a m me m bers are e x pecte d t o treat patie nts acc or di n g t o t he 
nat i onall y esta blis he d sta n dar ds of care f or dia betes ma na ge me nt i n res pect i ve partici pati n g 
c o u ntries, e xce pt w here t hat treat me nt w o ul d be i n c o nflict wit h t he pr ot oc ol -pr o vi de d treat m e nt 
re q uire me nts.  If t here are n o l ocal sta n dar ds of  care f or dia betes, t he i n vesti gat ors s h o ul d f oll ow 
c urre nt p u blis he d sta n dar ds of care fr o m t he A merica n Dia betes Ass ociati o n a n d t he E ur o pea n 
Ass oci at i on f or St u d y of Dia betes (Da vies et al. 2 0 1 8) d uri n g t heir patie nts ’ part ici pati on i n t his 
st u d y.
7. 4. 2. 2.
M a n a g e m e nt of H y p o gl y c e mi a Ri s k
I n t his st u d y, i ncrease d ris k of h y p o gl yce mia is defi ne d as ha vi n g a si n gle e pis o de of se vere 
h y p o gl yce mia or ha vi n g m ore t ha n 1 e pis o de of d oc u me nte d s y m pt o mat ic h y p o gl yce mia wit hi n 
a 1-wee k peri o d at a n y t i me d uri n g t he treat me nt perio d.  I n cases w here a patie nt e x perie nces 
h y p o gl yce mia as descri be d a b o ve, t o c o nfir m t he i ncrease d ris k, t he st u d y  sit es must e ns ure t hat 
t he patie nt has bee n f ull y c o mplia nt wi t h t he assi g ne d t hera pe utic re gi me n a n d als o t hat t here is 
n o e vi de n ce of ot her p ossi ble ca uses of h y p o gl yce mia (f or e xa m ple, o missi o n of meal, 
u ne x pecte d i ncrease i n e xercise).  T he i n vest i gat or m ust als o c o nfir m t he y ha ve re d uce d or 
di sc o nti n ue d metf or mi n as descri be d i n Secti on 7. 7. 1 . If t he patie nt f ulfills t he defi nit i on of 
i ncrease d ris k of h y p o gl yce mia e ve n w he n met f or mi n has bee n disc o nt i n ue d, t he i n vesti gat or 
s h o uld disc o nt i n ue t he patie nt fr o m st u d y treat me nt a n d f oll o w t he g ui da nce f or ma na ge me nt of 
pati e nts t o per ma ne nt l y disc o nti n ue t he st u d y dr u gs as o utli ne d i n Secti on 8. 1. 1 . 
7. 4. 2. 3.
M a n a g e m e nt of P ati e nt s wit h S e v er e, P er si st e nt H y p er gl y c e mi a d uri n g 
t h e Tr e at m e nt P eri o d
Se vere, persiste nt h y per gl yce mia will be assesse d d uri n g t he trial t o deter mi ne 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 plicat i 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 dit i 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 mizat i on.
Resc ue me dicat i 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 nti n ue t o fol l ow t he pr ot oc ol -s pecifie d visit sc he d ule.  Resc ue treat me nt wit h pra mli nt i de, 

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di pe pt i dyl pe pt i dase- 4 (D P P - 4) i n hi bit ors, or G L P-1 rece pt or a g o nists will n ot be all o we d.   See 
Secti o n 7. 7. 2 f or details a b o ut t he all o we d a nti h y per gl yce mic me dicati on.
A d d -o n gl yce mic resc ue t hera p y  will be all o we d f or pati e nts w h o meet a n y o ne of t he f oll o wi n g 
pres pecifie d criteria f or se vere, persiste nt h y per gl yce mia a n d n o i nterc urre nt ca use of t he 
h y per gl yce mia ca n b e i de nt ifie d (i n vesti gat ors s h o ul d first c o nfir m t hat t he patie nt is f ull y 
c o mplia nt  wit h t he assi g ne d t hera pe utic re gi me n a n d t hat he or s he d oes n ot ha ve a n ac ute 
c o n ditio n ca usi n g se vere h y per gl yce mia): 
(a) a vera ge dail y B G fr o m t he o nce-wee kl y  4-p oi nt S M B G pr ofile > 2 7 0 m g/ d L 
( > 1 5. 0 m m o l/L) o ver at l east a c o nsec ut i ve 2-wee k peri o d a n y time d uri n g t he first 
8 wee ks p ost ra n d o mizat i on; 
O R
( b) a vera ge dail y B G fr o m t he o nce-wee kl y  4-p oi nt S M B G pr ofile > 2 4 0 m g/ d L 
( > 1 3. 3 m m o l/L) o ver a c o nsec ut i ve 2-wee k peri o d at a n y  ti me 9 t o 1 6 wee ks p ost 
ra n d omizat i on; 
O R
(c) a vera ge dail y B G fr o m t he o nce-wee kl y  4-p oi nt S M B G pr ofile > 2 0 0 m g/ d L 
( > 1 1. 1 m m o l/L) o ver a c o nsec ut i ve 2-wee k peri o d at a n y  ti me be yo n d t he first 1 6 wee ks 
p ost ra n d o mizat i on;
O R
( d) H b A 1c ≥8. 5 % at 2 4 wee ks, wit h i na de q uate res p o nse t o t he e xisti n g re gi me n defi ne d as 
i m pr o ve me nt i n H b A 1c o ver t he last 3 mo nt hs ( wee k 1 2 t o wee k 2 4) t hat is < 0. 3 % .
7. 4. 2. 4.
M a n a g e m e nt of P ati e nt s P er m a n e ntl y Di s c o nti n ui n g St u d y Dr u g s
Ci rc u msta nces u n der w hic h patient s ma y be re q uire d t o pre mat urel y disc o nti n ue st u d y dr u g are 
o utli ne d i n Sect i on 8. 1 .  Patie nts w h o st o p t he st u d y dr u g per ma ne ntl y will c o nti n ue partici pati n g 
i n t he trial acc or di n g t o t he pr ot oc ol t o c ollect all pla n ne d efficac y a n d safety meas ure me nts a n d
s h o uld recei ve a n ot her a nti h y per gl yce mic me dicat i o n ( Secti o n 7. 7. 2 ).  T he ne w 
a nt i h y per gl yce mic me dicati 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 s uc h
me dicat i ons.
T o ass ure ti mel y i nit iati on of a n ot her a nti h y per gl yce mic me dicat i on after per ma ne nt 
di sc o nti n uati on of st u d y  dr u g, patie nts s h o uld be a d vise d t o pr o m pt l y n otif y  t he site w he n t his 
sit u atio n occ urs.  T he i n vest i gat or s h o ul d e valuate t he nee d f or a d dit i onal a nt i h y per gl yce mic 
me dicat i on at t hi s ti me (as o utli ne d i n Secti on 7. 7. 2 ) a n d i nitiate t he a d diti onal i nter ve nt i on 
acc or di n g l y.  A n u nsc he d ule d visit s h o ul d be use d as nee de d f or m ore ti mel y ini tiat i on if 
warra nte d base d o n t he i n vest i gat or’s cli nical j u d g me nt.

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7. 4. 2. 5.
M a n a g e m e nt of P ati e nt s wit h G a str oi nt e sti n al S y m pt o m s
Tirze p ati de
I n t he P hase 2 pr o gra m, t he m ost c o m m onl y  re p orte d treat me nt-e mer ge nt A Es ( T E A Es) f or 
pati e nts recei vi n g tirze pat i de were na usea, v o miti n g, a n d diarr hea.
T he ti rze pati de d ose escalati on sc he me has bee n desi g ne d t o mi ni mize t he de vel o p me nt of GI 
s y m pt o ms.  T he escalati on peri o d i s c o nsi dere d t o be 2 4 wee ks, w hic h all o ws 2 0 wee ks t o 
escalate t o 1 5 m g a n d a d dit i on al  4 wee ks t o reac h stea d y state.  D uri n g t he d ose escalati on 
p eri o d, e ver y  eff ort s h o uld b e m a de b y t he i n vestigat or t o be a ble 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 ma na ge patie nts wit h i nt olera ble GI A Es d uri n g t he escalati on 
p eri o d ( Wee k 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 plitti 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.

prescri be s y m pt o mat ic me dicat i on (f or e xa m ple, a nt iemet ic or a nti diarr heal me dicati 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.

bef ore per ma ne nt l y disc o nti n ui n g tirze pati de, c o nsi der a te m p orar y i nterr u pti o n (f or 
e xa m ple, o mit 1 d ose, t he patie nt will ta ke 3 of 4 d oses at t hat d ose le vel ).  
o
At  a ma xi m u m, 1 d ose ca n be o mitte d per 4 wee ks ( u p t o 6 d oses c o ul d be 
o mitt e d d uri n g t he escalat i on peri o d , 2 4 wee ks).   
o
After i nterr u pti o n, t he i n vest i gat or s h o ul d restart t he d ose, or escalate t he d ose as 
re q uire d, 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 .  
o
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 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 g.  De-escalat i on of st u d y  dr u g will n ot be al l owe d.  Patie nts w h o 
st o p t he st u d y dr u g per ma ne nt l y will recei ve a n ot her gl uc ose-l oweri n g i nter ve nti o n 
( Sectio n 7. 7. 2 ) 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 
pl a 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 ollecti n g a nti h y per gl yce mic me dicati ons.
I n t he e ve nt of i nt olera ble persistent  GI s y m pt o ms t hat occ ur after t he escalati o n peri o d (after 
Wee k 2 4), t he i n vest i gat or ca n a d vise o n be ha vi oral c ha n ges a n d c o nsi der prescri bi n g 
s y m pt o mat ic me dicat i on 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 
p er m a ne nt l y a n d init iati n g a n ot her gl uc ose- l oweri n g i nter ve nt i on. 

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Se m a gl uti de
I n t he se ma gl uti de P hase 3 pr o gra m, t he most c o m m o nl y  re p orte d T E A Es were na usea, 
v o mit i n g, a n d diarr hea ( Mars o et al. 2 0 1 6; A hré n et al. 2 0 1 7; Ar o da et al. 2 0 1 7; S orli et al. 2 0 1 7; 
Pr atl e y et al. 2 0 1 8; R o d bar d et al. 2 0 1 8). 
T o mit i gate GI s y m pt o ms a n d ma na ge patie nts wit h i nt olera ble GI A Es d uri n g t he escalati on 
p eri o d , wit h a n a d dit i onal 4 wee ks t o reac h stea d y  state wit h 1 m g d ose ( Wee k 0 t o 1 2), 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 plitti 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.

prescri be s y m pt o mat ic me dicat i on (f or e xa m ple, a nt iemet ic or a nti diarr heal me dicati on) 
per l o c al  c o u ntr y a vaila bilit y a n d i n di vi d ual patie nt nee ds.  Use of s y m pt o matic 
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.

bef ore per ma ne nt l y disc o nti n ui n g se ma gl uti de, c o nsi der a te m p orar y i nterr u pti o n (f or 
e xa m ple, o mit 1 d ose, a n d ha ve t he patie nt ta ke 3 of 4 doses at t hat d ose le vel ).  
o
At  a ma xi m u m, u p t o 3 d oses c o ul d be o mitte d d uri n g t he escalat i on peri o d 
( 1 2 wee ks).
o
After i nterr u pti o n, t he i n vest i gat or s h o ul d restart t he d ose, or escalate t he d ose as 
re q uire d, wit h t he patie nt ta ki n g me dicat i on t o alle vi ate t heir GI s y m pt o ms.  
o
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 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 d e t o disc o nt i n ue st u d y dr u g.  De-escalat i on of st u d y  dr u g will n ot be all o we d.  Patie nts w h o 
st o p t he st u d y dr u g per ma ne nt l y will recei ve a n ot her gl uc ose-l oweri n g i nter ve nti o n 
( Sectio n 7. 7. 2 ) 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 
pl a 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 ollecti n g a nt i h y per gl yce mic me dicati ons.
I n t he e ve nt of i nt olera ble persiste nt GI s y m pt o ms t hat occ ur after t he escalati o n peri o d (after 
Wee k 1 2 ), t he i n vesti gat or ca n a d vise o n be ha vi oral c ha n ges a n d c o nsi der prescri bi n g 
s y m pt o mat ic me dicat i on 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 
p er m a ne nt l y a n d i nit iati n g a n ot her gl uc ose- l oweri n g i nter ve nt i on.
7. 5.
Pr e p ar ati o n/ H a n dli n g/ St or a g e/ A c c o u nt a bilit y
T he i n vest i gat or or his or her desi g nee is res p o nsi ble f or t he f oll o wi n g:

co nfi r mi n g a p pr o priat e t e mperat ure c o n di tio ns ha ve bee n mai ntai ne d d uri n g 
tra nsit for all st u d y  treat me nt recei ve d a n d a n y discre pa ncies are re p orte d a n d 
res ol ve d bef ore use of t he st u d y tr e at me nt.

I8F-MC-GPGL(b) Clinical Protocol
Page 44
LY3298176

ensuring that only participants enrolled in the study may receive study treatment 
and only authorized site staff may supply 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 may 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 into the patient 
diary and reviewed by the investigator at each study visit.

The patients will be instructed to return any unused study drug in the original 
carton and/or empty cartons at the next visit to the study site for the purpose of 
performing drug accountability. Patients will be instructed to discard used pens in 
a closeable, puncture-resistant container according to local regulations.
In the 3 tirzepatide treatment groups, as well as the semaglutide group, treatment compliance for 
each visit interval is defined as taking at least 75% of the required doses of study drug.  
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 procedures will be assessed at each visit based on the 
patient’s adherence to the visit schedule, compliance with the required concomitant therapy with 
metformin, completion of study diaries, the results of home BG monitoring, and any other 
parameters the investigator considers necessary.
Patients considered to be poorly 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 compliance.
7.7.
Concomitant Therapy
7.7.1. Background Therapy with Metformin
Patients in this study must be treated with metformin for at least 3 months prior to Visit 1; the 
minimum required dose during this time will be 1500 mg/day.  The prescreening dose and 

I 8 F-M C -G P G L ( b) Cli ni c al Pr ot o c ol
P a g e 4 5
L Y 3 2 9 8 1 7 6
f or mulat i on (s h ort -acti n g or l o n g -acti n g) s h o ul d be mai ntai ne d d uri n g t he scree ni n g a n d lea d-in 
p eri o ds, t hr o u g h ra n d o mizat i on at Vi sit 3.
After ra n d omizat i on, di sc o nti n uati on of metf or mi n or c ha n ge i n d osa ge a n d f or mulat i on is n ot 
per mitte d, e xce pt i n t he fol l owi n g si t u atio ns:
1.
I n t he e ve nt of a h y p o gl yce mic e pis o de(s) (cli nical s y m pt o ms of h y p o gl yce mia a n d/ or 
B G -c o nfir me d s y m pt o mat ic B G h y p o gl yce mia: gl uc ose c o nce ntrati o n < 3. 0 m m o l/ L [ 5 4
m g/ d L]):   Patie nts ma y re d uce/ disc o nt i n ue t he d ose of metf or mi n.  
2.
I n certai n sit uati ons t hat re q uire s h ort -t er m disc o nti n uati on i n li ne wit h 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 d ye). 
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 is res ol ve d, treat me nt 
s h o uld be restarte d at i n vest i gat or discreti o n.
3.
If a patie nt de vel o ps c o ntrai n dicati ons t o met f or mi n s uc h t hat t he use of t he dr u g is 
c o ntrai n dicate d acc or di n g t o t he c o u ntr y-s pecific la bel.
4.
If patient  meets t he criteria f or se vere, persiste nt h y per gl yce mia ( Secti o n 7. 4. 2. 3 ) or 
di sc o nti n ues st u d y dr u g, t he n metfor m i n d ose ma y be i ncrease d acc or di n g t o c o u ntr y-
s pecific la bel as lo n g as t hat i s n ot t he s ole i nter ve nt i on ( Ta ble G P G L . 4).
A pat ient  will be c o nsi dere d n o nc om p lia nt wit h t he pr ot oc ol ( pr ot oc ol de viati on) if he or s he 
c ha n ges t he d ose or disc o nt i n ues metf or mi n f or reas o ns ot her t ha n t h ose descri be d here.  
D ose re d ucti o n/ disc o nt i n uati on of metf or mi n d uri n g t he trial s h o ul d be pr o perl y  d oc u me nte d a n d
rec or de d o n t he a p pr o priate e C R F.
7. 7. 2.
I niti ati o n of N e w A nti h y p er gl y c e mi c M e di c ati o n
T he i ntr o d ucti o n of ne w a nt i h y per gl yce mic me dicati o n is e x pecte d d uri n g t he st u d y o nl y i n t he 
f oll owi n g sit uat i ons:

As a n a nt i h y per gl yce mic i nter ve nti on f or se vere, persiste nt h yper gl yce mia ( “resc ue 
t hera p y”), as defi ne d i n Secti on 7. 4. 2. 3

I n t h ose patie nts w h o re q uire per ma ne nt disc o nti n uati o n of st u d y dr u g, b ut re mai n i n t he 
st u d y ( Sectio n 8. 1. 1 )

D uri n g t he safet y f oll ow- u p peri o d ( bet w ee n Visit 1 1 [ Wee k 4 0] or E T a n d Visit 8 0 1)
If a ne w a nti h y per gl yce mic me dicati on is i ntr o d uce d d uri n g t he treat me nt peri o d (t hat is, pri or t o 
Vi sit 1 1), t he patie nt s h o uld be treate d wit h a l ocall y  a p pr o ve d gluc ose -l oweri n g a ge nt (e xce pt 
ot her G L P -1 rece p t or a g o nists, D P P-4 i n hi bit ors, a n d pra mli nt i de) acc or di n g t o t he f oll owi n g 
or der of prefere nce base d o n t he u p date d 2 0 1 8 A D A/ E A S D c o nse ns us state me nt ( Da vies et al. 
2 0 1 8):
1.
S o di u m -gl uc ose c o -tra ns p orter 2 ( S G L T 2) i n hi bit ors are rec o m me n de d first , u nless a 
c o ntrai n dicat i on is prese nt.
2.
If a c o ntrai n dicati o n t o S G L T 2 i n hi bit or is prese nt, t he n a s ulf on yl urea or 
t hiaz o li di ne di one ca n be c o nsi dere d.

I 8 F-M C -G P G L ( b) Cli ni c al Pr ot o c ol
P a g e 4 6
L Y 3 2 9 8 1 7 6
3.
If gl yce mic c o ntr ol re mai ns i na de q uate des pite i ntr o d ucti o n of ne w a nti h y per gl yce mic 
me dicat i on ( f or e xa m ple, aft er 3 mo nt hs or wi t hi n a ti mefra me deter mi ne d b y t he 
i n vesti gat or), t he n a d diti on of basal i ns uli n t hera p y s h o ul d be c o nsi dere d.  If i ns uli n is 
prescri be d as a resc ue t hera p y  for h y per gl yce mia or as a ne w a nt i h y per gl yce mic 
me dicat i on i n patient s re q uirin g st u d y dr u g disc o nti n uati on, i t must be differe nt iate d fr o m 
s h ort-t er m us e 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.
4.
I nitiatio n of  ins uli n as t he first resc ue i nter ve nt i on f or h y per gl yce mia s h o ul d be reser ve d 
f or p atie nts wit h severe, persiste nt h y per gl yce mia ( Secti o n 7. 4. 2. 3 ) wit h a n a vera ge 
fasti n g ser u m gl uc ose ≥3 0 0 m g/ d L ( ≥1 6. 7 m m o l/ L), i n patie nts wit h s y m pt o ms of 
h y per gl y ce mia, or i n ot her cli nical sit uat i ons w here t he i n vesti gat or belie ves m ore ra pi d 
gl yce mic c o ntr ol is warra nte d.
7. 7. 3.
O t h er C o n c o mit a nt Me di c ati o n s
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 (Ta ble G P G L . 4).
I n vesti gati ve site staff will  inf or m  patient s t hat t he y m ust c o ns ult wit h t he i n vesti gat or or a 
desi g nate d site staff me m ber u p o n bei n g prescri be d a n y ne w me dicat i ons d uri n g t he st u d y .  T his 
ma y n ot be p ossi ble w he n i nit iate d f or treat me nt of me dical e mer ge ncies, i n w hic h case, t he 
pati e nt will i nf or m t he i n vest i gat or or a desi g nate d site staff me m ber as s o o n as p ossi ble.  A n y 
a d ditio nal  me dicat i on i nitiate d d uri n g t he c o urse of t he st u d y (i ncl u di n g O T C dr u gs, s uc h as 
paraceta m o l or as pi rin) m ust be d oc u m e nte d, a n d t he na me of t he dr u g a n d t he date(s) of 
a d mi nistrati o n m ust be rec or de d o n t he “ C o nc o mit a nt Me dicat i ons” sect i on of t he e C R F. 
A nt i h y per gl yce mic me dicati ons ot her t ha n st u d y  dr u gs a n d met f or mi n are n ot all o we d at a n y 
ti me d uri n g t he st u d y e xce pt as all o we d f or t hose patie nt s w h o re q uire per ma ne nt disc o nti n uati o n 
of  st u d y dr u g, b ut re mai n i n t he st u d y; resc ue t hera p y after ra n d o mizatio n d ue t o se vere, 
persiste nt h y per gl yce mia; or d uri n g t he safet y f oll o w-u p peri o d ( Secti o n 7. 7. 2 ).  S h ort -t er m 
i ns uli n use f or u p t o 1 4 da ys is all o we d f or certai n cli nical sit uati ons (f or e xa m ple, elect i ve 
s ur ger y, d uri n g h os pitalizatio n, h y per os m ol ar states) a n d m ust be differe nt iate d fr o m i ns uli n use 
as resc ue t hera p y w he n re p orte d in t he e C R F. 
All n o nst u d y  me dicatio ns will be rec or de d o n t he e C R F at all visit s.
N o nst u d y  me dicat i ons ta ke n b y  patient s w h o are scree ne d b ut n ot ra n d o ml y assi g ne d t o 
treat me nt will n ot be re p orte d t o Lill y u nless a n S A E or A E occ urs t hat t he i n vest i gat or belie ves 
ma y ha v e bee n ca use d b y a st u d y pr oce d ure.

I 8 F-M C -G P G L ( b) Cli ni c al Pr ot o c ol
P a g e 4 7
L Y 3 2 9 8 1 7 6
T a bl e G P G L . 4.
Crit eri a f or U s e of C o n c o mit a nt M e di c ati o n s t h at M a y I nt erf er e wit h 
Effi c a c y a n d S af et y A s s e s s m e nt s i n St u d y G P G L
A b bre viati o ns: D P P - 4 = di pe pti d yl pe pti dase -4; G L P -1 R A = gl uca g o n -li ke pe pti de-1 rece pt or a g o nist; N = n o; 
N/ A = n ot a p plica ble; S G L T - 2i = s o di u m-gl uc ose c o -tra ns p orter 2 i n hi bit or; Y = yes.
a
A c ute t hera p y = treat me nt f or u p t o 1 4 da ys.
b
I ncl u des Sa xe n da ® (lira gl uti de 3. 0 m g), Xe nical® ( orlistat), Meri dia® (si b utra mi ne), Sa n ore x® ( mazi n d ol), 
A pi de x ® ( p he nter mi ne), B E L VI Q® (l orcaseri n), Qs y mia® ( p he nter mi ne/t o pira mate c o m bi nati o n), C o ntra ve®
( naltre x o ne/ b u pr o pri o n), or si milar ot her b o d y wei g ht l oss me dicati o ns i ncl u di n g o ver -t he-c o u nter me dicati o ns 
(f or e xa m ple; allī® ) wit hi n 3 m o nt hs pri or t o Visit 1 or a n y ti me d uri n g t he trial. 
c
Fr o m 1 m o nt h pri or t o Visit 1 or bet wee n Visits 1 a n d 3; d oes n ot a p pl y t o t o pical, i ntra oc ular, i ntra nasal, 
i ntra-artic ular, or i n hale d pre parati o ns. 
d
Metf or mi n prescree ni n g d ose a n d f or m ulati o n (s h ort -acti n g or l o n g-acti n g) s h o ul d be mai nta i ne d t hr o u g h o ut t he 
st u d y, e xce pt as s pecifie d i n Secti o n 7. 7. 1 . 
e
I n creasi n g t he metf or mi n d ose s h o ul d n ot be use d as t he s ole i nter ve nti o n f or resc ue t hera p y or  after pre mat ure 
st u d y dr u g disc o nti n uati o n.
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 mplet 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 t o p atie nts aft er c o nclusi o n of  t he st u d y.
Dr u g Cl ass
Use d uri n g 
Scree ni n g/ Le a d -I n
C o n diti o ns f or Use a fter R a n d o miz ati o n
Ac ute 
T her a p y a
Resc ue 
T her a p y/ P ost 
St u d y Dr u g 
Disc o nti n u ati o n 
D uri n g S afet y 
F oll o w -U p Peri o d
Dr u gs wit h a p pr o ve d wei g ht l oss 
i n dicati o nb
E xcl u de d
N
N/ A
Y
S y ste mic gl uc oc ortic oi d t hera p yc
E xcl u de d e xce pt 
f or ac ute t hera p ya
Y
N/ A
Y
A nti h y per gl yce mia me dicati o ns
Ot her G L P -1 R As
E xcl u de d
N
N
N
D P P -4 i n hi bit ors
E xcl u de d
N
N
N
Pra mli nti de
E xcl u de d
N
N
N
S G L T - 2i
E xcl u de d
N
Y
Y
I ns uli ns
E xcl u de d e xce pt 
f or ac ute t hera p y a
Y
Y
Y
Me gliti ni des
E xcl u de d
N
Y
Y
Al p ha- gl uc osi dase i n hi bit ors
E xcl u de d
N
Y
Y
S ul p h o n yl ureas
E xcl u de d
N
Y
Y
T hiaz oli di ne di o nes
E xcl u de d
N
Y
Y
Metf or mi n
d
Re q uire d
N/ A
Y e
Y

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

I 8 F-M C -G P G L ( b) Cli ni c al Pr ot o c ol
P a g e 4 9
L Y 3 2 9 8 1 7 6

If a patie nt is dia g n ose d wit h a n acti ve or u ntreate d mali g na nc y ( ot her t ha n basal or 
s qu a m o us cell  s ki n ca ncer, i n sit u carci n o mas of t he cer vi x, or i n sit u pr ostate ca ncer) 
after ra n d o mizati on

A n y si g nifica nt st u d y  dr u g-r elate d h y perse nsit i vity reacti o n

A n y 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 gator 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 nt i on 
(Secti o n 7. 7. 2 ) 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 
pl a 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 eC R F s pecifie d f or c ollecti n g a nt i h y per gl yce mic me dicati ons.
P ati e nts disc o nti n ui n g fr om t he i n vest i gati onal pr o d uct pre mat urel y f or a n y  reas o n s h o uld 
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 ati o n fr o m St u d y Tr e at m e nt
I n certai n sit uati ons after ra n d o mizat i on, t he i n vesti gat or ma y nee d t o te m p ora ril y i nterr u pt st u d y 
dr u g (f or e xa m ple, ac ute ill ness, s ur ger y, or h os pitalizat i on ).  If st u d y dr u g i nterr u pti o 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 t he pr oce d ures i n Secti o n 9. 2 of  
t his pr ot oc ol.  E ver y  eff ort s h o uld be ma de b y t he i n vesti gat or t o mai ntai n patie nts o n st u d y  dr u g 
a n d t o restart st u d y dr u g aft er 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. 
Tirze p ati de

If t he n u m ber of c o nsec ut i ve misse d d oses i s ≤2, tirze patide ca n be restarte d at t he 
sa me d ose, if t he dr u g was well t olerate d prior t o disc o nti n uat i on.

If t he n u m ber of c o nsec ut i ve misse d d oses is ≥3, t he n tirze patid e s h o uld be restarte d 
at 5 m g 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 (see Ta ble G P G L . 3).

T he i n vest i gat or will use t he I W R S t o recei ve t he a p pr o priate st u d y dr u g dis pe nsi n g 
i nf or mat i on t o preser ve bli n di n g o f t he tirze patide d ose. 

If t he a b o ve sit uati o ns occ ur a gai n d uri n g t he c o urse of t he st u d y, t he i n vest i gat or i n 
c o ns ultati o n wit h s p o ns or or desi g nee will  disc uss t he ne xt treat me nt o pti o n.
Se m a gl uti de

If t he n u m ber of c o nsec ut i ve misse d d oses i s ≤2, s e ma gl ut i de ca n be restarte d at 1 m g
d uri n g t he mai nte na nce peri o d. If t he d oses are misse d d uri n g t he escalati on peri o d,
t he i n vest i gat or s h o ul d e val uate eac h case base d o n his/ her cli nical j u d ge me nt a n d 
deci de h o w t o restart se ma gl ut i de. 

I 8 F-M C -G P G L ( b) Cli ni c al Pr ot o c ol
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
If t he n u m ber of c o nsec ut i ve misse d d oses is 3 or 4, se ma gl utide treat m e nt s h o uld be 
c o nti n ued wi t h 4 wee ks o n 0. 5 m g Q W bef ore escalat i on t o t he mai nte na nce d ose of 
1 m g Q W .

If t he n u m ber of c o nsec uti ve misse d d oses is 5 or m ore, a f ull d ose escalat i on s h o ul d 
be perf or m e d ( 0. 2 5 m g Q W f or 4 wee ks f oll o we d b y 0. 5 m g Q W f or 4 wee ks, a n d 
t he n escalat i on t o t he mai nte na nce d ose of 1 m g ).

If t he a b o ve sit uati o ns occ ur a gai n d uri n g t he c o urse of t he st u d y, t he i n vest i gat or i n 
c o ns ultati o n wit h s p o ns or or desi g nee will  disc uss t he ne xt treat me nt o pti o n.
If t he st u d y dr u g i nterr u pti o n is d ue t o i nt olera ble persiste nt GI A E (f or e xa m ple, na usea, 
v o mit i n g, or diarr hea), t he patie nts s h o ul d be treate d as s u g geste d i n Secti on 7. 4. 2. 5 .  
T he data relate d t o te m p or ar y  int err u ptio n of  st u d y treat me nt will be d oc u me nte d i n s o urce 
d oc u m e nts a n d e ntere d o n t he e C R F.
8. 1. 3.
Di s c o nti n u ati o n of I n a d v ert e ntl y E nr oll e d P ati e nt s
If t he s p o ns or or i n vesti gat or i de ntifies a patie nt w h o di d n ot meet e nr oll me nt criteria a n d was 
i na d verte ntl y e nr olle d, t he n t he patie nt s h o ul d be disc o nti n ue d fr om st u d y treat me nt u nless t here 
are e xte n uat i n g circ u msta nces t hat ma ke it me dicall y necessar y f or t he patie nt t o c o nti n ue o n 
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 cli nical researc h p h ysicia n (C R P ) a gree t hat 
it is me dicall y a p pr o priate t o c o nti n ue, t he i n vest i gat or must o btai n d oc u me nte d a p pr o val fr o m 
t he s p o ns or C R P t o all o w t he i na d verte nt l y e nr olle d pati e nt t o c o nti n ue i n t he st u d y wit h or 
wi t ho ut treat m e nt wit h in vest i gati onal pr o d uct. Safet y f oll ow- u p s h o ul d be perf or me d as 
o utli ne d i n Sect i on 2 ( Sc he d ule of Acti vities), Secti on 9. 2 ( A d verse E ve nts), a n d Secti o n 9. 4
( Safety)  of t he pr ot oc ol.
8. 2.
Di s c o nti n u ati o n fr o m t h e St u d y
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 pla n ne d 
i n t he stu d y  pr ot oc ol, e ver y att e mpt will be m a de t o kee p patie nts i n t he st u d y irres pecti ve of t he 
f oll owi n g:

a d here nce t o st u d y dr u g,

a d here nce t o visit sc he d ule ,

missi n g assess me nts ,

st u d y dr u g disc o nti n uati on d ue t o a n A E ,

de vel o p me nt of c o m or bi dit ies, a n d

de vel o p me nt of cli nical o utc o mes .
T he ci rc u msta nces liste d a b o ve are n ot vali d reas o ns f or disc o nti n uati on fr om t he st u d y. 
P ati e nts will be disc o nt i n ue d fr om t he st u d y i n t he f oll owi n g circ u msta nces:

E nr oll me nt i n a n y ot her cli nical st u d y  i n v ol vi n g a n i n vesti gati onal pr o d uct or 
e nr o ll me nt i n a n y ot her t y pe of me d ical researc h j u d ge d n ot t o be 
scie ntificall y or me dicall y c om pati ble wit h t his st u d y

I 8 F-M C -G P G L ( b) Cli ni c al Pr ot o c ol
P a g e 5 1
L Y 3 2 9 8 1 7 6

P arti cip ati o n i n t he st u d y  nee ds t o be st o p pe d f or me dical, safet y,  re g ulat or y, 
or ot her reas o ns c o nsiste nt wit h a p plica ble la ws, re g ulat i ons, a n d g o o d cli nical 
practi ce 

If a fe male patient  bec omes pre g na nt

If a patie nt is dia g n ose d wit h T 1 D M

P atie nt re q uests t o be wit h dra w n fr o m t he st u d y
P ati e nts w h o a gree t o pr o vi de i nf or mat i on rel e va nt t o a n y st u d y e n d p oi nt at t he e n d of t he st u d y 
are n ot c o nsi dere d t o ha ve disc o nti n ue d fr o m t he st u d y .
A pat ient  w h o wit hdra ws c o nse nt a n d clearl y i n dicates t hat t here will be n o f urt her c o ntact of a n y 
ki n d wit h t he site will be c o nsi dere d t o ha ve disc o nt i n ue d fr om t he st u d y.
P rior t o earl y  st u d y disc o nti n uatio n, t he pati e nt ma y disc o nt i n ue st u d y dr u g a n d will ha ve 
e n d-of -st u d y pr oce d ures ( E T visit) p erfor m e d as s h o w n i n t he Sc he d ule of Act i vities ( Sectio n 2 ).  
D uri n g t he E T visit, t he patie nt will i nitiate a ne w gl uc ose -l oweri n g t hera p y per t he di screti on of 
t he i n vest i gat or.  Visit 8 0 1 (safet y f oll ow- u p visi t) 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 disc o nti n ui n g fr om t he st u d y pr e mat urel y f or a n y reas o n s h o uld c o m plete a d verse e ve nt
a n d ot her safet y f oll ow- u p per Secti o n 2 ( Sc he d ule of Acti vities), Secti o n 9. 2 ( A d verse E ve nts), 
a n d Sect i on 9. 4 ( Safet y) of t his pr ot oc ol.
8. 3.
L o st t o F oll o w -U p
A pat ient will be c o nsi dere d l ost t o f o ll ow- u p if he or s he re peate dl y  fails t o ret ur n f or sc he d ule d 
visit s a n d is una ble t o be c o n tacte d b y t he st u d y sit e.  E ver y  att e mpt will  be ma de t o mi ni mize 
t he n u m ber of patie nts c o nsi dere d l ost t o f o ll ow- u p at t he e n d of t he st u d y .  P atie nts will be 
i nf or me d a b o ut t he i m p orta nce of c o m plet i n g t he st u d y a n d pr o vidi n g u p date d c o ntact 
i nf or mat i on t o t he st u d y  site w he n necessar y.

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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 dures 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 he r wise state d in 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 ulati ons, or 
la b orat or y certificatio n sta n dar ds.
9. 1.
Effi c a c y A s s e s s m e nt s
9. 1. 1.
Pri m ar y Effi c a c y A s s e s s m e nt
T he pri mar y  efficac y meas ure me nt i n t his st u d y is mea n c ha n ge i n H b A 1c val ues fr o m baseli ne 
t o 4 0 wee ks, as deter mi ne d fr o m t he ce ntral la b orat or y val ues .  Blo o d sa m pl es f or H b A 1c 
meas ure me nts will be c ollecte 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 Ef fi 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 (Secti o n 2 ):

Ke y sec o n d ar y effic ac y assess me nt (c o ntr olle d f or t y pe 1 err 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  w eig ht f r o m baseli ne

Pr o p orti o n of  patie nts wit h H b A 1c tar get values of < 7. 0 % ( 5 3 m m o l/ m ol)

A d diti o n al sec o n d ar y effic ac y assess me nt ( n ot c o ntr olle d f or t y pe 1 err or)

Pr o p orti o n of  patie nts ac hie vi n g a n H b A 1c tar get val ue of  ≤6. 5 % ( 4 8 m m o l/ m ol)

Pr o p orti o n of  patie nts ac hie vi n g a n H b A 1c tar get val ue of < 5. 7 % ( 3 9 m m ol/ m ol)

Mea n c ha n ge i n fast i n g ser u m gl uc ose (ce ntral lab orat or y ) fr o m baseli ne 

Mea n c ha n ge i n 7 -p oi nt S M B G 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

P ati e nt -re p orte d o utc o mes:
o
D T S Qs/ D T S Qc
o
I W-S P
o
A P P A D L

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9. 1. 3.
E x pl or at or y A s s e s s m e nt s a n d Pr o c e d ur e s
T he f oll owi n g e x p l or at or y meas ures will be calc ulate d 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 ).

P ati e nt -re p orte d o utc o mes:
o
E Q - 5 D- 5 L
o
I W Q O L-Li t e-C T

C ha n ges i n f ast i n g gl uca g o n, C-pe pti de, a n d i ns uli n le vel s

C ha n ge s i n li pi ds (t otal c h olester ol, H D L, V L D L, a n d trigl yceri des )

C ha n ges fr o m baseli ne i n mea n B MI

Mea n c ha n ge i n waist circ u mfere nce 

Bi o m ar kers
9. 1. 4.
B o d y W ei g ht, H ei g ht, a n d B o d y M a s s I n d e x
B o d y  wei g ht will be meas ure d at pre s pecifie d ti me p oi nts ( Sc he d ule of Acti vities, Secti o n 2 ).
Eac h patie nt’s wei g ht s h o ul d be meas ure d acc or di n g t o a sta n dar dize d pr ot oc ol a n d rec or de d o n
t he e C R F t o t he nearest o ne- te nt h k g ( A p pe n di x 7 ).
B MI will be c o m p ute d fr o m t he patie nt’s wei g ht a n d hei g ht. B MI s h o ul d be r o u n de d t o t he 
nearest w h ole n u m ber f or p ur p oses of I ncl usi on C rit erio n [ 4 ] ( Sectio n 6. 1 ).
9. 1. 5.
A p pr o pri at e n e s s of A s s e s s m e nt s
Efficac y a n d safet y assess me nts i ncl u de d i n t his st u d y are ge nerall y re gar de d as relia ble a n d 
acc urate wit h res pect t o t he efficac y a n d safet y assess me nts i n i ndi vi d uals a n d p o p ul at i ons wit h 
T 2 D M.
9. 2.
A d v er s e E v e nt s
I n vesti gat ors are res p o nsi ble f or m o nit ori n g t he safet y of pat ient s w h o ha ve e ntere d t his st u d y  
a n d f or alerti n g Lill y or its desi g nee t o a n y e ve nt t hat see ms u n us ual, e ve n if t his e ve nt ma y be 
c o nsi dere d a n u na nt ici pate d be nefit t o t he patie nt.
T he i n vest i gat or is res p o nsi ble f or t he a p pr o priate me dical care of pat ient s d uri n g t he st u d y.
I n vesti gat ors m ust d oc u me nt t heir re vie w of eac h la b orat or y safet y re p ort.
T he i n vest i gat or re mai ns res p o nsi ble f or f oll owi n g, t hr o u g h a n a p pr o priate healt h care o pti o n,
A Es t hat are seri o us or ot her wise me dicall y i m p orta nt, c o nsi dere d relate d t o t he i n vest i gati onal 
pr o d uct or t he st u d y , or t hat ca use d t he pati e nt t o disc o nti n ue t he i n vesti gati onal pr o d uct bef ore 
c o mplet i ng t he st u d y .  T he pati e nt s h o uld be f ol l owe d u nt il t he e ve nt res ol ves or sta bilizes wit h 
a p pr o priate dia g n ostic e val uati o n.  T he fre q ue nc y of f o ll ow- u p e val uat i ons o f t he A E is left t o 
t he discret i on of t he i n vest i gat or.
Lac k of dr u g effect is n ot a n A E i n cli nical st u dies, beca use t he p ur p ose of t he cli nical st u d y is t o 
esta blis h treat me nt effect.

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T he i n vest i gat or will rec or d all rele va nt A E a n d S A E i nf or mati on i n t he e C R F.  After t he I C F is 
sig ne d, st u d y  site pers o n nel will rec or d via e C R F t he occ urre nce a n d nat ure of eac h pat ient ’s 
pree xist i n g c o n diti ons, i ncl u di n g cli nicall y si g nifica nt si g ns a n d s y m pt o ms of t he disease u n der 
treat me nt i n t he st u d y.  I n a d ditio n, si te pers o n nel will rec or d a n y c ha n ge i n t he c o n ditio n(s) a n d 
a n y ne w c o n dit i ons as A Es.  F o r eac h A E, t he o nset a n d d urati o n, t he seri o us ness a n d se verity,  
a n d t he acti o ns ta ke n wit h res pect t o st u d y tr e at me nt will be rec or de d. I n vesti gat ors s h o ul d 
rec or d t heir assess me nt of t he p ote ntial relate d ness of eac h A E t o pr ot oc ol pr oce d ure a n d 
i n vesti gati onal pr o d uct via a n e C R F.
Pr oce d ures a n d assess me nts perf or me d pri or t o Visit 3 are c o nsi dere d scree ni n g pr oce d ures .  T he 
res ults of t hese pr oce d ures a n d assess me nts s h o ul d be c o nsi dere d pree xisti n g c o n diti ons a n d 
s h o uld be re p orte d as m e dical hist or y  or c o nc o mita nt ill ness.  
T he i n vest i gat or will i nter pret a n d d oc u me nt w het her or n ot a n A E has a reas o na ble p ossi bility 
of  bei n g relate d t o st u d y treat me nt, st u d y de vice, or a st u d y pr oce d ure, ta kin g i nt o acc o u nt t he 
di sease, c o nc o mita nt treat me nt, or pat h ol o gies.
A “reas o na ble p ossi bilit y” mea ns t hat t here is a ca use a n d effect relat i ons hi p bet wee n t he 
i n vesti gati onal pr o d uct, st u d y  de vice a n d/ or st u d y pr oce d ure, a n d t he A E.
T he i n vest i gat or a ns wers yes/ n o w he n ma ki n g t his assess me nt.
Pl a n ne d s ur geries a n d n o ns ur gical i nter ve nti ons s h o ul d n ot be re p orte d as A Es u nless t he 
u n derl yi n g me dical c o n dit i on has w orse ne d d uri n g t he c o urse of t he st u d y .
If a patie nt’s i n vesti gati o nal pr o d uct is disc o nti n ue d as a res ult of a n A E, st u d y site pers o n nel 
m us t re p ort t his t o Lill y or its desi g nee via a n e C R F, clarif yi n g, if p ossi ble, t he circ u msta nces 
lea di n g t o a n y d osa ge mo dificati o ns or di sc o nti n uati o ns of treat me nt.
9. 2. 1.
S eri o u s A d v er s e E v e nt s
A n S A E is a n y  AE f r o m t his st u d y t hat res ults i n o ne of t he f oll owi n g o utc o m es:

deat h

i nitial or pr ol o n ge d i n patie nt h os pitalizati on

a life-t hreate ni n g e x perie nce (t hat is, i m me diate ris k of d yi n g)

persiste nt or si g nifica nt disa bilit y/ i nca pacity

c o n ge nital a n o ma l y/ birt h defect

i m p orta nt me dical e ve nts t hat ma y n ot be i m me diatel y life-t hreate ni n g or res ult i n 
deat h or h os pitalizat i on b ut m a y je o par dize t he patie nt or ma y re q uire i nter ve nti on 
t o pre ve nt o ne of t he ot her o utc o mes liste d i n t he defi niti on a b o ve.  E xa m ples of 
s uc h me dical e ve nts i ncl u de aller gic br o nc h os pas m re q uiri n g i nte nsi ve treat me nt 
i n a n e mer ge nc y r o o m or at h o me, blo o d d y scrasias or c o n v ulsi o ns t hat d o n ot 
res ult i n i n patient  h os pitalizati on, or t he de vel o p me nt of dr u g de pe n de nc y  or dr u g 
a b use.

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All A Es occ urri n g after si g ni n g t he I C F are rec or de d i n t he e C R F a n d assesse d f or seri o us 
criteria.  T he S A E re p orti n g t o t he s p o ns or be gi ns after t he patie 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 n otificati o n o n st u d y -s pecific S A E f or ms.  T his 
2 4 -h o ur n otificat i 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 wit h a seri o us he pat ic A E 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 mater nal or pater nal e x p os ure t o i n vest i gati onal pr o d uct) d oes n ot meet t he 
defi nit i on o f a n A E.  H o we ver, t o f ulfill re g ulat or y re q uire me nts, a n y pre g na nc y s h o ul d be 
re p orte d f oll owi n g t he S A E pr ocess t o c ollect data o n t he o utc o me f or b ot h m ot h er 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 patient s o nce t he y ha ve 
di sc o nti n ue d a n d/ or c o m plete d t he st u d y (t he pati e nt dis p osit i on C R F has bee n c o m plete d).  
H o we ver, if t he i n vest i gat or lear ns of a n y S A E, i ncl u din g a deat h, at a n y  ti me after a patie nt has 
bee n disc har ge d fr o m t he st u d y  a n d he/s he c o nsiders t he e ve nt reas o na bl y p ossi bl y  relate d t o t he 
st u d y tr e at me nt or st u d y p artici pat i on, t he i n vest i gat or must pr o m ptl y n otif y Lill y .
9. 2. 1. 1.
S u s p e ct e d U n e x p e ct e d S eri o u s A d v er s e R e a cti o n s
S us pecte d u ne x pecte d seri o us a d verse react i ons ( S U S A Rs) are seri o us e ve nts t hat are n ot liste d 
i n t he I B a n d t hat t he i n vesti gat or i de ntifies as relate d t o i n vesti gati o nal pr o d uct or pr oce d ure.  
U nite d States 2 1 C F R 3 1 2. 3 2 a n d E ur o pea n U ni o n Cli nical  Tri al Direct i ve 2 0 0 1/ 2 0/ E C a n d t he 
ass ociate d detaile d g ui da nces or nati o nal re g ulat or y  re q uire me nts i n partici pat i n g c o u ntries 
re q uire t he re p orti n g of S U S A Rs. Lill y has pr oce d ures t hat will be f o ll owe d f or t he 
i de ntificati on, rec or di n g a n d ex pe di te d re p ortin g of S U S A Rs t hat are c o nsiste nt wit h gl o bal 
re g ulat i ons a n d t he ass ociate d detaile d g ui da nces.
9. 2. 2.
A d v er s e E v e nt s of S p e ci al I nt er e st
9. 2. 2. 1.
H y p o gl y c e mi a
P ati e nts will c ollect i nf or mat i on o n e pi s o des of h y p o gl yce mia starti n g fr o m Visit 3 u nt il t he last
st u d y visit (fol l ow- u p v isit or E T v isit).  F or t hat p ur p ose, patie nts will be trai ne d a b o ut si g ns a n d 
s y m pt o ms of h y p o gl yce mia, h o w t o treat h yp o gl yce mia, a n d h o w t o c ollect a p pr o priate 
i nf or mat i on f or eac h e pis o de of h y p o gl yce mia i n t he st u d y acc or di ng t o t he Sc he d ule of 
Act i vities ( Sectio n 2 ).  Site pers o n nel will e nter t his i nf or mati on i nto t he e C R F at eac h visit. 
I n vesti gat ors s h o ul d use t he f oll owi n g defi nit i ons a n d criteria w he n dia g n osi n g a n d cate g orizi n g 
a n e pis o de c o nsi dere d t o be relate d t o h yp o gl yce mia (t he pl as ma gl uc ose [P G ] val ues i n t his 
secti on refer t o val ues deter mi ne d b y a la b orat or y  or I nter natio nal Fe derat i on of Cli nical 

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Chemistry and Laboratory Medicine plasma-equivalent glucose meters and strips) (ADA 2019a,
2019b):
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 or 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).

Documented unspecified hypoglycemia is defined as any event with no 
information about symptoms of hypoglycemia available, but with a measured PG 
<54 mg/dL (<3.0 mmol/L).
Severe hypoglycemia (Level 3):

Severe hypoglycemia is defined as an episode with severe cognitive impairment 
requiring the assistance of another person to actively administer carbohydrate, 
glucagon, or other resuscitative actions.  These episodes may be associated with 
sufficient neuroglycopenia to induce seizure or coma. Blood glucose 
measurements may not be available during such an event, but neurological 
recovery attributable to the restoration of BG to normal is considered sufficient 
evidence that the event was induced by a low BG concentration.
Other hypoglycemia categories:

Nocturnal hypoglycemia is defined as any hypoglycemic event that occurs 
between bedtime and waking.
If a hypoglycemic event meets the criteria of severe, it needs to be recorded as serious on the AE 
CRF and reported to Lilly as an SAE.
To avoid duplicate reporting, all consecutive BG values ≤70 mg/dL (3.9 mmol/L) occurring 
within 1-hour period may be considered to be a single hypoglycemic event (Weinberg et al. 2010; 
Danne et al. 2013).  

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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 ysic al e xercise ( or a n y ot her c o ntri b uti n g fact or) i n 
t he de vel o p me nt of a n e ve nt s h o ul d be esta blis he d.  T he patie nt s h o ul d recei ve a d dit i onal 
e d ucati o n, if dee me d a p pr o priate.  Pl ease refer t o Sectio n 7. 4. 2. 3 f or g ui da nce o n ma na ge me nt of 
i ncrease d h y p o gl yce mia ris ks.  T he d ose of met f or mi n ma y nee d t o be re d uce d as o utli ne d i n 
Secti o n 7. 7. 1 .
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 assesse d d uri n g t he trial t o deter mi ne 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 plicatio n of  crit 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 mizat i on .  
Resc ue me di cat i on will be prescri be d as a n a d d-o n t o ra n d o mize d treat me nt, a n d patie nts will 
c o nti n ue t o fol l ow t he pr ot oc ol -s pecifie d visit sc he d ule as descri be d i n Sect i on 7. 4. 2. 3 .
9. 2. 2. 3.
P a n cr e atiti s
Ac ute pa ncreat itis is defi ne d as a n A E of i nterest i n all trials wit h tirze pati de i ncl u di n g t his trial.  
Ac ute pa ncreat itis is a n ac ute i nfla m mat or y pr ocess of t he pa ncreas t hat ma y als o i n v ol ve 
p eri pa ncreat ic tiss ues a n d/ or re m ote or ga n s yste ms (Ba n ks a n d Free ma n 2 0 0 6 ).  T he dia g n osis of 
ac ute pa ncreatit is re q uires 2 of t he f oll owi n g 3 fea t ures:

a b d o mi nal pai n, c haracterist ic of ac ute pa ncreatitis ( ge nerall y l ocate d i n t he 
e pig astri u m a n d ra di ates t o t he bac k i n a p pr o xi matel y half t he cases 
[Ba n ks a n d Free ma n 2 0 0 6 ; K o iz umi et al . 2 0 0 6]; t he pai n is ofte n ass oc iate d wit h 
na usea a n d v o mit i n g)

ser u m a m ylase (t otal a n d/ or pa ncreatic) a n d/ or li pase ≥3 X U L N

c haracterist ic fi n di n gs of ac ute pa ncreatitis o n c o m p uted t o m o gra p h y  ( C T) sca n or 
ma g net ic res o na nce i ma gi n g ( M RI)
If ac ute pa ncreatitis is s us pecte d, a p pr o priate la b orat or y tests (i ncl u di n g le vels of pa ncreatic 
a m ylase [ p-a m ylase] a n d li pase) s h o ul d be o btai ne d via t he ce ntral la b orat or y (a n d locall y, if 
nee de d).  I m a gi n g st u dies, s uc h as a b d o mi nal C T sca n wit h or wit h o ut c o ntrast, M RI, or 
gall bla d der ultras o u n d, s h o ul d be perf or me d.  If la b orat or y val ues a n d/ or a b d o mi nal i ma gi n g 
s u p p ort t he dia g n osis of ac ute pa ncreat itis, t he patie nt m ust disc o nti n ue t hera p y wi t h 
i n vesti gati onal pr o d uct(s) , b ut will c o nt i n ue i n t he st u d y o n a n ot her gluc ose -l oweri n g re gi me n 
( details o n resc ue i nter ve nti on will be pr o vi de d).  T he m ost a p pr o priate dia betes t hera pe utic 
re gi me n will be deci de d b y t he i n vesti gat or, base d o n t he patie nt’s cli nical stat us.  A re vie w of 
t he patie nt’s c o nc o mita nt me dicat i ons s h o ul d be c o n d ucte d t o assess a n y p ote ntial ca usal 
r elat i ons hi p wit h pa ncreat itis.
Eac h case o f a n A E of pa ncreat itis m ust be re p orte d.  If t y pical si g ns a n d/ or s y m pt o ms of 
pa ncreat itis are prese nt a n d c o nfir me d b y la b orat or y val ues (li pase or a m ylase [t otal a n d/ or 

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pa ncreat ic]) a n d i ma gi n g st u dies, t he e ve nt m ust be re p orte d as a n S A E.  F or a p ote ntial case t hat 
d oes n ot m eet all of t hese criteria, it is u p t o t he i n vesti gat o r t o deter mi ne t he seri o us ness of t he 
case ( A E or S A E) a n d t he relate d ness o f t he e ve nt t o st u d y dr u g(s).
Eac h patie nt will ha ve meas ure me nts of  p-a m ylase a n d li pase (assesse d at t he ce ntral la b orat or y) 
as s h o w n o n t he Sc he d ule o f Act i vities ( Sectio n 2 ) t o assess t he effects of  t he i n vestig ati o n al  
d oses of ti rze patid e o n pa ncreat ic e nz y me le vels. S eri al meas ures of pa ncreat ic e nz y mes ha ve 
li mite d cli nical val ue f or pre dicti n g e pis o des of ac ute pa ncreatitis i n as y m pt o matic patient s 
(Na uc k et al. 2 0 1 7 ; Stei n ber g et al. 2 0 1 7a, 2 0 1 7 b ). T h us, f urt her dia g n ostic f o ll ow- u p of  cases 
of  as y m pt o matic pa ncreat ic h y pere nz y me mia (li pase a n d/ or p -a m ylase ≥3 X U L N) is n ot 
ma n date d b ut ma y be perf or me d base d o n t he i n vesti gat or’s cli nical j u d g me nt a n d assess me nt of 
t he patie nt’s o verall cli nical c o n dit i 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 ditio nal  di a g n ostic fol l ow- u p a n d/ or are acc o m pa nie d b y s y m pt o ms s u g gest i ve of pa ncreatitis 
will be s u b mitte d f or a dj u dicat i on.
All s us pecte d cases of ac ute or c hr o nic pa ncreatitis will be a dj u dicate d b y a n i n de pe n de nt 
cli nical e n d p o i nt c o m mittee ( C E C).  I n 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 data fr o m patie nts wit h ac ute or c hr o nic 
pa ncreat itis a n d t h ose wit h se vere or seri o us a b d o mi nal pai n will be e ntere d i nt o a s pecificall y 
desi g ne d e C R F pa ge b y st u d y  site or Lill y st aff. T he a dj u dicat i on c o m mittee re prese ntati ve will 
e nter t he res ults of a dj 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 E N- 2
will be e xcl u de d fr o m t he 
st u d y.  T h e assess me nt of t h yr oid safet y d uri n g t he st u d y will i ncl u de re p orti n g of  a n y case of 
t h yr oid mali g na nc y i ncl u di n g M T C
a n d pa pillar y carci n o ma a n d meas ure me nts of calcit o ni n.
T his data will be ca pt ure d i n s pecific e C R Fs. T he p ur p ose of calcit o ni n meas ure me nts i s t o 
assess t he p ote ntial of tirze pati de t o affect t h yr oid C -cell f u nct i on, w hic h ma y  in dicate 
de vel o p me nt of C -cell h y per pl asia a n d ne o plas ms.
Ti rze patid e s h o uld be disc o nt i n ue d (after first c o nfir mi n g t he val ue) if p os tra n d o mizati on 
calcit o ni n value 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 ogist) s h o ul d be o btai ne d.   If t he i ncrease d 
calcit o ni n val ue (≥3 5 n g/ L a n d i ncreases b y ≥5 0 % c o m pare d wi t h baseli ne) is o bser ve d i n a 
pati e nt w h o has a d mi nistere d a me dicat i on t hat i s k n ow n t o i ncrease ser u m calcit o ni n, t his 
me dicat i on s h o ul d be st o p pe d a n d calcit o ni n le vels s h o uld be m eas ure d after a n a p pr o priate 
was h o ut peri o d.  If t he c o nfir me d calcit o ni n v al ue is < 3 5 n g/ L, tirze pati de s h o uld be restarte d 
w he n it i s 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 dj u dicate d b y a c o m mittee of p h ysicia ns e xter nal t o Lill y 
wi t h car diol o g y  e x pertise.  T he n o nfatal CV 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

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
h os pi talizatio n f or heart fail ure

c or o nar y int er ve nt i ons (s uc h as c or o nar y  arter y b y pass graft or perc uta ne o us c or o nar y 
i nter ve nt i on)

cere br o vasc ular e ve nts, i ncl u di n g cere br o vasc 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 Arr h yt h mi a s a n d C ar di a c C o n d u cti o n Di s or d er s
Treat me nt -e mer ge nt car diac c o n d ucti o n dis or ders will be f urt her e val uate d.  Patient s w h o 
de vel o p a n y e ve nt fr o m t h is gr o u p of di s or ders s h o uld u n der g o a n E C G , w hic h s h o ul d be 
s u b mitte d t o t he ce ntral rea di n g ce nter. A d dit i onal dia g n ostic tests t o deter mi ne e xact dia g n osis 
s h o uld be perf or m e d, as nee de d. T he s pecific dia g n osis will be rec or de d as a n A E. E ve nts t hat 
meet criteria f or seri o us c o n diti o ns as descri be d i n Secti o n 9. 2. 1 m ust 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, 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. 4. 4 .  St u d y  dr u g(s) s h o uld be te m p oraril y i nterr u pte d i n a n y i n di vi d ual 
s us pecte d of ha vi n g a se vere or seri o us aller gic reacti o n t o t he st u d y dr u g(s).  St u d y dr u g(s) ma y 
be restarte d w he n/if it is safe t o d o s o, i n t he o pi ni o n o f t he i n vest i gat or.  If st u d y dr u g(s) is 
p er m a ne nt l y disc o nti n ue d, t he patie nt will recei ve a n ot her gl uc ose-l oweri n g treat m e nt, ju d ge d b y 
t he i n vest i gat or t o be a p pr o priate base d o n t he patie nt’s cli nical stat us, a n d will c o nti n ue i n t he 
trial t o c ollect all pla nn e d efficac y a n d safety me as ure me nts. 
9. 2. 2. 7. 1.
I nj e cti o n Sit e R e a cti o n s
I njecti on site reacti o ns will be c o llecte d o n t he e C R F se parate fr o m t he h y perse nsiti vity reacti on 
e C R F.  At t he ti me of A E occ urre nce i n t he tirze pati de gr o u p, sa m ples will be c o llecte d f or 
meas ure me nt of tirze pat i de a nti-dr u g b o dies ( A D A s) a n d tirze pati de c o nce ntrati o n.
9. 2. 2. 7. 2.
A nti -Dr u g A nti b o di e s
T he occ urre nce of A D A f or mat i on will be assesse d as o utli ne d i n Secti o n 9. 4. 4 .
9. 2. 2. 8.
Di a b eti c R eti n o p at h y C o m pli c ati o n s
Dilate d reti nal f u n d os c o pi c e xa mi nat i on will be perf or me d b y  a q ualifie d e ye care pr ofessi onal 
( o p ht hal m ol ogist or o pt o metrist) f or all patie nts bet wee n Visit 2 a n d Visit 3 t o e xcl u de patie nts 
wi t h pr oliferati ve reti n o pat h y a n d/ or ma c ulo p at h y .  T he res ults fr o m t his e xa mi nat i on will be 
rec or de d o n a s pecific reti n o pat h y e C R F as a baseli ne meas ure of reti n o pat h y.  
A f oll ow- u p dilate d f u n d os c o pi c e xa mi nat i on s h o ul d be perf o r me d b y a q ualifie d e ye care 
pr of essi o nal ( o p ht hal m o l ogist or o pt o m etrist) w he n cli nicall y i n dicate d b y a n y A E s us pecte d of 
w orse ni n g reti n o pat h y , a n d t he fi n di n gs s h o ul d be rec or de d o n t he reti n o pat h y e C R F.  
9. 2. 2. 9.
H e p at o bili ar y Di s or d er s
All e ve nts of T E biliar y c o lic, c h olec ystitis, or ot her s us pecte d e ve nts relate d t o gall bla d der 
di sease s h o uld be e val uate d a n d a d dit i onal dia g n ostic tests perf or me d, as nee de d. I n cases of 

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ele vate d li ver mar kers, he patic mo ni t ori n g s h o uld be i nit iate d as o utli ne d i n Secti on 9. 4. 5. 1 a n d
A p pe n di x 4 .
9. 2. 2. 1 0. S e v er e G a str oi nt e sti n al A d v er s e E v e nt s
Ti rze patid e m a 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 wil l be c o llecte d i n t he e C R F.  F or 
detaile d i nf or mat i on 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. 4. 2. 5 .
9. 2. 2. 1 1. A c ut e R e n al E v e nt s
Re nal safet y  will be assesse d base d o n re peate d re nal f u nct i onal assess me nt as well as 
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 t irze pat i de, i ncl u di n g na usea, diarr hea, a n d vo m iti 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 deteri orati o n i n re nal f u ncti o n, i ncl u di n g ac u te re nal fail ure.  
P ati e nts s h o uld be a d vise d t o n otif y i n vest i gat ors i n case of se vere na usea, fre q ue nt v o miti n g, or 
s y m pt o ms of de h y drati on.
9. 2. 2. 1 2. M et a b oli c A ci d o si s,
In cl u di n g Di a b eti c K et o a ci d o si s
Ket oaci d osis, a seri o us life -t hreate ni n g c o n diti on re q uiri n g ur ge nt h os pi talizati on, has bee n 
re p orte d rarel y in patie nts wi t h T 2 D M.  Patie nts w h o prese nt wit h si g ns a n d s y m pt o ms c o nsiste nt 
wi t h se vere meta b olic aci d osis s h o ul d be assesse d f or ket oaci d osis re gar dless of prese nti n g B G 
le vels, as ket oaci d osis ma y be prese nt e ve n if B G le vels are less t ha n 2 5 0 m g/ d L.  Treat me nt of 
ket oaci d osis ma y  re q uire i ns uli n, fl ui d, a n d car b o h y drate re place me nt.   R o ut i ne bicar b o nate 
assess me nt will be perf or me d d uri n g t he c o urse of t he st u d y .  If lact ic aci d osis is s us pecte d, 
met f or mi n s h o ul d be te m p oraril y disc o nti n ue d u ntil t he res ol uti on of t he e ve nt.
9. 2. 2. 1 3. A m p ut ati o n/ P eri p h er al R e v a s c ul ari z ati o n
All cases of a m p utati o n a n d peri p heral re vasc ularizati o n s h o ul d be re p orte d as a n A E.
9. 2. 2. 1 4. M aj or D e pr e s si v e Di s or d er/ S ui ci d al I d e ati o n
T he pre vale nce of de pressi ve s y m pt o ms a n d dis or ders is i ncrease d i n patie nts wit h T 1 D M or T 2 D M 
( A D A 2 0 19 a).  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 will be i nstr ucte d t o c o ntact t he i n vesti gat or as s o o n as p ossi ble if he o r s he has a 
c o mplai nt or pr o bl e m wit h t he i n vesti gati onal pr o d uct s o t hat t he sit uati o n ca n be assesse d.
9. 3.
Tr e at m e nt of O v er d o s e
St u d y  dr u g o ver d ose ( m ore t ha n t he s pecifie d n u m ber of i njecti o ns) will be re p orte d as a n A E.  
I n t he e ve nt of o ver d ose, refer t o t he I B f or tirze pati de or t he Pr o d uct La bel f or se ma gl ut i de, as 
a p plica ble (Oze m pic ® U S PI [ W W W] ).

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9. 4.
S af et y
9. 4. 1.
El e ctr o c ar di o gr a m s
F or eac h patie nt, E C Gs s h o ul d be c o llecte d acc or di n g t o t he Sc he d ule of Acti vities ( Sectio n 2 ).
E C Gs s h o uld be p erf or me d aft er vit al si g ns are c ollecte d a n d pri or t o t he c o llecti on of bl o o d 
sa m ples f or la b orat or y testi n g if t he patient  is n ot a d versel y affecte d b y t h e fasti n g c o n ditio n .
P ati e nts s h o uld be s u pi ne f or a p pr o xi matel y  5 t o 1 0 mi n utes bef ore E C G c ollect i on a n d re m ai n 
s u pi ne, b ut a wa ke, d uri n g E C G c ollect i on. El ectr ocar dio gr a m s s h o uld be rec or de d acc or di n g t o 
t he st u d y-s pecific rec o m me n dati o ns.  
Electr ocar di o gra ms will i nitiall y be i nter prete d b y a q ualifie d p h ysicia n (t he i n vesti gat or or 
q ualifie d desi g nee) at t he site as s o o n after t he ti me of E C G c ollecti o n as p ossi ble, a n d i deall y  
w hile t he pati e nt is still prese nt, f or i m me diate patie nt ma na ge me nt, s h o ul d a n y cli nicall y 
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 orte d t o Lill y or its desi g nee as a n A E vi a t he e C R F.
All di gital E C Gs will be o btai ne d usi n g ce ntrall y pr o vi de d E C G mac hi nes a n d will be 
ele ctr o nicall y tra ns mitte d t o a desi g nate d ce ntral E C G la b orat or y . T he ce ntral E C G la b orat or y  
will perf or m a basic q ualit y c o ntr ol c hec k (f or e xa m ple, de 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 
or t o m eet re g ulat or y r e q uire ment s. T he m ac hi ne-rea d E C G i nter vals a n d heart rate ma y be use d 
f or data a nal ysis a n d re p ort writ i n g p ur p oses, u nless a car di ol o gist o verrea di n g of t he E C Gs is 
c o n d ucte d prior t o c o m plet i on of t he fi nal st u d y  re p ort (i n w hic h case, t he o verrea d data w o ul d 
be use d).
9. 4. 2.
Vit al Si g n s
Vi t al si g n meas ure me nts s h o uld be ta ke n bef ore o btai ni n g a n E C G traci n g a n d bef ore c ollect i on 
of  blo o d s a m pl es f or l a b orat or y testi n g, at visits w here re q uire d.  T he participa nt s h o ul d si t 
q ui et l y f or 5 mi n utes bef ore vital si g n meas ure me nts are ta ke n.  F o r eac h patie nt, vital si g n 
meas ure me nts s h o ul d be c o n d ucte d acc or di n g t o t he Sc he d ule of Act i vities ( Sectio n 2 ) a n d 
f oll owi n g t he st u d y -s pecific rec o m me n dati o ns.
A n y cli nicall y  sig nifica nt fi n di n gs fr o m vital si g n meas ure me nt s t hat res ult i n a dia g n osis a n d 
t hat occ ur after t he patie nt recei ves t he first d ose of st u d y tr e at me nt s h o uld be re p orte d t o Lill y or 
its desi g nee as a n A E via e C R F.
9. 4. 3.
L a b or at or y T e st s
F or eac h patie nt, lab orat or y  tests detaile d i n A p pe n di x 2 s h o uld be c o n d ucte d acc or di n g t o t he 
Sc he d ule of Act i vities ( Secti o n 2 ). 
U nless ot her wise n ote d i n A p pe n di x 2 , Lill y or i ts desi g nee will pr o vi de t he i n vesti 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 is use d f or t he cli nical 
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A n y cli nicall y  sig ni fica nt fi n di n gs fr om la b orat or y tests t hat res ult i n a dia g n osis a n d t hat occ ur 
after t he pati e nt recei ves t he first d ose of i n vesti gati onal pr o d uct s h o ul d be re p orte d t o Lill y or its 
desi g nee as a n A E via e C R F.
9. 4. 4.
I m m u n o g e ni cit y A s s e s s m e nt s
W here l ocal re g ulati ons a n d E R Bs all o w, bl o o d sa m ples f or i m m u n o ge nicit y testi n g will be 
c ollecte d t o deter mi ne a nt i b o d y pr o d uctio n a gai nst tirze pati de as s pecifie d i n t he Sc he d ule of 
Act i vities ( Secti o n 2 ).
At  t he visits a n d ti mes s pecifie d i n t he Sc he d ule of Acti vities ( Sectio n 2 ), ve n o us bl o o d sa m ples 
wi ll be c o llecte d t o deter mi ne a nti b o d y pr o d uctio n a gai nst tirze pati de.  T o int er pret t he res ults of 
i m m u n o ge nicity,  a P K sa m ple will be c ollecte d at t he sa me t i me p oi nts as t he i m m u n o ge nicit y 
sa m ple.  All sa m ples f or i m m u n o ge nicity s h o uld be ta ke n bef ore d o se w he n a p plica ble a n d 
p ossi ble.  I n t he e ve nt of dr u g h y perse nsi tivi t y r e a ctio ns (i m me diate or n o n i m me diate), 
a d ditio nal  sa m ples will be c ollecte d (i ncl u di n g A D A, P K, a n d e x pl orat or y im m u ne safet y 
sa m ple) as cl ose t o t he o nset of t he e ve nt as p ossi ble, at t he res oluti o n of  t he e ve nt, a n d 3 0 da ys 
f oll owi n g t he o nset of t he e ve nt.  I nstr ucti o ns f or t he c o llecti on a n d ha n dli n g of bl o o d sa m ples 
will be pr o vi de d b y t he s p o ns or.  Sa m ple c o llecte d at Visit 8 0 1 will assess i m m u n o ge nicity at 
was h o ut of tirze pati de ( 5 half-li ves p ost e n d of treat me nt).
Treat me nt -e mer ge nt A D As are defi ne d i n Sect i on 1 0. 3. 5 .
S a m ples wi t h tirze pati de A D A detecte d will be titere d a n d e val uate d f or t heir a bilit y t o ne utralize 
t he acti vit y of  assi g ne d treat me nt (tirze patid e -ne utralizi n g a nt i b odies).  Sa m ples wi t h tirze pati de 
A D A detecte d will als o be teste d f or cr oss -reacti ve bi n di n g t o nati ve GI P a n d G L P-1, a n d, if 
s uc h is detecte d, t hen f or ne utralizi n g a nti b o dies a gai nst nati ve GI P a n d G L P- 1.
S a m ples will  be retai ne d f or a ma xi m u m of 1 5 years after t he last patie nt visit or f or a s h orter 
p eri o d if l ocal  re g ulati ons a n d E R Bs all o w at a facilit y selecte d b y t he s p o ns or.  T he d uratio n 
allo 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 ye d.
9. 4. 5.
S af et y M o nit ori n g
Lill y will peri o dicall y  re vie w e v ol vi n g a g gre gate safety data wi t hi n t he st u d y b y a p pr o priate 
met h o ds.   T he st u d y t e a m will re vie w safety re p orts i n a bli n de d fas hi on acc or di n g t o t he 
sc he d ule pr o vi de d i n t he Trial-Le vel Safet y Re vie w pla n. Lill y will als o re vie w S A Es wit hi n 
ti me fra mes ma n date d b y c o mpa n y pr oce d ures. T he Lill y C R P will, as a p pr o priate, c o ns 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.
9. 4. 5. 1.
H e p ati c S af et y M o nit ori n g
If a st u d y p atie 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 be re peate d wi t hi n 3 t o 5 da ys i ncl u di n g A L T, A S T, 
A L P, T B L, direct bilir u bi n, ga m ma -gl uta m yl  tra nsferase, a n d creati 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 la b orat or y  mo ni t ori n g s h o uld be i ni tiate d b y t he i n vesti gat or a n d i n 

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c o ns ultati o n wit h t he st u d y  me dical m o nit or.  M o ni t ori n g of  A L T, A S T, T B L, a n d A L P s h o ul d 
c o nti n ue u ntil le vels n or malize or ret ur n t o a p pr o xi mate baseli ne le vels.
He p atic S afet y D at a C ollecti o n
A d dit i onal safety data s h o ul d be c o llecte d via t he e C R F if 1 or m ore of t he f oll owi n g c o n di tio ns 
occ ur: 

Ele vat i on o f ser u m A L T t o ≥5 X U L N o n 2 or m ore c o nsec uti ve bl o o d tests

Ele vat i on of ser u m T B L t o ≥2 X U L N (e xce pt f or cases of k n o w n Gil bert’s 
s y n dr ome)

Ele vat i on of ser u m A L P t o ≥2 X U L N o n 2 or m ore c o nsec uti ve bl o o d tests

P ati e nt disc o nt i n uati on fr o m treat me nt d ue t o a he patic e ve nt or a b n or mality 
of  li ver tests

He pati c e ve nt c o nsidere d t o be a n S A E
9. 5.
P h ar m a c o ki n eti c s
A P K sa m ple will be c ollecte d at t he sa me ti me p oi nts as t he i m m u n o ge nicit y sa m ple per t he
St u d y  Sc he d ule of Act i vities ( Secti on 2 ). All sa m ples f or P K assess me nt s h o ul d be ta ke n
pre d ose.
C o nce ntrati o ns of tirze pat i de will be assa ye d usi n g a vali date d li q ui d c hr omat o gra p h y  mass
s pectr o metr y met h o d.
Bi oa nal y tic al sa m ples c ollecte d t o meas ure tirze patide c o nce ntrati o ns will be retai ne d f or a
ma xi m u m o f 1 y ear after t he last patie nt visit for t he st u d y .
9. 6.
P h ar m a c o d y n a mi c s
N ot a p plica ble.
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 arm 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 netic a nal ysis as s pecifie d i n t he 
Sc he d ule of Act i vities ( Secti o n 2 ) w here lo c al  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 b le res p o nse t o tirze pati de a n d t o 
i n vesti gate ge netic varia nts t h o u g h t t o pla y a r ole i n T 2 D M.  Assess me nt of varia ble res p o nse 
ma y i ncl u de e val 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 nd 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 for a s h orter peri o d if l o cal re g ulati ons a n d/ or 

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E R Bs/I R Bs i m p ose s h orter ti me li mits.  T his rete nti on peri o d e na bles use of ne w tec h n o l ogi es, 
res p o nse t o re g ulat or y q uesti ons, a n d i n vest i gati on of varia ble res p o nse t hat ma y n ot be o bser ve d 
u nt il later i n t he de vel o p ment  of tirze pati de 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 we ver, e xisti n g a p pr oac hes i ncl u de ge n ome -wi de ass ociat i on 
st u dies a n d ca n di date ge ne st u dies.  Re gar dless of tec h n o l 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 sect i 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 act i on, varia bilit y of  patie nt res p o nse (i ncl u di n g safet y), a n d 
cli nical o utc o me.  Sa m ple c o llecti on is i nc or p orate d i nt o cli nical st u dies t o e na ble e xa mi nati on of 
t hese q uest i ons t hr o u g h meas ure me n t of bio m ol e c ules, i ncl u di n g D N A, R N A, pr otei ns, li pi ds, 
a n d ot her cell ular ele me nts.
S er u m  a n d plas ma sa m ples f or bi o mar 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 ( Secti o n 2 ) w here l ocal re g ulat i ons all o w.
S a m ples will  be use d f or researc h o n t he dr u g tar get, disease pr ocess, varia ble res p o nse t o 
tirze pati de, pat h wa ys ass ociate d wit h T 2 D M, mec ha nis m of actio n of  tirze pati de, a n d/ or researc h 
met h o d or i n vali dat i n g dia g n ostic t o ols or assa y(s) relate d t o T 2 D M.  
All sa m ples will be c o de d wit h t he 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 y ears 
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 o cal re g ulati ons 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 re s p o nse t hat ma y n ot be o bser ve d u nt il later 
i n t he c o urse of t he de vel o p me nt a n d c o m mercializati o n of b ot h st u d y dr u gs.
9. 9.
H e alt h E c o n o mi c s
T he f oll owi n g q uest 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 or pr o gress i n t h e st u d y wit h t he 
i n vesti gat or a n d/ or site staff a n d bef ore a n y ot her st u d y pr oce d ures if t he patient  is n ot a d versel y 
affecte d b y t heir fasti n g c o n diti on.
9. 9. 1.
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 
a n d h y p o gl yce mia.  T he q uesti o n naire c o ntai ns 8 ite ms ( Bra dle y 1 9 9 4).  Eac h ite m is rate d o n a 
7 -p oi nt Li kert scale.  Si x ite ms ( 1 a n d 4 t hr o u g h 8) are s u m me d t o pr o d uce a meas ure of 

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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”).
9.9.2. Impact of Weight on Self-Perception Questionnaire
The IW-SP questionnaire contains 3 items that assess how often the patients’ body weight affects 
how happy they are with their appearance and how often they feel self-conscious when out in 
public (Hayes and DeLozier 2015).  Each item is rated on a 5-point scale ranging from “always” 
to “never.”  Total scores for the IW-SP are derived by summing the item scores and dividing by 
the number of items.  The score can also be transformed to a range from 0 to 100.  Higher IW-SP 
scores correspond to better self-perception (Hayes and DeLozier 2015).
9.9.3. Ability to Perform Physical Activities of Daily Living
The APPADL questionnaire contains 7 items that assess how difficult it is for patients to engage 
in certain activities considered to be integral to normal daily life, such as walking, standing, and 
climbing stairs (Hayes et al. 2012).  Items are scored on a 5-point numeric rating scale, where 
5 = “not at all difficult” and 1 = “unable to do.”  A raw overall score is calculated by simply 
summing the scores of the 7 items, and a transformed overall score is obtained by linearly 
transforming the raw overall score to a 0 to 100 scale.  A higher raw overall score and a higher 
transformed overall score are indicative of better ability to perform activities of daily living.  
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, and 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) and 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.

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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).
9.9.5. Impact of Weight on Quality of Life-Lite Clinical Trials Version
The IWQOL-Lite-CT is a 20-item, obesity-specific patient-reported outcome (PRO) instrument 
developed for use in obesity clinical trials. It assesses 2 primary domains of obesity-related 
health-related quality of life:  physical (7 items), and psychosocial (13 items). A 5-item subset of 
the physical domain – the physical function composite is also supported. Items in the physical 
function composite describe physical impacts related to general and specific physical activities. 
All items are rated on either a 5-point frequency (“never” to “always”) scale or a 5-point truth 
(“not at all true” to “completely true”) scale (Kolotkin et al. 2017, 2018).

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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
A p pr o xi mat el y 1 8 7 2 pat ient s ( 4 6 8 per gr o u p) will be ra n d o ml y assi g ne 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 Q W , or se ma gl ut i de 1 m g Q W .  Patie nt ra n d o mizati o n will be 
stratifie d base d o n c o u ntr y a n d baseli ne H b A 1c (≤8. 5 % or > 8. 5 % [ 6 9 m m o l/ m ol]). 
T he tri al is p o were d t o assess n o ni nferi ority of  tirze patide 1 0 m g a n d/ or tirze pat i de 1 5 m g Q W t o 
se ma gl uti de 1 m g Q W , r elat i 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 om baseli ne 
t o 4 0 wee ks .  
T he p o wer i s assesse d base d o n t he f oll owi n g ass u m pt i ons:  

eac h of t he 1 0-m g a n d 1 5 -m g tirze pat i de Q W  treat me nt gr o u ps will be teste d i n parallel 
a gai nst se ma gl utid e 1 m g Q W at 2-si de d 0. 0 2 5 si g nifica nce le vel

use of 2 -sa mple t test utilizi n g H b A 1c data c ollecte d bef ore i nitiati o n of a n y resc ue 
me dicat i on or pre mat ure treat me nt disc o nti n uati o n wit h n o m ore t ha n 2 8 % of  patie nts
i nitiati n g a n y resc ue me dicati on or pre mat ure treat me nt disc o nt i n uati on i n eac h treat me nt 
gr o u p

n o differe nce bet wee n tirze pati de d oses a n d se ma gl ut i de 1 m g relati ve t o t he pri mar y 
e nd p oi nt

a n o ni nferi orit y mar gi n o f 0. 3 % , a n d

a c o m m o n sta n dar d de viat i on ( S D) of 1. 1 %.  
O n t he basis of t hese ass u m pt i ons, ra n d o m l y assi g ni n g a p pr o xi matel y 1 8 7 2 patie nts t o t he 
4 treat me nts usi n g a 1: 1: 1: 1 rati o will pr o vi de at least 9 0 % p o wer t o de m o nstrate n o ni nferi orit y  
of  tirze pati de 1 0 m g a n d/ or 1 5 m g Q W  d oses t o se ma gl ut i de 1 m g Q W , relat i ve t o t he pri mar y 
e n d p o i nt f or t he “efficac y” est i ma n d.  F urt her more, t hi s sa m ple size will e ns ure 9 0 % p o wer t o 
d e m o nstrate n o ni nferi ori t y f or t he “treat me nt -re gi me n” est i ma n d c o n d ucte d usi n g a n a nal ysis of 
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 .
Missi n g data will be 
i m p ute d wit h a c o nser vati ve m ult i ple i m p utati o n met h o d (as descri be d i n Sect i on 1 0. 3. 3 ) if S D 
were t o i ncrease u p t o 1. 3 % d ue t o t he i ncl usi o n of data o n resc ue me dicat i ons, i ncl usi o n of data 
after pre mat ure treat me nt disc o nt i n uati on, a n d i m p utati o n of t he missi n g data.  

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10.2. Populations for Analyses
For purposes of the analyses, the following populations are defined:
Population
Description
Screened patients
All participants who sign informed consent
Randomly assigned patients
All patients who are randomly assigned to a treatment group
Modified intent-to-treat (mITT) 
population
All randomly assigned patients who are exposed to at least 1 dose of study 
drug.  In the event of a treatment error, patients will be analyzed according to 
the treatment they were randomly assigned to.
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 (FAS)
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 Period 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 the clinical study report.  Additional exploratory analyses of the 
data may 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 randomly assigned.
There will be 2 estimands of interest in comparing efficacy of tirzepatide doses with 
semaglutide. The first estimand, “efficacy,” represents efficacy prior to discontinuation of study 
drug without confounding effects of antihyperglycemic rescue therapy.  The second estimand, 
“treatment-regimen,” represents the efficacy irrespective of adherence to study drug or initiation 
of rescue antidiabetic drugs.
The primary efficacy assessment for change from baseline in HbA1c, guided by the “efficacy” 
estimand, will be conducted using the efficacy analysis set (EAS).  The primary efficacy 
assessment, guided by the “treatment-regimen” estimand, will be conducted using the full 
analysis set (FAS).  As they are intended for different purposes, no multiplicity adjustments will 
be made for conducting 2 primary efficacy assessments relative to the “efficacy” and “treatment-
regimen” estimands.
Unless specified otherwise, safety assessments will be guided by an estimand comparing safety
of tirzepatide doses with semaglutide irrespective of adherence to study drug or initiation of 

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antihyperglycemic rescue therapy.  Thus, safety analysis will be conducted using the safety 
analysis set (SS).  Selected safety analyses may be conducted after excluding data on rescue 
therapy or data after starting another antihyperglycemic medication.
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-effects model for 
repeated measures (MMRM) with terms for: 

treatment 

visit

treatment-by-visit interaction 

country 

baseline HbA1c category (≤8.5% or >8.5% [69 mmol/mol]), and

baseline measurement as a covariate.  
For analyses with HbA1c, the baseline HbA1c category will not be included in the model.  An 
unstructured covariance structure 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.  The negative binomial regression model will 
be used for the treatment comparison of discrete count measures if deemed appropriate.
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, randomly assigned, and receiving at 
least 1 dose of study drug will be presented by treatment groups.  A listing of randomly assigned 
patients not receiving study drug will be provided.  Of the patients in the mITT set, frequency, 
counts, and percentages of patients completing the study; prematurely discontinuing the study 
including the reason for premature discontinuation; and prematurely discontinuing study drug 
including the reason for premature discontinuation of study drug will be presented by treatment 
groups.  A Kaplan-Meier analyses of time from randomization to premature discontinuation from 
study and premature discontinuation from study drug 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 set.

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1 0. 3. 2. 3. C o n c o mit a nt T h er a p y 
C o nc o mita nt me dicat i ons will be s u m marize d b y  a nat o mical t hera pe utic c he mical classificati on 
a n d treat me nt gr o u p usi n g t he mI T T p o p ulati o n.  I n partic ular, t he i nci de nce of i nitiati on of 
resc ue t hera p y for se vere, persiste nt h y per gl yce mia will be a nal yze d a n d s u m marize d as a n 
e x pl orat or y s afet y e n d p o i nt.  D o se m o dificati ons of met f or mi n will als o be s u m marize d. 
1 0. 3. 2. 4. Tr e at m e nt C o m pli a n c e 
Treat me nt c o m plia nce f or eac h visit i nter val is defi ne d as ta ki n g at least 7 5 % of re q uire d 
i njecti ons o f st u d y dr u gs.  O verall treat me nt c o m plia nce f or eac h pat ient  will be c o m p ute d b y t he 
n u m ber of i njecti o ns di vi de d b y  t he t otal pla n ne d n u m ber of i njecti o ns t he patie nt s h o ul d ta ke 
d uri n g t he st u d y .  Fre q ue nc y c o u nts a n d perce nta ges of patie nts c o m plia nt t o st u d y dr u g wil l be 
s u m marize d b y tr e at me nt gr o u ps 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 mary efficac y a nal yses c o n d ucte d t o esta blis h 
n o ni nferi orit y of  tirze pati de 1 0 m g a n d/ or 1 5 m g Q W  t o se ma gl utid e 1 m g Q W relati ve t o mea n 
c ha n ge i n H b A 1c val ues fr o m baseli ne t o t he 4 0 -wee k visit.
F or t he F D A a n d p ossi bl y ot her re g ulat or y  a ge ncies, t he pri mar y  efficac y a nal ysis will be g ui de d 
b y t he “treat me nt -re gi me n” esti ma n d defi ne d i n Secti o n 1 0. 3. 1 usi n g t he F A S dataset .  T his 
assess me nt will a nalyze c ha n ge i n H b A 1c val ues fr o m baseli ne o btai ne d at t he 4 0 -wee k visit 
usi n g a n a nal ysis o f c o varia nce ( A N C O V A) wi t h t er ms f or:  

treat me nt 

c o u ntr y, a n d

baseli ne H b A 1c as a c o variat e.  
As i nit ial ste p, a 2 -si de d 9 7. 5 % CI f or t he differe nce i n 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 bet wee n 1 0 m g t irze pati de Q W a n d se ma gl ut i de 1 m g Q W, as well as bet wee n 
1 5 m g t irze pat i de Q W a n d se ma gl uti de 1 m g Q W, will be c o nstr ucte d.  If t he u p per li mit of t he 
CI is bel o w 0. 3 %, t he tirze pati de d ose will be declare d n o ni nferi or t o se ma gl ut i de. A gra p hical 
testi n g a p pr oac h ( Bretz et al. 2 0 1 1) will be e m pl o ye d t o c o ntr ol t he fa mil y -wise t y pe 1 err or at 
5 % l e vel f or t he pri mar y a n d ke y sec o n dar y e nd p oi nts. Details will be descri be d i n t he S A P.
Missi n g H b A 1c
val ues at t he 4 0 -wee k visit will be i m p ute d base d o n o bser ve d data i n t he sa me 
treat me nt gr o u p fr om pati e nts 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 nitiati on of resc ue a nti h y per gl yce mic me dicat i on.  T hi s anal 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 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 Secti 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 will 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 val ues fr o m baseli ne o btai ne d at eac h sc he d ule d p ost baseli ne 

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visit.  T he i n de pe n de nt varia bles of t he M M R M m o del are treat me nt, visit, treat me nt - b y-visit 
i nteract i on, a n d c o u ntr y as fi xe d effects, a n d base li ne H b A 1c as a c o variate.
Si nce t he y  are i nte n de d f or differe nt p ur p oses, eac h of t he 2 pri mar y efficac y assess me nts 
r elat i ve t o t he “efficac y” a n d “tr e at me nt -re gi me n” esti ma n ds will be c o n d ucte d at a fa mil y-wise 
t ype 1 err or rate of 0. 0 5.  A d dit i onal d etails, i ncl u di n g a nal ysis met h o ds f or ke y sec o n dar y 
e n d p o i nts a n d a strate g y for c o ntr olli n g t he o verall fa mil y -wise t y pe 1 err or rate at a n al p ha o f 
0. 0 5 f or pri mar y a n d ke y  sec o n dar y e n d p oi nt e val uatio n , will be pr o vi de d i n t he S A P.
1 0. 3. 3. 2. S e c o n d ar y A n al y s e s
T he sec o n dar y st u d y  o bject i ves s u bject t o t ype 1 err or rate c o ntr ol are as f oll o ws:

N o ni nferi ori t y of  tirze pati de 5 m g Q W t o se ma gl uti de 1 m g Q W r elat i ve t o 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

S u peri ori t y of tirze patid e 5 m g, 1 0 m g, a n d/ or 1 5 m g Q W  t o se ma gl ut i de 1 m g r elat i ve 
t o:
o
mea n c ha n ge i n b o d y  wei g ht fr o m baseli ne t o t he 4 0-wee k visit
o
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
o
pr o p orti o n of  patient s ac hie vi n g t he tar get val ue of H b A 1c < 7 % ( < 5 3 m m o l/ m ol) 
at t he 4 0- wee k visit .
T he t y pe 1 err or -c o nt r olle d strate g y f or t he pri mar y a n d sec o n dar y e n d p oi nts will be descri be d i n 
t he S A P.  All t y pe 1 err or -c o nt r olle d sec o n dar y efficac y a nal yses will be c o n d ucte d se paratel y 
f or b ot h esti ma n ds, t he “efficac y” est i ma n d a n d t he “t reat me nt -re gi me n” esti ma n d.
A nal ysis of c ha n ge fr o m baseli ne i n b o d y  wei g ht at t he 4 0-wee k visit will be c o n d ucte d i n a 
ma n ner si milar t o t he pri mar y efficac y a nal yses wit h baseli ne H b A 1 c cate g or y ( ≤8. 5 % or > 8. 5 %
[6 9 m m o l/ m ol]) a d de d i n t he mo d el , a n d baseli ne of t he c orres p o n di n g varia ble as a c o variate.  
T he M M R M a nal yses are descri be d i n Sect i on 1 0. 3. 1 . 
C o m paris o ns a m o n g tr e at me nts relati ve t o t he pr o p orti o n of patie nts ac hie vi n g t he H b A 1c tar get 
val ue of < 7. 0 % ( < 5 3 m m o l/ m ol) at t he 4 0-wee k visit will be c o n d ucte d usi n g a l o gist ic 
re gressi o n a nal ysis wit h ter ms f or: treat me nt, c o u ntr y, a n d baseli ne H b A 1c as a c o variate. I n t he 
a nal ysis of pat ient s ac hie vi n g t he H b A 1c tar get val ue relati ve t o t he “efficac y” est i ma n d, patie nts 
wi t h missi n g val ues at t he 4 0-wee k visit will be e xcl u de d.  I n t he a nal ysis o f pati e nts ac hie vi n g 
t he H b A 1c tar get val ue relat i ve t o t he “treat me nt-re gi me n” esti ma n d, missi n g val ues at t he 
4 0 -wee k visit will be i m p ute d base d o n o bser ve d data at res pecti ve visits fr o m pati e nts i n t he 
sa me treat me nt gr o u p w h o ha d t heir efficac y assesse d after earl y disc o nti n uati on of st u d y  dr u g 
a n d/ or i nit iati on of resc ue me dicat i on.  T he a nal ysis will be c o n d ucte d wit h m ult i ple i m p utati o ns 
a n d statist ical infere nce o ver m ul tiple 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).

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10.3.3.3. Tertiary/Exploratory Analyses
All exploratory efficacy analyses will be guided by the “efficacy” estimand 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 semaglutide 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 after excluding data on rescue therapy or data after starting another 
antihyperglycemic medication.
AEs 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, and study discontinuation due to AEs, 
study drug discontinuation due to AEs, or deaths from the time of first dose through end of safety 
follow-up.  Counts and proportions of patients 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 will be 
summarized and compared between tirzepatide doses and semaglutide.  Rate of hypoglycemic 
episodes will be analyzed using a generalized linear mixed-effects model assuming negative 
binomial distribution for hypoglycemic episodes if data warrant. Some analyses may be 
conducted excluding data after introducing another antihyperglycemic 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 event, first dose and last dose of study 
drug, and time from randomization to the event will be listed.
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 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 

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L Y 3 2 9 8 1 7 6
hi g h li mit at a n y  ti me d uri n g St u d y Perio ds I I a n d III.  A T E l ow res ult is defi ne d as a c ha n ge 
fr om a value greater t ha n or e q ual t o t he l o w li mit at baseli ne t o a val ue less t ha n t he l o w li mit at 
a n y ti me d uri n g St u d y  P eri o ds II a n d III.   T he hi g h a n d l o w li mit s will be pr o vi de d i n t he S A P.
1 0. 3. 5. E v al u ati o n of I m m u n o g e ni cit y
T he fre q ue nc y a n d perce nta ge of patie nts wit h pree xist i n g A D A, wit h T E A D A, a n d wit h 
ne utralizi n g T E A D A t o tirze pati de will be ta b ulate d b y tirze pati de d ose. Treat me nt -e mer ge nt 
A D As are defi ne d as t h ose wit h a titer 2 -f ol d ( 1 dil uti o n) greater t ha n t he mi ni m u m re q uire d 
dil ut i on if n o A D As were detecte d at baseli ne (treat me nt -i n d uce d A D A) or t h ose wit h a 4-f ol d 
( 2 dil ut i ons) i ncrease i n t iter c o m pare d t o baseli ne if A D As were detecte d at baseli ne 
(treat me nt-b o oste d A D A).  T he mi ni m u m re q uire d dil ut i on of t he A D A assa y is 1: 1 0. F or t he 
pati e nts wit h TE A D A , t h e distri b utio n of  ma xi m u m titers will be descri be d.  T he fre q ue nc y of 
ne utralizi n g a nt i b o dies t o tirze patide a n d/ or cr oss -reacti ve a n d ne utralizi n g a nti b o dies t o 
e n d o ge n o us c o u nter parts will be ta b ulate d i n patient s wit h T E A D A.
T he relat i ons hi p bet wee n t he prese nce of a nt i b o dies a n d tirze patid e P K a n d P D res p o nse
i ncl u di n g safety a n d efficac y t o tirze patid e ma y be assesse d.
1 0. 3. 6. Ot h er A n al y s e s
1 0. 3. 6. 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 P R O sc ores will be c o n d ucte d usi n g li near 
m o dels wi t 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. 6. 2. S u b gr o u p A n al y s e s
S u b gr o u p a nal yses of mea n c ha n ge i n H b A 1c val ues fr o m baseli ne t o Visit 1 1 will be pr o vi de d 
b y

a ge 

race

et h nicit y 

ge n der 

d urati o n of  dia betes, a n d

baseli ne H b A 1c ( ≤8. 5 % a n d > 8. 5 % [6 9 m m o l/ m ol]).
1 0. 3. 7. 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 ne d 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 i t is necessar y t o a me n d t he pr ot oc ol.

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11.
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the vasoactive effect of GIP regulating adipose tissue metabolism in humans. J Clin 
Endocrinol Metab. 2016;101(8):3155-3162.
Banks PA, Freeman ML. Practice guidelines in acute pancreatitis. Am J Gastroenterol.
2006;101(10):2379-2400.
Bradley C. The diabetes treatment satisfaction questionnaire: DTSQ. In: Bradley C, editor.
Handbook of Psychology and Diabetes: a guide to psychological measurement in diabetes 
research and practice. Chur, Switzerland: Harwood Academic Publishers; 1994.
Bretz F, Posch M, Glimm E, Klinglmueller F, Maurer W, Rohmeyer K. Graphical approaches for 
multiple comparison procedures using weighted Bonferroni, Simes, or parametric tests. Biom 
J. 2011;53(6):894-913.
Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, Cui X, Briere DA, 
Cabrera O, Roell WC, Kuchibhotla U, Moyers JS, Benson CT, Gimeno RE, D’Alessio DA, 
Haupt A. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 
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Danne T, Philotheou A, Goldman D, Guo X, Ping L, Cali A, Johnston P. A randomized trial 
comparing the rate of hypoglycemia – assessed using continuous glucose monitoring – in 125 
preschool children with type 1 diabetes treated with insulin glargine or NPH insulin (the
PRESCHOOL study). Pediatr Diabetes. 2013;14(8):593-601. 
Davies MJ, D’Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, Rossing P, Tsapas 
A, Wexler DJ, Buse JB. Management of hyperglycemia in type 2 diabetes, 2018. A consensus 
report by the American Diabetes Association (ADA) and the European Association for the 
Study of Diabetes (EASD). Diabetes Care. 2018;41(12):2669-2701.
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 
agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active 
comparator-controlled phase 2 trial. Lancet. 2018;392(10160):2180-2193.
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instrument. Version 2.1. Available at: https://euroqol.org/wp-content/uploads/2016/09/EQ-5D-
5L_UserGuide_2015.pdf. Published April 2015. Accessed August 06, 2018.
Hayes RP, DeLozier AM. Reliability, validity, and responsiveness of the Impact of Weight on 
Self-Perceptions Questionnaire (IW-SP) in individuals with type 2 diabetes and obesity. 
Diabetes Technol Ther. 2015;17(3):210-214.
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 
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of acute pancreatitis: diagnostic criteria for acute pancreatitis. J Hepatobiliary Pancreat Surg.
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Kolotkin RL, Ervin CM, Meincke HH, Højbjerre L, Fehnel SE. Development of a clinical trials 
version of the Impact of Weight on Quality of Life-Lite questionnaire (IWQOL-Lite Clinical 
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a new measure of quality of life in obesity trials: IWQOL – Lite Clinical Trials Version. Poster 
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Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N 
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acute pancreatitis and/or pancreatic cancer: reassuring data from cardio-vascular outcome 
trials. Diabetes Obes Metab. 2017;19(9):1327-1328.
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SUSTAIN 7 investigators. Semaglutide versus dulaglutide once weekly in patients with type 2 
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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-
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Rubin DB. Multiple imputation for nonresponse in surveys. New York: John Wiley & Sons Inc.; 
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Sorli C, Harashima SI, Tsoukas GM, Unger J, Karsbøl JD, Hansen T, Bain SC. Efficacy and 
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A1c, blood pressure, and LDL goals among people with diabetes, 1988-2010. Diabetes Care.
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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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Steinberg WM, Rosenstock J, Wadden TA, Donsmark M, Jensen CB, DeVries JH. Impact of 
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Weinberg ME, Bacchetti P, Rushakoff RJ. Frequently repeated glucose measurements 
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12.
Appendices

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Appendix 1.
Abbreviations and Definitions
Term
Definition
ADA
anti-drug antibody
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
patient 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
In the context of this study, double-blind means that the patient, the investigator/site 
staff, and sponsor staff are blinded.  
BMI
body mass index
CEC
clinical endpoint committee
CHF
congestive heart failure
CI
confidence interval
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
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.
CT
computed tomography

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CV
cardiovascular
DPP-4
dipeptidyl peptidase-4
DTSQc
Diabetes Treatment Satisfaction Questionnaire change
DTSQs
Diabetes Treatment Satisfaction Questionnaire status
EAS
efficacy analysis set
ECG
electrocardiogram
eCRF
electronic case report form
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: 5 dimensions, 5 levels
ERB
ethical review board
ET
early termination
FAS
full analysis set
FSH
follicle-stimulating hormone
GI
gastrointestinal
GIP
glucose-dependent insulinotropic polypeptide
GLP-1
glucagon-like peptide-1
HbA1c
hemoglobin A1c
HDL
high-density lipoprotein
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.
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.

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ITT
intent to treat:  The principle that asserts that the effect of a treatment policy can be best 
assessed by evaluating on the basis of the intent 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.
IWQOL-Lite-CT
Impact of Weight on Quality of Life-Lite Clinical Trials Version
IWRS
interactive web-response system
IW-SP
Impact of Weight on Self-Perception
MedDRA
Medical Dictionary for Regulatory Activities
MEN2
multiple endocrine neoplasia type 2
mITT
modified intent-to-treat
MMRM
mixed-effects model for repeated measures
MRI
magnetic resonance imaging
MTC
medullary thyroid carcinoma
NAFLD
nonalcoholic fatty liver disease
OAM
oral antihyperglycemic medications 
OTC
over the counter
p-amylase
pancreatic amylase
PG
plasma glucose
PK/PD
pharmacokinetics/pharmacodynamics
PRO/ePRO
patient-reported outcomes/electronic patient-reported outcomes
QW
once weekly
SAD
single ascending dose
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. 

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SD
standard deviation
SGLT2
sodium-glucose co-transporter 2
SMBG
self-monitored 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.
ULN
upper limit of normal
VLDL
very low-density lipoprotein

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Appendix 2.
Clinical Laboratory Tests
Clinical Laboratory Testsa
Hematology
Chemistry Panel
Hemoglobin
Sodium
Hematocrit
Potassium
Erythrocyte count (RBC)
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)
Urine Chemistries
Microalbumin
Creatinine
Urine microalbumin/creatinine ratiod
Pregnancy test (serum and urine; females only)b
Follicle-stimulating hormone (FSH)c
Estradiolc
HbA1c
Endocrine
eGFR (calculated by CKD-EPI equation)d
Glucagon (fasting)
Insulin (fasting)
Calcitonin
C-peptide (fasting)
Immunogenicity
Tirzepatide anti-drug antibody
PK sample for immunogenicity
Pancreas (Exocrine) Panel
Pancreatic amylase
Lipase
Anti-GAD Antibodies
Lipid Panel (Fasting)
Total cholesterol
LDL
HDL
VLDL
Triglycerides
Pharmacogenetic Stored Sample
Nonpharmacogenetic Stored Samples
EDTA plasma
Serum
P800 plasma

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Abbreviations:  CKD-EPI = Chronic Kidney Disease-Epidemiology; EDTA = ethylenediaminetetraacetic acid; 
eGFR = estimated glomerular filtration rate; FSH = follicle-stimulating hormone; GAD = glutamic acid 
decarboxylase; 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 6, 9, and 11.  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
FSH 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
Urine microalbumin/creatinine ratio and 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 ICF 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 

other relevant documents (for example, curricula vitae, advertisements)

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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 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

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.

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
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-GPGL 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 normalized 
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 GPGL 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). Last accessed February 8, 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 (~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 11) 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 11, 
minimize missing data, and preserve the intended conduct of the study, the visit window 
for Visit 11 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 11.  
2) For patients requiring an extension for Visit 11 up to Week 44, additional study drug 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 per local regulations will be obtained for those 
patients who will be dispensed additional study drug 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 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-MC-GPGL(b)
A Phase 3, Randomized, Open-Label Trial Comparing 
Efficacy and Safety of Tirzepatide versus Semaglutide 
Once Weekly as Add-on Therapy to Metformin in 
Patients with Type 2 Diabetes (SURPASS-2)
Overview
Protocol I8F-MC-GPGL titled “A Phase 3, Randomized, Open-Label Trial Comparing Efficacy 
and Safety of Tirzepatide versus Semaglutide Once Weekly as Add-on Therapy to Metformin in 
Patients with Type 2 Diabetes (SURPASS-2)” 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-GPGL 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  =  5 7 c 3 b 8 7 9 - 7 4 b 5 - 4 b 5 6 - 9 3 b 2 - a f 1 d 0 6 a 5 7 c 7 0
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 6 : 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 : 5 0 : 0 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