Clinical trial NCT03954834
Conditions: Type 2 Diabetes Mellitus
Keywords: glucose-dependent insulinotropic polypeptide (GIP) glucagon-like peptide-1 (GLP-1) GIP/GLP-1 dual receptor agonist T2DM
Sponsor: Eli Lilly and Company
Start date: 2019-06-03; Completion date: 2020-10-28
Enrollment: 478 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal for this study is to evaluate the efficacy and safety of tirzepatide versus placebo in participants with type 2 diabetes not under control with diet and exercise alone. The study will last approximately 47 weeks and may include about 15 visits.

Detailed description:

Arms: arm 1: Participants received 5 milligrams (mg) of tirzepatide as subcutaneous injection once a week. arm 2: Participants received 10mg of tirzepatide as subcutaneous injection once a week. arm 3: Participants received 15mg of tirzepatide as subcutaneous injection once a week. arm 4: Participants received placebo as subcutaneous injection once a week.
Interventions: intervention 1: Tirzepatide intervention 2: Placebo
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered SC

Protocol documents:
Prot_000.pdf: 
Pr ot oc ol I 8 F- M C- G P G K( b)
A Ra n d o mize d, D o u ble- bli n d, Place b o- C o ntr olle d Trial C o m pari n g t he Efficac y a n d Safet y of T hree 
Tirze pati de D oses Vers us Place b o i n Patie nts Wit h T y pe 2 Dia betes, I na de q uatel y C o ntr olle d Wit h Diet a n d 
E xercise Al o ne
N C T 0 3 9 5 4 8 3 4  
A p pr o val Date: 1 5- A pr- 2 0 2 0


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


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


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


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


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


I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 6
L Y 3 2 9 8 1 7 6
Li st of T a bl e s
T a bl e
P a g e
Ta ble G P G K. 1.
Sc he d ule of Act i vities....................................................................................1 4
Ta ble G P G K. 2.
O bject i ves a n d E n d p oi nts...............................................................................2 3
Ta ble G P G K. 3.
Treat me nt Re gi me ns ......................................................................................3 5
Ta ble G P G K. 4.
Descri pt i on of A nal ysis P o p ulat i on a n d Data Sets ..........................................6 1


I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 7
L Y 3 2 9 8 1 7 6
Li st of Fi g ur e s
Fi g ur e
P a g e
Fi g ure G P G K. 1.
Ill ustratio n of  st u d y desi g n f or Cli nical Pr ot oc ol I 8 F-M C -G P G K. ..................2 5


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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starti n g at a l o w d ose of 2. 5 m g acc o m pa nie d b y d ose escalat i on of 2. 5 m g i ncre me nts e ver y  4-
wee k w o ul d per mit ti me f or de vel o p me nt of  t olera nce t o GI e ve nts a n d are pre dicte d t o mi ni mize 
GI t ol era bilit y c o ncer ns.
T he m a xi m u m pr o p ose d d ose of 1 5 mg m ai ntai ns a n e x p os ure mul tiple o f 1. 6 t o 2. 4 t o t he n o -
o bser ve d -a d verse-effect le vel d oses i n 6-m o nt h m o n ke y a n d rat t o xic ol o g y  st u dies.
T he selecte d d ose a n d escalati o n sc he me w o ul d e na ble f urt her e val uat i on of be nefit/ris k 
c o nsi derati o ns f or 5 -m g, 1 0 -m g, a n d 1 5 -m g d oses of tirze pati de.


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


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


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


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


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


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


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


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


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


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


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


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


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8.
Di s c o nti n u ati o n Crit eri a
8. 1.
Di s c o nti n u ati o n fr o m St u d y Tr e at m e nt
8. 1. 1.
P er m a n e nt Di s c o nti n u ati o n fr o m St u d y Tr e at m e nt
P ossi ble r eas o ns lea di n g t o per ma ne nt disc o nti n uati o n of i n vesti gati onal pr o d uct :

P atie nt Decisi o n
o
T he patie nt re q uests t o disc o nti n ue i n vesti gati onal pr o d uct.

Disc o nti n u ati o n d ue t o i ncre ase d ris k of h y p o gl yce mi a
Pl ease refer t o S ecti o n 7. 8. 2. 2 f or details.

Disc o nti n u ati o n d ue t o a he p atic e ve nt or li ver test a b n or m alit y
P ati e nts w h o are disc o nt in ue d fr o m i n vesti gati onal pr o d uct d ue t o a he pat ic e ve nt or li ver 
test a b n or malit y s h o uld ha ve a d di tio n al he pat ic safet y data c ollecte d via a n eC R F.
Di sc o nti n uatio n of  t he i n vesti gati onal pr o d uct f or a b n or mal li ver tests s h o ul d be
c o nsi dere d b y t he i n vestigat or w he n a patie nt meets o ne of t he f o ll owi n g c o n di tio ns af t er 
c o ns ultati o n wit h t he Lill y -desi g nate d m e dical mo ni t or:

A L T or as partate a mi n otra nsferase ( A S T) > 8 X U L N

A L T or A S T > 5 X U L N f or m ore t ha n 2 wee ks

A L T or A S T > 3 X U L N a n d t otal bilir u bi n le vel ( T B L) >2 X U L N or 
i nter nat i onal n or m alize d ratio > 1. 5

A L T or A S T > 3 X U L N wit h t he a p peara nce of fat i g ue, na usea, v omit i n g, 
rig ht u p per q ua dra nt pai n or te n der ness, fe ver, ras h, a n d/ or e osi n o p hilia 
( > 5 %)

alkali ne p h os p hatase ( A L P) > 3 X U L N

A L P > 2. 5 X U L N a n d T B L > 2 X U L N

A L P > 2. 5 X U L N wit h t he a p peara nce of fati g ue, na usea, v o mit i n g, ri g ht 
q ua dra nt pai n or te n der ness, fe ver, ras h, a n d/ or e osi n o p hilia ( > 5 %)
I n a d diti on, patie nts will be disc o nt i n ue d fr om t he i n vesti gat i onal pr o d uct i n t he 
f oll owi n g circ u msta nces :

If a patie nt is i na d verte ntl y e nr olle d a n d it is deter mi ne d t hat c o nti n ue d treat me nt 
wi t h st u d y dr u g w o uld n ot be m e dicall y a p pr o priate, see Sectio n 8. 1. 3

Ac ute or c hr o nic p a ncreat itis 

If a patie nt is dia g n ose d wit h M T C after ra n d o mizati o n or has a p ostra n d o mizat i on 
calcit o ni n val ue ≥3 5 n g/ L t hat has i ncrease d at least 5 0 % o ver baseli ne

If a patie nt i s dia g n ose d wit h a n acti ve or u ntreate d mali g na nc y ( ot her t ha n basal or 
s q ua m o us cell s ki n ca ncer, i n sit u carci n o mas of t he cer vi x, or i n sit u pr ostate ca ncer) 
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
A n y si g nifica nt st u d y  dr u g-r elate d h y perse nsit i vity reacti o n

A n y o t her T E A E, S A E, or cli nicall y si g nifica nt la b orat or y val ue f or w hic h t he 
i n vesti gat or belie ves t hat per ma ne nt st u d y dr u g disc o nti n uati on is t he a p pr o priate 
meas ure t o be ta ke n

If fe male patie nt bec ome s pre g na nt

If a patie nt is dia g n ose d wit h T 1 D M
P ati e nts w h o st o p t he st u d y  dr u g per ma ne ntl y will recei ve a n ot her gl uc ose-l oweri n g i nter ve nti o n
a n d will c o nt i n ue partici pati n g i n t he trial acc or di n g t o t he pr ot oc ol t o c ollect all pla n ne d efficac y  
a n d safet y meas ure me nts.
T he ne w gl uc ose -l oweri n g i nter ve nt i on will be rec or de d o n t he e C R F 
s pecifie d f or c ollecti n g a nti h y per gl yce mic me dicati o ns.
P ati e nts di sc o nti n ui n g fr om t he i n vesti gati onal pr o d uct pre mat urel y f or a n y reas o n s h o ul d 
c o mplete a d verse e ve nt a n d ot her f oll ow- u p pr oce d ures per Secti o n 2 ( Sc he d ule of Acti vities),
Secti o n 9. 2 ( A d verse E ve nts), a n d Secti o n 9. 4 ( Safet y) of t his pr ot oc ol.
8. 1. 2.
T e m p or ar y Di s c o nti n u ati o n fr o m St u d y Tr e at m e nt
I n certai n sit uati ons after ra n d o mizat i on, t he i n vesti gat or ma y nee d t o te m p oraril y i nterr u pt st u d y  
dr u g (f or e xa m ple, A E) .  If st u d y dr u g i nterr u ptio n is d ue t o a n A E, t he e ve nt is t o be 
d oc u m e nte d a n d f o ll owe d acc or di n g t o t he pr oce d ures i n Secti o n 9. 2 of  t his pr ot oc ol.  E ver y  
eff ort s h o ul d be ma de b y t he i n vesti gat or t o mai ntai n patie nts o n st u d y dr u g a n d t o restart st u d y 
dr u g after a n y  t e mp orar y  int err u ptio n, as s o o n as i t is safe t o d o s o. 

If t he n u m ber of c o nsec ut i ve misse d d oses i s ≤2, t he treat me nt ca n be restarte d at t he 
sa me d ose, if t he dr u g was well t olerate d prior t o disc o nti n uat i on,

If t he n u m ber of c o nsec ut i ve misse d d oses is ≥3, t he n t he treat me nt s h o ul d be restarte d at 
5 m g or m atc he d place b o irres pecti ve of t he d ose t he patient  was recei vi n g bef ore t he 
i nterr u ptio n a n d s u bse q ue nt l y escalate d as re q uire d b y pr ot oc ol.

If t he a b o ve sit uati o ns occ ur a gai n d uri n g t he c o urse of t he st u d y, t he i n vest i gat or i n 
c o ns ultati o n wit h s p o ns or or desi g nee w ill disc uss t he ne xt treat me nt o pti o n.

T he i n vesti gat or will use t he I W R S t o recei ve t he a p pr o priate st u d y dr u g dis pe nsi n g 
i nf or mat i on t o preser ve bli n di n g o f t he st u d y dr u g
If t he st u d y dr u g i nterr u pti o n is d ue t o i nt olera ble persiste nt GI A E (f or e xa m ple, na usea, 
v o mit i n g, or diarr hea), t he patie nts s h o ul d be treate d as s u g geste d i n Sect i on 7. 8. 2. 5 .  
T he data relate d t o te m p orar y  int err u ptio n of  st u d y treat me nt will be d oc u me nte d i n s o urce 
d oc u m e nts a n d e ntere d o n t he e C R F.
8. 1. 3.
Di s c o nti n u ati o n of I n a d v ert e ntl y E nr oll e d P ati e nt s
If t he s p o ns or or i n vesti gat or i de ntifies a patie nt w h o di d n ot meet e nr oll me nt criteria a n d was 
i na d verte ntl y e nr olle d, t he n t he patie nt s h o ul d be disc o nti n ue d fr om st u d y treat me nt u nless t here 
are e xte n uat i n g circ u msta nces t hat ma ke it me dicall y necessar y f or t he patie nt t o c o nti n ue o n 


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


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


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


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


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Pr oce d ures a n d assess me nts perf or me d pri or t o Visit 3 are c o nsi dere d scree ni n g pr oce d ures .  T he 
res ults of t hese pr oce d ures a n d assess me nts s h o ul d be c o nsi dere d pree xist i n g c o n diti ons a n d 
s h o uld be re p orte d as m e dical hist or y or c o nc o mita nt ill ness.  
T he i n vest i gat or will i nter pret a n d d oc u me nt w het her or n ot a n A E has a reas o na ble p ossi bility 
of  bei n g relate d t o st u d y treat me nt, st u d y de vice, or a st u d y pr oce d ure, ta kin g i nt o acc o u nt t he 
di sease, c o nc o mita nt treat me nt, or pat h ol o gies.
A “reas o na ble p ossi bilit y” mea ns t hat t here is a ca use a n d effect relat i ons hi p bet wee n t he 
i n vesti gati onal pr o d uct, st u d y  de vice a n d/ or st u d y pr oce d ure, a n d t he A E.
T he i n vest i gat or a ns wers yes/ n o w he n ma ki n g t his assess me nt.
Pl a n ne d s ur geries a n d n o ns ur gical i nter ve nt i ons s h o ul d n ot be re p orte d as A Es u nless t he 
u n derl yi n g me dical c o n dit i on has w orse ne d d uri n g t he c o urse of t he st u d y .
If a patie nt ’s i n vesti gati o nal pr o d uct is disc o nti n ue d as a res ult of a n A E, st u d y site pers o n nel 
m ust re p ort t his t o Lill y or its desi g nee via a n e C R F, clarif yi n g, if p ossi ble, t he circ u msta nces 
lea di n g t o a n y d osa ge m o dificati o ns or disc o nt i n uati o ns of treat me nt.
9. 2. 1.
S eri o u s A d v er s e E v e nt s
A n S A E is a n y  AE f r o m t his st u d y t hat res ults i n o ne of t he f oll owi n g o utc o m es:

deat h

i nitial or pr ol o n ge d i n patie nt h os pitalizati on

a life-t hreate ni n g e x perie nce (t hat is, i m me diate ris k of d yi n g)

persiste nt or si g nifica nt disa bilit y/ i nca pacity

c o n ge nital a n o ma l y/ birt h defect

i m p orta nt me dical e ve nts t hat ma y n ot be i m me diatel y life-t hreate ni n g or res ult i n 
deat h or h os pitali zat i on b ut m a y je o par dize t he patie nt or ma y re q uire i nter ve nti on 
t o pre ve nt o ne of t he ot her o utc o mes liste d i n t he defi niti on a b o ve.   E xa m ples of 
s uc h me dical e ve nts i ncl u de aller gic br o nc h os pas m re q uiri n g i nte nsi ve treat me nt 
i n a n e mer ge nc y r o o m or at h o me, blo o d d y scrasias or c o n v ulsi o ns t hat d o n ot 
res ult i n i n patient  h os pitalizati on, or t he de vel o p me nt of dr u g de pe n de nc y  or dr u g 
a buse.
All A Es occ urri n g after si g ni n g t he I C F are rec or de d i n t he e C R F a n d assesse d f or seri o us 
criteria.  T he S A E re p orti n g t o t he s p o ns or be gi ns after t he pati e nt has si g ne d t he I C F a n d has 
recei ve d i n vesti gati onal pr o d uct.  H o we ver, if a n S A E occ urs afte r sig ni n g t he I C F, b ut pri or t o 
recei vi n g i n vesti gati onal pr o d uct, t he S A E s h o ul d be re p orte d t o t he s p o ns or as per S A E -
re p orti n g re q uire me nts a n d ti meli nes (see Secti on 9. 2 ) if it is c o nsi dere d reas o na bl y p ossi bl y 
r elate d t o st u d y pr oce d ure.
St u d y  site pers o n nel must al ert Lill y or its desig nee of  a n y S A E wit hi n 2 4 h o urs of i n vesti gat or 
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are t o be i m me diatel y f o ll ow e d wi t h official notificati o n o n st u d y -s pecific S A E f or ms.  T his 2 4-
h o ur n otificat i on re q uire me nt refers t o t he i nit ial S A E i nf or mati on a n d all f o ll ow- u p S A E 
i nf or mat i on. Patie nts wi t h a serio us he pat ic A E s h o uld ha ve a d di tio nal data c ollecte d usi n g t he 
e C R F.
Pre g na nc y ( d uri n g mat er nal or pater nal e x p os ure t o i n vest i gati onal pr o d uct) d oes n ot meet t he 
defi nit i on o f a n A E.  H o we ver, t o f ulfill re g ulat or y re q uire me nts , a n y pre g na nc y s h o ul d be 
re p orte d f oll owi n g t he S A E pr ocess t o c ollect data o n t he o utc o me f or b ot h m ot her a n d fet us.
I n vesti gat ors are n ot o bli gate d t o activ el y see k A Es or S A Es i n pat ient s o nce t he y  ha ve 
di sc o nti n ue d a n d/ or c o m plete d t he st u d y (t he pati e nt dis p osit i on C R F has bee n c o m plete d).  
H o we ver, if t he i n vest i gat or lear ns of a n y S A E, i ncl u di n g a deat h, at a n y ti me after a pati e nt has 
bee n disc har ge d fr o m t he st u d y  a n d he/s he c o nsiders t he e ve nt reas o na bl y p ossi bl y  relate d t o t he 
st u d y tr e at me nt or st u d y p artici pat i on, t he i n vest i gat or must pr o m ptl y n otif y Lill y .
9. 2. 1. 1.
S u s p e ct e d U n e x p e ct e d S eri o u s A d v er s e R e a cti o n s
S us pecte d u ne x pecte d seri o us a d verse react i ons ( S U S A Rs) are seri o us e ve nts t hat are n ot liste d 
i n t he I B a n d t hat t he i n vesti gat or i de ntifies as relate d t o i n vesti gati o nal pr o d uct or pr oce d ure.  
U nite d States 2 1 C F R 3 1 2. 3 2 a n d E ur o pea n U ni o n Cli nical Trial Direct i ve 2 0 0 1/ 2 0/ E C a n d t he 
ass ociate d detaile d g ui da nces or nati o nal re g ulat or y  re q uire me nts i n partici pat i n g c o u ntries 
re q uire t he re porti n g of S U S A Rs.  Lill y has pr oce d ures t hat will be f oll o we d f or t he 
i de ntificati on, rec or di n g, a n d e x pe dite d re p orti n g of S U S A Rs t hat are c o nsiste nt wit h gl o bal 
re g ulat i ons a n d t he ass ociate d detaile d g ui da nces.
9. 2. 2.
A d v er s e E v e nt of S p e ci al I nt er e st
9. 2. 2. 1.
H y p o gl y c e mi a
P ati e nts will c ollect i nf or mat i on o n e pi s o des of h y p o gl yce mia starti n g fr o m Visit 3 u nt il t he last 
st u d y visit ( F ollo w -u p Vi sit or E T Visit).  F or t hat p ur p ose, patie nts will be trai ne d a b o ut si g ns 
a n d s y m pt o ms of h y p o gl yce mia, h o w t o treat h yp o gl yce mia, a n d h o w t o c ollect a p pr o priate 
i nf or mat i on f or eac h e pis o de of h y p o gl yce mia i n t he st u d y acc or di n g t o t he Sc he d ule of 
Act i vities ( Secti on 2 ).  Site pers o n nel will e nter t his i nf or mati on i nto t he e C R F at eac h visit. 
I n vesti gat ors s h o ul d use t he f oll owi n g defi nit i ons a n d criteria w he n dia g n osi n g a n d cate g orizi n g 
a n e pis o de c o nsi dere d t o be relate d t o h yp o gl yce mia (t he pl as ma gl uc ose [P G ] val ues i n t his 
secti on refer t o val ues deter mi ne d b y a la b orat or y  or I nter natio nal  Fe derat i on of Cli nical 
C he mistr y  a n d La b orat or y Me dici ne plas ma-e q ui vale nt gluc ose m eters a n d stri ps) ( A D A 2 0 1 7, 
A D A 2 0 1 8 ):
Gl uc ose Alert V al ue ( Level 1):

D oc u me nte d s y m pt o m atic h y p o gl yce mi a is defi ne d as a n y ti me a patient  feels 
t hat he or s he is e x perie nci n g s y m pt o ms a n d/ or si g ns ass ociate d wit h 
h y p o gl yce mia, a n d has a P G le vel of ≤7 0 m g/ d L ( ≤3. 9 m m o l/ L).

D oc u me nte d as y m pt o m atic h y p o gl yce mi a is defi ne d as a n y e ve nt n ot 
acc o m pa nie d b y t y p ical s y m pt o ms of h y p o gl yce mia, b ut wit h a meas ure d P G 
≤7 0 m g/ d L (≤3. 9 m m o l/L) .


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
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1 2.
A p p e n di c e s


I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 7 1
L Y 3 2 9 8 1 7 6
A p p e n di x 1.
A b br e vi ati o n s a n d D efi niti o n s
T er m
D efi niti o n
A D A
a nti -dr u g a nti b o d y
A E
a d verse e ve nt :  A n y u nt o war d me dical occ urre nce i n a patie nt or cli nical i n vesti gati o n 
patie nt a d mi nistere d a p har mace utical pr o d uct t hat d oes n ot necessaril y ha ve a ca usal 
relati ons hi p wit h t his treat me nt.  A n a d verse e ve nt ca n t heref ore be a n y u nfa v ora ble a n d 
u ni nte n de d si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g), s y m pt o m, or disease 
te m p orall y ass ociate d wit h t he use of a me dici nal (i n vesti gati o nal) pr o d uct, w het her or 
n ot relate d t o t he me dici nal (i n vesti gati o nal) pr o d uct.
A L P
al kali ne p h os p hatase
A L T
ala ni ne a mi n otra nsferase
A N C O V A
a nal ysis of c o varia nce
A P P A D L
A bilit y t o Perf or m P h ysical Acti vities of Dail y Li vi n g
A S T
as partate a mi n otra nsferase
B G
bl o o d gl uc ose
bli n di n g/ m a s ki n g
A d o u ble -bli n d st u d y is o ne i n w hi c h neit her t he patie nt n or a n y of t he i n vesti gat or or 
s p o ns or staff w h o are i n v ol ve d i n t he treat me nt or cli nical e valuati o n of t he patie nts are 
a ware of t he treat me nt recei ve d.
B M I
b o d y mass i n de x
C E C
cli nical e n d p oi nt c o m mittee
C H F
c o n gesti ve heart fail ure
c o m pl ai nt
A c o m plai nt is a n y writte n, electr o nic, or oral c o m m u nicati o n t hat alle ges deficie ncies 
relate d t o t he i de ntit y, q ualit y, p urit y, d ura bilit y, relia bilit y, safet y or effecti ve ness, or 
perf or ma nce of a dr u g or dr u g deli ver y s yste m.
c o m pli a n c e
A d here nce t o all st u d y -relate d g o o d cli nical practice ( G C P) a n d a p plica ble re g ulat or y 
re q uire me nts.
C O VI D -1 9
C or o na vir us Disease 2 0 1 9
C R P
cli nical researc h p h ysicia n: I n di vi d ual res p o nsi ble f or t he me dical c o n d uct of t he st u d y.  
Res p o nsi bilities of t he C R P ma y be perf or me d b y a p h ysicia n, cli nical researc h 
scie ntist, gl o bal safet y p h ysicia n or ot her me dical officer.
C T
c o m p ute d t o m o gra p h y


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


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


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


I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 7 5
L Y 3 2 9 8 1 7 6
A p p e n di x 2.
Cli ni c al L a b or at or y  T e st s 
Cli nic al L a b or at or y Te stsa
He m at ol o g y
Cli nic al C he mistr y
He m o gl o bi n
Ser u m C o nce ntr ati o ns of
He mat ocrit
S o di u m
Er y t hr oc yte c o u nt (R B C )
Mea n cell v ol u me
P otassi u m
Bicar b o nate
Mea n cell he m o gl o bi n c o nce ntrati o n
T otal bilir u bi n
Le u k oc ytes ( W B C)
Direct bilir u bi n
Ne utr o p hils, se g me nte d
Al kali ne p h os p hatase
L y m p h oc y t es
Ala ni ne a mi n otra nsferase ( A L T)
M o n oc ytes
As partate a mi n otra nsferase ( A S T)
E osi n o p hils
Bl o o d urea nitr o ge n ( B U N)
Bas o p hils
Creati ni ne
Platelets
Ur ic aci d
Calci u m
Gl uc ose , fasti n gb
Uri n al ysis
Al b u mi n
Creati ni ne
Pre g n a nc y Test (fe males o nl y)c
F ollicle -sti m ulati n g h or m o ne ( F S H) d
Estra di ol c
H b A 1c
E n d ocri ne
e G F R (calc ulate d b y C K D-E PI e q uati o n) e
Fasti n g plas ma gl uca g o n
Fasti n g ser u m Ins uli n
Calcit o ni n
Fasti n g C- pe pti de
I m m u n o ge nicit y
Tirze pati de a nti-dr u g a nti b o d y
P K sa m ple f or i m m u n o ge nicit y
P a ncre as (e x ocri ne)
Ser u m pa ncreatic a m ylase
Ser u m li pase
N o n p h ar m ac o ge netic St ore d S a m ples
E D T A plas ma
Ser u m
P 8 0 0 plas ma
P h ar m ac o ge netic St ore d S a m ples
S a m ples f or P h ar m ac o ki netic A n a l ysis
Li pi d P a nel (f asti n g)
T otal c h olester ol
L D L
H D L
V L D L
Tri gl yceri d es
A b bre viati o ns :  C K D -E PI = C hr o nic Ki d ne y Disease -E pi de mi ol o g y; E D T A = et h yle ne dia mi netetraacetic aci d; 
e G F R = esti mate d gl o mer ular filtrati o n rate; H b A 1c = he m o gl o bi n A 1c; H D L = hi g h -de nsit y li p o pr otei n; 
L D L = l o w-de nsit y  li p o pr otei n; R B C = re d bl o o d cells; V L D L = ver y l o w -de nsit y  li p o pr otei n; W B C = w h ite 
bl o o d cells.


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


I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 7 7
L Y 3 2 9 8 1 7 6
A p p e n di x 3.
St u d y  G o v er n a n c e C o n si d er ati o n s


I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 7 8
L Y 3 2 9 8 1 7 6
A p p e n di x 3. 1 . R e g ul at or y a n d Et hi c al C o n si d er ati o n s, I n cl u di n g t h e 
I nf or m e d C o n s e nt Pr o c e s s
A p p e n di x 3. 1. 1 .
I nf or m e d C o n s e nt
T he i n vest i gat or is res p o nsi ble f or

e ns uri n g t hat t he pati e nt u n dersta n ds t he nat ure of t he st u d y, t he p ote ntial 
ris ks a n d be nefits of partici pat i n g i n t he st u d y, a n d t hat t heir partici pat i on is 
v o l unt ar y.

e ns uri n g t hat i nf or me d c o nse nt is gi ve n b y eac h pati e nt or le gal 
re prese ntati ve.  T his i ncl u des o btai ni n g t he a p pr o priate si g nat ures a n d dates 
o n t he i nf or me d c o nse nt f or m (I C F) pri or t o t he perf or ma nce o f a n y pr ot oc ol 
pr oce d ures a n d pri or t o t he a d mi nistrati o n of i n vesti gat i onal pr o d uct.

a ns weri n g a n y q uest i ons t he pati e nt  ma y ha ve t hr o u g h o ut t he st u d y  a n d 
s hari n g i n a ti mel y ma n ner a n y  ne w i nf or mat i on t hat m a y be rele va nt t o t he 
pati e nt ’s willi n g ness t o c o nti n ue his or her partici pati o n i n t he st u d y.

e ns uri n g t hat a c o p y of t he I C F is pr o vide d t o t he partici pa nt or t he 
part ici pa nt’s le gal re prese ntati ve a n d is ke pt o n file.

e ns uri n g t hat t he me dical rec or d i ncl u des a state me nt t hat writte n i nf or me d 
c o nse nt was o btai ne d bef ore t he partici pa nt was e nr olle d i n t he st u d y  a n d t he 
date t he writte n c o nse nt was o btai ne d. T he a ut h or ize d pers o n o btai ni n g t he 
i nf or me d c o nse nt must al s o sig n t he I C F.
A p p e n di x 3. 1. 2 .
R e cr uit m e nt
Lill y or i ts desig nee is res p o nsi ble f or t he ce ntral recr uitme nt  strate g y for pati e nts.  I n di vi d ual 
i n vesti gat ors ma y ha ve a d diti onal l ocal re q uire me nts or pr ocesses.
A p p e n di x 3. 1. 3.
Et hi c al R e vi e w
T he i n vest i gat or (or a n a p pr o pri ate lo c al  re prese ntati ve) m u st gi ve ass ura nce t hat t he et hical 
re vie w b oar d ( E R B) was pr o perl y c o nstit ute d a n d c o n ve ne d as re q uire d b y I nter nati onal C o u ncil
f or H ar mo nisat i on (I C H) g ui deli nes a n d ot her a p plica ble la ws a n d re g ulati o ns.
D oc u m e nt atio n of  E R B a p pr o val of t he pr ot oc ol a n d t he I C F m u st be pr o vi de d t o Lill y before t he 
st u d y ma y be gi n at t he i n vestigati ve si te(s).  Lill y or its re prese ntati ves m ust a p pr o ve t he I C F, 
i ncl u di n g a n y c ha n ges ma de b y t he E R Bs, bef ore it is use d at t he i n vesti gati ve site(s).  All I C Fs 
m ust be c o m plia nt wi t h t he I C H g uideli ne o n G o o d Cli nical Pract ice (G C P ).
T he st u d y  site’s E R B(s) s h o uld be pr o vi de d wi t h t h e fol l owi n g:

t he pr ot oc ol a n d relate d a me n d me nts a n d a d de n da , c urre nt I n vesti gat or 
Br oc h ure ( I B), a n d u p dates d uri n g t he c o urse of t he st u d y

i nf or me d c o nse nt f or m 

ot her rele va nt d oc u m e nts ( f or e xa m ple, c urric ula vit a e, a d vertise me nts)


I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 7 9
L Y 3 2 9 8 1 7 6
A p p e n di x 3. 1. 4.
R e g ul at or y C o n si d er ati o n s
T his st u d y  will be c o n d ucte d i n acc or da nce with t he pr ot oc ol a n d wit h t he

c o nse ns us et hics pri nci ples deri ve d fr o m i nter nat i onal et hics g ui deli nes, i ncl u di n g 
t he Declarat i on of Helsi n ki a n d C o u ncil f or I nter nati o nal Or ga nizati o ns of
Me dical
Scie nces (CI O M S ) I nter natio nal Et hi cal G uideli nes

a p plica ble I C H G C P g ui deli nes

a p plica ble la ws a n d re g ulati o ns
S o m e of t he o bli gati ons of  t he s p o ns or will be assi g ne d t o a t hir d part y .
A p p e n di x 3. 1 . 5.
I n v e sti g at or I nf or m ati o n
P h ysicia ns wit h a s pecialt y i n dia betes/e n d ocri n ol o g y , i nter nal me dici ne, fa mil y me dici ne, 
ge neral me dici ne , or a n y  ot her s pecialt y p h ysicia n w h o have e x perie nce tre at i n g T 2 D M a n d 
cli nical researc h i n T 2 D M will partici pate as i n vesti gat ors i n t his cli nical st u d y.
A p p e n di x 3. 1. 6.
Pr ot o c ol Si g n at ur e s
T he s p o ns or’s res p o nsi ble me dical o fficer will a p pr o ve t he pr ot oc ol, c o nfir mi n g t hat, t o t he best 
of  his or her k n o wle d ge, t he pr ot oc ol acc uratel y descri bes t he pla n ne d desi g n a n d c o n d uct of t he 
st u d y.
After rea di n g t he pr ot oc ol, eac h pri nci pal i n vest i gat or will si g n t he pr ot oc ol si g nat ure pa ge a n d 
se n d a c o p y of t he si g ne d pa ge t o a Lill y re prese ntati ve.
A p p e n di x 3 . 1.7.
Fi n al R e p ort Si g n at ur e
T he C li nical S t u d y Re p ort ( C S R) c o or di nat i n g i n vesti gat or will si g n t he fi nal C S R f or t his st u d y, 
i n dicati n g a gree me nt t hat, t o t he best of his or her k n o wle d ge, t he re p ort acc uratel y descri bes t he 
c o n d uct a n d res ults of t he st u d y.
A q ualifie d i n vest i gat or will ser ve as t he C S R c o or di nati n g i n vesti gat or.  If t his i n vesti gat or is 
u na ble t o f ulfill t his f u nct i on, a n ot her i n vest i gat or will be c h ose n b y Lill y t o ser ve as t he C S R 
c o or di nat i n g i n vesti gat or.
T he s p o ns or’s res p o nsi ble me dical o fficer a n d statisticia n will  a p pr o ve t he fi nal C S R f or t his 
st u d y, c o nfir mi n g t hat, t o t he best of his or her k n o wle d ge, t he re p ort acc uratel y descri bes t he 
c o n d uct a n d res ults of t he st u d y.
A p p e n di x 3. 2.
D at a Q u alit y A s s ur a n c e
T o e ns ure acc urate, c o m plete, a n d relia ble data, Lill y or its re prese ntati ves will d o t he f o ll owi n g:

pr o vi de i nstr ucti o nal materi al t o t he st u d y sites, as a p pr o priate

pr o vi de s p o ns or start-u p trai ni n g t o i nstr uct t he i n vesti gat ors a n d st u d y 
c o or di nat ors.  T his trai ni n g will gi ve i nstr ucti o n o n t he pr ot oc ol, t he c o m pleti on 
of  t he C R Fs, a n d st u d y pr oce d ures.


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


I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 8 1
L Y 3 2 9 8 1 7 6
St u d y  sit e p artici pat i on ma y be disc o nt i n ue d if Lill y  or its desig nee , the i n vesti gat or, or t he E R B 
of  t he st u d y sit e j u d ges it necessar y f or me dical, safety,  re g ulat or y, or ot her reas o ns c o nsiste nt 
wi t h a p plica ble la ws, re g ulat i ons, a n d G C P.
A p p e n di x 3. 3. 2.
Di s c o nti n u ati o n of t h e St u d y
T he st u d y  will b e disc o nti n ue d if Lill y or i ts desig nee j u d ges it necessar y for m e dical, safet y,  
re g ulat or y, or ot her reas o ns c o nsiste nt wit h a p plica ble la ws, re g ulati ons, a n d G C P.
A p p e n di x 3. 4.
P u bli c ati o n P oli c y
T h e p u blicat i on p o lic y f or St u d y I 8 R-M C -G P G K is descri be d i n t he Cli nical Trial A gree me nt.


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


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


I 8 F-M C -G P G K( b) Cli ni c al Pr ot o c ol
P a g e 8 4
L Y 3 2 9 8 1 7 6
A p p e n di x 6.
Cl a s sifi c ati o n of C o ntr a c e pti v e 
M et h o d s
Hi g hl y Effecti ve Met h o ds of C o ntr ace pti o n:

C o m bi ne d oral c o ntrace pti ve pill a n d mi ni pill

N u va Ri n g

I mpla nta ble c o ntrace pti ves

I njecta ble c o ntrace pti ves (s uc h as De p o-Pr o vera ® )

I ntra uteri ne de vice (s uc h as Mire na® a n d Para Gar d ® )

C o ntrace pti ve patc h – O N L Y w o me n < 1 9 8 p o u n ds or 9 0 k g

T ot al  a bsti ne nce (if t his is t heir preferre d a n d us ual lifest yle) or i n a sa me-se x relat i ons hi p 
wi t h n o se x ual r el atio ns hi p wi t h males (as part of t heir preferre d a n d us ual lifest yle).  
N ote:  peri o dic a bst i ne nce (f or e xa m ple, c ale n dar, o v ul at i on, s y m pt ot her mal, 
p ost o v ulat i on met h o ds), declarat i on of a bst i ne nce j ust f or t he d urati o n of a trial, a n d 
wi t hdra wal  are n ot acce pta ble met h o ds of c o ntrace pti o n

Vasect o m y  – f or me n i n cli nical st u dies
Effecti ve Met h o ds of C o ntr ace pti o n ( m ust use c o m bi n ati o n of 2 met h o ds):

Male c o n d o m wit h s per mici de

Fe male c o n d o m wi t h s per mici de

Di a p hra g m wit h s per mici de

Cer vical s p o n ge

Cer vical ca p wit h s per mici de
Me n, re gar dless of t heir fertilit y stat us, wit h n o n pre g na nt w o me n of c hil d beari n g p ote ntial 
part ners m ust a gree t o eit her re mai n a bsti ne nt (if t his is t heir preferre d a n d us ual lifest yle) or use 
c o n d o ms pl us 1 a d ditio nal hi g hl y  effecti ve (less t ha n 1 % failure rate) m et h o d of c o ntrace pti o n 
(s uc h as c om bi nat i on oral  c o ntrace pti ves, i m pla nte d c o ntrace pti ves, or i ntra uteri ne de vice) or 
effect i ve met h o d of c o ntrace pti o n (s uc h as dia p hra g ms wit h s per mici de or cer vical s p o n ge) f or 
t he d urati o n of t he st u d y a n d f or at least 3 mo nt hs after t he l ast i njecti o n.
Me n wi t h pre g na nt part ners s h o ul d use c o n d o ms d uri n g i nterc o urse f or t he d urati o n of t he st u d y 
a n d u ntil t he e n d of est i mate d rele va nt p ote ntial e x p os ure i n w o me n of c hil d beari n g p ote ntial. 
Me n w h o are i n e xcl u si vel y sa me se x relati ons hi ps (as t heir preferre d a n d us ual lifest yle) are n ot 
re q uire d t o use c o ntrace pti o n. 


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


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


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


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


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


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

SAP_001.pdf: 
Statistical A nal ysis Pla n I 8 F- M C- G P G K( b)
A Ra n d o mize d, D o u ble- bli n d, Place b o- C o ntr olle d Trial C o m pari n g t he Efficac y a n d Safet y of T hree 
Tirze pati de D oses Vers us Place b o i n Patie nts Wit h T y pe 2 Dia betes, I na de q uatel y C o ntr olle d Wit h Diet a n d 
E xercise Al o ne
N C T 0 3 9 5 4 8 3 4  
A p pr o val Date: 2 0- N o v- 2 0 2 0


I 8 F-M C -G P G K St ati sti c al A n al y si s Pl a n V er si o n 3
P a g e 1
L Y 3 2 9 8 1 7 6
1.
St ati sti c al A n al y si s Pl a n I 8 F-M C -G P G K : A R a n d o mi z e d, 
D o u bl e -bli n d, Pl a c e b o -C o ntr oll e d Tri al C o m p ari n g t h e 
Effi c a c y  a n d S af et y of T hr e e Tir z e p ati d e D o s e s v er s u s 
Pl a c e b o i n P ati e nt s wit h T y p e 2 Di a b et e s I n a d e q u at el y 
C o ntr oll e d wit h Di et a n d E x er ci s e A l o n e ( S U R P AS S -1 )
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt i s c o nfi d e nti al a n d t h e i nf or m ati o n c o nt ai n e d 
wit hi n it 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 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.
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 f or T y p e 2 Di a b et e s M ellit u s
P h a s e 3 , r a n d o mi z e d, d o u bl e-bli n d, pl a c e b o -c o ntr oll e d tri al c o m p ari n g 3 d o s e s of 
tir z e p ati d e t o p l ac e b o i n p ati e nt s wit h T y p e 2 d i a b et e s.
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 I 8 F-M C -G P G K
P h a s e 3
St ati sti c al A n al y si s Pl a n 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 1 J u n e 2 0 1 9
St ati sti c al A n al y si s Pl a n V er si o n 2 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 2 N o v e m b er 2 0 2 0 .
St ati sti c al A n al y si s Pl a n V er si o n 3 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 
d at e pr o vi d e d b el o w.
A p pr o v al D at e: 2 0- N o v- 2 0 2 0 G M T


I 8 F-M C -G P G K St ati sti c al A n al y si s Pl a n V er si o n 3
P a g e 2
L Y 3 2 9 8 1 7 6
2.
T a bl e of C o nt e nt s
S e cti o n
P a g e
1.
Stati stical A nal ysis Pla n I 8 F -M C -G P G K: A Ra n d o mize d, D o u ble -
bli n d, Place b o -C o ntr olle d Trial C o m par i n g t he Efficac y a n d Safety 
of  T hree Tirze pati de D oses vers us Place b o i n Patie nts wit h T y pe 2 
Di a betes I na de q uatel y C o ntr olle d wit h Diet a n d E xercise Al one 
( S U R P A S S-1) .....................................................................................................................1
2.
Ta ble of C o nte nts ................................................................................................................2
3.
Re visi o n Hist or y .................................................................................................................8
4.
St u d y  O bjecti ves.................................................................................................................9
4. 1.
Pri ma r y O bjecti ves.........................................................................................................9
4. 2.
Ke y Sec o n dar y  O bjecti ves S u bject t o Str o n g T ype 1 Err or Rate 
C o ntr ol ...........................................................................................................................9
4. 3.
Ot her Sec o n dar y  a n d E x plor at or y  Efficac y O bjecti ves N ot S u bject 
t o T ype 1 Err or Rate C o n tr ol..........................................................................................9
4. 4.
S af et y O bjecti ves .........................................................................................................1 0
4. 5.
P har mac o ki net ics .........................................................................................................1 0
5.
St u d y  Desi g n.....................................................................................................................1 1
5. 1.
S u m mar y  of St u d y Desi g n............................................................................................1 1
5. 2.
Met h o d of Assi g n me nt t o Treat me nt
............................................................................1 2
6.
A Pri ori  St atistical Met h o ds ..............................................................................................1 3
6. 1.
P o p ul at i ons f or A nal yses..............................................................................................1 3
6. 2.
Ge neral C o nsi derati o ns ................................................................................................1 3
6. 3.
A d j ustme nt s for C o vari ates ..........................................................................................1 4
6. 4.
Ha n dli n g of Dr o p o uts or Missi n g Data .........................................................................1 4
6. 5.
M ul tice nter St u dies ......................................................................................................1 5
6. 6.
M ul tipl e C o m paris o ns/ M ult i plicity A d j ustme nt s ..........................................................1 5
6. 7.
P ati e nt Dis p ositio n .......................................................................................................1 5
6. 8.
P ati e nt C haracteristics..................................................................................................1 5
6. 9.
C o nc o mita nt T hera p y ...................................................................................................1 5
6. 1 0.
Tr eat me nt E x p os ure a n d C o m plia nce ...........................................................................1 6
6. 1 0. 1.
E x p os ure a n d C o m plia nce t o Tirze pat i de .............................................................1 6
6. 1 1.
I mp orta nt Pr ot oc ol De viat i ons ......................................................................................1 6
6. 1 2.
Efficac y A nal ysis .........................................................................................................1 6
6. 1 2. 1.
Pri mar y Efficac y  A nal ysis....................................................................................1 7
6. 1 2. 1. 1.
Pri mar y A nal ysis Relati ve t o t he Efficac y Est i ma n d .......................................1 7
6. 1 2. 1. 2.
A nal ysis Relat i ve t o t he Treat me nt-Re gi me n Esti ma n d ...................................1 7


I 8 F-M C -G P G K St ati sti c al A n al y si s Pl a n V er si o n 3
P a g e 3
L Y 3 2 9 8 1 7 6
6. 1 2. 1. 3.
Met h o ds f or M ulti ple I mp ut ati o ns ..................................................................1 8
6. 1 2. 2.
Sec o n dar y  Efficac y A nal yses S u bject t o T ype 1 Err or Rate 
C o ntr ol .................................................................................................................1 8
6. 1 2. 2. 1.
Mea n C ha n ge i n B o d y  Wei g ht a n d Fasti n g Ser u m 
Gl uc ose Fr o m  Baseli ne at t he 4 0-Wee k Visit ..................................................1 8
6. 1 2. 2. 2.
Pr o p orti o n of  P atie nts Ac hie vi n g H b A 1c < 7 % a n d < 5. 7 % 
at t he 4 0 Wee k Visit .......................................................................................1 8
6. 1 2. 3.
T y pe 1 Err or Rate C o nt r ol Strate g y for Pri mar y  a n d Ke y 
Sec o n dar y  Efficac y A nal ysis................................................................................1 9
6. 1 2. 4.
Ot her Sec o n dar y  a n d E x plor at or y  Efficac y A nal yses............................................2 1
6. 1 3.
S af et y A nal ysis ............................................................................................................2 2
6. 1 3. 1.
A d ve rse E ve nts ....................................................................................................2 3
6. 1 3. 1. 1.
Deat hs ............................................................................................................2 4
6. 1 3. 1. 2.
Ot her Seri o us A d verse E ve nts ........................................................................2 4
6. 1 3. 1. 3.
Di sc o nti n uatio n Fr o m  St u d y D ue t o A d verse E ve nt........................................2 4
6. 1 3. 1. 4.
Di sc o nti n uatio n Fr o m  St u d y Dr u g D ue t o A d verse E ve nt ...............................2 5
6. 1 3. 1. 5.
Treat me nt of O ver d ose ...................................................................................2 5
6. 1 3. 2.
S peci al Safet y T o pi cs ...........................................................................................2 5
6. 1 3 . 2. 1.
H y p o gl yce mic E ve nts .....................................................................................2 5
6. 1 3. 2. 2.
Se vere Persiste nt H y per gl yce mia ....................................................................2 6
6. 1 3. 2. 3.
Pa ncreat itis.....................................................................................................2 6
6. 1 3. 2. 3. 1 .
Pa ncreat ic E nz y me Assess me nt ................................................................2 6
6. 1 3. 2. 4.
T h y r oid Mali g na ncies a n d C -Cell H y per plasia ................................................2 6
6. 1 3. 2. 5.
Mali g na nc y .....................................................................................................2 6
6. 1 3. 2. 6.
Ca lcit o ni n.......................................................................................................2 7
6. 1 3. 2. 7.
Maj or A d verse Car di o vasc ular E ve nts ............................................................2 7
6. 1 3. 2. 8.
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 ........................................................................................................2 7
6. 1 3. 2. 9.
H y perse nsi tivi t y E ve nts..................................................................................2 7
6. 1 3. 2. 1 0.
I njecti on Si te Reactio ns ..................................................................................2 8
6. 1 3. 2. 1 1.
Di a bet ic Reti n o pat h y C o mplicat i ons ...............................................................2 8
6. 1 3. 2. 1 2.
He pat o biliar y  S af et y.......................................................................................2 8
6. 1 3. 2. 1 2. 1.
He pat o biliar y  Dis or ders............................................................................2 8
6. 1 3. 2. 1 2. 2.
Ac ute Gall bla d der Disease ........................................................................2 8
6. 1 3. 2. 1 2. 3.
Li ver E nz y mes ..........................................................................................2 8
6. 1 3. 2. 1 3.
Gastr oi ntesti nal Safet y ....................................................................................2 9
6. 1 3. 2. 1 4.
Ac ute Re nal E ve nts ........................................................................................2 9
6. 1 3. 2. 1 5.
De h y drat i on ....................................................................................................2 9
6. 1 3. 2. 1 6.
Meta b o lic Aci d osis, i ncl u di n g Dia bet ic Ket oaci d osis......................................3 0


I 8 F-M C -G P G K St ati sti c al A n al y si s Pl a n V er si o n 3
P a g e 4
L Y 3 2 9 8 1 7 6
6. 1 3. 2. 1 7.
A m p utati o n/ Peri p heral Re vasc ularizat i on .......................................................3 0
6. 1 3. 2. 1 8.
Maj or De pressi ve Dis or der/ S uici dal I deat i on ..................................................3 0
6. 1 3. 3.
Vi t al Sig ns ...........................................................................................................3 0
6. 1 3. 4.
Electr ocar di o gra ms ..............................................................................................3 1
6. 1 3. 5.
Cli nical La b orat or y  E val uati on .............................................................................3 1
6. 1 3. 6.
I mm u n o ge nicit y ...................................................................................................3 2
6. 1 4.
Heal t h O ut c o mes ..........................................................................................................3 2
6. 1 4. 1.
E Q -5 D -5 L ............................................................................................................3 2
6. 1 4. 2.
I mpact of Wei g ht o n Self -Perce pt i ons Q uest i on naire ............................................3 3
6. 1 4. 3.
A bilit y t o Perf or m P h ysical Acti vities of Dail y Li vi n g .........................................3 3
6. 1 5.
S u b gr o u p A nal yses .......................................................................................................3 3
6. 1 5. 1.
S u b gr o u p A nal ysis o f H b A 1c C ha n ge at 4 0 Wee ks ..............................................3 3
6. 1 5. 2.
S u b gr o u p A nal ysis o f Wei g ht C ha n ge at 4 0 Wee ks ..............................................3 3
6. 1 6.
I nteri m A nal yses a n d Data M o nit ori n g C o m mittee.......................................................3 4
6. 1 7.
C O VI D -1 9 I m pact Assess me nt ....................................................................................3 4
6. 1 7. 1.
P ati e nts I mpacte d b y  C O VI D-1 9 ..........................................................................3 4
6. 1 7. 2.
A d verse E ve nts ....................................................................................................3 4
6. 1 7. 3.
P ati e nt Dis p ositio n ...............................................................................................3 4
6. 1 7. 4 .
St u d y  Visits..........................................................................................................3 4
6. 1 7. 5.
Mi tigat i on S u m mar y ............................................................................................3 4
6. 1 7. 6.
Meas ures Relate d t o Pri mar y  a n d Ke y Sec o n dar y O bjecti ves ...............................3 4
7.
U n bli n di n g Pla n ................................................................................................................3 5
8.
Refere nces ........................................................................................................................3 6
9.
A p pe n dices .......................................................................................................................3 7


I 8 F-M C -G P G K St ati sti c al A n al y si s Pl a n V er si o n 3
P a g e 5
L Y 3 2 9 8 1 7 6
T a bl e of C o nt e nt s
T a bl e
P a g e
Ta ble G P G K. 6. 1.
A nal ysis P o p ulat i ons/ Data Sets ...............................................................1 3
Ta ble G P G K. 6. 2.
Sec o n dar y  a n d E x plor at or y  Efficac y A nal yses n ot 
C o ntr olle d f or T y pe I Err or .....................................................................2 1
Ta ble G P G K. 6. 3.
Defi nit i ons of H y p o gl yce mic E ve nt Cate g ories ......................................2 5
Ta ble G P G K. 6. 4.
Cate g orical Criteria f or A b n or mal Bl o o d Press ure 
a n d P ulse Meas ure me nts .........................................................................3 0
Ta ble G P G K. 6. 5.
S el ecte d Cate g orical Li mits for E C G Data ..............................................3 1


I 8 F-M C -G P G K St ati sti c al A n al y si s Pl a n V er si o n 3
P a g e 6
L Y 3 2 9 8 1 7 6
T a bl e of C o nt e nt s
Fi g ur e
P a g e
Fi g ure G P G K. 5 . 1.
Ill ustratio n of  st u d y desi g n f or Cli nical Pr ot oc ol 
I 8 F-M C -G P G K. ......................................................................................1 1
Fi g ure G P G K. 6. 1.
T y pe 1 err or c o n tr ol strate g y for pri mar y  a n d k e y  
sec o n dar y efficac y e n d p oi nts..................................................................2 0


I 8 F-M C -G P G K St ati sti c al A n al y si s Pl a n V er si o n 3
P a g e 7
L Y 3 2 9 8 1 7 6
T a bl e of C o nt e nt s
A p p e n di x
P a g e
A p pe n di x 1 .
Stati stical A nal ysis f or Ja pa n ..................................................................3 8
A p pe n di x 2.
Searc hi n g Criteria f or A d verse E ve nts of S pecial 
I nterest ( A E SI) .......................................................................................3 9


I8F-MC-GPGK Statistical Analysis Plan Version 3
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LY3298176
3.
Revision History
Statistical Analysis Plan (SAP) Version 1 was approved prior to the first patient receiving study 
drug.
The second version was approved before the final database lock. The following represent major 
changes made for the second version:
1. Update definition of analysis set. Per agreement with the US FDA, exclude patients 
discontinuing study drug due to inadvertent enrollment from efficacy analyses.
2. Update baseline definition for selected measures to minimize missing values at baseline. 
3. Update the language to handle lack of convergence in longitudinal logistic regression 
analysis due to low number of events for hemoglobin A1c (HbA1c) and weight loss 
target analyses.
4. Remove subgroup analyses for adverse events due to low incidence.
5. Add section to assess SARS-CoV-2 (COVID-19) impact.    
The third version is approved before the final database lock. The following represents changes 
made for the Version 3:
1. Modified the definition of “retrieved dropout.”
2. Clarified conditions under which the placebo guided imputation method will be used in 
lieu of the “retrieved dropout” method.


I 8 F-M C -G P G K St ati sti c al A n al y si s Pl a n V er si o n 3
P a g e 9
L Y 3 2 9 8 1 7 6
4.
St u d y  O bj e cti v e s
4. 1.
Pri m ar y  O bj e cti v es
Pri mar y o bject i ves of t he st u d y are t o de m o nstrate t hat tirze pati de o nce wee kl y ( Q W ) 5 m g , 
a n d/ or 1 0 m g, a n d / or 1 5 m g are s u perior t o pl ace b o i n he m o gl o bi n A 1c ( H b A 1c ) c ha n ge fr o m 
baseli ne t o 4 0 wee ks .
4. 2.
K e y S e c o n d ar y O bj e cti v e s S u bj e ct t o S tr o n g T y p e 1 E rr or R at e 
C o ntr ol
T o get her wit h t he pri mar y o bject i ves, t he f oll o wi n g sec o n dar y o bjecti ves are s u bjecte d t o str o n g 
c o ntr ol of t ype 1 err or rate (see Secti o n 6. 1 2. 3 ). 

T o de m o nstrate s u peri orit y of Q W t irze pat i de 5 m g a n d/ or 1 0 m g, a n d/ or 1 5 m g t o 
pl ace b o f or c ha n ge fr om baseli ne i n b o d y  wei g ht at 4 0 wee ks .

T o de m o nstrate s u peri ori t y of Q W tirze pat i de 5 m g a n d/ or 1 0 m g, a n d/ or 1 5 m g t o 
pl ace b o f or t he 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 o l/ m ol) at 4 0 wee ks.

T o de m o nstrate s u peri ori t y of Q W tirze pat i de 5 m g a n d/ or 1 0 m g, a n d/ or 1 5 m g t o 
pl ace b o f or c ha n ge fr o m baseli ne i n fast i n g ser u m gl uc ose (ce ntral la b orat or y) at 
4 0 wee ks.

T o de m o nstrate s u peri ori t y of Q W tirze pat i de 5 m g a n d/ or 1 0 m g, a n d/ or 1 5 m g t o 
pl ace b o f or t he pr o p orti o n of patie nts wit h H b A 1c tar get val ues of < 5. 7 % 
( 3 9 m m o l/ m ol) at 4 0 wee ks.
4. 3.
Ot h er S e c o n d ar y a n d E x pl or at or y Effi c a c y O bj e cti v e s N ot 
S u bj e ct t o T y p e 1 E rr or R at e C o ntr ol
T he f o ll owi n g o bj ect i ves are sec o n dar y a n d n ot s u bjecte d t o str o n g c o ntr ol of t y pe 1 err or rate.
T o c o m pare Q W  tirze pati de 5 m g, 1 0 m g, a n d 1 5 m g t o place b o at 4 0 wee ks f or:

t he pr o p ortio n of  p atie 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 o l)

mea n c ha n ge i n dail y a vera ge 7 -p oi nt self -m o nit ore d bl o o d gl uc ose ( S M B G) pr ofiles 
fr om baseli ne

pr o p orti o n of  patient s 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
T he f o ll owi n g are e x pl orat or y  o bjecti ves.
T o c o m pare Q W  tirze pati de 5 m g, 1 0 m g, a n d 1 5 m g t o place b o at 4 0 wee ks f or:

cha n ge i n fast i n g gl uca g o n, C-pe pti de, a n d i ns uli n le vel

m ea n c ha n ge i n li pi ds (t otal c h o lester ol, hi g h -de nsit y  li p o pr otei n [H D L ], l ow -de nsit y 
li p o pr otei n [L D L ], ver y -l ow -de nsit y li p o pr otein [V L D L ], a n d trigl yceri des [T G ])


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
mean change in waist circumference

changes from baseline in mean body mass index (BMI)

biomarkers

patient-reported outcomes
o
ability to perform physical activities of daily living (APPADL)
o
5-level EQ-5D version (EQ-5D-5L) scores
o
impact of weight on self-perception (IW-SP)
4.4.
Safety Objectives
To compare the safety of tirzepatide 5 mg, 10 mg, and 15 mg to placebo for:

treatment-emergent adverse events (TEAEs)

early discontinuations of study drug due to adverse events (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 

time to initiation of rescue therapy for severe persistent hyperglycemia
4.5.
Pharmacokinetics
To characterize the pharmacokinetics (PK) of tirzepatide 5 mg, 10 mg, and 15 mg doses and 
evaluate the relationships between tirzepatide exposure and safety, tolerability, and efficacy 
measures for population PK and PD parameters.


I 8 F-M C -G P G K St ati sti c al A n al y si s Pl a n V er si o n 3
P a g e 1 1
L Y 3 2 9 8 1 7 6
5.
St u d y  D e si g n
5. 1.
S u m m ar y of St u d y D e si g n
St u d y  G P G K is a P hase 3, d o u ble bli n d, place b o c o ntr olle d , mul tice nter, parallel-ar m, 
ra n d omize d st u d y t o c o m pare t he safet y a n d efficac y of 3 d oses of tirze pati de wi t h place b o i n 
pati e nts wit h t ype 2 dia betes m ellit us ( T 2 D M ) nai ve t o dia betes i njecta ble t hera p y, i na de q uatel y 
c o ntr olle d wit h diet a n d e xercise al o ne, a n d ha ve n ot bee n treate d wit h a n y oral a nt i dia betic 
me dicat i on d uri n g t he 3 m o nt hs prece di n g t o t he start of t he st u d y . T he pri mar y  e n d p oi nt will be 
t he mea n c ha n ge i n H b A 1c fr o m baseli ne t o 4 0 wee ks. 
Fi g ure G P G K .5 .1 ill ustrates t he st u d y desi g n.
A b bre viati o n: Q W = o nce -wee kl y.
Fi g ur e G P G K .5 .1 .
Ill u str ati o n of st u d y d e si g n f or Cli ni c al Pr ot o c ol I 8 F-M C -G P G K .
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 [ Wee k -3 ])
T he p ur p ose of scree ni n g pr oce d ures at Visit 1 is t o esta blis h i nit ial eli gi bility a n d t o o btai n 
bl o o d sa m ples f or l a b orat or y assess me nts nee de d t o c o nfir m eli gi bility at Visit 2. T he patie nt 
will si g n t he i nf or me d c o nse nt f or m (I C F) bef ore a n y st u d y pr oce d ures are perf or me d.


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Lead-in (Visit 2 [Week -2] to Visit 3 [Week 0])
At Visit 2, the screening laboratory results will be reviewed and patient eligibility will be 
established with the exception of retinopathy status. A dilated fundoscopic exam will be 
performed between Visit 2 and Visit 3 as results are required to confirm eligibility.
Study Period II (40-week treatment period)
Randomization (Visit 3 [Week 0])
At Visit 3, patients will perform all required baseline study procedures (including the collection 
of all baseline laboratory measures) prior to randomization and prior to taking the first dose of 
study drug.
Postrandomization period (end of Visit 3 [Week 0] to Visit 14 [Week 40]):
The starting dose of tirzepatide will be 2.5 mg QW for 4 weeks, followed by an increase to 5 mg 
QW, for the duration of the study low-dose arm. For the 10-mg arm, the starting dose of 
tirzepatide will be 2.5 mg QW for 4 weeks, then the dose will be increased by 2.5 mg every 
4 weeks (2.5 to 5 to 7.5 to 10 mg) until the 10-mg dose is reached and maintained for the 
duration of the study. For the 15-mg arm, the starting dose of tirzepatide will be 2.5 mg QW for 
4 weeks, then the dose will be increased by 2.5 mg every 4 weeks (2.5 to 5 to 7.5 to 10 to 12.5 to 
15 mg) until the 15-mg dose is reached and maintained for the duration of the study.
Study Period III (safety follow-up period)
Safety follow-up (Visit 801 [4 weeks post end of treatment]) visits:
All patients who complete the treatment period are required to complete Visit 801, a safety 
follow-up visit approximately 4 weeks after their last visit. Patients discontinuing the study early 
and performing an early termination (ET) visit will also be asked to perform the safety follow-up 
visit, so that the safety follow-up visit will be their final visit. During the safety follow-up period, 
patients will not receive study drug. Initiation of new antihyperglycemic therapy for the safety 
follow-up period will not be classified as “rescue therapy.”
5.2.
Method of Assignment to Treatment
Around 472 patients who meet all criteria for enrollment will be randomized to 1 of the study 
treatment arms at Visit 3. Assignment to treatment arms will be determined by a computer-
generated random sequence using an interactive web-response system (IWRS). Patients will be 
randomized in a 1:1:1:1 ratio to receive 5 mg tirzepatide, 10 mg tirzepatide, 15 mg tirzepatide, or 
placebo. The randomization will be stratified by country, baseline HbA1c concentration (≤8.5%, 
>8.5% [≤69, >69 mmol/mol]), and past prior use of oral antidiabetic medication (OAM) (Yes or 
No).


I 8 F-M C -G P G K St ati sti c al A n al y si s Pl a n V er si o n 3
P a g e 1 3
L Y 3 2 9 8 1 7 6
6.
A Pri ori St ati sti c al M et h o d s
6. 1.
P o p ul ati o n s f or A n al y s e s
F or p ur p oses of a nal ysis, Ta ble G P G K .6 .1 d efi nes t he f o ll owi n g a nal ysis sets:
T a bl e G P G K .6 .1 .
A n al y s i s P o p ul ati o n s/ D at a S et s
P o p ul ati o n / D at a Set
Descri pti o n
Scree ne d p o p ulati o n 
All partici pa nts w h o si g n i nf or me d c o nse nt
Ra n d o mize d p o p ulati o n
All patie nts w h o are ra n d o ml y assi g ne d a treat me nt ar m
M o difie d i nte nt -t o-treat 
( mI T T) p o p ulati o n
All ra n d o ml y assi g ne d partici pa nts w h o t o o k at least 1 d ose of st u d y dr u g . I n t he e ve nt 
of a treat me nt err or, partici pa nts will be a nal yze d acc or di n g t o t he treat me nt t he y were 
ra n d o mize d.
Efficac y a nal ysis set 
( E A S)
Data o btai ne d d uri n g St u d y Peri o d II fr o m mI T T, e xcl u di n g patie nts disc o nti n ui n g 
st u d y dr u g d ue t o i na d verte nt e nr oll me nt a n d data after i nitiati n g resc ue 
a nti h yp er gl y ce mic me dicati o n or pr e mat urel y st o p pi n g st u d y dr u g (last d ose date + 7 
da y s).
F ull a nal ysis set ( F A S) 
All a vaila ble d ata o btai ne d d uri n g St u d y Peri o d II fr o m mI T T, e xcl u di n g patie nts 
disc o nti n ui n g st u d y dr u g d ue t o i na d verte nt e nr oll m e nt, re gar dless of a d here nce t o st u d y 
dr u g o r i nitiati on of resc ue a nti h y per gl yce mic me dicati o n .
Safet y a nal ysis set ( S S)
All a vaila ble d ata o btai ne d d uri n g St u d y Peri o d II or III fr o m mI T T p o p ulati o n , 
re gar dless of a d here nce t o st u d y dr u g or i nitiati o n of ne w a nti h yp er gl y ce mic me dicati o n.
6. 2.
G e n er al C o n si d er ati o n s
Stati stical a nal ysis of t his st u d y will be t he res p o nsi bilit y of  Eli Lill y a n d C o mp a n y  ( Lill y) or i ts 
desi g nee. All st atistical a nal yses will be c o n d ucte d wit h S A S Versi o n 9. 4 or hi g her u nless 
ot her wi se state d. A n y c ha n ge t o t he data a nal ysis met h o ds descri be d i n t he pr ot oc ol will re q uire 
a n a me n d me nt O N L Y if it c ha n ges a pri nci pal feat ure of t he pr ot oc ol. A n y ot her c ha n ges t o t he 
data a nal ysis met h o ds descri be d i n t he pr ot oc ol, a n d t he j ust ificati on f or ma ki n g t he c ha n ge, will 
be descri be d i n t he S A P or t he cli nical st u d y  re p ort ( C S R). S o me a nal yses a n d s u m maries
descri be d i n t his a nal ysis pla n ma y n ot be c o n d ucte d if n ot warra nte d b y d at a (e g, fe w e ve nts t o 
j ustif y c o n d ucti n g a n a nal ysis). List i n g of e ve nts will be pr o vi de d i n s uc h sit uati ons . A d dit i onal 
a nal yses o f t he data ma y be c o n d ucte d as dee me d a p pr o priate wit h o ut f urt her c ha n ges ma de t o 
t he pr ot oc ol or S A P, e ve n after t he pri mar y or fi nal  data base loc ks ( D B L).
A d dit i onall y , u nless state d ot her wise, statistical s u m maries a n d a nal yses will be c o n d ucte d base d 
o n ra n d o mize d mai nte na nce d ose re gar dless of t he act ual tr e at me nt recei ve d b y t he patient .
U nless s pecifie d ot her wise, t he l ast meas ur e me nt d uri n g Visit 1 t o Visit 3 (i ncl u di n g 
u nsc he d ule d visits ) c ollecte d prior t o or o n t he first d ose da y  will ser ve as baseli ne. F or 
i m m u n o ge nicity,  data c ollecte d pri or t o t he first d ose ti me will ser ve as baseli ne. F or la b a n d 
E C G, baseli ne n ee ds t o be prior t o or wi t hi n o ne h o ur after t he first d ose ti me. F or patie nt 
re p orte d o utc o m es, data c ollecte d at  Visit 3, re gar dless of t he ti mi n g relati ve t o first d ose, will
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T here will be 2 esti ma n ds o f i nterest i n e val uati n g pri mar y  a n d sec o n dar y efficac y o bject i ves.
Fi rst esti ma n d, t he “efficac y” esti ma n d, re prese nts efficac y prior t o disc o nt i n uati on of st u d y  dr u g 
or i nit iati n g resc ue t hera p y for p ersi ste nt se vere h y per gl yce mia. A nal ysis rel ative t o “efficac y” 
esti ma n d will be c o n d ucte d usi n g efficac y a nal ysis set ( E A S ). Sec o n d esti ma n d, t he “treat me nt -
re gi me n” esti ma n d, re prese nts t he efficac y irres pecti ve of a d here nce t o i n vesti gati onal pr o d uct or 
i ntr o d uctio n of  resc ue t hera p y for p ersi ste nt se vere h yper gl yce mia . A nal ysis r elative t o 
“tr e at me nt -re gi me n” esti ma n d will be c o n d ucte d usi n g f ull a nal ysis set (F A S ).
U nless s pecifie d ot her wise, safet y a nal yses will be c o n d ucte d relat i ve t o “t reat me nt-re gi me n”
esti ma n d usi n g t he safet y a nal ysis set ( S S).
E n d of st u d y  p artici pat i on f or a patie nt will be t he earliest of date of deat h, date of wit h dra wal 
fr om f urt her parti ci pat i on i n t he st u d y, or date of safety f oll ow -u p visit ( visit 8 0 1). F o r patie nts 
c o nsi dere d t o be l ost t o f oll ow -u p, e n d of st u d y  participat i on will be t he date of l ost t o f oll ow -u p 
re p orte d b y t he i n vestig at or . Patie nt data i ncl u de d i n data base after t he last date of st u d y  
parti ci pat i on ( date of deat h, date of earl y ter mi nati o n, or date of safet y  fol l ow -u p) will  b e 
e xcl u de d fr o m st atistica l a nal ysis. List i n g of s uc h data ma y be pr o vi de d.
S u m mar y  statistics f or cate g orical meas ures (i ncl u di n g cate g orize d c o nti n u o us meas ures) will 
i ncl u de sa m ple size, fre q ue nc y, a n d perce nta ges. S u m mar y  st atistics f or c o nti n u o us meas ures 
will i ncl u de sa m ple s i z e, mea n, sta n dar d de viati on ( S D ), me dia n, mi ni m u m, a n d ma xi m u m. T he
s u m mar y statistics will be prese nte d b y t he n omi nal visi t.
Stati stical treat me nt c o m paris o ns will o nl y be perf or me d bet wee n tirze pati de d oses a n d place b o .
Si nce t he trials are n ot a de q uatel y p o were d t o detect differe nces a mo n g ti rze patide d oses , 
c o mparis o ns a m o n g ti rze pati de ar ms will n ot be perf or me d u nless ot h er wise s pecifie d.
Stati stical s u m maries a n d res ults of st atistical a nal ysis will be dis pla ye d i n t he f oll owi n g 
treat me nt o r der: 5 m g tirze pati de, 1 0 m g tirze pati de, 15 m g tirze pati de, a n d p lace b o.
6. 3.
A dj u st m e nt s f or C o v ari at e s
T he st u d y  is stratifie d b y c o u ntr y, baseli ne H b A 1c (≤8. 5 %, > 8. 5 % [ ≤6 9, > 6 9 m m o l/m o l]), a n d 
past O A M use ( Yes or N o). W here necessar y t o be i ncl u de d as a stratificat i on fact or, c o u ntries 
wi t h fe wer t ha n 1 0 ra n d o mize d patie nts will be p o ole d i nt o 1 cate g or y ( p o ole d c o u ntr y). F or 
H b A 1c relate d a nal yses, t he p o ole d c o u ntr y  a n d past O A M use will be use d as stratificat i on 
fact ors a n d baseli ne H b A 1c as a c o variat e. F or ot her efficac y a nal yses, t he p o ol e d c o u ntr y,
baseli ne H b A 1c ( ≤8. 5 %, > 8. 5 % [ ≤6 9, > 6 9 m m o l/ m ol]), a n d past O A M use ( Yes or N o) will be 
use d as stratificat i on fact ors a n d res pecti ve baseli ne val ue as a c o variat e. Strati ficati o n fact ors
will be bas e d o n t he i nf or mati o n c o llecte d i n cli nical data base .
6. 4.
H a n dli n g of Dr o p o ut s or Mi s si n g D at a
F or t he pri mar y  a n d sec o n dar y efficac y e n d p oi nt a nal yses s u bject t o t ype 1 err or rate c o ntr ol ,
data f or patie nts wi t h missi n g val ues at t he 4 0 -wee k visit will be i m p ute d base d o n t he met h o d 
descri be i n Secti o n 6. 1 2. 1. 3 . U nless s pecifie d ot her wise , i m p utati o n of missi n g data will be 
li mite d t o pri mar y a n d k e y sec o n dar y efficac y e n d p oi nt a nal ysis. Missi n g
ot h er sec o n dar y or 


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e x pl orat or y efficac y p ar a meter val ues a n d missi n g safet y la b orat or y val ues w ill n ot be e x plicit l y 
i m p ute d.
6. 5.
M ulti c e nt er S t u di e s
T o i n vesti gate p ote ntial re gi o nal i nfl ue nce o n efficac y, c o u ntr y / p o ole d c o u ntr y will  be use d as a 
fi xe d fact or i n pri mar y a n d sec o n dar y efficac y a nal ysis.
6. 6.
M ulti pl e C o m p ari s o n s/ M ulti pli cit y A dj u s t m e nt s
T y pe 1 err or rate c o ntro l strate g y for pri mar y a n d k e y  sec o n dar y efficac y o bjecti ves is ill ustrate d 
i n Secti o n 6. 1 2. 3 . N o m ult i plicity a dj ust me nts will be ma de f or c o n d ucti n g se parate a nal yses 
r elat i ve t o “efficac y” a n d “t reat me nt -re gi me n” esti ma n ds, e val uat i n g ot her sec o n dar y a n d 
e x pl orat or y efficac y o bjecti ves, a n d safet y assess me nts.
6. 7.
P ati e nt Di s p o siti o n
R eas o ns f or scree n fail ure as re p orte d b y in vest i gat ors will be s u m marize d.
Lis tin g of fi nal st u d y  dis p ositio n a n d a list i n g of ra n d omize d treat me nt assi g n me nt ( pla n ne d 
treat me nt) for all  ra n d o mize d patient s will be pr o vi de d. F i nal st u d y dis p ositio n a n d st u d y  
treat me nt dis p osit i on f or all ra n d omize d pat ient s will be s u m marize d b y pla n ne d st u d y  tr e at me nt.
6. 8.
P ati e nt C h ar a ct eri sti c s
List i n g of patie nt de m o gra p hics will be pr o vi de d f or all ra n d omize d patie nts . All de mo gra p hic 
a n d baseli ne cli nical c haracterist ics will be s u m marize d b y st u d y tr e at me nt for all ra n d o mize d 
pati e nts. Baseli ne de mo gra p hic a n d cli nical  c haracteristics of s pecial i nterest i ncl u de a n d n ot 
li mit t o: a ge, ge n der, race, et h nicit y,  wei g ht, c o u ntr y  of e nr oll me nt, H b A 1c, fasti n g ser u m 
gl uc ose, d urati o n of  T 2 D M , e G F R.
6. 9.
C o n c o mit a nt T h er a p y
T he pres pecifie d c o nc o mit a nt me dicatio ns of i nterest will be s u m marize d b y  tr e at me nt at 
ra n d omizat i on. A d dit i onall y me dicat i ons of i nterest i nit iate d after ra n d o mizati on will be 
s u m marize d . T he c o nc o mita nt t hera pies will be ma p pe d usi n g t he W orl d Healt h Or ga nizat i on 
( W H O) D R U G dicti onar y i n t he cli nical trial data base a n d will be f urt her classifie d usi n g 
A nat o mic -T hera pe uti c-C he mical  ( AT C) c o des f or re p orti n g p ur p oses .
T he c o nc o mita nt me dicat i ons o f i nterest i ncl u de t he f o ll owi n g gr o u ps of m e dicatio n:

b aseli ne a nt i h y perte nsi ve t hera p y, b y t yp e

b aseli ne li pi d l o weri n g t hera p y, b y t ype 

p rior use of a nt i h y per gl yce mic t hera p y

u tilizati on of  ot her a nti h y per gl yce mic t hera p y i n S t u d y P erio d II, a n d als o i n S t u d y 
P erio d II a n d III

resc ue t hera p y d ue t o se vere persiste nt h y per gl yce mia


I 8 F-M C -G P G K St ati sti c al A n al y si s Pl a n V er si o n 3
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
ini tiat i on of f oll owi n g m e dicat i on s i n St u d y Peri o d II:
o
ant i diarr heal me dicati on
o
ant iemet ic me dicat i on 
6. 1 0. Tr e at m e nt E x p o s ur e a n d C o m pli a n c e
List i n g of  p atie nts ra n d o mize d b ut n ot recei vi n g st u d y treat me nt will be pr o vide d , if a p plica ble.
T he list i n g will i ncl u de patient  i de ntificati on , ra n d o mize d treat me nt ar m, a n d t he reas o n f or n ot 
recei vi n g st u d y treat me nt .
S u m mar y  of d uratio n t o e n d of t he st u d y ( defi ne d as ti me i n da ys fr om date of ra n d o mizati o n t o 
date of safet y f oll ow -u p or date of earl y st u d y  disc o nti n uati on ) a n d d urati o n o n st u d y treat me nt 
( defi ne d as ti me i n da ys fr om date of first d ose of st u d y  treat me nt t o date of last d ose of st u d y 
treat me nt plus 7 d a y s) will be pr o vide d b y st u d y treat me nt . 
6. 1 0. 1. E x p o s ur e a n d C o m pli a n c e t o T ir z e p ati d e
N u m ber of patie nts pre mat urel y disc o nt i n ui n g st u d y treat me nt pri or t o t he 4 0 -wee k visit will be 
pr o vi de d b y st u d y  treat me nt. Reas o ns f or pre mat urel y disc o nt i n ui n g st u d y treat me nt prior t o t he 
4 0 -wee k visit will be pr o vi de d b y st u d y  tr e at me nt. Ti me -t o-e ve nt a nal ysis o f pr e m at ure st u d y 
treat me nt disc o nt i n uati on will be c o n d ucte d.
If data warra nt, pr o p orti o n of patient s recei vi n g 2. 5 m g, 5 m g, 7. 5 m g, 1 0 m g, 1 2. 5 m g or 1 5 m g
f or tirze pati de treat me nt gr o u ps ma y be prese nte d b y ra n d o mize d treat me nt a n d ti me i nter vals
fr om first d ose. A listi n g of patient s w h o re-i nitiate d ue t o missi n g ≥3 c o nsec uti ve d oses ma y be 
pr o d uce d.
O verall tr e at me nt c o mplia nce will be defi ne d as ta ki n g at least 7 5 % of t he sc he d ule d tirze pati de 
d oses . C o m p lia nce will be calc ulate d b y  ta ki n g t he n u m ber of d oses a d mi nistere d (re gar dless of  
t he act ual d ose a d mi nistere d) di vi de d b y t he t otal n u m ber of d oses e x pecte d t o be a d mi nistere d
× 1 0 0. O verall t reat me nt c o m plia nce will be s u m marize d descri pti vel y b y treat m e nt usi n g t he 
m I T T P o p ulat i on. 
6. 1 1. I m p ort a nt Pr ot o c ol D e vi ati o n s
I mp orta nt pr ot oc ol de viat i ons is s pecifie d i n Trial Iss ues Ma na ge me nt Pla n (TI M P) . A list i n g 
a n d a s u m mar y of im p orta nt pr ot oc ol de viat i ons (I P D) b y  treat me nt will be pr o vi de d .
6. 1 2. Effi c a c y A n al y si s
F or t he F o o d a n d Dr u g A d mi nistrati o n ( F D A ) a n d p ote ntiall y for ot her re g ul at or y a ge ncies, all
efficac y assess me nts will be g ui de d b y t he “treat me nt-re gi me n” esti ma n d c o n d ucte d usi n g F A S .
Assess me nt of t he pri mar y a n d sec o n dar y efficac y o bject i ves s u bject t o t ype 1 err or rate c o ntr ol 
( k e y sec o n dar y) will be c o n d ucte d wit h m ult i ple i m p utati o n of missi n g data (see 
S ectio n 6. 1 2. 1. 3 ) at  4 0 wee ks . Assess me nt of o t her efficac y o bject i ves will be c o n d ucte d wit h o ut 
i m p utatio n of  missi n g data. F o r p u blicati o ns a n d ot her p ur p oses i ncl u di n g s ome ot her re g ulator y  
s u b missi ons , t he assess me nt of efficac y o bjecti ves will be g ui de d b y t he “efficac y” esti ma n d 


I8F-MC-GPGK Statistical Analysis Plan Version 3
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using EAS data set without explicit imputation of missing data. A listing of patients randomized 
but not included in efficacy analyses (ie, not treated, discontinued treatment due to inadvertent 
enrollment) will be provided.
6.12.1. Primary Efficacy Analysis
The primary efficacy measure will be change in HbA1c (% and mmol/mol) from baseline
(postbaseline – baseline) to 40 weeks. Both HbA1c values as well as change from baseline in 
HbA1c will be summarized by treatment and nominal visit (week). When applicable, HbA1c 
data from local lab will be used when central lab data is not available. If scheduled HbA1c data 
at the primary endpoint visit is not available, unscheduled HbA1c data collected for the primary 
endpoint visit will be included in analysis.
6.12.1.1. Primary Analysis Relative to the Efficacy Estimand
The analysis will be conducted utilizing HbA1c data in EAS from baseline through the 40-week 
visit with the aid of a mixed model for repeated measures (MMRM). Restricted maximum 
likelihood (REML) will be used to obtain model parameter estimates and Kenward-Roger option 
will be used to estimate denominator degrees of freedom. The response variable of the MMRM 
model will be the primary measure and model terms will include treatment, visit, treatment by 
visit interaction, country/pooled country, and past use of OAM as fixed effects, and baseline 
HbA1c as a covariate. An unstructured covariance structure will be used to model the within-
patient errors. If this model fails to converge, the following covariance structures will be tested 
in order: 

Heterogeneous Toeplitz 

Heterogeneous First Order Autoregressive 

Heterogeneous Compound Symmetry 

Toeplitz 

First Order Autoregressive 

Compound Symmetry. 
The first covariance structure that converges will be used. The resulting least squares mean 
(LSM) estimate of mean change from baseline in HbA1c will be summarized by visit and by 
study treatment.
With the aid of the MMRM analysis, p-values and 2-sided 95% confidence interval (CI) for 
mean change in HbA1c from baseline through 40-week visit for 5 mg, 10 mg, and 15 mg
tirzepatide compared to placebo will be derived and summarized.
6.12.1.2. Analysis Relative to the Treatment-Regimen Estimand
The analysis will be conducted utilizing HbA1c data in FAS at baseline and at the 40-week visit 
with the aid of an analysis of covariance (ANCOVA). The response variable will be the primary 
measure and model terms will include treatment, country/pooled country, past use of OAM as 


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fi xe d effects, a n d baseli ne H b A 1c as a c o variate. T he A N C O V A a nal ysis will be c o n d ucte d wit h 
m ult i ple i m p utati o n of missi n g pri mar y meas ure (see Secti o n 6. 1 2. 1. 3 f or details) a n d st atistical 
i nfere nce o ver m ulti ple i m p utatio n of  missi n g data g ui de d b y R u bi n ( 1 9 8 7) .
Wit h t he ai d of t he A N C O V A a nal ysis , p-v al ues a n d 2 -side d 9 5 % C I for m ea n c ha n ge i n H bA 1c 
fr om baseli ne t o 4 0 -wee k visit f or 5 m g, 1 0 m g, a n d 1 5 m g tirze pati de c o m pare d t o place b o will 
be deri ve d a n d s u m marize d .
6. 1 2. 1. 3. M et h o d s f or M ulti pl e I m p ut ati o n s
F or efficac y  a nal ysis relati ve t o “treat me nt-re gi me n esti ma n d,” missi n g H b A 1c data at t he 
4 0 -wee k visit will be i m p ute d base d o n “r etrie ve d dr o p o uts,” defi ne d as pat ient s w h o ha d t heir 
H b A 1c val ue meas ure d at t he 4 0 -wee k visit i n t he sa me treat me nt ar m w h o pre mat urel y 
di sc o nti n ue d st u d y dr u g. I n cases w here t here are n ot e n o u g h retrie ve d dr o p o uts t o pr o vide a 
relia ble i m p utati o n m o del (i.e., at least 1 ar m ha s< 8 pati e nts w h o disc o nti n ue d st u d y tr e at me nt 
earl y a nd ha ve e n d p o i nt visit meas ure me nt s, or t he m o d el i m ple me nte d b y t he S A S pr o gra m 
d oes n ot c o n ver ge) , a n alter nati ve m u lti ple i m p utati on met h o d wi t h r efere nce t o t he place b o 
gr o u p ( place b o mul tiple i m p utati o n) will be use d . If val ue o f t he i mp ute d H b A 1c c ha n ge fr o m 
baseli ne is < -6. 0 % or > 6. 0 %, t hat val ue will be set t o -6. 0 % or 6. 0 %, res pecti vel y, t o a v oi d 
u nrealist ic i m p ute d val ues.
6. 1 2. 2. S e c o n d ar y Effi c a c y A n al y s e s S u bj e ct t o T y p e 1 E rr or R at e 
C o ntr ol
6. 1 2. 2. 1. M e a n C h a n g e i n B o d y W ei g ht a n d F a sti n g S er u m G l u c o s e F r o m B a s eli n e
at t h e 4 0 -W e e k V i sit
T he a nal ysis f or c ha n ge i n b o d y wei g ht a n d fast i n g ser u m gl uc ose fr om baseli ne ( p ost baseli ne -
baseli ne) will be c o n d ucte d i n a ma n ner si mi lar t o t he pri mar y a nal ysis i n Sect i on 6. 1 2. 1 .
B aseli ne H b A 1c cate g or y (≤8. 5 %, > 8. 5 % [ ≤6 9, > 6 9 m m o l/ m ol]) will be use d as a fi xe d fact or i n 
pl ace o f baseli ne H b A 1c as a c o variate a n d b aseli ne of  t he c orres p o n di n g varia ble will be use d as
a n a d dit i onal c o variate i n t he statistical mo d el . Least sq uares m ea n esti mate of mea n c ha n ge i n 
b o d y  wei g ht a n d fast i n g ser u m gl uc ose fr o m baseli ne will be s u m marize d b y n o mi nal visi t a n d 
b y st u d y treat me nt. W he n a p plica ble, fasti n g ser u m gl uc ose data fr o m  lo c al  la b will be use d 
w he n ce ntral la b data is n ot a vail a ble. F or t he mul ti ple i m p utatio n of  missi n g val ues, if val ue of 
t he i m p ute d wei g ht c ha n ge fr o m baseli ne is < -5 0 k g or > 5 0 k g , t hat val ue will be set t o -5 0 k g or 
5 0 k g , res pecti vely,  t o a v oid u nrealist ic i m p ute d val ues; if val ue of t he i m p ute d fasti n g ser u m 
gl uc ose c ha n ge fr o m baseli ne is < -2 0 m m o l/ L or > 2 0 m m o l/ L, t hat value will be set t o -2 0 
m m o l/ L or 2 0 m m o l/ L, res pecti vel y, t o a v oi d u nrealistic i m p ute d val ues.
6. 1 2. 2. 2. Pr o p orti o n of P ati e nt s A c hi e vi n g H b A 1 c < 7 % a n d < 5. 7 % at t h e 4 0 W e e k 
Vi sit
T he a nal ysis relati ve t o t he “efficac y” esti ma n d f or t he e n d p oi nt at 4 0 wee ks will be p erf or m e d 
usi n g E A S wi t h missi n g val ues i m p ute d fr om a n M M R M m o d el a n d t he n dic h ot o mize d. T he 
M M R M m o d el  i ncl u des tr e at me nt, stratificati on fact ors, visit, a n d treat me nt -b y -visit i nteractio n 
as fi xe d effec ts, a n d baseli ne H b A 1c as a c o variate. After dic h ot o mizi n g c o nti n u o us H b A 1c, t he 


I 8 F-M C -G P G K St ati sti c al A n al y si s Pl a n V er si o n 3
P a g e 1 9
L Y 3 2 9 8 1 7 6
data i s a nal yze d usi n g a lo gi stic re gressi o n m o del wit h treat me nt, c o u ntr y / p o ole d c o u ntr y, past 
use of O A M as fixe d effects, a n d baseli ne H b A 1c as a c o variate . I n a d diti on, a nal ysis will be 
c o n d ucte d utilizi n g data usi n g E A S fr o m baseli ne t hr o u g h t he 4 0 -wee k visit wit h t he ai d of a 
l on git u di nal l o gist ic re gressi on wi t h re peate d meas ure me nts wit h c o u ntr y / p o ole d c o u ntr y, past 
use of O A M , treat me nt, visit, tr e at me nt -b y -visit i nteracti o n as fi xe d effects, a n d baseli ne H b A 1c 
as a c o variate. I n case l o n git u di nal l o gistic m o d el  d oes n ot c on ver ge d ue t o s mall nu m ber of
e ve nts, l ogist ic re gressi on will be u tilize d t o a nal yze pr o p orti o n of  p at ient s ac hie vi n g 
H b A 1c < 7 % at n o mi nal visits .
A nal ysis relat i ve t o “treat me nt-re gi me n” esti ma n d will be c o n d ucte d b y ut ilizi n g H b A 1c data i n 
F A S at baseli ne a n d at t he 4 0 -wee k visit wit h t he ai d of  a l ogi stic re gressi on wi t h mul tiple 
i m p utatio n of  missi n g H b A 1c data at t he 4 0 -wee k visit (see Sect i on 6. 1 2. 1. 3 f or details). M o del 
t er ms will i ncl u de treat me nt, c o u ntr y/ p o ole d c o u ntr y, past use of  O A M as fi xe d effects, a n d 
baseli ne H b A 1c as a c o variate a n d st atistical i nfere nce o ver m ulti ple i m p utati o ns will  be g ui de d 
b y R u bi n ( 1 9 8 7).
Si milar a nal yses will be perf or me d f or pr o p orti o n of patie nts ac hie vi n g H b A 1 c < 5. 7 %.
6. 1 2. 3. T y p e 1 E rr or R at e C o ntr ol S tr at e g y f or Pri m ar y a n d K e y 
S e c o n d ar y Effi c a c y A n al y si s
Si nce t he y  are i nte n de d f or differe nt p ur p oses, n o t y pe 1 err or rate a dj ust me nt s will be ma de f or 
c o n d ucti n g a nal ysis relati ve t o “efficac y” a n d “treat me nt -re gi me n” esti ma n ds. F or a nal ysis 
wi t hi n eac h esti ma n d, ty pe 1 err or rate c o ntr ol strate g y f or e val uat i on of pri mar y  a n d k e y  
sec o n dar y o bjecti ves is ill ustrate d in Fi g ure G P G K .6 .1 . T he t y pe I err or rate c o ntr ol strate g y f or 
t he P har mace uticals a n d Me dical De vices A ge nc y (P M D A ) is i n A p pe n di x 1 . 
T he pri mar y  a n d ke y sec o n dar y o bjecti ve h y p ot heses are as f oll o ws, 

H 5, 1 , H1 0 ,1 , a n d H 1 5, 1 : S u peri orit y t est of  tirze pati de 5 m g, 1 0 m g, 1 5 m g v ers us place b o 
i n H b A 1c c ha n ge fr o m baseli ne at 4 0 wee ks res pecti vel y.

H 5, 2, H1 0, 2, a n d H 1 5, 2 : S u peri orit y test of  tirze pati de 5 m g, 1 0 m g, 1 5 m g v ers us place b o 
i n b o d y  wei g ht c ha n ge fr o m baseli ne at 4 0 wee ks res pecti vel y.

H 5, 3, H1 0, 3, a n d H 1 5, 3 : S u peri orit y test of  tirze pati de 5 m g, 1 0 m g, 1 5 m g v ers us place b o 
i n pr o p orti o n of  p atie nts ac hie ve H b A 1 c< 7 % at 4 0 wee ks res pecti vel y.

H 5, 4, H 1 0, 4, a n d H 1 5, 4 : S u peri orit y test of  tirze pati de 5 m g, 1 0 m g, 1 5 m g v ers us place b o 
i n fasti n g ser u m gl uc ose (F S G ) c ha n ge fr o m baseli ne at 4 0 wee ks res pecti vel y .

H 5, 5, H1 0, 5, a n d H 1 5, 5 : S u peri orit y test of  tirze pati de 5 m g, 1 0 m g, 1 5 m g v ers us place b o 
i n pr o p ortio n of  p atie nts ac hie ve H b A 1 c< 5. 7 % at 4 0 wee ks res pecti vel y.


I 8 F-M C -G P G K St ati sti c al A n al y si s Pl a n V er si o n 3
P a g e 2 0
L Y 3 2 9 8 1 7 6
H 5, 1 , H 1 0, 1 , a n d H 1 5, 1 will be i nitiall y t este d eac h at 0. 0 1 6 6 7 sig nifica nce l e v el. A gra p hical 
testi n g sc he me ( Bretz et al. 2 0 0 9, 2 0 1 1) prese nte d i n Fi g ure G P G K .6 .1 will be use d t o 
str o n gl y c o ntr ol for t y pe 1 err or . 
Fi g ur e G P G K .6 .1 .
T y p e 1 e rr or c o ntr ol s tr at e g y f or pri m ar y a n d k e y s e c o n d ar y 
effi c a c y e n d p oi nt s.


I 8 F-M C -G P G K St ati sti c al A n al y si s Pl a n V er si o n 3
P a g e 2 1
L Y 3 2 9 8 1 7 6
6. 1 2. 4. Ot h er S e c o n d ar y a n d E x pl or at or y E ffi c a c y A n al y s e s
Ot her sec o n dar y  a n d ex pl orat or y efficac y meas ures will be s u m marize d b y tr e at me nt a n d 
n o mi nal visi t. U nless ot her wise s pecifie d, m issi n g data will n ot be i m p ute d a n d assess me nts are 
n ot s u bject t o t ype 1 err or rate c o ntr ol. See Ta ble G P G K. 6 .2 .
T a bl e G P G K. 6 .2 .
S e c o n d ar y a n d E x pl or at or y Effi c a c y A n al y s e s n ot C o ntr oll e d f or 
T y p e I Err or
O bjecti ve 
Rel ati ve t o t he effic ac y 
me as ure:
A n al ysis 
C o n d ucte d i n a 
m a n ner si mil ar 
t o: 
A d diti o n al I nf or m ati o n
T o c o m pare tirze pati de 
5 m g, 1 0 m g, a n d 
1 5 m g t o place b o
C ha n ge fro m baseli ne i n 7 -
p oi nt self -m o nit ore d bl o o d 
gl uc ose ( S M B G) pr ofiles 
6. 1 2. 1
Use baseli ne H b A 1c strata as a fi xe d 
effect i n place of baseli ne H b A 1c as a 
c o variate. Use baseli ne S M B G as a 
c o variate. L S M esti mates will be
s u m marize d b y treat me nt a n d 7 -
p oi nts.
I n a d diti on t o t he a nal yses o n eac h of
t he 7-p oi nts, si milar a nal yses will be
d o ne f or t he 2 -h o ur m o r ni n g, mi d da y,
a n d e ve ni n g meal e xc ursi o ns, t he
mea n of all meals 2 -h o ur e xc ursi o n,
t he mea n of all 7-p oi nt meas ure me nts,
t he mea n of all pre-meal
meas ure me nts, a n d t he mea n of all 2-
h o ur p ost pra n dial meas ure me nts.
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 ol/ m ol)
6. 1 2. 2. 2
N o ne
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 < 8 % 
( 6 4 m m ol/ m ol) 
6. 1 2. 2. 2
N o ne
pr o p orti o n of patie nts w h o 
ac hie ve d wei g ht l oss of 
≥5 %, fr o m baseli ne
6. 1 2. 2. 2
Use baseli ne H b A 1c strata as a fi xe d 
effect i n place of baseli ne H b A 1c as a 
c o variate a n d baseli ne wei g ht as a 
c o variate
pr o p orti o n of patie nts w h o 
ac hie ve d wei g ht l oss of
≥1 0 % f r om baseli n e
6. 1 2. 2. 2
Use baseli ne H b A 1c strata as a fi xe d 
effect i n place of baseli ne H b A 1c as a 
c o variate a n d baseli ne wei g ht as a 
c o variate
pr o p orti o n of patie nts w h o 
ac hie ve d wei g ht l oss of 
≥1 5 % f r om baseli ne
6. 1 2. 2. 2
Use baseli ne H b A 1c strata as a fi xe d 
effect i n place of baseli ne H b A 1c as a 
c o variate a n d baseli ne wei g ht as a 
c o variate


I 8 F-M C -G P G K St ati sti c al A n al y si s Pl a n V er si o n 3
P a g e 2 2
L Y 3 2 9 8 1 7 6
Sec o n d ar y a n d E x pl or at or y Effic ac y A n al yses n ot C o ntr olle d f or T y pe I Err or
O bjecti ve 
Rel ati ve t o t he effic ac y 
me as ure:
A n al ysis 
C o n d ucte d i n a 
m a n ner si mil ar 
t o: 
A d diti o n al I nf or m ati o n
C ha n ge fro m baseli ne i n 
waist circ u mfere nce 
6. 1 2. 1
Use baseli ne H b A 1c strata as a fi xe d 
effect i n place of baseli ne H b A 1c as a 
c o variate. Use baseli ne waist 
circ u mfere nce as a c o variate.
C ha n ge f r om baseli ne i n 
B MI 
6. 1 2. 1
Use baseli ne H b A 1c strata as a fi xe d 
effect i n place of baseli ne H b A 1c as a 
c o variate. Use baseli ne B MI as a 
c o variate. 
Perce nta ge c ha n ge i n b o d y 
wei g ht
6. 1 2. 1
Use baseli ne H b A 1c strata as a fi xe d 
effect i n place of baseli ne H b A 1c as a 
c o variate. Use baseli ne b o d y wei g ht
as a c o variate.
C ha n ge f r om baseli ne i n 
fasti n g gl uca g o n, c-
pe pti de, i ns uli n le vel, 
H O M A -B, H O M A -S, a n d 
H O M A -I R
6. 1 2. 1
Use baseli ne H b A 1c strata as a fi xe d 
effect i n place of baseli ne H b A 1c as a 
c o variate. Use c orres p o n di n g baseli ne 
para meter as a c o variate. A n al ysis 
will be base d o n l o g tra nsf or me d 
meas ure.
C ha n ge f r om baseli ne i n 
li pi d para meters ( T otal-
C h olester ol, H D L -C, 
V L D L -C, T G , L D L-C )
6. 1 2. 1
Use baseli ne H b A 1c strata as a fi xe d 
effect i n place of baseli ne H b A 1c as a 
c o variate. Use c orres p o n di n g baseli ne 
li pi d para meter as a c o variate.
A nal y sis will be base d o n l o g 
tra nsf or me d meas ure.
C ha n ge f r om baseli ne i n 
patie nt re p orte d o utc o mes :
A P P A D L, E Q -5 D -5 L, a n d 
I W-S P
6. 1 2. 1. 2
Use baseli ne H b A 1c strata as a fi xe d 
effect i n place of baseli ne H b A 1c as a 
c o variate. Use c orres p o n di n g baseli ne 
patie nt o utc o me sc ore as a c o variate.
T o c haracterize 
efficac y ( be y o n d t he 
e n d of treat me nt ) wit h 
tirze pati de 5 m g, 1 0 
m g, a n d 1 5 m g 
C ha n ge f r om baseli ne i n 
H b A 1c , b o d y wei g ht
6. 1 2. 1
T he a nal y sis will be c o n d ucte d 
utilizi n g H b A 1c ( b o d y wei g ht) data 
fr o m baseli ne t hr o u g h t he e n d of 
f oll o w-u p ( 4 4 wee ks)
A b bre viati o ns: 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 Q uesti o n naire ; B MI = b o d y mass 
i n de x; E Q -5 D -5 L = 5 -le vel E Q-5 D versi o n ; H b A 1c = he m o gl o bi n A 1c; H D L -C = hi g h -de nsit y li p o pr otei n 
c h olester ol; H O M A -B = h o me ostatic m o del assess me nt f or β -cell f u ncti o n ; H O M A -I R = h o me ostatic m o del 
assess me nt f or i ns uli n resista nce; H O M A -S = h o me ostatic m o del assess me nt f or i ns uli n se nsiti vit y; 
I W-S P = I m pact of Wei g ht o n Self -Perce pti o ns Q uesti o n naire; L D L -C = l o w -de nsit y  li p o pr otei n c h olester ol;
V L D L -C = ver y -l o w-de nsit y  li p o pr otei n c h olester ol; T G = tri gl yceri des.
6. 1 3. S af et y A n al y si s
U nless s pecifie d ot her wise, safet y assess me nts will be base d o n t he S S (see Ta ble G P G K .6 .1 ).
All e ve nts t hat occ ur bet wee n t he date of first d ose of st u d y dr u g t o t he date of patie nt’s safet y  


I 8 F-M C -G P G K St ati sti c al A n al y si s Pl a n V er si o n 3
P a g e 2 3
L Y 3 2 9 8 1 7 6
f oll ow -u p visit or patie nt’s e n d of st u d y  participati o n will be i ncl u de d. F or assessi n g be nefit a n d 
ris k pr ofile t hr o u g h 4 0 -wee ks, s electe d safet y a nal yses ma y be c o n d ucte d b y  utilizi n g safety data 
fr om first d ose t hr o u g h t he date of 4 0 -wee k visit . F o r rare e ve nts (< 1 0 patie nts ha ve t he e ve nts), 
s u m mar y ta bles ma y not be ge nerate d, a n d i n di vi d ual pat ient  le vel data will be liste d.
U nless s pecifie d ot her wise, co m paris o ns of tirze patide d oses t o place b o will be perf or me d.
F or selecte d c o nti n u o us safety para m eters, differe nce a m o n g treat me nt mea n c ha n ge fr o m 
baseli ne at sc he d ule d visit s will be assesse d via a M M R M usi n g R E M L.
T he m o d el  will i ncl u de
c o u ntr y/ p o ole d c o u ntr y, baseli ne H b A 1c (≤8. 5 %, > 8. 5 % [ ≤6 9, > 6 9 m m o l/m o l]), past O A M use 
( Yes or N o), treat me nt gr o u p, visit, a n d treat me nt -b y -visit i nteracti o n as fi xe d effects, a n d 
baseli ne val ue of t he safety p ara meter as a c o variate. T o m o del t he c o varia nce str uct ure wit hi n 
pati e nts, t he u nstr uct ure d c o varia nce matri x will be use d . If t his m o del fails t o c o n ver ge, t he 
c o varia nce str uct ures s pecifie d i n Secti on 6. 1 2. 1. 1 wi ll be teste d i n or der.
F or selecte d safet y para m eters, ti me-t o-first-e ve nt a nal ysis via c o x -pr o p orti o nal hazar ds m o del 
ma y be c o n d ucte d. F o r patie nts e x perie nci n g a n e ve nt, “ti me-t o-first-e ve nt” will be t he ti me (i n 
wee ks ) t o t he first occ urre nce of t he e ve nt . F or patie nts wit h o ut t he e ve nt, “t i me-t o-e ve nt” will 
be ce ns ore d at e n d of st u d y  p artici pat i on (st u d y  disc o nti n uati on , safety f oll ow -u p visi t, or date of 
deat h ).
W here s pecifie d, rate of e ve nts will be a nal yze d usi n g a ge neralize d li near mi xe d -effects mo d el  
ass u mi n g t he n u m ber of e ve nts f oll ow a ne gati ve bi n o mial distri b ut i on , a n d wit h tr e at me nt as a 
fi xe d effect. T he l o garit h m o f ye ars i n s pecifie d ti me i nter val will  be a dj uste d as a n offset t o 
acc o u nt f or p ossi ble u ne q ual treat me nt d urati o n i n s pecifie d ti me i nter val bet wee n patie nts.
6. 1 3. 1. A d v er s e E v e nt s
A treat me nt -e mer ge nt a d verse e ve nt ( T E A E ) is defi ne d as a n e ve nt t hat first occ urre d or 
w orse ne d i n se verit y aft er t he first d ose . T he Me d D R A L o west Le vel Ter m ( L L T) will be use d 
i n t he treat me nt-e mer ge nt deri vat i on . T he m a xi m u m se verit y for eac h L L T d uri n g t he baseli ne 
p eri o d i ncl u di n g o n g oi n g me dical hist or y will be use d as baseli ne se verity . F or e ve nts wit h a 
missi n g se verit y d uri n g t he baseli ne peri o d, it will be treate d as ‘mil d ’ i n se verity f or deter mi ni n g 
treat me nt -e mer ge nce. E ve nts wit h a missi n g se verit y  d uri n g t he p ost baseli ne peri o d will be 
treate d as ‘se vere’ a n d treat me nt -e mer ge nce will be deter mi ne d b y c o m par i n g t o baseline
se verity.
T he perce nta ges of pat ient s wi t h T E A Es will be s u m marize d b y treat me nt usi n g Me d D R A P T
neste d wit hi n S O C . Statist ical c o mparis o ns will be a p plie d at b ot h t he S O C a n d P T le vels.
E ve nts will be or dere d b y  decreasi n g fre q ue nc y wit hi n S O C , wit h the S O C i n al p ha bet ical or der.
F or e ve nts t hat are se x-s pecific, t he de n omi nat or a n d c o m p utati o n of t he perce nta ge will i ncl u de 
o nl y  patie nts fr om t he give n se x.
O ver vie w of t he n u m ber a n d perce nta ge of pati e nt w h o e x perie nce d a T E A E, seri o us a d verse 
e ve nt ( S A E), deat h , disc o nt i n ue d fr o m st u d y treat me nt d ue t o a n A E , disc o nt i n ue d fr om st u d y
d ue t o a n A E, as well as r elat i ons hi p t o st u d y  dr u g, will be s u m marize d b y treat me nt.


I8F-MC-GPGK Statistical Analysis Plan Version 3
Page 24
LY3298176
The percentages of patients with TEAEs, overall and common (common TEAEs occurred in 
≥5% of patients before rounding), will be summarized by treatment using MedDRA PT. Events 
will be ordered by decreasing frequency.
The percentages of patients with TEAEs by maximum severity will be summarized by treatment 
using MedDRA PT. For each patient and TEAE, the maximum severity for the MedDRA PT is 
the maximum postbaseline severity observed from all associated LLTs mapping to the MedDRA 
PT. The maximum severity will be determined based on the non-missing severities. If all 
severities are missing for the defined postbaseline period of interest, it will show as missing in 
the table. Only counts and percentages will be included for the TEAEs by maximum severity.
Patient narratives will be provided for all patients who experience any of the following “notable” 
events:

deaths

serious adverse events

pregnancy

permanent discontinuations of study treatment due to AEs

severe adverse events of special interest
Patient narratives will be provided for patients who experience severe AESI as well.
6.13.1.1. Deaths
A listing of all deaths will be provided. Listing will include patient identification including the 
treatment, site number, date of death, age at the time of enrollment, gender, MedDRA PT of 
associated AE, time from first dose of study drug to death, time from last dose of study drug to 
death (if patient had discontinued study drug), cause of death as reported by investigator, caused 
of death as adjudicated by Clinical Endpoint Committee (CEC).
6.13.1.2. Other Serious Adverse Events
The number and percentage of patients who experienced an SAE (including deaths and SAEs 
temporally associated or preceding deaths) during the study will be summarized by treatment 
using MedDRA PT nested within SOC. Events will be ordered by decreasing frequency within 
SOC.
A listing of all SAEs will be provided. Listing will include and not limit to treatment, patient
identification including the site number, treatment group, date of event, age at the time of 
enrollment, gender, MedDRA SOC and PT, severity, action taken, outcome, relationship to study 
drug, time from first dose of study drug to the event, and event duration.
6.13.1.3. Discontinuation From Study Due to Adverse Event
The number and percentage of patients who prematurely discontinue the study due to an AE will 
be summarized by treatment using MedDRA PT nested within SOC. Events will be ordered by 
decreasing frequency within SOC.


I 8 F-M C -G P G K St ati sti c al A n al y si s Pl a n V er si o n 3
P a g e 2 5
L Y 3 2 9 8 1 7 6
6. 1 3. 1. 4. Di s c o nti n u ati o n F r o m St u d y Dr u g D u e t o A d v er s e E v e nt
T he n u m ber a n d perce nta ge of patie nts w h o pre mat urel y  disc o nti n ue st u d y dr u g d ue t o a n A E 
will be s u m marize d b y  tr e at me nt usi n g Me d D R A P T neste d wit hi n S O C. E ve nts will be or dere d 
b y decreasi n g fre q ue nc y  wit hi n S O C. Ti me -t o-e ve nt a nal yses will be c o n d ucte d b y treat me nt o n 
ti me t o st u d y dr u g disc o nti n uati on.
6. 1 3. 1. 5. Tr e at m e nt of O v er d o s e
A listi n g of patie nts rep orti n g o ver -d osi n g of tirze patide will be pr o vi de d as a pr ot oc ol de viati on .
6. 1 3. 2. S p e ci al S af et y T o pi c s
6. 1 3. 2. 1. H y p o gl y c e mi c E v e nt s
Defi nit i ons of differe nt cate g ories of h y p o gl yce mic e ve nts are i ncl u de d i n Ta ble G P G K .6 .3 .
T a bl e G P G K .6 .3 .
D efi niti o n s of H y p o gl y c e mi c E v e nt C at e g ori e s
S y m pt o ms a n d/ or Si g ns 
of H y p o gl yce mi a
Bl o o d Gl uc ose Le vel
Gl uc ose Alert Val ue:
    D oc u me nte d s y m pt o matic h y p o gl yce mia
Yes
≤7 0 m g/ d L ( 3. 9 m m ol/ L)
    D oc u me nte d as y m pt o matic h y p o gl yce mia
N o
≤7 0 m g/ d L ( 3. 9 m m ol/ L)
    D oc u me nte d u ns pecifie d h y p o gl yce mia
U n k n o w n
≤7 0 m g/ d L ( 3. 9 m m ol/ L)
Cli nicall y Si g nifica nt H y p o gl yce mia ( Le vel 2):
   D oc u me nte d s y m pt o matic h y p o gl yce mia
Yes
< 5 4 m g/ d L ( 3. 0 m m ol/ L)
   D oc u me nte d as y m pt o matic h y p o gl yce mia
N o
< 5 4 m g/ d L ( 3. 0 m m ol/ L)
   D oc u me nte d u ns pecifie d h y p o gl yce mia
U n k n o w n
< 5 4 m g/ d L ( 3. 0 m m ol/ L)
Se vere H y p o gl yce mia ( Le vel 3)
Se vere h y p o gl yce mi a: Defi ne d as a n e pis o de wit h se vere c o g nit i ve i m pair me nt re q uiri n g t he 
assista nce of a n ot her pers o n t o acti vel y a d mi nister car b o h y drate, gl uca g o n, or ot her res uscitati ve 
actio ns. Se vere h y p o gl yce mia will be re p orte d as a n S A E. Se vere h y p o gl yce m ia will be 
c o nsi dere d as A E SI .
N oct ur n al h y p o gl yce mi a: Defi ne d as a n y h y p o gl yce mic e ve nt t hat occ urs bet wee n be dt i me a n d 
wa ki n g.
T o a v oi d d u plicate re p orti n g, all c o nsec ut i ve bl o o d gl uc ose ( B G ) val ues ≤7 0 m g/ d L 
( 3. 9 m m o l/L) occ urri n g wit hi n a 1 -h o ur peri o d ma y be c o nsi dere d t o be a si n gle h y p o gl yce mic 
e ve nt.
Stati stical s u m maries a n d a nal yses will e xcl u de h y p o gl yce mic e ve nts occ urri n g after i nitiat i on of 
a ne w a nti h y per gl yce mic t hera p y. F or se vere h y p o gl yce mia a n d lev el  2 h y p o gl yce mia , 
i nci de nce as well as rate per patie nt ye ar of e x p os ure will be pr o vi de d b y treat me nt at  s pecifie d 
ti me i nter vals. A listi n g of h y p o gl yce mic e ve nts will als o be pr o vi de d.
T he i nci de nce of h y p o gl yce mic e ve nt will be a nal yze d usi n g l o gistic re gressi on wi t h tr e at me nt
a n d stratificatio n fact ors as fi xe d effects. T he rate of h y p o gl yce mic e pis o des per pati e nt year ma y


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be a nal yze d usi n g a ge neralize d li near mi xe d -effects mo d el  ass u mi n g t he n u m ber of 
h y p o gl yce mic e pis o des f o ll ows a ne gat i ve bi n omial distri b ut i on wi t h t h e me a n mo d el e d usi n g 
stratificati on fact ors a n d treat me nt as fi xe d effects. W he n
t he n u m ber of h y p o gl yce mic e ve nts is 
less 1 0, a listi n g of h y p o gl yce mic e ve nts will be pr o vi de d i nstea d.
6. 1 3. 2. 2. S e v er e P er si st e nt H y p er gl y c e mi a
A s u m mar y  of init iati on of resc ue t hera p y  in res p o nse t o se vere, persiste nt h yper gl yce mia will be 
pr o vi de d b y treat me nt. If t here are s ufficie nt n u m ber of e pis o des (≥1 0) , ti me-t o-first-e ve nt 
a nal yses f or t he i nit iati on of resc ue t hera p y  will be c o n d ucte d b y tr e at me nt usi n g a c o x 
pr o p orti o nal re gressi o n m o d el . F or pati e nts wit ho ut e ve nt “ti me -t o-e ve nt”, e ve nt ti me will  be 
ce ns ore d at  e n d of treat me nt p erio d. A list i n g of patie nts w h o i nit iate d resc ue t hera p y will be 
pr o vi de d.
6. 1 3. 2. 3. P a n cr e atiti s
If data warra nts, su m maries of a dj u dicate d a n d i n vesti gat or -re p orte d pa ncreatic e ve nts will be 
pr o vi de d b y treat me nt. Deter mi nat i on of i n vest i gat or-re p orte d e ve nts will be t hr o u g h t he pre -
defi ne d S M Q searc h f or ac ute pa ncreatit is a n d Me d D R A
P T of  pa ncreat itis c hr o nic. Detaile d 
searc hi n g criteria ca n be f o u n d i n A p pe n di x 2 . T reat me nt-e mer ge nt a dj u dicat i on -c o nfir me d
pa ncreat itis will be c o nsi dere d as A E SI.
6. 1 3. 2. 3. 1.
P a n cr e ati c E n z y m e A s s e s s m e nt
O bser ve d pa ncreat ic e nz y me data ( p-a m ylase a n d li pase) will be s u m marize d b y treat me nt a n d 
n o mi nal visi t. T he n u m ber a n d pr o p orti o n of patie nts wit h ma xi m u m p ost baseli ne pa ncreat ic 
e nz y me val ues e xcee di n g t he f oll o wi n g t hres h o l ds will be pr o vi de d b y ma xi m u m baseli ne 
pa ncreat ic e nzy me val ue ( ≤1 × u p per li mit of  nor mal  [U L N ], >1 × U L N), a n d treat me nt: ≤1 × U L N ,
( > 1 t o ≤3) × U L N, ( > 3 t o ≤5) × U L N, ( > 5 t o ≤1 0) × U L N, > 1 0 × U L N.
A n M M R M a nal ysis will be use d t o a nal yze eac h pa ncreat ic e nz y me with a l o g tra nsf or m e d 
( p ost baseli ne me as ure/ baseli ne meas ure) res p o nse varia ble a n d stratificati on fact ors, treat me nt, 
n o mi nal visi t, a n d treat me nt -b y -n o mi nal visit i nteracti o n as fi xe d effects , a n d baseli ne val ue as a 
c o variat e.
6. 1 3. 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
Treat me nt -e mer ge nt t h yr o i d mali g na ncies a n d C -cell h y p er plasia, will be i de nt ifie d usi n g pre-
defi ne d Me d D R A H i g h L e vel T er ms ( H L Ts) of t h yr oi d ne o plas ms mali g na nt , a n d P T of t h yr oid 
C -cell h y per plasia. Detaile d searc hi n g cri t eria ca n be f o u n d i n A p pe n di x 2 . A s u m mar y  b y 
treat me nt a n d P T / P T wit hi n S M Q a n d H L T will be pr o vi de d . T h y r oid mali g na n cies a n d C-cell 
h y per plasia will be c o nsi dere d as A E SI .
6. 1 3. 2. 5. M ali g n a n c y
T he A E data base will be searc he d usi n g pre -defi ne d S M Q s t o ide nt if y e ve nts c o nsiste nt wit h 
mali g na nc y . Detaile d searc hi n g criteria ca n be f o u n d i n A p pe n di x 2 . A s u m mar y b y treat me nt 
a n d P T wi t hi n S M Q a n d a list i n g of  T E A Es will be pr o vi de d . M ali g na nc y will be c o nsi dere d as 
A E SI.


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6. 1 3. 2. 6. C al cit o ni n
O bser ve d calcit o ni n data will be s u m marize d b y treat me nt a n d n o mi nal visit. A d dit i onall y , t he 
n u m ber a n d pr o p orti o n of pat ient s wit h a ma xi m u m p ost baseli ne calcit o ni n val ue e xcee di n g t he 
f oll owi n g t hres h o l ds will be pr o vi de d b y treat me nt a n d ma xi m u m baseli ne calcit o ni n val ue 
(≤2 0 n g/ L, > 2 0 n g/ L t o ≤3 5 n g/ L, > 3 5 n g/ L ): ≤2 0 n g/ L , > 2 0 n g/ L t o ≤3 5 n g/ L , > 3 5 n g/ L t o 
≤5 0 n g/ L, > 5 0 n g/ L t o ≤1 0 0 n g/ L , > 1 0 0 n g/ L.
6. 1 3. 2. 7. M aj or A d v er s e C ar di o v a s c ul ar E v e nt s
Maj or a d verse car di o vasc ular e ve nts ( M A C E) re p orte d b y i n vesti gat ors are a dj u dicate d b y a n 
i n de pe n de nt C E C i n a bli n de d fas hi on. T he M A C E e ve nt s of s pecial i nterest i ncl u de: deat hs d ue 
t o car di o vasc ular ca use, m y ocar dial i nfarcti on, h os pitalizat i on f or u nsta ble a n gi na, 
h os pi talizatio n f or heart fail ure, c or o nar y  int er ve nti o ns (s uc h as c or o nar y  arter y b y pass graft 
[ C A B G] or perc uta ne o us c or o nar y int er ve nt i on [ P CI]); a n d cere br o vasc ular e ve nts, i ncl u di n g 
cere br o vasc ular acci de nt (str o ke) a n d tra nsie nt isc he mic attac k ( TI A).
A listi n g of patie nts re p orti n g M A C E e ve nts, eit her re p orte d b y in vest i gat or or i de ntifie d b y t he 
C E C, will be pr o vi de d. T he li sti n g will i ncl u de treat me nt, patie nt i de ntificati on i ncl u di n g t he site 
n u m ber, date of e ve nt, t y pe of e ve nt as re p orte d b y t he i n vesti gat or, t y pe of e ve nt as a dj u dicate d 
b y t he C E C, ti me fr o m first d ose of st u d y dr u g t o t he e ve nt, a n d ti me fr om last d ose t o t he e ve nt 
(if pat ient  has disc o nti n ue d st u d y dr u g prior t o t he e ve nt). O nl y p o sitivel y a dj u dicate d M A C E 
will be c o nsi dere d as A E SI.
6. 1 3. 2. 8. 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
T he A E data base will be searc he d usi n g pre -defi ne d S M Q or Me d D R A H L T t o ide nt if y e ve nts 
c o nsiste nt wit h s u pra ve ntric ular arr h yt h mias a n d car diac c o n d uct i on dis or ders. Detaile d 
searc hi n g criteria ca n be f o u n d i n A p pe n di x 2 . I nci de nce of t he res ulti n g T E A Es will be 
s u m marize d b y tr e at me nt a n d P T wit hi n S M Q a n d H L T . Treat me nt -e mer ge nt se vere/serio us 
s u pra ve ntric ular arr h yt hmias a n d car diac c o n d ucti o n dis or ders will be c o nsi dere d as A E SI.
6. 1 3. 2. 9. H y p er s e n siti vit y E v e nt s
H y perse nsi tivi t y reacti ons a n d relate d i nf or mat i on re p orte d via t he “ H y perse nsiti vity a n d 
A na p h ylactic React i ons” electr o nic case re p ort f or m ( e C R F) will be s u m marize d b y  tr e at me nt.
T w o m ai n a nal yses are perf or me d:

P ote nti al I m me di ate H y perse nsiti vit y: A na l ysis of T E A Es occ urri n g fr om t he start of 
st u d y dr u g a d mi nistratio n u p t o 2 4 h o urs after t he e n d of st u d y  dr u g a d mi nistratio n. F or 
e ve nts wit h o ut t he h y perse nsit i vity e C R F, o nl y date ( n o ti me) i nf or mat i on are c ollecte d, 
t he e ve nt s occ urre d o n t he sa me dat e as t he st u d y dr u g i njecti on date will be i ncl u de d.

P ote nti al N o n -I m me di ate H y perse nsiti vit y: A nal ysis o f T E A Es occ urri n g m ore t ha n 
2 4 h o urs after t he e n d of st u d y  dr u g a d mi nistrati o n, b ut pri or t o s u bse q ue nt st u d y dr u g 
a d mi nistrati o n.
S u m maries of all p ot e nti al h y perse nsitivi t y r e a ctio ns will  be ge nerate d b y P T wit h decreasi n g 
fre q ue nc y b y tr e at me nt. T he A E data base will be searc he d usi n g pre -defi ne d S M Qs t o ide nt if y
e ve nts c o nsiste nt wit h h y perse nsit i vity e ve nts. Detaile d searc hi n g criteria f or h y perse n sitivi t y 


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e ve nts ca n be f o u n d i n A p pe n di x 2 . S e vere/serio us h y perse nsi tivi t y e ve nts i de ntifie d b y pre -
defi ne d S M Q searc h will be c o nsi dere d as A E SIs.
6. 1 3. 2. 1 0.
I nj e cti o n Sit e R e a cti o n s
I njecti on site reacti o ns, i nci de nce, a n d relate d i nf o r mat i on re p orte d via t he “I nject i on Si t e 
React i ons” e C R F will be s u m marize d b y treat me nt. I nf or mati on t o be s u m marize d i ncl u des t he 
ti mi n g of t he reacti o n relati ve t o st u d y dr u g a d mi nistrati o n, a n d c haracterist ics of t he i njecti on 
site reactio n: er yt he ma, i n d urat i on, pai n, pr uri t us a n d e de ma.
A d dit i onall y , p ot e ntial inject i on site reacti o ns will be searc he d b y pre -defi ne d Me d D R A H L Ts 
of  inject i on site reacti o ns , a d mi nistrati o n site reacti o ns, a n d i nf usi on rel ate d reactio ns . Detaile d 
searc hi n g criteria f or i njecti on site reactio n e ve nts ca n be f o u n d i n A p pe n di x 2 . T he P T will be 
use d f or s u m mar y b y treat m e nt wit hi n eac h H L T cate g or y. O nl y t he se vere/seri o us i nject i on site 
reactio ns will  be c o nsidere d as A E SI.
6. 1 3. 2. 1 1.
Di a b eti c R eti n o p at h y C o m pli c ati o n s
Res ul ts of t he baseli ne dilate d f u n d osc o pic e xa m will be s u m marize d b y treat me nt. A n y T E A E 
s us pecte d of w orse ni n g reti n o pat h y trig gers a f oll o w -u p dilate d f u n d osc o pic e xa m. A s u m mar y of 
T E A Es s us pecte d of w orse ni n g reti n o pat h y  a nd a s u m mar y of t he res ults of t he fol low -u p dilate d 
f u n d osc o pic e xa m will be s u m marize d b y treat me nt a n d P T. T he cases wi t h re peate d f u n d osc o p y 
d uri n g t he c o urse of t he tr ial, base d o n cli nical s us picio n  of w orse ni n g reti n o pat h y t hat ha ve eit her 
fi n di n gs of de n o v o reti n o pat h y or pr o gressio n o f reti n o pat h y, a n d se vere/serio us a d verse e ve nts fr o m 
t he P Ts defi ne d i n searc hi n g criteria i n A p pe n di x 2 will be c o nsi dere d as A E SI a n d s u m marize d.
6. 1 3. 2. 1 2.
H e p at o bili ar y S af et y
6. 1 3. 2. 1 2. 1.
H e p at o bili ar y Di s or d er s
T he A E data base will be searc he d usi n g S M Qs t o i de ntif y e ve nts c o nsiste nt wit h he pat o biliar y 
dis or ders. Detaile d searc hi n g criteria ca n be f o u n d i n A p pe n di x 2 . A s u m mar y b y treat me nt a n d P T 
wit hi n S M Q will be pr o vi de d . Se vere/seri o us h e pat o biliar y dis or ders will be c o nsi dere d as A E SI.
6. 1 3. 2. 1 2. 2.
A c ut e G all bl a d d er Di s e a s e
T he A E data base will be searc he d usi n g pre-defi ne d S M Q s t o ide nt if y e ve nts c o nsiste nt wit h 
ac ute gall bla d der diseases. Detaile d searc hi n g criteria f or t hese A Es ca n be f o u n d i n A p pe n di x 2 .
A s u m mar y  b y treat me nt a n d P T wit hi n S M Q will be pr o vi de d . Se vere/seri o us ac ute gall bla d der 
di seases will be c o nsi dere d as A E SI.
6. 1 3. 2. 1 2. 3.
Li v er E n z y m e s
A nal yses f or la b orat or y  a nal yt e meas ure me nts are descri be d i n Secti o n 6. 1 3. 5 . T his sect i on 
descri bes a d dit i on al  a nal yses of li ver e nz y mes. I n a d diti on, t he f o ll owi n g will be pr o vi de d b y 
treat me nt gr o u p:

A s hift ta ble of ma xi m u m t o ma xi m u m ala ni ne a mi n otra nsferase ( A L T) meas ure me nt 
fr om baseli ne (≤1 × U L N , > 1 × U L N) t o p ost baseli ne wit h t he f oll owi n g cate g ori es:
≤1 × U L N, > 1 t o < 3 × U L N, ≥3 t o < 5 × U L N, ≥5 t o < 1 0 × U L N, ≥1 0 × U L N.


I 8 F-M C -G P G K St ati sti c al A n al y si s Pl a n V er si o n 3
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
A s hift ta ble of ma xi m u m t o ma xi m u m as partate tra nsa mi nase ( A S T) meas ure me nt fr o m 
baseli ne (≤1 × U L N , > 1 × U L N) t o p ost baseli ne wit h t he f oll o wi n g cate g ories:
≤1 × U L N, > 1 t o < 3 × U L N, ≥3 t o < 5 × U L N, ≥5 t o < 1 0 × U L N, ≥1 0 × U L N.

S hift ta bles of ma xi m u m t o ma xi m u m t otal bilir u bi n a n d direct bilir u bi n fr o m baseli ne t o 
p ost baseli ne wit h t he f o ll ow i n g cate g ories: ≤1 × U L N, > 1 t o < 2 × U L N, ≥2 × U L N.

S hift ta bles of ser u m al kali ne p h os p hatase ( A L P) fr o m baseli ne t o p ost baseli ne wit h t he 
f oll owi n g cate g ori es: ≤1 × U L N, > 1 t o < 2 × U L N, ≥2 × U L N.
Ma xi m u m baseli ne will be t he ma xi m u m n o n -missi n g o bser va tio n i n t he baseli ne peri o d. T he 
ma xi m u m p ost baseli ne val ue will be t he ma xi m u m n o n -missi n g val ue fr o m t he p ost baseli ne 
p eri o d. Pl a n ne d a n d u n pla n ne d meas ur e me nts will be i ncl u de d.
6. 1 3. 2. 1 3.
G a str oi nt e sti n al S af et y
T he ti me c o urses of pre vale nce a n d i nci de nce ( ne wl y-occ urri n g e pis o des) of na usea , v o mit i n g, 
di arr hea, a n d c o m bi ne d will be pl otte d b y  tr e at me nt a n d ma xi m u m se verity.
T he m a xi m u m s e v erit y a n d d uratio n of  treat me nt -e mer ge nt na usea , v o mit i n g, di arr ho ea, a n d 
c o m bi ne d t hr o u g h t he e n d of t he st u d y will be s u m marize d b y treat me nt.
T he P Ts i n t he gastr oi ntesti nal S O C will be use d t o i de ntif y gastr oi ntesti nal A E s. T he i nci de nce 
of  t he res ultin g T E A Es will be s u m marize d b y treat me nt a n d P T . P Ts wi t h se vere/serio us cases
i n t he gastr oi ntesti nal S O C will be c o nsi dere d as A E SIs.
6. 1 3. 2. 1 4.
A c ut e R e n al E v e nt s
La b orat or y  meas ures relate d t o re nal safety will be a nal yze d as s pecifie d f or la b orat or y  
meas ure me nts i n Secti on 6. 1 3. 5 .
T w o s hift ta bles e xa mi ni n g re nal f u nct i on will be create d. A mi n -t o-mi n s hift ta ble o f est i mate d 
gl o m er ular filtrat i on rate (e G F R) esti mate d b y t he C hr o nic Ki d ne y Disease E pi de mi o l og y  
C olla b or atio n ( C K D -E PI) e q uati o n wi t h u nits mL / mi n/ 1. 7 3 m2 , usi n g cate g ories ( < 3 0, ≥3 0 t o 
< 4 5, ≥4 5 t o < 6 0, ≥6 0 t o < 9 0, a n d ≥9 0 m L/ mi n/ 1. 7 3 m 2 ). A ma x -t o-ma x s hift ta ble of uri ne 
al b u mi n-t o-creati ni ne rati o ( U A C R), usi n g t he cate g ories U A C R < 3 0 m g/ g, 3 0 m g/ g ≤ U A C R 
≤3 0 0 m g/ g, U A C R > 3 0 0 m g/ g (res pecti vel y, t hese re prese nt n or mal, micr oal b u mi n uria, a n d 
macr oal b u mi n uria).
T he A E data base will be searc he d usi n g S M Qs of  ac ute re nal fail ure a n d c hr o nic ki d ne y disease
t o ide nt if y e ve nts c o nsiste nt wit h ac ute re nal e ve nts . T he i nci de nce of t he res ult i n g T E A Es will 
be s u m marize d b y treat me nt a n d P T . Detaile d searc hi n g criteria ca n be f o u n d i n A p pe n di x 2 . 
Se vere/seri o us acute re nal  e ve nts will be c o nsi dere d as A E SI.
6. 1 3. 2. 1 5.
D e h y dr ati o n
T he A E data base will be searc he d usi n g S M Q of de h y drat i on t o ide nt if y e ve nts c o nsiste nt wit h
de h y drat i on . Detaile d searc hi n g criteria ca n be f o u n d i n A p pe n di x 2 . Se vere/seri o us d e h y dratio n 
e ve nts will be c o nsi dere d as A E SIs.


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6. 1 3. 2. 1 6.
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
T he A E data base will be searc he d usi n g Me d D R A P T t o i de nt if y e ve nts c o nsiste nt wit h 
meta b o lic aci d osis, i ncl u di n g dia bet ic ket oaci d osis. Detaile d searc hi n g criteria ca n be f o u n d i n 
A p pe n di x 2 . T he i nci de nce o f t he res ultin g T E A Es will be s u m marize d b y treat me nt a n d P T.
Se vere/seri o us m eta b o lic aci d osis, i ncl u di n g d iabetic k et oacid osis will be c o nsi dere d as A E SIs.
6. 1 3. 2. 1 7.
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
T he A E data base will be searc he d usi n g Me d D R A P T t o i de nt if y e ve nts f or a m p utati o n or 
p eri p heral  re vasc ularizati on. T he i nci de nce of t he res ult i n g T E A Es will be s u m marize d b y 
treat me nt a n d P T. A m p utati o n/ Peri p heral Re vasc ularizat i on will be c o nsi dere d as A E SIs.
6. 1 3. 2. 1 8.
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 A E data base will be searc he d usi n g S M Qs t o i de ntif y e ve nts c o nsiste nt wit h maj or 
de pressi ve dis or der or s uici dal i deat i on. Detaile d searc hi n g criteria ca n be f o u n d i n A p pe n di x 2 .
T he i nci de nce of t he res ult i n g T E A Es will be s u m marize d b y treat me nt a n d P T. Se vere/seri o us 
m ajor de pressi ve dis or der/s ui ci dal id e ati o n or be ha vi or will be c o nsi dere d as A E SI s.
6. 1 3. 3. Vit al Si g n s
Descri pt i ve s u m maries b y treat me nt a n d b y n omi nal visit will be pr o vi de d f or baseli ne a n d 
p ost baseli ne val ues as well as c ha n ge fr o m baseli ne val ues. If 2 rec or ds are ta ke n at t he sa me 
visit, t he y  will be a vera ge d pri or t o bei n g use d f or data s u m maries a n d a nal yses.
A n M M R M usi n g R E M L will be use d t o fit t he c ha n ges fr o m baseli ne i n vital si g ns at all 
sc he d ule d p ost baseli ne visit s. T he m o d el  will i nclu de c o u ntr y / p o ole d c o u ntr y, baseli ne H b A 1c 
(≤8. 5 %, > 8. 5 % [ ≤6 9, > 6 9 m m o l/m o l]), past O A M use ( Ye s or N o), treat me nt gr o u p, visit, a n d 
treat me nt -b y -visit i nteracti o n as fi xe d effects, a n d baseli ne val ue of t he de pe n de nt varia ble as a 
c o variate.
C o u nts a n d perce nta ges of patie nts wit h a b n or mal sitti n g s yst olic bl o o d press ure ( B P ), sitti n g 
di ast olic B P, a n d p ulse will be prese nte d b y  treat me nt. T he criteria f or i de nt if yi n g patient s wit h 
treat me nt -e mer ge nt vital si g n a b n or malit ies are state d i n Ta ble G P G K .6 .4 .
T a bl e G P G K .6 .4 .
C at e g ori c al Crit eri a f or A b n or m al Bl o o d Pr e s s ur e a n d P ul s e 
M e a s ur e m e nt s
P ar a meter
L o w
Hi g h
S y st olic B P ( m m H g)
( S u pi ne or sitti n g – f orear m 
at heart le vel)
≤9 0 a n d decrease fr o m baseli ne ≥2 0
≥1 4 0 a n d i ncrease fr o m baseli ne ≥2 0
Diast olic B P ( m m H g)
( S u pi ne or sitti n g – f orear m 
at heart le vel)
≤5 0 a n d decrease fr o m baseli ne ≥1 0
≥9 0 a n d i ncrease fr o m baseli ne ≥1 0
P ulse ( b p m)
( S u pi ne or sitti n g)
< 5 0 a n d decrease fr o m baseli ne ≥1 5
> 1 0 0 a n d i ncrease fr o m baseli ne ≥1 5
A b bre viati o n: B P = bl o o d press ure.


I 8 F-M C -G P G K St ati sti c al A n al y si s Pl a n V er si o n 3
P a g e 3 1
L Y 3 2 9 8 1 7 6
6. 1 3. 4. El e ctr o c ar di o gr a m s
S u m mar y  statistics b y tr e at me nt a n d b y n o mi nal visit will be pr o vi de d f or electr ocar di o gra m 
( E C G) para meters ( heart rate, P R, Q R S, Q T, a n d Q T c orrecte d usi n g Fr i dericia’s c orrectio n 
fact or [ Q Tc F]). W he n t he Q R S is pr ol o n ge d (f or e xa m ple, a c o m plete b u n dle bra nc h bl oc k), Q T 
a n d Q Tc s h o ul d n ot be use d t o assess ve ntric ular re p olarizat i on. T h us, f or a partic ular E C G, t he 
f oll owi n g will be set t o missi n g (f or a nal y sis p ur p oses) w he n Q R S is ≥1 2 0 msec: Q T a n d Q Tc F.
T he cri t eria for i de nt if yi n g patient s wit h treat me nt -e mer ge nt q ua ntitati ve E C G a b n or malities is 
base d o n Ta ble G P G K .6 .5 .
I n a d diti o n, t he perce nta ge of patie nts wit h Q T greater t ha n 5 0 0 msec will be s u m marize d, a n d t he 
perce nta ge of patie nts wit h Q Tc F greater t ha n 5 0 0 msec will be s u m marize d .
T he perce nta ge of patie nts w h o e x perie nce d a treat me nt -e mer ge nt i ncrease fr om baseli ne i n 
Q Tc F i nter val o f greater t ha n 3 0 msec, 6 0 msec, or 7 5 msec at a n y  ti me will be s u m marize d. T he 
ma xi m u m val ue d uri n g t he st u d y  fol l ow -u p will be a nal yze d. Pl a n ne d a n d u n pla n ne d 
meas ure me nts will be i ncl u de d.
T a bl e G P G K .6 .5 .
S el e ct e d C at e g ori c al Li mit s f or E C G D at a
L o w
Hi g h
P ar a meter
M ales
Fe m ales
M ales
Fe m ales
Heart Rate
( b p m)
< 5 0 a n d decrease ≥1 5
< 5 0 a n d decrease ≥1 5
> 1 0 0 a n d 
i ncrease ≥1 5
> 1 0 0 a n d i ncrease 
≥1 5
P R I nter val
( msec)
< 1 2 0
< 1 2 0
≥2 2 0
≥2 2 0
Q R S I nter val
( msec)
< 6 0
< 6 0
≥1 2 0
≥1 2 0
Q Tc F 
( msec)
< 3 3 0
< 3 4 0
> 4 5 0
> 4 7 0
A b bre viati o ns: b p m = beats per mi n ute; E C G = electr ocar di o gra m; Q T C F = Fr i dericia’s c orrecte d Q T i nter val.
6. 1 3. 5. Cli ni c al L a b o r at or y E v al u ati o n
All la b orat or y data will be re p orte d i n t he I nter nati o nal S yste m of U nits a n d C o n ve nt i onal U nits .
V al ues t hat are o utsi de of refere nce ra n ges will be fla g ge d as hi g h ( H) or l o w ( L) i n t he list i n gs. 
Descri pt i ve s u m maries b y treat me nt a n d b y n omi nal visit will be pr o vi de d f or t he b aseli ne a n d 
p ost baseli ne val ues as well as t he c ha n ge fr o m baseli ne val ues f or sele ct e d meas ure me nts .
O bser ve d a n d c ha n ge fr o m baseli ne val ues f or selecte d meas ure me nts f or eac h visit will be 
di s pla ye d gra p hicall y f or p atie nts w h o ha ve b ot h a baseli ne a n d a p ost baseli ne pla n ne d 
meas ure me nt. U n pla n ne d meas ure me nts will be e xcl u de d fr o m gra p hs .
S hift ta bles will be pr o d uce d f or selecte d meas ure me nts. A s hift ta ble will i ncl u de u n pla n ne d 
meas ure me nts. T he s hift ta ble will i ncl u de t he n u m ber a n d perce nta ge of p atie nts wit hi n eac h 
baseli ne cate g or y  (lo w, n or m al, hi g h, or missi n g) vers us eac h p ost baseli ne cate g or y (lo w, 
n or m al, hig h, or missi n g) b y treat m e nt. T he pr o p orti o n of patie nts s hifte d will be c o m pare d 
bet wee n treat me nts.


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A listing of abnormal findings will be created for laboratory analyte measurements. The listing 
will include patient ID, treatment group, laboratory collection date, study day, analyte name, and 
analyte finding.
6.13.6. Immunogenicity
Treatment-emergent anti-drug antibodies (TE ADA) are defined as those with a titer 2-fold 
(1 dilution) greater than the minimum required dilution (1:10) if no ADAs were detected at 
baseline (treatment-induced ADA) or those with a 4-fold (2 dilutions) increase in titer compared 
to baseline if ADAs were detected at baseline (treatment-boosted ADA). A patient is evaluable 
for TE ADA if the patient has a non-missing baseline ADA result, and at least 1 non-missing 
postbaseline ADA result.
The frequency and percentage of patients with preexisting ADA, with TE ADA, with cross-
reactive antibodies and with neutralizing antibodies will be tabulated by dose, where proportions 
are relative to the number of patients who are TE ADA evaluable. The frequency and percentage 
of patients with hypersensitivity and injection site reaction TEAEs by TE ADA status will be 
tabulated if data warrant.
A listing will be provided of all immunogenicity assessments for those patients who at any time 
had ADA present. This includes the tirzepatide concentration from a simultaneous PK sample, 
and the clinical interpretation result.
A listing will be provided for all participant who had ADA present at any time (including 
baseline) or had any hypersensitivity or injection site reaction TEAE.
Depending on the number of patients with TE ADA, selected efficacy and safety subgroup 
analyses by TE ADA categories may be performed if deemed necessary.
Treatment-emergent ADA that are associated with AEs of either severe/serious hypersensitivity 
or severe/serious injection site reaction will be classified as AESIs.
6.14. Health Outcomes
The patient-reported outcome questionnaires will be completed by the patients at baseline and at 
40 weeks (or ET visit prior to 40 weeks). These include use of the mITT population on the EAS 
and use of a 2-sided alpha level of 0.05 and a 2-sided 95% CI for comparisons of tirzepatide 
doses to placebo.
No multiplicity adjustment will be made in the evaluation of health outcome measures. Item-
level missingness is dealt with as per the instrument developers’ instruction.
6.14.1. EQ-5D-5L
A descriptive frequency table of individual items in EQ-5D-5L questionnaire will present 
baseline, observed endpoint, and endpoint including last observation carried forward (LOCF, 
exclude baseline observation) values as separate summaries. Using EAS, the changes from 
baseline to Week 40,with and without LOCF in the index and visual analog scale (VAS) scores 
will be analyzed using an ANCOVA model with model terms of treatment, country/pooled 


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country, baseline HbA1c (≤8.5%, >8.5% [≤69, >69 mmol/mol]), and past OAM use (Yes or No) 
as fixed effects, and baseline EQ-5D-5L score as a covariate. ANCOVA analyses on FAS will be 
performed as a sensitivity analysis.
6.14.2. Impact of Weight on Self-Perceptions Questionnaire
A descriptive frequency table of individual items in IW-SP questionnaire will present baseline, 
observed endpoint, and endpoint including last observation carried forward (LOCF, exclude 
baseline observation) values as separate summaries. Using EAS, treatment comparisons of the 
raw and transformed overall IW-SP score changes from baseline to Week 40, with and without 
LOCF, will be analyzed using an ANCOVA model with model terms of treatment,
country/pooled country, baseline HbA1c (≤8.5%, >8.5% [≤69, >69 mmol/mol]), and past OAM 
use (Yes or No) as fixed effects, and baseline IW-SP score as a covariate. ANCOVA analyses on 
FAS will be performed as a sensitivity analysis.
6.14.3. Ability to Perform Physical Activities of Daily Living
A descriptive frequency table of individual items in APPADL questionnaire will present 
baseline, observed endpoint, and endpoint including last observation carried forward (LOCF, 
exclude baseline observation) values as separate summaries. Using EAS, treatment comparisons 
of the raw and transformed overall APPADL score changes from baseline to Week 40, with and 
without LOCF, will be analyzed using an ANCOVA model with model terms of treatment, 
country/pooled country, baseline HbA1c (≤8.5%, >8.5% [≤69, >69 mmol/mol]), and past OAM 
use (Yes or No) as fixed effects, and baseline APPADL score as a covariate. ANCOVA analyses 
on FAS will be performed as a sensitivity analysis.
6.15. Subgroup Analyses
Efficacy subgroup analyses will be guided by the efficacy estimand.
Subgroup analyses may be done by country/pooled country to support local regulatory 
registrations. Subgroups with few subjects may be excluded from subgroup analyses when 
appropriate.
6.15.1. Subgroup Analysis of HbA1c Change at 40 Weeks
Subgroup analyses by the following baseline characteristics will be provided: age group (<65, 
≥65 years), age group (<75, ≥75 years), race, gender, ethnicity, prior use of OAM (Yes, No), 
region of enrollment (US, OUS), duration of diabetes (<median, ≥median), duration of diabetes 
(≤5, >5 to ≤10, >10 years), HbA1c (≤8.5%, >8.5%), renal impairment (eGFR <60, ≥60
mL/min/1.73m2), BMI group (<27, ≥27 kg/m2) and BMI group (<30, ≥30 to <35, ≥35 kg/m2).
6.15.2. Subgroup Analysis of Weight Change at 40 Weeks
Subgroup analyses by the following baseline characteristics will be provided: gender, BMI group 
(<27, ≥27 kg/m2) and BMI group (<30, ≥30 to <35, ≥35 kg/m2).


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6.16. Interim Analyses and Data Monitoring Committee
No interim analyses is planned for this study.
6.17. COVID-19 Impact Assessment
This section lists the potential statistical analyses that may be performed to assess the impact of 
COVID-19 pandemic when appropriate.
6.17.1. Patients Impacted by COVID-19
Listings of patients with protocol deviation or mitigation due to COVID-19, patients with 
COVID-19 adverse events or death, and patients dispositions with reasons related to COVID-19
will be provided. 
6.17.2. Adverse Events
A summary table for patients with adverse events related to COVID-19, including death due to 
COVID-19, serious COVID-19 adverse events, and COVID-19 adverse events, will be provided 
by study treatment. 
6.17.3. Patient Disposition
Patient disposition with reasons related to COVID-19 (such as COVID-19 adverse event etc.) 
will be summarized for study and study treatment discontinuation by treatment group.
6.17.4. Study Visits
A summary of patients with study visit impacted by COVID-19 will be provided by treatment 
group. In this table, number and proportion of patients missing study visit including primary 
endpoint visit, having home health visit and virtual visit will be summarized.
6.17.5. Mitigation Summary
A summary table for patients having protocol deviation and mitigation due to COVID-19 (such 
as missing study visit, having home health visit, etc.) will be provided by treatment group.
Additional summary may be provided by country of enrollment and treatment group.
6.17.6. Measures Related to Primary and Key Secondary Objectives
Patients missing measures (HbA1C, fasting glucose, and body weight) related to primary and 
key secondary objectives will be summarized by visit and treatment group. In addition, the 
number of patients utilizing alternative options to in-person visits (such as local lab, home health 
visits etc.) to collect primary and key secondary measures may be summarized by visit and 
treatment group.


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7.
Unblinding Plan
Unblinding plan is created in a separate document.


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8.
References
Bretz F, Maurer W, Brannath B, Posch M. A graphical approach to sequentially rejective 
multiple test procedures. Stat Med. 2009;28(4):586-604.
Bretz F, Maurer W, Hommel G. Test and power considerations for multiple endpoint analyses 
using sequentially rejective graphical procedures. Stat Med. 2011;30(13):1489–1501.
Rubin DB. Multiple imputation for nonresponse in surveys. New York: John Wiley & Sons Inc.; 
1987.


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9.
Appendices


I 8 F-M C -G P G K St ati sti c al A n al y si s Pl a n V er si o n 3
P a g e 3 8
L Y 3 2 9 8 1 7 6
A p p e n di x 1.
St ati sti c al A n al y si s f or J a p a n
Stati stical a nal ysis met h o ds f or t he pri mar y efficac y a nal ysis f or t he P har mace uticals a n d 
Me dical De vices A ge nc y ( P M D A) is sa me as descri be d i n Sect i on 6. 1 2. 1 . F or t he P M D A, t he 
pri mar y  efficac y assess me nt will be g ui de d b y t he “efficac y” est i ma n d, wit h c o ntr olli n g o verall 
fa mil y-wise t y pe 1 err or rate at  a 2-side d al p h a of  0. 0 5 o nl y for pri mar y  e n d p oi nt a n d b o d y 
w ei g ht e val uat i on t hat ti rze pati de Q W is s u peri or t o place b o i n H b A 1c a n d b o d y wei g ht c ha n ge 
fr om baseli ne t o 4 0 wee ks. T he pri mar y  o bjecti ve h y p ot heses a n d t he k e y  sec o n dar y f or b o d y  
w ei g ht f or t he P M D A are as f o ll ows,
1.
H 5, 1 , H1 0, 1 , a n d H 1 5, 1 : S u peri orit y test of tirze pati de 5 m g, 1 0 m g, 1 5 m g v ers us 
pl ace b o i n H b A 1 C c ha n ge fr o m baseli ne at 4 0 wee ks res pecti vel y.
2.
H 5 , 2, H 1 0, 2 , a n d H 1 5, 2 : S u peri orit y test of tirze pati de 5 m g, 1 0 m g, 1 5 m g v ers us 
pl ace b o i n b o d y wei g ht c ha n ge fr o m baseli ne at 4 0 wee ks res pecti vel y.
T he stati stical testi n g sc he me f or t he P M D A is descri be d i n t he f oll owi n g di a gra m. H 1 0, 1 a n d 
H 1 5, 1 will be i nit iall y teste d eac h at 0. 0 2 5 si g nifica nce le vel.
S u b gr o u p a nal yses f or patie nt dis p osit i on, pati e nt c haracterist ics, k e y efficac y a n d safety 
meas ures b y  c o u ntr y (Ja pa nese/ n o n-Ja pa nese) will be pr o vi de d t o s u p p ort Ja pa n re g ulat or y 
r e gistr atio n.


I 8 F-M C -G P G K St ati sti c al A n al y si s Pl a n V er si o n 3
P a g e 3 9
L Y 3 2 9 8 1 7 6
A p p e n di x 2.
S e ar c hi n g Crit eri a f or A d v er s e E v e nt s of 
S p e ci al I nt er e st ( AE SI)
T he A E SI a nal yse s are detaile d i n S ect i on 6. 1 3. 2 . T he searc h criteria f or eac h A E SI are st ore d i n 
C CI


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